August 2006 Release

ROME III - Newly revised

and greatly expanded!
25% increase in
text—over 1,000 pages

ROME III is the latest update,

and the most comprehensive
collection of information
that can be found for the
evaluation and care of
patients having functional
gastrointestinal disorders.

Douglas A. Drossman, MD,

Senior Editor
Soft Cover - $99.00
Hard Back - $125.00

To Reserve Your
Copy of Rome III
Order Now Online At
www.romecriteria.org

Rome III is designed for “one stop” learning. It serves as a valuable resource to general
and specialist physicians, mental health professionals, and basic and clinical investigators involved
in the study and care of patients with functional GI disorders.
Now expanded with 17 chapters to address the needs of both investigators and clinicians.
Provides the most up to date information on the epidemiology, pathophysiology, diagnosis and treatment
of irritable bowel syndrome, and over 20 more functional GI disorders commonly seen in clinical practice.
New chapters include pharmacology and pharmacokinetics, sociocultural
influences relating to gender, age, and cultural influences, functional abdominal
pain and two chapters on pediatrics for the neonate/toddler and child/adolescent.
“Red flag” questions to aid the clinician in identifying symptoms and signs that would suggest
further evaluation to exclude other diagnoses or when needed to make a mental health referral.
A table is included that compares the Rome II and new Rome III diagnostic criteria.
Gastroenterology
Official Journal of the American Gastroenterological Association Institute

INTRODUCTION 1377 The Functional Gastrointestinal Disorders and the Rome III
Volume 130
No. 5
April 2006

Process
D. A. Drossman

1391 Fundamentals of Neurogastroenterology: Basic Science

D. Grundy, E. D. Al–Chaer, Q. Aziz, S. M. Collins, M. Ke, Y. Taché,
and J. D. Wood

1412 Applied Principles of Neurogastroenterology:

Physiology/Motility Sensation
J. E. Kellow, F. Azpiroz, M. Delvaux, G. F. Gebhart, H. R. Mertz,
E. M. M. Quigley, and A. J. P. M. Smout

1421 Pharmacological and Pharmacokinetic Aspects of Functional

Gastrointestinal Disorders
M. Camilleri, L. Bueno, F. de Ponti, J. Fioramonti, R. B. Lydiard, and J. Tack

1435 Gender, Age, Society, Culture, and the Patient’s Perspective in

the Functional Gastrointestinal Disorders
L. Chang, B. B. Toner, S. Fukudo, E. Guthrie, G. R. Locke, N. J. Norton,
and A. D. Sperber

1447 Psychosocial Aspects of the Functional Gastrointestinal

Disorders
R. L. Levy, K. W. Olden, B. D. Naliboff, L. A. Bradley, C. Francisconi,
D. A. Drossman, and F. Creed

1459 Functional Esophageal Disorders

J. P. Galmiche, R. E. Clouse, A. Bálint, I. J. Cook, P. J. Kahrilas,
W. G. Paterson, and A. J. P. M. Smout

ON THE COVER 1466 Functional Gastroduodenal Disorders

J. Tack, N. J. Talley, M. Camilleri, G. Holtmann, P. Hu, J.-R. Malagelada,
This issue launches the new Rome III
diagnostic criteria and updates knowledge and V. Stanghellini
on the functional GI disorders. As noted
on the cover, these disorders are associated
with abnormal motility, visceral hypersen-
sitivity and dysregulation of brain-gut
function. ‹ Editorial accompanies this article. Additional online content available.

GASTROENTEROLOGY (ISSN 0016-5085) is published monthly (semimonthly in May) in two indexed volumes per year by Elsevier (For Post Office
use only: Volume 130 issue 5 of 6). Corporate and editorial offices: Elsevier, 1600 John F. Kennedy Boulevard, Philadelphia,
Pennsylvania 19103-2899. Accounting and circulation offices: 6277 Sea Harbor Drive, Orlando, Florida 32887-4800. 2006 U.S. subscription rates:
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1480 Functional Bowel Disorders
G. F. Longstreth, W. G. Thompson, W. D. Chey, L. A. Houghton, F. Mearin,
and R. C. Spiller

1492 Functional Abdominal Pain Syndrome

R. E. Clouse, E. A. Mayer, Q. Aziz, D. A. Drossman, D. L. Dumitrascu,
H. Mönnikes, and B. D. Naliboff

1498 Functional Gallbladder and Sphincter of Oddi Disorders

J. Behar, E. Corazziari, M. Guelrud, W. Hogan, S. Sherman, and J. Toouli

1510 Functional Anorectal Disorders

A. E. Bharucha, A. Wald, P. Enck, and S. Rao

1519 Childhood Functional Gastrointestinal Disorders:

Neonate/Toddler
P. E. Hyman, P. J. Milla, M. A. Benninga, G. P. Davidson, D. F. Fleisher,
and J. Taminiau

1527 Childhood Functional Gastrointestinal Disorders:

Child/Adolescent
A. Rasquin, C. Di Lorenzo, D. Forbes, E. Guiraldes, J. S. Hyams, A. Staiano,
and L. S. Walker

1538 Design of Treatment Trials for Functional Gastrointestinal

Disorders
E. J. Irvine, W. E. Whitehead, W. D. Chey, K. Matsueda, M. Shaw, N. J. Talley,
and S. J. O. Veldhuyzen van Zanten

1552 The Road to Rome

W. G. Thompson
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Gastroenterology
Official Journal of the American Gastroenterological Association Institute

David A. Brenner
Editor Senior
Associate Editor
Editorial Staff
Erin Dubnansky, Director of Editorial Services
Columbia University R. Balfour Sartor Christopher Lowe, Production Manager
New York, New York University of North Carolina at Chapel Hill Nya Crymes, Production Coordinator
Chapel Hill, North Carolina Debra Raden, Editorial and Production Assistant
Rose Fox, Editorial Assistant
Christopher Daniels, Vice President of Publishing
Associate Editors
Jonathan A. Cohn Rodger A. Liddle William E. Whitehead
Duke University Medical Center Duke University Medical Center University of North Carolina
Durham, North Carolina Durham, North Carolina Chapel Hill, North Carolina
Douglas A. Drossman P. Kay Lund Associate Editor for Nutrition
University of North Carolina University of North Carolina Samuel Klein
Chapel Hill, North Carolina Chapel Hill, North Carolina Washington University School of Medicine
Raymond N. DuBois Lloyd Mayer St. Louis, Missouri
Vanderbilt University Medical Center Mount Sinai Medical Center Consulting Biostatistician
Nashville, Tennessee New York, New York
Joseph A. Galanko
Michael W. Fried David F. Ransohoff University of North Carolina
University of North Carolina University of North Carolina Chapel Hill, North Carolina
Chapel Hill, North Carolina Chapel Hill, North Carolina
John J. Lemasters Robert S. Sandler
University of North Carolina University of North Carolina
Chapel Hill, North Carolina Chapel Hill, North Carolina
Special Section Editors
This Month in GASTROENTEROLOGY Eugene B. Chang, Chicago, Illinois Clinical Management Loren Laine, Los Angeles, California
Image of the Month David M. Warshauer, Chapel Hill, North Carolina Print and Media Reviews Ian S. Grimm, Chapel Hill, North Carolina
Gastroenterology News Anil K. Rustgi, Philadelphia, Pennsylvania CME Section Eugene B. Chang and Laura Harrell, Chicago, Illinois
Selected Summaries Henry J. Binder, New Haven, Connecticut
Editorial Board
Gianfranco Alpini, Temple, Texas Sanjeev Gupta, Bronx, New York Barbara Rehermann, Bethesda, Maryland
Gavin Arteel, Louisville, Kentucky Hartmut Jaeschke, Little Rock, Arkansas William Sandborn, Rochester, Minnesota
Ramon Bataller, Barcelona, Spain Christian Jobin, Chapel Hill, North Carolina Michael Sarr, Rochester, Minnesota
Charles Bernstein, Winnipeg, Canada Peter Kahrilas, Chicago, Illinois Jack Satsangi, Edinburgh, Scotland
Anthony Bauer, San Diego, California James Lewis, Philadelphia, Pennsylvania Roland Schmid, Ulm, Germany
Richard Boland, San Diego, California Gary Lichtenstein, Philadelphia, Pennsylvania Stefan Schreiber, Kiel, Germany
Jaime Bosch, Barcelona, Spain Keith Lindor, Rochester, Minnesota Detlef Schuppan, Erlangen, Germany
James L. Boyer, New Haven, Connecticut Edward V. Loftus, Rochester, Minnesota Vijay Shah, Rochester, Minnesota
Alan Charney, New York, New York Averil I. Ma, Chicago, Illinois Nick Shaheen, Chapel Hill, North Carolina
Judy Cho, Chicago, Illinois Thomas MacDonald, Southampton, Stuart Spechler, Dallas, Texas
Pierre A. Clavien, Zurich, Switzerland United Kingdom William F. Stenson, St. Louis, Missouri
Mark Czaja, Bronx, New York Kenneth McColl, Glasgow, Scotland Yvette Tache, Los Angeles, California
Paul Dawson, Winston-Salem, North Carolina Kari North, Chapel Hill, North Carolina Christian Trautwein, Hannover, Germany
Anna Mae Diehl, Durham, North Carolina Stephen Pandol, Los Angeles, California Hide Tsukamoto, Los Angeles, California
Peter Bryan Ernst, Charlottesville, Virginia Chuck Parkos, Atlanta, Georgia John Wallace, Calgary, Alberta, Canada
B. Mark Evers, Galveston, Texas Richard M. Peek, Nashville, Tennessee John A. Williams, Ann Arbor, Michigan
Scott Friedman, New York, New York Antonello Pietrangelo, Modeno, Italy Teresa Wright, San Francisco, California
Gregory Gores, Rochester, Minnesota Daniel K. Podolsky, Boston, Massachusetts Vincent Yang, Atlanta, Georgia
William Grady, Seattle, Washington Lawrie W. Powell, Brisbane, Australia
Officers of the American Gastroenterological Association Institute
President David A. Peura President-Elect Mark Donowitz
Charlottesville, Virginia Baltimore, Maryland
Vice President Nicholas F. LaRusso Secretary/Treasurer Ian L. Taylor
Rochester, Minnesota New Orleans, Louisiana
Secretary/Treasurer-Elect Damian H. Augustyn
San Francisco, California
Advancing the Science and Practice of Gastroenterology
Published by Elsevier, 1600 John F. Kennedy Boulevard, Philadelphia, Pennsylvania 19103-2899
 GASTROENTEROLOGY 2006;130:1377–1390

INTRODUCTION

The Functional Gastrointestinal Disorders and the Rome III

Process

DOUGLAS A. DROSSMAN, Guest Editor

Division of Gastroenterology and Hepatology, UNC Center for Functional GI and Motility Disorders, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina

hroughout recorded history, and alongside struc- FGIDs as psychological disorders or merely the absence
T tural diseases of the intestinal tract, are maladies
that have produced multiple symptoms of pain, nausea,
of organic disease and often ascribe pejorative features to
the patient.3 Some physicians deny the very existence of
vomiting, bloating, diarrhea, constipation, or difficult the functional GI disorders,7 whereas others exhibit dis-
passage of food or feces.1 Although structural diseases can missive or negative attitudes toward patients.4,8,9 Some
be identified by pathologists and at times cured by physicians may pursue unneeded diagnostic studies to
medical technology, the nonstructural symptoms that we find something “real”,10 resulting in increased health care
describe as “functional” remain enigmatic and less ame- costs and possibly inappropriate care.11 These types of
nable to explanation or effective treatment. Often con- beliefs and behaviors can “delegitimize” the FGIDs and
sidered “problems of living,” there are physiological, the patients who experience them.
intrapsychic, and sociocultural factors that amplify per- What is missing in these attitudes and behaviors is a
ception of these symptoms so they are experienced as proper understanding of the true genesis of FGID symp-
severe, troublesome, or threatening, with subsequent toms, an acknowledgment of their impact on patients,
impact on daily life activities. Those suffering from such and a rational basis for diagnosing and treating them. In
symptoms attribute them to an illness and self-treat or the last few decades, several important events have oc-
seek medical care. Traditionally trained physicians then curred that brought these common disorders into the
search for a disease (inflammatory, infectious, neoplastic forefront of clinical care, scientific investigation, and
and other structural abnormalities) in order to make a public awareness, and in the process, have made them
diagnosis and offer treatment specific to the diagnosis. In scientifically exciting and clinically legitimate.
most cases,2 no structural etiology is found, the doctor The first event began 3 decades ago with a paradigm
concludes that the patient has a “functional” problem, shift that moved away from conceptualizing illness and
and the patient is evaluated and treated accordingly. disease based on a 3-century-old reductionistic model of
This clinical approach results from a faulty conceptu- disease in which the effort was to identify a single
alization of functional gastrointestinal disorders (FGIDs) underlying biological etiology to a more integrated, bio-
and in the inaccurate, demeaning and potentially harm- psychosocial model of illness and disease.12–14 The former
ful implications that some physicians, patients, and the disease-based model had its roots with Descartes’ sepa-
general public attribute to them.3 Some clinicians feel ill ration of mind and body and at the time was a concept
at ease when making a diagnosis of an FGID because they that harmonized prevailing societal views of separation of
are trained to seek pathology.4 In a random sample church and state.1,13 What resulted was permission to
survey of 704 members of the American Gastroenter- dissect the human body (which was previously forbid-
ological Association,5 the most common endorsement of den), so disease was defined by what was seen (ie, pa-
a functional gastrointestinal (GI) disorder was “ . . .. no thology based on abnormal morphology). This approach
known structural (ie, no pathological or radiological) led to centuries of valuable research producing effective
abnormalities, or infectious, or metabolic causes” (81%). treatments for many diseases. The concept of the mind
Next came “a stress-disorder” (57% practitioners and (ie, the central nervous system [CNS]) as being amenable
34% academicians and trainees), and last was a “motility to scientific study or as playing a role in illness and
disorder” (43% practitioners and 26% academicians/ disease was marginalized, however. The mind was con-
trainees.6 A more recent survey of international investi- sidered the seat of the soul, not to be tampered with.
gators agreed that in their countries, physicians view the This idea seems to have had a profound effect on Western
1378 DOUGLAS A. DROSSMAN GASTROENTEROLOGY Vol. 130, No. 5

Figure 1. This biopsychosocial

conceptualization of the patho-
genesis and clinical expression
of the functional GI disorders
shows the relationships between
psychosocial and physiological
factors, functional GI symptoms,
and clinical outcome.

society where mental illness or even the effects of stress a syndrome (eg, postinfectious irritable bowel syndrome
on physiological function became less available for study [IBS] or dyspepsia), go to the physician frequently, and
and even stigmatized. More recent scientific studies link have a generally poorer outcome.16 –20 Furthermore, the
the mind and body as part of a system where their clinical outcome will, in turn, affect the severity of the
dysregulation can produce illness (the person’s experience disorder (note double-sided arrow in Figure 1). Thus, a
of ill health) and disease. By embracing this integrated family that addresses the illness behavior adaptively and
understanding, the biopsychosocial model allows for attends to the individual and his or her psychosocial
symptoms to be both physiologically multidetermined concerns may reduce the impact of the illness experience
and modifiable by sociocultural and psychosocial influ- and resultant behaviors. Conversely, a family that is
ences. overly solicitous to the person’s illness21 or a societal
Figure 1 illustrates the relationships between psycho- group that interprets certain symptoms with threat may
social and physiological factors and functional GI symp- amplify the symptoms and illness behaviors.22 In the
toms and clinical outcome. Early in life, genetics, in health care field, when the physician acknowledges the
addition to environmental factors such as family influ- reality of the patient’s complaints, provides empathy,
ences on illness expression, abuse, major losses, or expo- and engages in an effective physician-patient interaction,
sure to infections, may affect one’s psychosocial develop- symptom severity and health care seeking are reduced.23
ment in terms of one’s susceptibility to life stress or Conversely, another physician who repeatedly performs
psychological state and coping skills, as well as suscep- unneeded diagnostic studies to rule out pathological
tibility to gut dysfunction—abnormal motility, altered disease, dismisses the patients concerns, or does not
mucosal immunity, or visceral hypersensitivity. Further- effectively collaborate in the patient’s care is likely to
more, these “brain-gut” variables reciprocally influence promote a vicious cycle of symptom anxiety and health
their expression. Therefore, an FGID is the clinical prod- care seeking.11,24
uct of this interaction of psychosocial factors and altered The second change over the last 2 decades has been the
gut physiology via the brain-gut axis.15 For example, an remarkable growth in investigative methods that allow
individual with a bacterial gastroenteritis or other bowel us to quantify these associations for the FGIDs. Within
disorder who has no concurrent psychosocial difficulties the gut, motility assessment has advanced,25–27 the
and good coping skills may not develop the clinical barostat is the standard for testing visceral hypersensi-
syndrome (or be aware of it) or if it does develop, may not tivity,28 and the investigation of peptides, mucosal im-
perceive the need to seek medical care. Another individ- munology, inflammation, and alterations in the bacterial
ual with coexistent psychosocial comorbidities, high life flora of the gut provide the translational basis for GI
stress, abuse history, or maladaptive coping, may develop symptom generation. With regard to the brain, imaging
April 2006 INTRODUCTION 1379

methods using positron emission tomography and func- nally, a discussion of the rationale and methods of the
tional magnetic resonance imaging offer a window into Rome III process leading to this publication.
the central modulation of GI function and its linkages to
emotional and cognitive areas,29 whereas more standard-
The Rome III Classification System
ized psychological instruments permit the categorization
and quantification of emotions, stress, cognitions, and
FGIDs
health-related quality of life. The use of these modalities The 28 adult and 17 pediatric FGIDs are pre-
in research is helping us determine their influences on sented in Table 1. These are symptom-based diagnostic
symptoms and health outcomes. criteria that are not explained by other pathologically
A third event over the last decade has been the devel- based disorders. In recent years, however, histological
opment and release of new pharmacological agents to findings have been identified that blur the distinction
treat the FGIDs. These include 5-HT agonists and an- between “functional” and “organic.”3,10,36 The FGIDs are
tagonists as well as other gut-receptor–active agents for better categorized by their motor and sensory physiology
constipation and diarrhea,30 –32 more centrally acting and CNS relationships that produce disorders of GI
agents to treat stress-mediated effects of CNS modula- functioning; as such, there can be clinical overlap of
tion of the gut,33–35 and many others covering a vast FGIDs with other disorders.
array of mechanisms. For better or worse, increasing The FGIDs are classified into six major domains for
media attention to these pharmaceutical agents has also adults: esophageal (category A); gastroduodenal (category
heightened awareness of the FGIDs within the medical B); bowel (category C); functional abdominal pain syn-
community and the general public. drome (FAPS) (category D); biliary (category E); and
We have come a long way since the 1980s. The FGIDs anorectal (category F). The pediatric system is classified
are now recognized as clinical entities. Researchers and first by age range (neonate/toddler [category G] and
clinicians worldwide are more involved with these dis- child/adolescent [category H]) and then by symptom
orders, and the Rome process has played an important pattern or area of symptom location. Each category site
role in the categorization and dissemination of the new contains several disorders, each having relatively specific
and evolving knowledge. The FGIDs are now a promi- clinical features. So, the functional bowel disorders (cat-
nent part of undergraduate and postgraduate medical egory C) include IBS (C1), functional bloating (C2),
curricula, clinical training programs, and international functional constipation (C3), and functional diarrhea
symposia. The number of articles in peer-reviewed jour- (C4), which anatomically is attributed to the small
nals has skyrocketed, as has attention to these disorders bowel, colon, and rectum. Although symptoms (eg, di-
through public media including television and cinema. arrhea, constipation, bloating, pain) may overlap across
There are now future challenges to be faced, which these disorders, IBS (C1) is more specifically defined as
include improved understanding of the relationships be- pain associated with change in bowel habit, and this is
tween the mind and gut, as well as the translation of distinct from functional diarrhea (C4) characterized by
basic neurotransmitter function into clinical symptoms loose stools and no pain, or functional bloating (C2)
and their impact on the patient. when there is no change in bowel habit. Each condition
The need still remains to educate clinicians and the also has different diagnostic and treatment approaches.
general public on this rapidly growing knowledge. This The symptoms of the FGIDs relate to combinations of
edition of GASTROENTEROLOGY is a compilation of the several known physiological determinants: increased mo-
Rome III documents. It provides a basis for understand- tor reactivity, enhanced visceral hypersensitivity, altered
ing the pathophysiological, diagnostic, and treatment mucosal immune and inflammatory function (which in-
aspects of the FGIDs and also includes the new Rome III cludes changes in bacterial flora), and altered CNS-en-
criteria for diagnosis of adult and pediatric FGIDs. A teric nervous system (ENS) regulation (as influenced by
more detailed review of this field will be provided in the psychosocial and sociocultural factors and exposures). For
Rome III textbook to be released later this year. We hope example, fecal incontinence (category F1) may primarily
the efforts of Rome III provide a valuable resource to be a disorder of motor function, whereas FAPS (category
clinicians and investigators, ultimately as a means to D) is primarily understood as amplified central percep-
help our patients and further legitimize these disorders tion of normal visceral input. IBS (category C1) is more
to society. complex and results from a combination of dysmotility,
The following sections summarize the Rome III clas- visceral hypersensitivity, mucosal immune dysregula-
sification, scientific observations that relate to the tion, alterations of bacterial flora, and CNS-ENS dys-
FGIDs, a generalized approach to patient care, and fi- regulation. The contribution of these factors may vary
1380 DOUGLAS A. DROSSMAN GASTROENTEROLOGY Vol. 130, No. 5

Table 1. Rome III Functional Gastrointestinal Disorders across different individuals or within the same individual
A. Functional esophageal disorders over time. Thus, the clinical value of separating the
A1. Functional heartburn functional GI symptoms into discrete conditions as
A2. Functional chest pain of presumed esophageal origin shown in Table 1 is that they can be reliably diagnosed
A3. Functional dysphagia
and more specifically treated.
A4. Globus
B. Functional gastroduodenal disorders
B1. Functional dyspepsia Scientific Observations on the
B1a. Postprandial distress syndrome
Pathophysiology of Functional GI
B1b. Epigastric pain syndrome
B2. Belching disorders Disorders
B2a. Aerophagia Using Figure 1 as a template, the following is a
B2b. Unspecified excessive belching
B3. Nausea and vomiting disorders
more detailed description of these associations.
B3a. Chronic idiopathic nausea
B3b. Functional vomiting
Genetic Predispositions
B3c. Cyclic vomiting syndrome Genetic factors may predispose some individuals
B4. Rumination syndrome in adults
to develop FGIDs, whereas in others, environmental
C. Functional bowel disorders
C1. Irritable bowel syndrome
factors contribute to the phenomic expression of these
C2. Functional bloating conditions, as well as patient attitudes and behaviors
C3. Functional constipation (including health care seeking) relating to it. Genetic
C4. Functional diarrhea factors may play a role in several pathways, including
C5. Unspecified functional bowel disorder lower levels of IL-10 —an anti-inflammatory cyto-
D. Functional abdominal pain syndrome
E. Functional gallbladder and Sphincter of Oddi (SO) disorders
kine—in some patients with IBS 37that may effect gut
E1. Functional gallbladder disorder mucosal neural sensitivity, serotonin reuptake trans-
E2. Functional biliary SO disorder porter polymorphisms that can effect levels of 5-HT
E3. Functional pancreatic SO disorder neurotransmitter, or the response to 5-HT blocking
F. Functional anorectal disorders agents,38,39 g-protein polymorphisms that can affect both
F1. Functional fecal incontinence
F2. Functional anorectal pain
CNS and gut-related actions,40 and ␣2-adrenoreceptor
F2a. Chronic proctalgia polymorphisms that affect motility.41 An area for future
F2a1. Levator ani syndrome study is the role of CNS-related genetic abnormalities as
F2a2. Unspecified functional anorectal pain identified in other conditions, for instance, with regard
F2b. Proctalgia fugax to hypothalamic-pituitary-adrenal corticotrophin-releas-
F3. Functional defecation disorders
ing hormone reactivity or linkages between IBS and
F3a. Dyssynergic defecation
F3b. Inadequate defecatory propulsion commonly observed co-morbidities such as posttrau-
G. Functional disorders: neonates and toddlers matic stress disorder, depression, and anxiety disorders.
G1. Infant regurgitation For example, serotonin reuptake transporter polymor-
G2. Infant rumination syndrome phisms have effects on mood disturbances 42and may be
G3. Cyclic vomiting syndrome
a genetic link to disorders of brain-gut function such as
G4. Infant colic
G5. Functional diarrhea
IBS.
G6. Infant dyschezia
G7. Functional constipation Early Family Environment
H. Functional disorders: children and adolescents The aggregation of FGIDs in families43 is not
H1. Vomiting and aerophagia
only genetic. What children learn from parents may
H1a. Adolescent rumination syndrome
H1b. Cyclic vomiting syndrome contribute to the risk of developing an FGID.44 In fact,
H1c. Aerophagia children of adult patients with IBS make more health
H2. Abdominal pain-related functional gastrointestinal disorders care visits (and incur more health care costs) than the
H2a. Functional dyspepsia children of non-IBS parents.45,46
H2b. Irritable bowel syndrome
H2c. Abdominal migraine Psychosocial Factors
H2d. Childhood functional abdominal pain
H2d1. Childhood functional abdominal pain syndrome Although psychosocial factors do not define the
H3. Constipation and incontinence FGIDs and are not required for diagnosis, they are mod-
H3a. Functional constipation ulators of the patient’s experience and behavior, and
H3b. Nonretentive fecal incontinence
ultimately, the clinical outcome. Research on the psy-
April 2006 INTRODUCTION 1381

chosocial aspects of patients with FGIDs yields three persensitivity may be amplified in patients with
general observations: (1) Psychological stress exacerbates FGIDs, a process called sensitization or stimulus hyper-
GI symptoms. Psychological stress affects GI function algesia. Repetitive balloon inflations in the colon lead
and produces symptoms in healthy subjects, but does so to a progressive increase in pain intensity that occurs
to a greater degree in patients with FGIDs; (2) Psycho- longer and to a greater degree in patients with FGIDs
social factors modify the experience of illness and illness than in controls.52 Hypersensitivity and sensitization
behaviors such as health care seeking. Although patients may occur through altered receptor sensitivity at the
with FGIDs show greater psychological disturbance than gut mucosa and myenteric plexis, which may be en-
otherwise healthy subjects and patients with medical abled by mucosal inflammation,36 degranulation of
disease, the data are drawn from patients seen at referral mast cells close to enteric nerves,53 or increased sero-
centers. Those with FGIDs who are non– health care tonin activity,54,55 possibly enhanced by alteration of
seekers do not show these appreciable differences in the bacterial environment or infection.56,57 There may
psychological disturbances from the general population. also be increased excitability via central sensitization58
This explains why psychosocial trauma (e.g., sexual or
and possibly growth of the spinal cord dorsal horn
physical abuse history) is more common in referral cen-
neurons due to chronic or repetitive visceral stimula-
ters than in primary care, may lower pain threshold and
tion, thus amplifying throughput to the CNS. Finally,
symptom reporting, and is associated with a poorer clin-
there may be altered central downregulation of vis-
ical outcome. These factors can be reduced or “buffered”
ceral afferent transmission, thus reducing pain.29,59
by adaptive coping skills and social support, and the
psychosocial response of family, society, and culture can
Inflammation
also have a palliative effect on the illness experience; (3)
A functional GI disorder may have psychosocial conse- For almost 15 years, investigators have proposed
quences. Any chronic illness has psychosocial conse- that increased inflammation in the enteric mucosa or
quences on one’s general well-being, daily function sta- neural plexi may contribute to symptom development,60
tus, one’s sense of control over the symptoms, and the yet only a few years ago was it recognized that about one
implications of the illness in terms of future functioning half of patients with IBS have increased activated muco-
at work and at home. This is understood in terms of one’s sal inflammatory cells.36 This information appears to
health-related quality of life. relate to other clinical observations that about one third
of patients with IBS or dyspepsia describe that their
Abnormal Motility
symptoms began after an acute enteric infection, and
In healthy subjects, strong emotion or environ- also, up to 25% of patients presenting with an acute
mental stress can lead to increased motility in the esoph- enteric infection will go on to develop IBS-like or dys-
agus, stomach, small intestine, and colon. The FGIDs, peptic symptoms61– 63; the mucosa of these individuals
however, are characterized by having an even greater typically have increased inflammatory cells and inflam-
motility response to stressors (psychological or physio- matory cytokine expression.17,64 It is likely that mucosal
logical) when compared to normal subjects.26,47– 49 These inflammation may, at least in part, be a determinant of
motor responses are partially correlated with bowel visceral hypersensitivity and sensitization as previously
symptoms, particularly vomiting, diarrhea and constipa- noted.
tion, but are not sufficient to explain reports of chronic or
recurrent abdominal pain. Bacterial Flora
Visceral Hypersensitivity Following from work that addresses a possible
Visceral hypersensitivity helps explain the poor role for bacterial overgrowth in some patients with IBS,65
association of pain with GI motility with many of the there is growing interest in the role of altered bacterial
functional GI disorders (eg, functional chest pain of flora contributing to the development of IBS. For exam-
presumed esophageal origin [A2], epigastric pain syn- ple,66 improvement in IBS symptoms in response to
drome [B1b], IBS[C1], and FAPS [D]).50,51 These Bifidobacter infantis was associated with alteration of IL-
patients have a lower pain threshold with balloon 10/IL-12 ratios, thus converting a more inflammatory
distension of the bowel (visceral hyperalgesia), or they cytokine environment seen in IBS to a more normal
have increased sensitivity even to normal intestinal setting as seen in healthy individuals. Future studies are
function (eg, allodynia), and there may be an increased needed to support this growing area of research in the
area of somatic referral of visceral pain. Visceral hy- FGIDs.
1382 DOUGLAS A. DROSSMAN GASTROENTEROLOGY Vol. 130, No. 5

Brain-Gut Interactions via the CNS-ENS role of the CNS in modulating visceral pain and motility.
Bidirectional “hardwiring” of brain-gut axis. The
In general, there is an association of anterior cingulate
brain-gut axis allows bi-directional input and thus links cortex (ACC) activation to rectal distension in IBS rela-
tive to controls.75 Studies using both functional mag-
emotional and cognitive centers of the brain with pe-
netic resonance imaging and positron emission tomog-
ripheral functioning of the GI tract and vice versa. So,
raphy show increases in activity of the ACC compared to
extrinsic (vision, smell, etc) or enteroceptive (emotion,
controls.79 – 84 Preliminary data also show that in IBS,
thought) information has, by nature of its neural con-
ACC activation to rectal distention correlates with anx-
nections from higher centers, the capability to affect GI
iety,85 stressful life events, maladaptive coping86 and a
sensation, motility, secretion, and inflammation. Con-
history of abuse.87 Furthermore, abuse history and IBS
versely, viscerotopic effects (eg, visceral afferent commu-
diagnosis appear to have synergistic effects causing even
nications to the brain) reciprocally affect central pain
greater activation of the perigenual ACC.88 Future stud-
perception, mood, and behavior. For example, spontane-
ies may help us view the responses to CNS treatments
ously induced contractions of the colon in rats leads to
like psychological89 and antidepressant90 therapies in
activation of the locus coeruleus in the pons, an area
IBS, thus predicting agents more amenable to such
closely connected to pain and emotional centers in the
treatments.
brain.67 Conversely, increased arousal or anxiety is asso-
Brain-gut peptides. A treatment approach consis-
ciated with a decrease in the frequency of migrating tent with the concept of brain-gut dysfunction is likely
motor complex activity of the small bowel68 and of to involve the neuropeptides and receptors present in the
heightened visceral hypersensitivity and autonomic reac- enteric and CNS. Putative agents include primarily
tivity among patients with IBS.69 5-HT and its congeners, the enkephalins and opioid
Stress and postinfectious FGID. A feature of the agonists, substance P, calcitonin gene-related polypep-
FGIDs is their increased motor and sensory reactivity to tide, and cholecystokinin, neurokinin receptor, and cor-
environmental stimuli, which also leads to greater gut ticotrophin-releasing hormone antagonists among oth-
physiological reactivity to stress69 or to its neurochemical ers. These neuropeptides have integrated activities on GI
mediators such as corticotrophin-releasing hormone.33,70 –72 function and human behavior depending upon their lo-
A good model for brain-gut interactions relates to postin- cation. Ongoing phase II and III pharmacological treat-
fectious IBS (PI-IBS). In two studies55,62 that compared ment trials using agents active at these receptor sites will
patients who develop PI-IBS to those who recover from hopefully address the diverse, but interconnected symp-
infection without developing IBS (recovered group) and to toms of pain, bowel dysfunction, and psychosocial dis-
a nonsymptomatic control group, the distinguishing fea- tress so commonly associated with the FGIDs.
tures relate to increased mucosal inflammation and higher
levels of psychological distress occurring at the onset of the
infection. In fact, there were no significant differences in
An Approach to the Care of
visceral sensation thresholds or motility between the PI-IBS Patients With Functional GI
and the recovered group, suggesting that CNS amplifica- Disorders
tion of peripheral signals occurring in the psychologically This section provides general care guidelines for
distressed PI-IBS group raised them to conscious awareness, patients with FGIDs. Further information can be found
thereby perpetuating the symptoms.73 Furthermore, it is elsewhere.91–95
possible that the CNS contributed to the increased expres-
sion of peripheral inflammatory/cytokine activity via altered The Therapeutic Relationship
hypothalamic-pituitary-adrenal axis reactivity to stress as is The basis for implementing an effective physi-
seen in IBS.74 These data suggest that for PI-IBS to become cian-patient relationship is supported by growing evi-
clinically expressed, there must be evidence for brain-gut dence of improved patient satisfaction, adherence to
dysfunction with both visceral sensitization and high levels treatment, symptom reduction, and other health out-
of psychological distress. comes.23,95–97 Table 2 provides the guidelines for the
Brain imaging. Brain imaging, using positron establishment of a therapeutic relationship.98
emission tomography, functional magnetic resonance Because the FGIDs are chronic, it is important to
imaging, or other modalities29,75,76 provides an opportu- determine the immediate reasons for the patient’s visit:
nity to assess brain function in response to visceral stim- (“What led you to see me at this time?”) and to evaluate
ulation77,78 among healthy subjects and patients with the patient’s verbal and nonverbal communication. Pos-
FGIDs. These studies may increase understanding of the sible causes include: (1) new exacerbating factors (dietary
April 2006 INTRODUCTION 1383

Table 2. Guidelines to Establish a Therapeutic Physician- pain, nausea, vomiting, diarrhea). The physician
Patient Relationship should emphasize that both physiologic and psycho-
1. Obtain the history through a nondirective, nonjudgmental, logical factors interact to produce symptoms.
patient-centered interview. 2. Reassurance. The physician should elicit patient wor-
2. Conduct a careful examination and cost-efficient investigation.
3. Determine how much the patient understands about the illness ries and concerns and provide appropriate reassurance.
and his or her concerns (“What do you think is causing your This can be an effective therapeutic intervention, but
symptoms?”). the patient will not accept it if it is communicated in
4. Provide a thorough explanation of the disorder that takes into
consideration the patient’s beliefs.
a perfunctory manner and before necessary tests are
5. Identify and respond realistically to the patient’s expectations completed.
for improvement (“How do you feel I can be helpful to you?”). 3. Diet and medication. Offending dietary substances (eg,
6. When possible, provide a link between stressors and symptoms
lactose, caffeine, fatty foods, alcohol, etc.) and medi-
that are consistent with the patient’s beliefs (“I understand you
don’t think stress is causing your pain, but the pain itself is so cations that adversely cause symptoms should be
severe and disabling that it’s causing you a great deal of identified and possibly eliminated. Sometimes a food
distress.”). diary is helpful.
7. Set consistent limits (“I appreciate how bad the pain must be,
but narcotic medication is not indicated.”). Moderate symptoms. A smaller proportion of
8. Involve the patient in the treatment (“Let me suggest some
treatments for you to consider.”).
patients usually seen in primary or secondary care report
9. Make recommendations consistent with patient interests moderate symptoms and have intermittent disruptions in
(“Antidepressants can be used for depression, but they are activity, for example, missing social functions, work, or
also used to “turn down” the pain and in doses lower than that
school. They may identify a close relationship between
used for depression.”).
10. Establish a long-term relationship with a primary care provider. symptoms and inciting events such as dietary indiscre-
tion, travel, or distressing experiences. They may be
more psychologically distressed than patients with mild
change, concurrent medical disorder, side effects of new symptoms. For this group, additional treatment options
medication), (2) personal concern about a serious disease are recommended:
(recent family death), (3) environmental stressors (eg,
1. Symptom monitoring. The patient can keep a symptom
major loss, abuse history), (4) psychiatric comorbidity
diary for 1 to 2 weeks to record the time, severity, and
(depression, anxiety), (5) impairment in daily function
presence of associated factors. This diary may help to
(recent inability to work or socialize), or (6) a “hidden
identify inciting factors such as dietary indiscretions
agenda” such as narcotic or laxative abuse, or pending
or specific stressors not previously considered. The
litigation or disability.
physician can then review possible dietary, lifestyle,
Once the reasons for the visit are determined, treat-
or behavioral influences with the patient. This step
ment may be based on the severity and nature of the
encourages the patient’s participation in treatment,
symptoms, the physiologic and psychosocial determi-
and as symptoms improve, increases his or her sense of
nants of the patient’s illness behavior, and the degree of
control over the illness.
functional impairment. Although illness severity exists
2. Pharmacotherapy directed as specific symptoms. Medication
on a continuum, it is arbitrarily separated into mild,
can be considered for symptom episodes that are
moderate, and severe categories.
distressing or that impair daily function. The choice
Mild symptoms. Patients with mild or infrequent
of medication will depend on the predominant symp-
symptoms are usually seen in primary care practices and
toms and is outlined in later chapters of this book. In
do not have major impairment in function or psycholog-
general, prescription medications should be consid-
ical disturbance. They may have concerns about the
ered as ancillary to dietary or lifestyle modifications
implications of their symptoms, but do not make fre-
for chronic symptoms, but can be used during periods
quent visits and usually maintain normal activity levels.
of acute symptom exacerbation.
Here, treatment is directed toward:
3. Psychological treatments. Psychological treatments may
1. Education. Indicate that the FGIDs are very real and be considered for motivated patients with moderate-
the intestine is overly responsive to a variety of stim- to-severe GI symptoms and for patients with pain. It
uli such as food, hormonal changes, medication, and is more helpful if the patient can associate symptoms
stress. Pain resulting from spasm or stretching of the with stressors. These treatments, which include cog-
gut, from a sensitive gut, or both, can be experienced nitive-behavioral therapy, relaxation, hypnosis, and
anywhere in the abdomen and can be associated with combination treatments, help to reduce anxiety lev-
changes in GI function leading to symptoms (eg, els, encourage health-promoting behaviors, give the
1384 DOUGLAS A. DROSSMAN GASTROENTEROLOGY Vol. 130, No. 5

patient greater responsibility and control regarding provide a multidisciplinary team approach toward
the treatment, and improve pain tolerance. See the rehabilitation of patients who have become seriously
article in this issue “Psychosocial Aspects of the Func- disabled.
tional Gastrointestinal Disorders” on page 1447 in
this issue for more details. The Rome Committees and Criteria
Severe symptoms. Only a small proportion of pa- Development
tients with FGIDs have severe and refractory symptoms. Beginning about 15–20 years ago, and with
These patients also have a high frequency of associated greater recognition of the FGIDs, the academic environ-
psychosocial difficulties including diagnoses of anxiety, de- ment was receptive to a classification system that could
pression or somatization, personality disturbance, and be used for research and clinical care. At this time, the
chronically impaired daily functioning. There may be a Rome working teams began, and have since served as the
history of major loss or abuse, poor social networks or nidus to modify and update information on these disor-
coping skills, and “catastrophizing” behaviors. These pa- ders. With no prior standards or evidence from research,
tients may see gastroenterology consultants frequently and the groups developed criteria by consensus (via the Del-
may hold unrealistic expectations to be “cured.” They may phi Approach).99,100 Over time and with acquisition of
deny a role for psychosocial factors in the illness and may be new data, the process has matured through three gener-
unresponsive to psychological treatment or to pharmacolog- ations, producing a series of publications (Rome I, II, and
ical agents directed at the gut. III), with an increased evidence-based approach to the
1. The physician’s approach. These patients need an ongoing recommendations. The Rome organization was incorpo-
relationship with a physician (gastroenterologist or pri- rated in 1996 as the Working Teams for Diagnosis of
mary care physician) who provides psychosocial support Functional GI Disorders, became a 501(c)3 tax-exempt
through repeated brief visits. In general, the physician organization in 1997, and was renamed the Rome Foun-
should: (1) perform diagnostic and therapeutic measures dation in 2003 to reflect the expansion of its activities
based on objective findings rather than in response to globally. The Foundation continues its mission to im-
patient demands, (2) set realistic treatment goals, such as prove knowledge of the science and practice relating to
improved quality of life rather than complete pain relief the functional GI disorders and has received support
or cure, (3) shift the responsibility for treatment to the from academic organizations, investigators and clini-
patient by giving therapeutic options, and (4) change cians, pharmaceutical regulatory agencies, pharmaceuti-
the focus of care from treatment of disease to adjustment cal companies, and federal research agencies. See “The
to chronic illness. Road to Rome” on page 1552 in this issue for a historical
2. Antidepressant treatment. The tricyclic antidepressants account of the Rome Committee work.
(e.g., desipramine, amitriptyline), and more recently,
the serotonin-noradrenergic reuptake inhibitors (e.g., Rationale for Symptom-Based Diagnostic
duloxetine) have a role in controlling pain via central Criteria
analgesia as well as relief of associated depressive The Rome III classification system is based on the
symptoms. The selective serotonin reuptake inhibi- premise that for each disorder, there are symptom clus-
tors (e.g., citalopram, fluoxetine, paroxetine) may ters that remain consistent across clinical and population
have an ancillary role as they are less effective for pain groups. This type of organization provides a framework
but can help reduce anxiety and associated depression. for identification of patients for research that are modi-
Antidepressants should be considered for patients fied as new scientific data emerges. The rationale for
with chronic pain and impaired daily functioning, classifying the functional GI disorders into symptom-
coexistent symptoms of major or atypical depression, based subgroups has several bases.101
symptom anxiety, or panic attacks. Even without Site-specific differences. Patients with func-
depressive symptoms, these agents may help when the tional GI disorders report a wide variety of symptoms
pain is dominant and consuming. A poor clinical affecting different regions of the GI tract. These symp-
response may be due to insufficient dose or failure to toms have in common disturbances in sensory and/or
adjust the dosage based on therapeutic response or motor GI function, or similarities in CNS processing of
side effects. Treatment should be instituted for at visceral and somatic signals. Despite overarching simi-
least 3 to 4 weeks. If effective, it can be continued for larities in CNS functioning amenable to central treat-
up to a year and then tapered. ments, many, if not most of the FGIDs have peripherally
3. Pain treatment center referral. Pain treatment centers generated symptoms that require more specific treat-
April 2006 INTRODUCTION 1385

ments (eg, for diarrhea or constipation). Furthermore, Other diseases may coexist that need to be ex-
epidemiological studies using factor analysis and other cluded. The high frequency of the FGIDs ensures their
methods provide the evidence for the existence of site- coexistence with other diseases. If 10%–15% of the
specific syndromes.102–104 population has IBS, then the same proportion with in-
Symptoms resulting from multiple influencing flammatory bowel disease will also have IBS, and the
factors. Unlike motility criteria that define motor dys- evidence suggests that there is more than a chance asso-
function, which can have varying or no symptoms (eg, ciation.113 In fact, inflammatory bowel disease may even
gastroparesis, pseudo-obstruction, or “nutcracker esoph- predispose to IBS.114,115 Similarly, Helicobacter pylori
agus”), symptom-based criteria are influenced not only needs to be excluded and/or treated among patients with
by abnormal motility, but also visceral hypersensitivity functional dyspepsia. For research purposes, it is neces-
and brain gut dysfunction. Therefore, each condition sary to exclude other diseases before a functional GI
may have varying contributions from these pathophysi- designation can be applied. Therefore, for all criteria, the
ological determinants. following statement holds: there is no evidence of an inflam-
Epidemiologic data. Epidemiological studies matory, anatomic, metabolic, or neoplastic process that explains
show similar frequencies for these conditions across var- the patient’s symptoms. Physicians are well aware that in
ious studies and populations in Western countries in- clinical situations, one must consider the presence of two
cluding USA, Australia, England, and France,105 but or more conditions and make judgments on the proper
may be lower in Asian countries and in African Ameri- treatments for both. One example would be a patient
cans.106,107 In addition, a factor analysis study using two with IBS and inflammatory bowel disease having pre-
community samples108 identified an irritable bowel fac-
dominant pain and diarrhea not sufficiently explained by
tor, and these symptoms were very similar to those
the morphological findings.
developed from a clinical population of patients with IBS
Symptoms may overlap with other functional GI
using discriminant function analysis (“Manning” crite-
disorders. It is common for functional GI disorders to
ria).109 When differences do exist, these may relate to the
coexist, and the criteria permit the coexistence of more
type of criteria used, which may over- or underrepresent
than one FGID. Examples are esophageal chest pain (A2)
the population being tested.110
or globus (A4), with IBS (C1) or fecal incontinence (F1).
Treatment implications. A critical value to the
There are situations, however, in which a hierarchical
use of symptom-based diagnostic criteria relates to the
ability to define patient subsets amenable to treatment classification of the FGIDs is required. For instance,
trials. Thus, centrally acting treatments can have over- when criteria for both IBS (C1) and epigastric pain
arching effects on pain in most all the FGIDs, whereas syndrome (B1b) are fulfilled, the diagnosis of IBS only is
treatments for diarrhea or constipation can be targeted to made when the epigastric pain is relieved by defecation.
appropriate subgroups using the specified criteria. Similarly, functional bloating (C2) exists only when IBS
Need for diagnostic standards in clinical care and and the dyspeptic conditions are excluded, because bloat-
research. Because there are no unique physiological fea- ing is common to both these other conditions, and a
tures that can characterize all the disorders, and because diagnosis of functional constipation (C3) is made only if
it is symptoms that patients bring to physicians, the use IBS criteria are not met.
of a symptom-based classification system is rational for Symptoms must have begun 6 months prior to
clinical care and research. Symptom-based criteria are diagnosis and be active for 3 months. This time frame
used in psychiatry (eg, the Diagnostic and Statistical is a modification of the Rome II criteria and is less
Manual of Mental Disorders-IV)111 and rheumatology112 restrictive. Thus, onset of symptoms should begin at
and are becoming increasingly accepted within gastro- least 6 months before clinical presentation and the diag-
enterology. Symptom-based criteria can help guide the nostic criteria must be fulfilled for the last 3 months
diagnostic and treatment approach, reduce the ordering (rather than 1 year for Rome II).
of unneeded diagnostic studies, and standardize patient Diagnostic categories do not include psychoso-
selection for clinical trials. cial criteria. Although psychosocial disturbances can af-
fect the onset, course, severity, and outcome of the
Qualifications for the Use of Symptom- FGIDs, they are not required for diagnosis. Psychosocial
Based Criteria disturbances are more common in patients seen in refer-
There are several limitations and qualifications to ral practices over primary care or in the community of
the use of symptom-based criteria.101 nonconsulters.
1386 DOUGLAS A. DROSSMAN GASTROENTEROLOGY Vol. 130, No. 5

Criteria are determined by clinical consensus and ical appraisal and modification of the information
existing evidence. The proposed diagnostic criteria orig- presented by all members.
inated by the consensus of experts in the field and have 6. The committee met for two days in November/
since been modified only if there is compelling evidence December 2004 to revise the documents. This face-
to do so. All changes in criteria relate to a rationale that to-face meeting led to consensus on the diagnostic
is provided in the chapter. In some cases, recommenda- criteria and scientific content.
tions for changes (e.g., dyspeptic criteria, subtypes of 7. The information was summarized and presented to
IBS) are not yet proven but are supported by compelling the full committee of chairs and co-chairs over 1 day
evidence. New criteria will be tested in future studies for feedback and harmonization of content across
now underway, which will form the basis for future committees.
modifications of the criteria. 8. The chair and co-chair then revised the documents
again (Document D) and sent them to up to six
The Rome Committee Process outside international experts, in addition to scien-
The process for developing these criteria is a tists in the pharmaceutical industry, for their review
rigorous one. The consensus process was initiated by and commentary. This process was handled in col-
Professor Aldo Torsoli for the International Congress of laboration with the Rome Foundation and the GAS-
Gastroenterology in Rome (Roma ‘88). Dr. Torsoli TROENTEROLOGY journal administrative staff.
charged the committees99 to use a “Delphi” method100 of 9. Concurrently, the copy editor identified areas that
decision making, which fosters a team effort to produce required revisions relating to style and format and
consistency in opinion or consensus (although not nec- sent the changes to the chairs and co-chairs for
essarily total agreement) for difficult questions not easily modification.
addressed. The Rome II committees and more recently, 10. The Editorial Board served as editors to facilitate
the Rome III Board took on the responsibility to enhance and respond to the review process. Each Board mem-
these activities further using a rigorous 4-year, 13-step ber was responsible for two committees.
process outlined in the following points. 11. The committee chairs responded to the editor’s and
reviewers’ comments either by modifying the manu-
1. The Editorial Board identified individuals who ful-
scripts as requested, or by providing a written re-
filled preset criteria (academic research record, name
sponse that addressed the reviewer’s concerns. In
recognition, ability to work in groups, and diversity
some cases, the manuscripts were reviewed and mod-
issues related to discipline, geographic location, and
ified three times before final acceptance.
gender) to chair and co-chair each of the 14 sub-
12. The revised manuscripts and the commentaries by
committees. The chair and co-chair were charged to
the reviewers and authors were then sent to the
coordinate their committee to develop a manuscript
Editorial Board who met in September and again in
for the GASTROENTEROLOGY journal and a larger
December 2005 to critically review these materials
manuscript for the Rome III book.
and submit any final comments back to the authors.
2. The chair and co-chair, with consultation from the
In some cases, edits were made by the editors and
Board, recommended an international panel of up to
five additional members fulfilling the same criteria were sent for approval to the committee chairs and
previously noted to join the subcommittee. co-chairs.
3. The chair and co-chair designated each committee 13. Finally, when the documents were completed, all
member to produce an initial document covering members signed off their approval before it was sent
their particular area of expertise. The members are to the copyeditor for a final check on content and
charged to critically synthesize the literature regard- style prior to publication.
ing the physiological, psychological, and diagnostic
Changes Made in Rome III
and treatment aspects of a particular functional dis-
order or scientific content area. The changes from Rome II to Rome III reflect
4. The chair and co-chair then incorporated all docu- mainly updates in the literature and committee recom-
ments into a manuscript that was sent back to the mendations derived from these new data. In addition, a
entire committee for review (Document A). few modifications in the categories and criteria were
5. This process of modification and re-review by the made. The following information summarizes the
committee, repeated two more times (Documents B changes, and the reader is referred to the relevant article
and C) over a 2-year period, is associated with crit- for details.
April 2006 INTRODUCTION 1387

1. Time frame change for FGIDs. Symptoms are now rec- used in Rome II for IBS-D and IBS-C is still accept-
ommended to originate 6 months before diagnosis able, however.
and be currently active (ie, meet criteria) for 3
We are hopeful that these changes will make the
months. This time frame is less restrictive when
Rome III criteria more useful for research and clinical
compared to Rome II (12 weeks of symptoms over 12
care. Future studies will be needed to confirm the valid-
months) and is easier to understand and apply in
ity of these changes.
research and clinical practice.
2. Changes in classification categories. Rumination syn-
Concluding Comments
drome moved from functional esophageal (category
A) to functional gastroduodenal disorders (category It is with great anticipation that we introduce this
B). This change reflects the evidence that this disorder issue of GASTROENTEROLOGY: Rome III, The Functional
originates from disturbances in the stomach and ab- Gastrointestinal Disorders. We hope that the informa-
domen. tion will help the reader gain a better understanding of
3. Removal of FAPS from functional bowel disorders (category these disorders and help clinicians in the diagnosis and
C) into its own category (category D). This revision is care of our patients. This work is the culmination of a
based on growing evidence that FAPS relates more to 5-year effort of 87 internationally recognized investiga-
CNS amplification of normal regulatory visceral sig- tors representing 18 countries. As we look back on the
nals rather than functional abnormalities per se process, the information we have obtained is comprehen-
within the GI tract. sive, although certainly not complete. It is likely that the
4. Creation of two pediatric categories. The Rome II cate- next 6 years will bring considerable advances in our
gory of Childhood Functional GI Disorders is now understanding and treatment of these disorders, and
when that occurs, we plan to revise the information as we
classified as Childhood Functional GI Disorders: Ne-
move to Rome IV. As we look forward, we have taken on
onate/Toddler (category G) and Childhood Functional
several new initiatives to continue our mission. These
GI Disorders: Child/Adolescent (category H). This
plans include new working team committees that have
change is due to the different clinical conditions that
been instituted to develop standardization of brain im-
arise between these two categories relating to growth
aging assessment and making recommendations relating
and development of the child.
to symptom severity for research and clinical care. We
5. Criteria changes. For Rome III, functional dyspepsia
have also begun to capture this work and future scientific
(B1) is de-emphasized as an entity for research due to
data into a CD slide set module for self-learning and
the heterogeneity of this symptom complex as de- lectures. Finally, we are looking to disseminate this
fined. Instead, the committees recommend two con- knowledge through additional educational products on a
ditions that are subsumed under the functional dys- global scale. The Rome process is a dynamic one, and we
pepsia “umbrella”: (1) postprandial distress syndrome look forward to future activities to help improve the
(B1a) and (2) epigastric pain syndrome (B1b). These science of the FGIDs and patient care.
conditions are similar to dysmotility-like and ulcer-
like dyspepsia of Rome II. They are now defined by a References
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value of a gastroenterology consultation in irritable bowel syn- Center for Functional GI and Motility Disorders, Division of Gastroen-
drome. Aliment Pharmacol Ther 2003;17:871– 880. terology and Hepatology, 4150 Bioinformatics Building, CB#7080,
98. Drossman DA, Thompson WG. The irritable bowel syndrome: University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
review and a graduated, multicomponent treatment approach. 27599-7080. e-mail: [email protected]; fax: (919) 966-2250.
Ann Intern Med 1992;116:1009 –1016. The Editorial Board is grateful to the 87 authors representing 18
99. Torsoli A, Corazziari E. The WTR’s, the Delphic Oracle and the countries whose knowledge, experience, and hard work led to this final
Roman Conclaves. Gastroenterol Int 1991;4:44 – 45. product. We thank our industry sponsors for helping bring the Rome III
100. Milholland AV, Wheeler SG, Heieck JJ. Medical assessment by project to fruition. The sponsors are Astellas, Astra Zeneca, Axcan,
a delphi group opinion technique. N Engl J Med 1973;298: Forest, GlaxoSmithKline, Microbia, Novartis, Procter & Gamble, Solvay,
1272–1275. Sucampo/Takeda, and Vela Pharmaceuticals. We also thank the
101. Drossman DA. Do the Rome criteria stand up? In: Goebell H, Rome Foundation Staff for their tireless contributions: George Degnon
Holtmann G, Talley NJ, eds. Functional dyspepsia and irritable of Degnon Associates, Executive Director of the Rome Foundation, for
bowel syndrome: concepts and controversies (Falk Symposium his vision and direction; Carlar Blackman, Administrative Director of
99). Dordrecht: Kluwer Academic Publishers, 1998:11–18. the Rome Foundation and Managing Editor of Rome III, for her cre-
102. Whitehead WE. Functional bowel disorders: are they indepen- ativity, ability to move us ahead, and to keep our many activities going;
dent diagnoses? In: Corazziari E, ed. NeUroGastroenterology. Kathy Haynes of Degnon Associates for her efficiency and care in
Berlin: Walter de Gruyter, 1996: 65–74. meeting and sponsorship organization; Chris Dalton for her assistance
103. Whitehead WE, Bassotti GA, Palsson O, Taub E, Cook EC, III, in the Rome III meeting; Patrice Ferriola and Diane Feldman for their
Drossman DA. Factor analysis of bowel symptoms in U.S. and superb copyediting skills; and Jerry Schoendorf for his graphic design.
Italian populations. Dig Liver Dis 2003;35:774 – 83. We also want to acknowledge the 60 external peer reviewers whose
104. Camilleri M, Dubois D, Coulie B, Jones M, Kahrilas PJ, Rentz expertise helped us to improve on the manuscripts as well as Erin
AM, et al. Prevalence and socioeconomic impact of upper gas- Dubnansky and the Gastroenterology journal administrative staff for
trointestinal disorders in the United States: results of the US helping us process the document reviews. In addition, we acknowl-
Upper Gastrointestinal Study 1. Clin Gastroenterol Hepatol edge the following professionals and organizations for their support or
2005;3:543–552. assistance: The US Food and Drug Administration, the International
105. Saito YA, Schoenfeld P, Locke GR, III. The epidemiology of Foundation for Functional Gastrointestinal Disorders, the Clinical Prac-
irritable bowel syndrome in North America: a systematic review. tice Committee and Motility Nerve-Gut Interactions Section of the
Am J Gastroenterol 2002;97:1910 –1915. American Gastroenterological Association, the World Congress of Gas-
106. Wigington WC, Johnson WD, Minocha A. Epidemiology of irrita- troenterology in Montreal 2005, and the Functional Brain-Gut Re-
ble bowel syndrome among African Americans as compared search Group.
 GASTROENTEROLOGY 2006;130:1391–1411

Fundamentals of Neurogastroenterology: Basic Science

DAVID GRUNDY,* ELIE D. AL–CHAER,‡ QASIM AZIZ,§ STEPHEN M. COLLINS,¶ MEIYUN KE,储
YVETTE TACHÉ,# and JACKIE D. WOOD**
*Department of Biomedical Sciences, University of Sheffield, Sheffield, England; ‡Neurobiology and Developmental Sciences, University of
Arkansas for Medical Sciences, Little Rock, Arkansas; §Gastroenterology Division, Hope Hospital, Salford, England; 储Gastroenterology
Division, McMaster University Medical Center, Hamilton, Ontario, Canada; ¶Gastroenterology Division, Peking Union Medical College, Beijing,
China; #Department of Medicine, University of California, Los Angeles, Los Angeles, California; and **Department of Physiology and Cell
Biology, College of Medicine and Public Health, Ohio State University, Columbus, Ohio

The focus of neurogastroenterology in Rome II was the vous system (CNS) mechanisms that process and inter-
enteric nervous system (ENS). To avoid duplication with pret the incoming sensory information that gives rise to
Rome II, only advances in ENS neurobiology after Rome visceral pain and influence the autonomic sympathetic
II are reviewed together with stronger emphasis on in- and parasympathetic outflows that, together with the
teractions of the brain, spinal cord, and the gut in terms ENS, control and coordinate digestive functions. Clinical
of relevance for abdominal pain and disordered gastro-
gastroenterology translates basic discovery into the diag-
intestinal function. A committee with expertise in selec-
nosis and treatment of FGIDs and includes the impact of
tive aspects of neurogastroenterology was invited to
evaluate the literature and provide a consensus over-
inflammation and psychological state on brain-gut inter-
view of the Fundamentals of Neurogastroenterology actions. This report continues the “fundamentals” with a
textbook as they relate to functional gastrointestinal primary focus on interactions of the brain, spinal cord,
disorders (FGIDs). This review is an abbreviated version ENS, and gut and the relevance for abdominal pain and
of a fuller account that appears in the forthcoming book, disordered GI function.
Rome III. This report reviews current basic science un-
derstanding of visceral sensation and its modulation by Visceral Pain and Sensation
inflammation and stress and advances in the neurophys-
iology of the ENS. Many of the concepts are derived from GI afferents mediate reflexes that control motil-
animal studies in which the physiologic mechanisms ity, secretion, and blood flow and also modulate immune
underlying visceral sensitivity and neural control of mo- responses.3 Moreover, sensory information reaching the
tility, secretion, and blood flow are examined. Impact of CNS gives rise to both painful and nonpainful sensation
inflammation and stress in experimental models rela- and influences feeding and illness behavior. Heightened
tive to FGIDs is reviewed as is human brain imaging, visceral sensitivity is a hallmark of FGIDs. Whether the
which provides a means for translating basic science to hypersensitivity reflects transmission of aberrant sensory
understanding FGID symptoms. Investigative evidence signals to the brain, normal signals that are interpreted
and emerging concepts implicate dysfunction in the inappropriately by the brain, or a combination of both
nervous system as a significant factor underlying patient remains an unresolved question.
symptoms in FGIDs. Continued focus on neurogastroen-
terologic factors that underlie the development of symp- Peripheral Sensory Physiology
toms will lead to mechanistic understanding that is
expected to directly benefit the large contingent of pa- Vagal and spinal afferent nerve fibers transmit
tients and care-givers who deal with FGIDs. sensory information from the GI tract to the CNS. Vagal
afferents have cell bodies in nodose ganglia and enter the

eurogastroenterology is an emerging area of scien-

N tific and clinical subspecialization that was intro-
duced in the early 1990s. Neurogastroenterology encom-
Abbreviations used in this paper: AT-II, angiotensin II; CNS, central
nervous system; CRF, corticotropin-releasing factor; EGC, enteric glial
cell; ENS, enteric nervous system; EPSP, excitatory postsynaptic po-
tential; FGID, functional gastrointestinal disorder; GI, gastrointestinal;
passes basic and clinical research dealing with function 5-HT, serotonin; IBS, irritable bowel syndrome; IL, interleukin; IPSP,
and dysfunction of the gastrointestinal (GI) tract and its inhibitory postsynaptic potential; IR, immunoreactivity; MMC, migrat-
neural innervation. In Rome II, attention was focused on ing motor complex; PAR, protease-activated receptor; TNBS, trinitro-
the enteric nervous system (ENS) and neuroeffector benzene sulfonic acid.
© 2006 by the American Gastroenterological Association Institute
mechanisms as they relate to functional gastrointestinal 0016-5085/06/$32.00
disorders (FGIDs).1,2 Also relevant are the central ner- doi:10.1053/j.gastro.2005.11.060
1392 GRUNDY ET AL GASTROENTEROLOGY Vol. 130, No. 5

brainstem. Cell bodies of spinal afferents are located in tion. Other endings detect changes in the submucosal
dorsal root ganglia and project to the dorsal horn of the chemical milieu following injury, ischemia, or infection
spinal cord and the dorsal column nuclei. Spinal afferents and may play a role in generating hypersensitivity to
are broadly subdivided into splanchnic and pelvic affer- distention and muscle contraction.5
ents that follow the paths of sympathetic and parasym- Intramural spinal afferent fibers have collateral
pathetic efferents to the gut wall. Somatic afferents, branches that innervate blood vessels and enteric ganglia.
which innervate the striated musculature of the pelvic These contain and release neurotransmitters during local
floor, project to the sacral spinal cord via the pudendal axon reflexes that influence GI blood flow, motility, and
nerve. secretory reflexes.9 Spinal afferents en route to the spinal
Peripheral endings of vagal and spinal sensory neurons cord also give off collaterals that innervate prevertebral
terminate within the musculature, mucosal epithelium, sympathetic ganglia.10 The same sensory information is
and ganglia of the ENS.3 Spinal afferents also terminate thereby transmitted to information-processing circuits in
in the serosa and mesenteric attachments and form a the spinal cord, ENS, and prevertebral ganglia. Calcito-
dense network around mesenteric blood vessels and their nin gene-related peptide and substance P are important
intramural tributaries. Vagal afferent endings in the neurotransmitters in this sensory pathway, and both of
mucosa are in close association with the lamina propria these peptides are implicated in the induction of neuro-
adjacent to the mucosal epithelium, where they directly genic inflammation.11
monitor the chemical nature of luminal contents either Sensory transduction ultimately depends on the mod-
directly following passage across the epithelium or indi- ulation of ion channels and/or receptors on the sensory
rectly via paracrine input from enteroendocrine cells in nerve terminal.3 Mechanosensitivity may arise indirectly
the epithelium.3 Luminal nutrients, for example, cross following the release of chemical mediators such as aden-
the epithelium by various transport mechanisms to reach osine triphosphate (ATP), which in turn can act on
the afferent nerve terminals in the lamina propria. In purinergic receptors present on afferent nerve terminals.
addition, luminal nutrients act before absorption to cause Alternatively, there may be direct activation via mech-
the release of messenger molecules (eg, cholecystokinin anosensitive ion channels in the afferent nerve terminals.5
and serotonin [5-HT]) from enteroendocrine cells in the Mechanical deformation of the nerve ending leads to the
mucosa. These molecules in turn act on afferent termi- opening or closing of the ion channels, which depolarizes
nals that lie in close proximity in the lamina propria.4,5 the terminal to threshold for action potential firing and
Vagal afferent endings in the GI wall are classified as transmission of the sensory information to the CNS.
either intramuscular arrays or intraganglionic laminar Vagal mechanoreceptors generally have low distention
endings. Intramuscular arrays are distributed within the thresholds of activation, as indicated by responses to
muscle sheets running parallel to the long axes of the increases in distending pressures of a few millimeters of
muscle fibers,6 where they appear to make direct contact mercury and maximal firing frequencies occurring within
with the muscle fibers and also form appositions with physiologic levels of distention.3 However, some vagal
intramuscular interstitial cells of Cajal. Intraganglionic fibers can convey information about high-intensity me-
laminar endings are basket-like structures associated chanical stimulation and may also respond to noxious
with myenteric ganglia in the ENS. The location of chemical stimulation.12 Spinal afferents are classified as
intraganglionic laminar endings between the circular and low-threshold, high-threshold, or silent mechanorecep-
longitudinal muscle layers exposes them to the shearing tors.13 Low-threshold afferents respond to physiologic
forces generated during muscle stretch or contraction and levels of distention and continue to encode excessive
determines their function as low-threshold mechanore- levels of distention that evoke pain in humans and pain
ceptors.7 Intraganglionic laminar endings are also behavior in animals. High-threshold afferents respond to
present in the pelvic supply to the rectal musculature.8 higher levels of distention that are in the noxious range.
Their location in regions from which graded sensory Silent nociceptors do not respond at all in the normal
experiences can arise in response to investigator-applied intestine but become responsive to distention when the
stimuli (eg, balloon distention) leads to a suggestion that intestine is injured or inflamed.12 This kind of receptor
these endings may signal nonpainful sensations of full- behavior illustrates how mechanosensitivity is not fixed,
ness. either in terms of the threshold for sensory activation or
Spinal afferents have multiple receptive fields extend- the relationship between stimulus and response. Injury
ing over relatively wide areas of bowel.3 Afferent endings and inflammation decrease the threshold and increase the
in the serosa and mesenteric attachments respond to magnitude of the response for a given stimulus, a phe-
distortion of the viscera during distention and contrac- nomenon known as peripheral sensitization.14 Inflamma-
April 2006 FUNDAMENTALS OF NEUROGASTROENTEROLOGY 1393

tory sensitization underlies the perception of a normally tions of abdominal pain and discomfort associated with
innocuous stimulus as being painful and exaggerates the FGIDs.
intensity of pain experienced during a painful stimulus
Spinal Cord
(ie, hypersensitivity).
Sensitizing mediators are released by a plethora of cell Visceral afferents constitute only 10% of all af-
types, including blood platelets, leukocytes, lympho- ferent inflow into the spinal cord, yet they have wide-
cytes, macrophages, mast cells, glia, fibroblasts, blood spread termination in laminae I, II, V, and X of the
vessels, muscle, epithelial cells, and neurons. Several dorsal horn.16 Input from visceral and somatic sensory
mediators can be released from a single cell type to act fields converges onto the same neurons in the dorsal
either directly on the sensory nerve terminal or indirectly horn, dorsal column nuclei, and supraspinal centers.17–20
by stimulating the release of agents from other cells in a Viscerovisceral convergence of sensory information onto
series of cascades. the same neurons also occurs in the spinal cord. For
A battery of chemical mediators, including biogenic example, pelvic visceral inputs from colon and rectum,
amines, purines, prostanoids, proteases, and cytokines, bladder, uterine cervix, and vagina all converge onto the
act in a promiscuous manner on a range of receptors same second-order spinal neurons.16,17 The low density of
expressed on any one sensory ending. Three distinct visceral nociceptors, the phenomenon of viscerovisceral
processes are involved in the actions of these substances convergence, and the functional divergence of visceral
on visceral afferent nerves. First, by direct activation of input within the CNS probably all contribute to the poor
receptors coupled to the opening of ion channels present localization of visceral pain to a specific bodily region.
on nerve terminals, the terminals are depolarized and Visceral nociceptive information is transmitted cen-
firing of impulses is initiated. The second is by sensiti- trally via spinothalamic, spinohypothalamic, spinosoli-
zation that develops in the absence of direct stimulation tary, spinoreticular, and spinoparabrachial tracts, all in
the anterolateral quadrant of the spinal cord. In addition,
and results in hyperexcitability to both chemical and
a recently discovered pathway in the dorsal columns,
mechanical modalities. Sensitization may involve postre-
which involves mainly postsynaptic neurons, is also in-
ceptor signal transduction that includes G protein– cou-
volved in viscerosensory processing and visceral pain
pled alterations in second messenger systems that in turn
transmission.18 –25 Pain signals in the dorsal columns are
lead to phosphorylation of membrane receptors and ion
then transmitted via the ipsilateral dorsal column nuclei
channels that control excitability of the afferent endings.
(ie, nucleus gracilis and nucleus cuneatus) to the con-
The third is by genetic changes in the phenotype of
tralateral ventroposterolateral nucleus of the thalamus.
mediators, channels, and receptors expressed by the af- Stimulation of the posterior columns in a patient with
ferent nerve; for example, a change in the ligand-binding severe irritable bowel syndrome (IBS) evokes an imme-
characteristics or coupling efficiency of newly expressed diate increase in the intensity of abdominal pain.27 The
receptors might alter the sensitivity of the afferent ter- evidence suggests that dorsal column pathways have a
minals. Neurotrophins, in particular nerve growth factor major role in visceral nociceptive transmission.
and glial-derived neurotropic factor, influence different
populations of visceral afferents and play an important Central Sensitization
role in adaptive responses to nerve injury and inflamma- Central sensitization is believed to be the mech-
tion.15 anism underlying secondary hyperalgesia, which is a
Peripheral sensitization can occur rapidly and be phenomenon of increased pain sensitivity in regions dis-
short-lived because the changes taking place at the level tant to the site of injury or inflammation. Secondary
of the sensory nerve terminal are dependent on release of hyperalgesia results from altered mechanisms of synaptic
one or more algesic mediators. However, in the event of transmission in the spinal cord, which leads to a decrease
sustained tissue injury or inflammatory states, changes in in threshold, increased responsiveness, and an expansion
gene expression can occur that prolong peripheral sensi- of spinal neuronal receptive fields.28 Central sensitization
tization. These changes include alterations in those genes might contribute to the visceral hypersensitivity to dis-
that determine the amount and pattern of neurotrans- tention found in patients with IBS. The changes in
mitters released from the sensory nerve terminals in the synaptic transmission persist beyond the period of initial
spinal cord and the brain, thereby altering the CNS injury or inflammation and can be associated with altered
processing of sensory information.5 Peripheral sensitiza- bowel function.29,30 Glutamate and substance P are the
tion integrated with central sensitization of this nature is main neurotransmitters released during the spinal pro-
undoubtedly a significant factor determining the sensa- cessing of visceral pain. Both N-methyl-D-aspartate and
1394 GRUNDY ET AL GASTROENTEROLOGY Vol. 130, No. 5

non–N-methyl-D-aspartate glutamate receptors and neu- creased metabolic activity occurs in response to sensory
rokinin receptors are implicated in the synaptic mecha- experience, are used to identify a network of brain areas
nisms underlying central sensitization. that process GI sensation.32–37 Unlike somatic sensation,
which has a strong homuncular representation in the
Descending Spinal Modulatory Pathways primary somatosensory cortex, visceral sensation is pri-
At the level of the spinal cord, inputs from non- marily represented in the secondary somatosensory cor-
nociceptive and nociceptive afferent pathways interact to tex. Representations in the primary somatosensory cortex
modify transmission of nociceptive information to higher are vague and diffuse, which might account for visceral
brain centers. The brain itself has modulatory systems sensation being poorly localized in comparison with so-
that affect the conscious perception of incoming sensory matic sensation. Visceral sensation is also represented in
stimuli. Spinal visceral nociceptive transmission is sub- paralimbic and limbic structures (eg, anterior insular
ject to modification by descending modulatory influences cortex, amygdala, anterior and posterior cingulate cortex)
from supraspinal structures (eg, periaqueductal gray, nu- and prefrontal and orbitofrontal cortices. These are the
cleus raphe magnus, locus ceruleus, nuclei reticularis areas that process the affective and cognitive components
gigantocellularis, and the ventrobasal complex of the of visceral sensation. Gender differences in cortical rep-
thalamus). Descending modulation is sometimes inhib- resentation of rectal sensation occur in healthy volun-
itory, facilitatory, or both, depending on the context of teers. While activation in the sensory-motor and parieto-
the visceral stimulus or the intensity of the descending occipital areas is common in men and women, greater
signal.30 The descending influence from the ventrome- activation in the anterior cingulated/prefrontal cortices
dial medulla is mediated mainly by pathways traveling was found in women.37 These gender differences in the
in the dorsolateral spinal cord31 and can be inhibitory or processing of sensory input are reminiscent of reports
facilitatory based on stimulus intensity. In contrast, de- that perceptual responses are exaggerated in female pa-
scending control from the thalamus is context specific in tients with FGIDs.
that it may facilitate or inhibit spinal nociceptive pro-
cessing depending on the presence or absence of central ENS
sensitization.31
Serotonergic, noradrenergic, and, to a lesser extent, The chapter on fundamentals of neurogastroenter-
dopaminergic projections are major components of de- ology in Rome II provided a review of the neurophysi-
scending modulatory pathways. Exaggeration of de- ology of the ENS that was up-to-date at the time.1,2
scending facilitative signals from the brain may partly Advances since Rome II appear in subsequent re-
explain the visceral hypersensitivity that is found in a views38 – 42 and are summarized in brief in this section.
subset of patients with IBS.27 Attention to the ENS continues to have central impor-
tance for neurogastroenterology and FGIDs because the
Representation of Sensation in the Brain digestive tract does not work without the integrative
Conscious experience of sensation is a multifac- functions of the ENS. Normal functioning of the neural
eted process that involves a complex interaction between networks of the ENS is necessary for effective motility,
sensory-discriminative, affective, and cognitive dimen- secretion, and blood flow and coordination of these func-
sions. Functional brain imaging techniques make it pos- tions into organized patterns of behavior at the level of
sible to study the complex interaction between a number the integrated organ system. As expected, malfunctions
of cortical and subcortical areas involved in sensory ex- of integrative ENS control of the gut’s effector systems
perience and may in the future help determine whether are increasingly recognized as underlying factors in GI
sensory dysfunction in patients with FGIDs is due to disorders, especially in the FGIDs, and therefore become
disordered sensory detection and transmission in the a target for drug therapy.41,43– 46
periphery (eg, tissue injury or inflammation), aberrant
processing of sensory information in the brain, or a Enteric Neural Signaling
combination of these peripheral and central factors. Fundamental mechanisms for chemically medi-
ated signaling in the ENS are the same as elsewhere in
Viscerocortical Pain Matrix the nervous system and may occur in the form of neu-
The functional brain imaging techniques of func- rocrine (ie, synaptic transmission), endocrine, or para-
tional magnetic resonance imaging and positron emis- crine signals. Transmitters at chemical synapses are re-
sion tomography, both of which rely on measurements of leased by Ca2⫹-triggered exocytosis from stores localized
blood flow in cortical and subcortical areas where in- in vesicles at axonal terminals or transaxonal varicosities.
April 2006 FUNDAMENTALS OF NEUROGASTROENTEROLOGY 1395

Release is triggered by the depolarizing action of action a specific nicotinic receptor are determined by the kinds
potentials when they arrive at the release site and open of subunits that form the pentameric receptor. The main
voltage-activated Ca2⫹ channels. Once released, enteric mediator of nicotinic fast EPSP-like responses in enteric
neurotransmitters bind to their specific postsynaptic re- neurons is a receptor composed of ␣3 and ␤4 subunits.54
ceptors to evoke ionotropic or metabotropic synaptic
events. When the receptors are directly coupled to the Purinergic Receptors
ionic channel, they are classified as “ionotropic.” They are P2X receptors are trimeric proteins formed by
“metabotropic receptors” when their effects to open or subunits with 2 transmembrane domains. There are at
close ionic channels are indirectly mediated by guanosine least 7 subtypes of P2X receptors, ranging from P2X1 to
triphosphate binding proteins and the induction of cy- P2X7. Immunohistochemical studies using specific P2X
toplasmic second messengers (eg, adenosine 3=,5=-cyclic receptor antibodies found at least 3 P2X receptor sub-
monophosphate, inositol 1,4,5-triphosphate, and diacyl- units in the ENS that were identified as P2X2, P2X3, and
glycerol).47 P2X7.58 – 61 The P2X2 receptor is expressed in neurons
The kinds of synaptic events in the ENS are basically that express immunoreactivity (IR) for the chemical
the same as in the brain and spinal cord. Fast and slow codes of inhibitory musculomotor neurons, noncholin-
excitatory postsynaptic potentials (EPSPs) and inhibitory ergic secretomotor neurons, and calbindin-immunoreac-
postsynaptic potentials (IPSPs) are principal synaptic tive neurons.60 Loss of the purinergic component of fast
events in the ENS. An enteric neuron may express mech- EPSPs in P2X2 knockout mice supports the suggestion
anisms for both slow and fast synaptic neurotransmis- that the P2X2 receptor is a major player in purinergic
sion. Fast synaptic potentials have durations in the mil- fast transmission in enteric neurons.53 P2X3 subunits
lisecond range; slow synaptic potentials last for several form heteromers with P2X2 subunits in aborally project-
seconds, minutes, or longer. Fast synaptic potentials are ing inhibitory musculomotor neurons. Calbindin-immu-
usually EPSPs. The slow synaptic events may be either noreactive enteric neurons do not express P2X3 receptor
EPSPs or IPSPs. IR.59,61
Fast EPSPs Serotonergic 5-HT3 Receptors
Fast EPSPs were reported for the earliest intracel- Responses mediated by 5-HT3 receptors are found
lular studies of myenteric neurons but were found only in on neurons in both plexuses throughout the GI tract,
S-type neurons in the early work of Hirst et al and Nishi including the stomach.62 Neither purinergic nor seroto-
and North.48,49 Fast EPSPs are rapidly activating depo- nergic fast EPSPs occur in each and every class of neurons
larizing responses with durations less than 50 millisec- (ie, based on chemical codes) in the guinea pig colon and
onds. Fast EPSPs were later reported to occur in AH- and elsewhere.55
S-type neurons in both myenteric and submucosal plex- Results obtained with patch clamp recording methods
uses.39 Fast EPSPs appear to be the sole mechanism of show that the nicotinic and 5-HT3 serotonergic receptors
transmission between vagal efferents and enteric neurons. connect directly to nonselective cationic channels. Open-
Most of the fast EPSPs are mediated by acetylcholine ing of these channels is responsible for the depolarizing
acting at nicotinic postsynaptic receptors. The actions of event.63 Rapid desensitization, within seconds in vitro, is
5-HT at the 5-HT3 serotonergic receptor subtype and a characteristic of both the nicotinic- and 5-HT3– oper-
purine nucleotides at P2X purinergic receptors behave ated channels, both of which are ionotropic. Purinergic
much like fast EPSPs, and it is possible that some fast “fast” depolarizing responses, like serotonergic 5-HT3
EPSPs are purely serotonergic or purinergic or reflect a receptor–mediated responses, reflect opening of ligand-
summation of purinergic and serotonergic input.50 –55 gated nonselective cationic channels.64
P2X receptors are potential therapeutic targets.56 Antag-
onists at 5-HT3 receptors have proved effective in treat- Fast EPSP Rundown
ment of diarrhea-predominant IBS.57 Amplitudes of nicotinic fast EPSPs in the intes-
tine become progressively smaller when they are evoked
Nicotinic Receptors repetitively by focal electrical stimulation applied to the
Different combinations of ␣ and ␤ subunits as- surface of the ganglion or interganglionic fiber tract in
semble in different combinations to form nicotinic re- vitro. Decrease in EPSP amplitude occurs at stimulus
ceptors in general. Functional receptors are formed by 5 frequencies as low as 0.1 Hz, and the rate of decline is a
subunits. Eight different ␣ subunits (ie, ␣2–9) and 9 ␤ direct function of stimulus frequency. Rundown of this
subunits (ie, ␤2– 4) have been identified. The properties of nature does not occur at the synapses in the stomach or
1396 GRUNDY ET AL GASTROENTEROLOGY Vol. 130, No. 5

gallbladder.65– 67 The rundown phenomenon reflects pre- and elevation of intraneuronal Ca2⫹ levels.47 Exposure to
synaptic inhibition of acetylcholine release by additional bradykinin, serine proteases, ATP, corticotropin-releas-
transmitter substances broadly released by the electrical ing factor (CRF), or angiotensin II (AT-II) has been
stimulus or by negative feedback involving autoinhibi- reported to mimic slow EPSPs in the ENS since publi-
tion of acetylcholine release mediated by presynaptic cation of Rome II in 1999 and 2000.1,2
inhibitory muscarinic receptors.68 Rundown cannot be Bradykinin. Bradykinin is an established inflam-
attributed to postsynaptic changes, because no decrease matory mediator derived from proteolytic action on
in the amplitude of the EPSPs occurs during repetitive plasma proteins as a result of tissue injury, anoxia, or
applications of acetylcholine from microejection pipettes. inflammation. Application of bradykinin evokes slow
EPSP-like excitation in AH- and S-type neurons.69 –71
Significance of Fast EPSPs The selective B2 bradykinin receptor antagonist Hoe 140
The importance of fast EPSPs emerges from their but not the selective B1 receptor antagonist des-arg10-
function in the rapid transfer and transformation of Hoe 140 suppresses responses to bradykinin. Reverse-
neurally coded information between axons and neuronal transcription polymerase chain reaction and Western
cell bodies and axons and dendrites that form the enteric blot analysis confirm the existence of B2 receptor mes-
neural networks. Fast EPSPs may or may not depolarize senger RNA and protein in guinea pig myenteric and
the membrane to its threshold for discharge of an action submucosal plexuses, and binding of fluo-HOE 140
potential. Summation of multiple inputs increases the (HOE741) reveals that the neurons are endowed with the
probability of reaching firing threshold. Fast EPSPs do B2 receptors and not the B1 receptor.69 The mechanism of
not reach threshold when the neuronal membranes are excitatory action of bradykinin is somewhat unique in
hyperpolarized during slow IPSPs. They are most likely that it acts at the neuronal B2 receptor to stimulate the
to reach spike threshold when the membranes are depo- neuron to synthesize and release prostaglandin E2, which
larized during slow EPSPs or depolarizing action of feeds back and acts at EP1 receptors to evoke excitation
modulators released in paracrine fashion from nonneuro- in the same neuron.70 Prostaglandin feedback accounts
nal cells. This effect of slow EPSPs and of slow EPSP-like for an earlier finding that bradykinin releases acetylcho-
paracrine mediators is an example of neuromodulation line from the myenteric plexus by a prostaglandin-me-
whereby the input-output relations of a neuron to one diated mechanism.72 Exposure to bradykinin also sup-
input (ie, fast EPSPs) are modified by a second synaptic presses the amplitude of both stimulus-evoked slow
or other kind of modulatory input. EPSPs and fast nicotinic EPSPs in the ENS.
Serine proteases and protease-activated recep-
Slow EPSPs tors. Serine proteases can be released from enteric mast
Slow EPSP and slow EPSP–like excitation evoked cells to mimic slow EPSPs by stimulating protease-
by substances released in endocrine or paracrine fashion activated receptors (PARs) on the neurons.73–76 Applica-
are major signaling events in the ENS microcircuitry, tion of thrombin, trypsin, or mast cell tryptase evokes
where many research advancements have been made. slow EPSP-like excitatory responses in AH- and S-type
Slow EPSPs in enteric neurons with S-type electrophysi- enteric neurons. Synthetic activating peptides for
ologic behavior and uniaxonal morphology differ from PAR-1, PAR-2, and PAR-4 receptors mimic these ac-
neurons with AH-type electrophysiologic behavior and tions. The depolarizing responses evoked by a majority of
multipolar Dogiel type II morphology.47 Slow EPSPs in PAR-sensitive uniaxonal enteric neurons express IR for
AH-type enteric neurons are associated with slowly ac- nitric oxide synthase.74 IR for nitric oxide synthase (ie,
tivating membrane depolarization, suppression of hyper- labeled antibodies raised against nitric oxide label the
polarizing afterpotentials, decreased membrane conduc- neurons) suggests that these neurons are descending in-
tance, and elevated excitability. Postreceptor signal hibitory motor neurons to the intestinal circular muscle.
transduction in AH-type neurons involves stimulation of ATP. Secretomotor neurons with vasoactive intes-
adenylate cyclase and elevation of intraneuronal adeno- tinal peptide IR in the submucosal plexus of guinea pig
sine 3=,5=-cyclic monophosphate levels. Slow EPSPs in intestine receive slow EPSP input that is mediated by
S-type uniaxonal neurons are also slowly activating de- synaptic release of ATP and its action at P2Y1 receptors
polarizing potentials associated with elevated excitabil- expressed by the neurons.76 MRS2179, a selective P2Y1
ity; however, unlike AH-type neurons, membrane con- purinergic receptor antagonist, blocks both the slow
ductance either increases or does not change during the EPSP and mimicry of the EPSP by exogenously applied
EPSP. The postreceptor signal transduction cascade in ATP. The submucosal secretomotor neurons receive their
these neurons involves stimulation of phospholipase C purinergic excitatory input from neighboring neurons in
April 2006 FUNDAMENTALS OF NEUROGASTROENTEROLOGY 1397

the same plexus, neurons in the myenteric plexus, and selective CRF2 receptor antagonist antisauvagine-30.80
sympathetic postganglionic neurons. The ATP-mediated Reverse-transcription polymerase chain reaction reveals
EPSPs occur coincident with fast nicotinic synaptic po- expression of messenger RNA transcripts for the CRF1
tentials evoked by projections from both myenteric neu- receptor but not the CRF2 receptor in both myenteric
rons and other submucosal neurons and with noradren- and submucosal plexuses of guinea pig. IR for the CRF1
ergic IPSPs that are evoked by firing of sympathetic receptor is distributed widely in the myenteric plexus of
fibers that innervated the same neurons. the stomach and small and large intestine and in the
The P2Y1 receptors on secretomotor neurons are submucosal plexus of the small and large intestine. CRF1
metabotropic receptors that are linked to activation of receptor IR is coexpressed with calbindin, choline acetyl-
phospholipase C, synthesis of inositol 1,4,5-triphosphate, transferase, and substance P in myenteric plexus neurons.
and mobilization of Ca2⫹ from intracellular stores. The In the submucosal plexus, CRF1 receptor IR is found in
purinergic neurons that synapse with and release ATP at neurons that express calbindin, substance P, choline
postsynaptic P2Y1 receptors on submucosal secretomotor acetyltransferase, or neuropeptide Y. The evidence im-
neurons themselves express excitatory serotonergic plicates the CRF1 receptor as the mediator of the exci-
5-HT3 receptors that respond to exogenously applied tatory actions of CRF on neurons in the ENS.
5-HT and might be stimulated by release of 5-HT from CRF-immunoreactive neurons do not express IR for
mucosal enterochromaffin cells.76 Purinergic P2Y1 sig- the CRF1 receptor. CRF1 IR is expressed in neuronal
naling to secretomotor neurons is currently recognized as neighbors of those with CRF IR, which suggests that
an important aspect of the functional regulation of in- secretomotor neurons expressing CRF IR might provide
testinal mucosal secretion.77,78 synaptic input to CRF1 receptors on neighboring cholin-
CRF. A later section on mechanisms underlying ergic neurons. A general conclusion is that actions on
the impact of stress on intestinal motor, secretory, and enteric neurons might underlie the neural mechanisms
immune functions presents evidence that stimulation of by which stress-related release of CRF in the periphery
receptors for CRF in the brain and the ENS of animal alters intestinal propulsive motor function, mucosal se-
models is a factor in stress-induced alteration of GI cretion, and mucosal barrier function.
functions and the exacerbation of FGID symptoms in Angiotensin. Two enzymes catalyze the conversion
humans.79 IR for CRF is expressed in both the myenteric of angiotensin I to AT-II, which is the biologically active
and the submucosal plexuses of all regions of the large form in the intestine. One of the enzymes, angiotensin-
and small intestine and the myenteric plexus of the converting enzyme, is expressed in a variety of tissues and
stomach of the guinea pig.80,81 Most of the CRF-immu- organs, including the brush border of the small intestinal
noreactive myenteric neurons have uniaxonal morphol- epithelium.82,83 Mast cell ␣ kinases are a second set of
ogy; the remainder has Dogiel type II multipolar mor- converting enzymes. ␣-Chymase is the major non–angio-
phology. CRF-immunoreactive cell bodies in the tensin-converting enzyme producer of AT-II in hu-
myenteric plexus of the ileum express IR for choline mans.84,85 Release of ␣-chymase accounts for the appearance
acetyltransferase, substance P, and nitric oxide synthase. of AT-II as one of the main products associated with de-
CRF IR never colocalizes with IR for calbindin, calreti- granulation of mast cells.85 Significantly elevated levels of
nin, neuropeptide Y, serotonin, or somatostatin in the AT-II are found in mucosal biopsy specimens from patients
myenteric plexus. CRF-immunoreactive cell bodies are with Crohn’s colitis, which suggests that elevated levels
more abundant in the submucosal plexus than in the might be associated with inflammatory states, including
myenteric plexus. All CRF-immunoreactive neurons in mast cell hyperplasia.86,87
submucosal ganglia express vasoactive intestinal peptide The predictable hypertensive action of systemically
IR and are likely to be secretomotor/vasodilator neurons. administered AT-II is well known. Systemic dosing with
Exposure to CRF evokes slowly activating depolariz- AT-II evokes vasoconstriction and reduced blood flow in
ing responses associated with elevated excitability in the intestinal mesenteric vasculature in parallel with
both myenteric and submucosal neurons.80 Histologic whole-body hypertension. Elevated vascular resistance
analysis of biocytin-filled neurons finds that both uniax- and decreased flow in the inferior mesenteric vascular bed
onal neurons with S-type electrophysiologic behavior and leads to ischemic colitis in pigs receiving pathophysio-
neurons with AH-type electrophysiologic behavior and logic doses of AT-II.88
Dogiel II morphology respond to CRF. The CRF-evoked AT-II also alters intestinal absorption of Na⫹ and
depolarizing responses are suppressed by the CRF1/CRF2 H2O. Low doses of AT-II (eg, 0 – 60 ng · kg⫺1 · min⫺1)
receptor antagonist astressin and the selective CRF1 re- stimulate Na⫹ and H2O absorption.89,90 Stimulation of
ceptor antagonist NBI 27914 and are unaffected by the absorption is secondary to elevated release of norepineph-
1398 GRUNDY ET AL GASTROENTEROLOGY Vol. 130, No. 5

rine from intramural sympathetic nerves in concert with Results of electrophysiologic studies in secretomotor
suppression of neuronal reuptake of norepinephrine.91 neurons suggest that AT-II enhances inhibitory sympa-
Intracerebroventricular administration of AT-II stimu- thetic noradrenergic neurotransmission to secretomotor
lates descending spinal pathways, which activate sympa- neurons and thereby suppresses mucosal secretion.98 Ex-
thetic outflow to the bowel.92 posure to AT-II depolarizes the membrane potential and
Inhibitory actions of norepinephrine on enteric secre- elevates neuronal excitability in small numbers of my-
tomotor neurons explain the action of AT-II to suppress enteric neurons (⬃25%) and submucosal neurons
mucosal secretion and induce an absorptive state. Secre- (⬃32%). On the other hand, hyperpolarizing responses
tomotor neurons are well recognized as excitatory motor (ie, inhibitory responses) are evoked by AT-II in nearly
neurons in the submucosal division of the ENS that one half of the neurons in both plexuses. The hyperpo-
innervate the intestinal crypts of Lieberkühn.93 Firing of larizing responses are suppressed by ␣2-noradrenergic
secretomotor neurons releases acetylcholine and/or vaso- receptor antagonists, which suggests that the hyperpo-
active intestinal peptide as neurotransmitters at their larizing responses reflect stimulation of norepinephrine
junctions in the crypts. Secretomotor axons also send release from sympathetic neurons. Exposure to AT-II
collaterals to innervate submucosal arterioles.94,95 Collat- enhances the amplitude and prolongs the duration of
eral innervation of the blood vessels links blood flow to noradrenergic IPSPs in secretomotor neurons and sup-
secretion by releasing acetylcholine simultaneously at presses the amplitude of both fast and slow EPSPs. The
neuroepithelial and neurovascular junctions. Once re- selective AT-II1 receptor antagonists ZD-7115 and lo-
leased, acetylcholine acts at the blood vessels to dilate the sartan, but not a selective AT-II2 receptor antagonist
vessels and increase blood flow in support of stimulated (PD-123319), suppress the actions of AT-II. Western
secretion. blot analysis and reverse-transcription polymerase chain
Secretomotor neurons have receptors that receive ex- reaction find expression of AT-II1 receptor protein and
the messenger RNA transcript for the AT-II1 receptor in
citatory and inhibitory synaptic input from neurons in
the ENS. No expression of AT-II2 receptor protein or
the integrative circuitry of the ENS and from sympa-
messenger RNA can be found in the guinea pig ENS.
thetic postganglionic neurons. Activation of the excita-
AT-II1 receptor IR is expressed by a majority of enteric
tory receptors on secretomotor neurons stimulates the
neurons in the gastric antrum and small and large
neurons to fire and release their transmitters at the
intestine.
junctions with the crypts and regional blood vessels. The
The evidence suggests that formation of AT-II might
overall result of secretomotor firing is stimulation of
have paracrine-like actions in the ENS, which would
the secretion of H2O, electrolytes, and mucus from the include alterations in neuronal excitability and facilitated
crypts. Elevated firing of secretomotor neurons converts release of norepinephrine from sympathetic postgangli-
the intestine in situ from an absorptive state to a secre- onic axons. The enhanced presence of norepinephrine is
tory state with increased liquidity of the luminal expected to suppress fast and slow excitatory neurotrans-
contents. mission in the enteric microcircuits and to suppress
Inhibitory inputs decrease the probability of secreto- neurogenic mucosal secretion. Hard-dry stools and
motor firing. The physiologic effect of inhibiting secre- chronic constipation in some patients might reflect en-
tomotor activity is suppression of mucosal secretion. hanced sympathetic nervous activity and elevated release
Postganglionic neurons of the sympathetic nervous sys- of norepinephrine. In such cases, it might be predicted
tem are one of the important sources of inhibitory input that treatment with an angiotensin-converting enzyme
to the secretomotor neurons.96,97 Submucosal soma- inhibitor would relieve the constipation.
tostatinergic neurons are another source of inhibitory
input.96 Norepinephrine released from sympathetic ax- Inflammation
ons acts at ␣2a-noradrenergic receptors to inhibit the Work to understand the actions of inflammatory/
secretomotor neurons. Inhibition of secretomotor firing immune mediators in the ENS began with histamine in
reduces the release of excitatory neurotransmitters in the 1975, when exposure to it was found to excite neurons in
crypts. The end result is conversion to an absorptive state the myenteric plexus of cat small intestine.99 Since then,
with reduced secretion of water and electrolytes. Sup- several putative mediators expected to be present in the
pression of secretion in this manner is postulated to be inflamed bowel or to be released in response to sensitiz-
part of the mechanism by which low-dose AT-II stimu- ing antigens in atopic bowel have been tested for their
lates absorption in association with augmented intramu- electrophysiologic actions on neuronal excitability and
ral sympathetic nervous activity. neurotransmission in the ENS. These include histamine,
April 2006 FUNDAMENTALS OF NEUROGASTROENTEROLOGY 1399

5-HT, adenosine, interleukin (IL)-1␤, IL-6, leukotrienes, evokes mast cell release of histamine, which acts at
prostaglandins, nitric oxide, and mast cell proteases, histamine H2 receptors to elevate neuronal excitability.
actions of which have been reviewed in detail.38 Most act The overlay of histamine on the neural networks also acts
to mimic slow EPSPs in AH-type enteric neurons, an at presynaptic inhibitory histamine H3 receptors on post-
action that includes membrane depolarization, decreased ganglionic sympathetic nerve terminals to suppress re-
membrane conductance, elevated excitability, and sup- lease of norepinephrine.109,110 Mast cells in the stomachs
pression of hyperpolarizing afterpotentials. Moreover, from the same animals do not become sensitized to the
most of the inflammatory/immune mediators act to sup- food antigen (ie, milk protein), and histamine has no
press fast nicotinic EPSPs and noradrenergic IPSPs. El- excitatory action on neurons in the gastric myenteric
evated excitability occurs also in submucosal secretomo- plexus.110
tor neurons. The elevation of excitability, which occurs Human mast cells. Mast cells from human in-
coincident with suppression of noradrenergic IPSPs and testine appear to behave in a manner similar to that of
removal of sympathetic braking action on secretomotor mast cells in the animal models. Mast cells, enzymat-
neurons, undoubtedly underlies the neurogenic secretory ically dispersed from human intestine and maintained
diarrhea associated with inflammatory states and re- in culture, can be stimulated to degranulate and si-
sponses to allergens. multaneously release multiple mediators by cross-
Animal models for intestinal inflammation, parasitic linking of their immunoglobulin E receptors with an
infection (eg, Trichinella spiralis or Nippostrongylus brasil- antibody that binds the Fc⑀ ␣ chain.111 The culture
iensis), and food allergy (eg, milk protein or ovalbumin) media, with the released mast cell products, are then
have proved useful for translating to the pathologic state centrifuged and stored frozen to await study of effects
of the whole bowel, the observations that have been on enteric neurons. Application of supernatants con-
obtained with experimental application of inflammatory/ taining mast cell secretory products to either guinea
immune mediators to single enteric neurons.38,100 –106 pig or human ENS preparations in vitro evokes ex-
Preparation of the inflammatory models involves rectal citatory responses in single neurons that are reminis-
injection of agents (eg, trinitrobenzene sulfonic acid cent of the effects of mast cell degranulation in food
[TNBS], acetic acid, turpentine, or mustard oil), which allergy and animal models for parasitic infection.107–111
results in local mucosal inflammation or transmural in- Unlike the findings in animal models, the products of
flammation depending on the agent used. human mast cell degranulation appeared not to sup-
Neuronal excitability of single enteric neurons is en- press fast nicotinic neurotransmission in the ENS
hanced during the inflammatory phase of infection with preparations, as determined by application of imaging
T spiralis as compared with uninfected animals.107,108 technology with voltage-sensitive dyes.111
Decreased resting membrane potentials, increased mem- Chemically induced inflammatory models. A mi-
brane input resistance, decreased threshold for action nor loss of enteric neurons occurs in the animal models
potential discharge, and suppression of the amplitude with TNBS-induced colitis.78 Elevated excitability of
and duration of hyperpolarizing afterpotentials occur in enteric neurons in this model is a constant finding when
AH-type neurons in preparations from infected guinea electrical and synaptic behavior are recorded with intra-
pigs. The state of augmented excitability in AH-type cellular microelectrodes.100,104 Hyperexcitability is espe-
neurons, which is found with electrophysiologic record- cially prominent in AH-type neurons in the TNBS
ing in single neurons, is reflected by increased cyto- guinea pig model. AH-type neurons, which generally fire
chrome oxidase activity and expression of c-Fos IR.108 only once or not at all in response to long-lasting depo-
Excitability in S-type enteric neurons is also elevated in larizing current pulses in their resting state in the normal
preparations from T spiralis–infected animals, as reflected intestine, fire repetitively in response to the same depo-
by elevated levels of spontaneous action potential dis- larizing pulses in the TNBS-inflamed intestine.104 Ele-
charge.107 vated excitability in the AH-type neurons in the TNBS
Mast cells. Mastocytosis occurs in T spiralis in- models is associated with shortening of the action po-
fection, and the excitatory effects of application of T tential duration and suppression of the characteristic
spiralis antigens to enteric neurons in preparations from hyperpolarizing after-spike potentials. No statistically
infected guinea pigs in vitro reflect mast cell release of significant change in either the membrane potential or
histamine and its excitatory action at histamine H2 re- input resistance of the AH-type neurons has been re-
ceptors on the neurons.38,107 The situation is the same in ported for the TNBS model.102,104
the small and large intestine of guinea pigs that are Some of the electrophysiologic changes in AH-type
sensitized to a food antigen. Exposure to the antigen neuronal behavior in the TNBS model are essentially the
1400 GRUNDY ET AL GASTROENTEROLOGY Vol. 130, No. 5

same as the behavior during slow synaptic excitation and EGCs express many of the properties of the astroglia in
the actions of putative paracrine inflammatory mediators the CNS and represent one of the several criteria often
(eg, histamine, prostaglandins, platelet-activating factor, evoked as justification for reference to the ENS as a
and so on).38 A “cocktail” of inflammatory mediators is “brain in the gut.” Contrary to past assumptions, accu-
undoubtedly “flooding” the ENS microcircuitry in the mulating evidence suggests that EGCs are more than
TNBS model and can be postulated to account for the passive scaffolding that supports the neurons in ENS
observed alterations in neuronal activity. Separate iden- ganglia. When positioned outside of the ganglia in the
tification of each of the involved mediators remains as a lamina propria, they are associated with submucosal
project for the future. Nevertheless, Linden et al103 re- blood vessels and the mucosal epithelium. EGCs form a
ported that activation of cyclooxygenase and associated dense latticework of cells in close apposition to the basal
prostaglandin production was one of the factors associ- side of the intestinal mucosal epithelium. Current evi-
ated with the hyperexcitability in the AH-type neurons. dence and concepts now interpret the EGCs as being
Prostaglandins are known to evoke slow EPSP-like re- actively involved in the integrated functions of the whole
sponses in AH-type neurons when applied exogenously organ. They are believed necessary for the structural and
to freshly dissected preparations in vitro and mimic the functional integrity of the ENS and maintenance of the
electrophysiologic changes found in TNBS-induced co- mucosal epithelial barrier and to be participants in in-
litis when stable analogues are applied over 2-day flammatory/immune responses.
periods.69,106,112 Intestinal protective functions. Fulminant and fa-
Whereas fast nicotinic neurotransmission is found to tal inflammation of the intestine, which is unrelated to
be suppressed by mast cell degranulation during expo- bacterial overgrowth, occurs in transgenic mouse models
sure to sensitizing antigens, fast and slow EPSPs are after ablation of their EGCs.118 The earliest pathologic
reported to be significantly larger in the TNBS-inflamed sign in the mice is a submucosal vasculitis followed by
colon of guinea pigs.102,104 Stimulus-evoked fast EPSPs inflammatory disruption of the mucosa. These observa-
in submucosal neurons lose some of their sensitivity to tions were among the first to implicate EGCs in regula-
blockade by hexamethonium in S-type neurons in the tion of permeability of the vascular endothelium and the
inflamed intestine.102 Fast EPSPs in the submucosal mucosal epithelium. Recent findings suggest that EGCs
plexus of the inflamed intestine develop sensitivity to are important factors in the maintenance of the integrity
of epithelial tight junctions and their role in establishing
suppression by purinergic P2X and 5-HT3 receptor an-
mucosal barrier function.119,120 Perturbation of EGCs in
tagonists that is not readily evident in normal controls.
animal models in vivo results in increases in paracellular
Presynaptic facilitation of neurotransmitter release has
permeability of the mucosal epithelium and changes in
been proposed as the mechanism underlying augmenta-
the expression of synthetic enzymes for neurotransmitters
tion of neurotransmission in the TNBS-inflamed
in enteric neurons (eg, nitric oxide synthase and choline
mucosa.102
acetyltransferase). Inclusion of EGCs in cocultures with
Postinfectious IBS. Following an acute bout of
intestinal epithelial cells (ie, Caco-2, HT29, and IEC-6
infectious enteritis, a significant proportion of patients
cells) increases electrical resistance as the epithelial cells
develop IBS-like symptoms.113–115 Hypochondriasis and
become confluent in monolayers, which is indicative of
adverse life events are reported to double the risk for
sealing of “tight” epithelial cell junctions and tightening
development of postinfective IBS.113–116 Nevertheless, of the “epithelial barrier” to movement of larger mole-
the question of whether the association between acute cules. EGCs also exert strong antiproliferative effects on
infectious enteritis and IBS reflects low-level inflamma- the various epithelial cell lines in culture, and this is
tion (eg, microscopic enteritis) and long-term exposure dependent on secretion of transforming growth factor
of the neural and glial elements of the ENS to elevated ␤1. The presence of EGCs after 2 days in coculture with
levels of 5-HT, histamine, or other inflammatory medi- the Caco-2 epithelial cell line significantly increases the
ators is suggested but remains to be fully resolved. surface area of the monolayers in the absence of Caco-2
cellular hypertrophy or mitosis.
Enteric Glial Cells
The influence of EGCs on the formation of an epithe-
Enteric glial cells (EGCs) were, until recently, a lial barrier appears to provide protection against trans-
generally overlooked component of the ENS. They are epithelial invasion by pathogens. In in vitro coculture
now becoming a focus of increasing attention in neuro- models, the presence of EGCs decreases crossing of the
gastroenterology, especially in terms of mucosal protec- epithelial barrier by Shigella flexneri and also suppresses
tion, inflammatory responses, and signaling.117 the inflammatory response to this organism.120
April 2006 FUNDAMENTALS OF NEUROGASTROENTEROLOGY 1401

Results obtained from studies in which EGCs are cells of Cajal account for the spontaneous myogenic
cocultured with enteric neurons suggest that the EGCs contractile behavior of the intestinal musculature.133 The
protect the neurons against neurodegeneration under slow waves propagate from interstitial cells of Cajal into
inflammatory conditions (eg, elevation of nitric oxide the intestinal circular muscle coat and trigger action
levels). Cytokine signals involving EGCs are central potentials, which in turn initiate contractions. Abnormal
events underlying the inflammation. Selective activation interstitial cells of Cajal have been reported in achalasia
of EGCs by proinflammatory cytokines reflects their role of the lower esophageal sphincter, infantile hypertrophic
in intestinal inflammation.121,122 Exposure to proinflam- pyloric stenosis, chronic intestinal pseudo-obstruction,
matory cytokines activates c-fos expression in EGCs in Hirschsprung’s disease, inflammatory bowel diseases, and
vitro, and c-fos expression is known to be up-regulated in slow-transit constipation.134
intestinal inflammation induced by intramural injection
Gastric Motility
of formalin in rat colon.123 Exposure of EGCs in purified
primary cultures to IL-1␤ stimulates the synthesis and Functionally, the stomach consists of a proximal
release of IL-6. This action of IL-1␤ is at IL-1 receptors reservoir and distal antral pump with distinct differences
that are expressed by the EGCs.124 At the level of the in motility between the 2 regions. The muscles of the
ENS, IL-1␤ and IL-6 act synergistically both to excite reservoir are adapted for maintaining continuous contrac-
submucosal secretomotor neurons and to suppress the tile tone (tonic contraction) and do not contract phasi-
braking action of norepinephrine release from sympa- cally, while the muscle of the antral pump contracts
thetic postganglionic terminals in submucosal phasically. The spread of ring-like contractions in the
ganglia.124 –126 antral pump propels the gastric contents toward the
Signaling in glial networks. EGCs are linked one gastroduodenal junction. Dysrhythmias in the antral
to another into networks by gap junctions that conduct pump are associated with disturbed gastric emptying and
ions and larger organic molecules.127 Mechanical or nausea and vomiting that can occur in motion sickness,
chemical stimulation of a single glial cell in an EGC gastric ischemia, and pregnancy.135
network in culture evokes a wave of Ca2⫹ release that The gastric reservoir has 2 primary functions. One is
travels from cell to cell throughout the network.128 The to accommodate the arrival of a meal, allowing the
propagation of the Ca2⫹ waves in the EGC networks stomach to fill without a significant increase in intragas-
appears as the same phenomenon in CNS astroglia in tric pressure. The second is to generate a compressive
culture129 and is reminiscent of the transmission of im- force to drive the contents of the gastric reservoir into the
pulses in nerve fibers. propulsive motor activity of the antral pump.
Like the networks of astroglia in the CNS, neurocrine, The gastric musculature is innervated by both excita-
endocrine, or paracrine signaling to the EGC networks is tory and inhibitory motor neurons of the ENS. The
suggested by the expression of receptors for a number of motor neurons are controlled by both efferent vagal
known signal molecules. EGC networks respond to ATP, nerves and intramural microcircuits of the ENS. Vagal
uridine triphosphate, 5-HT, histamine, and bradyki- efferent nerve fibers release acetylcholine at nicotinic
nin.130 Like ENS neurons, EGC networks also express postsynaptic receptors on both excitatory and inhibitory
PAR-1 and PAR-2 and can respond to mast cell pro- enteric motor neurons. Excitatory motor neurons release
teases with propagating Ca2⫹ waves.74,75,131 Application acetylcholine at postjunctional muscarinic receptors and
of endothelin to EGC networks likewise stimulates en- substance P at neurokinin-1 receptors on the muscula-
dothelin B receptors to evoke elevation of intracellular ture. Relaxation is mediated by release of nitric oxide,
Ca2⫹ levels. The dynamics of Ca2⫹ homeostasis in this ATP, and vasoactive intestinal peptide from the inhibi-
case involve release from intracellular stores followed by tory motor innervation of the musculature. The relative
capacitative Ca2⫹ entry into the cells from the extracel- balance of excitatory and inhibitory input to the muscu-
lular milieu.132 lature adjusts the volume and pressure of the reservoir to
the amount of solid and/or liquid present while main-
taining constant compressive forces on the contents.136
GI Neuromotor Control During ingestion of a meal and during emptying of the
The smooth muscles of the GI tract are classified meal, continuous adjustments in the volume and pres-
as unitary-type smooth muscle. Unitary-type smooth sure within the reservoir are required. Integrative inter-
muscle contracts spontaneously in the absence of neural actions between the brainstem and ENS in the form of
or endocrine influence and contracts in response to vagovagal reflexes determine the minute-to-minute be-
stretch. Electrical slow waves generated by interstitial havior of the reservoir.
1402 GRUNDY ET AL GASTROENTEROLOGY Vol. 130, No. 5

Increased firing of excitatory motor neurons in the movements, power propulsion, and neurally pro-
ENS, coordinated with decreased activity of inhibitory grammed musculomotor quiescence (sometimes called
motor neurons, results in increased contractile tone in physiologic ileus). The integrative microcircuitry of the
the reservoir, decreased volume, and increased intrares- ENS contains the programs for each of these patterns.
ervoir pressure. Increased firing of inhibitory motor neu- The MMC is a specific pattern of motor activity in the
rons, coincident with decreased activity of excitatory stomach and small intestine during fasting in most
motor neurons, results in decreased contractile tone in mammalian species, including humans.141 The MMC
the reservoir, expanded volume, and decreased intrares- continues in the small intestine after a vagotomy or
ervoir pressure.137 Inhibitory motor neurons in the gas- sympathectomy but stops when it reaches a region of the
tric reservoir express the serotonergic 5-HT1 receptor, intestine where the ENS has been interrupted.142 Pre-
which, when activated, stimulates neuronal firing and sumably, command signals to the enteric neural circuits
release of inhibitory neurotransmitters that relax the in the form of neural synaptic input or overlay of a
musculature of the reservoir. Stimulation of the 5-HT1 paracrine or hormonal signal substance initiate and sus-
receptors on inhibitory motor neurons by sumatriptan tain the MMC. Levels of the hormone motilin reach a
has reported efficacy in treatment of dyspeptic symptoms peak in the plasma coincident with the onset of the
of early postprandial fullness and satiety.138 Animal stud- MMC in the antrum.143 The adaptive significance of the
ies also suggest that the 5-HT receptor on gastric inhib- MMC appears also to include a mechanism for clearing
itory motor neurons might be the 5-HT1 receptor sub- indigestible debris from the intestinal lumen during the
type.139 fasting state. Bacterial overgrowth in the small intestine
Neurally mediated decreases in tonic contracture of the is associated with absence of the MMC.144,145 This con-
musculature are responsible for relaxation of the gastric dition suggests that the MMC may play a “housekeeper”
reservoir (ie, increased volume). Three kinds of relaxation role in preventing the overgrowth of microorganisms
are recognized. (1) Receptive relaxation is initiated by the that might occur in the small intestine if the contents
act of swallowing. It is a reflex triggered by stimulation of were allowed to stagnate in the lumen. Small intestinal
mechanoreceptors in the pharynx followed by transmission bacterial overgrowth was recently proposed as the under-
over afferents to the dorsal vagal complex (ie, the nucleus lying pathophysiology of IBS symptoms.146,147
tractus solitarius and dorsal motor nucleus of the vagus) and A mixing pattern of motility (segmentation) replaces
subsequent activation of efferent vagal fibers to inhibitory the MMC when the small intestine is in the digestive
motor neurons in the gastric ENS. (2) Adaptive relaxation is state following ingestion of a meal. Volume and caloric
triggered by distention of the gastric reservoir. It is a content of the meal determine the duration of the post-
vagovagal reflex triggered by stretch receptors in the gastric prandial motility pattern. Lipids, particularly medium-
wall, transmission over vagal afferents to the dorsal vagal chain triglycerides, are most effective in suppressing the
complex, and efferent vagal fibers to inhibitory motor neu- neural program for the MMC and calling up the program
rons in the gastric ENS. (3) Feedback relaxation is evoked for the segmentation pattern of the digestive state.148
by the presence of nutrients in the small intestine mediated During the postprandial pattern, peristaltic contractions,
by both vagal and enteric reflexes triggered by paracrine which propagate for only very short distances, account
signaling actions of cholecystokinin and/or 5-HT on vagal for the segmental appearance of the bowel on x-ray film.
afferent terminals.140 Adaptive relaxation is impaired in Signals transmitted from the brainstem by vagal efferent
patients who have experienced iatrogenic injury to the nerves to the ENS interrupt the MMC and initiate the
vagus nerves during procedures such as laparoscopic fundo- neural mixing program during ingestion of a meal. In-
plication surgery. The loss of adaptive relaxation following terruption of the MMC by a meal does not occur in
vagal injury is associated with a lowered threshold for extrinsically denervated segments of small intestine in
sensations of fullness and pain during gastric filling. De- dog models.149 Blockade of vagal nerve conduction pre-
scending influences from higher brain regions modulate vents the conversion from the interdigestive to the post-
vagovagal transmission and account for emotional and be- prandial motility state in all regions of extrinsically
havioral influences on gastric function (eg, during stress). innervated small intestine.150,151
These influences can extend throughout the GI tract. The power propulsion motor pattern is relevant for
understanding the symptoms of cramping abdominal
Intestinal Motility pain, diarrhea and fecal urgency in infectious enteritis,
Four fundamental patterns of small intestinal mo- inflammatory bowel disease, radiation-induced enteritis,
tility are the interdigestive migrating motor complex and FGIDs. It is peristaltic propulsion characterized by
(MMC) pattern, the postprandial pattern of mixing strong, long-lasting contractions of the circular muscle
April 2006 FUNDAMENTALS OF NEUROGASTROENTEROLOGY 1403

that propagate for extended distances along the small and inhibitory innervation relaxes muscle tension and tran-
large intestine. The circular muscle contractions during siently opens the sphincter to permit forward passage of
power propulsion are sometimes referred to as “giant luminal contents. Sphincteric achalasia occurs when ENS
migrating contractions” because they are considerably inhibitory motor neurons to the sphincter are lost or fail
stronger than the phasic contractions during the MMC or to function.
mixing pattern.152 Giant migrating contractions last Tonic contraction of the internal anal sphincter and
18 –20 seconds and span several cycles of the electrical the puborectalis muscle blocks the passage of feces into
slow waves. They are a component of a highly efficient the anal canal and maintains continence with small vol-
propulsive mechanism that rapidly strips the lumen umes in the rectum. Rapid influx of feces and consequent
clean as it travels rapidly over long lengths of bowel. distention of the rectum activates the rectoanal reflex,
Power propulsion occurs in the retrograde direction which relaxes the internal sphincter and simultaneously
during emesis in the small intestine and in the ortho- contracts the external sphincter. The rectoanal reflex
grade direction in response to noxious stimulation in involves stimulation of distention receptors in the rectal
both the small and large intestine. Abdominal cramping wall and processing of the sensory information by neural
pain and sometimes diarrhea are associated with this networks in the ENS and spinal cord (see Visceral Pain
motor pattern.153 Application of irritants to the mucosa, and Sensation). Processing in the ENS leads to reflex
the introduction of luminal parasites, enterotoxins from excitation of inhibitory motor neurons to relax tension in
pathogenic bacteria, allergic reactions, and exposure to the smooth muscle of the internal anal sphincter. Pro-
ionizing radiation each activate the powerful propulsive cessing in the spinal cord leads to excitation of spinal
motor program. These characteristics suggest that power motor neurons to contract the external anal sphincter.
propulsion is a defensive adaptation for rapid clearance of Conscious sensation of rectal fullness in the lower abdo-
noxious or threatening contents from the intestinal lu- men is experienced as the rectum fills and reflects CNS
men. It also accomplishes mass movement of intralumi- processing of input from mechanoreceptors in the pelvic
nal contents in normal states, especially in the large floor musculature. Sensory physiology of afferents from
intestine (eg, defecation). the pelvic floor differs significantly from splanchnic af-
ferents.158,159 Pelvic mechanosensitive afferents respond
Motility of the Anorectum and Pelvic Floor to lower stimulus intensities, have larger response mag-
The levator ani, puborectalis, and external anal nitudes, and adapt less completely to sustained stimula-
sphincter muscles are of concern in consideration of tion. Pelvic floor afferents also differ from intestinal
defecatory mechanisms, fecal continence and inconti- afferents by having a lack of sensitivity to application of
nence, and pelvic pain. The levator ani are overlapping inflammatory mediators. Most intestinal afferents are
sheets of skeletal muscle that form the pelvic floor. The stimulated by application of bradykinin or ATP, while
levator ani contract and relax in concert with the pubo- pelvic floor afferents are resistant to these agents and to
rectalis and the external anal sphincter as components of stimulation by capsaicin.
a functioning unit necessary for the maintenance of fecal Relaxation of the internal anal sphincter allows con-
continence and normal defecation. The pelvic floor and tact of the rectal contents with the sensory receptors in
anorectal musculature have properties like those of the the lining of the anal canal. Sensory signals that reach the
tonic somatic muscles that maintain upright bodily pos- brain from the anal canal serve as an early warning of the
ture against the forces of gravity.154,155 Weakening of the possibility of a breakdown of maintenance of continence.
musculature (eg, in advanced age) or traumatic damage Continence in this situation is maintained by reflex and
to the musculature or its innervation (eg, during child- conscious voluntary contraction of the external anal
birth) can underlie fecal incontinence and disordered sphincter and puborectalis muscle. The external sphinc-
defecation.156 Like other skeletal muscles, weakening of ter closes the anal canal and the puborectalis sharpens the
the pelvic floor musculature can often be corrected anorectal angle to form a mechanical barrier to onward
through targeted isometric exercise.157 movement of the feces.
The internal and external anal sphincters surround the Power propulsion in diarrheal states (eg, diarrhea-
anal canal. The external sphincter is skeletal muscle that predominant IBS or infectious enteritis) moves large
contracts and closes the anal orifice. The internal anal volumes of liquid stool with high velocity into the
sphincter is a modified extension of the circular muscle rectum with potential for overwhelming the mechanisms
coat of the rectum. It is fatigue-resistant smooth muscle of continence and the embarrassment of soiling.153,160
that, like other sphincteric muscles, contracts tonically to Sensory detection of rectal distention by rapid influx of
sustain closure of the anal canal. Timed activation of its large volumes of liquid stool, transmission to the spinal
1404 GRUNDY ET AL GASTROENTEROLOGY Vol. 130, No. 5

cord, and supraspinal processing of the information un- CRF-immunoreactive nerve fibers in the intestine are all
derlie the sensations of fecal urgency in diarrheal states. derived from enteric neurons; neither sympathetic post-
ganglionic fibers nor sensory afferent fibers express CRF
Stress GI Function and Visceral IR. Only the CRF1 receptor subtype is expressed by
enteric neurons.80
Pain
Activation of central CRF-CRF1 signaling has
Brain-gut interactions are reflected by the pertur- emerged as a key factor for understanding stress-induced
bations of GI motor and mucosal function and visceral behavioral changes in animal models.172 These include
sensitivity that are induced by various stressors.161 In anxiousness, impairment in cognitive performance and
animals and humans, a number of stressors inhibit gas- locomotor activity, altered sleep patterns, and addictive
tric and small intestinal transit while stimulating colonic behaviors, all of which take place independently of the
motility.79 Stress also elevates intestinal secretion of elec- adrenal cortical endocrine response.172 Likewise, in hu-
trolytes, mucus, and H2O coincident with enhanced mans, stress-associated dysfunction of the CRF-CRF1
permeability that permits penetration of antigens and neuronal circuitry in the brain is implicated in the onset
commensal microbes into the lamina propria in ro- and persistence of affective disorders such as anxiety,
dents.162,163 In a primate stress model, exposure to fecal major depression, and early stress.172 Comorbidity of IBS
antigens initiates inflammatory responses that resemble with anxiety and depression might be explained in the
ulcerative colitis and a progression to colon cancer.164 context of hyperactivity of CRF-CRF1 signaling path-
Genetic or environmental factors and previous visceral ways in the brain. Activation of specific hypothalamic
inflammation influence the outcome of acute stress on areas (eg, paraventricular nucleus) or pontine areas (eg,
colonic barrier function, mucosal immunity, motor func- locus ceruleus and Barrington’s nucleus) by exogenously
tion, and visceral sensitivity.165 applied CRF or by exposure to stress results in behavior
Psychological stress exacerbates the symptoms of IBS, symptomatic of anxiety and/or depression coincident
of which cramping abdominal pain associated with ur- with colonic motor dysfunction.161 Administration of
gency and explosive watery diarrhea predominate.166 The CRF1 receptor antagonists alleviates these effects in ro-
association with stress is further reflected by observations dents.161 Of interest in this respect are reports that
that psychotherapy and treatment with low-dose antide- activation of neurons in the locus ceruleus by colorectal
pressants (eg, tricyclic antidepressants and selective se- distention in rats involves stimulation of the CRF1 re-
rotonin reuptake inhibitors) are often effective.167–169 ceptor.173 Increased firing of neurons in the locus ce-
The simultaneous impact of stress on colonic motor, ruleus, in response to exteroceptive or interoceptive
secretory, and immune functions and the partial depen- stressful input, results in widespread activation of nor-
dence on stimulation of CRF receptors in the brain and adrenergic neurons, which project to forebrain sites as-
the ENS of animal models support a hypothesis that CRF sociated with arousal and focused attention.174 Enhanced
neural signaling is a contributory factor in the stress- activity in these forebrain projections is postulated to
related exacerbation of symptoms in patients with IBS. underlie the stress-related alterations in perceptual
threshold to colorectal distention and the hyperreactivity
CRF and Stress
associated with stress in patients with IBS.175 The col-
CRF and 3 related peptides (urocortin 1, 2, and 3) lective evidence from animal models suggests that block-
bind to CRF1 and CRF2, which are distinct G protein– ade of CRF1 receptor signaling in the brain has the
coupled receptors.170 CRF interaction with the pituitary beneficial effect of preventing stress-related gut dysfunc-
CRF1 receptor is essential for the glucocorticoid increase tion and visceral hypersensitivity.172
induced by stress.171 Activation of brain CRF1 receptors
mediates stress-induced colonic motor response and vis-
ceral sensitization to colorectal distention.79,161 Intestinal Neuroimmunology
CRF1 receptors on enteric cholinergic neurons also con- Several cell types of immune/inflammatory
tribute to colonic motor responses to stress.161 The aug- cells, which include polymorphonuclear leukocytes,
mentation of colonic mucosal secretion and disruption of lymphocytes, macrophages, dendrocytes, and mast
mucosal barrier function induced by stress are also me- cells, are present in continuously varying numbers in
diated by intramural CRF receptors and related degran- the intestinal mucosa, lamina propria, and smooth
ulation of enteric mast cells.161 IR for CRF is expressed muscle. Each of these cell types may be situated in
in nerve cell bodies and fibers in both the myenteric and close association with the neuronal elements of the
submucosal plexuses in most regions of the GI tract.81 ENS, vagal nerve fibers, and spinal sensory nerves and
April 2006 FUNDAMENTALS OF NEUROGASTROENTEROLOGY 1405

are the source of paracrine signals that initiate and leading to augmented sensory input to the CNS.188 Mast
modulate reflex responses.75,176 –178 cells in colonic mucosal biopsy specimens from patients
with diarrhea-predominant IBS release more histamine
Enteric Mast Cells than normal subjects.181 Elevated release of histamine
Mast cells are equipped and strategically located onto the neural networks that control the secretomotor
to recognize foreign agents that threaten whole body innervation of the intestinal crypts in this subset of
integrity and to signal the ENS to program a defensive patients with IBS might lead to secretory diarrhea like
response.38 Enteric mast cells express high-affinity recep- that associated with infectious agents and food allergies.
tors for immunoglobulin E antibodies or other immuno- Histaminergic receptor antagonists have been used effec-
globulins on their surfaces. Antigen recognition by an- tively to treat watery diarrhea associated with mastocy-
tibodies bound to the sensitized mast cells triggers tosis and microscopic colitis.189 The H2 receptor antag-
degranulation and release of the mast cell mediators. onist cimetidine was used effectively for treatment of
After release, the mediators become paracrine signals to diarrhea associated with short-bowel syndrome in pa-
the ENS, which responds by “running” a defense pro- tients with Crohn’s disease.190
gram designed to eliminate the antigen from the lumen.
Copious secretion and increased blood flow followed by Serotonin and FGIDs
orthograde power propulsion of the luminal contents are Serotonin is the predominant paracrine mediator
the behavioral components of the program. expressed by mucosal enterochromaffin cells.191 Many of
Enteric mast cells are used also by the CNS as a link the GI responses to 5-HT arise from activation of recep-
for sending chemical signals to the ENS.1,2,38,41 This is a tors on enteric neurons and sensory afferent neurons.
brain-gut interaction in which central psychological sta- Several distinct families of receptors mediate the excita-
tus might be linked to irritable states of the digestive tory actions of 5-HT. Metabotropic G protein– coupled
tract by way of mast cell degranulation and release of receptors of the 5-HT4 and 5-HT1P subtype and iono-
mediators. Mast cell degranulation evoked by psycholog- tropic 5-HT3 receptors mediate the actions of 5-HT on
ical stress activates the ENS “alarm program” to produce enteric neurons and sensory afferents. A selective antag-
the same symptoms of diarrhea and abdominal distress as onist for the 5-HT7 receptor subtype suppresses stimu-
antigen-evoked degranulation.38 Colonic mucosal biopsy lus-evoked slow EPSPs in the ENS and the slow EPSP-
specimens from patients with IBS contain elevated num- like action of exogenously applied 5-HT.192 Slow EPSP-
bers of mast cells.179 –182 In experimental animals, de- like actions of 5-HT were attributed to stimulation of
granulation of enteric mast cells results in a reduced 5-HT1P receptors in the past.62,193–196 The 5-HT1P re-
threshold for pain responses to intestinal distention, and ceptor now appears to be a hetero-oligomeric combina-
this is prevented by treatment with mast cell–stabilizing tion of 5-HT1B and dopamine D2 receptors.197 Elevated
drugs.183,184 levels of 5-HT in the hepatic portal circulation in the
postprandial state reflect stimulated release from mucosal
Mast Cell Mediators enterochromaffin cells. The postprandial release of 5-HT
As mentioned in an earlier section, several of the is reported to be augmented in patients with IBS and has
mast cell– derived mediators described have neurophar- been suggested to underlie the IBS symptoms of cramp-
macologic actions on the electrical and synaptic behavior ing abdominal pain, diarrhea, and fecal urgency in pa-
of neurons in the ENS. Histamine is one of the key tients with diarrhea-predominant IBS.116 This observa-
mediators in orchestrating intestinal defensive programs tion is reinforced by findings of elevated numbers of
and serves as an example of the way mast cell mediators enterochromaffin cells in rectal mucosal biopsy speci-
influence ENS function and afferent signaling. One ac- mens from patients with IBS.180
tion of histamine in the ENS occurs at the level of Application of 5-HT evokes increased firing in extrin-
neuronal cell bodies, where it gives rise to long-lasting sic afferents via 5-HT3 receptors that can be blocked by
excitation mediated by histamine H2 receptors in guinea selective antagonists (eg, alosetron).3,5,198 Intramural ter-
pigs.185 Another is at fast excitatory nicotinic synapses, minals of both spinal and vagal afferents express 5-HT3
where it acts at presynaptic inhibitory histamine H3 receptors. Reported efficacy of alosetron in the treatment
receptors to suppress cholinergic synaptic transmis- of abdominal pain and discomfort in the diarrhea-pre-
sion.186 A third action is to prevent inhibition of secre- dominant form of IBS in women suggest that these
tomotor-evoked mucosal secretion by the sympathetic symptoms reflect disordered endogenous release of
innervation.187 Histamine also acts on extrinsic splanch- 5-HT.57 Similarly, ligands acting at 5-HT4 receptors
nic afferents to evoke an H1 receptor–mediated excitation might also modulate afferent sensitivity199 and may con-
1406 GRUNDY ET AL GASTROENTEROLOGY Vol. 130, No. 5

tribute to the efficacy of such ligands in constipation- which release substances that alter the activity of
predominant IBS.200 neurons.21,25,26,32,73,86,175,184
Serotonergic signaling in the mucosa and the ENS is
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 GASTROENTEROLOGY 2006;130:1412–1420

Applied Principles of Neurogastroenterology:

Physiology/Motility Sensation

JOHN E. KELLOW,*,‡ FERNANDO AZPIROZ,§ MICHEL DELVAUX,¶ G. F. GEBHART,储

HOWARD R. MERTZ,# EAMONN M. M. QUIGLEY,** and ANDRÉ J. P. M. SMOUT‡‡
*Departments of Medicine and ‡Gastroenterology, Royal North Shore Hospital, University of Sydney, Sydney, Australia; §Digestive
Department, University Hospital Vall d’Hebron, Barcelona, Spain; ¶Department of Internal Medicine and Digestive Pathology, Hôpitaux de
Brabois, CHU de Nancy, Vandoeuvreles-Nancy, France; 储Department of Pharmacology, The University of Iowa, Iowa City, Iowa; #Department of
Medicine, Vanderbilt University, Nashville, Tennessee; **Alimentary Pharmabiotic Center, Department of Medicine, Cork University Hospital,
National University of Ireland, Cork, Ireland; and ‡‡Department of Gastroenterology, University Medical Center, Utrecht, The Netherlands

Many of the symptoms prominent in the functional gas- contractions, tone, compliance, accommodation, and
trointestinal disorders (FGIDs) are consistent with dys- transit, is regulated by reflex mechanisms and is inti-
function of the sensory and/or motor apparatus of the mately related to gut sensitivity. In the FGIDs, sustained
digestive tract. Assessment of these phenomena in man and inappropriate gut hypersensitivity, as well as gut
can be undertaken by using a wide variety of invasive dysmotility, are well documented. These sensory-motor
and noninvasive techniques, some well established and dysfunctions seem related to alterations in neural pro-
others requiring further validation. By using such tech-
cessing in the brain-gut axis and in visceral reflex path-
niques, alterations in both sensory and motor function
ways. Their underlying causes and their relevance to
have been reported in the FGIDs; various combinations
of such dysfunction occur in different regions of the
symptom generation are the subject of ongoing research.
digestive tract in the FGIDs. Our understanding of the The aim of this article is to summarize the key principles
origins of this gut sensorimotor dysfunction is gradually of applied neurogastroenterology as they relate to the
increasing. Thus, inflammatory, immunologic, and other FGIDs.
processes, as well as psychosocial factors such as
stress, can alter the normal patterns of sensitivity and Basic Concepts
motility through alterations in local reflex activity or via
altered neural processing along the brain-gut axis. In this Sensation
context, a potential role of genetic factors, early-life Although sensation refers to a conscious experi-
influences, enteric flora, dietary components, and auto- ence, the term sensitivity, when applied to the gastroin-
nomic dysfunction also should be considered in the testinal tract, has been used to refer both to conscious
disease model. A firm relationship between sensorimo- perception of gut stimuli and to afferent input within
tor dysfunction and the production of symptoms, how- gastrointestinal sensory pathways, whether related to
ever, has been difficult to show, and so the clinical
perception or to reflex responses. For the purpose of this
relevance of the former requires continuing exploration.
review, the term sensitivity is restricted to the processes
Based on the conceptual framework established to date,
a number of recommendations for further progress can
leading to conscious perception.
be made. Unlike other tissues in the body, the viscera are
unique in that each organ is innervated by 2 sets of
nerves, vagal and splanchnic spinal nerves or pelvic and
he digestive tract is fitted with a complex wiring
T system that modulates its response to the internal
and external environment. The 2 aspects of gut physiol-
splanchnic spinal nerves. Both systems participate in the
reflex control of gut function, but their involvement in
sensation differs.1 Discomfort and pain from the gastro-
ogy most relevant to the functional gastrointestinal dis- intestinal tract are conveyed to the central nervous sys-
orders (FGIDs) are sensation and motility. In health, tem (CNS) principally by spinal afferents. Activation of
physiological stimuli from the gut induce motor reflexes,
but these remain largely unperceived, with the exception Abbreviations used in this paper: CNS, central nervous system; ENS,
of those related to ingestion and excretion. Visceral af- enteric nervous system; FD, functional dyspepsia; FGID, functional
ferent pathways, however, also serve as an “alarm” system gastrointestinal disorder; IBS, irritable bowel syndrome.
© 2006 by the American Gastroenterological Association Institute
to induce conscious perception when appropriate. Gut 0016-5085/06/$32.00
motility, encompassing myoelectrical activity, phasic doi:10.1053/j.gastro.2005.08.061
April 2006 NEUROGASTROENTEROLOGY AND FGIDs 1413

vagal afferents is not considered to give rise to sensations including the capacity (diameter) of the organ, the resis-
perceived as pain; their activation may, however, modu- tance of surrounding organs, the elastic properties of the
late spinal visceral (and somatic) pain. From second-order gut wall, and its muscular activity. Wall tension, related
neurons in the spinal dorsal horn, which receive direct to compliance, describes the force acting on the gut wall
input from spinal visceral afferent fibers, visceral sensory and results from the interaction between intraluminal
information is conveyed to supraspinal sites and finally to content and the elasticity of the wall. Gut sensation is
cortical areas in which conscious perceptions arise. Per- influenced by tonic or phasic contractions, and several
ception pathways can be activated in healthy subjects by observations suggest that this is mediated in part by an
mechanical distention of the gut, but the final conscious effect on wall tension; assessment of wall tension is
perception is modulated by various interacting factors. therefore important in the interpretation of results of
For instance, intestinal nutrients, especially fat, enhance tests assessing perception of visceral stimuli.
such perception.2,3 Transit refers to the time taken for intraluminal con-
In addition to mechanosensitive structures and poly- tents to traverse a specified region of the gastrointestinal
modal endings, the viscera are innervated by a group of tract. It reflects the combined effects of the various
mechanically insensitive afferent fibers. Normally, these phenomena outlined earlier. Most measurements of tran-
endings in the viscera are unresponsive (“silent”) to me- sit are based on detecting intraluminal movements of an
chanical stimulation, but, after organ insult, acquire extrinsic marker labelling the luminal content. Transit
spontaneous activity and mechanosensitivity and con- depends on many factors, such as the physical (eg, solid,
tribute significant input to the CNS. Increases in neuron liquid, and gas) and chemical (eg, pH, osmolality, and
excitability both peripherally and in the spinal cord lead nutrient composition) nature of both gut contents and
to visceral hypersensitivity, a characteristic feature of the the administered marker. Measurement of transit is in-
FGIDs. Neurons in supraspinal sites also exhibit in- fluenced by the state of gut motility at the time of
creases in excitability, particularly in brain areas associ- marker administration (eg, fasted vs fed motility) and
ated with descending modulation of spinal sensory trans- any preparation of the gut (eg, cleansing of the colon).
mission.1 These modulatory circuits can be influenced in In the context of the FGIDs, gastrointestinal dysmo-
turn by cognitive, affective, and stressful influences, as tility can develop through dysfunction of the control
well as by expectation and prior experience. mechanisms at any level from the gut to the CNS. For
example, inflammatory, immune, infiltrative, degenera-
Motility
tive, or other processes may directly affect the muscle
The major functions of human digestive tract and/or other elements of the enteric nervous system,
motility are to accomplish propulsion along the gut, to whereas psychosocial stressors can induce profound alter-
mix gut contents with digestive secretions and expose ations in motility. Because patients with FGID tend to
them to the absorptive surface, to facilitate temporary have a greater gastrointestinal motor response to stressful
storage in certain regions of the gut, to prevent retro- conditions than do healthy subjects, psychosocial stres-
grade movement of contents from one region to another, sors are particularly relevant to the symptomatic mani-
and to dispose of residues. Motility is controlled by festations of the FGIDs.
reflexes, both central and peripheral, as well as by de-
scending modulation from the brain-gut axis. Commu-
Evaluation of Digestive Tract
nication between various regions of the gut is facilitated
by the transmission of myogenic and neurogenic signals Sensorimotor Function
longitudinally along the gut.4 Gastrointestinal contrac- The presence of altered visceral sensitivity and/or
tions may be classified on the basis of their duration; enteric dysmotility is usually evaluated by measuring
contractions may be of short duration (phasic contrac- responses to test stimuli applied to the gut under various
tions) or may be more sustained (tone). Tone is clearly physiological and nonphysiological experimental condi-
recognized in organs with reservoir function, such as the tions. This form of provocative testing involves 3 key
proximal stomach (accommodation response to a meal) components: stimulation type and technique, measure-
and the colon (response to feeding), as well as in sphinc- ment of the responses, and modulatory factors that may
ter regions. Compliance refers to the capability of a affect the responses (Figure 1). Physiological stimuli,
region of the gut to adapt to its content; it is expressed such as orally or intraluminally administered nutrients,
as the ratio of the change in volume to the change in can be used to study reflex motor responses, but supra-
pressure and is obtained from the pressure-volume curve. physiological stimuli, such as gut distention or overload-
Compliance reflects the contribution of several factors, ing with nutrients, are required to activate sensory path-
1414 KELLOW ET AL GASTROENTEROLOGY Vol. 130, No. 5

evaluated simultaneously and correlated (eg, conscious

perception and motor or autonomic reflexes).
Many factors, both local and extraintestinal, can mod-
ify the previously described responses to stimuli and
require attention in the testing of sensorimotor function.
For example, anticipatory knowledge increases percep-
tion of gut distention,8 whereas anxiety and fear of
impending pain can trigger brain activation patterns
similar to those evoked by actual rectal stimulation.9

Table 1. Measurement of Gastrointestinal Motor

Responses
Recording techniques Main applications
I. Transit
Radio-opaque markers and x-raya Gastric emptying, colonic
transit
Hydrogen breath testsa Orocecal transit
Scintigraphya Esophageal transit
Figure 1. Provocative testing schema for the evaluation of gut sen- Gastric emptying
sation and motility in the functional gastrointestinal disorders. SC, Small bowel and colonic
spinal cord. transit
Bile flow
Dynamics of defecation
Labelled C-substrate breath testsa Gastric emptying
ways and induce perception. Various paradigms can be Orocecal transit
Magnetic resonance imaging Gastric emptying
used to blind the stimuli and make them less predict- Pharmacologic markers
able.5 Acetaminophen Gastric emptying of liquids
A range of responses to gut stimulation can be mea- Sulfasalazine Orocecal transit time
Intraluminal impedance monitoring Esophageal transit
sured, including conscious perception, afferent signalling II. Reflux
within the brain and spinal cord, gut motor activity, and X-raya Gastroesophageal reflux
autonomic responses. Assessment of conscious perception Scintigraphy
includes the quality, intensity, and affective dimensions, pH monitoringa
Bilirubin absorbance monitoring
as well as the location and referral of the perceived Intraluminal impedance monitoring
sensations. A rating scale such as a visual analog scale or III. Wall motion
threshold detection paradigms (ie, the magnitude of Ultrasonography Antropyloric contractions
Gastric areas and volume
stimulus required to reach a certain level of perception, Gallbladder volume
such as discomfort or pain) can be used. Detection of Scintigraphy Antral contractions
afferent signals within the brain can be achieved using a Magnetic resonance imaging Antral contractions
SPECT Gastric accommodation
variety of techniques, including cortical-evoked poten- IV. Intraluminal pressure
tials, magnetoencephalography, positron-emission to- Water-perfused manometrya Phasic contractions and
mography, functional magnetic resonance imaging, and sphincter
single-photon– emission computed tomography.6 Simi- Solid-state transducers Tone at all levels of the
digestive tract
larly, a variety of recording techniques can be used to V. Myoelectrical activity
measure digestive tract motor activity during basal con- Electrogastrography Gastric surface electrical
ditions and in response to stimuli; the latter also enables activity
Intraluminal electromyography Gastric, small intestinal,
testing of specific enteric reflexes (Table 1). In the ab- and colonic electrical
sence of a widely accepted and convenient test of visceral activity
autonomic integrity, autonomic responses to visceral Needle electromyography Anal sphincter and pelvic
floor muscle activity
stimuli are usually measured with tests of primarily VI. Tone, compliance & wall tension
cardiac autonomic innervation, such as heart rate vari- Barostat Tone and compliance at all
ability;7 it is not known, however, whether this measure- levels of the Gl tract
ment is representative of other autonomic responses to aMost widely available techniques. Modified and reprinted with

gut stimuli. Finally, different types of responses can be permission.75

April 2006 NEUROGASTROENTEROLOGY AND FGIDs 1415

Some tests are designed specifically to evaluate these thereby contributing to the generation of clinical symp-
modulatory mechanisms.10 toms in the absence of major motor dysfunction.14
In irritable bowel syndrome (IBS), hypersensitivity to
rectal or sigmoid balloon distention can be shown in
Sensorimotor Dysfunction and
50% to 70% of patients. As well, at least half of patients
Symptoms in the FGID perceive the stimuli over wider referral areas than healthy
Hypersensitivity to distention affecting various subjects, and the proportion of patients reported as hy-
regions of the gastrointestinal tract has been a consistent persensitive thus depends, among other factors, on
finding in many FGIDs; there appears to be some spec- whether such abnormal viscerosomatic referral is in-
ificity for individual FGIDs, at least with respect to the cluded. In IBS patients without concomitant FD, rectal
organ considered most relevant in the pathophysiology of hypersensitivity appears to be present in isolation,
the disorder.11 Likewise, abnormal motor responses to whereas if FD is also present, gastric, as well as rectal,
gut stimuli have frequently been documented in the hypersensitivity is often demonstrable.11 Cerebral re-
FGIDs. Sensory and motor dysfunctions may interact to sponses to rectal balloon distention appear to be abnor-
produce symptoms, the specific clinical syndrome de- mal in IBS, supporting the concept of visceral hypersen-
pending on the pathways, and territories affected, but sitivity. Although there is diversity in the literature, the
these aspects require further study. largest brain-imaging studies suggest that IBS patients
In functional dyspepsia (FD), gastric hypersensitivity, show augmented activation in the dorsal portion of the
delayed gastric emptying, and impaired accommodation anterior cingulate cortex, in association with increased
of the proximal stomach have been well documented, but subjective pain reports to the stimuli.9,19,20 These data do
the prevalence of these abnormalities (around 50%) de- not necessarily indicate a cerebral etiology for visceral
pends on the population studied. Impaired gastric ac- hypersensitivity; they could in fact reflect a normal ce-
commodation has been shown to not necessarily be as- rebral response to a heightened incoming sensory signal.
sociated with gastric hypersensitivity, delayed gastric However, brain areas important in descending pain in-
hibition, namely the perigenual anterior cingulate cortex
emptying, or the presence of Helicobacter pylori;12 in this
and the periaqueductal gray region of the brainstem,
latter study, the symptom of early satiety was indepen-
appear to be underactive in IBS,9,21 and further studies
dently associated with impaired accommodation. In a
are required.
scintigraphic study13 of the intragastric distribution of a
Both rectal and small bowel hypersensitivity in IBS
meal, early satiety was correlated with early redistribu-
have been associated with motor hyperreactivity in re-
tion of liquids to the antrum, whereas the symptom of
sponse to gut stimuli.22,23 Alterations in the colonic
fullness was correlated with late proximal gastric reten-
motor24,25 and sensory26 response to feeding have been
tion. The reproducibility of hypersensitivity appears to documented. A temporal correlation between high-am-
be greatest with fundic distention in patients with post- plitude propagating contractions and abdominal pain
prandial symptoms and with antral distention in pain- episodes has been observed in the ileocecal region27 and
predominant FD patients, whereas nutrients exaggerate sigmoid colon25 in IBS patients. However, these high-
the gastric hypersensitivity.14 Normally, antral filling amplitude contractions were also observed in the absence
elicits a reflex relaxation of the proximal stomach that of pain in IBS patients and did not differ manometrically
contributes to meal accommodation. Accommodation is from those associated with pain. Moreover, only a pro-
then further modulated by enterogastric reflexes depend- portion of the IBS patients in these studies showed such
ing on the load and composition of intestinal chyme. contractions. The colorectal tonic reflex, namely the nor-
Impaired gastrogastric and enterogastric reflexes in dys- mal increase in rectal tone in response to distention of the
pepsia14 may result in a defective relaxation of the prox- descending colon, has been reported to be attenuated in
imal, but not the distal stomach, with consequent alter- IBS patients.28
ation in the intragastric distribution of contents and Recent studies evaluating intestinal gas dynamics fur-
antral overload. Evidence for a relationship between ther substantiate the role of combined sensory and motor
symptom subgroups and different pathophysiologic and disturbances in symptom production. Gas-transit studies
psychopathologic mechanisms continues to increase,15 have revealed that patients with bloating exhibit im-
although this aspect remains controversial16 –18 and is paired reflex control of gut handling of contents.29,30
likely influenced by studies of different patient popula- Segmental pooling, either of gas or alternatively of solid/
tions. Gastric hyporeflexia may be a factor in the reduced liquid components, may induce the sensation of bloating,
tolerance of FD patients to intragastric volume increase, particularly in patients with hypersensitivity. Further-
1416 KELLOW ET AL GASTROENTEROLOGY Vol. 130, No. 5

more, altered viscerosomatic reflexes may contribute to via tryptase activation of specific protease-activated re-
abdominal wall protrusion and objective distention, even ceptors on sensory nerves and the development of visceral
without major intra-abdominal volume increment. hypersensitivity. These findings support the possible in-
volvement of a neuroimmune axis in the pathophysiology
Putative Origins of Sensorimotor of IBS.43,44 Indeed some studies indicate that IBS pa-
Dysfunction tients may have a relative deficiency of anti-inflammatory
cytokines34 and/or increased expression of the proinflam-
Several potential causes of the sensorimotor dys-
matory cytokines.45 In FD, an increase in mucosal mast
function in the FGID have been identified. The most
cells also has been documented,46 and a likely infectious
important of these are discussed briefly.
antecedent to the development of impaired fundic ac-
Genetic and Early-Life Factors commodation identified in some patients.47
It should be acknowledged that some studies report-
There is now a body of evidence that documents
ing an association between IBS and immune activation
various genetic alterations in both FD31 and IBS.32 The
importance of early-life experiences and social learning in would not be designated as IBS based on current criteria
the etiopathogenesis of the FGIDs is also increasingly because they involve the description of pathologic find-
recognized. These 2 areas are reviewed in accompanying ings indicative of other diagnoses, for example, inflam-
articles. Also of note in IBS are reported alterations in the matory bowel disease, celiac disease, or microscopic co-
synthesis, uptake, and turnover of secreted serotonin in litis. Although these reports reflect the nonspecificity of
the gut mucosa.33,34 Given the role of mucosal serotonin symptoms of intestinal origin, they also provide avenues
in intestinal motility and possibly sensation, it is con- for the exploration of the mechanisms whereby inflam-
ceivable that such alterations contribute to sensorimotor mation, of any grade, may induce symptoms. However, it
dysfunction in IBS, but further work is required. must also be stressed that evidence of immune activation
has been provided by studies of patients who do not
Enteric Inflammation and Immune appear to have an alternative diagnosis and who truly
Activation appear to suffer from IBS.
The entity of postinfectious IBS is well recog-
nized, with a prevalence of up to 30% after an acute Alterations in Enteric Flora
episode of bacterial gastroenteritis.35–39 Significant risk Bacteria commensal to the gut can influence en-
factors for the development of this condition include teric motor activity, can modulate the host immune
female sex; a prolonged or severe acute initial illness; and system development and function, and can enhance ep-
higher scores for anxiety, depression, somatization, and ithelial barrier function. It is thus feasible that chronic
neurosis.35 Histologic features include increased numbers alterations of the enteric flora may play a role in the
of mucosal chronic inflammatory cells, enteroendocrine development of the FGIDs, particularly IBS, and there is
cells, and intraepithelial lymphocytes.36 –39 Even in IBS limited evidence that counts of colonic bacteria48 and the
patients without a history of prior infection, an increase
fermentative activity of enteric flora49 are different in IBS
in intraepithelial lymphocytes and CD25⫹ cells in the
when compared with health. More recently, increased
lamina propria has been documented,40 whereas in pa-
bacterial colonization (overgrowth) of the small intestine
tients with severe IBS, low-grade infiltration of lympho-
in IBS has been suggested50 and associated with a lower-
cytes has been shown in the myenteric plexus.41 In some
of these latter patients, there was an associated increase in than-normal frequency of small intestinal–migrating
intraepithelial lymphocytes, evidence of neuronal degen- motor complexes. However, these data, based on lactu-
eration, longitudinal muscle hypertrophy, and abnormal- lose breath testing, have been seriously questioned,51 and
ities in the number and size of interstitial cells of Cajal. studies in larger populations of IBS are required. An
Physiological dysfunction of the gut documented in association between antibiotic use and IBS52 has been
postinfectious IBS includes altered rectal sensorimotor reported; it is conceivable that antibiotics, by disrupting
activity, altered colonic transit, and altered small bowel the normal flora, may facilitate the enteric effects of
permeability.36,37 potentially immunogenic or pathogenic bacteria. Prelim-
Prior infection may also explain the increase in termi- inary data suggest that IBS patients may respond symp-
nal ileal and colonic mucosal mast cells documented in tomatically to manipulation of the flora through the use
IBS.39,42– 44 The close proximity of mast cells with enteric of probiotic bacterial preparations,53 but further work is
nerves in IBS has been related to symptoms,44 perhaps required before definitive conclusions can be reached.
April 2006 NEUROGASTROENTEROLOGY AND FGIDs 1417

Dietary Components chological stress impairs mucosal defences against lumi-

Patients with both FD and IBS commonly report nal bacteria, and intestinal permeability is increased dur-
a postprandial exacerbation of their symptoms and as- ing stress via a cholinergic mechanism that requires the
sume that this close temporal relationship implies either presence of mucosal mast cells.64 Other potential medi-
an allergy or an intolerance to specific food items or ators of stress-induced gastrointestinal sensorimotor re-
sponses include norepinephrine and corticotropin releas-
constituents.54 This relationship between eating and
ing factor (CRF). Two CRF receptors have been
symptoms remains poorly understood. Exaggerated sen-
identified; CRF-1 mediates stress-induced increases in
sorimotor effects of certain nutrients, especially fat, have
colonic contractility, whereas CRF-2 mediates stress-
been reported in both FD14 and IBS2,29 and could explain
induced gastric hypomotility and surgical ileus.65 Hu-
symptom provocation without invoking either allergy or
man data suggests that IBS patients are particularly
intolerance. The incomplete absorption in the small in-
sensitive to CRF effects on colonic motility,66 and infu-
testine of substances such as fructose and sorbitol has
sion of CRF increases rectal sensitivity in healthy volun-
been proposed as one dietary factor provoking symptoms
teers.67 It is conceivable that either heightened release of
in IBS,55 but there is little clinical evidence to incrimi-
CRF or heightened effects of CRF contributes to FGID
nate firmly other specific foods or chemical substances in
pathophysiology.
the pathogenesis of IBS.54 Furthermore, trials of elimi-
nation diets have provided conflicting and generally dis- Autonomic Dysfunction
appointing results,56 although a recent study reported
In FD, it has been proposed that abnormal prox-
some success with elimination diets based on the results
imal gastric accommodation may be caused by an under-
of testing for immunoglobulin G (but not immunoglob-
lying vagal defect.68 On the other hand, studies of vec-
ulin E) antibodies to foods.57 The increased intestinal
tion-induced nausea and gastric dysrhythmias69 have
permeability in some IBS patients,39 however, does raise
raised the possibility of central neurohumoral dysfunc-
the possibility that food and other antigens may gain
tion in the pathogenesis of FD. In IBS, constipation-
more ready access than usual to the mucosal compart-
predominant patients may exhibit vagal dysfunction,70
ment of the gut, enabling overly prolonged stimulation
whereas diarrhea-predominant patients may exhibit sym-
of the musosal immune system and the enteric nervous pathetic adrenergic dysfunction70 or a postprandial de-
system (ENS). In this regard, it is of interest that patients crease in cardiovagal tone.71 Other reports in IBS have
with celiac disease can fulfil symptom criteria for IBS.58 documented increased sympathetic activity at rest and
impaired suppression of parasympathetic activity during
Psychosocial Stress and Other Cognitive
orthostatic stress72 and an autonomic hyperresponsive-
Factors
ness to visceral stimuli that is independent of acutely
For both FD and IBS, it appears that severe perceived gut symptoms and not associated with HPA
chronic life stress threat (arising from relationship diffi- activation.73 It remains unclear, however, whether the
culties, divorce, lawsuits, business failures, housing dif- autonomic alterations in the FGIDs are a primary phe-
ficulties, forced redundancies, and so on), together with nomenon or merely reflect the bidirectional interactions
the prolonged and effortful coping associated with the of CNS-ENS dysregulation.
stressor, has significant and consistent effects on symp-
tom onset and exacerbation over time.59 In this context, A Disease Model
it is relevant that psychological stress and other cognitive Although some of the factors outlined earlier,
aspects can also be related to sensorimotor dysfunction in such as genetic makeup and early-life experiences, may
FGID patients.60 For example, in IBS, the severity of be regarded as predisposing factors to sensorimotor dys-
psychosocial disturbance parallels the degree of small function and the FGIDs, others such as the enteric
bowel motor and/or sensory dysfunction,23 whereas ex- inflammation and psychosocial stress documented in IBS
posure to psychological stress provokes rectal hypersen- may be regarded as trigger factors. A theoretical disease
sitivity.61 Hypervigilance is another factor that influ- model for the CNS-ENS dysregulation observed in IBS
ences symptom reporting by IBS patients during rectal patients, based on the biopsychosocial model,74 is de-
distention testing.21 In FD, cognitive factors have been picted in Figure 2; a similar schema can be proposed for
implicated in both symptom induction62 and sensorimo- other FGIDs. It should be noted, however, that in some
tor dysfunction.63 instances the precise role of a given factor, that is
The physiological effects on the gut of chronic stress whether a predisposing, triggering, or modifying influ-
are receiving greater attention. In the rat, chronic psy- ence, remains unclear.
1418 KELLOW ET AL GASTROENTEROLOGY Vol. 130, No. 5

Figure 2. Schematic disease model of the putative importance of chronic life stress and enteric infection/inflammation and their potential
interactions with both early life factors and concurrent modifying factors, in the genesis of the CNS-ENS dysregulation present in irritable bowel
syndrome. GI, gastrointestinal; EI, extraintestinal. Modified and reprinted with permission.59

Recommendations for Further although the study of an inflammatory basis to IBS is

Progress in its infancy, this concept provides a tangible basis
for constructing novel animal models enabling inves-
The concepts of sensory and reflex dysfunction
leading to visceral hypersensitivity and enteric dysmo- tigation of luminal factors, including the enteric flora
tility have provided a conceptual framework for plausible and dietary constituents, that initiate and/or perpet-
mechanisms of symptom production in the FGIDs. Ad- uate gut sensorimotor dysfunction via immune acti-
vances in a range of areas are of crucial importance, vation. Important data on genetic predisposing fac-
however, to further clarify the clinical relevance of this tors and the dietary regulation of gene expression,
sensorimotor dysfunction. Three such areas are as follows: including the effects of different probiotics, are
awaited with great interest.
1. A greater understanding of the basic origins of gut 3. More precise delineation of the relationships between
perception: the key question in comparing animal and
sensorimotor dysfunction, individual symptoms, and
human research data is what is important for the
individual FGIDs: conceivably, the clinical manifes-
encoding of information that ultimately determines
tations in FGID patients depend on the specific sen-
the sensation consciously perceived. No data currently
sory and/or reflex pathways and territories affected.
are available in this area, but increasingly sophisti-
Improved symptom criteria, together with quantita-
cated brain-imaging techniques, as well as spinal
recording techniques, are required to probe the inter- tive data relating to physiological dysfunction (eg,
actions between cognitive factors and luminal causes hypersensitivity, dysmotility, and reflex dysfunction),
of ENS activation in the modulation of cerebral acti- to mucosal inflammation/immune/endocrine activa-
vation patterns. Sensory testing, including evoked tion and to autonomic dysfunction, and in the future
brain or spinal cord responses, could in the future be to molecular risk factors, should enable better cate-
used to categorize FGID patients to determine appro- gorization of patient subgroups using techniques such
priate therapeutics. as cluster analysis. More sophisticated techniques to
2. More detailed information about the interactions be- assess compliance, wall tension, and accommodation
tween both the afferent fiber sensory endings in the and to assess more precisely the flow of luminal
gut and the ENS, and their local environments, such content and gas and the effects of dietary constituents
as the presence of low-grade inflammation, different on sensorimotor function are required. In this regard,
luminal contents, hormonal fluctuations, and so on: the development of minimally or noninvasive tech-
April 2006 NEUROGASTROENTEROLOGY AND FGIDs 1419

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in irritable bowel syndrome and control subjects with painful and
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visceral and cutaneous hypersensitivity in the irritable bowel
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52. Maxwell PR, Rink E, Kumar D, Mendall MA. Antibiotics increase 71. Elsenbruch S, Orr W. Diarrhea- and constipation-predominant IBS
functional abdominal symptoms. Am J Gastroenterol 2002;97: patients differ in postprandial autonomic and cortisol responses.
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53. O’Mahony L, McCarthy, J, Kelly P, et al. A randomized, placebo- 72. Adeyemi EO, Desai KD, Towsey M, Ghista D. Characterisation of
controlled, double-blind comparison of the probiotic bacteria lac- autonomic dysfunction in patients with the irritable bowel syn-
tobacillus and bifidobacterium in irritable bowel syndrome (IBS): drome by means of heart rate variability studies. Am J Gastroen-
symptom responses and relationship to cytokine profiles. Gas- terol 1999;94:816 – 823.
troenterology 2005;128:541–551. 73. Elsenbruch S, Holtmann G, Oezcan D, et al. Are there alterations
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57. Atkinson W, Sheldon TA, Shaath N, et al. Food elimination based
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 GASTROENTEROLOGY 2006;130:1421–1434

Pharmacological and Pharmacokinetic Aspects of Functional

Gastrointestinal Disorders

MICHAEL CAMILLERI,* LIONEL BUENO,# FABRIZIO de PONTI,§ JEAN FIORAMONTI,‡

R. BRUCE LYDIARD,储 and JAN TACK¶
*Mayo Clinic College of Medicine, Rochester, Minnesota; #Unité de Neurogastroentérologie INRA; ‡INSERM, Toulouse, France; §University of
Bologna, Bologna, Italy; 储University of South Carolina, Charleston, South Carolina; and ¶Catholic University, Leuven, Belgium

Medications are commonly used for the treatment of Animal Pharmacology: Models
patients with functional gastrointestinal disorders. Validated for the Study of
The general goal of this report is to review the phar- Sensation and Motility
macokinetics and pharmacology of medications used
in functional gastrointestinal disorders. Methods in- The development of new drugs for the treatment
cluded literature review, consensus evaluation of the of patients with FGIDs is facilitated by preclinical ani-
evidence for each topic assigned originally to 1 or 2 mal models that must reproduce the pathophysiology of
authors, and broader review at a harmonization ses- FGIDs as closely as possible. This section reviews the
sion as part of the Rome III process. This report most commonly used animal models of visceral pain and
reviews the animal models that have been validated disturbed gastrointestinal motility.
for the study of effects of pharmacologic agents on
sensation and motility; the preclinical pharmacology, Visceral Pain
pharmacokinetics, and toxicology usually required for There are several forms of stimulation and end
introduction of novel therapeutic agents; the biomar- points to measure visceral pain.
kers validated for studies of sensation and motility Mechanical stimuli. Experiments are performed
end points with experimental medications in humans; in awake or anesthetized rats, and the most frequently
the pharmacogenomics applied to these medications
used stimulus of pain in animals is distention of a gut
and disorders; and the pharmacology of agents that
segment with a balloon connected to a barostat to
are applied or have potential for treatment of func-
measure simultaneously compliance and the response
tional gastrointestinal disorders, including psycho-
pharmacologic agents. Clinician and basic investiga- to the painful stimulus. Such a balloon can be chron-
tors involved in the treatment or investigation of ically implanted in the gut1; variability in balloon
functional gastrointestinal disorders or disease mod- construction and unfolding influences the reproduc-
els need to have a comprehensive understanding of a ibility of experiments. Arterial embolectomy probes2
vast range of medications. It is anticipated that the have a very reproducible diameter but do not permit
interaction between investigators of basic science, accurate measurement of pressure-volume relation-
basic and applied pharmacology, and clinical trials ships (or compliance).
will lead to better treatment of these disorders. Chemical stimuli. In rats, infusion of glycerol
into the colon through a chronically implanted catheter
induces abdominal cramps.3
n relation to functional gastrointestinal disorders
I (FGIDs), this report reviews animal models that have
been validated for the study of effects of pharmacologic
Other stimuli. Other stimuli have been used to
investigate visceral pain modulation in animal models,
including other chemical irritants (such as trinitroben-
agents on sensation and motility; the preclinical phar-
zene sulfuric acid, dioctyl sodium sulfosuccinate, zymo-
macology, pharmacokinetics, and toxicology usually re-
gen) and parasite infestations (such as Nippostrongylus
quired for introduction of novel therapeutic agents; the
biomarkers validated for studies of sensation and motility
Abbreviations used in this paper: FGID, functional gastrointestinal
end points with experimental medications in humans; disorder; 5-HT, serotonin/5-hydroxytryptamine; IBS, irritable bowel syn-
the pharmacogenomics applied to these medications and drome; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selec-
disorders; and the pharmacology of agents that are ap- tive serotonin reuptake inhibitor.
© 2006 by the American Gastroenterological Association Institute
plied or have potential for treatment, including psycho- 0016-5085/06/$32.00
pharmacologic agents. doi:10.1053/j.gastro.2005.08.062
1422 CAMILLERI ET AL GASTROENTEROLOGY Vol. 130, No. 5

brasiliensis or Trichinella spiralis). The “writhing test,” of sensitivity to distention) and hyperalgesia (en-
consisting of an intraperitoneal injection of an irritant hanced response to painful stimulus). Gastric hyper-
compound such as acetic acid, is used for pharmacologic sensitivity to distention has been induced by inflam-
studies of analgesic compounds, but it reflects peritoneal mation6 and intestinal hypersensitivity by helminth
irritation (and activates somatic pain) rather than visceral infection.11 Colonic and rectal hypersensitivity are
pain. At present, there is no consensus as to the best induced with stress (eg, maternal deprivation, water
model to study visceral pain. avoidance models),12 inflammation,2 and lipopolysac-
End points. Nociceptive responses to stimuli, charide injection.13 Long-term colonic hyperalgesia
called “pseudoaffective” responses, are brainstem or spi- may be induced by neonatal maternal deprivation14 or
nal reflexes that cease when the noxious stimulus is colonic inflammation.15
terminated. The most commonly used end point is the
contraction of abdominal muscles induced by rectal or Motility
colorectal distention in the rat; the contractions are typ-
ically recorded by electromyography.2,4 The number of The techniques used to record motility or measure
spike bursts or integrated signals correspond to abdom- transit in animals may differ from techniques used in
inal contractions over the period of distention, and they humans, but the end points are identical.
correlate with the intensity of the stimulus applied.2 In Delayed gastric emptying. Stress inhibits gastric
mice, colorectal distention triggers only one sustained emptying in animals and humans. Numerous stressors
contraction at the onset of the distention.5 Gastric dis- have been proposed to inhibit gastric emptying in rats,
tention in rats does not induce abdominal contractions, including restraint, acoustic stress, cold stress, combined
but stretching of the body or raising of the head and acoustic and cold stress, and passive avoidance. Pro-
electromyography of neck muscles has been used as a longed colonic distention16 inhibits gastric emptying,
biomarker of the nociceptive response to gastric disten- and this is considered relevant because, in humans, vol-
tion.6 It is, however, also possible that the electromyo- untary suppression of defecation for 4 days inhibits gas-
graphic recording may reflect contractions associated tric emptying.17 Another experimental method to in-
with a distention-induced defecation reflex rather than hibit gastric emptying is the duodenal infusion of lipids
being a measure of pain. in humans or animals.
Visceral distention also induces viscerovisceral reflexes, Altered duodenojejunal migrating motor complex
such as relaxation of anal sphincters during rectal distention pattern. Acute stress affects migrating motor complex
or rectocolonic inhibition of gastric emptying.7 patterns18; however, there are no models of chronic dis-
Change in blood pressure is a pseudoaffective response ruption of the migrating motor complex in animals.
widely used to assess visceral pain. Cardiovascular and Altered colonic motility and transit. Colonic mo-
muscular responses are mediated via brainstem reflexes; tility can be inhibited by several pharmacologic com-
both are vigorous in decerebrated but not spinalized rats. pounds, such as ␣2-adrenergic and ␮-opioid receptor
Electrophysiologic recordings from sensory neurons agonists. Stress has been used to stimulate colonic mo-
or second-order neurons in the spinal cord may pro-
tility, colonic transit, and fecal excretion in rats.19
vide the most direct evidence that a pharmacologic
In summary, because the present knowledge of the
agent alters afferent function.8,9 Measurements of the
pathophysiology of FGIDs is limited, selection of one or
effect of the medication on viscus compliance are
more definitive animal models of visceral hyperalgesia is
essential to differentiate effects on volume thresholds
to activate sensory fibers from drug-induced contrac- not possible. It is also difficult, based on results in a
tion or relaxation.10 single animal model, to predict efficacy of a compound in
Several behavioral end points have been used and clinical trials. Using results from more than one animal
involve brain centers higher than the brainstem. They do model may enhance the probability of selecting effective
not cease when the noxious stimulus is terminated and drugs for further development. To date, only 2 medica-
therefore are not pseudoaffective responses. Referred so- tions (tegaserod and cilansetron) have had a track record
matic hyperalgesia is evaluated in mice by application of of proven efficacy in animal models (for both transit and
von Frey hairs with forces from 1 to 32 mN on the sensation) and proven clinical efficacy. In addition, it is
abdomen; the subsequent behavioral response is a mea- worth emphasizing that pain is not the only symptom of
sure of sensation. FGIDs affecting quality of life, and animal models pro-
Allodynia and hyperalgesia. These models per- viding information on motility effects may be relevant to
mit evaluation of allodynia (decrease in the threshold the assessment of new compounds.
April 2006 PHARMACOLOGIC AND PHARMACOKINETIC ASPECTS OF FGIDS 1423

Preclinical Pharmacology, inadequate dose because phase 2 studies did not suggest
Pharmacokinetics, and Toxicology a higher dose was more effective; hence, there is the need
Required for Novel Therapeutic to consider using multiple therapies or “designed” mul-
Agents tiple ligands to enhance the benefit/risk ratio. For in-
stance, a 5-HT3 receptor antagonist with partial agonist
This section outlines some general pharmacody- action at 5-HT4 receptors may be less constipating than
namic, pharmacokinetic, and safety aspects that are im- a pure 5-HT3 receptor antagonist. Another example is
portant for the development of new drugs for FGIDs. provided by tachykinin receptor antagonists; it has been
suggested that the analgesic efficacy and motility inhi-
The Pharmacodynamic Target
bition of multi-tachykinin or pan-tachykinin receptor
Drug selectivity. Selectivity refers to the ability of antagonists are superior to that of monoreceptor
a compound to interact with only one receptor subtype, antagonists.26,27
leaving other receptors unaffected at concentrations Pharmacodynamic versus pathophysiologic tar-
achieved at clinically used doses and avoiding side ef- get. When drugs target a single receptor mechanism,
fects. Although this definition was considered key to heterogeneity in pathophysiology (eg, dysmotility vs hy-
finding effective new or experimental medications, there persensitivity) has a negative impact on the therapeutic
are several important pitfalls in this approach. gain if patients are not selected on the basis of the specific
First, drug selectivity is a relative concept, and the disorder. Indeed, some of the disappointing results of the
tendency to label a drug as a “selective” ligand for a given past decade can be attributed to the heterogeneity of
receptor subtype ignores the fact that a single molecule, functional disorders, lack of understanding of pathophys-
at therapeutic doses, may have several, sometimes differ- iology, and lack of short-term mechanistic studies that
ent, biological targets. For instance, cisapride was found can predict clinical outcome. New drugs should target
to be a partial 5-HT4 receptor agonist,20 a 5-HT3 recep- the entire pathophysiologic mechanism(s) contributing
tor antagonist, and a fairly potent HERG K⫹ channel to the functional disorder rather than only an individual
blocker.21 part or a specific receptor. Thus, nonselective agents
The second pitfall is that, because of the multifactorial designed to modulate multiple targets of the whole
pathophysiology of FGIDs, single-receptor modulating pathophysiologic process (eg, dysmotility, sensory disor-
drugs may be less likely to achieve a substantial thera- der, inflammation) would be advantageous over highly
peutic gain. In several fields,22 evidence suggests that selective medications addressing a single mechanism.
balanced modulation of multiple targets may provide a Appropriate patient subgroups should be recruited to
superior therapeutic effect and side effect profile com- show the therapeutic properties of a medication, al-
pared with the action of a selective ligand. Rational though this may reduce the generalizability of the results
approaches in which structural features from selective of the trial.
ligands are combined have produced designed multiple
ligands that span a large variety of targets.22 A key Pharmacokinetics
challenge in the design of a ligand with multiple actions Pharmacokinetics may help to achieve gut selec-
is to achieve a balanced potency and activity at each tivity. This approach is particularly relevant when there
target of interest and a suitable pharmacokinetic profile. are potential actions outside the gut. For example, pe-
The less selective a ligand is, the harder it is to predict ripherally restricted opioid receptor antagonists such as
toxicity; once toxicity occurs, it becomes even more methylnaltrexone and alvimopan do not cross the blood-
difficult to provide a mechanistic explanation for it. This brain barrier and, in addition, have very low oral bio-
may jeopardize the development and regulatory approval availability.28,29 This offers the potential to modulate
of such a less selective ligand. intestinal motility without systemic effects. Moreover,
Third, it is likely that the mechanisms responsible for targeted drug delivery to the colon with pH- or time-
symptoms in FGIDs may differ from one patient to dependent release30,31 or bacterial activation of a prodrug
another and a single target may not achieve adequate offer potential new approaches for FGIDs.
efficacy in a patient population. With the selective ap- Another important pharmacokinetic property is the
proach to relieving symptoms or groups of symptoms lack of interactions with food or other drugs. CYP2D6
(eg, pain and constipation or diarrhea), experience shows (10% slow metabolizers in the community), CYP3A4,
that primary clinical end points were achieved in ⬍70% and CYP2C19 are important isoenzymes because of their
of patients with agents such as tegaserod or alos- involvement in the metabolism of many drugs and drug-
etron.23–25 The lack of efficacy is unlikely to reflect an drug interactions. Significant interactions with these en-
1424 CAMILLERI ET AL GASTROENTEROLOGY Vol. 130, No. 5

zymes should be ruled out in early drug discovery and colon,39 but to date no convincing beneficial therapeutic
may be achieved by computational prediction. Specifi- effects have been reported in FGIDs. Several 5-HT re-
cally, it is important to distinguish between pharmaco- ceptor types are present on both nerves and smooth
kinetic modification resulting from drug metabolism by muscle and mediate a number of different actions.40
one of the enzymes versus drug interactions at one of the 5-HT3 receptor antagonists, such as alosetron, delay
enzymes, which may be inhibition or induction. In both orocecal and colonic transit times and reduce colonic
situations, drug-drug interactions may occur if inhibi- compliance but not sensitivity to isobaric disten-
tion or induction occurs at clinically relevant doses. tion.41– 43 Several clinical studies confirmed the efficacy of
alosetron in diarrhea-predominant irritable bowel syn-
Safety Aspects drome (IBS).25 Shortly after its introduction, alosetron
Apart from the standard safety evaluations of was withdrawn due to suspected side effects of ischemic
every new medicinal product, 2 examples deserve special colitis/colonic ischemia33 and is now available for re-
attention because of recent experience: cisapride resulted stricted use in the United States only. Preliminary data
in tachyarrhythmia associated with prolongation of the suggest a therapeutic potential for cilansetron,44 al-
QT interval of the electrocardiogram due to blockade of though there is also potential for ischemic colitis.45
the HERG K⫹ channels32 and alosetron or cilansetron 5-HT4 receptor agonists, such as tegaserod or prucalo-
were associated with ischemic colitis.33 Although these pride, act on intrinsic neurons to stimulate gastric, small
are very rare events, even a low risk is not acceptable for bowel, and colonic transit in health, in constipation, and
drugs that target pathophysiologic mechanisms and pro- in constipation-predominant IBS.46 – 48 In the stomach,
vide relief of nonfatal diseases such as FGIDs, and the 5-HT4 receptor agonists enhance (postprandial) proximal
drug development process should identify such undesired gastric volumes in health but have no effects on sensa-
effects as early as possible.34 Overall, low risk of these tion.49 In healthy subjects, tegaserod does not alter sen-
adverse effects or minor adverse events may be acceptable sory thresholds or sensory ratings during rectal disten-
in patients with severe FGIDs that affect daily living. A tion but reduces the inhibition of the RIII reflex caused
third issue of particular relevance in FGIDs is the po- by slow-ramp colorectal distention, which was proposed
tential for drug interactions, given the problem of poly- as a surrogate marker of visceral pain.50,51 Tegaserod
pharmacy and the frequent use of psychotropic agents improves constipation, provides relief of pain/discomfort
(which often depend on CYP2D6 metabolism). and bloating, and is approved for women with constipa-
tion-predominant IBS and for men and women younger
Human Pharmacology: than 65 years with chronic constipation.24,52,53 Prucalo-
Nonpsychotropic Agents pride and tegaserod were shown to be effective in the
Gastrointestinal motor and sensory function can treatment of constipation.54,55
be altered through several pharmacologic approaches; the Activation of 5-HT1A receptors on enteric neurons
most important are summarized in Table 1 and are inhibits the release of acetylcholine.56 In humans,
discussed in this section. However, it is also important to 5-HT1A receptor agonists such as buspirone inhibit mo-
recognize 2 other classes of agents that are commonly tility and decrease gastric tone, but therapeutic useful-
used in FGIDs, that is, laxatives in the treatment of ness has not been established.57
constipation (alone or in association with IBS)35 and
Motilides
probiotics.36
Several meta-analyses of pharmacologic treatments for Activation of motilin receptors on smooth muscle
IBS have been published in recent years.37 The pharma- and on cholinergic nerves enhances gastric contractil-
cology of agents directed to amine receptors or peptides ity.58 Motilin receptor agonists, such as erythromycin or
is summarized (Table 1). the macrolide prokinetic ABT-229, enhance antral con-
tractility, fundic tone, and gastric emptying in health
Serotonergic Agents and in gastroparesis (Cuomo et al, manuscript in sub-
Serotonin, or 5-hydroxytryptamine (5-HT), plays mission).59 – 62 The symptomatic impact of enhanced
a key role in the control of gastrointestinal motility, emptying by erythromycin in gastroparesis has been
sensitivity, and secretion. Actions of 5-HT are termi- questioned,63 and no symptomatic benefit (but rather
nated by a reuptake system, which is inhibited by anti- some symptom aggravation) was found in studies with
depressants.38 Selective serotonin reuptake inhibitors ABT-229.64 The occurrence of tachyphylaxis with moti-
(SSRIs) alter motility in the stomach, small bowel, and lides may be an important factor.65
April 2006 PHARMACOLOGIC AND PHARMACOKINETIC ASPECTS OF FGIDS 1425

Table 1. Agents Directed to Amines/Receptors and Peptides

Pharmacologic action in Pharmacologic action in
Target receptor Type of ligand Distribution of receptors animals humans
Amines/receptors
5-HT 5-HT3 receptor antagonists Intrinsic and extrinsic neurons Inhibits visceral sensitivity, Slows transit, increases colonic
(eg, alosetron, absorption/secretion, compliance
cilansetron) motility
5-HT4 receptor agonists Enteric neurons, smooth Enhances secretion and Accelerates transit, increases
(eg, tegaserod, muscle cells motility, reduces visceral colonic high-amplitude
renzapride, prucalopride) sensitivity propagated contractions and
gastric accommodation,
reduces inhibition of R1II
reflex during rectal distention
5-HT1A receptor agonists Enteric neurons, extrinsic Inhibits motility and Increases accommodation
(eg, buspirone) afferent neurons enhances compliance
Ach (muscarinic) M3 receptor antagonists Smooth muscle Increases smooth muscle No published data
relaxation, compliance
M1 and M2 receptor Enteric neurons and smooth Increases gastric emptying May enhance accommodation
antagonists muscle
Adrenoceptors ␤3-adrenoceptor agonists Smooth muscle Inhibits motility No published data
␣2-adrenoceptor agonists Enteric neurons and Reduces secretion, Reduces secretion, enhances
enterocytes enhances compliance, compliance, and reduces
and reduces motility and motility and tone and
tone sensation
Dopamine D2 receptor antagonists Area postrema, smooth Contracts muscle Antiemetic, prokinetic, reduced
(eg, domperidone, muscle, enteric neurons sensation?
levosulpiride,
metoclopramide)

Peptides
Motilin Motilides Smooth muscle, enteric Motility stimulation Motility and transit stimulation
neurons
Opioid ␮-receptor agonists (eg, Enterocyte, enteric neurons, Reduces intestinal Slows colonic transit,
loperamide) afferent neurons, and secretion and transit antidiarrheal, increases
inflammation resting anal tone
␮-receptor antagonists Enteric neurons, afferent Reverses opioid effects on Accelerates colonic transit;
(eg, naloxone, methyl- neurons, and inflammation motility reverses effect of opiates on
naltrexone, and bowel dysfunction; reduces
alvimopan) duration of postoperative
ileus
␬-receptor agonists (eg, Enteric neurons and afferent Reduces sensation, Reduces sensation
fedotozine asimadoline) neurons variable effect on
motility
Somatostatin SSR-2 receptor agonists Enterocyte, submucosal Retards transit, reduces Retards transit, reduces
(eg, octreotide, neurons, myenteric neurons afferent firing and sensitivity, enhances
lanreotide) sensation absorption
Tachykinin NK1 receptor antagonists Enteric neurons, interstitial Inhibits motility, fluid Antiemetic
(eg, aprepitant) cells of Cajal, smooth secretion, vagal afferent
muscle, immune cells sensation, and
inflammation
NK2 receptor antagonists Enteric neurons, smooth Inhibits motility, fluid Inhibits NKA-induced motility
(eg, nepadutant) muscle, extrinsic afferents secretion, sensation,
and inflammation
NK3 receptor antagonists Enteric neurons, extrinsic Inhibits motility and No published data
(eg, talnetant) afferents sensation
Cholecystokinin Cholecystokinin-1 receptor Afferent vagal nerves and Accelerates gastric Inhibits lipid-induced gastric
antagonists (eg, enteric neurons emptying, inhibits TLESR motor effects, inhibits TLESR
dexloxiglumide)

NK, neurokinin; TLESR, transient lower esophageal sphincter relaxation.

Tachykinin Receptor Antagonists endogenous tachykinins substance P, neurokinin A, and

Three distinct receptors, neurokinin 1, neuroki- neurokinin B in the gastrointestinal tract. Through the
nin 2, and neurokinin 3, mediate the biological effects of locations of neurokinin receptors on intrinsic nerves,
1426 CAMILLERI ET AL GASTROENTEROLOGY Vol. 130, No. 5

extrinsic nerves, inflammatory cells, and smooth muscle, may be up-regulated in some FGIDs.80 Long-term ad-
inhibition of tachykinin receptors has the potential to ministration of capsaicin, which is believed to desensitize
inhibit motility, sensitivity, secretion, and inflammation TRPV1, was more effective than placebo in decreasing
in the gastrointestinal tract.27,66 Neurokinin 1 receptor symptoms in functional dyspepsia.81
antagonists also have antiemetic properties.27 Several Dopamine2 receptor antagonists have gastroprokinetic
tachykinin receptor antagonists are currently under eval- effects and central antiemetic properties resulting in
uation for treatment of FGIDs. suppression of nausea and vomiting. Although clinically
used in the treatment of FGIDs and gastroparesis,82
Adrenoceptor Agonists efficacy has not been established by high-quality stud-
The ␣2-adrenoceptor agonist clonidine was shown ies.83,84
to reduce colonic tone and pain sensation in response to Muscarinic receptor antagonists and smooth muscle
distention.67– 69 A preliminary study of clonidine in di- relaxants are used in some countries for the treatment of
arrhea-predominant IBS suggested therapeutic potential IBS. Meta-analysis suggests they are superior to placebo
for clonidine, but clinical application is hampered by in IBS-related pain,85 although the quality of trials has
dose-limiting side effects such as somnolence or hypo- been questioned.
tension. Somatostatin and its stable analogues such as oc-
treotide inhibit rapid gastric and small bowel transit as
Opioid Receptor Ligands well as sensitivity to rectal or colonic distention in
Three types of opioid receptors, ␮, ␦, and ␬ humans.86 – 88 The need for multiple subcutaneous injec-
receptors, located in the enteric nervous system and on tions, high cost, and potential side effects limit its
nociceptive pathways, have effects on human gastroin- present use in FGIDs.
testinal function. Opioid receptor activation reduces vis- Cannabinoid CB1 receptors are expressed on nocicep-
ceral pain through peripheral (spinal afferents) and cen- tive afferents and enteric nervous system neurons,
tral mechanisms and inhibits motility through decreased whereas CB2 receptors are expressed on immune cells.
acetylcholine release. ␬-opioid receptor agonists have Activation of CB1 receptors slows gastrointestinal transit
been proposed as a pharmacologic approach to the treat- in animals through inhibition of acetylcholine release.
ment of hypersensitivity in FGIDs. Acute studies with The nonspecific agonist ␦-9-tetrahydrocannabinol has
fedotozine and asimadoline showed decreased sensitivity strong antiemetic properties and delays gastric emptying
to gastric or colonic distention.70 –73 However, therapeu- in humans.89,90 It is unclear whether the potential for
tic studies in IBS and functional dyspepsia with fe- abuse of CB1 agonists would preclude their regulatory
dotozine have been disappointing.74,75 The ␮-opioid re- approval. Inverse CB1 agonists (which function as antag-
ceptor agonist loperamide, used in the treatment of onists at constitutively active CB1 receptors)91 are being
diarrhea, inhibits secretion, reduces colonic transit, and developed for treatment of obesity, because they may
increases resting anal sphincter tone.76 Peripherally re- induce nausea and vomiting. The effects on stomach
stricted ␮-opioid receptor antagonists, such as N-meth- function are unclear. On the other hand, agonists at the
ylnaltrexone and alvimopan, normalize bowel function in nonneuronal CB2 receptors have no abuse potential and
opiate-treated patients without compromising central exert antinociceptive effects in pain associated with in-
opioid analgesia.29 The use of these agents in constipa- flammation.92
tion and in constipation-predominant IBS is under in-
vestigation. Pharmacodynamics: Biomarkers for
Miscellaneous Agents Sensation and Motility End Points
in Experimental Medicine
Cholecystokinin has a large number of effects on
gastrointestinal contractility and secretion.77 Cholecysto- This section reviews the application of physio-
kinin-1 receptor antagonists such as loxiglumide and logic tests as potential biomarkers to understand mode of
dexloxiglumide enhance gastric emptying in health and action and to predict efficacy of an experimental medi-
in constipation-predominant IBS, although effects on cine in FGIDs.
colonic motility are unclear.78,79 So far, clinical useful-
ness has not been established. Measurements of Colonic Transit
The transient receptor potential ion channel of the The radiopaque marker test for colonic transit is
vanilloid type 1 (TRPV1), expressed by primary afferent commonly performed and widely available to assess
neurons, is viewed as a trigger for chemonociception and whole gut transit time. Studies with fiber or loperamide
April 2006 PHARMACOLOGIC AND PHARMACOKINETIC ASPECTS OF FGIDS 1427

suggest that overall effects of these therapies can be tying as with single photon emission computed tomog-
predicted by the marker transit test, although there was raphy, ultrasonography, or magnetic resonance imaging
considerable overlap.93,94 Examples from the literature may be useful because it simultaneously measures several
support the use of detailed scintigraphic colonic transit of the previously mentioned potential biomarkers.103,104
measurement in the development of medications for
IBS-associated changes in bowel function. Alosetron, a
Principles of Pharmacogenomics in
5-HT3 receptor antagonist that slows colonic transit, was
shown to be effective in diarrhea-predominant IBS,25 and
FGIDs
tegaserod, a 5-HT4 receptor agonist that accelerates co- Pharmacogenetics refers to the study of individual
lonic transit, was shown to be effective in constipation- variations in DNA sequence related to drug response.
predominant IBS.24,52,53 Pharmacogenomics is the study of the variability of the
expression of individual genes relevant to disease suscep-
Intraluminal Measurements of Rectal or tibility and drug response at cellular, tissue, individual,
Colonic Motility and Sensitivity or population levels.
Intracolonic measurements of postprandial tone Polymorphisms may be markers associated with pre-
showed the potential of 5-HT3 receptor antagonists to disposition to FGIDs. Examples in the literature include
prevent diarrhea and other postprandial symptoms in patients with IBS having significantly reduced frequen-
diseases including IBS and carcinoid diarrhea.95 Measure- cies of the high producer genotype for interleukin-10
ments of rectal or colonic sensation have not been con- than controls, suggesting that at least some patients with
sistent in predicting therapeutic efficacy. Changes in IBS may be genetically predisposed to produce lower
rectal sensitivity have been associated with responsive- amounts of this anti-inflammatory cytokine. This lends
ness to octreotide86 – 88,96 and opiates,97 but rectal sensory some support to the hypothesis that there may be an
thresholds do not seem to be significantly altered by inflammatory or genetic component in some cases of
tegaserod when using rapid distention.51 IBS.105 There are contradictory data in the literature
suggesting an association of IBS subgroups with poly-
Gastric Biomarkers in Functional Dyspepsia morphisms of the serotonin transporter (SERT).106 A
Scintigraphic gastric emptying has been a classi- polymorphism (C825T) in the gene controlling G-pro-
cal investigation for drug development for gastropare- tein synthesis has been described in functional dyspepsia
sis98; however, the prediction of clinical efficacy is not and IBS.107 Clearly, more studies are needed to confirm
consistent.63,98 This analysis is also complicated by the or refute the genotype associations for interleukin-10 and
occurrence of tachyphylaxis to some medications and by GN␤3.
changes in gastric emptying rate with placebo.62,64,99,100 A second aspect is genetic variations influencing re-
A second approach is to use the gastric barostat to sponse to medications. There may be genetic polymor-
measure compliance, tone, and sensitivity. Studies with phism in drug metabolism. For instance, the number of
the ␬-opioid agonist fedotozine and with the 5-HT1A functional CYP2D6 genes determines the pharmacoki-
receptor agonist R-137696 showed acute effects on netics and plasma levels of the commonly used tricyclic
barostat measurements of sensitivity or tone that did not agent nortriptyline108 or the action of codeine (which has
translate into significant clinical benefit during placebo- to be converted to morphine by the CYP2D6 isoenzyme
controlled studies of oral administration of these medi- to be effective). Note also that several antidepressants are
cations for several weeks in patients with functional metabolized by these enzymes, and this may affect their
dyspepsia.57,74 clinical efficacy and safety.
A recent approach in evaluating symptoms in dyspep- Genetic polymorphism may also involve transport-
sia has used the symptoms induced by a standardized ers109 that may influence drug response. Two examples of
provocative meal, which is either water or a liquid nu- pharmacodynamic variation are provided from the field
trient drink or a solid meal.101,102 Although these tests of FGIDs. 5-HT undergoes reuptake by SERT. Polymor-
separated healthy controls from patients with functional phisms in the promoter for synthesis of SERT (SERT-P)
dyspepsia, it is unclear whether changes in symptom influence response to serotonergic medications in de-
severity after meal provocative tests will prove effective pressed individuals. SERT polymorphisms were associ-
predictors of the clinical efficacy of medications. ated with a greater colonic transit response in those with
As a further development along this line, the com- long homozygous than those with heterozygous or short
bined use of the nutrient drink test with assessment of homozygous polymorphisms in diarrhea-predominant
symptoms and measurement of gastric volume and emp- IBS.110
1428 CAMILLERI ET AL GASTROENTEROLOGY Vol. 130, No. 5

Table 2. Pharmacologic Actions of Psychotropic Drugs on Monoamine Reuptake and Receptors

Neurotransmitter reuptake blockade Receptor blockade

5-HT Norepinephrine Dopamine ␣1 ␣2 H1 Ach 5-HT1A 5-HT2

Tricyclic antidepressants
Amitriptyline ⫹⫹⫹⫹⫹ ⫹⫹⫹ ⫺ ⫹⫹⫹ ⫹ ⫹⫹⫹⫹ ⫹⫹⫹ ⫹ ⫹⫹⫹
Imipramine ⫹⫹⫹⫹ ⫹⫹⫹⫹⫹ ⫺ ⫹⫹ ⫹ ⫹⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹
Desipramine ⫹⫹⫹ ⫹⫹⫹⫹⫹ ⫺ ⫹⫹ ⫹ ⫹⫹ ⫹⫹ ⫺ ⫺
Clomipramine ⫹⫹⫹⫹⫹ ⫹⫹⫹ ⫺ ⫹⫹ ⫹⫹⫹ ⫹⫹ ⫺ ⫺
SSRIs
Fluoxetine ⫹⫹⫹⫹⫹ ⫹⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
Paroxetine ⫹⫹⫹⫹⫹ ⫹⫹⫹ ⫹⫺ ⫺ 0 ⫹⫹ ⫺ ⫺
Sertraline ⫹⫹⫹⫹⫹ ⫹ ⫹⫹⫹ ⫹⫹ ⫹ 0 ⫹ ⫺ ⫺
Citalopram ⫹⫹⫹⫹⫹ ⫺ 0 ⫹ ⫹ ⫹ 0 ⫺ ⫺
SNRIs
Venlafaxine ⫹⫹⫹⫹ ⫹ ⫺ 0 0 0 0 0 0
Duloxetine ⫹⫹⫹⫹⫹ ⫹⫹⫹⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
Atypical agents
Bupropion 0 ⫹ ⫹ ⫺ ⫺ ⫺ 0 ⫺ ⫺
Nefazodone ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹ ⫺ ⫹⫹ ⫺ ⫹⫹⫹
Mirtazapinea ⫺ 0 0 ⫹ ⫹⫹⫹⫹ ⫹ ⫹⫹⫹
Azapirones
Buspirone 0 0 0 0 0 0 0 ⫹⫹ 0

␣, ␣-adrenergic; H, histamine; Ach, muscarinic cholinoceptors; ⫹ to ⫹⫹⫹⫹⫹, increasing levels of potency; ⫺, weak; 0, no effect.
aMirtazapine also blocks 5-HT receptors (⫹⫹⫹), which reduces nausea and has acute anxiolytic effects in humans.
3

A second observation is that drug response in patients Long-term treatment with any antidepressant alters
with functional dyspepsia may be influenced by genetic receptor sensitivity, which in all cases is believed to
variation in GN␤3 translation. Holtmann et al found result in enhanced 5-HT neurotransmission. Tricyclic
that G-protein polymorphisms were predictors of symp- antidepressants, but not SSRIs or serotonin-norepineph-
tom outcome in functional dyspepsia, based on the ra- rine reuptake inhibitors (SNRIs), increase the sensitivity
tionale that G proteins act as second messengers and may of postsynaptic 5-HT receptors and down-regulate ␣2
influence multiple receptor-mediated mechanisms.107 presynaptic receptors and heteroreceptors. The analgesic
These results require confirmation, but they suggest effect of tricyclic antidepressants is also mediated by
that pharmacogenetics may affect drug response and need blockage of a class of voltage-dependent sodium channels
to be considered in drug development programs and in in extrinsic sensory neurons. SSRIs and SNRIs reduce the
clinical therapeutics. Pharmacogenetics may also provide sensitivity of 5-HT1A autoreceptors and heteroreceptors.
new insights on the mechanism or pathophysiology of Buspirone (which is an anxiolytic, not an antidepressant)
FGIDs. down-regulates 5-HT1A somatodendritic autoreceptors
to produce anxiolysis. Down-regulation of 5-HT1A re-
Psychopharmacology of FGIDs ceptors is believed to play the most important role in
The acute effects of various psychotropic drugs are antidepressant, anxiolytic, and analgesic effects of anti-
shown in Table 2. 5-HT1A receptors and ␣2 adrenocep- depressants.
tors are both presynaptic and postsynaptic receptors and Benzodiazepines enhance the inhibitory effects of
heteroreceptors (ie, they modulate norepinephrine and ␥-aminobutyric acid via potentiation at the GABAA
5-HT neurotransmission, respectively, via presynaptic receptors, indirectly enhance 5-HT, and diminish nor-
somatodendritic receptors). When administered long- epinephrine neurotransmission and antagonize the effects
term, all antidepressants also enhance glucocorticoid sig- of cholecystokinin in brain and gut. This results in
naling and inhibit overactivity of corticotrophin-releas- immediate anxiolytic activity.
ing factor in the brain and presumably in the periphery.
Each class affects several transmitters via reciprocal ac- Evidence for Efficacy of Psychotropic
tions between amine and neuropeptide systems and re- Treatments in FGIDs
duces excessive cytokine release associated with various Psychotropic agents are commonly used to treat
conditions in which inflammatory cytokines play a patients with FGIDs.112 Two groups examined the ac-
role.111 crued evidence for efficacy of antidepressants for IBS and
April 2006 PHARMACOLOGIC AND PHARMACOKINETIC ASPECTS OF FGIDS 1429

reached remarkably different conclusions. Jackson et al113 Table 3. Dosing Guidelines for Antidepressants and
conducted a meta-analysis of randomized controlled tri- Anxiolytics for FGIDs
als published between 1966 and 1988, focused on the Treatment
effectiveness of antidepressants for FGIDs, and suggested (6–8 wk)
Antidepressants (mg) Starting dose (mg)
that antidepressants were as effective for IBS as other
Tricyclic antidepressants
commonly prescribed treatments, such as antispasmodics
Imipramine 100 10
and antidiarrheals. However, there is justifiable debate Desipramine 100 10
over the conclusions drawn due to the inclusion of one Clomipramine 75 2.5–10
study showing an unusually large treatment effect, with- SSRIs/SNRIs
Sertraline 50 12.5–25
out which the findings would have been less conclusive. Paroxetine 20 5–10
Brandt et al114 assessed randomized controlled trials for Fluoxetine 20 2–5
all studies published between 1980 and 2001 that ex- Escitalopram 10 5
Citalopram 20 10
amined the efficacy of different IBS treatments, includ- Fluvoxamine 50 25
ing tricyclic antidepressants. They concluded that none Venlafaxine 75 18.75
of the tricyclic antidepressant studies was sufficiently High-potency benzodiazepinesa
Alprazolam 2 0.25–0.5 3 times daily
long or used sufficiently large sample sizes to assure
Clonazepam 1 0.25–0.5 twice daily
efficacy. These studies were considered to have a high
probability of type I or II errors; tricyclic antidepressants NOTE. Some patients may still benefit from dosages lower than
indicated. For treatment of major depression or anxiety disorders,
are not superior to placebo for global IBS symptoms, but dosages are at least double what is indicated.
there was “limited evidence that tricyclic antidepressants aNot useful as antidepressants.

may decrease abdominal pain.”

Newer Studies of Psychotropic Agents in
pared 12 weeks of flexible-dose treatment with parox-
FGIDs
etine (10 – 40 mg/day) with placebo in 81 patients with
Tricyclic antidepressants. Drossman et al115 com- IBS. Treatment with paroxetine was associated with sig-
pared the efficacy of the tricyclic antidepressant desipramine nificantly higher improvement of overall well-being and
(on average 100 mg/day) with placebo in women with patient preference compared with placebo. Abdominal
moderate to severe IBS. In the intention-to-treat analysis, pain and bloating were not significantly better after
treatment with desipramine failed to reach statistical supe- treatment with paroxetine.
riority over placebo in the overall sample. Post hoc analysis Two open-label treatment studies with paroxetine in
of subjects completing therapy and a separate analysis that IBS have been recently reported. Creed et al119 reported
excluded subjects with undetectable desipramine levels (as- significant improvement of abdominal pain severity in
sumed to be noncompliant with therapy) favored desipra- 86 patients with severe IBS during 12 weeks of treat-
mine over placebo on the main outcome measure and on ment with paroxetine 20 mg/day. Masand et al120 re-
quality of life and pain (P ⫽ .09 each) and on patient-rated ported improvement in overall pain, pain severity, and
“satisfaction with treatment” (desipramine ⬎ placebo; P ⫽ frequency in 20 patients with IBS treated for 12 weeks
.011). It was concluded that because most of the patients with paroxetine (mean dose, 31 mg), with a trend toward
who dropped out did so due to side effects and a significant greater improvement in pain in patients with anxiety
portion had nondetectable desipramine levels, tolerability of disorder. These results should be interpreted cautiously
desipramine treatment ultimately limited the statistical due to the open-label design.
power of this study.
SSRIs. Clinically, SSRIs appear to be useful for
Indication and Choice of Psychotropic
some patients with FGIDs. Kuiken et al116 reported that Agents in FGIDs
6 weeks of treatment with fluoxetine 20 mg daily was Psychotropic agents are indicated in the presence
not superior to placebo overall but did reduce abdominal of significant psychiatric symptoms. The goal of therapy
pain in the subgroup with rectal hypersensitivity. These is to achieve relief of gastrointestinal and psychosocial
findings need confirmation. In a pediatric population distress. Patients with prior mania, prominent suicidal
with recurrent abdominal pain, a response was reported ideation, or a history of worrisome or unstable behavior
in 21 of 24 subjects (ages 7–18 years) after 12 weeks of should be referred promptly for assessment by a mental
treatment with flexible-dose citalopram.117 health specialist.
In the only placebo-controlled, randomized, controlled All the antidepressant classes and the anxiolytics
trial of the SSRI paroxetine to date, Tabas et al118 com- shown in Table 3 have efficacy in placebo-controlled,
1430 CAMILLERI ET AL GASTROENTEROLOGY Vol. 130, No. 5

Figure 1. Algorithm for use of treatment with psychotropics for psychiatric symptoms in FGIDs in clinical practice. BZ, benzodiazepines; SNRI,
serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant.

randomized, controlled trials for the disorders shown. Buspirone is a partial 5-HT1A receptor agonist that is
However, not all antidepressants are broadly effective efficacious in general anxiety disorder, but efficacy in
anxiolytics. The SNRIs and SSRIs are generally consid- FGIDs needs to be studied.
ered to be equivalent in efficacy and tolerability, and Starting psychotropic drugs for FGIDs at a low dosage
either class is a reasonable first-line approach. They are may help reduce exacerbation of preexisting gastrointestinal
broadly efficacious as antidepressants and anxiolytics and and other symptoms. An algorithm for the use of psycho-
are safer and more tolerable than the traditional antide- tropic agents is outlined in Figure 1. Achieving full remis-
pressants. The relative advantages and disadvantages of sion is not a reasonable goal for the initial 6- to 8-week
each of the available treatments should be anticipated for treatment and may require 4 – 6 months or even longer. For
the individual patient, and participation in the initial some patients, the use of concomitant benzodiazepines for
treatment choice should be negotiated with the patient anxiety control may help with compliance and allow more
as an active partner in the process in the interest of optimal control of symptoms.
maximizing compliance. For some patients, finding a In summary, the presence of clinically significant psy-
tolerable and effective choice may require using more chiatric symptoms in patients with FGIDs is an indica-
than one medication. Obtaining tricyclic agent plasma tion for psychotropic agents, especially when stress reac-
levels (8 –12 hours after the last dose) after initiating tivity is observed. Enthusiasm for newer antidepressants
therapy can assure continued patient safety. for FGIDs is based on their broad efficacy in the psychi-
If patients are intolerant of antidepressants and have atric conditions and potential efficacy on core IBS symp-
prominent anxiety, they can be treated with benzodiaz- toms. Confirmation of existing practice with randomized
epine monotherapy.121 However, long-term use in pa- controlled trials is still needed.
tients with FGIDs is discouraged due to a number of
factors. Treatment with benzodiazepines may be associ-
ated with the development of tolerance, physical depen- Conclusions
dence, abuse, sedation, cognitive impairment, and, in Clinician and basic investigators involved in the
particular, inability to discontinue benzodiazepines when treatment or investigation of FGIDs or disease models
their use is no longer clinically indicated. need to have a comprehensive understanding of a vast
April 2006 PHARMACOLOGIC AND PHARMACOKINETIC ASPECTS OF FGIDS 1431

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McGraw-Hill, 2001. Gastroenterol 2004;99:914 –920.
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technical review on irritable bowel syndrome. Gastroenterology Rigby C, Thompson D, Tomenson B. The cost-effectiveness of
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drome. Gastroenterology 2003;124:303–317.
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son W, Quigley E, Schoenfeld P, Schuster M, Talley N. System-
what are the links? J Clin Psychiatry 2001;62(Suppl 8):38 – 45.
atic review on the management of irritable bowel syndrome in
North America. Am J Gastroenterol 2002;97(Suppl):S7–S26.
115. Drossman DA, Toner BB, Whitehead WE, Diamant NE, Dalton Received January 31, 2005. Accepted August 5, 2005.
CB, Duncan S, Emmott S, Proffitt V, Akman D, Frusciante K, Le Address requests for reprints to: Michael Camilleri, MD, Mayo Clinic,
T, Meyer K, Bradshaw B, Mikula K, Morris CB, Blackman CJ, Hu Charlton 8-110, 200 First Street Southwest, Rochester, Minnesota
Y, Jia H, Li JZ, Koch GG, Bangdiwala SI. Cognitive-behavioral 55905. e-mail: [email protected].
 GASTROENTEROLOGY 2006;130:1435–1446

Gender, Age, Society, Culture, and the Patient’s Perspective in

the Functional Gastrointestinal Disorders

LIN CHANG,*,‡ BRENDA B. TONER,§,储 SHIN FUKUDO,¶ ELSPETH GUTHRIE,# G. RICHARD LOCKE,**
NANCY J. NORTON,‡‡ and AMI D. SPERBER§§
*CNS/WH: Center for Neurovisceral Sciences and Women’s Health, ‡Department of Medicine, David Geffen School of Medicine, University
of California, Los Angeles, California; §Centre for Addiction and Mental Health, 储University of Toronto, Toronto, Ontario, Canada; ¶Department
of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; #University of Manchester, Manchester, United
Kingdom; **Mayo Clinic College of Medicine, Rochester, Minnesota; ‡‡International Foundation of Functional Gastrointestinal Disorders,
Milwaukee, Wisconsin; and §§Department of Gastroenterology, Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of
the Negev Beer-Sheva, Beer-Sheva, Israel

Patients with functional gastrointestinal disorders design of research protocols to provide a more compre-
(FGID) often experience emotional distress, a perceived hensive understanding of these disorders from both a
lack of validation, and an unsatisfactory experience with theoretical and a methodological perspective. Failure to
health care providers. A health care provider can provide consider these variables may result in an overly simplistic
the patient with a framework in which to understand and incomplete interpretation of research data. The ma-
and legitimize their symptoms, remove self-doubt or
jority of studies that are discussed focus on irritable
blame, and identify factors that contribute to symptoms
bowel syndrome (IBS) because it is the most studied of
that the patient can influence or control. This framework
can be strengthened with the consideration of various the FGID. We also recognize that knowledge generation
important factors that impact FGID but are often over- and transfer has been traditionally given to the “expert,”
looked. These include gender, age, society, culture, and who is usually a scientist or clinician rather than the
the patient’s perspective. There is evidence for sex- and individual who has the specific condition under study.
gender-related differences in FGID, particularly irritable For these reasons, this review starts with the patient’s
bowel syndrome (IBS). Whereas the majority of FGID, perspective.
including IBS, bloating, constipation, chronic functional
abdominal pain, and pelvic floor dysfunction, are more The Patient’s Perspective
prevalent in women than men, functional esophageal
and gastroduodenal disorders do not appear to vary by The illness experience of persons with FGID, such
gender. Limited studies suggest that sex differences in as IBS, is similar to that of those who live with other
visceral perception, cardioautonomic responses, gastro- chronic conditions of uncertain etiology and ambiguous
intestinal motility, and brain activation patterns to vis- diagnostic criteria. Chronic illnesses are characterized by
ceral stimuli exist in IBS. Gender differences in social long-term courses, unpredictable symptom episodes, and
factors, psychological symptoms, and response to psy- disabling effects that are often accompanied by mini-
chological treatments have not been adequately stud- mally effective treatments, social stigma, and isolation.1
ied. However, there appears to be a greater clinical Symptoms place demands on families as well as patients,
response to serotonergic agents developed for IBS in and impair functioning while placing perpetual demands
women compared to men. The impact of social and on the individual patient.
cultural factors on the meaning, expression, and course
of FGID are important. The prevalence of IBS appears to Living With IBS
be lower in non-Western than Western countries. Al-
though further studies are needed, the existing literature What matters most to patients with chronic
suggests that they are important to consider from both illness is how well they are able to function and how
research and clinical perspectives. they feel about their day-to-day lives. Whether their

Abbreviations used in this paper: FGID, functional gastrointestinal

his review has been developed to discuss important
T variables that have been largely overlooked in the
study of functional gastrointestinal disorders (FGID),
disorder; HRQol, health-related quality of life; IBS-C, constipation-pre-
dominant irritable bowel syndrome; IBS-D, diarrhea-predominant irri-
table bowel syndrome.
© 2006 by the American Gastroenterological Association
namely gender, age, society, culture, and the patient’s 0016-5085/06/$32.00
perspective. These variables should be included in the doi:10.1053/j.gastro.2005.09.071
1436 CHANG ET AL GASTROENTEROLOGY Vol. 130, No. 5

symptoms are mild or severe, persons with IBS repeat- is integral to coping with chronic IBS in daily life.5
edly experience unpredictable symptoms of discomfort Empowerment provides the patient with a framework in
or pain and altered bowel habits, accompanied by which to understand and legitimize the symptoms, re-
emotional distress over the lack of control of symp- move self-doubt or blame, and identify internal or ex-
toms. Two IBS patient surveys, one qualitative2 and ternal factors that may contribute to symptoms that the
the other quantitative,3 demonstrated that symptoms patient can influence or control within the context of his
caused major interferences in daily life. Personal sac- or her own experiences.6 Although the term patient–
rifices were common as individuals struggled to ac- physician is used, it refers to all health care providers.
commodate symptoms. Anticipation and worry over
when and where the next symptom episode would
occur imposed limitations on planning and daily life.
Gender
Frustration, isolation, and a perceived lack of valida- Sex, Gender, and Gender Role
tion for the disorder were also considered major prob- Sex is generally used to refer to a person’s biolog-
lems. Patients reported high health care utilization. ical femaleness or maleness. Gender is generally used to
Yet less than one third reported satisfaction with the refer to the nonbiological aspects of being female or
drugs and remedies they were using to treat their male, in other words, the social or cultural expectations
symptoms. In another study conducted in IBS patients associated with femininity or masculinity.10 However,
belonging to a health maintenance organization, over- we know that most differences between males and fe-
all 57% of patients reported satisfactory relief of their males are a function of the interaction between biology
bowel symptoms after 6 months of usual medical care,
and environment. In this review, gender is used as a more
which included education, dietary and lifestyle advice,
inclusive term. Sex is used for the classification of indi-
and medications. However, only 22% reported that
viduals based on their reproductive organs and functions
symptom severity was reduced by half.4
assigned by chromosomal complement. Gender roles are
The Patient–Physician Encounter based on sex stereotypes, which are socially shared beliefs
that biological sex determines certain qualities.10
The patient–physician encounter in IBS is chal-
lenging and often frustrating to both parties. Patients Gender and Epidemiology
who seek diagnosis and treatment often report an
unsatisfactory or unhelpful experience with health care Symptoms of FGID are quite prevalent in the
professionals. Physicians share frustration with the community. The effects of sex on the prevalences of
patients over the poorly understood nature of IBS as a FGID are summarized in Table 1. The majority of FGID
disease, as well as lack of treatments.5 To the patient, are more prevalent in women than men. Women are
unsatisfactory explanations may be experienced as a more likely to report globus, dysphagia, IBS, bloating,
denial of the legitimacy of their reported symptoms, constipation, chronic functional abdominal pain, sphinc-
an implication that negative test results imply an ter of Oddi dysfunction, fecal incontinence (at home),
absence of cause, and a lack of understanding or belief functional anorectal pain, and pelvic floor dysfunction.
in their suffering.6 Additional information on these FGID is provided in the
other articles. In one study, the prevalence of IBS in the
The Patient and Physician Working United States was equal between men and women,11
Together whereas the majority reported female-to-male ratios of
A strong physician–patient relationship is funda- 2–3:1.12,13 Increasing evidence from limited studies sup-
mental to successful management. Patients need con- ports similar prevalence rates for pain-related symptoms
vincing explanations about the diagnosis and nature of in IBS,14 but a greater female predominance in non–
their symptoms that encourages the view of IBS as a pain-associated symptoms of constipation, bloating, and
legitimate disorder for which a clear pathogenesis has not extraintestinal manifestations.15–18
yet been found.5– 8 They also need information about how Studies have demonstrated that functional esophageal
it will influence their ongoing daily lives.7 Physicians can and gastroduodenal disorders, including functional chest
help by eliciting and addressing patient concerns9; offer- pain, functional heartburn, dyspepsia, and functional
ing a positive diagnosis; providing clear, understandable, vomiting, do not vary by gender.12,19 However, female
and legitimizing explanations of the disorder; and help- gender has also been associated with delayed gastric
ing to identify factors within the context of the patient’s emptying20,21 and lower tolerance of the water-loading
own illness that they can influence and control. Self-care test in patients with functional dyspepsia.22
April 2006 PERSPECTIVES IN THE FUNCTIONAL GI DISORDERS 1437

Table 1. The Effect of Sex and Age on the Prevalence of in healthy men and women,27 but differences in pressure
FGID thresholds to pain were not found.27 Two other studies
FGID Effect of Sex Change With Age have compared colorectal distention in healthy women
Esophageal and men.28,29 In one study, women appeared to have
Globus F⬎M12,88 212,88,89 higher perceptual ratings (ie, increased perception) com-
Rumination F⫽M12 212,88,89
pared to men, but there were no significant differences
Functional chest F⫽M12,88,89 212,88,89
pain before or after a meal.28 The second study found that
Functional heartburn F⫽M88 ⫽12 healthy women had reduced perceptual responses to
Dysphagia F⬎M12,88 112 rectosigmoid stimuli compared to healthy men.29 No
Gastroduodenal
Dyspepsia F⫽M12,19 290–92 attempts to control for menstrual cycle were made in
Aerophagia M⬎F12,20 212,119 these studies.
Functional vomiting F⫽M19,90 219,90 Although there have been multiple studies that have
Biliary tract F12 112
Lower GI tract
shown enhanced visceral perception in a subgroup of
IBS F11,12 212,126 patients with FGID, including atypical chest pain,30
Functional F11,12,90,120,121 135,95,96 functional dyspepsia,31,32 and IBS,33–36 relative to
constipation
healthy control subjects, there are relatively few that
Functional diarrhea M⬎F11,12,90,120,121,122 290
Functional bloating Discordant12,123 Discordant12,123,127 have compared visceral perception in men and women
CFAP F⬎M12 212 with IBS. Two studies have demonstrated enhanced rec-
Fecal incontinence F⬎M (at home)124 112,94,98,99 tal perception (ie, decreased rectal thresholds) in women
M⬎F (nursing
homes)125 with IBS compared to men with IBS.29,37 A third study
Functional anorectal F⬎M12 212,100 measured duodenal perceptual thresholds to distention in
pain relatively small patient groups with functional dyspepsia
Outlet delay F100
alone, functional dyspepsia and IBS, IBS alone, and
Note. Some of the data in this table are based on single studies or healthy controls.38 Whereas the patient groups had sig-
multiple small-scale studies and should be taken with caution.
nificantly lower thresholds to first perception and then
CFAP, chronic functional abdominal pain; F, female; FGID, functional
gastrointestinal disorders; GI, gastrointestinal; IBS, irritable bowel pain (increased perception) compared to the control
syndrome; M, male. group, no significant differences between men and
women were found.
There appears to be an effect of female sex hormones
Although there is little evidence that symptoms of on rectal sensitivity in women with IBS, but not healthy
functional dyspepsia are influenced by menstrual cycle women. Rectal sensitivity was compared across the 4
phase or menopausal status, evidence supports that IBS phases of the menstrual cycle (menses, follicular phase,
symptoms are influenced by menstrual cycle, with an luteal phase, and premenstrual phase) in healthy women
amplification of symptoms during the late luteal and and women with IBS. In healthy female volunteers, no
early menses phases.23–25 Heitkemper et al25 recently differences were found in measures of rectal sensitivity,
found that GI symptoms tended to be elevated across all distention-induced rectal motility, and rectal compliance
cycle phases in women with IBS compared to healthy across the different phases of the menstrual cycle.39 In
women, but both groups demonstrated a similar increase contrast, perceptual thresholds were lower during menses
in severity immediately prior to or at the onset of men- compared to other menstrual cycle phases in women with
ses. IBS.
GI motility. Studies have demonstrated either
Gender and Biological Factors shorter40 – 43 or equivalent44,45 GI transit times in healthy
FGID are best viewed as biopsychosocial disorders men compared with healthy women. Two studies com-
with dysregulation of the brain– gut axis.26 This results pared colonic motility in healthy women and men.28,46 In
in alterations in visceral pain perception, autonomic one study using standard colonic motility and barostat
function, and central processing of visceral stimuli. Gen- testing, there were no gender differences in fasting,
der differences in these mechanisms have been evaluated postprandial frequency of contractions, motility index, or
primarily in IBS. compliance of the left colon.28 However, the second
Visceral pain perception. Studies in healthy men study utilized ambulatory 24-hour colonic manometry
and women have not supported an enhanced perception and demonstrated significantly less pressure activity in
to visceral stimuli in women relative to men. Two stud- the colon during daytime hours in women compared to
ies measured esophageal thresholds to balloon distention men.46 There was no attempt to control for phase of
1438 CHANG ET AL GASTROENTEROLOGY Vol. 130, No. 5

Table 2. Studies in FGID Reporting Gender Differences on Psychological Measures

Study Number (% women) FGID Criteria Findings
Corney and Stanton,17 42 (74%) IBS—Abdominal pain and Women reported more psychological distress
alteration in bowel habit and were more likely to have psychiatric
for 6 months diagnosis than men
Blewett et al,54 76 (66%) IBS—Manning criteria No difference in prevalence of psychiatric
disorder between men and women
Simren et al,15 343 (73%) IBS—Rome I Women ⬎ men for fatigue, depression, and
anxiety, differences more marked for
outpatients than primary care
Fock et al,56 43 (63%) IBS—Manning criteria 62% of women had psychiatric diagnoses
compared to 17% of women with organic
GI illness, but no difference between men
with IBS or organic disease
Lee et al,22 714 (67%) IBS—Rome I No difference in psychological symptoms
Blanchard et al,55 341 (70%) IBS—Rome I (retrospective) Women were more depressed and showed
greater trait anxiety than men. No
difference on state anxiety or percent of
patients with an Axis I psychiatric disorder
Westbrook et al,128 748 (54%) Dyspepsia—Rome I Women had poorer physical and mental well-
being than men

FGID, functional gastrointestinal disorder; GI, gastrointestinal; IBS, irritable bowel syndrome.

menstrual cycle in both of these studies. There are no to rectal distention, and women showed greater activa-
published nondrug studies comparing colonic motility in tion in the anterior cingulate and insular cortices, both
women and men with IBS. regions associated with greater sensory and affective re-
Comparison of anorectal function in 15 healthy men sponses to noxious stimuli.
(mean age, 41 ⫾ 3 years) and 20 women (mean age, 43 Only 2 neuroimaging studies have examined gender
⫾ 2 years, 5 nulliparous) was performed by Sun and differences in IBS.52,53 Naliboff et al53 found that men
Read.47 Healthy men had higher minimum and maxi- and women with IBS had significant differences in brain
mum basal anal sphincter pressures, higher anal pressures response to aversive pelvic visceral stimuli. Although
during maximum conscious sphincter contraction, lower both groups of patients showed activation of the expected
rectal volumes required to cause an anal relaxation, and pain regions, men with IBS showed greater activation of
higher volumes to induce a desire to defecate. In addi- the lateral prefrontal cortex, dorsal anterior cingulate
tion, significantly fewer men experienced pain during a cortex, and dorsal pons/periaqueductal gray, which may
1-minute 100-mL rectal distention (using syringe infla- be involved in endogenous pain inhibition, relative to
tion) compared to women (13% versus 55%). These women with IBS. In contrast, women with IBS showed
results suggest that healthy men have stronger anal greater activation of limbic and paralimbic regions, in-
sphincter pressures and that women have either lower cluding the amygdala, anterior cingulate cortex, and
rectal compliance or increased rectal sensitivity. infragenual cingulate cortex, which may be part of a
Cardioautonomic tone. Heart rate variability, pain-facilitation circuit, relative to men with IBS. These
which measures cardioautonomic tone, is becoming an findings suggest that men and women with IBS may
increasingly common noninvasive technique of assessing process aversive information originating from pelvic vis-
autonomic function. One study demonstrated that men cera differently.
with IBS have greater cardiosympathetic and lower car-
diovagal tone in response to rectosigmoid distention than Gender and Psychological Factors
women with IBS.48 Although there are many studies of psychological
Central processing of visceral stimuli. Proposed functioning in FGID, relatively few investigators have
alterations in central processing of visceral stimuli in examined gender differences. The majority of studies
FGID have been supported by recent findings in func- have included a psychological evaluation and have been
tional neuroimaging studies49,50; however, only a few carried out in the general hospital setting and in GI
studies have addressed gender differences in health and outpatient clinics. The ratio of women to men in these
GI disease. In a functional magnetic resonance imaging studies has varied from 1:1 to 4:1 (Table 2), although
study of healthy individuals, Kern et al51 found that men most have recruited a larger proportion of women than
showed activation in sensory and parieto-occipital areas men, and some investigators have chosen to exclusively
April 2006 PERSPECTIVES IN THE FUNCTIONAL GI DISORDERS 1439

study women. Thus, most studies have not been powered cial support, and social factors that have been assessed by
to undertake a comparative analysis of gender differences. quality-of-life scales.
In general, the findings of most studies suggest that Life stress. Several studies found that IBS pa-
patients with FGID who are seen in outpatient GI treat- tients report more lifetime and daily stressors compared
ment settings have high rates of a psychiatric disorder with medical control groups or healthy controls.58 – 64
and psychological distress (between 40% and 60%). In Stress has been found to be associated with both symp-
studies that have examined for gender differences in tom onset and severity,62,64 – 66 and to adversely affect
FGID, or reported on certain aspects of gender, relatively health status and clinical outcome in patients with
few studies have reported differences in psychological IBS.61,65,67 However, there are no studies to date that
symptom scores between men and women (Table 2). have assessed gender differences in life stress related to
Blewett et al54 and Lee et al23 found no difference in FGID.
psychological symptoms between men and women. Blan- History of sexual, physical, and emotional abuse.
chard et al55 found small differences between men and One form of social stress or oppression that has received
women in patients seeking psychological treatment for increased attention in the past decade in the study of
IBS using a psychological self-report measure, but no FGID is sexual, physical, or emotional abuse. However,
difference using a diagnostic interview. Two small stud- most work in this area has included only women.57 In the
ies, one from the United Kingdom and one from Singa- few studies investigating abuse histories that have in-
pore, have reported differences between men and women cluded men, significant differences are either not statis-
with IBS,17,56 with women reporting higher rates of tically reported or quantified owing to insufficient num-
psychological distress than men. In the former study, the bers of men in the sample. Two studies reported that
General Health Questionnaire was used, whereas the sexual abuse was more common in women with
study from Singapore used the Eysenck Personality FGID,68,69 but a third study found no gender differences
Questionnaire. Another study demonstrated that female in the history of sexual, physical, emotional, or verbal
hospital outpatients with IBS had a poorer health-related abuse.70 Clearly, further research is needed to determine
quality of life (HRQoL) and greater psychological dis- whether there are gender differences in history of abuse
tress on some HRQoL measures than female primary care in FGID.
Gender role socialization. One important social
patients, but this difference was not seen in men.15 Of
factor that impacts on health and well-being, which
note, some psychological tests have different norms for
begins in early life and continues throughout, is gender
men and women, and this could affect the interpretation
role socialization. The literature suggests that many of
of these studies.
the physical and mental health concerns experienced by
At present, there are relatively few studies that have
women are influenced by socialization into the female
examined gender differences in psychological symptoms
gender role. Despite postulated links between health
in FGID, and there is no convincing evidence of any
problems such as eating disorders, depression, anxiety
major differences between men and women with FGID.
disorders, and functional somatic disorders (including
Those differences that have been reported are most likely
FGID), there have been few empirical investigations.
to reflect the differences between men and women in the
Toner et al71 identified several common gender role
general population, in relation to psychological symptom
concerns or themes that have been highly salient and
reporting, rather than any specific gut-related phenom- meaningful to women with FGID.
enon. Shame and bodily functions. One central theme is
that women with IBS commonly report feelings of shame
Gender and Social Factors
associated with losing control of bodily functions.
It is important to acknowledge that health and Women are taught that bodily functions are something
illness, including FGID, occur within a larger social to be kept private and secret as compared to men. One
context. Although there have been many studies evalu- important implication of such teachings is that for
ating the role of stress and abuse in FGID, there has been women, bowel functioning becomes a source of shame
relatively little effort to date directed toward identifying and embarrassment more so than it does for men.72
other social factors that have been associated with Bloating and physical appearance. Women often
FGID.57 The few social determinants that have been score higher on indices of bloating and constipation.
investigated in FGID include life stressors (including Society’s focus on how women look, and its perpetuation
history of sexual, physical, and emotional abuse), early of thinness as a necessary standard of attractiveness,62,63
life experiences (including gender role socialization), so- may lead women to experience bloating not only as a
1440 CHANG ET AL GASTROENTEROLOGY Vol. 130, No. 5

source of physical discomfort, but of psychological dis- patterns to cognitive– behavioral treatments for IBS, but
tress (eg, worry and shame) as well. The physical and the studies were not powered to detect gender differ-
psychological distress that women may experience with ences. Guthrie et al77 reported advantages for women in
abdominal discomfort, coupled with the perception that response to therapy compared to men, but in a predictor
their pain is being minimized or trivialized by health analysis, gender was not selected into the final model.
care professionals, may lead women to respond by be- A recent large evaluation of hypnotherapy, carried out
coming more hypervigilant to any sign of pain or in Manchester, United Kingdom, has reported different
discomfort. response patterns for men and women. The study was not
Pleasing others, assertion, and anger. Women, as a randomized controlled trial, but a before and after
compared with men, are socialized to please others, often evaluation of 250 patients with IBS (50 men and 200
at the expense of their own needs.72,73 This may contrib- women). Although most patients had a good treatment
ute to women’s higher rates of doctor visits and multiple response to hypnotherapy, there was greater overall im-
consultations, in that patients who believe that their provement in women compared to men (52% in women
physician does not understand their experience may seek and 33% in men, P ⬍ .001). The poor response with
help elsewhere, rather than show displeasure with their men was largely seen in those with diarrhea-predominant
current physician. Women who express anger, make IBS (IBS-D; 20% improvement), whereas men with con-
demands, or question authority are often given the label stipation-predominant IBS (IBS-C) appeared to have a
“hysteric,” have their complaints dismissed, or have their good response to hypnotherapy (78% improvement), but
femininity called into question.72 These potential reper- the numbers in this group were very small (n ⫽ 8). For
cussions for women who express their own wants and women, the equivalent response rates were 53% im-
needs are often sufficient to keep women silent. One provement for those with IBS-D and 55% for those with
study found that women with IBS score higher on mea- IBS-C. Further work by Gonsalkorale et al78 has shown
sures of self-silencing than patients with inflammatory that men have a poorer long-term outcome following
bowel disease.74 hypnotherapy than women (42% versus 25%).
HRQoL. Several studies have found that patients Pharmacologic treatment. There is evidence to
with IBS and functional dyspepsia have impaired suggest that gender-related differences may exist with
HRQoL compared with other chronic conditions. Few respect to response to pharmacologic therapy, although
studies have investigated whether women and men with relatively small numbers of men have been studied com-
FGID differ on HRQoL measures. In a study of referral pared with women. Alosetron is a 5-HT3 antagonist
center and primary care patients, Simren et al15 found currently indicated only for women with severe, chronic
that women with IBS reported a lower HRQoL compared IBS-D who have failed conventional therapy. An initial
to men with IBS. In another study, Lee et al23 also found dose-ranging study demonstrated a significant improve-
that women with IBS reported lower HRQoL scores; ment in the multiple symptoms of IBS-D in women, but
however, after they controlled for gender differences in not men.79 However, a subsequent male-only study with
the general population, most of the gender effects disap- alosetron showed significant improvement of IBS pain,
peared. The only remaining gender effect was greater discomfort, and stool consistency, but not of the other
bodily pain scores in women with IBS. Dancey et al75 symptoms of IBS.80
found that IBS symptom severity exerted a significant Cilansetron is a novel 5-HT3 receptor antagonist that
impact on quality of life in women. For men, the psy- has been shown to be efficacious in treating the symp-
chosocial impact of illness intrusiveness was greater in toms of IBS-D in men and women.81– 83 Analyses by
every domain except sexual relations. The authors sug- gender demonstrated that although there was an overall
gest that these results have implications for how gender marked significant improvement in men, the treatment
socialization shapes sex differences in the wider experi- difference for men was smaller relative to women.
ence of IBS. Several studies have suggested that there may also be
a preference of the 5-HT4 agonist, tegaserod, for efficacy
Gender and Treatment Response in women compared with men with IBS-C.84 – 86 Because
Psychological treatment. Psychological treatment of the small numbers of men in these studies, it was not
studies have not been powered to examine different possible to make any conclusions concerning the efficacy
response patterns between men and women, and many of tegaserod in men, although there was an up to 10%
studies have recruited more women than men, reflecting therapeutic gain noted that was not statistically signifi-
gender differences in health treatment settings. Blan- cant.86 However, tegaserod has been recently approved
chard et al55 and Corney76 reported similar response by the US Food and Drug Administration for the treat-
April 2006 PERSPECTIVES IN THE FUNCTIONAL GI DISORDERS 1441

ment of chronic constipation in women and men under problems are treated as “not real” and due to a psycho-
the age of 65.87 Although tegaserod was shown to be logical or moral defect or weakness.101 It is often con-
efficacious in both women and men with chronic consti- trasted with organic disease and thought to be less
pation, the efficacy in women appeared to be more robust legitimate or real.
than in men. Several societal myths associated with FGID, in par-
Although there is no definitive evidence to suggest ticular IBS, persist today: symptoms are trivial or unim-
that men and women have a differential response to portant; symptoms are all in the person’s head; IBS is
psychological and pharmacologic treatments, women simply caused by stress; IBS is a psychiatric disorder;
with FGID appear to respond well to psychological nothing can help persons with IBS; if pain is severe, there
treatment and the newer serotonergic agents, such as must be an organic cause; patients with IBS may “ben-
5-HT3 antagonists and 5-HT4 agonists, but the response efit” from the “sick role”; and people with IBS are
in men seems to be less robust than in women. However, difficult patients.102 Society mistakenly feels that people
most studies have been insufficiently powered to deter- with IBS are malingerers and hold negative attitudes.103
mine whether there are different response patterns for Negative social labels75 can affect self-esteem and self-
men and women, and further study is required. efficacy (belief in one’s own ability to cope with situa-
tions)104 and lead individuals with FGID to hide their
Age condition and restrict life experiences including leisure,
travel, diet, employment, social life, and sex life.105
In regard to the functional esophageal disorders,
In summary, a multitude of social factors may impact
the prevalence of most of these disorders decreases with
the meaning, expression, and course of illnesses. Al-
age (Table 1). Specifically, globus, rumination syndrome,
though some of these factors are evidence based, others
and self-reported functional chest pain are all more com-
are speculations. These factors are applicable not only to
mon in younger people.12,88,89 The prevalence of heart-
FGID, but to functional syndromes in general, and are
burn overall is similar among people ages 25–74.88 The
often overlooked by health care providers. Acknowledg-
prevalence of dysphagia in one study increased with age,
ing and incorporating them into clinical practice will
most notably in participants in the 65- to 74-year-old
increase the quality of patient care, patient–physician
category.88
relationship, and health outcomes.
Some studies have suggested that the prevalence of
dyspepsia decreases with age.90 –92 The distribution of
subtypes of functional dyspepsia (ulcer-like and dysmo- Culture
tility-like) does not vary by age. Young people are Culture is the values, beliefs, norms, and practices
slightly more likely to report aerophagia than older of a particular group that are learned and shared and that
people. Vomiting decreases with age.19,90 guide thinking, decisions, and actions in a patterned
In general, the prevalence of IBS gradually decreases way.106 Culture-related factors can affect the type of
with age.12,18 However, among the elderly, the preva- health care and health outcomes.
lence of IBS was found to increase with age from 8%
among those 65–74 years old to ⬎12% for those ⱖ85.93 The Clinical Perspective
Although the prevalence of chronic constipation has
Patients have explanatory models, which are
been shown to increase with advancing age,94 –96 one
symptom- or disease-related beliefs that affect their con-
study found that it affects the young and elderly with
cerns, anxieties, and expectations from the health care
similar frequency.97 Functional diarrhea90 and chronic
process.107,108 Cultural background, socioeconomic sta-
functional abdominal pain appear to decrease with age.12
tus, educational level, and gender interact in the devel-
Fecal incontinence has been extensively studied and in-
opment of explanatory models.109 It is important to elicit
creases with age.12,94,98,99 Functional anorectal pain has
the patient’s explanatory model, understand the cultural
decreasing rates with age.12 The prevalence of rectal
background in which it developed, and negotiate a cul-
outlet delay does not vary by age.100
turally appropriate treatment partnership.110
Some population subgroups are more likely to receive
Society suboptimal health care than others.6 Many individuals in
In spite of our growing understanding of so-called cultural subgroups do not have health literacy skills,111
functional somatic disorders in general, and disorders particularly in a second language, and have difficulty
associated with FGID, the stigma associated with a func- understanding diagnoses, discharge instructions, and
tional disorder may lead patients to believe that their treatment recommendations.112,113
1442 CHANG ET AL GASTROENTEROLOGY Vol. 130, No. 5

Cultural competence is the ability of medical staff and swered questions concerning gender, age, society, cul-
health care professionals to function under cross-cultural ture, and the patient’s perspective in FGID. Because of
circumstances. All physician–patient encounters have the the female predominance and greater likelihood of
potential for cross-cultural misunderstanding including women to participate in research studies, there are insuf-
differing attitudes to authority, physical contact, com- ficient numbers of male participants to make meaningful
munication style, gender, sexuality, and family.110 interpretations and adequately assess gender differences
in psychological, physiological, and treatment studies.
The Research Perspective
Another major methodologic concern is that most stud-
Cross-cultural research competence describes the ies have involved a cross-sectional design, which limits
skill required to conduct research involving subgroups of the more comprehensive understanding of the pathogen-
differing cultural backgrounds, including a culturally esis, development, course, and impact of these disorders
appropriate research protocol and culturally suitable in men and women.
study instruments appropriately translated into and val-
idated in other languages.114,115 Conclusion and Future Directions
Cross-Cultural Studies of GI Disorders of This review examined the literature regarding the
Function relationship between gender, age, society, culture, and
The majority of published studies on IBS are FGID. Important factors pertaining to FGID that were
ethnocentric with predominantly Western, white popu- emphasized include (1) the importance of the patient’s
lations. However, some studies have focused on other experience and perspective; (2) the influence of society,
populations. Zuckerman et al111,116 conducted a compar- culture, gender, and age on all aspects of the individual’s
ative study of IBS between Hispanic and non-Hispanic experience; (3) the influential role of an individual’s sex
whites in Texas. The difference between the 2 groups in on the biologic and physiologic processes of brain– gut
IBS prevalence was not statistically significant after the interactions; and (4) the potential of the health care
investigators controlled for gender, age, socioeconomic provider in influencing patient outcome.
status, diet, and laxative use. Hispanics tended to self- To advance the field of FGID, the following are sug-
medicate more than non-Hispanic whites, using folk gested.
remedies for relief of their bowel problems, and had a
From a Research Perspective
poorer perception of their general health condition.117
The investigators concluded that ethnicity determines, 1. Studies to identify positive aspects of patient–pro-
in part, the perception of health and bowel function and vider interactions that improve outcome should be
affects health care behavior.111 performed and include recognition of the patient’s
A recently published study compared rates of IBS perspective, cultural and gender sensitivity, and im-
between Israeli Bedouins still living under rural condi- plementation into patient care programs.
tions with those who made a stressful transition to 2. Studies using quantitative and qualitative methods
permanent towns.118 The prevalence of IBS among Be- are needed to better understand the patient’s illness
douins who resettled in permanent towns was found to experience and his or her views of the health care
be significantly higher than those still living in tradi- system.
tional rural settings. Although these differences may be 3. Studies of varied populations around the world should
related to the stress of the transition, other possible be performed with appropriate tools to measure cul-
explanations include changes in nutrition and other life- tural and societal influences.
style variables. 4. Studies evaluating sufficient numbers of men with
In summary, recognition and understanding of the IBS, and also making comparisons between healthy
association between culture and health are important for men and women, are needed to determine if gender
patient care and research. To integrate this awareness differences in FGID are disease specific.
into clinical practice and research, clinical cultural com-
petence and cross-cultural research competence should be From a Clinical Practice Perspective
fostered. 1. Recognize that FGID patients view their conditions as
illnesses associated with uncertainty, stigma, and social
Methodologic Issues in FGID isolation. Physicians can help patients to manage their
Because of methodologic issues, which have lim- condition by eliciting and addressing patient concerns;
ited interpretation of studies, there remain many unan- offering a positive diagnosis; providing clear, under-
April 2006 PERSPECTIVES IN THE FUNCTIONAL GI DISORDERS 1443

standable, and legitimizing explanations of the disorder; gastrointestinal disorders. Prevalence, sociodemography, and
health impact. Dig Dis Sci 1993;38:1569 –1580.
and helping identify factors within the context of the
13. Sandler RS. Epidemiology of irritable bowel syndrome in the
patient’s own illness that he or she can influence and United States. Gastroenterology 1990;99:409 – 415.
control. 14. Taub E, Cuevas JL, Cook EW III, Crowell M, Whitehead WE.
2. There are a number of sex- and gender-related factors Irritable bowel syndrome defined by factor analysis. Gender and
race comparisons. Dig Dis Sci 1995;40:2647–2655.
that may impact the clinical symptoms and response
15. Simren M, Abrahamsson H, Svedlund J, Bjornsson ES. Quality of
to treatment of IBS and should be considered, for life in patients with irritable bowel syndrome seen in referral
example, gender role, sociocultural differences, hor- centers versus primary care: the impact of gender and predom-
monal effects such as menstrual cycle variation, and inant bowel pattern. Scand J Gastroenterol 2001;36:545–552.
16. Talley NJ, Boyce P, Jones M. Identification of distinct upper and
biological differences influencing gut function and lower gastrointestinal symptom groupings in an urban popula-
treatment response. tion. Gut 1998;42:690 – 695.
3. Both men and women in clinical settings have psy- 17. Corney RH, Stanton R. Physical symptom severity, psychological
chological issues that may need to be addressed and and social dysfunction in a series of outpatients with irritable
bowel syndrome. J Psychosom Res 1990;34:483– 491.
there is a possibility that men may not do as well with 18. Talley NJ, Zinsmeister AR, Melton LJ III. Irritable bowel syndrome
psychological treatment as women. in a community: symptom subgroups, risk factors, and health
4. Recognition and understanding of the association be- care utilization. Am J Epidemiol 1995;142:76 – 83.
tween culture and health are also important for pa- 19. Talley NJ, Zinsmeister AR, Schleck CD, Melton LJ III. Dyspepsia
and dyspepsia subgroups: a population-based study. Gastroen-
tient care. It may be helpful to discuss with patients terology 1992;102:1259 –1268.
any cultural issues that may impact their clinical 20. Talley NJ, Verlinden M, Jones M. Can symptoms discriminate
presentation or management of their condition. In among those with delayed or normal gastric emptying in dysmo-
addition, medical training and continuing medical tility-like dyspepsia? Am J Gastroenterol 2001;96:1422–1428.
21. Stanghellini V, Tosetti C, Paternic A, Barbara G, Morselli-Labate
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Abu-Rashid M, Abeldour K, Alkranawi O, Eisenberg A, Kazanovis
A, Mazingar L, Fich A. Rates of functional bowel disorders Received July 28, 2005. Accepted September 14, 2005.
among Israeli Bedouins in rural areas compared to those who Address requests for reprints to: Lin Chang, MD, Center for Neuro-
moved to permanent towns. Clin Gastroenterol Hepatol 2005; visceral Sciences and Women’s Health, CURE: Digestive Diseases
3:342–348. Research Center, UCLA Division of Digestive Diseases, VAGLAHS,
119. Frexinos J, Denis P, Allemand H, Allouche S, Los F, Bonnelye G. 11301 Wilshire Boulevard, Building 115, Room 223, Los Angeles,
[Descriptive study of digestive functional symptoms in the California 90073. e-mail: [email protected]; fax: (310) 794-2864.
 GASTROENTEROLOGY 2006;130:1447–1458

Psychosocial Aspects of the Functional Gastrointestinal

Disorders

RONA L. LEVY,* KEVIN W. OLDEN,‡ BRUCE D. NALIBOFF,§ LAURENCE A. BRADLEY,储

CARLOS FRANCISCONI,¶ DOUGLAS A. DROSSMAN,** and FRANCIS CREED‡‡
*University of Washington, Seattle, Washington; ‡University of South Alabama, Mobile, Alabama; §University of California at Los Angeles,
Los Angeles, California; 储University of Alabama at Birmingham, Birmingham, Alabama; ¶Hospital de Clinicas de Porto, Porto Alegre, Brazil;
**University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and ‡‡University of Manchester, Manchester, England

This report reviews recent research on the psychosocial The biopsychosocial model provides the conceptual
aspects of the functional gastrointestinal disorders basis of this report (Figure 1). Early life experiences,
(FGIDs). A review and evaluation of existing literature adult stressors (eg, divorce or bereavement), social sup-
was conducted by a multidisciplinary committee of ex- port, and other social learning experiences affect both an
perts in this field. This report is a synopsis of a chapter individual’s physiologic and psychological responses, in-
published in the Rome III book. The committee reached
cluding distress, psychiatric disorders, and beliefs and
consensus in finding considerable evidence supporting
coping strategies. The gut responds to environmental
the association between psychological distress, child-
hood trauma and recent environmental stress, and sev- and physiology factors, but it also interacts directly with
eral of the FGIDs but noted that this association is not the brain, thereby providing 2-way interactions along
specific to FGIDs. There is also considerable evidence the “brain-gut” axis (central nervous system/enteric ner-
that psychosocial variables are important determinants vous system connections; see the neurogastroenterology
of the outcomes of global well-being, health-related report in this supplement). Genetic factors can have
quality of life, and health care seeking. In line with these direct physiologic effects, and the genetic makeup of an
descriptive findings, there is now increasing evidence individual can also make him or her more susceptible to
that a number of psychological treatments and antide- environmental or social factors, thus leading to changes
pressants are helpful in reducing symptoms and other in physiology.
consequences of the FGIDs in children and adults. The Therefore, while not specific to the FGIDs, psycho-
FGIDs are a result of complex interactions between
logical and social influences can affect the perception of
biological, psychological, and social factors, and they
symptoms, health care–seeking behaviors, and outcomes
can only be treated satisfactorily when all these factors
are considered and addressed. Therefore, knowledge in patients with FGIDs. These psychosocial influences
about the psychosocial aspects of FGIDs is fundamental affect gut function, the experience of pain, health-related
and critical to the understanding, assessment, and treat- quality of life, work absenteeism, health care use, and
ment of these disorders. More extensive physician train- medical and societal costs. This report provides recent
ing is needed if these aspects of treatment are to be evidence of these interactions and explores the mecha-
used effectively and widely in clinical practice. nisms by which this biopsychosocial approach affects the
illness experience and clinical outcome of patients with
FGIDs. The report also discusses ways to apply this more
nowledge about the psychosocial aspects of the
K functional gastrointestinal disorders (FGIDs) is
fundamental and critical to the understanding of the
integrated approach in clinical practice.

FGIDs and their effective treatment. Because physicians Genetics and Childhood Learning
are traditionally trained to look for pathophysiologic There is substantial evidence of family aggrega-
explanations of observed phenomena, they may feel un- tion of irritable bowel syndrome (IBS) and related dis-
certain when faced with syndromes such as the FGIDs,
chronic fatigue syndrome, and fibromyalgia, which can- Abbreviations used in this paper: CBT, cognitive-behavioral therapy;
not be explained in this manner. The FGIDs do not fit a FGID, functional gastrointestinal disorder; GI, gastrointestinal; IBS,
simple pathophysiologic model. Rather, they result from irritable bowel syndrome; SNRI, serotonin-norepinephrine reuptake
complex interactions of biological, psychological, and inhibitor; SSRI, selective serotonin reuptake inhibitor.
© 2006 by the American Gastroenterological Association Institute
social factors, and this report provides an up-to-date 0016-5085/06/$32.00
synthesis of current research in the area. doi:10.1053/j.gastro.2005.11.057
1448 LEVY ET AL GASTROENTEROLOGY Vol. 130, No. 5

episodes of pain over a 3-month period that affect the

child’s activities11). Preliminary research has shown that
when parents of children with recurrent abdominal pain
are taught to reduce positive or sympathetic responses to
their children’s reports of pain, the frequency of these
complaints decreases.12

Environmental Stress in Childhood

and Adult Life
Abuse History
High frequency rates of sexual, physical, and emo-
tional abuse in patients with FGIDs (30%–56%) have
been reported from many different referral centers in the
United States and Europe,13–17 especially in specialist or
secondary care clinics,18,19 and these figures are signifi-
Figure 1. Conceptual model illustrating the relationships among psy- cantly higher than those in healthy control groups. A
chological and environmental factors, physiologic variables, and out-
come of FGIDs.
similar high rate of abuse history is also found in non-GI
painful conditions (eg, pelvic pain, headaches, fibromy-
algia).
orders, which reflects genetic and environmental influ- Most, but not all, national probability studies have
ences.1 One study has found that a polymorphism in the shown that abuse is associated with increased risk of
serotonin reuptake transporter (SERT) gene that is asso- abdominal pain and FGIDs.20 –22 Compared with those
ciated with fibromyalgia2,3 and affective or anxiety dis- without such a history, patients with FGIDs with abuse
orders is also associated with diarrhea-predominant IBS,4 histories report more severe pain, greater psychological
although negative findings regarding this relationship distress, greater impairment of functioning in their daily
also have been reported.5 Additional association studies lives, and more frequent visits to the doctor.23–26 Certain
regarding polymorphisms in SERT and similar genes (eg, types of abuse, such as rape, repeated or multiple abuses,
the enzyme catechol-O-methyltransferase6) may clarify and life-threatening physical abuse, are more likely to
the possible influence of genetic factors on the develop- produce marked symptom severity, disability, and other
ment of functional bowel disorders. In addition, children adverse health outcomes than other forms of abuse.27 In
learn behaviors from their parents who have FGIDs, and a rare study that examined the relationship between
this learning appears to make an even stronger contri- posttraumatic stress disorder and IBS, Irwin et al found
bution to the risk of developing an FGID than genetic
44% of 50 consecutive patients with IBS reported a
influences.7
trauma history and 36% were diagnosed with posttrau-
A number of social learning phenomena can influence
matic stress disorder.28
the clinical expression of abdominal pain, including
Possible mechanisms. Possible mechanisms
modeling (ie, where children observe and learn to display
mediating the association between abuse history and
the illness behavior of their parents) and positive rein-
forcement. Children of adult patients with IBS make poor outcome include (1) concurrent psychiatric dis-
more health care visits than the children of parents orders, moderate levels of psychological distress, and
without IBS, and this increased medical help seeking is the tendency to report a large number of bodily symp-
not confined to gastrointestinal (GI) symptoms.8 Retro- toms29 –32; (2) altered appraisal of bodily symptoms
spective and prospective studies have shown that chil- (ie, increased hypervigilance to normal bodily sensa-
dren whose mothers reinforce illness behaviors experience tions) and maladaptive coping styles (eg, “catastroph-
more severe stomachaches and miss more school than izing,” feelings of helplessness or inability to control
other children.9,10 Additional research supporting this symptoms)25,33,34; (3) impaired adult relationships
mechanism comes from studies of children with recur- (lack of social support)35; (4) centrally lowered thresh-
rent abdominal pain (a child is considered to have recur- old for perceiving afferent GI signals; and (5) in-
rent abdominal pain when, in the absence of physical or creased autonomic function and/or intestinal motility
laboratory findings, he or she has experienced at least 3 due to hyperarousal.23,36
April 2006 PSYCHOSOCIAL ASPECTS 1449

Stressful Life Events itant psychiatric diagnosis may also manifest alterations
Stressful life events are associated with symptom in gut-related autonomic nervous system function, af-
exacerbation among adults with IBS37 and heartburn38 fecting gut motility and sensation. Psychiatric disorders
and children with recurrent abdominal pain and are also may directly impair health-related quality of life.30,48
associated with frequent health care seeking for patients
with IBS.37,39 Chronic life stress has been found to be the Psychophysiology: Affect and
main predictor of IBS symptom intensity over 16 Stress Modulation of GI Function
months, even after adjusting for IBS symptom severity,
Environmental stressors and related changes in
anxiety, and demographic features.40 These data indicate
mood alter the function of the GI tract and GI symptom
a direct relationship between stress and outcomes in
perception in persons with GI diseases such as gastro-
patients with FGIDs and show that this relationship can
esophageal reflux disease and those with FGIDs. The
be mediated by psychiatric disorders.
relationship of stressors to GI function is viewed as a
direct consequence of the bidirectional modulation of GI
Psychological States and Traits function by the central nervous system, including motor
Patients with IBS, like many other medical patient responses, pain modulation, and even immune func-
groups, experience levels of depression and anxiety interme- tion.49 –51 These interactive relationships are important
diate between groups of psychiatric patients and healthy for FGIDs in that they provide the foundation for hy-
controls.41 There is also an increased prevalence (40%– potheses of central nervous system dysregulation as caus-
60%) of psychiatric disorders in clinic patients with some ative in FGID symptom onset and maintenance.50,52,53
FGIDs (notably IBS) compared with healthy controls Patients with IBS may show exaggerated motility to
(⬍20%) and patients with similar abdominal symptoms psychological stress, balloon distention, eating, and in-
that can be explained by underlying organic GI disease jection of cholecystokinin.54 –56 Such contractions are
(⬍25%).42 The most common disorders are anxiety, depres- principally nonperistaltic (but can also be propulsive)
sive, panic, posttraumatic stress, and somatization disorders. contractions that could contribute to IBS symptoms by
These disorders frequently precede or occur simultaneously retarding (or accelerating) the movement of gas and stool
with the FGID, indicating that the psychiatric disorder or by more direct pain mechanisms. Laboratory stressors
cannot always be regarded as a response to the FGID. also produce increased smooth muscle tone in the rec-
The self-reporting of numerous bodily symptoms (so- tum, which has been associated with IBS.57 However, a
matization) is a common phenomenon among clinic pa- critical role for motility disturbance in producing symp-
tients with FGIDs and in population-based studies of toms in a majority of patients with IBS has not been
FGIDs.43 Recent work suggests there is a separate di- clearly shown.
mension of somatic distress that may be partly geneti- Although the literature on autonomic nervous system
cally determined and that also overlaps with anxiety and function suggests that abnormalities exist among pa-
depression.44 Although seen less commonly, some pa- tients with FGIDs,58 the prevalence of these abnormali-
tients experience numerous bodily symptoms that have ties and their role in the pathophysiology of functional
been present for many years and are associated with symptom generation or exacerbation are unclear. Most
marked disability. This picture is recognized in the studies are of small samples with mixed symptom fea-
psychiatric literature as “somatization disorder” and is tures and poor control of potentially confounding vari-
overrepresented in specialist clinics.45 ables, such as menstrual cycle in women, psychological
Children with recurrent abdominal pain also have higher status, and comorbid conditions. Cardiovascular auto-
levels of anxiety and depression than healthy children, and nomic nervous system measures used in these studies
levels of anxiety and depression are often related to the may not be sensitive markers for GI autonomic nervous
duration of symptoms in these children.46 Depressed chil- system function; pancreatic polypeptide levels (ie, ab-
dren with recurrent abdominal pain report numerous bodily dominal vagal activation) and mucosal blood flow may
symptoms in response to daily stressors, suggesting that provide better measures.
stress reactivity is important in these children.39
Possible Mechanisms
Possible Mechanisms A variety of neuroendocrine pathways have been
Psychiatric disorders are associated with alter- implicated in stress-induced alterations in GI func-
ations in the processing of visceral sensation in patients tion.53,59 Activation of central nervous system circuits
with FGIDs.47 Patients with FGIDs who have a concom- that include the emotional motor system lead to neu-
1450 LEVY ET AL GASTROENTEROLOGY Vol. 130, No. 5

roendocrine responses such as the release of corticotro- FGIDs, we suggest that physicians include a brief psy-
phin-releasing factor, cortisol, and norepinephrine and chosocial assessment of each patient with FGID. A more
epinephrine. There is a positive correlation between sub- in-depth psychosocial assessment, often performed by a
jective sleep disturbances and GI symptoms, but whether psychologist or a psychiatrist, is particularly useful for
this is purely a secondary phenomenon is not clear.60 patients with severe symptoms, previous treatment fail-
ure, poor adherence to a treatment regimen, and evidence
Outcomes Influenced by of poor coping with illness. Standardized self-report mea-
Psychological Factors sures are more likely to be used under these circum-
stances.
Health-Related Quality of Life Whether brief or in depth, the assessment should
It is well recognized that patients with IBS and include the following areas (suggested screening instru-
other FGIDs experience considerable impairment of ments are included for each): (1) depression and anxiety
health-related quality of life.61,62 Several recent studies (including potential red flags, see Figure 2) (Hospital
have shown that only some of this impairment can be Anxiety and Depression Scale73), (2) somatization (the
accounted for by the symptoms of FGIDs; psychological general tendency to report numerous bodily symptoms)
factors have a major and unique negative impact on (Patient Health Questionnaire74), (3) health beliefs and
health-related quality of life that can be reversible with coping (Cognitive Strategies Questionnaire–Catastophiz-
appropriate psychological treatment.30,48,63– 65 ing or Visceral Sensitivity Index),75,76 (4) illness impact
and health-related quality of life (IBS-Quality of Life),77
Health Care Seeking and (5) exploration of the chronological “coincidences”
The factors differentiating patients with IBS who between psychosocial factors and periods of worsening or
seek medical help from those people in the community improvement of symptoms. For screening purposes, the
with IBS symptoms who do not consult (IBS noncon- Hospital Anxiety and Depression Scale for mood and
sulters) can be explained by the biopsychosocial model. Patient Health Questionnaire 15 to assess somatization
These factors include greater pain severity, greater dura- would probably be satisfactory. Assessment of psychoso-
tion of pain, increased concern about illness, greater cial factors is facilitated if the physician interviews the
anxiety and depression, and seeing the disorder as unre- patient in a confidential venue, explains the routine
lated to stress.26,66 – 68 Some patients with FGIDs make nature of the questions, and is prepared to discuss the
very frequent visits to physicians for GI and non-GI findings, including their clinical relevance.
symptoms and have increased hospitalizations and sur- Success in treating patients with FGIDs does not only
gical procedures.24 In a UK study comparing patients involve assessing the patient’s psychological and social
with IBS and control subjects, attendance at primary care status; an effective physician-patient relationship should
was increased by 43%, prescriptions were increased by be developed in which questions arise and information is
85%, and gastroenterology appointments were increased passed from the physician to the patient and vice versa.
by 68% in the IBS group.61 These data are comparable to The physician should adopt an active listening approach
other studies,69 but the costs are highly skewed. Half of and an enthusiastic, positive, and encouraging attitude
a population-based sample of patients with IBS incur
with regard to treatment. The most successful approach
costs comparable to the general population, and 14%
is likely to be a patient-centered one, in which the
incur costs 5 times that of the general population70; the
physician elicits and addresses the patient’s concerns such
latter is comparable to patients with severe IBS seen in a
as fears of cancer.
gastroenterology clinic.31 This high health care use is
The physician may find it helpful to predict negative
partly attributable to psychosocial factors such as depres-
results to investigations, when this seems likely, as a first
sion and somatization in addition to symptoms related to
the FGID itself48,71 and may be reduced by at least 25% step away from regarding organic disease as the cause of
following psychological treatment.72 the symptoms. The physician should be prepared to
address psychosocial issues directly. This may involve
prescription of an antidepressant or similar drug and
Assessment to Be Performed by possibly referring the patient to a mental health profes-
Physicians sional. This approach should help the patient to adopt an
In view of the importance of physiologic, social, appropriate way of coping with the symptoms rather
and psychological factors in determining outcomes of the than expecting a complete cure from medication.
April 2006 PSYCHOSOCIAL ASPECTS 1451

Figure 2. Treatment algorithm for patients with FGIDs. “Red Flags” are indications for consideration of early referral to a mental health
professional. TCA, tricyclic antidepressant.

Overview of Psychological been shown to often have distortions about their symp-
Treatment Approaches toms,79 CBT may be particularly valuable for these pa-
tients because it may help patients recognize how par-
Psychological treatments are often appropriate for
ticular beliefs about symptoms may help perpetuate pain
patients with FGIDs because of the psychosocial factors
listed in the previous sections (see Lackner for meta- and pain-related activities. Relaxation/stress manage-
analytic review).78 In clinical practice, 2 or more forms of ment is often incorporated into CBT packages because of
psychological therapy may be used concurrently. its effect in reducing autonomic arousal and anxiety in
IBS.80 One recent study has shown CBT to be more
Cognitive-Behavioral Therapy effective than an educational intervention in terms of
The theoretical basis of cognitive-behavioral ther- satisfaction, overall symptom relief, and global well-
apy (CBT) lies in social learning, which includes the being after 3 months, but there was little or no difference
concept that behavior is shaped by its consequences. CBT in pain scores.81 Often patients reported that “the pain is
recognizes that social consequences produced in the en- still there but I’m managing it better,” indicating im-
vironment may influence cognitions, motor behavior, proved coping. Such improvement may be associated
and physiologic responses; in turn, how individuals re- with less time off work and less treatment seeking.72
spond may influence the reaction they get from their CBT was effective regardless of the severity of the IBS
environment. Thus, CBT interventions address the and whether an abuse history or current depression was
thoughts, behaviors, and responses that result from pa- present.81 Similar approaches in children with recurrent
tients’ daily interactions. Because patients with IBS have abdominal pain lead to significantly more pain-free days
1452 LEVY ET AL GASTROENTEROLOGY Vol. 130, No. 5

compared with standard medical care or symptom mon- of these psychological treatment studies found that very
itoring.82 few trials were methodologically strong.78,85 Many used
waiting list or “treatment as usual” as control conditions
Relaxation Training (thus not controlling for potentially confounding and
Relaxation or arousal reduction techniques (in- powerful effects of attention and support), studies often
cluding progressive muscle relaxation, biofeedback, au- included very small numbers, and participants were re-
togenic training, and meditation) teach patients to coun- cruited by advertisement from the general population
teract the physiologic sequelae of stress or anxiety and (raising questions of their generalizability to clinic pop-
may lead to a significant reduction in GI symptoms.83 ulations). Both reviews, however, indicated superiority of
psychological treatments over control conditions in
Combined Psychotherapies terms of abdominal pain, bowel dysfunction, depression,
Nine studies have combined progressive muscle and anxiety. Furthermore, more methodologically rigor-
relaxation training with CBT, and all of them reported ous recent trials discussed previously do permit greater
this treatment combination to be superior to a waiting confidence in their conclusions, and we expect that fur-
list control group or conventional medical therapy.84 ther information will become available as additional
Results are less clear in the studies that used an active methodologically strong studies are conducted.
placebo control.78,85 Multicomponent behavioral ther-
apy, including progressive muscle relaxation, training in Pharmacologic Treatment
illness-related knowledge, and cognitive coping strate-
gies, problem solving, and assertiveness training, showed In addition to the effect on anxiety and depression
significantly greater IBS symptom reduction than stan- described previously, antidepressants have direct analge-
dardized medical treatment with a gastroenterologist.86 sic effects that are useful in treating patients with
FGIDs.
Dynamic Psychotherapy
This form of therapy (similar to brief interper- Antidepressants
sonal psychotherapy) requires a close relationship be- In a meta-analysis of 11 randomized placebo-
tween the patient and the therapist, in which the patient controlled trials of acceptable quality, the summary odds
can learn how he or she responds in such a relationship. ratio for improvement of FGIDs using antidepressants
A recent, large study showed that brief psychodynamic compared with placebo was 4.2 (95% confidence inter-
therapy can be used in routine clinical practice for pa- val, 2.3–7.9).93 In this study, the antidepressants ami-
tients with severe IBS and that this treatment is cost- triptyline, clomipramine, desipramine, doxepin, trimi-
effective.72 Like a selective serotonin reuptake inhibitor pramine, and mianserin were studied. All these studies
(SSRI) antidepressant (paroxetine), psychodynamic inter- were randomized controlled trials and yielded positive
personal therapy led to a marked improvement in health- results. The main outcome measure was pain. Another
related quality of life in the long-term compared with systematic review included 6 randomized control trials of
treatment as usual.72 This result could not be explained antidepressant therapy in FGIDs.94 Although the trials
by improvement in pain or improved psychological sta- were of low quality, the investigators concluded that
tus. Recent reviews conflict in their support for these tricyclic antidepressants were ineffective in relieving
therapies in IBS.78,87,88 global IBS symptoms but did lead to improved abdom-
inal pain. Neither review could draw any clear conclu-
Hypnotherapy sions regarding the utility of SSRIs in the treatment of
Controlled trials of hypnotherapy in IBS and IBS or distinguish clearly between the analgesic and
functional dyspepsia have shown that this can be an antidepressant effects of the drugs.
effective treatment, with benefits that persist over The more recent antidepressant treatment trials for
time.89 –91 However, little is known about the applica- functional bowel disorders with satisfactory trial design
bility of the technique in a wide range of patients, have shown that both desipramine and paroxetine have
because most studies have been performed on patients significant general beneficial effects, at least in those
seeking this type of treatment at selected centers. Some patients who complied fully with the treatment to which
uncontrolled studies support the efficacy of both indi- they were randomized72,81; dropouts were numerous in
vidual and group hypnotherapy at other locations.92 both studies. In patients with IBS who had not re-
We would like to add a caveat to the interpretation of sponded to a high-fiber diet, paroxetine has shown su-
many of the studies described previously. Careful reviews periority over placebo in terms of overall well-being,
April 2006 PSYCHOSOCIAL ASPECTS 1453

quality-of-life scores, fewer problems with stool passage, aptic 5-HT1A receptors, may be more useful because they
and IBS-related anxiety but not in abdominal pain.95 potentiate the action of antidepressants, are well toler-
The published studies provide reasonable evidence ated, and have no addictive potential.
that tricyclic antidepressants produce benefit for patients
with moderate to severe IBS, provided the patients ad- Algorithm for Treatment of
here to the prescribed medications. They are currently Psychological Aspects of the FGIDs
the favored antidepressant for treating patients with IBS
In clinical practice, the use of psychological and
based on the available literature. The evidence for SSRIs
antidepressant therapies depends on the severity of the
is more equivocal; possibly without the noradrenergic
FGID and any associated psychosocial factors. We rec-
effect of the tricyclic antidepressants there is theoretically
ommend a “stepped care” approach (Figure 2).
less benefit for pain, although the effect in reducing
central anxiety may have secondary effects on global 1. In the initial assessment, the physician has 3 tasks:
well-being.64 Similarly, in one study,96 the SSRI fluox- develop a satisfactory physician-patient relationship,
etine did not change rectal sensitivity but did lower pain make a positive diagnosis of the FGID, and identify
perception. The serotonin-norepinephrine reuptake in- any “red flag” indications that indicate a psycholog-
hibitors (SNRIs) are a relatively new class of antidepres- ical management strategy (see Figure 2).
sants that have substantial serotonergic and noradrener- 2. Facilitate the patient’s understanding of the disorder.
gic effects (unlike the SSRIs) to reduce pain but without 3. Recommend symptomatic medical therapies and/or
the antihistaminic and anticholinergic effects of the tri- simple behavioral/lifestyle changes. Medical therapies
cyclic antidepressants that lead to most of the side ef- refer to strategies such as dietary manipulation, pro-
fects. Venlafaxine, an SNRI, reduced sensation during kinetics, H2 blockers or proton pump inhibitors, lax-
colonic distention in healthy humans97 but has limited atives, bulking agents, antidiarrheals, and antispas-
usefulness in the FGIDs due to its tendency to produce modics. Preferred behavioral/lifestyle changes may be
GI distress, particularly nausea and vomiting. Dulox- determined by assessing situations in which the pa-
etine, a more recently marketed SNRI, has been studied tient’s symptoms deteriorate or improve. In general,
for the treatment of major depressive disorder associated if stress is a likely factor, several forms of relaxation
with pain and has an indication for the pain of peripheral training (eg, yoga, relaxation classes, meditation, and
neuropathy and proven efficacy for fibromyalgia.98 Thus, so on) may be available.
it may find a role for treatment of patients with FGIDs, 4. Select psychopharmacologic medication or more spe-
although the main side effect is nausea. cific psychological management. This selection may
In clinical practice, side effects of antidepressants can be determined in part by patient preferences, time or
limit their usefulness unless clinicians warn patients cost constraints (of medications and testing), health
about these and emphasize that these reduce with time as insurance, referral physician assumptions, and the
the beneficial effect becomes more prominent. If a pa- opportunity for referral to a psychologist or other
tient cannot tolerate one antidepressant, it is reasonable professional who is trained to treat patients with
to change to another drug in the same class or switch to FGIDs, among other factors. If the psychological
another class of agents. This has been shown to be route is chosen, a detailed psychosocial assessment is
effective in psychopharmacology practice.99 Continued performed by the psychologist or other mental health
failure to improve suggests that a referral to a psychia- professional. If the psychopharmacologic route is cho-
trist may be appropriate. A psychiatrist can be particu- sen, the physician should be knowledgeable about
larly helpful in determining further drug or dosage appropriate psychopharmacologic agents for this pop-
changes. ulation and be prepared to monitor the patient’s
progress.
Anxiolytics 5. Consider adding the second form of treatment (psy-
Anxiolytic agents can be used in patients with chopharmacologic or lifestyle/behavioral) to the first.
FGIDs, especially when there are comorbid generalized There is evidence in favor of such combined treatment
anxiety and panic disorders. However, the risk of addic- in several disorders.100 –103 There are also good theo-
tion with the benzodiazepines and their tendency to retical grounds for combined treatment in patients
produce mild transient cognitive dysfunction means that with FGIDs, because antidepressants have some direct
they have very limited use in the GI setting. A newer action on pain, anxiety, and depression and can in-
class of antianxiety agents, the azapirones (eg, buspi- crease the patient’s motivation to engage in therapy.
rone), which act by serotonin agonist activity at presyn- Psychological treatments are effective in modifying
1454 LEVY ET AL GASTROENTEROLOGY Vol. 130, No. 5

health anxiety, selective attention, catastrophizing, 3. How cost-effective are the different interventions in
and aspects of poor coping and can also increase real-life clinical settings?
adherence to psychopharmacologic treatments.
Clinical Questions
Recommended Training Curriculum 1. Which treatments are effective for which subgroups
of Psychosocial Aspects of FGIDs of patients (characteristics, cultural groups, and so
for Gastroenterologists and Primary on), and are differential responses based on severity of
Care Physicians pain, presence of marked anxiety, depression, or so-
To optimize care for patients with FGIDs along matization?
the principles of the biopsychosocial model, physicians 2. What is the relative efficacy of tricyclic, SSRI, and
may need additional training in the following areas so SNRI antidepressants in treating patients with
they can follow adequately the recommendations for FGIDs?
assessment and treatment proposed in this report: 3. Is it possible to identify preventative strategies for
development of FGIDs in high-risk populations?
● Interviewing skills: establishing rapport and empa- 4. Because treatments for patients with posttraumatic
thy, providing education and reassurance, facilitat- stress disorder (eg, exposure-type therapies) address
ing patient disclosure of psychosocial information, only whether symptoms of posttraumatic stress dis-
facilitating patient involvement in care, and elicit- order improve, we need to determine whether FGIDs
ing patient disclosure of thoughts and feelings (and other associated health problems) are also helped
● Application of biopsychosocial principles in assess- by this treatment.
ment and treatment
Transcultural, Ethnicity, and Gender
● Ability to screen for anxiety, depression, and som- Questions
atization within a clinical interview
Where current knowledge is limited to Western
● Ability to use appropriate psychotropic medications cultures and specific gender or ethnic groups, would
in clinical practice similar findings be obtained in different cultures and
● Skills in working within a multidisciplinary team, groups regarding treatment effectiveness and the rela-
including knowledge and skills concerning when tionships between psychosocial factors and the FGIDs?
and how to refer to mental health professionals and See the report in this supplement on gender, age, society,
providing continuity of care culture, and the patient’s perspective for further infor-
mation about current knowledge on culture and FGIDs.
● Awareness of physician’s personal reactions and ap-
propriate response to difficulties in physician- Mechanism Questions
patient relationship.
1. How is childhood trauma (in all its forms) related to
the development and course of FGIDs?
Recommendations for Future
2. What are the mechanisms linking psychosocial fac-
Research tors to symptom expression and outcomes in FGIDs?
This review suggests a number of questions that 3. How do positive factors, such as social support and
need to be addressed in future research. coping mechanisms, protect from the development of
FGIDs?
Health Services Research Questions
4. Are the mechanisms of treatment response from psy-
1. How we can best integrate our knowledge of psycho- chological and pharmacologic interventions similar or
social factors into routine clinical practice? The prob- different? If the latter, what is the effect of combined
lem is not confined to gastroenterological practice; treatment?
the problem of underdetection and treatment of de- 5. To what extent can the physiologic abnormalities
pression and anxiety is also well recognized in pri- observed in FGIDs be explained by psychological
mary care.104 distress and psychiatric disorders?
2. Is screening for the psychosocial factors effective, and 6. What are the mechanisms involved in the pain expe-
which forms of physician education make a difference, rience? In line with the biopsychosocial model, neu-
especially the evaluation of clinical guidelines and robiological and psychosocial factors need to be stud-
treatment algorithms? ied simultaneously, not separately.
April 2006 PSYCHOSOCIAL ASPECTS 1455

Conclusions response to gastrointestinal symptoms. Am J Gastroenterol

2004;99:2442–2451.
Considerable research has shown the interrelation- 10. Whitehead WE, Crowell MD, Heller BR, Robinson JC, Schuster
ships among biological, psychological, and social factors MM, Horn S. Modeling and reinforcement of the sick role during
childhood predicts adult illness behavior. Psychosom Med
and the development and maintenance of the FGIDs. 1994;6:541–550.
Several promising lines of research have also been inves- 11. Apley J, Naish N. Recurrent abdominal pains: a field survey of
tigating possible mechanisms for these relationships. 1000 children. Arch Dis Child 1958;33:165–170.
Many treatment strategies have also been shown to be 12. Levy RL, Garner MD, Christie DL, Whitsett SF, Whitehead WE,
Walker LS, Feld A. Changes in childhood recurrent abdominal
effective, including behavioral/lifestyle recommendations pain and parental responses with cognitive behavior therapy
and psychological and psychopharmacologic treatments. (abstr). Gastroenterology 2003;124(Suppl 1):A-530.
Although many unanswered questions remain, our abil- 13. Talley NJ, Fett SL, Zinsmeister AR. Self-reported abuse and
gastrointestinal disease in outpatients: association with irrita-
ity to have confidence in our recommendations of critical
ble bowel-type symptoms. Am J Gastroenterol 1995;90:366 –
areas of assessment and treatment has grown considerably 371.
in recent years. We expect this trend to continue as 14. Delvaux M, Denis P, Allemand H, French Club of Digestive
research in this area evolves and physicians and other Motility. Sexual and physical abuses are more frequently re-
ported by IBS patients than by patients with organic digestive
health and mental health care workers receive more diseases or controls. Results of a multicenter inquiry. Eur J
training in the biopsychosocial aspects of these disorders. Gastroenterol Hepatol 1997;9:345–352.
We also want to particularly encourage training in psy- 15. Scarinci IC, McDonald-Haile JM, Bradley LA, Richter JE. Altered
chosocial assessment as part of GI fellowship training and pain perception and psychosocial features among women with
gastrointestinal disorders and history of abuse: a preliminary
perhaps even recertification. We believe this report has model. Am J Med 1994;97:108 –118.
shown that the ability to take and utilize a psychosocial 16. Heitkemper M, Jarrett M, Walker E, Landenburger K, Bond EF.
history and assessment is as important to practice as most Effect of sexual and physical abuse on symptom experiences in
women with irritable bowel syndrome. Nurs Res 2001;50:1–9.
GI procedures commonly taught in training programs.
17. Ali A, Toner BB, Stuckless N, Gallop R, Diamant NE, Gould M,
Vidins E. Emotional abuse, self-blame and self-silencing in
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their combination for the treatment of chronic depression. Adolescents With Depression Study (TADS) Team. Fluoxetine,
N Engl J Med 2000;342:1462–1470. cognitive-behavioral therapy, and their combination for
101. Barlow DH, Gorman JM, Shear MK, Woods SW. Cognitive-be- adolescents with depression: Treatment for Adolescents With
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2536. 104. Gelenberg A. Depression is still underrecognized and under-
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Buchin J, Sickinger AH, Fava M. Effects of adding cognitive
therapy to fluoxetine dose increase on risk of relapse and
residual depressive symptoms in continuation treatment of ma-
jor depressive disorder. J Clin Psychopharmacol 2002;22:474 – Received February 8, 2005. Accepted November 3, 2005.
480. Address requests for reprints to: Rona L. Levy, PhD, Mailstop
103. March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns 354900, University of Washington, Seattle, Washington 98105.
B, Domino M, McNulty S, Vitiello B, Severe J, Treatment for e-mail: [email protected].
 GASTROENTEROLOGY 2006;130:1459 –1465

Functional Esophageal Disorders

JEAN PAUL GALMICHE,* RAY E. CLOUSE,‡ ANDRÁS BÁLINT,§ IAN J. COOK,储 PETER J. KAHRILAS,¶
WILLIAM G. PATERSON,# and ANDRE J. P. M. SMOUT**
*University of Nantes, Nantes, France; ‡Washington University, St. Louis, Missouri; §Semmelweis University, Budapest, Hungary; 储University
of New South Wales, Sydney, Australia; ¶Northwestern University, Chicago, Illinois; #Queen’s University, Kingston, Ontario, Canada; and
**University of Utrecht, Utrecht, the Netherlands

Functional esophageal disorders represent processes histopathologic bases (eg, achalasia, scleroderma esopha-
accompanied by typical esophageal symptoms (heart- gus) must not be the primary symptom source.
burn, chest pain, dysphagia, globus) that are not ex- An important modification in threshold for the third
plained by structural disorders, histopathology-based uniform criterion has occurred in this reevaluation of the
motor disturbances, or gastroesophageal reflux disease. functional esophageal disorders.1 Satisfactory evidence of
Gastroesophageal reflux disease is the preferred diag- a symptom relationship with acid reflux events, either by
nosis when reflux esophagitis or excessive esophageal analytical determination from an ambulatory pH study
acid exposure is present or when symptoms are closely
or through subjective outcome from therapeutic antire-
related to acid reflux events or respond to antireflux
flux trials, even in the absence of objective GERD evi-
therapy. A singular, well-defined pathogenetic mecha-
dence, now is sufficient to incriminate GERD (Figure 1).
nism is unavailable for any of these disorders; combina-
tions of sensory and motor abnormalities involving both The purpose of this modification is to preferentially
central and peripheral neural dysfunction have been diagnose GERD over a functional disorder in the initial
invoked for some. Treatments remain empirical, al- evaluation so that effective GERD treatments are not
though the efficacy of several interventions has been overlooked in management. Consequently, the acid-sen-
established in the case of functional chest pain. Man- sitive esophagus is now excluded from the group of
agement approaches that modulate central symptom functional esophageal disorders and considered within
perception or amplification often are required once local the realm of GERD, even if physiologic data indicate
provoking factors (eg, noxious esophageal stimuli) have that hypersensitivity of the esophagus in this setting can
been eliminated. Future research directions include fur- encompass stimuli other than acid. Presumably symp-
ther determination of fundamental mechanisms respon- toms that persist despite GERD interventions or that are
sible for symptoms, development of novel management out of proportion to the GERD findings ultimately
strategies, and definition of the most cost-effective di- would be reconsidered toward a functional diagnosis.
agnostic and treatment approaches. The role of weakly acidic reflux events (reflux events with
pH values between 4 and 7) remains unclear, and tech-
unctional esophageal disorders represent chronic nological advances (eg, applications of multichannel in-
F symptoms typifying esophageal disease that have no
readily identified structural or metabolic basis (Table 1).
traluminal impedance monitoring) are expected to fur-
ther define the small proportion with functional
Although mechanisms responsible for the disorders re- heartburn truly meeting all stated criteria.2
main poorly understood, a combination of physiologic
and psychosocial factors likely contributes toward pro- Table 1. Functional Gastrointestinal Disorders
voking and escalating symptoms to a clinically signifi- A. Functional esophageal disorders
cant level. Several diagnostic requirements are uniform A1. Functional heartburn
A2. Functional chest pain of presumed esophageal origin
across the disorders: (1) exclusion of structural or meta- A3. Functional dysphagia
bolic disorders potentially responsible for symptoms is A4. Globus
essential; (2) an arbitrary requirement of at least 3
months of symptoms with onset at least 6 months before
diagnosis is applied to each diagnosis to establish some Abbreviations used in this paper: GERD, gastroesophageal reflux
degree of chronicity; (3) gastroesophageal reflux disease disease; PPI, proton pump inhibitor.
© 2006 by the American Gastroenterological Association Institute
(GERD) must be excluded as an explanation for symp- 0016-5085/06/$32.00
toms; and (4) a motor disorder of the types with known doi:10.1053/j.gastro.2005.08.060
1460 GALMICHE ET AL GASTROENTEROLOGY Vol. 130, No. 5

A1. Functional Heartburn Clinical Evaluation

Definition Clarification of the nature of the symptom is an
essential first step to avoid overlooking extraesophageal
Retrosternal burning in the absence of GERD
symptom sources. Additional evaluation primarily is ori-
that meets other essential criteria for the functional
ented toward establishing or excluding the presence of
esophageal disorders typifies this diagnosis. Constraints
GERD.6,7 Endoscopy that reveals no evidence of esoph-
in the ability to fully recognize the presence or impor-
agitis is insufficient in this regard, especially in those
tance of GERD in individual subjects likely result in a
subjects who are evaluated while remaining on or shortly
heterogeneous subject group.1 after discontinuing antireflux therapy. Ambulatory pH
monitoring can better classify patients who have normal
Epidemiology
findings on endoscopic evaluation, including those whose
Heartburn is reported by 20%– 40% of subjects symptoms persist despite therapy. A favorable response
in Western populations, depending on thresholds for a to a brief therapeutic trial using high dosages of a proton
positive response. Studies using both endoscopy and pump inhibitor (PPI) is not specific,8 but lack of response
ambulatory pH monitoring to objectively establish evi- probably has a high negative predictive value for GERD.
dence of GERD indicate that functional heartburn rep- Physiologic Features
resents ⬍10% of patients with heartburn presenting to
gastroenterologists.3 The proportion may be higher in Much of the available literature is clouded by
primary care settings. inclusion of subjects with undetected GERD in pa-
tient groups with presumed functional heartburn. The
prevailing view is to consider disturbed visceral per-
ception as a major factor involved in pathogenesis.9
A1. Diagnostic Criteria* for Functional
Enhanced sensitivity to refluxate having slight pH
Heartburn
alterations from normal may be responsible in some
Must include all of the following: instances. The focus has remained on intraluminal
1. Burning retrosternal discomfort or pain noxious stimulation; little direct evidence for alter-
2. Absence of evidence that gastroesophageal ation in central signal processing is available in these
acid reflux is the cause of the symptom subjects with heartburn, although it is suspected.
3. Absence of histopathology-based esophageal
motility disorders
*Criteria fulfilled for the last 3 months with symptom onset
at least 6 months before diagnosis.

Justification for Change in Diagnostic

Criteria
The threshold for the second criterion has been
revised to exclude patients with normal esophageal acid
exposure yet acid-related symptom events on ambulatory
pH monitoring or symptomatic response to antireflux
therapy. This group resembles other patients with
GERD in terms of presentation, manometric findings,
impact on quality of life, and natural history. Outcome is
less satisfactory with antireflux therapy, however, and
some subjects within this group will be shown to have
functional symptoms that persist once their relationship Figure 1. Further classification of patients with heartburn and no
evidence of esophagitis at endoscopy using ambulatory pH monitoring
to reflux events is eliminated with therapy.4 Two or more and response to a therapeutic trial of PPIs. The subset with functional
days weekly of mild heartburn is sufficient in GERD to heartburn has no findings that would support a presumptive diagnosis
influence quality of life, but thresholds for symptom of endoscopy-negative reflux disease (ENRD). The precise thresholds
for separation of subjects at each step remain uncertain. This figure
frequency or severity have not been determined for func- shows classification categories by findings and is not meant to sug-
tional heartburn.5 gest a diagnostic management algorithm for use in clinical practice.
April 2006 FUNCTIONAL ESOPHAGEAL DISORDERS 1461

Psychological Features householders survey, and the sexes were equally

Acute experimental stress enhances perception represented.14
of esophageal acid in patients with GERD without
promoting reflux events.10 Enhanced perception is in-
A2. Diagnostic Criteria* for Functional
fluenced by the psychological status of the patient.
Chest Pain of Presumed Esophageal
Thus, psychological factors may participate in heart-
Origin
burn reporting when evidence of a noxious esophageal
stimulus is limited. Psychological profiles do not dif- Must include all of the following:
ferentiate subjects with normal esophageal acid expo- 1. Midline chest pain or discomfort that is not of
sure and no esophagitis from those with elevated acid burning quality
exposure times, but patients whose heartburn does not 2. Absence of evidence that gastroesophageal re-
correlate well with acid reflux events on an ambulatory flux is the cause of the symptom
pH study do demonstrate greater anxiety and somati- 3. Absence of histopathology-based esophageal
zation scores as well as poor social support than those motility disorders
with reflux-provoked symptoms.11
*Criteria fulfilled for the last 3 months with symptom onset
Treatment at least 6 months before diagnosis
Persisting symptoms unrelated to GERD may
respond to low-dose tricyclic antidepressants, other Justification for Change in Diagnostic
antidepressants, or psychological therapies used in Criteria
many functional syndromes, although controlled trials As for other functional esophageal disorders, pain
demonstrating efficacy are unavailable. Reduction in episodes linked to reflux events are now considered to fall
transient lower esophageal sphincter relaxations with within the spectrum of symptomatic GERD.
agents such as baclofen is being investigated.12 Anti-
Clinical Evaluation
reflux surgery in patients with functional heartburn
and non–acid reflux events has not been fully evalu- Exclusion of cardiac disease is of pivotal impor-
ated, but surgical management would not be expected tance. Likewise, identification of GERD as the cause of
to be as beneficial as in GERD considering known the symptom is essential for diagnostic categorization
outcome predictors for these operations. and management. Exclusion of GERD cannot rely on
endoscopy alone, because esophagitis is found in ⬍20%
of patients with unexplained chest pain.15 Ambulatory
A2. Functional Chest Pain of pH monitoring plays a useful role, and determining the
Presumed Esophageal Origin statistical relationship between symptoms and reflux
Definition events is the most sensitive approach.16,17 When com-
bining subjects with and without abnormal acid expo-
This disorder is characterized by episodes of un-
sure, 40% of patients with normal findings on coronary
explained chest pain that usually are midline in location
angiograms may have acid-related pain.1 A brief thera-
and of visceral quality and therefore potentially of esoph-
peutic trial with a high-dose PPI regimen is a rapid way
ageal origin. The pain easily is confused with cardiac of determining clinically relevant reflux-symptom asso-
angina and pain from other esophageal disorders, includ- ciations and is recommended for its simplicity and cost-
ing achalasia and GERD. effectiveness.18 The diagnostic accuracy remains uncer-
tain. Other diagnostic studies, including esophageal
Epidemiology
manometry, have a limited yield when chest pain is the
Inferential data extracted from cardiac evalua- sole symptom.
tions for chest pain indicate that this is a common
disorder. Findings on 15%–30% of coronary angio- Physiologic Features
grams performed in patients with chest pain are nor- Abnormalities have been detected in 3 categories:
mal.13 Although once considered a diagnosis of elderly sensory abnormalities, distorted central signal process-
women, chest pain without specific explanation was ing, and abnormal esophageal motility. Motility abnor-
reported twice as commonly by subjects 15–34 years malities, particularly spastic motor disorders, are con-
of age than by subjects older than 45 years of age in a spicuous, but their primary role in production of chest
1462 GALMICHE ET AL GASTROENTEROLOGY Vol. 130, No. 5

pain is not well established. The relationship of recently physiologic or psychological characteristic. Interest in a
observed sustained contraction of longitudinal muscle to psychological intervention is reported by the majority of
pain is being studied. Enhanced sensitivity to intralumi- patients who are asked, particularly when activity limi-
nal stimuli, including acid and esophageal distention, tation and pain intensity or frequency are high.
may be a primary abnormality. Patients with chest pain
can be completely segregated from control subjects by A3. Functional Dysphagia
pressure thresholds using impedance planimetry.19 How
Definition
subjects with functional chest pain reach the hypersen-
sitivity state is not clear. Intermittent stimulation by The disorder is characterized by a sensation of
physiologic acid reflux or spontaneous distention events abnormal bolus transit through the esophageal body.
with swallowing or belching may be relevant. Recent Thorough exclusion of structural lesions, GERD, and
studies also verify alterations in central nervous system histopathology-based esophageal motor disorders is re-
processing of afferent signals. A variety of investigational quired for establishing the diagnosis.
paradigms involving sensory decision theory, electrical
stimulation and cortical evoked potentials, and heart rate Epidemiology
variability indicate that chest pain reproduced by local Little information is available regarding the prev-
esophageal stimulation is accompanied by errors in cen- alence of functional dysphagia, largely because of the
tral signal processing and an autonomic response.20 –22 In degree of exclusionary evaluation required. Between 7%
acid-sensitive subjects, the findings are further provoked and 8% of respondents from a householders survey re-
by acid instillation. ported dysphagia that was unexplained by questionnaire-
ascertained disorders.14 Less than 1% report frequent
Psychological Features dysphagia. Functional dysphagia is the least prevalent of
Psychological factors appear relevant in functional these functional esophageal disorders.
chest pain, with their role potentially being complex.
Psychiatric diagnoses, particularly anxiety disorders, de-
pression, and somatization disorder, are overrepresented A3. Diagnostic Criteria* for Functional
in patients with chronic chest pain.23 These disorders Dysphagia
have not segregated well with specific physiologic find- Must include all of the following:
ings, suggesting that they may interact toward produc-
ing the symptomatic state, possibly by mediating symp- 1. Sense of solid and/or liquid foods sticking,
tom severity and health care utilization.24 Psychological lodging, or passing abnormally through the
factors also influence well-being, functioning, and qual- esophagus
ity of life, which are important outcomes in an otherwise 2. Absence of evidence that gastroesophageal re-
nonmorbid disease. flux is the cause of the symptom
3. Absence of histopathology-based esophageal
Treatment motility disorders
Systematic management is recommended, because *Criteria fulfilled for the last 3 months with symptom onset
continued pain is associated with impaired functional at least 6 months before diagnosis
status and increased health care utilization and sponta-
neous recovery is rare. Exclusionary evaluation including
Justification for Change in Diagnostic
a therapeutic trial for GERD is indicated. Once the
Criteria
exclusionary evaluation is completed, management op-
tions for functional chest pain become limited. Smooth Dysphagia is not easily linked to reflux events.
muscle relaxants are ineffective in controlled trials. In- Nevertheless, the modification of the threshold used for
jection of botulinum toxin into the lower esophageal the second criterion (see the introduction) would at-
sphincter and esophageal body has had anecdotal use.25,26 tribute the symptom to GERD rather than a functional
The most encouraging outcomes come from antidepres- diagnosis if the link were established, even in the absence
sant and psychological/behavioral interventions.27,28 Ef- of other objective GERD indicators.
ficacy is demonstrated in controlled trials for both tricy-
clic antidepressants and more contemporary agents (eg, Clinical Evaluation
selective serotonin reuptake inhibitors).29,30 Benefits have Fastidious exclusion of structural disorders is re-
not been dependent on the presence of any particular quired initially.31 Endoscopy and esophageal barium ra-
April 2006 FUNCTIONAL ESOPHAGEAL DISORDERS 1463

diography are necessary to exclude intrinsic and extrinsic A4. Globus

lesions, with radiographic studies being augmented with
Definition
radio-opaque bolus challenge during fluoroscopy if re-
quired.32 Biopsies at the time of endoscopy are recom- Globus is defined as a sense of a lump, a retained
mended for excluding eosinophilic esophagitis. Esopha- food bolus, or tightness in the throat. The symptom is
geal manometry, primarily for detection of achalasia, is nonpainful, frequently improves with eating, commonly
recommended if endoscopy and barium radiography fail is episodic, and is unassociated with dysphagia or
to provide a specific diagnosis. Ambulatory pH monitor- odynophagia. Globus is unexplained by structural le-
ing plays a small role but may be helpful in patients sions, GERD, or histopathology-based esophageal motil-
whose dysphagia is associated with heartburn or regur- ity disorders.
gitation, but a brief therapeutic trial with a high-dose
Epidemiology
PPI regimen usually is satisfactory for identifying pa-
tients with subtle GERD as a cause for dysphagia.33 Globus is a common symptom and is reported by
up to 46% of apparently healthy individuals, with a peak
Physiologic Features incidence in middle age.14 It is uncommon in subjects
Mechanisms responsible for this disorder are younger than 20 years of age. The symptom is equally
poorly understood. Peristaltic dysfunction may be re- prevalent in men and women among healthy individuals
sponsible in some subjects. Rapid propagation velocity is in the community, but women are more likely to seek
accompanied by poor barium clearance that may be health care for this symptom.37
perceived as dysphagia.34 Likewise, failed or low-ampli-
tude contraction sequences impair esophageal emptying
and can result in dysphagia.35 Dysphagia also can be A4. Diagnostic Criteria* for Globus
induced by intraluminal acid and balloon distention, Must include all of the following:
suggesting that abnormal esophageal sensory perception
may be a factor in some subjects.36 1. Persistent or intermittent, nonpainful sensa-
tion of a lump or foreign body in the throat
Psychological Features 2. Occurrence of the sensation between meals
Acute stress experiments suggest that central fac- 3. Absence of dysphagia or odynophagia
tors can precipitate motor abnormalities potentially re- 4. Absence of evidence that gastroesophageal re-
sponsible for dysphagia.1 Barium transit is adversely flux is the cause of the symptom
altered in asymptomatic and symptomatic subjects dur- 5. Absence of histopathology-based esophageal
ing recollection of unpleasant topics or stressful, unpleas- motility disorders
ant interviews. Noxious auditory stimuli or difficult *Criteria fulfilled for the last 3 months with symptom onset
cognitive tasks alter manometric recordings by increas- at least 6 months before diagnosis
ing contraction wave amplitude and occasionally induc-
ing simultaneous contraction sequences. The relevance of
Justification for Change in Diagnostic
these findings to functional dysphagia remains conjec-
Criteria
tural.
By factor analysis, globus is distinct from pain,
Treatment and pain often is indicative of a local structural disor-
Management includes reassurance, avoidance of der.38 As for other functional esophageal disorders, dem-
precipitating factors, careful mastication of food, and onstration that the symptom is directly related to reflux
modification of any psychological abnormality that seems events would indicate a diagnosis of GERD, even in the
directly relevant to symptom production. Symptom absence of other objective evidence of GERD.
modulation with antidepressants and psychological ther-
apies can be attempted, considering their effects in other Clinical Evaluation
disorders. Empirical dilation may be indicated.32 Smooth The diagnosis is made from a compatible clinical
muscle relaxants, botulinum toxin injection, or even history, including clarification that dysphagia is absent.
pneumatic dilation can be useful in some patients with Physical examination of the neck followed by nasolaryn-
spastic disorders, particularly if incomplete lower esoph- goscopic examination of the pharynx and larynx are
ageal sphincter relaxation and delay of distal esophageal advised, although routine use of nasolaryngoscopy in
emptying on barium radiography are evident. patients with typical symptoms remains debated. Fur-
1464 GALMICHE ET AL GASTROENTEROLOGY Vol. 130, No. 5

ther investigation of the simple symptom is not well Recommendations for Future
supported; dysphagia, odynophagia, pain, weight loss, Research
hoarseness, or other alarm symptoms mandate more ex-
Despite their high prevalence rates, functional
tensive evaluation. There are grounds for a therapeutic esophageal disorders have not been well studied. In par-
trial of a PPI when uninvestigated patients present with ticular, highly effective management approaches have
the symptom of globus, particularly when typical reflux not been established. Several areas requiring additional
symptoms coexist. research were identified.
Physiologic Features 1. Studies validating the diagnostic criteria are needed,
and a method for improving the accuracy of symp-
Consistent evidence is lacking to attribute globus
tom-based criteria while limiting exclusionary
to any specific anatomic abnormality, including the cri-
workup would be welcomed.
copharyngeal bar. Upper esophageal sphincter mechanics 2. The fundamental mechanisms of symptom produc-
do not seem relevant, and the pharyngeal swallow mech- tion remain poorly defined. Further application of
anism is normal. Urge to swallow and increased swallow new technologies for measuring reflux events, motor
frequency might contribute to the symptom by period- physiology, and esophageal sensation as well as cen-
ically causing air entrapment in the proximal esophagus. tral signal modulation is recommended (eg, mul-
Esophageal balloon distention can reproduce globus sen- tichannel intraluminal impedance monitoring, high-
sation at low distending thresholds, suggesting some resolution manometry).
degree of esophageal hypersensitivity.39 Likewise, globus 3. Well-structured, controlled treatment trials would be
is more common in conjunction with reflux symptoms, welcomed in any of these disorders, because manage-
although a strong relationship between GERD and glo- ment remains highly empirical.
bus has not been established.40 Additionally, the symp- 4. Treatment trials should include measures of quality of
tom does not respond well to antireflux therapy. Al- life and functional outcome when determining both
though gastroesophageal reflux and distal esophageal short-term and long-term effects. The impact of in-
motility disorders can include globus in their presenta- terventions on functional impairment and health care
tions, these mechanisms are believed to play a minimal resource use, important indicators of morbidity from
role in the pathophysiology of globus. the functional esophageal disorders, should be a focus
in measuring treatment success.
Psychological Features
No specific psychological characteristic has been References
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wireless esophageal pH monitoring in evaluating gastroesopha-
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21. Hollerbach S, Bulat R, May A, Kamath MV, Upton AR, Fallen EL, 41. Harris MB, Deary IJ, Wilson JA. Life events and difficulties in
Tougas G. Abnormal cerebral processing of oesophageal stimuli relation to the onset of globus pharyngis. J Psychosom Res
in patients with noncardiac chest pain (NCCP). Neurogastroen- 1996;40:603– 615.
terol Motil 2000;12:555–565. 42. Thompson WG, Heaton KW. Heartburn and globus in apparently
22. Tougas G, Spaziani R, Hollerbach S, Djuric V, Pang C, Upton AR, healthy people. Can Med Assoc J 1982;126:46 – 48.
Fallen EL, Kamath MV. Cardiac autonomic function and oesoph- 43. Timon C, O’Dwyer T, Cagney D, Walsh M. Globus pharyngeus:
ageal acid sensitivity in patients with non-cardiac chest pain. Gut long-term follow-up and prognostic factors. Ann Otol Rhinol Lar-
2001;49:706 –712. yngol 1991;100:351–354.
23. Clouse RE, Carney RM. The psychological profile of non-cardiac 44. Brown SR, Schwartz JM, Summergrad P, Jenike MA. Globus
chest pain patients. Eur J Gastroenterol Hepatol 1995;7:1160 – hystericus syndrome responsive to antidepressants. Am J Psy-
1165. chiatry 1986;143:917–918.
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ageal symptoms, psychometric abnormalities and dysmotility. Received January 31, 2005. Accepted August 31, 2005.
Am J Gastroenterol 2001;96:2312–2316. Address requests for reprints to: Ray E. Clouse, MD, Division of
25. Miller LS, Pullela SV, Parkman HP, Schiano TD, Cassidy MJ, Cohen Gastroenterology, Washington University School of Medicine, 660
S, Fisher RS. Treatment of chest pain in patients with noncardiac, South Euclid Avenue, Campus Box 8124, St Louis, Missouri 63110.
nonreflux, nonachalasia spastic esophageal motor disorders using e-mail: [email protected]; fax: (314) 454-5107.
 GASTROENTEROLOGY 2006;130:1466 –1479

Functional Gastroduodenal Disorders

JAN TACK,* NICHOLAS J. TALLEY,‡ MICHAEL CAMILLERI,‡ GERALD HOLTMANN,§ PINJIN HU,¶
JUAN-R. MALAGELADA,储 and VINCENZO STANGHELLINI#
*Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium; ‡C.E.N.T.E.R., Mayo Clinic, Rochester, Minnesota; §Royal
Adelaide Hospital, Adelaide, Australia; ¶Department of Gastroenterology of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou,
China; 储Department of Gastroenterology, Vall Hebron Hospital, Barcelona, Spain; and #Department of Internal Medicine and
Gastroenterology, University of Bologna, Bologna, Italy

A numerically important group of patients with functional functional dyspepsia (FD) (category B1, comprising post-
gastrointestinal disorders have chronic symptoms that can prandial distress syndrome [PDS] and epigastric pain syn-
be attributed to the gastroduodenal region. Based on the drome [EPS]), belching disorders (category B2, comprising
consensus opinion of an international panel of clinical aerophagia and unspecified belching), functional nausea and
investigators who reviewed the available evidence, a clas- vomiting disorders (category B3, comprising chronic idio-
sification of the functional gastroduodenal disorders is pro- pathic nausea [CIN], functional vomiting, and cyclic vom-
posed. Four categories of functional gastroduodenal dis- iting syndrome [CVS]), and the rumination syndrome (cat-
orders are distinguished. The first category, functional dys-
egory B4) is recommended.
pepsia, groups patients with symptoms thought to origi-
nate from the gastroduodenal region, specifically epigas-
tric pain or burning, postprandial fullness, or early B1. Functional Dyspepsia
satiation. Based on recent evidence and clinical experi-
Definition of Functional Dyspepsia
ence, a subgroup classification is proposed for postpran-
dial distress syndrome (early satiation or postprandial full- Many different sets of symptoms have been used
ness) and epigastric pain syndrome (pain or burning in the synonymously with the term dyspepsia, which has caused
epigastrium). The second category, belching disorders, confusion. Most patients do not recognize the term dys-
comprises aerophagia (troublesome repetitive belching pepsia, and historically physicians have interpreted the
with observed excessive air swallowing) and unspecified meaning of dyspepsia very variably.
belching (no evidence of excessive air swallowing). The Hence, the committee recommended the following
third category, nausea and vomiting disorders, comprises pragmatic definition: FD is defined as the presence of
chronic idiopathic nausea (frequent bothersome nausea symptoms thought to originate in the gastroduodenal
without vomiting), functional vomiting (recurrent vomiting region, in the absence of any organic, systemic, or met-
in the absence of self-induced vomiting, or underlying eat-
abolic disease that is likely to explain the symptoms.
ing disorders, metabolic disorders, drug intake, or psychi-
These symptoms are listed in Table 2. However, partic-
atric or central nervous system disorders), and cyclic vom-
ularly for experimental purposes, the term functional
iting syndrome (stereotypical episodes of vomiting with
vomiting-free intervals). The rumination syndrome is a dyspepsia should preferably be replaced by more distinc-
fourth category of functional gastroduodenal disorder char- tively defined disorders, for which there is now increas-
acterized by effortless regurgitation of recently ingested ing evidence in the literature. These are the new
food into the mouth followed by rechewing and reswallow- diagnostic categories of (1) meal-induced dyspeptic
ing or expulsion. The proposed classification requires fur- symptoms (PDS), and (2) epigastric pain (EPS).
ther research and careful validation but the criteria should Patients with 1 or more of these symptoms (postpran-
be of value for clinical practice; for epidemiological, patho- dial fullness, early satiation, or epigastric pain or burn-
physiological, and clinical management studies; and for ing) are referred to as patients with dyspepsia. Previous
drug development. Rome committees defined dyspepsia as pain or discom-

large group of patients with functional gastrointesti- Abbreviations used in this paper: CIN, chronic idiopathic nausea;

A nal disorders have chronic symptoms that can be at-

tributed to the gastroduodenal region (Table 1). Based on
EPS, epigastric pain syndrome; FD, functional dyspepsia; GERD, gas-
troesophageal reflux disease; NSAID, nonsteroidal anti-inflammatory
drugs; PDS, postprandial distress syndrome; PPI, proton pump inhibi-
the consensus opinion of an international panel of clinical tor.
© 2006 by the American Gastroenterological Association Institute
investigators who reviewed the available evidence, a classi- 0016-5085/06/$32.00
fication of the functional gastroduodenal disorders into doi:10.1053/j.gastro.2005.11.059
April 2006 FUNCTIONAL GASTRODUODENAL DISORDERS 1467

Table 1. Functional Gastrointestinal Disorders cluded from the definition of dyspepsia even though it
B. Functional gastroduodenal disorders may occur simultaneously with gastroduodenal symp-
B1. Functional dyspepsia toms. Similarly, retrosternal pain suggestive of esopha-
B1a. Postprandial distress syndrome
geal disease or of a type embraced by the term noncardiac
B1b. Epigastric pain syndrome
B2. Belching disorders chest pain is excluded from dyspepsia.
B2a. Aerophagia Uninvestigated versus investigated dyspepsia. Espe-
B2b. Unspecified excessive belching cially when considering epidemiological data, it is im-
B3. Nausea and vomiting disorders
B3a. Chronic idiopathic nausea portant to distinguish the subjects with dyspeptic symp-
B3b. Functional vomiting toms who have not been investigated from patients with
B3c. Cyclic vomiting syndrome a diagnostic label after investigation, with or without an
B4. Rumination syndrome in adults
identified causal abnormality.
Organic versus idiopathic dyspepsia. From an
etiological viewpoint, patients with dyspeptic symptoms
fort centered in the upper abdomen and excluded reflux can be subdivided into 2 main categories:
symptoms.1 However, it has remained unsettled whether
discomfort is a mild variant of pain or a separate symp- 1. Those with an identified organic or metabolic cause for
tom complex.1,2 Moreover, discomfort comprised a large the symptoms where, if the disease improves or is elim-
number of nonpainful symptoms including upper ab- inated, symptoms also improve or resolve (eg, peptic
dominal fullness, early satiety, bloating, or nausea. Bloat- ulcer disease, GERD with or without esophagitis, ma-
ing is an unpleasant sensation of tightness and should be lignancy, pancreaticobiliary disease, or medication use).
distinguished from visible distention; usually, this symp- 2. Those with no identifiable explanation for the symp-
tom is not well localized and often occurs in IBS so toms. In some of these patients, an identifiable patho-
bloating was not considered a cardinal symptom of dys- physiological or microbiologic abnormality of uncer-
pepsia. Nausea (queasiness or sick sensation or a feeling tain clinical relevance (eg, Helicobacter pylori gastritis)
of the need to vomit) may occur with dyspepsia or IBS may be present, which is not thought to explain the
but is often from central origin and is also not considered symptoms. Others have abnormal motor or sensory
a localizing symptom.1– 4 Whether or not individual dysfunction (eg, altered gastric emptying, fundic dys-
symptoms such as upper abdominal fullness or bloating accommodation, or gastroduodenal hypersensitivity)
are labeled as pain by the patient may depend on cultural of uncertain significance. This broad group of patients
and linguistic factors and possibly education level.2 with idiopathic dyspepsia has previously been referred
Heartburn has been defined by the esophageal com- to as nonulcer dyspepsia, essential dyspepsia, idio-
mittee. A burning sensation confined to the epigastrium pathic dyspepsia, or FD. FD is currently the most
is not considered to be heartburn unless it also radiates recognized term in the literature.
retrosternally. In the past, heartburn (as well as acid
regurgitation) has often been included as sufficient on its Epidemiology
own to define dyspepsia.3 Heartburn is not considered a Approximately 20% to 30% of people in the com-
symptom that primarily arises from the gastroduode- munity each year report chronic or recurrent dyspeptic
num, and there is evidence that heartburn has moderate symptoms.6,7 Although these data represent uninvestigated
specificity for gastroesophageal reflux disease (GERD).4,5 dyspepsia and often also included heartburn, an organic
Hence, the committee concluded that heartburn is ex- cause is found in only a minority of dyspeptic subjects who

Table 2. Dyspeptic symptoms and their definitions

Symptom Definition
Epigastric pain Epigastric refers to the region between the umbilicus and lower end of the sternum, and marked by the
midclavicular lines. Pain refers to a subjective, unpleasant sensation; some patients may feel that
tissue damage is occurring. Other symptoms may be extremely bothersome without being interpreted
by the patient as pain.
Epigastric burning Epigastric refers to the region between the umbilicus and lower end of the sternum, and marked by the
midclavicular lines. Burning refers to an unpleasant subjective sensation of heat.
Postprandial fullness An unpleasant sensation like the prolonged persistence of food in the stomach
Early satiation A feeling that the stomach is overfilled soon after starting to eat, out of proportion to the size of the meal
being eaten, so that the meal cannot be finished. Previously, the term “early satiety” was used, but
satiation is the correct term for the disappearance of the sensation of appetite during food ingestion.
1468 TACK ET AL GASTROENTEROLOGY Vol. 130, No. 5

are investigated, and hence it is reasonable to assume that

B1. Diagnostic Criteria* for Functional
the majority would have functional dyspepsia.8,9 Based on
Dyspepsia
prospective studies of subjects who report dyspeptic symp- Must include
toms for the first time, the incidence is approximately 1%
1. One or more of:
per year.7,10 The majority of patients with unexplained
a. Bothersome postprandial fullness
dyspeptic symptoms continue to be symptomatic over the b. Early satiation
long-term despite periods of remission.11 Approximately, 1 c. Epigastric pain
in 2 subjects is estimated to seek health care for their d. Epigastric burning
dyspeptic symptoms at some time in their life.12 Pain AND
severity and anxiety (including fear of serious disease) appear 2. No evidence of structural disease (including at up-
to be factors associated with consulting behavior.12,13 per endoscopy) that is likely to explain the
Heterogeneity of FD Symptoms: Subgroups symptoms
It seems likely that chronic unexplained dyspepsia *Criteria fulfilled for the last 3 months with symptom onset
includes different types of patients with distinct underlying at least 6 months before diagnosis
pathophysiologies who require different management ap- B1a. Diagnostic Criteria* for Postprandial
proaches. However, it has been particularly difficult to Distress Syndrome
identify these subgroups reliably. Subclasses based on symp- Must include one or both of the following:
tom clusters have been proposed.6,14 In clinical practice, 1. Bothersome postprandial fullness, occurring
however, this classification showed great overlap between after ordinary sized meals, at least several
subclasses, limiting its value.7,15 times per week
Identifying the predominant symptom was shown to 2. Early satiation that prevents finishing a regular
distinguish subgroups with different demographic and meal, at least several times per week
symptomatic properties and with some relationship to pu- *Criteria fulfilled for the last 3 months with symptom onset
tative pathophysiological mechanisms like delayed gastric at least 6 months before diagnosis
emptying and presence of H pylori.15 Thus, the Rome II Supportive criteria
committee proposed a subdivision according to the predom- 1. Upper abdominal bloating or postprandial nausea
inant symptom being pain or discomfort, but this subdivi- or excessive belching can be present
sion has also been criticized because of the difficulty distin- 2. EPS may coexist
guishing pain from discomfort, the lack of an accepted
definition of the term predominant, number of patients who B1b. Diagnostic Criteria* for Epigastric Pain
Syndrome
do not fit into one of the subgroups, and especially the lack
of stability, even over short time periods.4,7,16 Must include all of the following:
A different approach was based on attempts to identify 1. Pain or burning localized to the epigastrium of at
pathophysiology-based subgroups. Thus, associations least moderate severity at least once per week
were shown between symptom patterns and delayed gas- 2. The pain is intermittent
3. Not generalized or localized to other abdomi-
tric emptying,17–19 impaired fundic accommodation,20
nal or chest regions
and visceral hypersensitivity.21 However, the association
4. Not relieved by defecation or passage of flatus
of these pathophysiological mechanisms with symptoms
5. Not fulfilling criteria for gallbladder and
has not been confirmed in other studies.22–24
sphincter of Oddi disorders
Diagnostic Criteria *Criteria fulfilled for the last 3 months with symptom onset
The committee proposed to define FD at 2 levels. A at least 6 months before diagnosis
general, more umbrella definition of FD, to be used mainly Supportive criteria
for clinical purposes, and although further research on more 1. The pain may be of a burning quality but without
specific definitions is ongoing, is provided under category a retrosternal component
B1. However, particularly for pathophysiological and ther- 2. The pain is commonly induced or relieved by
apeutic research purposes, newly defined entities of (1) ingestion of a meal but may occur while fasting
meal-induced dyspeptic symptoms (PDS, defined under 3. Postprandial distress syndrome may coexist
category B1a), and (2) epigastric pain (EPS, defined under
category B1b), should be used operatively.
April 2006 FUNCTIONAL GASTRODUODENAL DISORDERS 1469

Overlap with GERD and IBS. Heartburn, consid- heterogeneity of putative underlying pathophysiological
ered an esophageal symptom, as well as dyspepsia are mechanisms, and the association of symptoms with
extremely common, and some overlap between both is mechanisms is better for certain symptoms than for the
likely. The Rome II definition proposed to exclude pa- overall dyspepsia symptom complex.17–21,32 Moreover,
tients with predominant heartburn from the dyspepsia there is evidence for different response to therapy for
spectrum,1 but recent studies have shown that the pre- different subgroups in therapeutic studies in functional
dominant symptom approach does not reliably identify dyspepsia.28,31
all patients with GERD.25–28 In general, overlap of In clinical practice, in the absence of medication ap-
GERD with PDS or EPS is probably frequent and needs proved for functional dyspepsia, therapy is usually di-
to be carefully considered in both clinical practice and rected toward individual symptoms (eg, symptomatic
experimental trials. The committee recommends that the treatment of nausea), rather than the full symptom com-
presence of frequent and typical reflux symptoms should plex. In many clinical trials, different therapeutic re-
lead to a provisional diagnosis of GERD.29 In clinical sponses for different symptoms seem expected because
practice and for clinical trials, recognition of frequent strategies are used to enrich the patient population for
heartburn may be improved by a simple descriptive certain symptom profiles.31,41– 43 Based on these limita-
questionnaire.26,27 The presence of heartburn does not tions, the committee proposes to focus the notion of FD
exclude a diagnosis of PDS or EPS if dyspepsia persists into more distinctively defined disorders.
despite a trial of adequate acid suppression therapy. Factor analysis studies in the general population and
Overlap between dyspeptic symptoms and IBS is also in patients with idiopathic dyspeptic symptoms gener-
commonly observed, and overlap between IBS on one ally conclude that dyspeptic symptoms comprise 3 or 4
hand and PDS or EPS on the other hand is likely to different symptom groupings33– 40 (Table 3). By defini-
occur. The presence of IBS does not exclude the diagnosis tion, certain symptoms such as early satiation or post-
of any of these functional gastroduodenal disorders be- prandial fullness are related to the ingestion of a meal.
cause coexisting IBS was found to have a minor impact The factor analysis studies have uniformly identified a
on symptom pattern and putative pathophysiological separate factor of meal-related symptoms.7,33– 40 System-
mechanisms in FD.30 atic studies revealed that symptoms are induced or wors-
ened by meal ingestion in the majority of, but not all,
Rationale for Changes in Criteria From patients with dyspeptic symptoms.37,44 The committee
Rome II considers a distinction between meal-induced symptoms
The rationale for the proposed new classification and meal-unrelated symptoms to be both pathophysi-
was based on the inadequacy of prior approaches such as ologically and clinically relevant. Other consistently
the predominant symptom, the results of factor analysis found symptom groupings include an epigastric pain
in tertiary care and in the general population, clinical factor and a nausea factor (with or without vomit-
experience, and new observations in the peer-reviewed ing)33– 40 (Table 3). In some studies, belching also ap-
literature. Previously, all patients without definite struc- pears as a separate symptom group.34,38
tural or biochemical explanation for dyspeptic symptoms
were considered to have functional dyspepsia. The com- Clinical Evaluation
mittee agreed that there is a lack of uniform interpreta- The management of the patient with uninvesti-
tion and acceptance of the term FD at different levels of gated dyspeptic symptoms should not be confused with
practice, in different countries and with regulatory au- the approach to the patient whose dyspepsia has been
thorities. Despite the Rome II recommendations, several investigated.
recent large studies included heartburn and even acid
regurgitation as “typical symptoms of dyspepsia.”25,28,31 Patients With Uninvestigated Dyspeptic
There is also increasing evidence for the existence of Symptoms
different entities within the “dyspepsia symptom com- Evidence-based analysis45 suggests the following
plex.” There is no single symptom that is present in all 6-point management strategy for primary care physicians
patients with FD, and there is considerable variation in first seeing patients with dyspepsia:
the symptom pattern between patients.32 Factor analysis
studies in the general population and in patients with 1. Gather clinical evidence that symptoms most likely
idiopathic dyspeptic symptoms7,33– 40 have failed to sup- arise in the upper gastrointestinal tract.
port the existence of FD as a homogeneous condition. 2. Exclude alarm features (eg, unexplained weight loss,
Pathophysiological studies have provided evidence for recurrent vomiting, progressive dysphagia, and gas-
1470 TACK ET AL GASTROENTEROLOGY Vol. 130, No. 5

Table 3. Factor Analysis Studies of Dyspeptic Symptoms in the General Population and in Tertiary Care Functional Dyspepsia
Patients
Study Setting Symptom groupings
Westbrook, 200255 Dyspepsia questionnaire in random 3 dyspeptic symptom factors: an epigastric pain factor, an early
population sample (n ⫽ 2300) satiation/postprandial fullness factor, and a nausea factor. In
addition, a heartburn/regurgitation factor
Fischler, 200356 Dyspepsia questionnaire in 438 tertiary 4 dyspeptic symptom factors: an epigastric pain factor, a
care patients with idiopathic postprandial fullness/bloating factor, a
dyspeptic symptoms nausea/vomiting/satiation factor, and a belching factor
Tack, 200357 Dyspepsia questionnaire in 636 tertiary 3 dyspeptic symptom factors: an epigastric pain/burning/belching
care patients with idiopathic factor, a postprandial fullness/bloating/early satiation factor,
dyspeptic symptoms and a nausea/vomiting/satiation factor
Jones, 200358 Dyspepsia questionnaire in random 3 dyspeptic symptom factors: an epigastric pain factor, a
population sample (n ⫽ 888) postprandial fullness/early satiation factor, and a
nausea/vomiting factor
Kwan, 200359 Rome II questionnaire in 1012 3 dyspeptic symptom factors: an epigastric pain/discomfort factor,
functional gastrointestinal patients a postprandial fullness/early satiation/bloating factor, and a
nausea/vomiting factor
Whitehead, 200360 Rome II questionnaire in 1041 4 dyspeptic symptom factors: 2 epigastric pain factors, a nausea/
functional gastrointestinal patients vomiting/early satiation factor, and an upper abdominal bloating
factor
Camilleri, 200561 Telephone survey in random population 3 dyspeptic symptom factors: an epigastric
US sample (n ⫽ 21,128) pain/bloating/postprandial fullness factor, an early satiation/
postprandial fullness/loss of appetite factor, and a nausea
factor. In addition, a heartburn/regurgitation factor
Piessevaux, Face-to-face interview of general 4 dyspeptic symptom factors: an epigastric pain factor, a
200562 population sample (n ⫽ 2025) postprandial fullness/early satiation factor, a nausea factor, and
a belching factor

trointestinal blood loss), which are less common in with a high prevalence of H pylori–related peptic ulcer
general practice and which have a low positive pre- disease. Test and treat effectiveness decreases in case
dictive value for organic disease when present but of a low prevalence, which makes false-positive test-
which should still prompt investigation to exclude ing more likely.
serious disease.29,46 6. Prompt endoscopy is recommended in patients with
3. Exclude ingestion of aspirin and nonaspirin nonste- alarm symptoms or patients over a threshold age
roidal anti-inflammatory drugs (NSAIDs).47 (45–55 years, depending on health care access and
4. In the presence of typical reflux symptoms, a provi- incidence of malignant disease). Current evidence in-
sional diagnosis of GERD should be made.29 Physi- dicates that endoscopy first may be more cost-effec-
cians may initially prescribe proton pump inhibitors tive in older patients, that Hp testing followed by
(PPIs) empirically in patients who also have heart- endoscopy in Hp-positive patients may not be cost-
burn but should take into account that these drugs effective, and that many patients with negative H
may be less effective in FD without heartburn.25,28 If pylori tests will still need to undergo endoscopy be-
EPS or PDS symptoms persist despite an adequate cause of alarm features or age.55,56
PPI trial, GERD is an unlikely explanation.
5. Noninvasive testing of H pylori infection, followed by Patients With Functional Dyspepsia
eradication (“test and treat”) is a cost-effective ap- The available data in the literature are based on
proach that decreases the number of endoscopies.48 –51 functional dyspepsia; no data are available on diagnostic
This strategy is indicated for the patient with no approaches to the categories EPS or PDS as defined by the
alarm features.52 Test and treat is recommended as Rome III committee. Performance of an upper endoscopy
this strategy will cure most underlying peptic ulcer during a symptomatic period off acid-suppressant therapy is
disease and prevent future gastroduodenal disease, essential to identify functional dyspepsia appropriately by
although many infected patients with functional dys- excluding other important structural diseases. It is recom-
pepsia will not gain symptomatic benefit.53,54 In mended that biopsies be routinely obtained at the time of
those who fail treatment despite Hp eradication, a endoscopy to detect H pylori infection and, in view of the
trial of PPI therapy is a reasonable next step. The association of H pylori with peptic ulcer disease and dyspep-
yield of this approach is therefore highest in places sia, eradication is recommended in all positive cases.53,54,57
April 2006 FUNCTIONAL GASTRODUODENAL DISORDERS 1471

A barium meal study is less sensitive and specific than

upper endoscopy, and hence it is not generally recom-
mended. Ultrasonography is not recommended as a routine
clinical test because the yield is low in the absence of
symptoms or clinical features or biochemical tests sugges-
tive of biliary tract or pancreatic disease.58 Barium x-ray
study of the small bowel is only useful in case of suspected
mechanical obstruction.
A gastric-emptying study (eg, scintigraphy, 13C-octanoic
acid, or ultrasonography) is not currently recommended as a
routine clinical test because the results uncommonly alter
management. Recent studies have shown that less than
25% of patients with FD have delayed gastric emptying,
even when considering exclusively the Rome II subgroup of Figure 1. Prevalence of gastric emptying in the community: blood
donors without and with dyspepsia, and patients with documented
dysmotility-like dyspepsia.19,24,31 Inconsistent correlations functional dyspepsia. Gastric emptying was significantly slower in
have been shown between symptoms and abnormalities of healthy blood donors with symptoms versus those without, and was
gastric function assessed by gastric barostat or electrogas- slower in patients with functional dyspepsia compared with healthy
trography.31 None of these tests can be advocated in routine asymptomatic blood donors. (Reprinted from Haag et al. Gut 2004;
53:1445–1451).
clinical practice.
Physiologic Features
The available data in the literature are based on ty,32,64 reduced frequency of interdigestive migrating motor
FD patients as a group; no data are available on the complexes,65 impaired duodenal motor responses to acid
physiological features of the categories EPS or PDS as and nutrient infusion,66 and excess of phasic contractions of
newly defined by the Rome III committee. the fundus after the meal.67 Several studies have docu-
Little is known about the influence of nutrient intake in mented the presence of gastric dysrhythmias especially in
the etiology of FD.59 Neither smoking, alcohol, or NSAIDs the postprandial period in patients with FD.33,68
are considered to be risk factors for FD.60 However, patients Evidence of gastric hypersensitivity in a subset of
with FD are more likely to develop symptoms when treated functional dyspepsia is well documented in the litera-
with NSAIDs.61 Basal gastric acid secretion is within nor- ture.21,32,69 The brain centers involved in sensation of
mal limits in patients with FD,62 but acid-related symp- gastric stimuli like distention have been documented in
toms (perhaps through gastric or duodenal hypersensitivity, health,70,71 and full reports of the brain centers involved
see later) may arise in a subgroup of patients. in functional dyspepsia are awaited. Altered intestinal
The role of H pylori infection in FD has been controver- sensitivity has been observed in response to balloon
sial, but recent meta-analyses suggest a small benefit from distention or in response to duodenal acid or lipid infu-
H pylori eradication in infected patients. No consistent sion.72–74 A subset of dyspeptic patients has spontane-
disturbances of motor or sensory function of the upper gut ously increased duodenal acid exposure, and this is asso-
have been reported in H pylori–infected individuals.32,63 ciated with higher symptom intensity.75 The role of
There are several lines of evidence that gastrointestinal altered parasympathetic and sympathetic activity, of al-
motility is abnormal in a proportion of patients with FD. tered secretion of gastrointestinal hormones, and of G-
The contribution of motor abnormalities to symptom gen- protein polymorphisms requires further study.63,76,77
eration is incompletely established. Impaired (typically de-
layed) gastric emptying of solids is the most widely studied Psychological Features
motility disorder in dyspepsia.32 Figure 1 shows that gastric In dyspepsia, there is evidence of an association with
emptying is slower in patients with FD compared with psychopathological factors, and comorbidity with psychiat-
healthy controls. The delay in gastric emptying may be ric disorders, especially anxiety disorders, is high.12,13,32,78,79
more common among patients with fullness, nausea, and It is still unclear whether these psychopathological factors
vomiting and in females, but this is controversial.17–19,32 determine health care–seeking behavior, whether they play
Several studies show that the accommodation or volume a key role in the pathophysiology of the dyspepsia symptom
response of the stomach after a meal is reduced in ⬃40% of complex, or whether they reflect a common predisposition
patients with functional dyspepsia.20,32 Other disturbances for functional and psychological disorders. Abnormalities of
of upper gut motility are postprandial antral hypomotili- several psychosocial dimensions were found to be associated
1472 TACK ET AL GASTROENTEROLOGY Vol. 130, No. 5

with epigastric pain and with hypersensitivity to gastric gastroparesis,85,86 but its side effects and tachyphylaxis limit
distention in FD.34 its clinical utility. ABT-229, a synthetic motilin-like pro-
kinetic drug without antibacterial activity, was of no sig-
Treatment nificant benefit in functional dyspepsia over placebo, possi-
The available data in the literature apply to FD bly because the drug impairs fundic relaxation.41 Several
patients as a group; no data are available on treatment other approaches to FD, including fundus-relaxing drugs,
approaches to the categories EPS or PDS as newly defined new prokinetics, selective serotonin reuptake inhibitors, and
by the Rome III committee. Evaluation of pharmacotherapy visceral analgesic drugs are currently under investiga-
in FD is confounded by high placebo response rates from tion.87– 89
20% to 60%.80 Reassurance and explanation represent the The value of antidepressants in FD is not established.
first management step and may be sufficient in many pa- In 1 crossover trial of 7 patients, amitryptiline in low
tients. Stopping smoking and ceasing consumption of cof- doses improved symptoms but not visceral hypersensi-
fee, alcohol, or NSAIDs is commonly recommended, but tivity or sleep.90 Limited promising data are available on
there is no convincing evidence of efficacy.60 Although it psychotherapy or hypnotherapy,91,92 but more studies are
seems plausible to recommend taking several small low-fat needed.
meals per day, this has not been formally investigated.
Acid suppression is safe and remains first-line therapy in the B2. Belching Disorders
absence of H pylori infection; an adequate trial of therapy should
be given and stepped up if unsuccessful initially. Patients with Air swallowing during eating and drinking is a
dyspepsia often take antacids, although there is no proof of normal physiological event and so is venting of the ingested
efficacy.81 A Cochrane meta-analysis evaluating the efficacy of air during transient relaxations of the lower esophageal
H2-receptor antagonists in functional dyspepsia reported a sig- sphincter.93 Hence, belching can only be considered a dis-
nificant benefit over placebo with a number needed to treat of order when it becomes troublesome. The committee distin-
8.82 However, these trials were relatively small and heteroge- guishes aerophagia from unspecified excessive belching.
neous and often misclassified reflux disease as functional dys-
pepsia, which may account for much of the benefit. A meta-
analysis of controlled, randomized trials with PPIs in functional B2a. Diagnostic Criteria* for Aerophagia
dyspepsia reported that this class of agents was superior to Must include all of the following:
placebo with a number needed to treat of 7.83 Much of this
benefit may be explained by unrecognized GERD.26,31,83 Fur- 1. Troublesome repetitive belching at least sev-
thermore, epigastric pain, but not meal-related symptoms, eral times a week
seems to respond to a PPI.28,31,83 There is no evidence that 2. Air swallowing that is objectively observed or
high-dose PPI therapy is beneficial over standard dosing, but measured
an empiric trial of high-dose PPI in practice may be considered *Criteria fulfilled for the last 3 months with symptom onset
in difficult cases. at least 6 months before diagnosis.
A Cochrane meta-analysis reported an 8% pooled rela-
tive-risk reduction with eradication of H pylori compared B2b. Diagnostic Criteria* for Unspecified
with placebo at 12 months of follow-up.53 The number Excessive Belching
needed to treat was calculated to be 17. Because H pylori
Must include all of the following:
eradication can induce sustained remission in a small mi-
nority of patients, this should be routinely considered once 1. Troublesome repetitive belching at least sev-
the benefit and risks have been carefully discussed with the eral times a week
patient. 2. No evidence that excessive air swallowing un-
Gastroprokinetic drugs like metoclopramide, domperi- derlies the symptom
done, and cisapride appear efficacious in functional dyspep- *Criteria fulfilled for the last 3 months with symptom onset
sia compared with placebo but have been poorly stud- at least 6 months before diagnosis.
ied.82,84 Publication bias may also account in part for some
of the positive meta-analyses in the literature.82 Cisapride
has been withdrawn from most markets in the world be- Justification for Changes to the Criteria
cause of rare fatal arrhythmias. The macrolide antibiotic In the previous Rome II classification, aerophagia
erythromycin acts on the motilin receptor to increase gastric was described as an unusual disorder with excessive
emptying rate in patients with diabetic and idiopathic belching due to air swallowing. The committee decided
April 2006 FUNCTIONAL GASTRODUODENAL DISORDERS 1473

to expand the category based on consensus that excessive Vomiting refers to the forceful oral expulsion of gastric
belching is a presenting symptom and based on recent or intestinal content associated with contraction of the
evidence, obtained with intraluminal impedance mea- abdominal and chest wall muscles. Vomiting must be
surement of air transport in the esophagus,93 which distinguished from regurgitation and rumination.
confirms that different mechanisms of excessive belching
occur.94 Belching is usually an unconscious act, and the
motility patterns of belching are quite similar to those B3a. Diagnostic Criteria* for Chronic
found in gastroesophageal reflux.93 A recent study per- Idiopathic Nausea
formed by using intraluminal impedance measurement
in aerophagia patients revealed swallowing of air that Must include all of the following:
enters the esophagus very rapidly and is expulsed almost 1. Bothersome nausea, occurring at least several
immediately in the oral direction.94 This phenomenon of times per week
“supragastric belching,” clearly distinct from “gastric” 2. Not usually associated with vomiting
belching, is not accompanied by transient relaxation of 3. Absence of abnormalities at upper endoscopy
the lower esophageal sphincter and is only observed in or metabolic disease that explains the nausea
aerophagia.94
*Criteria fulfilled for the last 3 months with symptom onset
Clinical Evaluation at least 6 months before diagnosis
A positive diagnosis is based on a careful history B3b. Diagnostic Criteria* for Functional
and observation of air swallowing. In typical cases, no Vomiting
investigation is required. Excessive belching may also
accompany GERD, and in difficult cases, pH monitoring Must include all of the following:
or empirical acid suppressive therapy may be consid- 1. On average, 1 or more episodes of vomiting
ered.95 Belching is also often reported in dyspepsia in per week
which it does not respond to acid suppressive therapy.95 2. Absence of criteria for an eating disorder, ru-
In FD, belching is associated with hypersensitivity to mination, or major psychiatric disease accord-
gastric distention,21,32,34 which supports the concept that ing to DSM-IV
belching is induced to relieve upper abdominal discom- 3. Absence of self-induced vomiting and chronic
fort. Rumination can usually be distinguished by the cannabinoid use and absence of abnormalities
history and observation. It may be important to screen in the central nervous system or metabolic
for psychiatric disease, but there is no evidence of excess diseases to explain the recurrent vomiting
psychopathology in aerophagia or in functional dyspepsia
with symptoms of belching.34 *Criteria fulfilled for the last 3 months with symptom onset
at least 6 months before diagnosis
Treatment
B3c. Diagnostic Criteria* for Cyclic Vomit-
Explanation of the symptoms and reassurance are
ing Syndrome
important. The habit can sometimes be inhibited by
showing chest expansion and air ingestion as the patient Must include all of the following:
belches. Dietary modification (avoiding sucking candies
1. Stereotypical episodes of vomiting regarding
or chewing gum, eating slowly and encouraging small
onset (acute) and duration (less than 1 week)
swallows, and avoiding carbonated beverages) is often
2. Three or more discrete episodes in the prior
recommended but has not been rigorously tested. Behav-
year
ioral therapy seems helpful in some cases, but clinical
3. Absence of nausea and vomiting between episodes
trials are lacking. Studies investigating drug therapy
specifically in aerophagia are also lacking. *Criteria fulfilled for the last 3 months with symptom onset
at least 6 months before diagnosis
B3. Nausea and Vomiting Disorders Supportive criterion
History or family history of migraine headaches.
Definition
Nausea is a subjective symptom and can be de-
fined as an unpleasant sensation of the imminent need to Rationale for changes in criteria. After review of
vomit typically experienced in the epigastrium or throat. the available literature, a new category, CIN was added.
1474 TACK ET AL GASTROENTEROLOGY Vol. 130, No. 5

In the Rome II criteria, nausea was considered a symp- computed tomography enterography are performed to
tom of motility-like dyspepsia,1 but the committee de- exclude gastroduodenal disease and small bowel obstruc-
cided to revise this on the basis of factor analysis data, on tion. Biochemical testing is also essential to exclude
clinical experience that persistent nausea is often of cen- electrolyte abnormalities, hypercalcemia, hypothyroid-
tral or psychological origin, and on the lack of respon- ism, and Addison’s disease. If these tests are normal, then
siveness of this symptom to empiric therapy. it is reasonable to consider gastric-emptying evaluation
The committee slightly modified the previous defini- or gastrointestinal manometry. The use of electrogastog-
tion of functional vomiting based on the setting of raphy is not widely accepted, although gastric dysrhyth-
threshold frequencies and on the recognition of cannabi- mias may be recorded in some patients with unexplained
noid use as a mechanism. A new category, cyclical vom- nausea and vomiting with normal gastric emptying.101
iting in adults, was added based on expert opinion and a
Treatment
better appreciation that those with stereotypical attacks
of cyclical vomiting differ from those with functional The treatment of chronic idiopathic nausea is not
vomiting. defined. Antinausea drugs provide limited benefit em-
pirically. Commonly used antinauseants like prochlor-
Clinical Features perazine, diphenhydrinate, and cyclizine promethazine
Nausea is a common symptom, and the differen- have not been systematically studied in unexplained
tial diagnosis is wide. The committee recognized a group nausea and have many side effects. Modest symptom
of patients exist who have frequent unexplained nausea improvement has been shown with the 5-hydroxytryp-
with little or no vomiting. The mechanisms remain tamine3 antagonists ondansetron and alosetron over pla-
unknown. cebo in functional dyspepsia, but nausea has not been
In children, the syndrome of cyclical vomiting is well specifically studied.42,89 Low-dose tricyclic antidepres-
described (See “Childhood Functional Gastrointestinal Dis- sant therapy may be helpful anecdotally.
orders: Neonate/Toddler” on page 1519 in this issue). Al- In functional vomiting, management of nutritional
though it is rare, adults may develop cyclical vomiting in status and psychosocial support is important. The role of
middle age, and both men and women are affected.96,97 dietary and pharmacological therapy, both frequently
Only 1 in 4 adults had a history of migraine headaches. used, has not been specifically tested. There is also no
Adults have a mean of 4 cycles of vomiting per year, with evidence that medications are particularly useful in this
a mean duration of 6 days (range, 1–21) and an average group, although anecdotal reports suggest that tricyclic
symptom-free interval of 3 months (range, 0.5– 6).96,97 antidepressants are helpful.97,100 Antiemetic drugs can be
The mechanisms underlying functional and cyclic tried but are often of little value. Data are lacking on the
vomiting remain unknown. Major depression has been value of behavioral or psychotherapy.
linked to habitual postprandial and irregular vomiting, Patients with cyclical vomiting syndrome may re-
whereas conversion disorder may explain some cases of quire hospital admission and supportive care during
continuous vomiting.98 In cyclical vomiting in adults, severe bouts. Empiric treatments of antimigraine
psychiatric disease appears to be uncommon, with the medications have been used with anecdotal reports of
largest adult series suggesting only 20% having anxiety success, and a trial of antimigraine medications is
or another psychiatric disorder.98 worthwhile, especially when there is a family history
of migraine headaches. There are anecdotal reports on
Clinical Evaluation the use of beta-blockers, tricyclic antidepressants,
The differential diagnosis of recurrent nausea or cyproheptadine, ketorolac, and several others.96,97,102
vomiting is extensive. Many drugs, including cannabi-
noid use, may cause nausea and vomiting.99,100 In pa- B4. Rumination Syndrome
tients with a history of “vomiting,” rumination and Rumination syndrome is a condition character-
eating disorders need to be excluded by careful clinical ized by the repetitive, effortless regurgitation of recently
evaluation. ingested food into the mouth followed by rechewing and
It is particularly important to exclude intestinal ob- reswallowing or expulsion.103 Although initially de-
struction, gastroparesis, and intestinal pseudo-obstruc- scribed in infants and the developmentally disabled (ref-
tion as well metabolic and central nervous system disease erence to pediatric chapter), it is now widely recognized
(eg, brainstem lesions on magnetic resonance imaging) in that rumination syndrome occurs in males and females of
adults presenting with recurrent unexplained vomit- all ages and cognitive abilities.103,104 In general, rumi-
ing.99 An upper endoscopy and a small bowel x-ray or nation is more common in females than males.
April 2006 FUNCTIONAL GASTRODUODENAL DISORDERS 1475

Epidemiology 5. Regurgitation may be preceded by brisk voluntary

The epidemiology of rumination syndrome in the contraction of the abdominis rectus.
adult general population remains to be carefully defined, 6. There is usually lack of retching or nausea preceding
but clinical impression suggests it is rare. the regurgitation.
7. Patients make a conscious decision regarding the
regurgitant once it is present in the oropharynx. The
choice may depend on the social situation at the time.
B4. Diagnostic Criteria* for Rumination
Rumination is typically a “meal-in, meal-out, day-in,
Syndrome
day-out” behavior.
Must include both of the following:
An association between rumination and bulimia ner-
1. Persistent or recurrent regurgitation of re- vosa has been described,105 although bulimic patients
cently ingested food into the mouth with sub- tend to expel rather than reswallow food and may self-
sequent spitting or remastication and swal- induce vomiting. Pathophysiological mechanisms in-
lowing volved in rumination syndrome remain somewhat un-
2. Regurgitation is not preceded by retching clear, although all observations suggest some adaptation
*Criteria fulfilled for the last 3 months with symptom onset of the belch reflex that overcomes the resistance to ret-
at least 6 months before diagnosis rograde flow provided by the lower esophageal sphinc-
ter.105,106 Many patients have evidence of “pathological
Supportive criteria
gastroesophageal reflux” because pH monitoring shows
1. Regurgitation events are usually not preceded by ⬎4% time with intraesophageal pH below 4. However,
nausea careful study shows that this is typically in the first hour
2. Cessation of the process when the regurgitated after a meal and that the time that esophageal pH is ⬍4
material becomes acidic may be paradoxically low because food buffers the gastric
3. Regurgitant contains recognizable food with a acid during the postprandial period when repetitive re-
pleasant taste gurgitation occurs.

Treatment
Clinical Evaluation
Reassurance, explanation, and behavioral therapy
Rumination syndrome is a probably underappre-
are currently the mainstays of treatment in adolescents
ciated condition in adults who are often misdiagnosed as
and adults of normal intelligence with rumination syn-
having vomiting secondary to gastroparesis or gastro-
drome. PPIs are frequently used to suppress heartburn
esophageal reflux or anorexia or bulimia nervosa. Clinical
and to protect the esophageal mucosa while therapy is
experience suggests that many individuals with rumina-
instituted. The preferred behavioral treatment for rumi-
tion have additional symptoms including nausea, heart-
nation syndrome consists of habit reversal by using dia-
burn, abdominal discomfort, diarrhea, and/or constipa-
phragmatic breathing techniques to compete with the
tion. Weight loss can also be a prominent feature of
urge to regurgitate.107 Treatment of rumination in bu-
rumination syndrome, particularly in the adolescent pop-
limics has been reported to be less successful.
ulation.103,104 Typical clinical features include the fol-
lowing:
Future Research
1. Repetitive regurgitation of gastric contents begin-
Rome III Definitions for Gastroduodenal
ning within minutes of the start of a meal; this is to
Disorders
be contrasted with the typical history of vomiting in
the later postprandial period in patients with gastro- The relationship of the newly defined disorders
paresis. (PDS, EPS, CIN, and CVS) to each other, to pathophys-
2. Episodes often last 1–2 hours. iological mechanisms, and to response to therapy needs
3. The regurgitant consists of partially recognizable to be assessed. The epidemiology of these disorders will
food, which often has a pleasant taste according to the also need to be studied carefully.
patients.
4. The regurgitation is effortless or preceded by a sen- Mechanisms of Symptom Production
sation of belching immediately before the regurgita- The goal should be that the field moves to therapy
tion or arrival of food in the pharynx. based on identified mechanisms. This requires more ex-
1476 TACK ET AL GASTROENTEROLOGY Vol. 130, No. 5

tensive understanding of the physiological mechanisms 12. Koloski NA, Talley NJ, Boyce PM. Predictors of health care
seeking for irritable bowel syndrome and nonulcer dyspepsia: a
causing symptoms. critical review of the literature on symptom and psychosocial
factors. Am J Gastroenterol 2001;96:1340 –1349.
Diagnostic Issues 13. Talley NJ, Boyce P, Jones M. Dyspepsia and health care seeking
There is a great need for validated noninvasive in a community: how important are psychological factors? Dig
Dis Sci 1998;43:1016 –1022.
diagnostic methods to help the clinician evaluate the 14. Drossman DA, Thompson GW, Talley NJ, Funch-Jensen P, Jans-
etiology of symptoms and to target appropriate treat- sens J, Whitehead WE. Identification of subgroups of functional
ment. The pros and cons of the nutrient drink test need gastrointestinal disorders. Gastroenterol Int 1990;3:159 –172.
to be more thoroughly understood. 15. Stanghellini V, Tosetti C, Paternicoá A, et al. Predominant symp-
toms identify different subgroups in functional dyspepsia. Am J
Therapeutic Issues Gastroenterol 1999;94:2080 –2085.
16. Laheij RJ, De Koning RW, Horrevorts AM, Rongen RJ, Rossum
There is a need for further development of vali- LG, Witteman EM, Hermsen JT, Jansen JB. Predominant symp-
tom behavior in patients with persistent dyspepsia during treat-
dated endpoints that may serve as biomarkers in the
ment. J Clin Gastroenterol 2004;38:490 – 495.
development of novel treatment approaches. Medications 17. Stanghellini V, Tosetti C, Paternico A, et al. Risk indicators of
affecting the putative pathophysiological mechanisms delayed gastric emptying of solids in patients with functional
require further development. Combination therapies dyspepsia. Gastroenterology 1996;110:1036 –1042.
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lying single pathophysiology, or to correct more than one role of Helicobacter pylori infection and delayed gastric empty-
pathophysiology. The peripheral and central effects of ing. Am J Gastroenterol 1998;93:2082–2088.
selective serotonin reuptake inhibitor, tricyclic antide- 19. Sarnelli G, Caenepeel P, Geypens B, Janssens J, Tack J. Symp-
toms associated with impaired gastric emptying of solids and
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in health and dyspepsia require thorough characteriza- 783–788.
tion. Appropriate pharmacoeconomic studies are also 20. Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J. Role
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 GASTROENTEROLOGY 2006;130:1480 –1491

Functional Bowel Disorders

GEORGE F. LONGSTRETH,* W. GRANT THOMPSON,‡ WILLIAM D. CHEY,§ LESLEY A. HOUGHTON,储

FERMIN MEARIN,¶ and ROBIN C. SPILLER#
*Kaiser Permanente Medical Care Program, San Diego, California; ‡University of Ottawa, Ottawa, Canada; §University of Michigan, Ann Arbor,
Michigan; 储South Manchester University Hospital, Manchester, United Kingdom; ¶Institute of Functional and Motor Digestive Disorders,
Centro Médico Teknon, Barcelona, Spain; and #University Hospital, Nottingham, United Kingdom

Employing a consensus approach, our working team IBS, functional bloating, functional constipation, func-
critically considered the available evidence and mul- tional diarrhea, and unspecified functional bowel disor-
tinational expert criticism, revised the Rome II diag- der.
nostic criteria for the functional bowel disorders, and To separate these chronic conditions from transient
updated diagnosis and treatment recommendations. gut symptoms, they must have occurred for the first
Diagnosis of a functional bowel disorder (FBD) re-
time ⱖ6 months before the patient presents, and their
quires characteristic symptoms during the last 3
presence on ⱖ3 days a month during the last 3 months
months and onset >6 months ago. Alarm symptoms
suggest the possibility of structural disease, but do indicates current activity. Previous diagnostic criteria
not necessarily negate a diagnosis of an FBD. Irritable presumed the absence of a structural or biochemical
bowel syndrome (IBS), functional bloating, functional disorder. However, research will likely confirm that
constipation, and functional diarrhea are best identi- functional gut disorders manifest such findings.
fied by symptom-based approaches. Subtyping of IBS Moreover, IBS, functional bloating, functional consti-
is controversial, and we suggest it be based on stool pation and functional diarrhea may have multiple
form, which can be aided by use of the Bristol Stool etiologies.
Form Scale. Diagnostic testing should be guided by
the patient’s age, primary symptom characteristics,
and other clinical and laboratory features. Treatment Table 1. Functional Gastrointestinal Disorders
of FBDs is based on an individualized evaluation, C. Functional bowel disorders
explanation, and reassurance. Alterations in diet, drug C1. Irritable bowel syndrome
treatment aimed at predominant symptoms, and psy- C2. Functional bloating
C3. Functional constipation
chotherapy may be beneficial.
C4. Functional diarrhea
C5. Unspecified functional bowel
disorder
he functional bowel disorders (Table 1) are identified
T only by symptoms. Therefore, a symptom-based
classification is necessary for clinical diagnosis, evidence- C1. Irritable Bowel Syndrome
based management, and research. This 2006 working
Definition
team is the fourth since 1989 to address the diagnosis of
irritable bowel syndrome (IBS). The diagnostic criteria IBS is a functional bowel disorder in which ab-
and management recommendations of the last 3 teams dominal pain or discomfort is associated with defecation
are known as Rome I, II, and III and, unlike the 1989 or a change in bowel habit, and with features of disor-
document, they include diagnostic criteria for functional dered defecation.
bowel disorders (FBDs) other than IBS (see “The Road to
Rome” on page 1552 in this issue).

Abbreviations used in this paper: IBS-A, alternating irritable bowel

syndrome; IBS-C, irritable bowel syndrome with constipation; IBS-D,
Functional Bowel Disorders irritable bowel syndrome with diarrhea; IBS-M, mixed irritable bowel
Functional bowel disorders are functional gastroin- syndrome; NNT, number needed to treat.
© 2006 by the American Gastroenterological Association Institute
testinal disorders with symptoms attributable to the 0016-5085/06/$32.00
middle or lower gastrointestinal tract. These include the doi:10.1053/j.gastro.2005.11.061
April 2006 FUNCTIONAL BOWEL DISORDERS 1481

Epidemiology Table 2. Subtyping IBS by Predominant Stool Pattern

Throughout the world, about 10%–20% of adults 1. IBS with constipation (IBS-C)—hard or lumpy stoolsa ⱖ25% and
loose (mushy) or watery stoolsb ⬍25% of bowel movements.c
and adolescents have symptoms consistent with IBS, and 2. IBS with diarrhea (IBS-D)—loose (mushy) or watery stoolsb
most studies find a female predominance.1–3 IBS symp- ⱖ25% and hard or lumpy stoola ⬍25% of bowel movements.c
toms come and go over time, often overlap with other 3. Mixed IBS (IBS-M)—hard or lumpy stoolsa ⱖ25% and loose
(mushy) or watery stoolsb ⱖ25% of bowel movements.c
functional disorders,4 impair quality of life,5 and result 4. Unsubtyped IBS—insufficient abnormality of stool consistency to
in high health care costs.6 meet criteria for IBS-C, D, or M.c

Note. To subtype patients according to bowel habit for research or

clinical trials, the following subsclassification may be used (see Figure
1). The validity and stability of such subtypes over time is unknown
C1. Diagnostic Criteria* for Irritable Bowel
and should be the subject of future research.
Syndrome aBristol Stool Form Scale 1–2 (separate hard lumps like nuts [difficult

to pass] or sausage shaped but lumpy).

Recurrent abdominal pain or discomfort** bBristol Stool Form Scale 6 –7 (fluffy pieces with ragged edges, a
at least 3 days per month in the last 3 months mushy stool or watery, no solid pieces, entirely liquid).
associated with 2 or more of the following: cIn the absence of use of antidiarrheals or laxatives

1. Improvement with defecation

2. Onset associated with a change in frequency of Patient reports of “diarrhea” and “constipation” may
stool mislead physicians. The stool may be solid, though def-
3. Onset associated with a change in form (ap- ecation is frequent (pseudodiarrhea).9 Conversely, strain-
pearance) of stool ing to defecate may occur with soft or watery stools.
Some patients feel constipated because they have unpro-
*Criteria fulfilled for the last 3 months with symptom onset ductive urges to defecate or feelings of incomplete evac-
at least 6 months prior to diagnosis. uation that prompt them to strain after passing stool.
**Discomfort means an uncomfortable sensation not The need for accurate symptom description is corrobo-
described as pain. In pathophysiology research and rated by reports of straining, urgency, and incomplete
clinical trials, a pain/discomfort frequency of at least 2 evacuation across the spectrum of stool form.10,11 In
days a week during screening evaluation for subject subgroups identified by cluster analysis12 or symptoms,13
eligibility. most patients have a stool frequency within the normal
range regardless of bowel pattern. However, stool form
Supportive symptoms that are not part of the (from watery to hard) reflects intestinal transit time.9
Therefore, assuming no use of antidiarrheals or laxa-
diagnostic criteria include abnormal stool frequency ([a]
tives, we propose the system shown in Table 2. Research-
ⱕ3 bowel movements per week or [b] ⬎3 bowel move-
ers and practitioners should consider using the Bristol
ments per day), abnormal stool form ([c] lumpy/hard
Stool Form Scale (Table 3)9 to identify constipation as
stool or [d] loose/watery stool), [e] defecation straining,
types 1 and 2 and diarrhea as types 6 and 7.
[f] urgency, or also a feeling of incomplete bowel move-
Figure 1 describes the 4 possible bowel pattern sub-
ment, passing mucus, and bloating.
types at a particular point in time. Individuals with
The Rome II working team suggested 2 systems for
neither diarrhea nor constipation by these characteristics
classifying patients into diarrhea-predominant and con-
have unsubtyped IBS. Researchers have classified subjects
stipation-predominant subgroups based on the first 6 of
not fitting the IBS with diarrhea (IBS-D) or IBS with
these features.7,8 The Rome II book classification based
constipation (IBS-C) subtypes as having either mixed IBS
on the first 6 supportive symptoms includes: Diarrhea
(IBS-M)14 or alternating IBS (IBS-A),15,16 or have con-
predominant: 1 or more of b, d, f, and none of a, c, e, or
ⱖ2 of b, d, f, and 1 of a or e (c, hard/lumpy stool
Table 3. The Bristol Stool Form Scale
excluded); and Constipation predominant: ⱖ1 of a, c, e,
and none of b, d, f, or ⱖ2 of a, c, e, and 1 of b, d, f.7 Type Description
Both variations exclude patients with hard stools from 1 Separate hard lumps like nuts (difficult to pass)
the diarrhea subtype,7,8 but 1 version can include pa- 2 Sausage shaped but lumpy
3 Like a sausage but with cracks on its surface
tients with watery stools in the constipation subgroup.7 4 Like a sausage or snake, smooth and soft
Investigators have used these methods and modifications 5 Soft blobs with clear-cut edges (passed easily)
of them to select patients for treatment trials targeting a 6 Fluffy pieces with ragged edges, a mushy stool
7 Watery, no solid pieces, entirely liquid
specific bowel pattern.
1482 LONGSTRETH ET AL GASTROENTEROLOGY Vol. 130, No. 5

The Rome II subtyping using multiple criteria were

complex and difficult to use in practice. We therefore
simplified them by using only the most reliable criterion,
stool form. Current evidence indicates that bowel pattern
subtyping is best done according to stool form rather than
bowel frequency,9 –13,18 particularly IBS-M15; however, we
emphasize that bowel pattern subtypes are highly unstable.
In a patient population with approximately 33% prevalence
rates of IBS-D, IBS-C, and IBS-M, 75% of patients change
subtypes and 29% switch between IBS-C and IBS-D over 1
year.14 Other investigators report the IBS-M subtype in
about 50% of referred patients according to 3 sets of crite-
ria,15 and IBS-M is the most prevalent group in primary
care.16 In addition, a majority of patients have rapidly
fluctuating symptoms lasting from ⬍1 hour to ⬍1
week.15,16 Therefore, the rate of documented bowel pattern
change is a function of the data collection frequency, and
there are insufficient data upon which to recommend a time
period for defining IBS-A. In drug studies on patients
Figure 1. Two-dimensional display of the 4 possible IBS subtypes
according to bowel form at a particular point in time. IBS-C, IBS with subtyped by stool form, investigators may want to assess
constipation; IBS-D, IBS with diarrhea; IBS-M, mixed IBS; IBS-U, un- pharmacologic effects on stool frequency, straining, ur-
subtyped IBS. gency, and incomplete evacuation as well as stool form.
Although the committee recommends a change in subtyp-
sidered these terms synonymous.13 We prefer IBS-M for ing from the multisymptom Rome II classification to one
individuals with both diarrhea and constipation ⱖ25% based on stool form only, there are insufficient data to
of bowel movements. Whereas this classification is a exclude either classification at this time. Further validation
useful way of describing individuals at presentation, studies are needed.
their bowel habits often vary over time, and we propose Because of the characteristic symptom instability, we
the term IBS-A for such cases. prefer the terms IBS with constipation and IBS with diarrhea
instead of constipation- and diarrhea-predominant IBS. In this
Rationale for Changes in the Diagnostic categorical system, many people whose features place them
Criteria close to a subtype boundary change pattern without a major
The symptom criteria are useful for clinical practice, change in pathophysiology. Moreover, the heterogeneity
epidemiologic surveys, pathophysiology research, and ther- and variable natural history of IBS significantly limit clin-
apeutic trials. The symptom frequencies suggested for the ical trials of motility-active drugs and drug therapy in
FBDs are arbitrary and may need to be modified for differ- practice. In both research and practice, it may be desirable
ent purposes. Epidemiologists should explore several fre- to base drug use on a stronger bowel pattern predominance
quencies to understand their significance. In therapeutic than the requirements of this system.
trials, the higher the symptom frequency threshold for
subject enrollment, the larger the potential treatment effect Clinical Evaluation
and the smaller the number of subjects that may be needed Diagnosis depends on careful interpretation of the
to show a significant difference. However, such patients temporal relationships of pain/discomfort, bowel habit,
may be less likely to achieve satisfactory relief, and such and stool characteristics. Pain/discomfort related to def-
studies are less applicable to the general population. Hence, ecation is likely to be of bowel origin, whereas that
enrollment symptom criteria are critical. The recommended associated with exercise, movement, urination, or men-
threshold for pain or discomfort of ⱖ2 days a week for struation usually has a different cause. Fever, gastroin-
pathophysiology studies and clinical trials is reported by a testinal bleeding, weight loss, anemia, abdominal mass,
majority of IBS patients.16 About three fourths of patients and other “alarm” symptoms or signs are not due to IBS,
who rated their pain as at least moderate (not ignorable, but but may accompany it.
without affect on lifestyle) also had pain ⱖ2 days a week.17 In women, so-called pelvic pain,19 worsening of IBS
Because relief of pain/discomfort with defecation may be symptoms during menstruation,20 and dyspareunia or
incomplete,11 improved with defecation replaces relieved. other gynecologic symptoms may obscure the diagnosis.
April 2006 FUNCTIONAL BOWEL DISORDERS 1483

Incorrect symptom attribution can lead to hospitaliza- ceral hyperalgesia, disturbance of brain– gut interaction,
tion and surgery, especially cholecystectomy, appendec- abnormal central processing, autonomic and hormonal
tomy, and hysterectomy.21 The recognition and evalua- events, genetic and environmental factors, postinfectious
tion of bowel dysfunction in patients with “pelvic” or sequels, and psychosocial disturbance are variably in-
abdominal pain may reduce unnecessary surgery. volved, depending on the individual.30
Heartburn, fibromyalgia, headache, backache, genito-
urinary symptoms, and others are often associated with Psychosocial Features
IBS, but are not useful in diagnosing it. These symptoms Psychological disturbance, especially in referred
increase as the severity of IBS increases and may be patients, includes psychiatric disorders (eg, panic disor-
associated with psychological factors.4 Obviously, a com- der, generalized anxiety disorder, mood disorder, and
mon disorder such as IBS may coexist with organic posttraumatic stress disorder), sleep disturbance, and
gastrointestinal disease. There are no discriminating dysfunctional coping.31,32 A history of childhood abuse is
physical signs of IBS, but abdominal tenderness may be common.33 Although stressful life events sometimes cor-
present. Tensing the abdominal wall increases local ten- relate with symptom exacerbation, the nature of the link
derness associated with abdominal wall pain, whereas it between psychosocial factors and IBS is unclear.
lessens visceral tenderness by protecting the abdominal
organs (Carnett test).22 Treatment
Few tests are required for patients who have typical IBS Management depends on a confident diagnosis,
symptoms and no alarm features.23,24 Unnecessary investi- explanation of why symptoms occur, and suggestions for
gations may be costly and even harmful.25 Testing is based coping with them. Education about healthy lifestyle
on the patient’s age, duration and severity of symptoms, behaviors, reassurance that the symptoms are not due to
psychosocial factors, alarm symptoms, and family history of a life-threatening disease such as cancer, and establish-
gastrointestinal disease. Investigations may include a sig- ment of a therapeutic relationship are essential, and
moidoscopy or colonoscopy to rule out inflammation, tu- patients have a greater expectation of benefit from life-
mors, or melanosis coli owing to regular laxative use. Stool style modification than drugs.34 For such counseling,
examination for occult blood, leukocytes, or ova and para- individual35 or group36 interactions are effective.
sites (eg, Giardia) where they are endemic may be indicated, Most IBS patients present to primary care where phy-
but routine rectal biopsy and abdominal ultrasonography sicians are best positioned to know their histories, per-
usually are not. Many people who report severe lactose sonalities, and families. Specialists’ patients are more
intolerance absorb lactose normally with negligible symp- likely to have severe symptoms, depression, anxiety,
toms,26 undermining the value of documenting lactase de- panic, or other complicating psychosocial disorders that
ficiency. The discovery of diverticulosis does not change the require special treatment. In addition to allaying fear,
diagnosis of IBS. Some patients with celiac sprue have IBS physicians should uncover any unstated worries or ag-
symptoms.27 In IBS patients who were HLA-DQ2–positive gravating factors. It is important to assess the patient’s
and had intestinal antibodies to gliadin and other dietary quality of life and level of daily functioning, personality,
proteins, stool frequency and intestinal IgA levels decreased recent life stress (eg, divorce, bereavement, or job loss),
after gluten restriction.28 However, the available data sug- and any psychological disturbance.
gest testing for celiac disease only if indicated by clinical The type and severity of symptoms and the nature of
features and local prevalence.29 associated psychosocial issues determine treatment.30,37
A confident diagnosis that holds up over time can Psychological factors may alter symptom perception, and
usually be made through careful history taking, exami- the patient’s reaction to the symptoms may be more
nation, and limited laboratory and structural evaluations important than the symptoms themselves. Most patients
individualized to each patient’s needs. IBS is often prop- respond to psychological support, a strong physician–
erly diagnosed without testing. After diagnosis, a change patient relationship, and multicomponent treatment ap-
in the clinical features may warrant additional investi- proaches38 that reduce health care utilization. The phy-
gation. However, persistence and recurrence is expected, sician should be understanding, maintain patient
and needless investigation may undermine the patient’s contact, and prevent overtesting and harmful treatments.
confidence in the diagnosis and in the physician.25 Unsatisfied patients may consult many physicians, un-
dergo unjustified and hazardous investigation, take un-
Physiologic Features proven medication, and have unneeded surgery.21,25
IBS is best viewed as an interaction of important Patients should avoid nutritionally depleted diets and
biological and psychosocial factors. Altered motility, vis- have regular, unhurried meals. Lactose restriction usually
1484 LONGSTRETH ET AL GASTROENTEROLOGY Vol. 130, No. 5

Table 4. Possible Drugs for a Dominant Symptom in IBSa is unsatisfactory, commercial fiber analogs may help.47
Symptom Drug Dose The heterogeneous smooth-muscle relaxants are ques-
Diarrhea Loperamide 2–4 mg when necessary/ tionably beneficial for pain; trial deficiencies leave their
maximum 12 g/d efficacy in doubt.48 Furthermore, their availability varies
Cholestyramine resin 4 g with meal in Australia, Canada, Europe, and the United States.44
Alosetronb 0.5–1 mg bid (for severe
IBS, women)
Antidepressant drug therapy in lower than antidepres-
Constipation Psyllium husk 3.4 g bid with meals, then sant doses may be beneficial even if there is no major
adjust psychiatric comorbidity. For example, desipramine ben-
Methylcellulose 2 g bid with meals, then
efits women with moderate to severe IBS who do not
adjust
Calcium 1 g qd to qid discontinue the drug owing to side effects,49 and the
polycarbophil effect appears unrelated to the drug dose.50 Paroxetine
Lactulose syrup 10–20 g bid improves the physical component of quality of life of
70% sorbitol 15 mL bid
Polyethylene glycol 17 g in 8 oz water qd patients with severe IBS51 and is more effective than a
3350 high-fiber diet in improving global status.52 The narrow
Tegaserodc 6 mg bid (for IBS, women) therapeutic window for antidepressants suggests they be
Magnesium 2–4 tbsp qd
hydroxide
limited to patients with moderate or severe IBS.
Abdominal pain Smooth-muscle qd to qid ac Alosetron, a selective serotonin 5-HT3 receptor antago-
relaxantd nist, can decrease pain, urgency, stool frequency, and in-
Tricyclic Start 25–50 mg hs, then
crease global status in women with diarrhea and IBS. Based
antidepressants adjust
Selective serotonin Begin small dose, increase on rigorous studies, the number needed to treat (NNT) is
reuptake inhibitors as needed 7.53 Ischemic colitis and severe obstipation led to its with-
aLocal cost should be considered in drug choice. drawal, but it was reintroduced only in the United States
bAvailable only in the U.S. with restricted access and a risk management program. It
cUnavailable in the European Union.
dSelective antimuscarinic agents unavailable in the United States.
was efficacious and safe in a 48-week trial.54 Well-designed
studies of tegaserod, a partial 5-HT4 receptor agonist, found
it can improve overall status, stool frequency and form, ease
fails to improve symptoms,39 and dietary calcium restric- of evacuation, and bloating in women with IBS and con-
tion may be harmful. Excessive fructose40 and artificial stipation. In 8 studies, the NNT for daily doses of 12 mg
sweeteners, such as sorbitol or mannitol, may cause di- and 4 mg was 14 and 20, respectively,55 and it is as effective
arrhea, bloating, cramping, or flatulence. More data are in retreating patients as during initial therapy.56 Published
necessary before testing for IgG antibodies to certain trials comparing alosetron and tegaserod with conventional
foods can be recommended.41 Dietary fiber for IBS is anitdiarrheals and laxatives, respectively, are not available,
time honored, inexpensive, and safe, but poorly substan- and interpretation of NNT values calculated from older
tiated by clinical trials. Indeed, many patients believe studies of these agents is compromised by trial deficiencies.
bran exacerbates their symptoms,42 and the only substan- Preliminary trials of probiotics are encouraging, espe-
tial randomized controlled trial of bran suggested it cially symptom improvement and normalization of the
exacerbated flatulence and did not relieve pain.43 blood mononuclear cell ratio of an anti-inflammatory to
Drug therapy is directed toward the dominant symp- a proinflammatory cytokine in patients taking Bifidobac-
toms44 (Table 4). Their changeable nature13–16 and the terium infantis,57 but these studies need repeating in
complex interactions between the central and enteric larger numbers of patients before they can be considered
nervous systems circumscribe the effectiveness of specific established treatments. Small bowel bacterial over-
therapies. Researchers are searching for biomarkers and growth, as diagnosed by lactulose hydrogen breath test-
genetic polymorphisms that might identify patients ing is a suggested58 but disputed59 cause of IBS, and
most likely to respond to drugs. Early therapeutic trials antibiotics provide only transient benefit60 and risk Clos-
had significant methodological inadequacies, and defi- tridium difficile infection, allergic reactions, antimicrobial
ciencies and publication bias persist45,46 (see “Design of resistance, and chronic functional symptoms.61
Treatment Trials for Functional Gastrointestinal Disor- Cognitive– behavioral therapy, standard psychotherapy,
ders” on page 1538 in this issue). Drugs help only some and hypnotherapy may help selected IBS patients. Weekly
symptoms in selected patients. Loperamide may prevent cognitive– behavioral therapy for 12 weeks was better than
diarrhea when taken before a meal or an activity that weekly educational sessions,49 but depressed patients did
often leads to the symptom. Constipation is treated not respond; quality of life but not pain improved. Hypno-
initially with dietary fiber supplementation. If response therapy, the most thoroughly evaluated psychological treat-
April 2006 FUNCTIONAL BOWEL DISORDERS 1485

ment, normalizes rectal sensation,62 and 12 sessions benefit Because of the lack of data on bloating frequency, the
quality of life, anxiety, and depression in refractory patients frequency criterion is arbitrary and may need to be
(except men with IBS and diarrhea), and the benefits last modified for different purposes. Additional epidemio-
ⱖ5 years.63 However, trials of psychological therapy cannot logic research should investigate functional bloating.
be double blind, and treatment is time consuming, costly, Clinical Evaluation
and often unavailable.
Bloating is distinguished from other causes of ab-
dominal distention by its diurnal pattern. It may follow
C2. Functional Bloating
ingestion of specific foods. Excessive burping or flatus is
Definition sometimes present, but these may be unrelated to the
Functional bloating is a recurrent sensation of ab- bloating. Diarrhea, weight loss, or nutritional deficiency
dominal distention that may or may not be associated should prompt investigation for intestinal disease.
with measurable distention, but is not part of another Physiologic Features
functional bowel or gastroduodenal disorder.
No unified pathophysiologic mechanism can be
Epidemiology applied to all patients. Food intolerance, abnormal gut
bacterial flora, weak abdominal musculature, and abnor-
Most of the research on bloating has dealt with
mal retention of fluid inside and outside the gut do not
subjects who also have other functional gastrointestinal
appear to be significant factors. However, studies have
disorders; up to 96% of IBS patients report this symp-
documented both increased intestinal gas accumulation
tom. Community surveys reveal that about 10%–30% of
and abnormal gas transit. Visceral hyperalgesia may be
individuals report bloating during the previous year.64,65
important in some patients.68
It is about twice as common in women as men,66 and is
often associated with menses.67 Typically, it worsens Psychosocial Features
after meals and throughout the day and improves or No uniform psychological factors have been iden-
disappears overnight. Abdominal inductance plethys- tified.
68
mography confirms increased abdominal girth in some
bloated IBS patients.68 Treatment
Although the functional bloating criteria require the
absence of other disorders, most research has been done on
C2. Diagnostic Criteria* for Functional patients who have IBS or another disorder; therefore, treat-
Bloating ment of bloating is similar whether it is isolated or associ-
ated with another functional disorder. Most treatments are
Must include both of the following:
designed to reduce flatus or gut gas, which are of unproved
1. Recurrent feeling of bloating or visible disten- importance in bloating, and most are of unproven efficacy.
tion at least 3 days/month in 3 months Bloating may decrease if an associated gut syndrome such as
2. Insufficient criteria for a diagnosis of func- IBS or constipation is improved. If bloating is accompanied
tional dyspepsia, IBS, or other functional GI by diarrhea and worsens after ingesting dairy products, fresh
disorder fruits, or juices, further investigation or a dietary exclusion
*Criteria fulfilled for the last 3 months with symptom onset trial may be worthwhile. However, even patients with
at least 6 months prior to diagnosis proven lactase deficiency experience little or no bloating
after drinking 240 mL of milk.26 Avoiding flatogenic foods,
exercising, losing excess weight, and taking activated char-
Rationale for the Criteria coal are safe but unproven remedies.69,70 Data regarding the
Because abdominal as a modifier of bloating is use of surfactants such as simethicone are conflicting. An-
redundant, it was omitted. Fullness was also deleted, tibiotics are unlikely to help, but trials of probiotics are
because it may imply postprandial satiety, yet bloating encouraging.71 Beano, an over-the-counter oral ␤-glycosi-
occurs throughout the day. Importantly, bloating over- dase solution, may reduce rectal passage of gas without
laps with other functional disorders (eg, functional con- decreasing bloating and pain.72 Pancreatic enzymes reduce
stipation, IBS, and functional dyspepsia), epidemiologic bloating, gas, and fullness during and after high-calorie,
surveys and factor analyses do not convincingly demon- high-fat meal ingestion.73 Tegaserod improves bloating (a
strate a distinct bloating group, and physiologic studies secondary outcome measure) in some constipated female
of bloating have mainly been done on patients with IBS. IBS patients.74
1486 LONGSTRETH ET AL GASTROENTEROLOGY Vol. 130, No. 5

C3. Functional Constipation Rationale for Changes to Diagnostic

Criteria
Definition
A required frequency of “ⱖ25%” is substituted
Functional constipation is a functional bowel disorder
for “⬎25%” to maintain consistency with other FBD
that presents as persistently difficult, infrequent, or seem-
criteria. Studies using Rome II criteria yield a lower
ingly incomplete defecation, which do not meet IBS crite-
prevalence than those using Rome I criteria, because the
ria.
Rome II criteria did not allow for laxative-induced loose
Subjective and objective definitions of constipation in-
stools,66 an anomaly that is corrected in the Rome III
clude (1) straining, hard stools or scybala (hard, inspissated
stool), unproductive calls (“want to but cannot”), infrequent criteria.
stools, or incomplete evacuation; (2) ⬍3 bowel movements Clinical Evaluation
per week, daily stool weight ⬍35 g/day, or straining
The physician should clarify what the patient
⬎25% of the time; and (3) prolonged whole gut or colonic
means by constipation. Manual maneuvers to assist def-
transit. Stool frequency correlates poorly with colonic tran-
ecation or straining to expel soft stools suggest anorectal
sit, but one can estimate gut transit using the Bristol Stool
dysfunction, but are diagnostically unreliable.77 Transit
Form Scale (Table 2).9 Usually, there is no demonstrable
time can be estimated using the Bristol Scale (Table 2).9
physiological abnormality.
Evaluation of the patient’s gut symptoms, general health,
Epidemiology psychological status, use of constipating medications,
dietary fiber intake, and signs of medical illnesses (eg,
Constipation occurs in up to 27% of people de- hypothyroidism) should guide investigation. Physicians
pending on demographic factors, sampling, and defini- should perform perianal and anal examination to detect
tion.75 It affects all ages and is most common in women fecal impaction, anal stricture, rectal prolapse, mass, or
and non-whites. In 1 survey, the prevalence was sought abnormal perineal descent with straining. Laboratory
by 3 means: patient complaint, Rome I criteria, and tests are rarely helpful. Endoscopic evaluation of the
transit time (using the Bristol Scale).9,76 Approximately colon may be justified for patients ⬎50 with new symp-
8% had constipation by each definition, but only 2% toms or patients with alarm features or a family history
were constipated by all 3. Therefore, the concept of of colon cancer.
constipation is complicated by disagreement among pa- If fiber supplementation fails to help or worsens the
tients and doctors about its nature. constipation, measurements of whole gut transit time
may identify cases of anorectal dysfunction or colon
inertia. Using radiopaque markers, measurement of
C3. Diagnostic Criteria* for Functional whole gut transit time (primarily colon transit) is inex-
Constipation pensive, simple, and safe. Several methods produce sim-
1. Must include 2 or more of the following: ilar results.78,79 Retention of markers in the proximal or
a. Straining during at least 25% of defecations transverse colon suggests colonic dysfunction, and reten-
b. Lumpy or hard stools in at least 25% of tion in the rectosigmoid area suggests obstructed defe-
defecations cation. A radioisotope technique involves less radiation
c. Sensation of incomplete evacuation for at than plain x-rays and may provide more information,
least 25% of defecations helping to differentiate proximal colon emptying, pan-
d. Sensation of anorectal obstruction/block- colonic inertia, and dyssynergic defecation.
age for at least 25% of defecations Physiologic Factors
e. Manual maneuvers to facilitate at least 25%
Severe, intractable constipation may be due to
of defecations (eg, digital evacuation, sup-
colonic inertia or anorectal dyssynergia. These disorders
port of the pelvic floor)
may coexist, but most patients complaining of constipa-
f. Fewer than 3 defecations per week
tion have normal colonic transit and anorectal function
2. Loose stools are rarely present without the use
(see “Functional Anorectal Disorders” on page 1510 in
of laxatives
this issue).
3. There are insufficient criteria for IBS
Psychosocial Factors
*Criteria fulfilled for the last 3 months with symptom onset
at least 6 months prior to diagnosis No uniform psychological profile is applicable to
patients with constipation; however, patients with severe
April 2006 FUNCTIONAL BOWEL DISORDERS 1487

constipation and normal intestinal transit often have

increased psychological distress, and depressed patients C4. Diagnostic Criterion* for Functional
may have constipation.80 Diarrhea
Loose (mushy) or watery stools without pain
Treatment occurring in at least 75% of stools
Reassurance may convince some patients that *Criterion fulfilled for the last 3 months with symptom onset
failure to evacuate for 2 or 3 days is harmless. In- at least 6 months before diagnosis
creased fluid intake and physical exercise are unproven
measures.81 Physicians should stop or reduce any con- Rationale for the Criteria
stipating medication the patient may be taking and
Most people apply the term diarrhea to loose or
treat depression and hypothyroidism when present.
watery stools. Fewer individuals relate it to increased
Pharmacologic therapy is not advisable until general
frequency and urgency.89 Because rapid transit increases
and dietary measures are exhausted. There are few
the percentage of water in stool, stool form correlates
published trials of some commonly used medical ther-
well with transit.9 Soft stools are 85% water, and watery
apies.47
stools 90% with greatly reduced stool viscosity.90 Stool
The severity and nature of the symptoms guide
viscosity is critical because watery stool is difficult to
further treatment. The indigestible matter in dietary
retain, and anal contact with fluid causes extreme ur-
fiber increases fecal bulk by promoting fecal water-
gency. However, urgency alone unreliably indicates di-
holding capacity and bacterial proliferation. Other
arrhea and may be reported by individuals with hard,
bulking agents include psyllium, methyl cellulose,
pelletlike stools. Thus, stool form, not frequency, defines
and calcium polycarbophil. Although stimulating lax-
diarrhea. How often a symptom must occur to be sig-
atives such as bisacodyl, sodium picosulphate, or sen-
nificant depends on its troublesomeness. Just 1 episode of
nosides may be tried, their effectiveness and long-term
fecal incontinence is a serious problem for a patient,
safety have not been determined by placebo-controlled
whereas an occasional loose stool may not be.
trials; they were introduced in an era when high-
quality trials were not performed.82 Polyethylene gly- Clinical Evaluation
col solution,47 lactulose, and sorbitol83 may be useful. The combination of abdominal pain with intermit-
Tegaserod is superior to placebo for patients with tent diarrhea and constipation is highly suggestive of IBS,
chronic constipation.84,85 Recent studies suggest that and small-volume, frequent defecation is likely functional.
prostaglandin analogs may be helpful.47 Therapy of Pseudodiarrhea9 (frequent defecation and urgency with
anorectal dysfunction is discussed in “Functional Ano- solid stools) is not diarrhea. A stool diary incorporating the
rectal Disorders” on page 1510 in this issue. Bristol Stool Form Scale is a useful method to verify stool
form (Table 2).9 Dietary history can disclose poorly ab-
sorbed carbohydrate intake, such as lactose by patients with
C4. Functional Diarrhea hypolactasia, or “sugar-free” products containing fructose,
Definition sorbitol, or mannitol. Alcohol can cause diarrhea by impair-
Functional diarrhea is a continuous or recurrent ing sodium and water absorption from the small bowel.
syndrome characterized by the passage of loose (mushy) Physical examination should seek signs of anemia or mal-
or watery stools without abdominal pain or discomfort. nutrition. An abdominal mass suggests Crohn’s disease in
the young patient and cancer in the elderly patient. Rectal
examination, colon endoscopy, and biopsy can exclude vil-
Epidemiology lous adenoma, microscopic colitis, and inflammatory bowel
There are few studies in which functional diarrhea disease.
was specifically diagnosed as distinct from IBS-D, so it is Abnormal results of blood or stool tests or other alarm
impossible to provide a precise frequency. Unspecified features necessitate further tests. Features of malabsorp-
diarrhea was reported by 9.6% of Minnesota residents86 tion (malnutrition, weight loss, non– blood-loss anemia,
and 4.8% of people throughout the United States87; or electrolyte abnormalities) should provoke the appro-
however, its duration and frequency are uncertain. Al- priate antibody tests and/or duodenal biopsy for celiac
though a common reason for consulting a gastroenterol- disease. Where relevant, giardiasis and tropical sprue
ogist, diarrhea was a presenting complaint of ⬍2% of should be excluded. Barium small bowel radiography
general practice patients.88 may be necessary. Rarely, persistent diarrhea may require
1488 LONGSTRETH ET AL GASTROENTEROLOGY Vol. 130, No. 5

tests for bile acid malabsorption or, more practically, a Future Research Directions
trial of the bile acid-binding resin cholestyramine.91 Development of the Rome Criteria is a continuing
process, and the criteria should be updated as data allow.
Physiologic Factors
We suggest the following topics for research.
Few studies have addressed the physiology of
functional diarrhea. One such study found decreased 1. Perform long-term, longitudinal studies on patients
nonpropagating colonic contractions and increased prop- with disorders of bowel function to better determine
agating colonic contractions.92 the natural history, specifically regarding changing
severity and interchange among disorders and the
Psychosocial Factors predominant symptom.
Psychosocial factors have also received little re- 2. Direct more research to patients in primary care.
search attention apart from the finding of accelerated 3. Compare the efficacy of new drugs with that of older
colonic transit inducible by acute stress.93 ones (eg, antidiarrheal agents, laxatives, and antide-
pressants) and placebos.
Treatment 4. Study bloating with distention defined as a true
increase in abdominal girth.
Discussion of possible psychosocial factors, symp- 5. Further investigate the epidemiology of functional
tom explanation, and reassurance is important. Restric- bloating.
tion of foods, such as those containing sorbitol or caf- 6. Determine what the symptom terms (eg, bloating
feine, which seem provocative, may help. Empiric and discomfort) mean to patients with different dis-
antidiarrheal therapy (eg, diphenoxylate or loperimide) is orders and whether the meanings change across cul-
usually effective, especially if taken prophylactically, tures and countries.
such as before meals or public engagements94 (Table 4). 7. Use unobtrusive and ambulatory, objective measures
Alosetron slows transit and reduces the gastrocolonic of abdominal girth to investigate the pathophysiol-
response in normal volunteers and may improve diar- ogy of distention in functional disorders and its
rhea.53 However, it is expensive and of limited availabil- response to drugs.
ity only in the United States; there are no published, 8. Investigate pharmacologic modulation of sensorimo-
randomized, controlled trials in patients with functional tor function and the gut microflora to identify
diarrhea. Cholestyramine, an ion-exchange resin that mechanisms of bloating and/or distention.
binds bile acids and renders them biologically inactive, is 9. Develop effective psychological treatments that can
occasionally very effective.91 The prognosis of functional be provided by primary physicians.
diarrhea is uncertain, but it is often self-limited.95 10. Determine the features of colonic transit and stool
water content in idiopathic diarrhea.
11. Investigate histologic changes in mucosal biopsies
C5. Unspecified Functional Bowel
from patients with idiopathic diarrhea; for example,
Disorder lymphocytic infiltration that does not meet criteria
Individual symptoms discussed in the previous sec- for lymphocytic colitis.
tions are very common in the population. These occasionally 12. Investigate the main differences between functional
lead to medical consultation, yet are unaccompanied by diarrhea and IBS-D, including demographic features
other symptoms that satisfy criteria for a syndrome. Such and symptom pattern and whether they require dif-
symptoms are best classified as unspecified. ferent treatments.
13. Perform repeated physiologic evaluations, including
visceral sensitivity and motility, on IBS patients
C5. Diagnostic Criterion* for Unspecified during periods of changing bowel habit and symp-
Functional Bowel Disorder tom severity.
Bowel symptoms not attributable to an or-
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 GASTROENTEROLOGY 2006;130:1492–1497

Functional Abdominal Pain Syndrome

RAY E. CLOUSE,* EMERAN A. MAYER,‡ QASIM AZIZ,§ DOUGLAS A. DROSSMAN,储

DAN L. DUMITRASCU,¶ HUBERT MÖNNIKES,# and BRUCE D. NALIBOFF‡‡
*Division of Gastroenterology, Washington University, St Louis, Missouri; ‡University of California Los Angeles, Los Angeles, California;
§
University of Manchester, Manchester, UK; 储University of North Carolina–Chapel Hill, Chapel Hill, North Carolina; ¶University of Medicine and
Pharmacy “Iuliu Hatieganu,” Cluj, Romania; #Universitatsklinikum Chariter, Berlin, Germany; ‡‡University of California Los Angeles and VA
GLAHS, Los Angeles, California

Functional abdominal pain syndrome (FAPS) differs D. Functional Abdominal Pain

from the other functional bowel disorders; it is less Syndrome
common, symptoms largely are unrelated to food intake
and defecation, and it has higher comorbidity with psy- Definition
chiatric disorders. The etiology and pathophysiology are FAPS represents a pain syndrome attributed to
incompletely understood. Because FAPS likely repre- the abdomen that is poorly related to gut function, is
sents a heterogenous group of disorders, peripheral neu- associated with some loss of daily activities, and has been
ropathic pain mechanisms, alterations in endogenous present for at least 6 months. The pain is constant, nearly
pain modulation systems, or both may be involved in constant, or at least frequently recurring. The principal
any one patient. The diagnosis of FAPS is made on the criterion differentiating FAPS from other functional gas-
basis of positive symptom criteria and a longstanding trointestinal disorders, such as irritable bowel syndrome
history of symptoms; in the absence of alarm symp- (IBS) and functional dyspepsia, is the lack of symptom
toms, an extensive diagnostic evaluation is not required.
relationship to food intake or defecation. FAPS com-
Management is based on a therapeutic physician-pa-
monly is associated with a tendency to experience and
tient relationship and empirical treatment algorithms
report other somatic symptoms of discomfort, including
using various classes of centrally acting drugs, including
chronic pain thought to be related to the gynecologic or
antidepressants and anticonvulsants. The choice, dose,
and combination of drugs are influenced by psychiatric urinary systems. Psychological disturbances are more
comorbidities. Psychological treatment options include likely when pain is persistent over a long period of time,
psychotherapy, relaxation techniques, and hypnosis. Re- is associated with chronic pain behaviors, and/or domi-
fractory FAPS patients may benefit from a multidisci- nates the patient’s life.1 In psychiatric nosology, FAPS
plinary pain clinic approach. would qualify as a somatoform pain disorder and satisfy
a pain criterion toward the diagnosis of somatization
disorder.2
unctional abdominal pain syndrome (FAPS) repre-
F sents a chronic pain disorder localized to the abdo-
men with features that differentiate it from other painful
Epidemiology
The epidemiology of FAPS is incompletely known
functional gastrointestinal disorders. Like other func-
because of limited available data and methodological diffi-
tional gastrointestinal disorders, symptoms are not ex- culties in establishing a diagnosis that can be differentiated
plainable by a structural or metabolic disorder by using from other more common functional gastrointestinal disor-
currently available diagnostic methods. FAPS appears ders, such as IBS and functional dyspepsia. However, it is
highly related to alterations in endogenous pain modu- generally considered that FAPS is a less common functional
lation systems, including dysfunction of descending pain disorder than either IBS or functional dyspepsia. Reported
modulation and cortical pain modulation circuits. There prevalence figures in North America range from 0.5% to
is only 1 recognized diagnosis in this category of func- 2% and do not differ from those reported in other coun-
tional gastrointestinal disorders (Table 1).
Abbreviations used in this paper: FAPS, functional abdominal pain
syndrome; IBS, irritable bowel syndrome; TCAs, tricyclic antidepres-
sants.
Table 1. Functional Gastrointestinal Disorders © 2006 by the American Gastroenterological Association Institute
0016-5085/06/$32.00
D. Functional abdominal pain syndrome (FAPS)
doi:10.1053/j.gastro.2005.11.062
April 2006 FUNCTIONAL ABDOMINAL PAIN SYNDROME 1493

tries.3–5 The disorder is more common in women (female: Table 2. Symptom-Related Behaviors Often Seen in
male ⫽ 3:2),6 with prevalence peaking in the fourth decade Patients With FAPS
of life.6,7 Patients with FAPS have high work absenteeism Expressing pain of varying intensity through verbal and nonverbal
and health care utilization and, thus, impose a significant methods, may diminish when the patient is engaged in
distracting activities, but increase when discussing a
economic burden.3,6,8 psychologically distressing issue or during examination
Urgent reporting of intense symptoms disproportionate to available
clinical and laboratory data (eg, always rating the pain as “10”
on a scale from 1 to 10)
D. Diagnostic Criteria* for Functional Minimizing or denying a role for psychosocial contributors, or of
Abdominal Pain Syndrome evident anxiety or depression, or attributing them to the presence
of the pain rather than to understandable life circumstances
Must include all of the following: Requesting diagnostic studies or even exploratory surgery to
validate the condition as “organic”
1. Continuous or nearly continuous abdominal Focusing attention on complete relief of symptoms rather than
pain adaptation to a chronic disorder
2. No or only occasional relationship of pain with Seeking health care frequently
Taking limited personal responsibility for self-management, while
physiological events (eg, eating, defecation, or placing high expectations on the physician to achieve symptom
menses) relief
3. Some loss of daily functioning Making requests for narcotic analgesics when other treatment
options have been implemented
4. The pain is not feigned (eg, malingering)
5. Insufficient symptoms to meet criteria for an-
other functional gastrointestinal disorder that
would explain the pain social assessment, observation of symptom reporting be-
haviors (Table 2), and a detailed physical examination.
*Criteria fulfilled for the last 3 months with symptom onset By answering a few questions, the physician effectively
at least 6 months before diagnosis can appraise the clinical features of FAPS, identify the
key psychosocial contributions to the disorder, and in-
Rationale for Changes From Previous crease confidence in the diagnosis (Table 3).11
Criteria Typically, FAPS patients describe abdominal pain in
emotional terms,12 as constant and not influenced by
Studies determining the reliability of these crite-
eating or defecation, as involving a large anatomic area
ria in identifying a homogeneous population are lacking,
rather than a precise location, as one of several other
and subjects with various different explanations for pain
painful symptoms, and as a continuum of painful expe-
(in particular, chronic pain attributed to pelvic viscera)
riences beginning in childhood or recurring over time.
may be represented.9 A lack of relationship of pain in
For patients meeting diagnostic criteria for FAPS who
FAPS with defecation separates this diagnosis from the
exhibit a longstanding history of pain behaviors and
functional bowel disorders, but the distinction from IBS
certain psychosocial correlates, the clinical evaluation
has acknowledged difficulties and is not clearly based on
typically fails to disclose any other specific medical eti-
scientific evidence.10 The requirements for some loss of
ology to explain the illness.11 In the absence of alarm
daily functioning and that pain is not feigned are derived
features common to the functional gastrointestinal dis-
from the diagnostic criteria for somatization disorder and
orders, conservative efforts should be taken to exclude
undifferentiated somatoform disorder.2 Qualifiers in the
other medical conditions in a cost-effective manner. Fur-
criteria (eg, “occasional” and “some”) remain subjectively
ther detail regarding the clinical evaluation is beyond the
defined. Although discussed in the context of this article
as a functional gastrointestinal disorder, FAPS also
would qualify as a pain symptom contributing toward Table 3. Questions for Appraising Clinical Features of FAPS
these diagnoses in psychiatric nosology. While Identifying Key Psychosocial Contributors

Clinical Evaluation 1. What is the patient’s life history of illness?

2. Why is the patient presenting now for medical care?
A host of disorders can produce chronic abdomi- 3. Is there a history of traumatic life events?
4. What is the patient’s understanding of the illness?
nal pain, and the clinician should be aware of the ex- 5. What is the impact of the pain on activities and quality of life?
tended differential diagnosis.11 Algorithms to diagnose 6. Is there an associated psychiatric diagnosis?
and treat FAPS are empirical because objective scientific 7. What is the role of family or culture?
evidence to support a singular approach does not exist. It 8. What are the patient’s psychosocial impairments and resources?

is suggested that evaluation consist of a clinical/psycho- Adapted and reprinted with permission.11
1494 CLOUSE ET AL GASTROENTEROLOGY Vol. 130, No. 5

scope of this article but can be found in prior reviews on anxiety has been proposed recently as having a more
the subject.1,11 direct influence on pain than general anxiety,23 and this
construct also has been investigated in functional gastro-
Physiological Features intestinal disorders including abdominal pain.24 FAPS
The observations that symptoms are reported as may be seen with other somatoform disorders (eg, som-
constant and unrelated to physiological events along atization disorder, conversion disorder, and hypochondri-
with the common responsiveness of FAPS symptoms to asis).2 In a study of somatization disorder identified in a
low-dose tricyclic antidepressants point toward central primary-care population, abdominal pain was present in
neuropathic pain as a likely pathophysiological process.13 30% of subjects and was the third most frequent somatic
The common comorbidity of FAPS with psychiatric dis- symptom (after headache and back pain).25
orders (in particular, anxiety, depression, and somatiza- Pain beliefs and coping strategies are important in
tion) and the fact that chronic abdominal pain is com- chronic pain and somatoform disorders and are signifi-
mon in major depressive disorder14 suggest a prominent cant predictors of quality of life impairment and treat-
role of the central nervous system in altering pain mod- ment response.26 Patients may exhibit ineffective coping
ulation (cognitive or emotional). This does not exclude strategies (eg, “catastrophizing”) or have poor social or
the possibility that, as in other neuropathic pain condi- family support.27–31 Unresolved losses, including onset
tions, peripheral factors play a role in initiating or per- or exacerbation of symptoms after the death of a parent
petuating this chronic pain state; scientific evidence to or spouse, personally meaningful surgery (eg, hysterec-
support such a mechanism, however, is not available. tomy and ostomy), or interference with the outcome of a
Descending pain modulation systems (opoidergic, sero- pregnancy (abortion, stillbirth), are common in
tonergic, and noradrenergic pathways) originate in dis- FAPS.12,32 Histories of sexual and physical abuse are
tinct brainstem regions and modulate spinal cord excit- prevalent,33,34 but elevated rates are not specific for this
ability. It has been speculated that patients with various diagnosis. These histories predict poorer health status,35
chronic pain syndromes, including fibromyalgia and medical refractoriness, increased diagnostic and thera-
FAPS, have compromised ability to activate such endog- peutic procedures, and more frequent health care visits.33
enous pain inhibition systems15,16 or exhibit an imbal- Such trauma may increase awareness of bodily sensations,
ance between facilitatory and inhibitory systems. Recent although visceral pain thresholds are not reduced.36,37
studies performed by using functional brain–imaging
techniques identify interactions between prefrontal cor- Treatment
tical regions, limbic regions, and brainstem regions that In contrast to IBS, treatment recommendations
could provide the neurobiological substrate for the in- for patients with FAPS are empirical and not based on
fluence of cognitive factors on symptom perception in results from well-designed clinical trials. The accepted
FAPS.17,18 Belief systems and coping styles characteris- basis for clinical management of FAPS relies on estab-
tically seen in FAPS patients are consistent with the lishing an effective patient-physician relationship, fol-
possibility of altered influences of cortical networks (in- lowing a general treatment approach, and offering more
cluding prefrontal and parietal cortical regions) on lim- specific management that often encompasses a combina-
bic and pain modulation circuits.19 tion of treatment options.38 – 40 Factors that contribute to
an effective patient-physician relationship11,39,40 include
Psychological Features empathy toward the patient,41,42 patient education, val-
FAPS shows a close relationship with a variety of idation of the illness, reassurance, treatment negotiation,
psychiatric and psychological conditions. Clinical evi- and establishment of reasonable limits in time and effort.
dence suggests that there is a strong association of aver- Before implementing specific forms of therapy (eg, anti-
sive early life events and certain types of psychosocial depressants and anticonvulsants), the following general
stressors with increased pain reports among patients with aspects of care should be considered: setting of treatment
functional gastrointestinal disorders.20,21 The combina- goals, helping the patient take responsibility, basing
tion of genetic factors, vulnerability factors, and adult treatment on symptom severity and the degree of dis-
stress may determine in part the effectiveness of endog- ability, and referring to a mental health care professional
enous pain modulation systems and thereby influence or, if available, to a multidisciplinary pain treatment
development of FAPS. Population- and patient-based center in selected patients, particularly those with refrac-
studies have confirmed the significant association be- tory symptoms. Unfortunately, establishing a diagnosis,
tween chronic abdominal pain and affective disorders, an effective patient-physician relationship, and a general
especially anxiety and depression.22 Symptom-specific treatment plan often is overlooked. Lack of confident
April 2006 FUNCTIONAL ABDOMINAL PAIN SYNDROME 1495

diagnosis, nontherapeutic physician attitudes, excessive treating disability from refractory chronic pain.60 Al-
testing and treatment (including unnecessary surgery), though the various psychological treatments described
and patient cognitions often contribute to a cycle of earlier have been shown to improve mood, coping, qual-
ineffective, costly management.43 ity of life, and health care costs, they have less demon-
Pharmacological therapies. Antidepressants, par- strable impact on specific visceral or somatic symptoms,
ticularly tricyclic antidepressants (TCAs) in low daily dos- suggesting that their best use may be in combination
ages, are helpful in treating chronic pain and other painful with symptomatic treatment.44,61 Psychological treat-
functional gastrointestinal disorders, such as IBS, and may ment may be most accepted if presented as a parallel
be useful for the treatment of FAPS for both direct pain intervention with ongoing medical care, a means for
management effects and antidepressant effects.44,45 How- managing pain, and an attempt to reduce psychological
ever, evidence from controlled clinical trials for the effec- distress from the symptoms.
tiveness of antidepressants in FAPS or superiority of any 1 Complementary therapies. Complementary and
agent or antidepressant class in this disorder is not available. alternative therapies, such as spinal manipulation,62,63
In other chronic pain conditions, trials with TCAs generally massage,64 and acupuncture65 commonly are used by
have been more successful than those using selective sero- patients with chronic pain disorders, including FAPS,
tonin-reuptake inhibitors.46,47 Newer agents with com- although data supporting their use are limited. Few
bined serotonin and norepinephrine reuptake activity reports have described the use of transcutaneous electrical
(SNRIs, such as venlafaxine and duloxetine) have recognized nerve stimulation in patients with FAPS, and uncon-
pain-reducing effects in some somatic pain conditions and trolled results are indeterminant.66 Although uncon-
may prove useful in FAPS.48 Both selective serotonin- trolled studies suggest a significant diagnostic and ther-
reuptake inhibitors and SNRIs may be useful in the patient apeutic benefit of laparoscopy with intended adhesiolysis
with comorbid depression or anxiety. Most analgesics (eg, in patients with chronic abdominal pain tentatively at-
aspirin and nonsteroidal anti-inflammatory drugs) offer lit- tributed to adhesions from prior surgical procedures,67– 69
tle benefit, possibly because their actions primarily are the outcome may be placebo related and unsuspected
peripheral in location. Narcotic analgesics should be diagnoses are rare.70 A blinded, randomized trial of 100
avoided because of the likelihood of addiction and possibil- patients undergoing either laparoscopic adhesiolysis or
ity of narcotic bowel syndrome.49 Anticonvulsants have diagnostic laparoscopy alone found no advantage to ad-
been evaluated in chronic pain syndromes, such as chronic hesiolysis.71 This study also reported a significant im-
neuropathic pain, as alternatives to TCAs with fewer side provement in chronic abdominal pain over 6 months
effects. The most studied have been gabapentin, carbamaz- whether laparoscopy alone or laparoscopic adhesiolysis
epine, and lamotrigine.50 They have not been examined were performed, suggesting spontaneous improvement
specifically in abdominal pain disorders or FAPS, although in these patients over time.
there is a rationale51,52 and evidence of efficacy in chronic
pain management remains limited despite rather wide-
spread use.53 These agents are relatively safe and nonhab- Topics for Future Research
ituating,54 also may interrupt the cycle between pain and FAPS remains an underinvestigated disorder with
depression,55 and might prove beneficial as adjunctive little evidence-based research appearing since the last
agents in some refractory patients, although direct evidence edition of the Rome criteria. Evaluation of both diag-
is lacking. In summary, anecdotal reports and observed nostic and treatment approaches for their effectiveness in
benefits of some compounds in other chronic pain condi- clinical settings and studies of the long-term outcome of
tions provide the basis for pharmacological treatment of these approaches toward morbidity reduction are re-
FAPS not scientific evidence from controlled clinical trials. quired. Specific areas of desired investigation include the
Psychological therapy. No psychological treat- following: (1) further characterization of patients with
ment study specifically has targeted adult FAPS. How- FAPS to augment the diagnostic criteria and improve
ever, studies in other painful functional gastrointestinal their specificity; (2) better identification of the central
disorders and nongastrointestinal pain conditions sug- neurophysiological processes involved in symptom pro-
gest that psychological treatments would be beneficial. duction and effects of treatment on these processes; (3)
Interventions of potential benefit include cognitive be- clearer definition of investigative and management algo-
havioral therapy,44,56 dynamic or interpersonal psycho- rithms depending on presenting characteristics or by
therapy,57,58 hypnotherapy,59 and stress management. identification of clinical subgroups; (4) improved under-
Referral to pain treatment centers for multidisciplinary standing of the relationship of somatization and somati-
treatment programs may be the most efficient method of zation disorder to the presentation, management, and
1496 CLOUSE ET AL GASTROENTEROLOGY Vol. 130, No. 5

outcome of FAPS; (5) assessment of physician role in 15. Edwards RR, Ness TJ, Weigent DA, Fillingim RB. Individual differ-
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activation of endogenous inhibitory mechanisms in irritable
with clarification of their optimal use; (7) investigation
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52. Holzer P. Gastrointestinal pain in functional bowel disorders:
sensory neurons as novel drug targets. Expert Opin Ther Targets
2004;8:107–123.
53. Wiffen P, Collins S, McQuay H, Carroll D, Jadad A, Moore A. Received January 31, 2005. Accepted November 3, 2005.
Anticonvulsant drugs for acute and chronic pain. Cochrane Data- Address requests for reprints to: Ray E. Clouse, MD, Division of
base Syst Rev 2000;CD001133. Gastroenterology, Washington University School of Medicine, 660
54. Hansen HC. Treatment of chronic pain with antiepileptic drugs: a South Euclid Avenue, Campus Box 8124, St Louis, Missouri 63110.
new era. South Med J 1999;92:642– 649. e-mail: [email protected]; fax: (314) 454-5107.
 GASTROENTEROLOGY 2006;130:1498 –1509

Functional Gallbladder and Sphincter of Oddi Disorders

JOSE BEHAR,* ENRICO CORAZZIARI,‡ MOISES GUELRUD,§ WALTER HOGAN,¶ STUART SHERMAN,储
and JAMES TOOULI#
*Rhode Island Hospital and Brown University School of Medicine, Providence, Rhode Island; ‡Dipartimento di Scienze Cliniche Policlinico
Umberto I, Università La Sapienza, Roma, Italy; §Tufts-New England Medical Center, Tufts University School of Medicine, Boston,
Massachussetts; ¶Medical College of Wisconsin, Milwaukee, Wisconsin; 储Indiana University, Indianapolis, Indiana; and #Department of
Surgery, Flinders University of South Australia, Adelaide SA, Australia.

The functional disorder of the gallbladder (GB) is a motility cystic duct reflex that relaxes the gallbladder (GB).1,2
disorder caused initially either by metabolic abnormalities These pressure changes create a gradient between the
or by a primary motility alteration. The functional disorders common bile duct and the GB diverting the bile flow
of the sphincter of Oddi (SO) encompass motor abnormal- toward the GB through the cystic duct. However,
ities of either the biliary or the pancreatic SO. Dysfunction
about 25% of the hepatic bile manages to enter into
of the GB and/or biliary SO produce similar patterns of
pain. The pain caused by a dysfunction of the pancreatic
the duodenum probably in between phasic contrac-
SO can be similar to that of acute pancreatitis. The symp- tions of the SO.3 It also appears that during the
tom-based diagnostic criteria of motility dysfunction of the interdigestive and digestive phases bile is continu-
GB and biliary SO are episodes of moderate to severe ously mobilized by propulsive and nonpropulsive con-
steady pain located in the epigastrium and right upper tractions within the GB and through the cystic duct.
abdominal quadrant that last at least 30 minutes. GB The bile flow through the cystic duct is complex, and
motility disorder is suspected after gallstones and other several studies have shown that the flow through the
structural abnormalities have been excluded. This diagno- cystic duct is bidirectional. The bidirectional flow
sis should then be confirmed by a decreased GB ejection through the cystic duct can be best explained by the
fraction induced by cholecystokinin at cholescintigraphy
GB functioning as a bellows contracting and relaxing
and after disappearance of the recurrent biliary pain after
cholecystectomy. Symptoms of biliary SO dysfunction may
intermittently.4,5 The net effect during the interdiges-
be accompanied by features of transient biliary obstruc- tive phase is storage, whereas in the digestive phase it
tion, and those of pancreatic SO dysfunction are associ- is net emptying of bile from the GB. Some of the
ated with elevation of pancreatic enzymes and even pan- contractions are associated with emptying, whereas
creatitis. Biliary-type SO dysfunction is more frequently others are nonpropulsive and simply appear to stir its
recognized in postcholecystectomy patients. SO manome- bile contents.6 The physiological significance of the
try is valuable to select patients with sphincter dysfunction; nonpropulsive contractions is unclear, although they
however, because of the high incidence of complications, may stir the GB contents to avoid precipitation of
these patients should be referred to an expert unit for such relatively insoluble constituents such as cholesterol
assessment. Thus invasive tests should be performed only
and bilirubin. These propulsive contractions become
in the presence of compelling clinical evidence and after
noninvasive testing has yielded negative findings. The com-
stronger and propulsive during the phase III of the
mittee recommends that division of the biliary or pancre- migrating motor complex of the antrum, resulting in
atic sphincters only be considered when the patient has partial GB emptying. In the digestive phase, there is
severe symptoms, meets the required criteria, and other net bile emptying into the duodenum because of the
diagnoses are excluded. GB contraction and SO relaxation initiated by the
sequential activation of cephalic, antral, and intestinal
neurohormonal mechanisms. The SO also plays a rel-
he biliary tract transports, stores, and regulates
T the continuous secretion of hepatic bile. Bile is
transported by the intra- and extrahepatic bile ducts Abbreviations used in this paper: ERCP, endoscopic retrograde
cholangiopancreatography; ES, endoscopic sphincterotomy; GB, gall-
and delivered into the duodenum to contribute to the bladder; GERD, gastroesophageal reflux disease; IBS, irritable bowel
digestion and absorption of fats. During the interdi- syndrome; MRCP, magnetic resonance cholangiography; SO, sphincter
gestive phase, the resistance of the sphincter of Oddi of Oddi; SOM, sphincter of Oddi manometry; US, ultrasonography.
© 2006 by the American Gastroenterological Association Institute
(SO), mainly because of its phasic contractions, in- 0016-5085/06/$32.00
creases intraductal pressures triggering a choledocho- doi:10.1053/j.gastro.2005.11.063
April 2006 FUNCTIONAL DISORDERS OF GB AND SO 1499

evant role in regulating the flow of pancreatic secre- aspects appear to be variably interrelated with functional
tions into the duodenum. Derangements of any of gastrointestinal disorders. These relationships also may
these components may lead to intermittent upper occur in patients with functional disorders of the GB and
abdominal pain, transient elevations of liver or pan- SO. Our knowledge of their influence in these disorders
creatic enzymes, common bile duct dilatation, or ep- is limited because appropriate epidemiological studies
isodes of pancreatitis. have not been performed because of the lack of uniform
diagnostic criteria of these conditions.
It is also possible that the syndrome of chronic functional
E. Functional GB and SO Disorders
abdominal pain (see “Functional Abdominal Pain Syn-
GB and SO dysfunctions are relatively rare condi- drome” on page 1492 in this issue) may manifest itself with
tions, but their main clinical presentation, pain in the upper clinical characteristics similar to biliary pain. This condition
right abdominal quadrant and in the epigastrum, is not should be suspected in those patients in whom repeated
easily distinguished from that occurring in high prevalence episodes of biliary-like pain are not associated with any
conditions such as gastroesophageal reflux disease (GERD), laboratory, endoscopic, ultrasonographic, radiologic, scinti-
irritable bowel syndrome (IBS), functional dyspepsia, and graphic, or manometric findings that support the presence
cholelithiasis and in high risk complications caused by of biliopancreatic alterations.
cholecystitis and pancreatitis. In addition, SO dysfunction Patients with upper abdominal pain who do not meet
itself can be the cause of liver and pancreatic abnormalities. the Rome III symptom-based criteria for functional GB
Therefore, these disorders need to be excluded before pa- and SO pain should not be submitted to endoscopic
tients suspected of having functional disorders of the GB retrograde cholangiopancreatography (ERCP) or other
and SO are submitted to extensive investigations with invasive procedures. Those qualifying with the Rome III
invasive procedures and to inappropriate endoscopic and criteria should be assessed initially with noninvasive
surgical treatments. procedures and eventually with therapeutic trials that
The present diagnostic criteria and guidelines for clin- will more likely identify the majority of patients whose
ical evaluation and treatment have been developed taking pain is not of biliopancreatic origin and therefore will not
into consideration the peculiar aspects of functional dis- require any further investigation. This approach will also
orders of GB and SO that differ substantially from other select a small minority of those patients who may require
functional gastrointestinal disorders. As noted in Table further invasive procedures and who should be referred to
1, the functional GB and SO disorders (category E) are dedicated centers to the study and treatment of biliopan-
subcategorized into functional GB disorder (E1), func- creatic disorders with proper equipment and trained staff
tional biliary SO disorder (E2), and functional pancreatic (see clinical evaluation). Furthermore, the Geenen–
SO disorder (E3). In comparison to the previous Rome II Hogan biliary subtypes classification of SO dysfunction
criteria, the major change in the proposed criteria is to has been revised to avoid early ERCP investigation by
make them more stringent to reduce the number of using noninvasive imaging tests.
unnecessary invasive procedures and surgical operations The caution to avoid performing unnecessary ERCPs is
in patients presenting with upper abdominal pain. Bil- because of the potential complications of this procedure,
iary and pancreatic pain should be defined by site, sever- mainly pancreatitis, which vary widely with the experience
ity, modality of onset, duration and by the absence of of the endoscopist and whether it is performed for diagnos-
typical symptoms of GERD, functional dyspepsia, and tic or therapeutic purposes. In the literature, the incidence
IBS. The characteristics of biliary and pancreatic pain in of postprocedure pancreatitis can approach 24%, and major
these functional disorders of the GB and SO are not complications and death have been reported to vary from
substantiated by any published evidence. They are based 1.4% to 1.8% and 0% to 0.3%, respectively, for diagnostic
on similarities with the characteristics of the pain expe- procedure, and 5.0% to 9.0% and 0.5% to 0.9%, respec-
rienced by patients with biliary lithiasis and in those tively, for therapeutic procedure.
with pancreatitis. It is also based on the consensus
reached by the authors of this article. Consequently,
these consensus-based symptomatic criteria should be
considered only as a generalization that does not neces- Table 1. Functional Gastrointestinal Disorders
sarily hold true in every patient. However, by excluding E. Functional gallbladder and sphincter of Oddi disorders
GERD, IBS, functional dyspepsia, and chronic abdomi- E1. Functional gallbladder disorder
nal pain, it will be possible to reduce unnecessary inva- E2. Functional biliary sphincter of Oddi disorder
E3. Functional pancreatic sphincter of Oddi disorder
sive procedures and surgical interventions. Psychosocial
1500 BEHAR ET AL GASTROENTEROLOGY Vol. 130, No. 5

subjects with GB in situ varies from 7.6% in men to

E. Diagnostic Criteria for Functional GB
20.7% in women.9,10
and SO Disorders
Must include episodes of pain located in the
epigastrium and/or right upper quadrant and all E1. Diagnostic Criteria for Functional GB
of the following: Disorder
1. Episodes lasting 30 minutes or longer Must include all of the following:
2. Recurrent symptoms occurring at different in-
1. Criteria for functional GB and SO disorders
tervals (not daily)
2. GB is present
3. The pain builds up to a steady level
3. Normal liver enzymes, conjugated bilirubin,
4. The pain is moderate to severe enough to in-
and amylase/lipase
terrupt the patient’s daily activities or lead to
an emergency department visit
5. The pain is not relieved by bowel movements Clinical Presentation
6. The pain is not relieved by postural change The most specific symptom attributed to func-
7. The pain is not relieved by antacids tional disorders of the GB appears to be biliary pain, and
8. Exclusion of other structural disease that therefore the crucial steps in the diagnosis are a thorough
would explain the symptoms history supported by objective evidence of GB dysfunc-
Supportive criteria tion and exclusion of structural abnormalities. However,
The pain may present with 1 or more of the following: further research will be necessary to assess whether these
1. Pain is associated with nausea and vomiting rigidly defined criteria will be able to select patients with
2. Pain radiates to the back and/or right infrasub- functional GB disorders. These patients will need to be
scapular region evaluated with longer follow-ups for at least 1 year after
3. Pain awakens from sleep in the middle of the night cholecystectomy. In the meantime, we are proposing the
following criteria for this diagnosis:
1. Absence of gallstones, biliary sludge, or microlithiasis
E1. Functional GB Disorder 2. An abnormal GB ejection fraction of less than 40% by
using a continuous intravenous cholecystokinin octapep-
Definition tide infusion over a 30-minute period
GB dysfunction is a motility disorder of the GB 3. A positive therapeutic response with absence of the
that manifests symptomatically with biliary pain as a recurrent pain for longer than 12 months after
consequence of either an initial metabolic disorder (ie, cholecystectomy
supersaturated bile with cholesterol7) or a primary
Laboratory and Instrumental Investigations
motility alteration of the GB in the absence, at least
initially, of any abnormalities of bile composition.8 It The symptoms of GB dysfunction must be differ-
is likely that the latter condition, by causing bile entiated from organic disease and other more common
stasis, may alter over a period of time, bile recycling functional disorders including functional dyspepsia and
and bile composition within the GB. Both conditions IBS in which symptoms do occur daily for at least short
may eventually lead, over a period of time, to the intervals (few days or weeks).
Tests of liver biochemistries and pancreatic enzymes
development of organic abnormalities (eg, gallstones
should be obtained in those patients with the previously
and acute cholecystitis). The symptoms of these or-
mentioned symptomatic criteria. These tests are normal
ganic and functional conditions appear to be in-
in the presence of GB motility dysfunction. The findings
distinguishable from one another, and therefore their
of abnormal liver or pancreatic enzyme levels or both
differential diagnoses require a careful diagnostic indicate that other diagnoses should be considered. To
workup. rule out calculus biliary disease, which can produce sim-
ilar symptoms, the following investigations need to be
Epidemiology
performed; however, some of them may not be available
The prevalence of GB dysfunction is not known. and some are obsolete.
Large population-based studies have reported that prev- Ultrasound. Transabdominal ultrasonographic
alence of biliary pain in ultrasonography (US)-negative study of the entire upper abdomen is mandatory in
April 2006 FUNCTIONAL DISORDERS OF GB AND SO 1501

patients with the previously mentioned symptoms. In

the presence of GB dysfunction, the biliary tract and
pancreas appear normal on US. In particular, gallstones
or sludge cannot be shown. US usually detects stones
within the GB equal to or greater than 3 to 5 mm in
diameter, but it has a low sensitivity to detect smaller
stones.11 US detection of stones or sludge within the
common bile duct is even more difficult. Endoscopic US
is more sensitive than traditional transabdominal US in
detecting microlithiasis (tiny stones ⬍3 mm) and sludge
within the biliary tract.12
Endoscopy. In the presence of normal laboratory
and ultrasonographic findings, an upper gastrointestinal
endoscopy is usually indicated. The diagnosis of GB dys-
function is suspected in the absence of significant abnor-
malities in the esophagus, stomach, and duodenum.
Microscopic bile examination. To exclude micro-
lithiasis as a cause for these symptoms, a careful micro-
scopic examination of GB bile could be performed. The Figure 1. Algorithm of the diagnostic workup and management of
detection of microlithiasis and cholesterol microcrystals functional GB disorders.
is best accomplished by a careful examination of GB bile
obtained directly at the time of ERCP or by aspiration evidence of impaired GB motor function that, in the
from the duodenum during endoscopy after cholecysto- absence of lithiasis, could identify patients with primary
kinin (CCK) stimulation. The resultant bile should ap- GB dysfunction.
pear deep golden yellow to dark green-brown. Pale yel- The most widely used and validated stimulus to con-
low bile from the common duct is not appropriate. Even tract the GB has been the slow intravenous infusion of
in those patients with cholesterol gallstones or sludge, CCK analogs, especially CCK-8 over a 30-minute pe-
this hepatic bile is often free of cholesterol microcrystals riod.16,17 In some countries, CCK preparations have not
being insufficiently concentrated to nucleate. The col- been approved for human use. Fatty meals and variable
lected bile should be immediately centrifuged and ex- bolus injections of CCK do not yield consistent results.
amined. Two types of deposits may be evident: choles- Reduced emptying can arise from either impaired GB
terol crystals and/or calcium bilirubinate granules. contraction or increased resistance of the SO because of
Cholesterol microcrystals are birifringent and rhomboid an elevated basal tone. Furthermore, several other con-
shaped and best visualized by polarizing microscopy. The ditions that do not necessarily present with biliary pain
presence of cholesterol crystals provides a reasonably high can be associated with reduced GB emptying such as
diagnostic accuracy for microlithiasis13–15 if properly per- obesity, diabetes, and several drugs (eg, calcium channel
formed. Bilirubinate granules are red-brown and can be antagonists and oral contraceptives). An accurate medical
detected by simple light microscopy. These crystals are history should exclude secondary causes of impaired GB
significant only in freshly analyzed bile. motility. Two systematic reviews that did not discrimi-
Tests of GB motor dysfunction are shown in Figure 1. nate between slow and rapid intravenous infusion of
Assessment of GB emptying by cholescintig- CCK have concluded that there is no sufficient evidence
raphy. Cholescintigraphy is performed after the admin- to recommend the use of CCK cholescintigraphy to select
istration of technetium 99m–labelled iminodiacetic acid patients for cholecystectomy.18,19
analogs. These compounds have a high affinity for he- Assessment of volume changes by transabdominal
patic uptake, are readily excreted into the biliary tract, real-time US. Unlike cholescintigraphy, this method mea-
and concentrated in the GB. The net activity-time curve sures GB volume and obtains serial measurements during
for the GB is then derived from subsequent serial obser- fasting or after a meal or the intravenous infusion of CCK
vations, after either CCK administration or the ingestion analogs. In addition, US allows for assessment of residual
of a meal containing fat. GB emptying is usually ex- volume after emptying and the rate of refilling after GB
pressed as GB ejection fraction, which is the percentage contraction.
change of net GB counts after the cholecystokinetic US may be helpful when radiation should be avoided.
stimulus. A low GB ejection fraction has been considered One deficiency in the technique is the fact that it is
1502 BEHAR ET AL GASTROENTEROLOGY Vol. 130, No. 5

operator dependent, and the results may not be repro- may be present in patients with an intact GB, most of
ducible between different centers; therefore, the diagnos- the clinical data concerning SO dysfunction has been
tic role, if any, of ultrasonographic assessment of GB obtained from postcholecystectomy patients.
emptying has not become the standard in GB dys-
function. Further prospective randomized studies are
needed to better understand the predictive value of E2. Diagnostic Criteria for Functional
CCK cholescintigraphy or CCK US to recommend cho- Biliary SO Disorder
lecystectomy in patients with suspected GB motility
Must include both of the following:
dysfunction.
Pain provocation test. A stimulation test with 1. Criteria for functional GB and SO disorder
CCK attempting to duplicate biliary pain has been his- 2. Normal amylase/lipase
torically used as a diagnostic investigation. This test has Supportive criterion
low sensitivity and specificity in selecting patients with Elevated serum transaminases, alkaline phosphatase,
GB dysfunction who respond to therapy. This may relate or conjugated bilirubin temporally related to at least
to problems in the subjective assessment of pain and the two pain episodes
use of bolus injections of CCK. The latter can induce
pain by stimulating intestinal contractions.
Epidemiology
Diagnostic Workup for Patients With The prevalence of symptoms suggesting SO dys-
Suspected Functional GB Disorder function was noted in 1.5% of cholecystectomized pa-
Based on the consensus reached by the authors of tients in a survey on functional gastrointestinal disor-
this article, the diagnostic workup reported in Figure 1 ders.20 This survey confirmed that SO dysfunction affects
is recommended. The following comments summarize females more frequently than males and indicated a high
the proposed diagnostic workup. incidence of work absenteeism, disability, and health care
use.20 SO dysfunction has been detected in less than 1%
1. Symptoms consistent with a biliary tract etiology of a large consecutive series of cholecystectomized pa-
should be evaluated by US examination of the biliary tients and in 14% of a selected group of patients com-
tract, liver biochemistry, and pancreatic enzyme mea- plaining of postcholecystectomy symptoms.21
surements. If the results are normal, upper gastroin- Patients with biliary SO dysfunction after cholecys-
testinal endoscopy is recommended. tectomy have been arbitrarily classified according to their
2. If any of these investigations detect abnormalities, clinical presentation, laboratory results, imaging tests,
appropriate investigation and treatment should fol- and ERCP findings.22 The authors of this article have
low. revised this classification system to make it more appli-
3. If no abnormal findings are detected, a dynamic cable to clinical practice and, whenever possible, to avoid
cholescintigraphic GB study with the administration the invasive ERCP procedure. In this revised classifica-
of a CCK analog should be performed. tion system, noninvasive methods, instead of ERCP, are
4. If GB emptying is abnormal (⬍40%) and there are no used to measure the common bile duct diameter and
other conditions associated with reduced GB empty- suggest that contrast drainage times are not required.
ing, the diagnosis of GB dysfunction is likely; This revision is in accordance with the use of noninvasive
cholecystectomy is therefore the most appropriate imaging technique, namely US, in the early phases of the
treatment. diagnostic workup of biliopancreatic disease and does not
require contrast drainage times. The authors of this
E2. Functional Biliary SO Disorder article acknowledge that such revised classification sys-
tem is based on opinion and should be validated in future
Definition clinical studies. Type I patients present with biliary-type
SO dysfunction is the term used to define motility pain; abnormal aspartate aminotransferase, alanine ami-
abnormalities of the SO associated with pain, elevations notransferase, bilirubin, or alkaline phosphatase ⬎2
of liver or pancreatic enzymes, common bile duct dila- times normal values documented on 2 or more occasions;
tation, or episodes of pancreatitis. The SO is situated and dilated bile duct greater than 8 mm diameter at US.
strategically at the duodenal junction of the biliary and In biliary type I, 65% to 95% of the patients have
pancreatic ducts. SO dysfunction may result in either manometric evidence of biliary SO dysfunction, mainly
biliary or pancreatic disorders. Although SO dysfunction because of what is thought to be structural alteration of
April 2006 FUNCTIONAL DISORDERS OF GB AND SO 1503

the SO (stenosis).22,23 Type II patients present with etry. This technique is not widely available and is inva-
biliary-type pain and one of the previously mentioned sive with potential and frequent complications. Pro-
laboratory or imaging abnormalities. In biliary type II, longed studies in expert hands not only result in
50% to 63% of the patients have manometric evidence of suboptimal investigations but also may be associated
biliary SO dysfunction.22,23 Type III patients only com- with increased risk of complications, often pancreatitis.
plain of recurrent biliary-type pain and none of the In such circumstances, less invasive procedures should be
previously mentioned laboratory or imaging criteria. In considered first, and if a conclusion cannot be made with
biliary type III, 12% to 59% of the patients have man- this approach, the patient should be referred to an expert
ometric evidence of biliary SO dysfunction.22,23 biliopancreatic unit for further assessment.
SO dysfunction can involve abnormalities in the bili-
ary sphincter, pancreatic sphincter, or both. The true Noninvasive Indirect Methods
frequency would then depend on whether 1 or both
Serum biochemistry. SO dysfunction should be
sphincters were studied. One sphincter could be abnor-
mal and the other normal. In a study that investigated suspected in patients with recurrent and transient eleva-
360 patients by using biliary and pancreatic manome- tion of liver tests in close temporal relationship to at least
try,24 basal sphincter pressures higher than 40 mm Hg 2 episodes of biliary pain. However, the diagnostic sen-
were present in 11.4% in the biliary SO alone, in 18.9% sitivity and specificity of these abnormal liver tests are
in the pancreatic SO, and in 31.4%, both sphincters were relatively low.28
involved. Furthermore, the frequency of SO dysfunction Magnetic resonance cholangiopancreatography.
did not differ whether they were typed by biliary or When SO dysfunction is suspected, it is essential to rule out
pancreatic criteria. These findings were supported by a stones, tumors, or other obstructing lesions of the biliary
second study25 with 214 patients, who were labelled type tree that may mimic SO dysfunction. Magnetic resonance
III; 31% had both sphincter pressures elevated, 11% had cholangiopancreatography is the best noninvasive method
the biliary one alone, and 17% had the pancreas one to obtain a cholangiogram or a pancreatogram.29
alone. Overall, 59% of patients were found to have Pain provocative test using morphine (⫾ prostigmine) to
abnormal basal sphincter pressures. In the same study, detect SO dysfunction was greatly limited by a low sensi-
among the 123 patients categorized as biliary type II, tivity and specificity. They are no longer recommended.
both sphincters were elevated in 32%, the biliary sphinc- Ultrasonographic assessment of duct diameter. In
ter alone in 11%, and the pancreas alone in 22%. Over- the fasting state, the maximal diameter of common he-
all, 65% of type II patients had an abnormal SO ma- patic bile duct is normally 6 mm or less.30 A dilated
nometry. common bile duct of 8 mm or greater usually indicates
Clinical Presentation the presence of increased resistance to bile flow at the
level of the SO; however, the diagnostic usefulness of this
Patients present with intermittent episodes of finding may be limited because 3% to 4% of asymptom-
biliary pain sometimes accompanied by biochemical fea- atic cholecystectomized subjects have a dilated common
tures of transient biliary tract obstruction: elevated se-
bile duct.21
rum transaminases, alkaline phosphatase, or conjugated
In the fatty meal (cholecystokinin) stimulation test,
bilirubin (Table 1). SO dysfunction may exist in the
the fatty meals increase the bile flow caused by the
presence of an intact biliary tract with the GB in
endogenous release of CCK without increasing the bile
situ.26,27 Because the symptoms of SO or GB dysfunction
cannot be readily separated, the diagnosis of SO dysfunc- duct diameter. However, in the presence of a dysfunc-
tion is usually made after cholecystectomy or, less fre- tional SO, the duct dilates because of obstruction to the
quently, after proper investigations have excluded GB flow.31 Typically, the bile duct diameter is monitored by
abnormalities (normal ejection fraction). transabdominal US. The diagnostic yield of this test has
not been satisfactory when compared with the results of
Laboratory and Instrumental Investigations SO manometry. It is likely that sensitivity and specificity
The symptoms of SO dysfunction must be differ- of the test decrease markedly from group I to group III.31
entiated from organic disease and other more common However, an advantage of the US with a fatty meal is
functional disorders including functional dyspepsia and that it can be used in patients with a functioning GB. Its
IBS in which the pain does occur daily for at least short diagnostic usefulness is limited, but it can be used to
intervals (few days or weeks). The only method that can screen high-risk patients with suspected partial bile duct
directly assess the motor function of the SO is manom- obstruction.
1504 BEHAR ET AL GASTROENTEROLOGY Vol. 130, No. 5

Table 2. Pressure Profile of Sphincter of Oddi Measured at Common Bile Duct and Pancreatic Duct
Normala Abnormalb

CBD PD CBD and PD

Duct pressure (mm Hg) 7.4 ⫾ 1.7 8.0 ⫾ 1.6
Basal pressure (mm Hg) (8–26) 16.2 ⫾ 5.8 17.3 ⫾ 5.8 ⬎40 mm Hg
Phasic contractions 136.5 ⫾ 25.9 127.5 ⫾ 21.5 ⬎350 mm Hg
Amplitude (mm Hg) (82–180) (90–160)
Duration (sec) 4.7 ⫾ 0.9 4.8 ⫾ 0.7
(3–6) (4–6)
Frequency (/min) (3–10) (3–10) 5.7 ⫾ 1.4 5.8 ⫾ 1.5 ⬎7/min
Propagation sequence (%)
Simultaneous 55 (10–100) 53 (10–90)
Antegrade 34 (0–70) 35 (10–70)
Retrograde 11 (0–40) 12 (0–40) ⬎50%

CBD, common bile duct; PD, pancreatic duct.

aValuesare means ⫾ standard deviations; ranges are given in parentheses.
bAbnormal values for the CBD36 and the PD.37

Choledochoscintigraphy ([99mTc]/HIDA [hepatic patients in randomized controlled trials to examine the

iminodiacetic acid] scan). Dysfunction of the biliary impact and timing of these therapeutic maneuvers on
sphincter in postcholecystectomy patients may become clinical outcome.35
apparent when the radionuclide flow into the duodenum
is delayed. Several variables have been used to define a Invasive Direct Methods
positive (abnormal) study. A prolonged duodenal arrival Manometry. SO manometry is performed at the
time (choledochoscintigraphy) and a high Johns–Hop- time of ERCP. The variables customarily assessed at SO
kins scintigraphic score have been used.32,33 There is a manometry are basal pressure and amplitude, duration,
good direct correlation between choledochoscintigraphy frequency, and propagation pattern of the phasic waves.
and SO manometry. Normal and abnormal reference values for the SO mea-
Irrespective of the variable and method used, the sured at the common bile duct and Wirsung duct are
specificity of hepatobiliary scintigraphy was at least reported in Table 2.36,37
90%.34 The level of sensitivity has been reported to vary Basal sphincter pressures higher than 40 mm Hg
substantially according to the investigated variable and are the only manometric criterion used to diagnose SO
the method used. Moreover, case studies have shown that dysfunction. Other manometric abnormalities of the
choledochoscintigraphy may predict the outcome of SO include increased amplitude of phasic waves, para-
sphincterotomy in SO dysfunction,32 but randomized doxic response to CCK analogs, increased frequency of
studies are needed to support this conclusion. Its role in phasic waves, and increased number of retrograde
the selection of patients for the treatment of biliary SO waves. More than one of these manometric findings
dysfunction awaits future studies. may be found in postcholecystectomy patients with no
apparent organic alterations. However, most authori-
lnvasive Indirect Methods ties accept only the basal sphincter pressure as an
ERCP. Certain radiologic features during ERCP indicator of SO dysfunction.
such as a common bile duct diameter exceeding 12 mm
may suggest SO dysfunction.22 However, the radio- Diagnostic Workup for Patients With
graphic findings obtained at ERCP are not diagnostic of Suspected Functional Biliary SO Disorder
SO dysfunction. ERCP alone is generally not recom- in Cholecystectomized Patients
mended in the assessment of patients with suspected SO The diagnostic workup of patients without a GB
dysfunction because of the frequency of complications. If for suspected SO dysfunction as a cause of biliary-type
SO dysfunction is suspected, ERCP must be coupled pain begins with liver biochemistries and pancreatic
with a diagnostic SO manometry (SOM), possibly dual enzymes, plus a careful elimination of potential struc-
endoscopic sphincterotomy (ES), and possibly placement tural abnormalities of the biliary and gastrointestinal
of a pancreatic stent. ERCP with SOM and ES should tract. This would include transabdominal US, computed
ideally be performed at referral centers dedicated to the tomography scan, endoscopic US, magnetic resonance
study of biliopancreatic disorders that may include these cholangiography (MRCP), and ERCP, depending on the
April 2006 FUNCTIONAL DISORDERS OF GB AND SO 1505

therapeutic trial with this drug may be warranted before

submitting the patients to invasive procedures.36 Two
crossover clinical trials of relatively short duration (⬃12
or 16 weeks) showed symptomatic improvement over
placebo.38,39 However, these therapies need to be evalu-
ated with long-term double-blind clinical trials. If SO
dysfunction is detected at manometry in biliary type II
and III patients not responding to conservative treat-
ment, endoscopic sphincterotomy is indicated.
Patients with GB in situ. The diagnostic workup
of patients with GB in situ is part of the same diagnostic
algorithm that has initially excluded the presence of a
GB dysfunction. Two main indications are biliary pain in
subjects with normal GB ejection fraction and idiopathic
recurrent pancreatitis.

Figure 2. Algorithm of the history, diagnostic workup, and treatment E3. Functional Pancreatic SO
of patients suspected with types I, II, and III functional biliary SO
disorder. Disorder
The association between the dysfunction of the
resources available. The most practical diagnostic se- SO motility and recurrent episodes of pancreatitis has
quence suggested by the authors of this article is as been reported in case series.40,41 It has also been re-
follows: liver and pancreatic enzymes followed by an US, ported41,42 that total division of the SO in manometri-
MRCP, and then ERCP with SO manometry as needed cally identified patients with SO dysfunction results in
(Figure 2). abolition of the recurrent episodes of pancreatitis. How-
Choledochoscintigraphy may be a valuable noninva- ever, randomized controlled studies are needed.
sive test before a decision to undertake SO manometry is Patients report recurrent episodes of epigastric pain
made. SO manometry is recommended in biliary type II that are usually not distinguishable from biliary pain,
patients. In patients with biliary type III, invasive pro- although it can radiate through to the back. The pain
cedures should be avoided unless a proper clinical assess- episode is accompanied by elevated serum amylase and/or
ment has concluded that potential benefits exceed the lipase. In the absence of the traditional causes of pancre-
risk of complications. Noninvasive investigations and atitis (no stones, alcohol abuse, pancreas divisum, or any
therapeutic trials with proton pump inhibitors, spasmo- other uncommon causes of pancreatitis), the diagnosis of
lytic drugs, calcium blockers (nifedipine), and psycho- idiopathic recurrent pancreatitis should be considered. In
tropic agents should be attempted before performing the last decade, there have been a number of studies that
ERCP and SO manometry. have looked at the genetic makeup of patients with
ERCP with SO manometry is indicated if the pain is
idiopathic recurrent pancreatitis. These have resulted in
disabling, noninvasive investigations have not detected
mutations and polymorphisms that have been described.
structural abnormalities, and there is no favorable re-
Mutations in 3 genes, PRSS1, CFTR, and SPINK1, have
sponse to conservative therapy. As stated in the National
been associated with pancreatitis.43,44 These genetic mu-
Institutes of Health State of the Sciences Conferences in
ERCP, perendoscopic SO manometry should ideally be tations have been associated with early onset of pancre-
performed at specific referral centers.35 Endoscopic atitis. In addition, R122H or N29I mutations in cationic
sphincterotomy is the treatment of choice if SOD is trypsinogen gene (PRSS1) responsible for classic autoso-
detected at manometry. mal dominant form of hereditary pancreatitis have been
noted in patients with nonhereditary idiopathic recurrent
Treatment pancreatitis. Although these mutations have been iden-
Patients presenting with the characteristics of tified, their penetrance is low and indeed may only be
biliary type I SO dysfunction may undergo endoscopic sporadic in relationship to idiopathic recurrent pancre-
sphincterotomy without SO manometry. Nifedipine has atitis. Their role in the pathogenesis of this disease has
been reported to benefit biliary type II patients and a not been defined.
1506 BEHAR ET AL GASTROENTEROLOGY Vol. 130, No. 5

Epidemiology However, the sensitivity and specificity of this investi-

The majority of patients who present with SO gation have not as yet been determined.
Endoscopic US. Endoscopic US has also been
dysfunction causing recurrent episodes of acute pancre-
atitis are female.45 This is similar to the incidence for used in patients who present with recurrent pancreatitis,
biliary SO dysfunction. In populations of patients with and this investigation has been important in identifying
idiopathic recurrent pancreatitis, patients have a median patients with microlithiasis as the cause of the recurrent
age in the 40s. The manometric evidence of pancreatic episodes of pancreatitis. The value of endoscopic US is in
SO dysfunction has been reported in these patients to its ability to select patients in whom a motility disorder
vary from 15% to 72%.23,24,46,47 of the sphincter may not be the primary cause of the
episodes of pancreatitis.52
Invasive Methods
E3. Diagnostic Criteria for Functional
Manometry. Manometry of the SO during ERCP,
Pancreatic SO Disorder
which was first described over 30 years ago, remains the
Must include both of the following: most direct and objective investigation that selects pa-
1. Criteria for functional GB and SO disorder tients with pancreatic SO dysfunction associated with
2. Elevated amylase/lipase recurrent episodes of pancreatitis. The manometric tech-
nique has been well described previously.47 It is impor-
tant to note that recording from the pancreatic SO in
Clinical Presentation
patients with recurrent pancreatitis is important because
Patients present with intermittent episodes of pain a normal biliary SO may exist in the presence of an
that occur at intervals of months rather than days and are abnormal pancreatic SO.53,54 The major complication
usually associated with a significant rise in serum amylase after SO manometry is pancreatitis that may require
and lipase. Liver enzymes or bilirubin may also be elevated, hospital treatment for 48 to 72 hours. It seems that
depending on the severity of the pancreatitis. According to certain types of patients, rather than SO manometry per
the anecdotal experience of the authors of this article, in se, play a major role in postmanometry pancreatitis.55 To
most instances, pancreatitis is not severe when standard minimize this complication, some units routinely use
severity scores are used to evaluate these patients. pancreatic duct stenting after the procedure.56 Others use
an aspiration manometry catheter57 or electronic micro-
Instrumental Investigations transducers58 in the belief that water perfusion is the
Noninvasive procedures should be considered first. cause of the pancreatitis. Although all of these tech-
Noninvasive procedures. US of the upper abdo- niques have been suggested to reduce the incidence of
men excludes the presence of gallstones, but it does not complications, none have been universally adopted be-
usually reveal any abnormalities during an episode of cause there are no major studies that have shown their
acute pancreatitis. However, in the investigation of these efficacy. Most recently, a back-perfused sleeve manomet-
patients, US has been used to monitor the diameter of ric device has been developed.59 Such a device accurately
the pancreatic duct during secretin infusion. After the records SO pressures without perfusing water into the
infusion of secretin (1 U/kg per minute) in normal pancreatic duct. Its efficacy and safety have not been
subjects, the pancreatic duct dilates as secretin causes determined as yet.
increased secretion of pancreatic juice. On cessation of Botulinum toxin. More recently, injection of Bo-
the secretin infusion, the duct diameter returns to nor- tox into the SO has been used to select patients who
mal within 15 minutes. In patients with pancreatic SO will respond to division of the pancreatic sphincter.60
dysfunction, the pancreatic duct may remain dilated for Botulinum toxin produces a chemical sphincterotomy
a longer period.48 This method has been suggested to that lasts for approximately 3 months. In a limited
diagnose SO dysfunction, but it is not widely used study, it has been shown to select patients who will
because of its low sensitivity.49 respond well to division of the sphincter. Further
MRCP. MRCP has been used more recently to studies are required before this test can be recom-
evaluate the pancreatic duct in patients presenting with mended for this indication.
recurrent episodes of pancreatitis. Secretin infusion has Stent drainage. Drainage of the pancreatic duct
also been used to enhance the MRCP images of the by inserting a stent has also been used to select patients
pancreatic duct, and these studies have defined abnor- who may subsequently respond to sphincterotomy.61 The
malities in the duct that were hitherto unidentified.50,51 results of this approach have varied in different units, and
April 2006 FUNCTIONAL DISORDERS OF GB AND SO 1507

there are questions regarding possible damage on the diameter stent for a short period of time.41 The use of
pancreatic duct by the stent. stents has reduced the incidence of post-ERCP pancre-
atitis.63 The initial results of endoscopic treatments show
Diagnostic Workup for Patients With an efficacy that is similar to that of the surgical approach.
Suspected Functional Pancreatic SO However, long-term results of this endoscopic treatment
Disorder are not available at this time.
The diagnostic workup of patients presenting Botulinum toxin has been used to treat patients with
with pain episodes associated with elevated amylase/ SO dysfunction. However, botulinum is not effective
lipase requires a careful exclusion of potential structural because its effects are temporary. Similarly, it has not
abnormalities such as microlithiasis or pancreas divisum been shown that stenting of the pancreatic ducts has a
as the cause of pancreatitis. This includes transabdominal long-term positive outcome.
US, computed tomography scan, endoscopic US, MRCP,
and ERCP, depending on the patient’s clinical picture Conclusion and Future Directions
and resources available. The most practical diagnostic
sequence in these patients suggested by the authors of Functional disorders of the GB and biliopancre-
this article in these patients is as follows: after all the atic SO cause significant clinical symptoms that are
traditional aetiologies of pancreatitis have been excluded, clearly associated with motility abnormalities of the GB
patients should undergo liver biochemistry and pancre- and SO. However, several aspects of their pathophysiol-
atic enzymes followed by an US, endoscopic US and/or ogy and clinical symptomatology remain to be clarified.
MRCP, and then ERCP with bile analysis and SO ma- Future investigations should include clinical studies to
nometry as needed. study the following:
The investigation that has stood the test of time in 1. The natural history of functional GB disorders clearly
selecting patients who will respond best to division of distinguished from those associated with lithogenic
the sphincter is SO manometry.51 In a patient with the bile with excess cholesterol; therefore, it should in-
appropriate clinical presentation, a manometric finding clude analysis of the GB bile constituents and histo-
of SO basal pressures in excess of 40 mm Hg does result logical and biochemical parameters of inflammation
in a successful clinical outcome to treatment.45 In pa- in cholecystectomized specimens
tients with idiopathic recurrent pancreatitis, it is impor- 2. The potential role of psychosocial conditions and
tant to record from both the biliary and the pancreatic genetic factors on the pathogenesis of functional bil-
duct sphincter because on occasion abnormalities in the iary and pancreatic SO disorders
pancreatic SO may be noted in the presence of a normal 3. The relation of these biliopancreatic disorders with
manometry in the biliary SO. other GI functional disorders particularly with IBS
Treatment and nonulcer dyspepsia
4. The relation to functional GB disorders with or with-
The best available treatment for SO dysfunction out lithogenic bile with functional SO motility ab-
that produces recurrent episodes of pancreatitis is total normalities
division of the SO.40 – 42 The division ensures that both 5. The origin and pathogenesis of biliary pain in these
the biliary and the pancreatic sphincters are divided to functional conditions and whether they are associated
allow free drainage of pancreatic juice and bile into the with visceral hyperalgesia, particularly in the contro-
duodenum.62 This treatment is recommended only in versial biliary SO dysfunction type III
patients who have been shown by endoscopic manometry
to have abnormal SO dysfunction as demonstrated by an A number of noninvasive investigations have been
elevated SO basal pressure in excess of 40 mm Hg. developed that help to confirm the diagnosis of these
Traditionally, total division of the SO has been per- conditions; however, further evaluations are needed to
formed by an open transduodenal approach to the SO.40 assess the specific roles of cholescintigraphy in the diag-
Nowadays, the treatment of choice for pancreatic SO nosis and therapeutic outcome prediction of symptom-
dysfunction is the endoscopic division of the pancreatic atic functional disorders of the GB and SO and MRCP in
sphincter.42 Similar to the surgical approach, these pa- the visualization and dynamic assessment of the papillary
tients undergo division of the biliary sphincter and sub- region.
sequently division of the septum between the biliary and Multicenter randomized clinical trials should be di-
pancreatic ducts using diathermy techniques. The stent rected to the therapy of these conditions to assess the
is often left in the duct after the procedure using a small following:14,15
1508 BEHAR ET AL GASTROENTEROLOGY Vol. 130, No. 5

1. The medical treatment of functional disorders of the come after cholecystectomy? Am J Gastroenterol 1990;85:
986 –990.
GB and SO (from bile acids [ursodeoxycholic acid], 17. Yap L, Wycherley AG, Morphett AD, et al. Acalculous biliary pain:
prokinetics, and relaxants to targeted analgesics). Ur- cholecystectomy alleviates symptoms in patients with abnormal
sodeoxycholic acid may have a therapeutic potential cholescintigraphy. Gastroenterology 1991;101:786 –793.
because it has been recently shown that this hydro- 18. Delgado-Aros S, Cremonin F, Bredemoord AJ, Camilleri M. Sys-
tematic review and meta-analysis: does gallbladder ejection frac-
philic acid not only decreases the excess of cholesterol tion on cholecystokinin cholescintigraphy predict outcome after
from muscle cells in GBs with lithogenic bile but also cholecystectomy in suspected functional biliary pain? Aliment
normalizes the effects of oxidative stress, which may Pharmacol Ther 2003;18:167–174.
be applicable to the treatment of functional GB dis- 19. Di Baise JK, Olejnikov D. Does gallbladder ejection fraction pre-
dict outcome after cholecystectomy for suspected chronic acal-
orders. colous gallbladder dysfunction? A systematic review. Am J Gas-
2. Improved modes of evaluation of outcome studies. troenterol 2003;98:2605–2611.
20. Drossman DA, Li Z, Andruzzi E, et al. Householder survey of
functional GI disorders: prevalence, sociodemography and health
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creatic manometry in the evaluation of sphincter of Oddi function: Address requests for reprints to: Jose Behar, MD, Division of Gas-
a comparative pilot study in patients with idiopathic recurrent troenterology, APC 421, 593 Eddy Street, Providence, Rhode Island
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 GASTROENTEROLOGY 2006;130:1510 –1518

Functional Anorectal Disorders

ADIL E. BHARUCHA,* ARNOLD WALD,‡ PAUL ENCK,§ and SATISH RAO储
*Mayo Clinic, Rochester, Minnesota; ‡University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; §University
Hospitals Tuebingen, Tuebingen, Germany; and 储University of Iowa Hospital and Clinic, Iowa City, Iowa

This report defines criteria for diagnosing functional ano- anorectal function or bowel symptoms may be unclear
rectal disorders (ie, fecal incontinence, anorectal pain, because such abnormalities (eg, small anal sphincter de-
and disorders of defecation). Functional fecal inconti- fects, rectoceles) are often observed in asymptomatic
nence is defined as the uncontrolled passage of fecal subjects. (2) Organic lesions are influenced by behavioral
material recurring for >3 months in an individual with a
adaptations. For example, repeated straining to defecate
developmental age of >4 years that is associated with:
(1) abnormal functioning of normally innervated and
may contribute to rectal prolapse or pudendal nerve
structurally intact muscles, and/or (2) no or minor ab- injury. (3) Patients may have several structural or func-
normalities of sphincter structure and/or innervation tional disturbances, each of which may contribute to but
insufficient to explain fecal incontinence, and/or (3) cannot solely explain symptoms. For example, diarrhea
normal or disordered bowel habits (ie, fecal retention or may lead to fecal incontinence in patients with previ-
diarrhea), and/or (4) psychological causes. However, ously asymptomatic sphincter weakness.
conditions wherein structural and/or neurogenic abnor- The functional anorectal disorders are defined primar-
malities explain the symptom, or are part of a general- ily on the basis of symptoms (Table 1).2 Because patients
ized process (eg, diabetic neuropathy) are not included may not accurately recall bowel symptoms,3 reliability of
within functional fecal incontinence. Functional fecal
symptom reports can be improved by prospectively ob-
incontinence is a common, but underrecognized symp-
tom, which is equally prevalent in men and women, and tained symptom diaries.
can often cause considerable distress. The clinical fea- This report and the associated recommendations are
tures are useful for guiding diagnostic testing and ther- based on a review of the world literature by investigators
apy. Functional anorectal pain syndromes include proc- with longstanding interest in anorectal disorders. The di-
talgia fugax (fleeting pain) and chronic proctalgia; agnostic criteria include a minimum duration of symptoms
chronic proctalgia may be subdivided into levator ani so as to avoid the inclusion of self-limited conditions.
syndrome and unspecified anorectal pain, which are
defined by arbitrary clinical criteria. Functional defeca-
Table 1. Functional Gastrointestinal Disorders
tion disorders are characterized by 2 or more symptoms
of constipation, with >2 of the following features during F. Functional anorectal disorders
F1. Functional fecal incontinence
defecation: impaired evacuation, inappropriate contrac- F2. Functional anorectal pain
tion of the pelvic floor muscles, and inadequate propul- F2a. Chronic proctalgia
sive forces. Functional disorders of defecation may be F2a1. Levator ani syndrome
amenable to pelvic floor retraining by biofeedback ther- F2a2. Unspecified functional anorectal pain
F2b. Proctalgia fugax
apy (such as dyssynergic defecation).
F3. Functional defecation disorders
F3a. Dyssynergic defecation
F3b. Inadequate defecatory propulsion
onsistent with the other disorders encompassed in
C this supplement, the anorectal disorders are defined
by specific symptoms, and in one instance (functional F1. Functional Fecal Incontinence
disorders of defecation), also by abnormal diagnostic
tests. Our concepts of the pathophysiology of anorectal Fecal incontinence (FI) is defined as uncontrolled pas-
disorders continue to evolve with an increasing array of sage of fecal material recurring for ⱖ3 months. Leakage of
sophisticated tools that can characterize anorectal struc- flatus alone should not be characterized as FI, partly because
ture and function.1 These assessments may reveal distur- it is difficult to define when passage of flatus is abnormal. FI
bances of anorectal structure and/or function in patients should not be considered a medical problem earlier than age
who were hitherto considered to have an “idiopathic” or
“functional” disorder. Likewise, the distinction between Abbreviations used in this paper: EMG, electromyography; FI, fecal
“organic” and “functional” anorectal disorders may be incontinence.
© 2006 by the American Gastroenterological Association Institute
difficult to make in individual patients because (1) the 0016-5085/06/$32.00
causal relationship between structural abnormalities and doi:10.1053/j.gastro.2005.11.064
April 2006 FUNCTIONAL ANORECTAL DISORDERS 1511

4 years. FI can also be associated with organic disorders (eg, Rationale for Changes in Diagnostic Criteria
dementia, multiple sclerosis, Crohn’s disease). The spectrum of “functional” FI is broader com-
Epidemiology pared to the Rome II criteria because

FI is a common problem with a prevalence rang- 1. The relationship of structural disturbances (eg, anal
ing from 2.2%–15% in the community, and up to 46% sphincter defects visualized by imaging) to FI is often
in nursing homes.4 Differences in prevalence rates among unclear because even asymptomatic women may have
studies may be explained by variation in survey methods, small anal sphincter defects. Therefore, structural ab-
definitions of FI, and age distribution of populations normalities are not necessarily inconsistent with the
surveyed. In a recent community survey of adults aged diagnosis of functional FI.
40 years and older in the UK, 1.4% reported major FI 2. Limitations of testing hinder a precise assessment of
and 0.7% had major FI with bowel symptoms that had certain dysfunctions (eg, pudendal neuropathy). Anal
an impact on quality of life.5 Despite this impact, pa- sphincter electromyography (EMG), the only accurate
tients may not disclose the symptom to their physician technique for assessing indirectly for a pudendal neu-
unless they are asked about it, partly out of embarrass- ropathy, is not widely available. The revised criteria
ment. Age, gender, physical limitations, and general recognize that many patients with anal sphincter weak-
health are risk factors for FI in the community. Other ness may exhibit evidence of denervation/reinnervation
identified risk factors include diarrhea and rectal urgen- changes. Such patients are included within the category
cy.6 Among the elderly, cognitive and mobility impair- of functional FI, provided they do not have a generalized
ment, diarrhea, and fecal retention are significant risk disease process (eg, diabetes with peripheral neuropathy)
factors for functional FI.7,8 The extent to which other risk that can cause a pudendal neuropathy
factors (eg, obstetric or iatrogenic anal sphincter trauma) 3. The demonstration of mild anal sphincter denerva-
contribute to FI in the community is unclear. tion/reinnervation changes does not prove causality of
FI, especially in the presence of coexistent small
sphincter defects.
F1. Diagnostic Criteria* for Functional Clinical Evaluation
Fecal Incontinence
Organic causes of FI (eg, diabetes with peripheral
1. Recurrent uncontrolled passage of fecal material neuropathy, scleroderma, neurologic disorders) are gen-
in an individual with a developmental age of at erally identified by detailed clinical evaluation.
least 4 years and 1 or more of the following: A comprehensive clinical assessment is useful to elucidate
a. Abnormal functioning of normally inner- the etiology and pathophysiology of FI, evaluate severity of
vated and structurally intact muscles incontinence, establish rapport with the patient, and guide
b. Minor abnormalities of sphincter structure testing and treatment. The history should characterize the
and/or innervation; and/or type and frequency of FI, bowel patterns, awareness of the
c. Normal or disordered bowel habits (fecal desire to defecate prior to FI, and identify risk factors for
retention or diarrhea); and/or anorectal injury. Staining, soiling, and seepage reflect the
d. Psychological causes nature and severity of FI.5 Soiling indicates more leakage
AND than staining of underwear; soiling can be specified further,
2. Exclusion of all of the following: namely, of underwear, outer clothing, or furnishings/bed-
a. Abnormal innervation caused by lesion(s) ding. Seepage refers to leakage of small amounts of stool.
within the brain (eg, dementia), spinal cord Symptoms also provide clues to the pathophysiology of FI.
or sacral nerve roots or mixed lesions (eg, Incontinence for solid stool suggests more severe sphincter
multiple sclerosis), or as part of a general- weakness than does liquid stool alone. Urge incontinence
ized peripheral or autonomic neuropathy (ie, an exaggerated sensation of the desire to defecate before
(eg, owing to diabetes) leakage) is associated with reduced squeeze pressures and
b. Anal sphincter abnormalities associated with squeeze duration,9,10 reduced rectal capacity, and increased
a multisystem disease (eg, scleroderma) perception of rectal balloon distention.11 In contrast, passive
c. Structural or neurogenic abnormalities be- incontinence (ie, incontinence without awareness of the
lieved to be the major or primary cause of FI desire to defecate) is associated with lower resting pres-
*Criteria fulfilled for the last 3 months sures.9 The severity of FI and its impact on quality of life
can be summarized by specialized scales.12
1512 BHARUCHA ET AL GASTROENTEROLOGY Vol. 130, No. 5

The rectum should be examined before enemas or laxa- ternal and external sphincter abnormalities, and less
tives are given. In patients with FI, the rectal examination costly than MRI. Endoanal MRI may be useful for iden-
may disclose stool impaction in patients with fecal reten- tifying external sphincter atrophy,11 particularly prior to
tion, gaping of the external anal sphincter in patients with surgical repair of external sphincter defects.
neurologic or traumatic sphincter involvement, weak con- Pudendal nerve terminal motor latencies are of question-
traction of the external sphincter and puborectalis to volun- able utility for identifying a pudendal neuropathy; an
tary command, and/or dyssynergia during simulated evac- American Gastroenterological Association technical review
uation (discussed in the section on category F3 disorders).13 recommended that pudendal nerve terminal motor latencies
Diagnostic testing. Diagnostic testing is tailored should not be used for evaluating patients with FI.19 Needle
to the patient’s age, probable etiologic factors, symptom EMG can identify myogenic, neurogenic, or mixed (neuro-
severity, impact on quality of life, and response to con- genic and myogenic) injury affecting the external anal
servative medical management. sphincter, and is recommended when there is a clinical
Endoscopic assessment of the rectosigmoid mucosa, suspicion of a proximal neurogenic lesion, that is, involving
with biopsies if necessary, should be considered in pa- the sacral roots, conus, or cauda. Surface EMG is used as a
tients who have diarrhea or a recent change in bowel biofeedback signal for pelvic floor retraining of the external
habit; a colonoscopy may be desirable in certain circum- anal sphincter in FI.20
stances (eg, if the differential diagnosis includes colon Physiologic Factors
cancer or age appropriate colon cancer screening).
Fecal continence is maintained by anatomic factors
Manometry assesses continence and defecatory mecha-
(the pelvic barrier, rectal curvatures, and transverse rectal
nisms by determining the (1) resting anal pressure; (2)
folds), recto-anal sensation, rectal compliance and fecal con-
amplitude and duration of the squeeze response; (3) recto-
sistency, and delivery to the rectum. Decreased anal resting
anal inhibitory reflex; (4) threshold volume of rectal disten-
pressure may be associated with structural or functional
tion required to elicit the first sensation of distention, a
disturbances (defects and/or thinning) of the internal
sustained feeling of urgency to defecate, and the pain
sphincter. External anal sphincter weakness may result from
threshold or maximum tolerable volume; and (5) recto-anal
sphincter damage, neuropathy, myopathy, or reduced cor-
pressure changes during attempted defecation (see below).
ticospinal input. In addition to the anal sphincters, pubo-
The methods for conducting and analyzing anorectal ma-
rectalis function may also be impaired in FI.21
nometry are detailed elsewhere.14
The importance of rectal compliance and/or sensation for
Anal endosonography identifies anal sphincter thin-
maintaining continence is emphasized by the finding that
ning and defects,15 which are often clinically unrecog-
sphincter pressures alone do not always distinguish conti-
nized16 and may be amenable to surgical repair. En-
nent from incontinent subjects. Reduced rectal sensation
dosonography reliably identifies anatomic defects or
allows stool to leak through the anal canal before the
thinning of the internal sphincter.17 Interpretation of
external sphincter contracts.22,23 Decreased rectal sensitivity
external sphincter images is much more subjective, op-
and increased rectal compliance may also contribute to fecal
erator dependent, and confounded by normal anatomic
retention by decreasing the frequency and intensity of the
variations of the external sphincter.18
urge (and hence the motivation) to defecate. Increased rectal
Defecography records anorectal anatomy and pelvic floor
perception in some patients with FI may be a marker of
motion at rest, and during coughing, squeezing, and strain-
coexistent irritable bowel syndrome, or may be associated
ing to expel barium from the rectum. Methods for testing
with reduced rectal compliance23,24 or reduced rectal capac-
and interpretation are incompletely standardized,19 and
ity.11 Therefore, FI is a heterogeneous disorder in which
some findings (eg, pelvic floor prolapse and rectoceles) are
patients often exhibit ⬎1 deficit.
relatively common in asymptomatic older women. Defecog-
raphy is useful only for selected patients with FI, namely, to Treatment
identify or confirm rectal prolapse, excessive perineal de- Management of functional FI should be tailored
scent, a significant rectocele, an enterocele, or internal rectal to clinical manifestations. Restoring normal bowel habits
intussusception, particularly prior to surgery. by antidiarrheal agents (eg, loperamide) for diarrhea, and
Pelvic magnetic resonance imaging (MRI) is the only laxatives and/or suppositories for constipation, is often
imaging modality that can visualize both anal sphincter the cornerstone to effectively managing incontinence.
anatomy and global pelvic floor motion in real time Although uncontrolled studies report improved conti-
without radiation exposure.11 Endosonography is the first nence in ⬃70% of patients with FI after biofeedback
choice for anal sphincter imaging in FI, because it is therapy,20 a controlled study reported similar symptom
widely available, reasonably accurate for identifying in- improvement (⬃50%) in incontinent patients random-
April 2006 FUNCTIONAL ANORECTAL DISORDERS 1513

ized to standard medical/nursing care, that is, advice Rationale for Changes in Diagnostic
only, advice plus verbal instruction on sphincter exer- Classification System
cises, hospital-based computer-assisted sphincter pres-
In the previous classification, patients who had
sure biofeedback, or hospital biofeedback plus use of a
the above symptoms were characterized as “highly likely”
home EMG biofeedback device.25 Sacral nerve stimula-
or “possible” levator ani syndrome based on presence or
tion is an emerging option for FI; multicenter trials are
in progress in the United States and will provide a clear absence of tenderness during posterior traction on the
view of the value of this technique.26 puborectalis, respectively. This distinction is emphasized
by modifying the nomenclature in the current version. It
F2. Functional Anorectal Pain is recognized that symptoms present for ⬍3 months that
The 2 functional anorectal pain disorders (chronic are otherwise consistent with the diagnosis may warrant
proctalgia and proctalgia fugax) are distinguished on the clinical diagnosis and treatment, but for research studies,
basis of duration, frequency, and characteristic quality of symptoms should be present for ⱖ3 months.
pain. It is necessary to exclude other causes of anorectal
pain such as ischemia, fissures, and inflammation. The Clinical Evaluation
prevalence of anorectal pain in a sample of US house-
holders was 6.6% and was more common in women.27 The diagnosis is based on the presence of charac-
teristic symptoms and physical examination. During pu-
F2a. Chronic Proctalgia
borectalis palpation, tenderness may be predominantly
Chronic proctalgia is also called levator ani syndrome,
left sided, and massage of this muscle generally elicits
levator spasm, puborectalis syndrome, pyriformis syndrome, or pelvic
the characteristic discomfort. Evaluation often is neces-
tension myalgia. This is described as a vague, dull ache or
sary to exclude alternative diseases.
pressure sensation high in the rectum, often worse with
sitting than with standing or lying down.
Chronic proctalgia may be further characterized into Physiologic and Psychological Factors
levator ani syndrome or unspecified anorectal pain based Levator ani syndrome is hypothesized to result
on digital rectal examination. from overly contracted pelvic floor muscles. The etiology
is unknown. The pathophysiology of unspecified func-
tional anorectal pain is also poorly understood. Some
F2a. Diagnostic Criteria* for Chronic reports suggest that these disorders are associated with
Proctalgia
psychological distress, tension, and anxiety.28
Must include all of the following:
1. Chronic or recurrent rectal pain or aching Treatment
2. Episodes last at least 20 minutes Uncontrolled studies have evaluated a variety
3. Exclusion of other causes of rectal pain such as of treatments including electrogalvanic stimulation,
ischemia, inflammatory bowel disease, crypti- biofeedback training, muscle relaxants, digital massage
tis, intramuscular abscess and fissure, hemor- of the levator ani muscles, and sitz baths. A recent
rhoids, prostatitis, and coccygodynia double-blind, placebo-controlled study showed no effi-
*Criteria fulfilled for the last 3 months with symptom onset cacy of intrasphincteric injection of botulinum toxin A in
at least 6 months prior to diagnosis. levator ani syndrome.29 Surgery should be avoided.

F2a1. Levator Ani Syndrome F2b. Proctalgia Fugax

Proctalgia fugax is sudden, severe pain in the anal
Diagnostic Criterion
Symptom criteria for chronic proctalgia and tender- area lasting several seconds or minutes, and then disap-
ness during posterior traction on the puborectalis. pearing completely. Attacks are infrequent, occurring
⬍5 times per year in 51% of patients.30
F2a2. Unspecified Functional Anorectal Pain Community prevalence estimates range from 8%–
Diagnostic Criterion 18%, and are similar in men and women.27 Proctalgia
Symptom criteria for chronic proctalgia but no ten- fugax can be associated with disability, but only 17%–
derness during posterior traction on the puborectalis. 20% report the symptoms to their physicians. Symptoms
rarely begin before puberty.
1514 BHARUCHA ET AL GASTROENTEROLOGY Vol. 130, No. 5

tients have neither and some fulfill criteria for both.

F2b. Diagnostic Criteria* for Proctalgia
Functional defecation disorders are characterized by par-
Fugax
adoxical contraction or inadequate relaxation of the pel-
Must include all of the following: vic floor muscles during attempted defecation (dyssyner-
1. Recurrent episodes of pain localized to the gic defecation) or inadequate propulsive forces during
anus or lower rectum attempted defecation (inadequate defecatory propulsion).
2. Episodes last from seconds to minutes Dyssynergic defecation is preferred to pelvic floor dyssynergia
3. There is no anorectal pain between episodes because many patients with dyssynergic defecation do
not report sexual or urinary symptoms.39
*For research purposes, criteria must be fulfilled for 3
months; however, clinical diagnosis and evaluation may be
made before 3 months
F3. Diagnostic Criteria* for Functional
Defecation Disorders
Symptoms present for ⬍3 months that are other-
wise consistent with the diagnosis may warrant diagnosis 1. The patient must satisfy diagnostic criteria for
and treatment in clinical practice. However, for research functional constipation**
studies, symptoms should be present for ⱖ3 months. 2. During repeated attempts to defecate must
have at least 2 of the following:
Clinical Evaluation a. Evidence of impaired evacuation, based on
Diagnosis is based on the presence of characteris- balloon expulsion test or imaging
tic symptoms as described and exclusion of anorectal and b. Inappropriate contraction of the pelvic floor
pelvic pathophysiology. Certain urogenital abnormalities muscles (ie, anal sphincter or puborectalis)
and chronic benign prostatitis may be mistaken for or less than 20% relaxation of basal resting
proctalgia fugax. sphincter pressure by manometry, imaging,
or EMG
Physiologic and Psychological Factors
c. Inadequate propulsive forces assessed by
The short duration and sporadic, infrequent na- manometry or imaging
ture of this disorder has made the identification of patho-
physiologic mechanisms difficult. Several studies suggest *Criteria fulfilled for the last 3 months with symptom onset
that abnormal smooth muscle contractions may be re- at least 6 months prior to diagnosis
sponsible for the pain.31,32 A familial form of proctalgia **Diagnostic criteria for functional constipation:
fugax was associated with hypertrophy of the internal 1. Must include two or more of the following: (a) Straining during
anal sphincter.33,34 Attacks of proctalgia fugax are often at least 25% of defecations, (b) Lumpy or hard stools at least
precipitated by stressful life events or anxiety.35 Psycho- 25% of defecations, (c) Sensation of incomplete evacuation at
least 25% of defecations, (d) Sensation of anorectal obstruction/
logical testing suggests that many patients are perfec-
blockage at least 25% of defecations, (e) Manual maneuvers to
tionistic, anxious, and/or hypochondriacal.36 facilitate at least 25% of defecations (eg, digital evacuation,
Treatment support of the pelvic floor), (f) Fewer than three defecations per
week
For most patients, episodes of pain are so brief and
2. Loose stools are rarely present without the use of laxatives
infrequent that reassurance and explanation suffice. Patients 3. There are insufficient criteria for IBS
who have frequent symptoms may require treatment. A
randomized, controlled trial showed that inhalation of sal-
Epidemiology
butamol (a ␤-adrenergic agonist) was more effective than
placebo for shortening the duration of episodes of proctalgia The prevalence of functional defecation disorders
for those uncommon patients in whom episodes lasted ⱖ20 in the general population is unknown. At tertiary referral
minutes.37 According to Rome criteria, these patients could centers, the prevalence of dyssynergic defecation among
overlap with chronic proctalgia. Others have recommended patients with chronic constipation has ranged widely,
the ␣ agonist clonidine,38 amylnitrite, or nitroglycerine, from 20%– 81%.40 – 42 The prevalence of dyssynergia
but with little or no evidence to support their efficacy. may have been overestimated owing to the high false-
positive rates seen in some studies.43,44 This may be a
F3. Functional Defecation Disorders result, in part, of anxiety in which patients are unable to
Functional constipation is commonly classified as relax in the artificial and public laboratory setting. In 1
slow colonic transit or outlet delay, although many pa- tertiary care center, the prevalence of dyssynergia was 3
April 2006 FUNCTIONAL ANORECTAL DISORDERS 1515

times higher in women than men, but was similar in evacuation and reduced pelvic floor descent on defecog-
younger and older individuals.39 raphy could expel the balloon, because maximum intra-
rectal pressure was reduced in this group. Thus, it ap-
pears that there are patients who demonstrate a pro-
F3a. Diagnostic Criteria for Dyssynergic longed evacuation time, decreased pelvic floor descent,
Defecation and decreased intrarectal pressures, which may result in
a functional disorder of defecation.
Inappropriate contraction of the pelvic floor
or less than 20% relaxation of basal resting Clinical Evaluation, Investigations, and
sphincter pressure with adequate propulsive Diagnostic Utility of Tests
forces during attempted defecation
The section on Functional Bowel Disorders deals
with laboratory testing for organic causes of constipation.
This section focuses on the evaluation for functional
F3b. Diagnostic Criteria for Inadequate disorders of defecation. In the absence of alarm symp-
Defecatory Propulsion toms or a family history of colon cancer, anorectal testing
Inadequate propulsive forces with or with- is not necessary until patients have failed conservative
out inappropriate contraction or less than 20% treatment (eg, increased dietary fiber and liquids; elim-
relaxation of the anal sphincter during attempted ination of medications with constipating side effects
defecation whenever possible). Osmotic or stimulant laxatives
should be tried in patients who fail to respond to con-
Rationale for Changes in Diagnostic Criteria servative management. Tegaserod should be tried in
patients who fail laxatives. Physiologic studies are indi-
Similar to the previous Working Team Report, cated if the response to laxatives and tegaserod is inad-
the criteria for functional defecation disorders require equate.
symptoms of constipation and abnormal diagnostic tests The rectal balloon expulsion test, performed by mea-
because symptoms alone do not consistently distinguish suring the time required to expel a rectal balloon filled
patients with from patients without functional defeca- with water or air, is a useful, sensitive, and specific test
tion disorders. Although retaining diagnostic criteria for for evacuation disorders.46,48,49 The balloon expulsion
dyssynergia, the revised criteria acknowledge recent test is a useful screening test, but does not define the
studies that suggest that inadequate propulsive forces mechanism of disordered defecation nor does a normal
may also cause functional defecation disorders.45,46 Four balloon expulsion study always exclude a functional def-
patterns of anal and rectal pressure changes have been ecation disorder.47 Additional research is needed to stan-
recognized during attempted defecation.47 A normal pat- dardize this test that does not always correlate with other
tern is characterized by increased intrarectal pressure tests of rectal emptying such as defecography and surface
associated with relaxation of the anal sphincter. The type EMG recordings of the anal sphincters.
I pattern is characterized by both adequate propulsive During manometry, measurement of intrarectal and
forces (intrarectal pressure ⱖ45 mm Hg) and increased anal pressures at rest and during attempted defecation is
anal pressure. The type III pattern is characterized by useful for identifying functional defecation disorders.
increased intrarectal pressure (ⱖ45 mm Hg) with absent However, even asymptomatic subjects can have features
or insufficient (⬍20%) relaxation of basal anal sphincter of dyssynergic defecation by manometry.
pressure. Both types I and III are defined as dyssynergic Defecography can detect structural abnormalities (rec-
defecation. The type II pattern is characterized by inad- tocele, enterocele, rectal prolapse) and assess functional
equate propulsion (intrarectal pressure ⬍45 mm Hg) and parameters (anorectal angle at rest and during straining,
insufficient relaxation or contraction of the anal sphinc- perineal descent, anal diameter, indentation of the pu-
ter. borectalis, amount of rectal and rectocele emptying).50,51
A previous study measured rectal evacuation of bar- The diagnostic value of defecography has been ques-
ium, and expulsion of a balloon, corroborating the con- tioned primarily because normal ranges for quantified
cept that impaired evacuation may result from inade- measures are inadequately defined and because some
quate rectal propulsive forces.45 A combination of pelvic parameters such as the anorectal angle cannot be mea-
floor descent and evacuation time on defecography cor- sured reliably because of variations in rectal contour.
rectly predicted maximum intrarectal pressure in 74% of Magnetic resonance defecography provides an alternative
cases, and no constipated patient with both prolonged approach to image anorectal motion and rectal evacua-
1516 BHARUCHA ET AL GASTROENTEROLOGY Vol. 130, No. 5

tion in real time without radiation exposure.52 Whether than sham biofeedback,64,65 although in one study, it was
magnetic resonance defecography will add a new dimen- no more effective than was placebo when assessed by
sion to the morphologic and functional assessment of patient satisfaction.64
these patients merits appraisal.
Colonic transit can provide useful physiologic infor- Directions for Future Research
mation in constipated patients who fail to respond to 1. Multicenter studies of the normal physiology of def-
conservative treatment. By itself, the test is not diagnos- ecation and fecal continence in large groups of sub-
tic of slow transit constipation because (1) slow-transit jects stratified by age, gender, and (in women) by
constipation exists independent of, or may be caused by, parity.
functional defecation disorders; and (2) these 2 mecha- 2. Studies to define the role if any, of rectal contraction
nisms for constipation cannot be reliably distinguished and sensation in functional defecation disorders, to
on the basis of symptoms. Colonic transit can be assessed clarify the overlap between colonic motor dysfunction
by radiopaque markers or scintigraphy.53,54 Left-sided or and functional defecation disorders, and the patho-
generalized colonic transit delays have been observed in physiology, natural history, and treatment outcomes
patients with functional defecation disorders.55–57 of dyssynergic defecation versus inadequate defecatory
Based on results of recent studies, abnormal manom- propulsion.
etry and a rectal balloon expulsion testing suffice to 3. A randomized, sham-controlled, blinded study of
diagnose a functional defecation disorder. If only one test biofeedback treatment for dyssynergic and inadequate
is abnormal, further testing (eg, defecography) may be defecatory propulsion.
required. 4. Studies to clarify the clinical features, psychologic
Physiologic and Psychological Factors characteristics, quality of life, and natural history of
anorectal pain syndromes, namely, proctalgia fugax
Functional defecation disorders are probably ac- and levator ani syndrome. A randomized, blinded
quired behavioral disorders because at least two thirds of study comparing the effectiveness of electrogalvanic
patients learn to relax the external anal sphincter and stimulation, biofeedback, and muscle relaxant drugs
puborectalis muscles appropriately when provided with for the treatment of levator ani syndrome should be
biofeedback training. It has been speculated that pain performed.
associated with repeated attempts to defecate large, hard 5. Studies comparing sacral nerve stimulation to sham
stools may lead to inadvertent anal sphincter contraction, treatment in functional FI, to clarify the effects of
to minimize discomfort during defecation. However, sacral nerve stimulation on anorectal functions, to
rectal discomfort is not more common in pelvic floor identify patients who will respond to stimulation.
dysfunction compared to normal or slow-transit consti- 6. Studies to assess the utility of biofeedback therapy in
pation.57 Anxiety and/or psychological stress may also incontinent patients who do not respond to conser-
contribute to dyssynergic defecation by increasing skel- vative approaches.
etal muscle tension. Uncontrolled studies have reported
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1040.
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50. Ekberg O, Mahiew PHG, Bartram CI, Piloni V. Defecography: 59. Kawimbe BM, Papachrysostomou M, Binnie NR, Clare N, Smith
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CM, Bharucha AE. Magnetic resonance imaging of anatomic and WE. Simple electromyographic biofeedback treatment for chronic
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Transit of solids through the human colon: regional quantification Biofeedback is superior to laxatives for normal transit constipa-
in the unprepared bowel. Am J Physiol 1990;258:856 – 862. tion due to pelvic floor dyssynergia. Gastroenterology 2006;130:
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65. Heymen S, Scarlett Y, Jones K, Drossman D, Ringel Y, Whitehead
56. Karlbom U, Pahlman L, Nilsson S, Graf W. Relationships between
WE. Randomized controlled trial shows biofeedback to be supe-
defecographic findings, rectal emptying, and colonic transit time
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ergia-type constipation. Gastroenterology 2005;128:A-266.
57. Grotz RL, Pemberton JH, Talley NJ, Rath DM, Zinsmeister AR.
Discriminant value of psychological distress, symptom profiles,
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idiopathic constipation. Gut 1994;35:798 – 802. Address requests for reprints to: Arnold Wald, MD, Section of Gas-
58. Leroi AM, Berkelmans I, Denis P, Hemond M, Devroede G. Anis- troenterology and Hepatology, University of Wisconsin School of Med-
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 GASTROENTEROLOGY 2006;130:1519 –1526

Childhood Functional Gastrointestinal Disorders:

Neonate/Toddler

PAUL E. HYMAN,* PETER J. MILLA,‡ MARC A. BENNINGA,§ GEOFF P. DAVIDSON,储

DAVID F. FLEISHER,¶ and JAN TAMINIAU§
*Pediatric Gastroenterology, University of Kansas Medical Center, Kansas City, Kansas; ‡Paediatric Gastroenterology, Great Ormond
Hospital for Children, London, England; §Department of Pediatrics, Emma Kinderziekenhuis ACM, Amsterdam, The Netherlands;
储
Gastroenterology Department, Women’s and Children’s Hospital, North Adelaide, South Australia, Australia; and ¶Department of Child
Health, University of Missouri School of Medicine, Columbia, Missouri

Recognizing the importance of childhood functional gas- organic and psychological disturbances. For an example
trointestinal disorders in understanding adult functional of development affecting expression of functional symp-
gastrointestinal disorders, and encouraging clinical and toms, consider infant regurgitation, which is a problem
research interest, the Rome Coordinating Committee for a few months of the first year. Similarly, toddlers’
added a pediatric working team to Rome II in 1999. For diarrhea affects infants and toddlers.
Rome III, there was an increase from 1 to 2 pediatric
The decision to seek medical care for symptoms arises
working teams. This report summarizes the current con-
from a parent’s or caretaker’s concern for the child. The
sensus concerning functional disorders in infants and
toddlers. Another report covers disorders diagnosed caretaker’s threshold for concern varies with his or her
more often in school-aged children and adolescents. The experiences and expectations, coping style, and percep-
symptoms from functional gastrointestinal disorders in tion of illness. For this reason, the office visit is not only
children younger than 5 years depend on maturational about the child’s symptom but also about the family’s
factors in anatomy, gastrointestinal physiology, and in- conscious and unconscious fears. The clinician must not
tellectual and affective functioning. There has been little only make a diagnosis but also recognize the impact of
or no change for infant regurgitation, infant rumination the symptom on the family’s emotions and ability to
syndrome, or infant dyschezia. Cyclic vomiting syndrome function. Therefore, any intervention plan must attend to
may be diagnosed after 2 rather than 3 episodes. The both the child and the family.
description of infant colic has been expanded, although Effective management depends on securing a thera-
there was consensus that infant colic does not reflect
peutic alliance with the parents. Through the first years,
gastrointestinal malfunction. The greatest change was
children cannot accurately report symptoms such as nau-
in functional constipation. Functional constipation and
functional fecal retention in the 1999 report were
sea or pain. The infant and preschool child cannot dis-
merged into a single entity: functional constipation. Data- criminate between emotional and physical distress.
driven changes in diagnostic criteria for functional con- Therefore, clinicians depend on the reports and interpre-
stipation appear to be less rigid and more inclusive than tations of the parents, who know their child best, and the
previous criteria. observations of the clinician, who is trained to differen-
tiate between health and illness.
nfant and toddler functional gastrointestinal disorders
I include a variable combination of often age-depen-
dent, chronic or recurrent symptoms not explained by
Table 1. Functional Gastrointestinal Disorders
G. Functional disorders: neonates and toddlers
G1. Infant regurgitation
structural or biochemical abnormalities (Table 1). Func- G2. Infant rumination syndrome
tional symptoms during childhood are sometimes accom- G3. Cyclic vomiting syndrome
paniments to normal development (eg, infant regurgita- G4. Infant colic
G5. Functional diarrhea
tion), or they may arise from maladaptive behavioral G6. Infant dyschezia
responses to internal or external stimuli (eg, in functional G7. Functional constipation
constipation, retention of feces is a learned response to
painful defecation).
The clinical expression of a functional gastrointestinal
© 2006 by the American Gastroenterological Association Institute
disorder depends on an individual’s autonomic, affective, 0016-5085/06/$32.00
and intellectual developmental stage and on concomitant doi:10.1053/j.gastro.2005.11.065
1520 HYMAN ET AL GASTROENTEROLOGY Vol. 130, No. 5

Disability from a functional symptom is related to symptoms cause more parental anxiety than in older
maladaptive coping. Childhood functional gastrointesti- children and adults.
nal disorders are not dangerous when the symptoms and Clinical evaluation. Regurgitation occurs more
parental concerns are addressed and contained. Con- than once a day in 67% of healthy 4-month-old infants.
versely, failed diagnosis and inappropriate treatments of Many parents believe regurgitation is abnormal; 24%
functional symptoms may cause needless physical and bring this symptom to their clinician’s attention during
emotional suffering. In severe cases, well-meaning clini- their infant’s sixth month.1 Daily regurgitation decreases
cians inadvertently cocreate unnecessarily complex and with age to 5% of infants 10 –12 months old. Prematu-
costly solutions to functional symptoms, prolonging rity, developmental delay, and congenital abnormalities
emotional stress and promoting disability. of the oropharynx, chest, lungs, central nervous system,
heart, or gastrointestinal tract are risk factors for gastro-
esophageal reflux disease. Milk allergy may be present
G1. Infant Regurgitation when frequent regurgitation is associated with eczema or
wheezing. Failure to thrive, hematemesis, occult blood in
Regurgitation of stomach contents into the
the stool, anemia or food refusal, and swallowing diffi-
esophagus and mouth is common and normal in infants.
culties should prompt an evaluation for gastroesophageal
Uncomplicated regurgitation in otherwise healthy in-
reflux disease. Moreover, regurgitation associated with
fants is a developmental issue, not a disease. Regurgita-
early satiety, food refusal, or excessive crying, with or
tion is the involuntary return of previously swallowed
without failure to thrive, may be a consequence of pain or
food or secretions into or out of the mouth. Regurgita-
emotional arousal rather than an innocent event. Regur-
tion is distinguished from vomiting, which is defined by
gitation persisting past the first year of life should be
a central nervous system reflex involving both autonomic
evaluated to exclude an anatomic abnormality such as
and skeletal muscles in which gastric contents are force-
malrotation or gastric outlet obstruction.
fully expelled through the mouth because of coordinated
A natural history of infant regurgitation is one of
movements of the small bowel, stomach, esophagus, and
spontaneous improvement,1 and therefore treatment
diaphragm. Gastroesophageal reflux refers to movement goals are to provide effective reassurance and symptom
of gastric contents retrograde and out of the stomach. relief while avoiding complications. Effective reassurance
When gastroesophageal reflux causes or contributes to includes the following: (1) an empathetic, accurate re-
tissue damage or inflammation (eg, esophagitis, obstruc- sponse to the stated and unstated fears of the caretakers,
tive apnea, reactive airway disease, pulmonary aspiration, such as “What is wrong with my baby? Is it dangerous?
feeding and swallowing difficulties, or failure to thrive), Will it go away? What can we do about it?” and (2) a
it is called gastroesophageal reflux disease. promise of continuing availability and reassessment.
Symptom relief requires adjustment in infant care. Left
side and prone position2 and thickened feedings reduce
G1. Diagnostic Criteria for Infant regurgitation.3,4 No drugs routinely reduce symptoms.5,6
Regurgitation Improving the maternal-child interaction is often aided
Must include all of the following in other- by (1) relieving the parent’s fears about the infant’s
wise healthy infants 3 weeks to 12 months of age: symptoms and (2) identifying sources of physical and
emotional distress and eliminating them. Stress may be
1. Regurgitation 2 or more times per day for 3 or
lessened by respite periods, particularly for the mother.
more weeks
2. No retching, hematemesis, aspiration, apnea,
failure to thrive, feeding or swallowing diffi- G2. Infant Rumination Syndrome
culties, or abnormal posturing Infant rumination syndrome is a rare disorder
characterized by voluntary, habitual regurgitation of
Rationale for change in diagnostic criteria. There stomach contents into the mouth for self-stimulation.
have been no changes from the Rome II criteria. The Rumination is regurgitation of recently swallowed food,
forcefulness of the regurgitation or its outflow through rechewing, and either reswallowing or spitting out the
the mouth or nares does not carry any diagnostic rele- food. Although rumination is a functional symptom,
vance. The duration of 3 weeks was chosen because infant rumination syndrome is a life-threatening psychi-
infants come to medical attention more quickly and atric disorder caused by social deprivation. Rumination
April 2006 INFANT AND TODDLER 1521

in healthy older children and adults is discussed in other G3. Cyclic Vomiting Syndrome
reports in this supplement.
Cyclic vomiting syndrome (CVS) consists of re-
current, stereotypic episodes of intense nausea and vom-
iting lasting hours to days that are separated by symp-
G2. Diagnostic Criteria for Infant
tom-free intervals lasting weeks to months.9 The
Rumination Syndrome
frequency of episodes ranges from 1 to 70 per year and
Must include all of the following for at least averages 12 per year. Attacks occur at regular intervals or
3 months: sporadically. Typically, episodes begin at the same time
1. Repetitive contractions of the abdominal mus- of day, most commonly during night or morning. Epi-
cles, diaphragm, and tongue sode duration tends to be the same in each patient. CVS
2. Regurgitation of gastric content into the reaches its highest intensity during the first hours. Vom-
mouth, which is either expectorated or re- iting tends to diminish thereafter, although nausea con-
chewed and reswallowed tinues until the episode ends. Episodes usually end as
3. Three or more of the following rapidly as they begin and are marked by prompt recovery
a. Onset between 3 and 8 months of well-being, provided the patient has not incurred
b. Does not respond to management for gastro- major deficits of fluids and electrolytes. Signs and symp-
esophageal reflux disease or to anticholinergic toms that accompany cyclic vomiting include pallor;
drugs, hand restraints, formula changes, and weakness; increased salivation; abdominal pain; intoler-
gavage or gastrostomy feedings ance to noise, light, and/or odors; headache; loose stools;
c. Unaccompanied by signs of nausea or distress fever; tachycardia; hypertension; skin blotching; and leu-
d. Does not occur during sleep and when the kocytosis.10 Eighty percent identify circumstances or
infant is interacting with individuals in the events that trigger attacks, such as heightened emotional
environment states, infections, asthma, or physical exhaustion.10

Rationale for change in diagnostic criteria. There

have been no changes from the Rome II criteria. G3. Diagnostic Criteria for Cyclic Vomiting
Clinical evaluation. Observing rumination is nec- Syndrome
essary for diagnosis. Such observations require time, pa- Must include both of the following:
tience, and stealth because rumination may cease as soon as
the infant notices the observer. Diagnostic efforts should be 1. Two or more periods of intense nausea and un-
directed toward the parents and the infant because infant remitting vomiting or retching lasting hours to
rumination syndrome results from malfunction in the in- days
fant-caregiver relationships.7 2. Return to usual state of health lasting weeks to
The emotional and sensory deprivation that prompts months
rumination may occur in sick infants living in environ-
ments that prevent normal handling (eg, neonatal inten- Rationale for change in diagnostic criteria. The
sive care units). It may also occur in otherwise healthy working team reached consensus that a diagnosis of CVS
infants whose mothers are emotionally unconnected. Loss requires just 2, not 3 episodes. We expect that this change
of previously swallowed food may cause progressive ina- will facilitate early recognition and reduce patient suffering.
nition and death.8 Eliminating rumination is accom- Clinical evaluation. Patients do not vomit between
plished by providing a temporary mother-substitute to episodes, but two thirds of those who can provide a history
hold, comfort, and feed the infant. The nurturing person have irritable bowel syndrome, and 11% have migraine
recognizes when the infant withdraws into the self- headaches. Motion sickness occurs in 40%. More than half
absorbed state that fosters rumination and promptly have family histories of irritable bowel syndrome, and nearly
responds by engaging the baby. Treatment includes half have a family history of migraine headache. CVS can
helping the mother improve her ability to recognize and occur at any age. The differential diagnosis includes diseases
respond to her infant’s physical and emotional needs. having similar presentations during at least part of their
Infant rumination may be exacerbated by the noxious courses. Brainstem gliomas may infiltrate the vomiting
stress of the workup that accompanies “diagnosis by centers and cranial nerves around the medulla, causing
exclusion.” After rumination subsides, it usually does not intermittent vomiting without obstruction of cerebrospinal
recur, even in families whose mental health remains poor. fluid flow or signs of increased intracranial pressure. Occult
1522 HYMAN ET AL GASTROENTEROLOGY Vol. 130, No. 5

upper respiratory tract infection, particularly if associated tine. In contrast, “infant colic” is a behavioral syndrome of
with vestibulitis, and obstructive uropathy may cause early infancy involving long crying bouts and hard-to-
symptoms indistinguishable from CVS. Gastrointestinal soothe behavior. Infant colic was defined as “paroxysms of
causes mimicking CVS include peptic disease with pyloric irritability, fussing or crying lasting ⬎3 hours per day and
outlet obstruction, enteropathy especially if there is a occurring ⬎3 days each week.”13 There is no proof that
marked duodenitis, recurrent pancreatitis, intermittent crying in infant colic is caused by pain in the abdomen or
small bowel obstruction, chronic intestinal pseudo-obstruc- any other body part. Nevertheless, parents often assume that
tion, and the vomiting crises of familial dysautonomia. the cause of excessive crying is abdominal pain of gastroin-
Endocrine and metabolic conditions include pheochromo- testinal origin.
cytoma, adrenal insufficiency, diabetes mellitus, ornithine Because infants with colic are often referred to pediatric
transcarbamylase deficiency and other urea cycle defects, gastroenterologists, the Working Team achieved consensus
medium-chain acyl coenzyme A dehydrogenase deficiency, to include infant colic in this report. Familiarity with infant
propionic acidemia, isovaleric acidemia (the chronic inter- colic is necessary to avoid diagnostic and therapeutic mis-
mittent form), and porphyria. Pediatric condition falsifica-
adventures.14 Although crying may occur from pain due to
tion may be erroneously diagnosed as CVS.
inflammation in infants who are sensitive to cow milk
Treatment. In patients with frequent, severe, and
protein,15 by definition, infant colic is not caused by organic
prolonged episodes, daily treatment with amitriptyline,
disease. Bouts of infant colic start and stop suddenly with-
pizotifen (in the United Kingdom and Australia), cypro-
heptadine, phenobarbital, or propranolol may reduce fre- out obvious cause and are likely to occur late in the day.
quency or eliminate episodes.11,12 Foods, emotional fac- Crying tends to resolve spontaneously by 3– 4 months of
tors, or physical stressors that trigger episodes may be age or, in the case of babies born prematurely, 3– 4 months
identified and avoided. Aborting episodes is possible in after term.16 On average, crying peaks at 6 weeks and then
some children with a recognizable prodrome. Before the diminishes by 12 weeks.17 Infant colic probably represents
onset of nausea, oral medications such as ondansetron or the upper end of the normal “crying curve” of healthy
a long-acting benzodiazepine may be useful. During the infants. Colic “is something infants do, rather than a con-
prodrome, it may be helpful to begin treatment with an dition they have.”16
oral acid-inhibiting drug agent to protect esophageal
mucosa and dental enamel and lorazepam for its anxio-
lytic, sedative, and antiemetic effects. Deep sleep for G4. Diagnostic Criteria for Infant Colic
several hours may prevent the episode. Must include all of the following in infants
Once an episode starts, patients should be sedated from birth to 4 months of age:
until the episode ends. Symptoms may be interrupted by
titrating intravenous lorazepam or another long-acting 1. Paroxysms of irritability, fussing, or crying
benzodiazepine until the patient enters restful sleep. that start and stop without obvious cause
Intravenous fluids, electrolytes, and H2-histamine recep- 2. Episodes lasting 3 or more hours per day and
tor antagonists are administered until the episode is over. occurring at least 3 days per week for at least 1
Complications during episodes include water and elec- week
trolyte deficits, hematemesis due to prolapse gastropathy, 3. No failure to thrive.
peptic esophagitis and/or Mallory–Weiss tears, deficits in
intracellular potassium and magnesium levels, hyperten-
sion, and inappropriate secretion of antidiuretic hor- Rationale for Change in Diagnostic Criteria
mone. When lorazepam is not effective, the goal contin-
Rome II excluded infant colic from consideration
ues to be inducing deep sleep so that suffering is
as a functional gastrointestinal disorder. Nevertheless,
eliminated and the patient is amnestic for the episode.
Continuous infusions of propofol or pentobarbital or the abdominal pain attribution persists and pediatric
intermittent intravenous diphenhydramine and chlor- gastroenterologists receive referrals of babies with refrac-
promazine are alternatives to lorazepam. tory colic or infants who cry excessively due to unsus-
pected colic. The Working Team achieved consensus to
include infant colic in the list of childhood functional
G4. Infant Colic gastrointestinal disorders because familiarity with the
The term “colic” implies abdominal pain caused by “colic syndrome” is necessary to avoid diagnostic and
obstruction to flow from the kidney, gallbladder, or intes- therapeutic misadventures.
April 2006 INFANT AND TODDLER 1523

Clinical Evaluation Rationale for Change in Diagnostic Criteria

The colicky crying pattern results from organic dis- There were no changes from the Rome II criteria.
ease in ⬍10%. Prolonged, inconsolable crying, crying after
feedings, facial grimace, abdominal distention, increased Clinical Evaluation
gas, flushing, and legs flexed over the abdomen are not
The clinician queries about recent enteric in-
indicative of pain or disease, but they explain parents’
fections, laxatives, antibiotics, or diet changes. Stools
concerns. A diagnosis of infant colic can be made in any
often contain mucus and/or visible undigested food. A
infant younger than 4 –5 months whose crying has temporal
diet history will assess overfeeding, excessive fruit
features of infant colic, who has no signs of central nervous
juice or sorbitol consumption, excessive carbohydrate
system or intrinsic developmental difficulties, is normal on ingestion with low fat intake, and food allergy. In the
physical examination, and has normal growth patterns. absence of failure to thrive, malabsorption is unex-
pected.
Treatment
Nonanalgesic, nonnutritive soothing maneuvers, Treatment
such as rhythmic rocking and patting 2–3 times per second
It is important to avoid restrictive diets that may
in a quiet environment, may quiet the baby who may
cause calorie deprivation.21 Children recover spontane-
nevertheless resume crying as soon as he or she is put down.
ously, and usually no treatment other than effective
A common maneuver that does not eliminate pain but stops
reassurance for the parents is necessary. A daily diet and
the crying (like a car ride) has diagnostic and therapeutic
defecation diary helps to document that specific foods are
value. Management consists of helping the parents get
not responsible for loose stools.
through it.18 –20 Any measure that parents perceive as help-
ful is worth continuing, provided it is harmless. If there is
a question of milk intolerance or esophagitis, a time-limited Disorders of Defecation
therapeutic trial of a hydrolyzed protein formula or medi- Defecation frequency in healthy infants and chil-
cation to suppress gastric acid secretion is warranted. Relief dren decreases with age.22 Breast-fed infants may defe-
should be apparent within 48 hours. cate as frequently as 12 times per day or as infrequently
as once in 3 or 4 weeks. Firm stools may occur from the
G5. Functional Diarrhea first weeks of life in formula-fed infants. These infants
may experience painful defecation and so have a predis-
Functional diarrhea is defined by daily painless, re- position toward developing functional constipation (see
current passage of 3 or more large, unformed stools for 4 or following text).
more weeks with onset in infancy or preschool years. There There is a decline in stool frequency from an average
is no evidence for failure to thrive if the diet has adequate of more than 4 stools daily in the first week of life to 1–2
calories. The child seems unperturbed by the loose stools, each day at 4 years of age. Approximately 97% of 1- to
and the symptom resolves spontaneously by school age. 4-year-old children pass stool 3 times daily to once every
other day.23 Acquisition of bowel and bladder control
cannot be accelerated by early or high-intensity toilet
G5. Diagnostic Criteria for Functional training.24,25 The child’s initiative is a reliable indicator
Diarrhea that the child is developmentally capable of being clean
and dry. Many children achieve partial voluntary bowel
Must include all of the following:
control by 18 months, but the age of complete control
1. Daily painless, recurrent passage of 3 or more varies. By 4 years, 98% of normal children are toilet
large, unformed stools trained. Concerns related to defecation problems are re-
2. Symptoms that last more than 4 weeks sponsible for 25% of outpatient visits to pediatric gas-
3. Onset of symptoms that begins between 6 and troenterologists.26
36 months of age
4. Passage of stools that occurs during waking G6. Infant Dyschezia
hours
5. There is no failure-to-thrive if caloric intake is Parents describe infants with dyschezia as strain-
adequate ing for many minutes, screaming, crying, and turning
red or purple in the face with effort. The symptoms
1524 HYMAN ET AL GASTROENTEROLOGY Vol. 130, No. 5

persist for 10 –20 minutes, until there is passage of soft

G7. Diagnostic Criteria for Functional
or liquid stool. Stools pass several times daily. The
Constipation
symptoms begin in the first months of life and resolve
spontaneously after a few weeks. Must include 1 month of at least 2 of the
following in infants up to 4 years of age:
1. Two or fewer defecations per week
2. At least 1 episode per week of incontinence
G6. Diagnostic Criteria for Infant after the acquisition of toileting skills
Dyschezia 3. History of excessive stool retention
Must include both of the following in an 4. History of painful or hard bowel movements
infant younger than 6 months of age: 5. Presence of a large fecal mass in the rectum
6. History of large-diameter stools that may ob-
1. At least 10 minutes of straining and crying
struct the toilet
before successful passage of soft stools
2. No other health problems Accompanying symptoms may include irritability,
decreased appetite and/or early satiety. The accompa-
nying symptoms disappear immediately following
passage of a large stool.
Rationale for change in diagnostic criteria.
There were no changes in the diagnostic criteria from
Rationale for change in diagnostic criteria. The
Rome II. change from 12 weeks to 1 month of symptoms is based
Clinical evaluation. The examiner performs a on data showing that the longer functional constipation
history (including diet), conducts a physical examina- goes unrecognized, the less successful treatment is. In
tion (including rectal examination) to exclude ano- constipated children younger than 4 years of age, prog-
rectal abnormalities, and charts the infant’s growth. nosis was better when the child was treated before 2 years
Parents are reassured by a methodical physical exam- of age.30 Recovery in children with fecal incontinence
ination completed in their presence. Failure to coor- was associated with shorter symptom duration.31,32
dinate increased intra-abdominal pressure with pelvic Diagnostic criteria for functional fecal retention are
floor relaxation results in infant dyschezia. The in- eliminated. Functional fecal retention was a term that
fant’s cries increase intra-abdominal pressure. Defeca- was not accepted by most clinicians. Functional fecal
tion requires increasing intra-abdominal pressure and retention put a high premium on retentive posturing,
simultaneously relaxing the pelvic floor. Coordination which was 1 of 2 obligatory diagnostic criteria. However,
of these 2 independent events to effect successful parents may not have observed or recognized retentive
defecation may occur by chance, but eventually defe- behavior.33 We now assess parents’ impression of exces-
cation is learned. Parents are happy to accept the sive stool retention as 1 of 6 criteria, but it is not
explanation that the child needs to learn to relax the essential.
pelvic floor at the same time as bearing down. To Clinical evaluation. Fecal incontinence (involun-
encourage the infant’s defecation learning, the parents tary passage of colon contents) may occur in infants and
are advised to avoid rectal stimulation, which produces toddlers who accumulate a rectal fecal mass. Two studies
artificial sensory experiences that may be noxious or that assessing the applicability of Rome II criteria recom-
may condition the child to wait for stimulation before mended that fecal incontinence should be added to re-
defecating. Laxatives are unnecessary. vised criteria. Incontinence is an objective marker for
monitoring treatment. A painful bowel movement has
been identified as an important cause for retentive be-
G7. Functional Constipation
havior.34 A fecal mass identified before evacuation (rec-
Constipation represents the chief complaint in ognized during physical examination) or after a bowel
3% of pediatric outpatient visits. Approximately 40% movement is a feature of functional constipation. The
of children with functional constipation develop painful evacuation of a fecal mass often conditions a child
symptoms during the first year of life.27,28 Sixteen to avoid defecation.
percent of parents of 22-month-old children reported Functional constipation is a diagnosis made by history
constipation.29 and physical examination.35 No testing is necessary or de-
April 2006 INFANT AND TODDLER 1525

sirable. Onset frequently occurs during 1 of 3 periods: (1) in child’s fear of painful defecation resolves. Parents must
infants with hard stools, often corresponding with the understand that coercive toilet training tactics are likely to
change from breast milk to commercial formula or intro- backfire into an unwinnable struggle for control. Next, the
duction of solids; (2) in toddlers acquiring toilet skills, as clinician, child, and parent agree on a plan for evacuating
they attempt to control bowel movements and find defeca- the rectal fecal mass. Most experts favor a daily nonstimu-
tion painful; and (3) as school starts and children avoid lant laxative such as polyethelene glycol, mineral oil, lactu-
defecation throughout the school day. Affected children are lose, or milk of magnesia, which slowly softens the mass
often described as standing on their toes, holding onto until the child chooses to pass it, days or weeks later. This
furniture, stiffening their legs, and hiding in a corner. nonintrusive approach returns the control of the child’s
Incontinence may be mistaken for diarrhea by some parents. pelvic floor to the child. The key to effective maintenance is
The physical examination includes assessing the size of the assuring painless defecation until the child is comfortable
rectal fecal mass, which is judged for height above the pelvic and acquisition of toilet learning is complete. Behavior
brim with bimanual palpation on either side of the rectus modification using rewards for successes in toilet learning is
sheath. A rectal examination is performed after establishing helpful.
rapport with the patient and the family. In functional Functional constipation is as common in children and
constipation, the initial attempt at rectal examination oc- adolescents as it is in infants and toddlers. Aspects of this
casionally causes the child to react with acute, intense fear disorder in the older child are covered in the next report.
and negative behaviors. An irrational fear of the rectal
examination typifies the child with functional constipation Recommendations for Future
and is rarely a problem in children with other complaints, Research
including other defecation disorders. When the history is
typical for functional constipation, the perineum should be 1. Validating the diagnostic criteria for the childhood
inspected but a digital rectal examination may be delayed to functional gastrointestinal disorders will be an im-
facilitate the therapeutic alliance between the child and the portant goal for the next decade. Epidemiologic com-
clinician until after a treatment trial fails. If the clinician munity-based studies and studies of populations be-
plans a consultation but no follow-up, a rectal examination lieved to be at risk (eg, children of patients with
is necessary to evaluate the child for the rare obstructing functional gastrointestinal disorders, female child
mass. Symptoms are explained by voluntary efforts to avoid abuse victims) are needed to determine the applica-
defecation. Pain results from normal colonic contractions bility of the diagnostic criteria, which were arrived at
pushing luminal contents against a closed anal sphincter. by consensus rather than by data analysis.
Incontinence occurs when stool seeps around the fecal mass 2. Clinical trials measuring symptom change as the pri-
and leaks out when the child relaxes the pelvic floor or anal mary outcome measure will help us to learn which
sphincter, either inadvertently (as in sleep), with fatigue, or interventions improve outcomes in the childhood
with attempts to pass flatus. Initiation of intensive training functional gastrointestinal disorders.
before 27 months does not correlate with earlier completion 3. Definitions and diagnostic criteria for currently un-
of toilet training, suggesting little benefit to training before recognized childhood functional gastrointestinal dis-
27 months.36 Parents of children at risk for functional con- orders are needed.
stipation seem to be inconsistent in their approach to toilet 4. A history of physical, sexual, and/or emotional abuse
training, varying from rigid to permissive.37 In most cases, will be elicited from some children with functional
fear of painful defecation is the cause for fecal retention.38 bowel disorders. There is a need for education and
Treatment. The first step in treatment is family training related to the evaluation and treatment of
education during the initial visit. The child and family child abuse for all clinicians who care for children
appreciate a clinician who explains the problem, absence of with functional gastrointestinal disorders.
disease, and safe and effective management. The clinician 5. The role of childhood functional gastrointestinal dis-
addresses the myths and fears: the child has functional orders in adult functional gastrointestinal disorders
constipation, the most common problem referred to the should be explored.
pediatric gastrointestinal specialist, and one of the most 6. There is increasing evidence in adult practice of the
common problems in pediatrics. It goes away in time, and role of inflammation in some functional gastrointes-
it is not dangerous. These statements assuage anxiety and tinal disorders. There are virtually no such studies in
create an expectation for positive change. Next, parents childhood. The role of inflammation in childhood
need to be helped to understand the child’s point of view. functional gastrointestinal disorders requires system-
For toddlers, toilet training will not proceed until the atic study.
1526 HYMAN ET AL GASTROENTEROLOGY Vol. 130, No. 5

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 GASTROENTEROLOGY 2006;130:1527–1537

Childhood Functional Gastrointestinal Disorders:

Child/Adolescent

ANDRÉE RASQUIN,* CARLO DI LORENZO,‡ DAVID FORBES,§ ERNESTO GUIRALDES,¶

JEFFREY S. HYAMS,储 ANNAMARIA STAIANO,# and LYNN S. WALKER**
*Division of Pediatric Gastroenterology and Nutrition, CHU Ste Justine, University of Montreal, Montreal, Quebec, Canada; ‡Division of
Pediatric Gastroenterology, Children’s Hospital of Colombus, The Ohio State University, Columbus, Ohio; §School of Pediatrics & Child
Health, University of Western Australia, Perth, West Australia, Australia; ¶Department of Pediatrics, Pontificia Universidad Catolica de Chile,
Santiago, Chile; 储Division of Digestive Diseases and Nutrition, Connecticut Children’s Medical Center, University of Connecticut School of
Medicine, Hartford, Connecticut; #Department of Pediatrics, University Federico II, Naples, Italy; and **Division of Adolescent Medicine and
Behavioral Science, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee

The Rome II pediatric criteria for functional gastrointes- This publication generated scientific interest and con-
tinal disorders (FGIDs) were defined in 1999 to be used tributed to the recognition of these disorders as diagnos-
as diagnostic tools and to advance empirical research. tic entities. A limited number of studies has been pub-
In this document, the Rome III Committee aimed to lished since. One study reported a preliminary validation
update and revise the pediatric criteria. The decision- of a questionnaire on pediatric gastrointestinal symptoms
making process to define Rome III criteria for children
and features related to FGIDs, as defined by the Rome II
aged 4 –18 years consisted of arriving at a consensus
based on clinical experience and review of the literature. criteria.2 Two publications using the same questionnaire
Whenever possible, changes in the criteria were evi- documented the prevalence of FGIDs in tertiary care
dence based. Otherwise, clinical experience was used clinics,3,4 and 1 study reported the prevalence of FGIDs
when deemed necessary. Few publications addressing in Italian children consulting primary care pediatri-
Rome II criteria were available to guide the committee. cians.5 One paper directly addressed the validation of the
The clinical entities addressed include (1) cyclic vomit- criteria.3 Six studies used the Rome II criteria to select
ing syndrome, rumination, and aerophagia; 2) abdomi- and/or compare children included in their study sam-
nal pain-related FGIDs including functional dyspepsia, ples,6 –11 and in 3 reviews on abdominal pain in children,
irritable bowel syndrome, abdominal migraine, and Rome II criteria were discussed.12–14 These publications
functional abdominal pain; and (3) functional constipa- have offered valid criticism of some disorders and pro-
tion and non-retentive fecal incontinence. Adolescent
vided preliminary validation of others.
rumination and functional constipation are newly de-
fined for this age group, and the previously designated
The goal of the committee members was to revise the
functional fecal retention is now included in functional Rome II criteria in light of emerging scientific research
constipation. Other notable changes from Rome II to and on the basis of their own clinical experience. The
Rome III criteria include the decrease from 3 to 2 Rome III process established 2 pediatric committees.
months in required symptom duration for noncyclic dis- This report by the Child/Adolescent Committee focuses
orders and the modification of the criteria for functional on the criteria for FGIDs in children aged 4 to 18 years
abdominal pain. The Rome III child and adolescent cri- (Table 1). The committee elected to continue basing the
teria represent an evolution from Rome II and should pediatric classification of FGIDs on the main complaints
prove useful for both clinicians and researchers dealing reported by children or their parents rather than on
with childhood FGIDs. The future availability of addi- targeted organs. Indeed, the criteria were designed to be
tional evidence-based data will likely continue to modify
used as diagnostic tools, and the committee believed that
pediatric criteria for FGIDs.
this symptom-based classification would better serve the
clinician. This was particularly true for abdominal pain-
unctional gastrointestinal disorders (FGIDs) are de-
F fined as a variable combination of chronic or recur-
rent gastrointestinal symptoms not explained by struc-
related FGIDs when care providers can consider func-

Abbreviations used in this paper: FAP(S), functional abdominal pain

tural or biochemical abnormalities. In 1997, a pediatric (syndrome); FGIDs, functional gastrointestinal disorders; IBS, irritable
working team met in Rome to standardize the diagnostic bowel syndrome.
© 2006 by the American Gastroenterological Association Institute
criteria for various FGIDs in children. The first pediatric 0016-5085/06/$32.00
Rome II criteria for FGIDs were published in 1999.1 doi:10.1053/j.gastro.2005.08.063
1528 RASQUIN ET AL GASTROENTEROLOGY Vol. 130, No. 5

Table 1. The Functional Gastrointestinal Disorders

H1a. Diagnostic Criteria* for Adolescent
H. Functional disorders: children and adolescents
H1. Vomiting and aerophagia
Rumination Syndrome
H1a. Adolescent rumination syndrome Must include all of the following
H1b. Cyclic vomiting syndrome
H1c. Aerophagia 1. Repeated painless regurgitation and rechew-
H2. Abdominal pain–related FGIDs
ing or expulsion of food that
H2a. Functional dyspepsia
H2b. Irritable bowel syndrome a. begin soon after ingestion of a meal
H2c. Abdominal migraine b. do not occur during sleep
H2d. Childhood functional abdominal pain c. do not respond to standard treatment for
H2d1. Childhood functional abdominal pain syndrome
H3. Constipation and incontinence gastroesophageal reflux
H3a. Functional constipation 2. No retching
H3b. Nonretentive fecal incontinence 3. No evidence of an inflammatory, anatomic,
metabolic, or neoplastic process that explains
the subject’s symptoms
tional abdominal pain as a diagnostic option only after *Criteria fulfilled at least once per week for at least 2
having eliminated the other abdominal pain-related months before diagnosis
FGIDs.
The committee members changed the required dura-
tion of symptoms from to 3 to 2 months for all the Justification for changes in diagnostic criteria. In
disorders except for abdominal migraine and cyclic vom- the context of the Rome criteria, rumination syndrome is
iting syndrome. This decision was based on the follow- defined in children and adolescents for the first time.
ing: (1) it allows 4 weeks for acute disease and 4 weeks Although 4 and 6 weeks’ duration have been proposed
to establish chronicity; (2) although children presenting for this age group,16,17 a period of 8 weeks has been
to tertiary care centers have symptoms of long duration,3 adopted to harmonize with the other pediatric criteria.
it was felt that primary care physicians should be able to The item “absence of nausea and vomiting” has been
make the diagnosis of FGIDs earlier than 3 months of omitted because up to 33% of affected adolescents
symptom duration; (3) a duration of 2 months is more present with one of these symptoms.16
inclusive and facilitates clinical research of FGIDs in Clinical evaluation. Effortless repetitive regur-
children; and (4) it was the consensus of the committee gitation, reswallowing, and/or spitting within min-
that 2 months better reflects clinical experience in chil- utes of starting a meal are diagnostic characteristics.
dren compared with adults. Age-appropriate question- The behavior lasts for about an hour and rarely occurs
naires have been created as part of the Rome III process, at night.16 Gastroesophageal reflux, esophageal acha-
and a threshold of “at least once per week” for inclusion lasia, gastroparesis, bulimia nervosa, and obstructive
of a diagnostic symptom has been chosen for all the anatomical disorders must be excluded by appropriate
disorders except the 2 cyclical ones: abdominal migraine diagnostic tests.
Physiological features. The characteristic mano-
and cyclic vomiting. The accompanying symptoms have
metric abnormality is a synchronous increase in pressure
to be present at least “sometimes” (ⱖ25% of the time).
(“r” waves) across multiple recording sites in the upper
The committee members acknowledge that, in some
gut. It is attributed to an increase in intra-abdominal
patients, both disorder and disease may coexist (eg, irri-
pressure generated by the contraction of the skeletal
table bowel syndrome [IBS] and Crohn’s disease). They
abdominal muscles. These characteristic waves were doc-
emphasize that when “absence of disease” is a criterion, a
umented in 40%– 67% of adolescents with rumination,
diagnosis of functional disorder can only be made if and mildly delayed gastric emptying was found in 46%
diseases that could account for the symptoms are absent of them.16,18
or inactive. Psychological features. Rumination appears to
serve the purpose of self-stimulation in intellectually
H1. Vomiting and Aerophagia handicapped children and may be associated with eating
disorders in adolescents. Psychological disturbances, in-
H1a. Adolescent Rumination Syndrome
cluding depression, anxiety, obsessive-compulsive behav-
Epidemiology. Rumination syndrome is most ior, and other disorders, are reported in up to one third
common in male infants and female adolescents.15,16 of affected individuals.16
April 2006 CHILDHOOD FUNCTIONAL GASTROINTESTINAL DISORDERS 1529

Treatment. In the absence of nutritional impair- Table 2. Alarm Symptoms, Signs, and Features in Children
ment, motivated patients improve with behavioral ther- and Adolescents With Noncyclic Abdominal Pain–
Related Functional Gastrointestinal Disorders
apy in up to 85% of subjects,16 and a multidisciplinary
approach is associated with satisfactory recovery in most Persistent right upper or right Pain that wakes the child
lower quadrant pain from sleep
patients.18 Tricyclic antidepressants have been used with Dysphagia Arthritis
some success.18 Postpyloric feedings, either through na- Persistent vomiting Perirectal disease
sojejunal or gastrojejunal feeding catheters, may be nec- Gastrointestinal blood loss Involuntary weight loss
Nocturnal diarrhea Deceleration of linear growth
essary when weight loss is significant.18
Family history of inflammatory Delayed puberty
bowel disease, celiac disease, Unexplained fever
H1b. Cyclic Vomiting Syndrome or peptic ulcer disease
Although cyclic vomiting often presents in chil-
dren and adolescents, this entity is discussed both in the
neonatal/toddler section and the adult section, and this
committee did not believe there are enough distinguish- Clinical evaluation. Air swallowing often goes
ing features in children to warrant different diagnostic unnoticed by parents and children themselves and
criteria in this age group. The criteria discussed in the should be objectively verified by the physician.20 Ex-
neonatal/toddler section should also be used for children cessive air swallowing is often caused by anxiety and
and adolescents. may accompany asthma crisis. Because of the concom-
itant abdominal distention, aerophagia is often con-
fused with motility disorders, such as chronic intesti-
H1b. Diagnostic Criteria for Cyclic nal pseudo-obstruction and malabsorption syndromes.
Vomiting Syndrome In patients with aerophagia, the abdominal distention
decreases or resolves during sleep. Hydrogen breath
Must include all of the following: tests can be used to rule out sugar malabsorption
1. Two or more periods of intense nausea and un- and/or bacterial overgrowth.
remitting vomiting or retching lasting hours to Treatment. Effective reassurance and explanation
days of symptoms to both parents and child are essential.
2. Return to usual state of health lasting weeks to Often, the clinician can help the child become aware of
months air swallowing during the visit. Eating slowly, avoidance
of chewing gum or drinking carbonated beverages, and
various psychotherapeutic strategies for alleviation of
H1c. Aerophagia
anxiety may be helpful.19
Epidemiology. Aerophagia has been observed in
8.8% of the institutionalized mentally handicapped pop- H2. Abdominal Pain–Related FGIDs
ulation.19 By using Rome II criteria, aerophagia was
In children with abdominal pain–related FGIDs,
diagnosed in 1.3% of children, aged 4 –18 years, pre-
the alarm features, signs, and symptoms listed in Table
senting to a pediatric gastroenterology clinic.3
2 are generally absent. The committee recognized the
great variability in the severity and phenotypic presen-
tation of children with abdominal pain–related FGIDs
H1c. Diagnostic Criteria* for Aerophagia
and therefore decided to split the previously inclusive
Must include at least 2 of the following: category of functional abdominal pain into 2 separate
1. Air swallowing disorders, childhood functional abdominal pain and
2. Abdominal distention because of intraluminal childhood functional abdominal pain syndrome (FAPS),
air so that studies done in this population may include more
3. Repetitive belching and/or increased flatus patients distributed within more homogenous categories.
Indeed, in studies performed in tertiary care centers, up
*Criteria fulfilled at least once per week for at least 2 to 47% of children with abdominal pain did not receive
months before diagnosis a Rome II diagnosis, and only a few met the very strict
criteria for FAPS.3,4 The current pediatric criteria for
Rationale for changes in diagnostic criteria. The functional abdominal pain differ from the criteria in
rationale for change in duration of the symptoms has adults, and further research may take these 2 categories
been discussed previously. into closer parallelism. The committee decided, much
1530 RASQUIN ET AL GASTROENTEROLOGY Vol. 130, No. 5

like the adult group, to omit the category of “unspecified The committee has eliminated the mandatory use of
functional abdominal pain” because the new pediatric upper gastrointestinal endoscopy in order to make this
criteria are more inclusive. diagnosis. In children, the likelihood of finding mucosal
Functional impairment, which is included in the abnormalities responsible for dyspeptic symptoms is
FAPS, can also be observed in other FGIDs such as much lower than in adults.22 Ulcer-like and dysmotility-
abdominal migraine and functional dyspepsia or IBS. In like subtypes of functional dyspepsia have been elimi-
abdominal migraine, it is now included in the definition, nated because epidemiologic data suggest that young
whereas in the other disorders it is not. Impairment of children do not fall into either category.3,4,22 The dis-
daily activity, although possibly present, has not tradi- tinction between discomfort and pain is difficult for
tionally been included in the definition of IBS and func- young children and their parents,3,4 and there is no
tional dyspepsia in adults. Severity of symptoms is ad- evidence that the symptoms of dysmotility-type dyspep-
dressed in a questionnaire developed as part of the Rome sia originate from disordered motility.
III process. Clinical evaluation and treatment of children Finally, the committee decided to specify that there
with abdominal pain–predominant disorders have been should be no evidence of an inflammatory, anatomic,
recently reviewed in 2 documents of the American Acad- metabolic, or neoplastic process considered likely to be
emy of Pediatrics and the North American Society for an explanation for the subject’s symptoms. There are
Pediatric Gastroenterology, Hepatology and Nutrition children with abdominal pain predominant FGID who
and will only be very briefly addressed here.14,21 may have evidence of mild, chronic inflammatory
changes on mucosal biopsies. In view of the evidence that
H2a. Functional Dyspepsia
FGID may follow an acute inflammatory event,24,25 such
Epidemiology. In community- and school-based changes should not impede a diagnosis of a FGID. This
studies, the prevalence of dyspepsia varies between 3.5 % terminology is also used for the other childhood FGIDs
and 27% according to gender and country of origin.22,23 presenting with abdominal pain or discomfort.
By using the Rome II criteria, the prevalence was 0.3% Clinical evaluation. Factors suggesting the pres-
among children (mean age, 52 months) seen by primary ence of disease are listed in Table 2.13,14,21 Dyspeptic
care pediatricians in Italy5 and between 12.5% and symptoms may follow a viral illness.24 The committee
15.9% among children aged 4 –18 years referred to members agreed that upper gastrointestinal endoscopy is
tertiary care clinics in North America.3,4 warranted in the presence of dysphagia in patients with
persistent symptoms despite the use of acid reducing
medications or in those who have recurrent symptoms
H2a. Diagnostic Criteria* for Functional upon cessation of such medications and to confirm the
Dyspepsia diagnosis of Helicobacter pylori–associated disease.26
Must include all of the following: Physiological features. Disordered gastric myo-
electrical activity,27,28 delayed gastric emptying,29,30 al-
1. Persistent or recurrent pain or discomfort cen-
tered antroduodenal motility,31 and reduced gastric vol-
tered in the upper abdomen (above the umbi-
ume response to feeding11 have been described in
licus)
children with functional dyspepsia. Rapid gastric emp-
2. Not relieved by defecation or associated with
tying associated with slow bowel transit was found in
the onset of a change in stool frequency or
dyspeptic children with bloating as predominant
stool form (ie, not IBS)
symptom.32
3. No evidence of an inflammatory, anatomic,
Treatment. Avoidance of nonsteroidal anti-
metabolic, or neoplastic process that explains
the subject’s symptoms inflammatory agents and foods that aggravate symptoms
(eg, caffeine and spicy and fatty foods) is recommended.
*Criteria fulfilled at least once per week for at least 2 Antisecretory agents (H2 blockers or proton pump in-
months before diagnosis hibitors) are often offered for pain predominant symp-
toms and prokinetics (metoclopramide, erythromycin,
Rationale for changes in diagnostic criteria. The and domperidone and cisapride where available) for
rationale for change in duration of the symptoms has symptoms associated with discomfort. The committee
been discussed in the Introduction section. Duration of 2 recognizes that the use of all these therapeutic modalities
months is sufficient to eliminate the likelihood of acute has not been validated by controlled trials.14,21 Psycho-
disease and to establish a reasonable degree of chronicity. logical comorbidity should be addressed.
April 2006 CHILDHOOD FUNCTIONAL GASTROINTESTINAL DISORDERS 1531

H2b. Irritable Bowel Syndrome physical examination and growth curve with the absence of
Epidemiology. In Western countries, IBS was diag-
alarm signals (Table 2) substantiate a positive diagnosis.
nosed in 6% of middle school and 14% of high school students Potential triggering events and psychosocial factors are im-
by using Rome I criteria.33 According to Rome II criteria, IBS portant to explore. Education about mechanisms leading to
was diagnosed in 0.2% of children (mean age, 52 months) seen IBS avoids unnecessary invasive testing.13
by primary care pediatricians and in 22%–45% of children Treatment. A confident diagnosis, confirmation,
aged 4–18 years presenting to tertiary care clinics.3–5 and explanation of pain experience and reassurance can
by itself be therapeutic.13 Specific goals of therapy in-
clude modifying severity and developing strategies for
dealing with symptoms. Controlled data on therapeutic
H2b. Diagnostic Criteria* for Irritable
interventions are limited to peppermint oil that may
Bowel Syndrome
provide some benefit in children with IBS but not in
Must include all of the following: adults.14,21 Inversely, the efficacy of some antidepressants
1. Abdominal discomfort (an uncomfortable sen- and serotonic agents is well shown in adults with IBS,
sation not described as pain) or pain associated but there are only anecdotal reports concerning their use
with 2 or more of the following at least 25% of in children with chronic abdominal pain.
the time: H2c. Abdominal Migraine
a. Improved with defecation
It has been suggested that abdominal migraine,
b. Onset associated with a change in frequency
cyclic vomiting syndrome, and migraine headache comprise
of stool
a continuum of a single disorder, with affected individuals
c. Onset associated with a change in form (ap-
often progressing from one clinical entity to another.40
pearance) of stool
Epidemiology. Abdominal migraine affects 1%–
2. No evidence of an inflammatory, anatomic,
4% of children.41,42 It is more common in girls than boys (3:2),
metabolic, or neoplastic process that explains
with a mean age of onset at 7 years and a peak at 10–12 years.
the subject’s symptoms
In pediatric gastroenterology clinics, it was diagnosed in
*Criteria fulfilled at least once per week for at least 2 2.2%–5% of children by using the Rome II criteria.3,4
months before diagnosis

Symptoms that cumulatively support the diagnosis of H2c. Diagnostic Criteria* for Abdominal
IBS are (1) abnormal stool frequency (4 or more stools per Migraine
day and 2 or less stools per week), (2) abnormal stool Must include all of the following:
form (lumpy/hard or loose/watery stool), (3) abnormal
stool passage (straining, urgency, or feeling of incom- 1. Paroxysmal episodes of intense, acute perium-
plete evacuation), (4) passage of mucus, and (5) bloating bilical pain that lasts for 1 hour or more
or feeling of abdominal distention. 2. Intervening periods of usual health lasting
Rationale for changes in diagnostic criteria. The
weeks to months
rationale for change in symptom duration from 3 to 2 3. The pain interferes with normal activities
months has been discussed earlier. 4. The pain is associated with 2 or more of the
Physiological features. Visceral hypersensitivity
following:
has been documented in children with IBS.6,7 It may be a. Anorexia
related to numerous processes, including infection, in- b. Nausea
flammation, intestinal trauma, or allergy, and may be c. Vomiting
associated with disordered gut motility.25,34 Genetic pre- d. Headache
disposition, early stressful events, and ineffective patient- e. Photophobia
coping mechanisms are compounding factors.25,35,36 f. Pallor
Psychological features. Anxiety, depression, and
5. No evidence of an inflammatory, anatomic,
multiple other somatic complaints have been reported by metabolic, or neoplastic process considered
IBS children and their parents.37 Social learning of illness that explains the subject’s symptoms
behavior may contribute to the development of IBS.38,39 *Criteria fulfilled 2 or more times in the preceding 12
Clinical evaluation. Symptoms of abdominal pain months
that meet Rome criteria for IBS in the presence of a normal
1532 RASQUIN ET AL GASTROENTEROLOGY Vol. 130, No. 5

Supportive criteria include a family history of mi- may include pizotifen, propanolol, cyproheptadine, or
graine and a history of motion sickness. sumatriptan.47 Limited data on pizotifen suggest its
Rationale for changes in diagnostic criteria. The efficacy in children with this entity.14,21
number of episodes required was changed from 3 to 2.
Recurrent can be defined with 2 episodes, and a recent H2d. Childhood Functional Abdominal Pain
review by experts in the field suggests that 2 episodes are Epidemiology. By using the Rome II criteria, the
sufficient for diagnosis.43 The minimum duration of an prevalence of FAP in 4 –18-year-old patients presenting to
episode was changed from 2 hours to 1 hour, according gastroenterology clinics varied between 0% to 7.5%.3,4 This
to the recommendations of the same experts.43 Most low prevalence was not unexpected considering that Rome
episodes generally last several hours to days. Pain is now II criteria were quite restrictive: the pain had to be contin-
specified in intensity as severe enough to affect activity. uous or nearly continuous, association with physiologic
Indeed, a hallmark of this syndrome is that the pain is events had to be absent, and there was a requirement for
often incapacitating. Adding this terminology to the some impairment in daily activities.
definition was also recommended in the review previ-
ously mentioned.43 Additional symptoms (anorexia, nau-
sea, vomiting, headache, and pallor) have been added to H2d. Diagnostic Criteria* for Childhood
the definition. These gastrointestinal and vasomotor Functional Abdominal Pain
symptoms are an integral part of the syndrome. The Must include all of the following:
necessity for a family history of migraine and aura was
1. Episodic or continuous abdominal pain
removed. These features are indeed not necessary and are
2. Insufficient criteria for other FGIDs
internally somewhat redundant. The presence of a history
3. No evidence of an inflammatory, anatomic,
of migraine in the proband and family is a supporting
metabolic, or neoplastic process that explains
feature. The decision to change from symptom-free in-
the subject’s symptoms
terval between episodes to “return to usual state of
health” was made in recognition of the fact that some *Criteria fulfilled at least once per week for at least 2
patients may have other chronic or recurrent symptoms months before diagnosis
unrelated to abdominal migraine.
Clinical evaluation. The paroxysmal nature of H2d1. Diagnostic Criteria* for Childhood
symptoms and the absence of the characteristic ab- Functional Abdominal Pain Syndrome
dominal pain between episodes make chronic inflam- Must include childhood functional abdom-
matory diseases less likely. When appropriate, ob- inal pain at least 25% of the time and 1 or more of
structive processes in the urologic or digestive tracts, the following:
biliary tract disease, recurrent pancreatitis, familial 1. Some loss of daily functioning
Mediterranean fever, and metabolic disorders such as 2. Additional somatic symptoms such as head-
porphyria should be ruled out. A favorable response to ache, limb pain, or difficulty sleeping
medications used for prophylaxis of migraine head-
aches supports the diagnosis. *Criteria fulfilled at least once per week for at least 2
Physiological features. Abdominal migraine, cy- months before diagnosis
clic vomiting syndrome, and migraine headache may
share pathophysiological mechanisms. Abnormal visual- Rationale for changes in diagnostic criteria. The
evoked responses, abnormalities in the hypothalamic- rationale for decreasing the duration of symptoms from 3
pituitary-adrenal axis, and autonomic dysfunction have to 2 months has already been discussed. The requirement
been described.44,45 for continuous or nearly continuous pain has been elim-
Psychological features. It is not known whether inated based on the clinical experience that children
psychological features such as anxiety, depression, and present with episodic or intermittent pain at least as
somatic complaints described in classical migraine and frequently as they do with more continuous pain. The
cyclic vomiting can be applied to abdominal migraine.46 previous criteria mentioned that the pain had to have no
Treatment. Potential triggers to be avoided in- or only occasional relation with physiological events.
clude caffeine-, nitrite-, and amine-containing foods as This criterion would exclude children who have some
well as emotional arousal, travel, prolonged fasting, al- features of IBS or dyspepsia but do not meet criteria for
tered sleep patterns, and exposure to flickering or glaring those entities (eg, children who only have 1 of the 2
lights. When episodes are frequent, prophylactic therapy bowel symptoms required for IBS). Children with FAP
April 2006 CHILDHOOD FUNCTIONAL GASTROINTESTINAL DISORDERS 1533

who have continuous abdominal pain will sometimes ments with or without tricyclic antidepressants.13,55 A
have pain also in association with physiological events.3 more recent open-label trial of citalopram in children
That the pain is not feigned was a requirement of the with recurrent abdominal pain reported a promising
Rome II criteria. This was a very challenging criterion to outcome.54
assess because pain is a subjective experience as reported
by the individual. The committee has elected to elimi-
H3. Constipation and Incontinence
nate the requirement for some loss of daily function in
the criteria for FAP because such a criterion confounded H3a. Functional Constipation
symptoms and function. It excluded motivated children The term “functional constipation” describes all
who continued activity despite the pain and children children in whom constipation does not have an organic
whose parents insisted that they continue activities. etiology. Because functional constipation and functional
However, it is recognized that there is a subgroup of fecal retention often overlap, the 2 disorders were merged
children in whom loss of daily functioning and/or ac- into 1 category named “functional constipation.”3,9
companying somatic symptoms form an important com- Epidemiology. Estimates of constipation have
ponent of their symptom complex. This group is now varied between 0.3% and 8% in the pediatric popula-
referred to as having FAPS. tion.56 It represents 3%–5% of general pediatric outpa-
Clinical evaluation. In FAP(S), a limited and rea- tient visits and up to 25% of pediatric gastroenterology
sonable screening includes a complete blood cell count, consultations.3,57 A positive family history has been
erythrocyte sedimentation rate or C-reactive protein found in 28%–50% of constipated children, and a higher
measurement, urinalysis, and urine culture. Other bio- incidence has been reported in monozygotic than dizy-
chemical profiles (liver and kidney) and diagnostic tests gotic twins.36 Peak incidence occurs at the time of toilet
(stool culture and examination for ova and parasites and training (between 2 and 4 years of age), with an increased
breath hydrogen testing for sugar malabsorption) can be prevalence in boys.58
performed at the discretion of the clinician, based on the
child’s predominant symptoms and degree of functional
impairment and parental anxiety.
H3a. Diagnostic Criteria* for Functional
Physiological features. In contrast to children
Constipation
with IBS, visceral hypersensitivity of the rectum was not
elicited in children with FAPS.6 This finding does not Must include 2 or more of the following in a
preclude the possibility that visceral hypersensitivity child with a developmental age of at least 4 years
may exist more proximally in the gastrointestinal tract. with insufficient criteria for diagnosis of IBS:
The presence of associated features and symptoms such as 1. Two or fewer defecations in the toilet per
headache, limb pain, and lower-pressure pain threshold week
remains to be validated and explained in children who 2. At least 1 episode of fecal incontinence per
meet the symptom-based Rome criteria for FAPS.48,49 week
Psychological features. The symptoms of anxi- 3. History of retentive posturing or excessive vo-
ety, depression, and somatization described in both chil- litional stool retention
dren with recurrent abdominal pain and their parents 4. History of painful or hard bowel movements
may apply to children with FAP(S) and those with IBS 5. Presence of a large fecal mass in the rectum
and functional dyspepsia seen in both the primary and 6. History of large diameter stools that may ob-
specialty care setting.14,21,50 –54 struct the toilet
Treatment. A biopsychosocial approach to chil-
dren with abdominal pain-related FGIDs is particularly *Criteria fulfilled at least once per week for at least 2
relevant in the case of children with FAP(S). Indeed, months before diagnosis
because the specific target is pain, it is important to
investigate the contribution of psychosocial factors. Re- Rationale for changes in diagnostic criteria. The
assurance and explanation of possible mechanisms in- change from 3 to 2 months of symptoms is based on both
volving the brain-gut interaction should be given to the clinical experience and data from the literature suggest-
child and parent. The possible role of psychosocial fac- ing that the longer functional constipation goes unrec-
tors, including triggering events, should be explained. ognized, the less successful is the treatment. Loening-
Two reports on children with abdominal pain-related Baucke56 studied the outcome in constipated young
FGIDs suggested possible benefit from behavioral treat- children (⬍4 years old) seen in a general pediatric prac-
1534 RASQUIN ET AL GASTROENTEROLOGY Vol. 130, No. 5

tice and found that prognosis was more favorable when children. The painful evacuation of such fecal mass often
the referral had been made before the age of 2 years. She leads the terrified child to trying to avoid further bowel
has also reported that recovery in encopretic children was movements. A large fecal mass in the rectum has been
associated with a shorter duration of symptoms.10 A found in 98% of children fulfilling the previous Rome II
recent long-term follow-up study of constipated children criteria for functional fecal retention.10 It is acknowl-
also found a trend toward a diminished number of suc- edged that the mention of a “large” mass in the criteria
cessfully treated children in those with a longer period of introduces a subjective element that can be interpreted
symptoms before referral to a subspecialty clinic.59 The differently by different individuals. The mention of
previous diagnostic criteria for functional fecal retention stools “clogging the toilet” represents an attempt to
put a high premium on retentive posturing, which was 1 provide an objective measure of the size of the fecal mass.
of the 2 criteria that had to be present to make a Clinical evaluation. A careful history needs to
diagnosis. It is now recommended that the history of
elicit the time after birth of the first bowel movement,
retentive posturing or volitional stool retention be 1 of
the time of onset of the problem, characteristics of stools
the 6 criteria, which may support the diagnosis but
(frequency, consistency, caliber, and volume), the pres-
without the requirement to be present in all subjects.
ence of associated symptoms (pain at defecation, abdom-
Children who have been constipated for years may have
had withholding behavior long before the visit to the inal pain, blood on the stool or the toilet paper, and fecal
physician, and by the time they are evaluated, the rectum incontinence), stool withholding behavior, urinary prob-
has become dilated and has accommodated to the point lems, and neurologic deficits. Fecal incontinence may be
that withholding is no longer necessary in order to delay mistaken for diarrhea by some parents. Urinary problems
the passage of stools. In other instances, the parents will are common in these children. During abdominal exam-
deny withholding misinterpreting the withholding for ination, a fecal mass is commonly found. External exam-
attempts to defecate or they have not paid enough at- inations of the perineum and perianal area exclude signs
tention to the child’s behavior to be able to describe it. of spinal dysraphism. Although controversy exists, the
It has been reported that 14% of parents of constipated North American Society for Gastroenterology, Hepatol-
children could not adequately answer questions regard- ogy, and Nutrition has recommended that digital rectal
ing retentive posturing,9 and in a recent study, adoles- examination be performed at least once.61 An abdominal
cents were not able to understand the concept of exces- radiograph can be useful in determining the presence of
sive withholding behavior.3 In more than 20% of fecal retention in a child who is obese or refuses a rectal
children older than 5 years presenting with incontinence examination.
because of constipation, parents do not report withhold- Physiological features. Functional constipation
ing behavior.10 The term excessive volitional stool reten- in children is often the result of repeated attempts of
tion is used to describe older children who still withhold voluntary withholding of feces. Abnormal defecation dy-
their stools without necessarily displaying retentive pos- namics or pelvic dyssynergia has been reported in 63% of
turing. Fecal incontinence (involuntary passage of fecal children with chronic constipation.62 Progressive fecal
material in the underwear) is one of the most common accumulation in the rectum eventually leads to pelvic
presentations of functional constipation, being found in floor muscle fatigue and anal sphincter poor competence
up to 84% of children at presentation.9 It causes a leading to fecal incontinence.
tremendous amount of distress for patients and their
Psychological features. Children presenting with
family. The 2 studies that have looked at the applicabil-
constipation have lower quality of life and exhibit poorer
ity of the Rome II criteria for FFR have both recom-
self-esteem and often some social withdrawal.63 Constipated
mended fecal incontinence be incorporated in the revised
children display more anxiety related to toilet training and
criteria.9,10 Incontinence may be useful as an objective
marker for the severity of functional constipation and in often evolve a coping style based on denial.64
monitoring effectiveness of treatment.60 Treatment. The clinician addresses the myths
A painful bowel movement has been identified as and fears, and these statements both decrease the child’s
having an important historical value in causing the re- and the family’s anxiety and create an expectation for
tentive behavior.57 The presence of a large fecal mass positive change. A dose of 1–1.5 g/kg/d polyethylene
either before evacuation (recognized during the physical glycol 3350 per 3 days is usually effective in treating
examination) or after having a bowel movement (ob- fecal impaction.65 For maintenance, stool softeners are
structing the toilet or causing severe discomfort), al- preferred to stimulant laxatives. Rewards for success in
though not a symptom, is a critical feature of constipated toilet learning are often helpful.
April 2006 CHILDHOOD FUNCTIONAL GASTROINTESTINAL DISORDERS 1535

H3b. Nonretentive Fecal Incontinence Treatment. Education, a nonaccusatory approach;

Nonretentive fecal incontinence represents the re- regular toilet use with rewards; and referral to a mental
peated, inappropriate passage of stool into a place other health professional when appropriate are part of the thera-
than the toilet in a child older than 4 years with no peutic regimen. Successful resolution of symptoms may
evidence of fecal retention.1,66 require prolonged treatment and follow-up.69
Epidemiology. Fecal incontinence is reported to
be responsible for 3% of referrals to teaching hospitals. Recommendations for Future
Its prevalence has been reported to be 4.1% in the Research
5– 6-year-old age group and 1.6% in the 11–12-year-old Many of the recommendations listed by the Rome
age group in the Netherlands and has been noted to be II committee remain valid. Other suggestions for future
more frequent among boys and children from families research topics in this area have recently been formulated
with lower socioeconomic status.67 Interestingly, only by other committees of several pediatric gastroenterology
38% of the 5– 6-year olds and 27% of the 11–12-year societies.70,71 The committee identified the following
olds who had fecal incontinence had ever seen a physician areas that are in need of research in the near future.
for this problem. The prevalence of nonretentive fecal
1. Further validation studies of the pediatric Rome cri-
incontinence among this group was undefined. Applying
teria need to be developed. Such studies need to be
the Rome II criteria, 21% of patients attending a sub-
performed in a wide range of clinical settings and
specialty clinic fulfilled the criteria for functional nonre-
patient populations by using validated question-
tentive fecal incontinence.9
naires. Specifically, the new proposed criteria for sub-
groups of dyspeptic disorders need to be studied in
children.
H3b. Diagnostic Criteria* for Nonretentive
2. Mechanistic studies will help us understand how clus-
Fecal Incontinence
ters of symptoms may be related to different patho-
Must include all of the following in a child physiological mechanisms, providing better targets
with a developmental age at least 4 years: for more tailored therapeutic interventions.
1. Defecation into places inappropriate to the 3. Large and well-designed studies need to be developed
social context at least once per month aimed at assessing epidemiology and health care im-
2. No evidence of an inflammatory, anatomic, pact of pediatric FGID.
metabolic, or neoplastic process that explains 4. The effect of early life events and intercurrent infec-
the subject’s symptoms tions on the future development of pediatric and
3. No evidence of fecal retention adult FGID will need further investigation.
5. The interaction between central nervous system, en-
*Criteria fulfilled for at least 2 months before diagnosis teric nervous system, and immune system needs to be
explored.
Rationale for changes in diagnostic criteria. The 6. Outcome studies of FGIDs need to explore the effects
duration of symptoms is 2 months to harmonize with the of different treatments on quality of life.
other criteria. 7. Multisite intervention studies of current and emerg-
Clinical evaluation. Pertinent information to be ing pharmacological agents need to be completed by
elicited in the clinical history is related to ruling out using standardized diagnostic criteria.
constipation (see related section). In these children, in- 8. Cohort studies need to address the natural history of
continence is diurnal, and no fecal mass is found on pediatric FGID.
physical examination. An abdominal radiograph may
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17. American Psychiatric Association. Diagnostic and Statistical 37. Caplan A, Lambrette P, Joly L, Bouin M, Boivin M, Rasquin A.
Manual of Mental Disorders. 4th ed. Washington, DC: American Intergenerational transmission of functional gastrointestinal dis-
Psychiatric Association, 1994. orders: children of IBS patients versus children with IBS, func-
18. Khan S, Hyman PE, Cocjin J, Di Lorenzo C. Rumination syndrome tional dyspepsia and functional abdominal pain. Gastroenterol-
in adolescents. J Pediatr 2000;136:528 –531. ogy 2003;124:A-533.
19. Loening-Baucke V. Aerophagia as cause of gaseous abdominal 38. Claar RL, Walker LS, Smith CA. Functional disability in adoles-
distention in a toddler. J Pediatr Gastroenterol Nutr 2000;31: cents and young adults with symptoms of irritable bowel syn-
204 –207. drome: the role of academic, social, and athletic competence.
20. Gauderer MW, Halpin TC Jr, Izant RJ Jr. Pathologic childhood J Pediatr Psychol 1999;24:271–280.
aerophagia: a recognizable clinical entity. J Pediatr Surg 1981; 39. Levy RL, Whitehead WE, Walker LS, Von Korff M, Feld AD, Garner
16:301–305. M, Christie D. Increased somatic complaints and health-care
21. Di Lorenzo C, Colletti RB, Lehmann HP, Boyle JT, Gerson WT, utilization in children: effects of parent IBS status and parent
Hyams JS, Squires RH Jr, Walker LS, Kanda PT. Chronic abdom- response to gastrointestinal symptoms. Am J Gastroenterol
inal pain in children: a clinical report of the American Academy of 2004;99:2442–2451.
Pediatrics and the North American Society for Pediatric Gastro- 40. Li BU, Balint JP. Cyclic vomiting syndrome: evolution in our un-
enterology, Hepatology and Nutrition. J Pediatr Gastroenterol derstanding of a brain-gut disorder. Adv Pediatr 2000;47:117–
Nutr 2005;40:245–248. 160.
22. Hyams JS, Davis P, Sylvester FA, Zeiter DK, Justinich CJ, Lerer T. 41. Mortimer MJ, Kay J, Jaron A. Clinical epidemiology of childhood
Dyspepsia in children and adolescents: a prospective study. abdominal migraine in an urban general practice. Dev Med Child
J Pediatr Gastroenterol Nutr 2000;30:413– 418. Neurol 1993;35:243–248.
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42. Abu-Arafeh I, Russell G. Prevalence and clinical features of ab- 59. Van Ginkel R, Reitsma JB, Buller HA, van Wijk MP, Taminiau JA,
dominal migraine compared with those of migraine headache. Benninga MA. Childhood constipation: longitudinal follow-up be-
Arch Dis Child 1995;72:413– 417. yond puberty. Gastroenterology 2003;125:357–363.
43. Dignan F, Abu-Arafeh I, Russell G. The prognosis of childhood 60. van der Plas RN, Benninga MA, Redekop WK, Taminiau JA, Buller
abdominal migraine. Arch Dis Child 2001;84:415– 418. HA. How accurate is the recall of bowel habits in children with
44. Mortimer MJ, Good PA. The VER as a diagnostic marker for defaecation disorders? Eur J Pediatr 1997;156:178 –181.
childhood abdominal migraine. Headache 1990;30:642– 645. 61. Baker SS, Liptak GS, Colletti RB, Croffie JM, Di Lorenzo C, Ector
45. Good PA. Neurologic investigations of childhood abdominal mi- W, Nurko S. Constipation in infants and children: evaluation and
graine: a combined electrophysiologic approach to diagnosis. treatment. A medical position statement of the North American
Society for Pediatric Gastroenterology and Nutrition. J Pediatr
J Pediatr Gastroenterol Nutr 1995;21(Suppl 1):S44 –S48.
Gastroenterol Nutr 1999;29:612– 626.
46. Withers GD, Silburn SR, Forbes DA. Precipitants and aetiology of
62. Loening-Baucke V, Cruikshank B, Savage C. Defecation dynamics
cyclic vomiting syndrome. Acta Paediatr 1998;87:272–277.
and behavior profiles in encopretic children. Pediatrics 1987;80:
47. Symon DN, Russell G. Abdominal migraine: a childhood syn-
672– 679.
drome defined. Cephalalgia 1986;6:223–228. 63. Landman GB, Rappaport L, Fenton T, Levine MD. Locus of control
48. Alfven G. One hundred cases of recurrent abdominal pain in and self-esteem in children with encopresis. J Dev Behav Pediatr
children: diagnostic procedures and criteria for a psychosomatic 1986;7:111–113.
diagnosis. Acta Paediatr 2003;92:43– 49. 64. Ahmad T, Steffen R, Banez G, Mahajan L, Feinberg L, Worley S.
49. Duarte MA, Goulart EM, Penna FJ. Pressure pain threshold in Defecation anxiety in children with functional constipation. J Pe-
children with recurrent abdominal pain. J Pediatr Gastroenterol diatr Gastroenterol Nutr 2003;37:328.
Nutr 2000;31:280 –285. 65. Youssef NN, Peters JM, Henderson W, Shultz-Peters S, Lockhart
50. Dorn LD, Campo JC, Thato S, Dahl RE, Lewin D, Chandra R, Di DK, Di Lorenzo C. Dose response of PEG 3350 for the treatment
Lorenzo C. Psychological comorbidity and stress reactivity in of childhood fecal impaction. J Pediatr 2002;141:410 – 414.
children and adolescents with recurrent abdominal pain and 66. Benninga MA, Buller HA, Heymans HS, Tytgat GN, Taminiau JA. Is
anxiety disorders. J Am Acad Child Adolesc Psychiatry 2003;42: encopresis always the result of constipation? Arch Dis Child
66 –75. 1994;71:186 –193.
51. Hodges K, Kline JJ, Barbero G, Flanery R. Depressive symptoms 67. van der Wal MF, Benninga MA, Hirasing RA. The prevalence of
in children with recurrent abdominal pain and in their families. encopresis in a multicultural population. J Pediatr Gastroenterol
J Pediatr 1985;107:622– 626. Nutr 2005;40:345–348.
52. Walker LS, Greene JW. Children with recurrent abdominal pain 68. Benninga MA, Voskuijl WP, Akkerhuis GW, Taminiau JA, Buller
HA. Colonic transit times and behaviour profiles in children with
and their parents: more somatic complaints, anxiety, and depres-
defecation disorders. Arch Dis Child 2004;89:13–16.
sion than other patient families? J Pediatr Psychol 1989;14:
69. Voskuijl WP, Reitsma JB, Van Ginkel R, Buller HA, Taminiau JA,
231–243.
Benninga MA. Functional non-retentive faecal soiling in children: 12
53. Campo JV, Bridge J, Ehmann M, Altman S, Lucas A, Birmaher B,
years of longitudinal follow-up. Gastroenterology 2005;128:A-462.
Di Lorenzo C, Iyengar S, Brent DA. Recurrent abdominal pain, 70. Di Lorenzo C, Benninga MA, Forbes D, Morais MB, Morera C,
anxiety, and depression in primary care. Pediatrics 2004;113: Rudolph C, Staiano A, Sullivan PB, Tobin J. Functional gastroin-
817– 824. testinal disorders, gastroesophageal reflux and neurogastroen-
54. Campo JV, Perel J, Lucas A, Bridge J, Ehmann M, Kalas C, Monk terology: Working Group report of the second World Congress of
K, Axelson D, Birmaher B, Ryan N, Di Lorenzo C, Brent DA. Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr
Citalopram treatment of pediatric recurrent abdominal pain and Gastroenterol Nutr 2004;39(Suppl 2):S616 –S625.
comorbid internalizing disorders: an exploratory study. J Am Acad 71. Li BU, Altschuler SM, Berseth CL, Di Lorenzo C, Rudolph CD,
Child Adolesc Psychiatry 2004;43:1234 –1242. Scott RB. Research agenda for pediatric gastroenterology, hepa-
55. Youssef NN, Rosh JR, Loughran M, Schuckalo SG, Cotter AN, tology and nutrition: motility disorders and functional gastrointes-
Verga BG, Mones RL. Treatment of functional abdominal pain in tinal disorders. Report of the North American Society for Pediatric
childhood with cognitive behavioral strategies. J Pediatr Gastro- Gastroenterology, Hepatology and Nutrition for the Children’s
enterol Nutr 2004;39:192–196. Digestive Health and Nutrition Foundation. J Pediatr Gastroen-
56. Loening-Baucke V. Constipation in early childhood: patient char- terol Nutr 2002;35(Suppl 3):S263–S267.
acteristics, treatment, and longterm follow up. Gut 1993;34:
1400 –1404. Received March 28, 2005. Accepted August 10, 2005.
57. Partin JC, Hamill SK, Fischel JE, Partin JS. Painful defecation and Address requests for reprints to: Andrée Rasquin, MD, Service de
fecal soiling in children. Pediatrics 1992;89:1007–1009. Gastro-entérologie, Hépatologie et Nutrition CHU Ste-Justine, 3175
58. Di Lorenzo C. Pediatric anorectal disorders. Gastroenterol Clin Côte Ste-Catherine, Montréal, QC, Canada H3T 1C5. e-mail: a.rasquin@
North Am 2001;30:269 –287. umontreal.ca; fax: (514) 345-4999.
 GASTROENTEROLOGY 2006;130:1538 –1551

Design of Treatment Trials for Functional Gastrointestinal

Disorders

Design of Treatment Trials Committee: E. JAN IRVINE,* WILLIAM E. WHITEHEAD,‡

WILLIAM D. CHEY,§ KEI MATSUEDA,储 MICHAEL SHAW,¶ NICHOLAS J. TALLEY,#,** and
SANDER J. O. VELDHUYZEN VAN ZANTEN‡‡
*Division of Gastroenterology, St. Michael’s Hospital and University of Toronto, Toronto, Ontario, Canada; ‡Division of Gastroenterology,
University of North Carolina–Chapel Hill, Chapel Hill, North Carolina; §Division of Gastroenterology, University of Michigan, Ann Arbor,
Michigan; 储Division of Gastroenterology, NCNP, Ichakawa City, Japan; ¶Division of Gastroenterology, Park Nicollet Clinic and University of
Minnesota, Minneapolis, Minnesota; #Division of Gastroenterology, Mayo Clinic College of Medicine and Division of Gastroenterology and
Hepatology, Rochester, Minnesota; **Department of Medicine, University of Sydney, Sydney, Australia; and ‡‡Division of Gastroenterology
Dalhousie University, Halifax, Nova Scotia, Canada

This document addresses the design of trials to assess the provide standards to help explain the mechanisms of
efficacy of new treatments for functional gastrointestinal therapeutic success and enable regulatory agencies, re-
disorders (FGID), emphasizing trials in irritable bowel syn- searchers, and providers to better evaluate the quality of
drome and dyspepsia, because most research has been published studies. This report focuses largely on designs
undertaken in these conditions. The double-blind, random- that evaluate treatment efficacy, with emphasis on irri-
ized, placebo-controlled, parallel group trial remains the
table bowel syndrome (IBS) and functional dyspepsia
preferred design. Randomized withdrawal designs, al-
(FD), because they have been studied most extensively.
though encouraged by the European Agency for the Eval-
uation of Medicinal Products, have the same potential Studies that address pathophysiology or mechanism of
disadvantages as a crossover design, including carryover treatment effects are not included in this review because
effects, unmasking (unblinding), and overestimation of the they require quite different and diverse study designs.
potential benefit for clinical practice. Innovative trial de- Recommendations in this article are based largely on
signs that evaluate intermittent (on demand) treatment consensus of the literature, except where specifically in-
are likely to become more common in the future. Investi- dicated. We refer readers to the corresponding chapter in
gators should include as broad a spectrum of patients as the Rome III book for a more detailed discussion with
possible and should report recruitment strategies, inclu- evidence-based examples.
sion/exclusion criteria, and attrition data. The primary
analysis should be based on the proportion of patients in
Identifying the Research Question
each treatment arm who satisfy an a priori treatment
responder definition, or a prespecified clinically meaningful and Hypothesis
change in a patient-reported symptom improvement mea- The goals of most treatment trials are to ascertain
sure. Such measures of improvement are psychometrically the impact of the intervention(s) on (1) the frequency and
validated subjective global assessments or a change from severity of symptoms, (2) health status and quality of life,
baseline in a validated symptom severity questionnaire. It (3) the patient’s ability to cope with symptoms, and/or
is unethical to change the responder definition after a trial
(4) the use of health care resources. Generally, a single
begins. Data analysis should address all patients enrolled,
trial can answer only 1 or 2 of these questions.1–3
using an intention-to-treat principle. Reporting of results
should follow the Consolidated Standards for Reporting Investigators should select their most important research ques-
Trials guidelines and include an analysis of harms data and tion(s), pertinent to the specific FGID, develop a hypothesis
secondary outcome measures to support or explain the based on available evidence, and design a study that will most
primary outcome. Trials should be registered in a public effectively answer the proposed research question.
location, prior to initiation, and should be published even if
the results are negative or inconclusive. Abbreviations used in this paper: CONSORT, Consolidated Standards
for Reporting Trials; EMEA, European Agency for the Evaluation of
Medicinal Products; FD, functional dyspepsia; FGID, functional gastro-
he committee’s aims were to review the literature on
T trial design for the functional gastrointestinal dis-
orders (FGIDs), to further develop guidelines1–3 to assist
intestinal disorder; ITT, intention to treat; NNH, number needed to
harm; NNT, number needed to treat; IBS, irritable bowel syndrome.
© 2006 by the American Gastroenterological Association Institute
0016-5085/06/$32.00
researchers in conducting treatment trials for the FGIDs, doi:10.1053/j.gastro.2005.11.058
April 2006 DESIGN OF TREATMENT TRIALS 1539

Patient Population Special recruitment strategies such as advertising have

been accepted in some countries to accelerate recruit-
A broad spectrum of patients should be included to
ment. A recent IBS study observed that patients re-
support the generalizability of the trial findings to patients
cruited by newspaper advertisement, in comparison to
outside of the trial. In pharmaceutical research, particularly,
patients enrolled by gastroenterologists, were older, more
regulatory agencies may limit licensed drug indications to
highly educated, more often depressed but less anxious,
the trial population. The study population should be se-
and had less severe IBS symptoms; primary care patients
lected based on the question, treatment (including possible
were also anxious but had symptom severity that was
side effects), expected results, and empirical data.2 A screen-
intermediate between patients recruited by advertise-
ing log, summarizing the most important demographic
ment and patients recruited from gastroenterology clin-
variables in patients entered or excluded and the reasons for
ics.10
exclusion, is strongly recommended.
Recruitment strategies should be clearly identified to allow
A screening log provides support for the generalizability of the
exploration of different patterns of treatment response.
results.
Specified inclusion and exclusion criteria are manda- Patient Characteristics
tory for all studies and should include the FGID case
definition. If enrollment is targeted to a special popula- Important patient characteristics to report include
tion to maximize treatment efficacy or minimize side age, gender, race, symptom severity, duration of disease,
prior treatments for the study condition (and response),
effects, the reasons must be carefully documented.2,4,5
and the use of coexisting medications, including over-
It is advisable to include as broad a spectrum of patients as
the-counter drugs and vitamins. These may impact out-
possible, defined by the ROME-specific FGID criteria. Restrict-
comes and should be tested as possible disease or effect
ing the study population must be justified and inclusion and
modifiers. For example, gender differences in drug re-
exclusion criteria must be specified.
sponse have become evident in clinical trials of certain
In clinical practice, many physicians avoid formal
serotonergic drugs in patients with IBS.11 Depending on
investigation in favor of a positive diagnosis, reassurance,
the hypothesis, investigators may choose to enroll only
and lifestyle modification. However, entry criteria for
one gender. However, if both women and men are to be
treatment trials must be more specific. The consensus
included, there should be sufficient numbers of both to
view is that the minimum evaluation should include a
allow meaningful subgroup analyses. As data accumulate
complete blood count, imaging of the relevant part of the
describing the genetics of the FGIDs in relation to drug
gastrointestinal tract within the previous 5 years, and
responsiveness, it may become relevant to assess these
other investigations determined by symptoms and family
parameters during clinical trials.11 It is also advisable to
history.6 Emerging evidence suggests that screening IBS
assess for psychological distress or prior mental health
patients for gluten enteropathy may also be desirable.7 problems; in trials of psychological interventions or psy-
When testing is required for study inclusion, it should choactive drugs, these may be important effect modifiers,
be consistent across all study arms, and the timing and in trials of nonpsychological treatments, they are
should be defined and recorded. potential confounders that could influence both baseline
The minimum screening investigation for eligibility should be symptom severity and response to treatment.12
specified. Potential disease modifiers/confounders that might affect re-
Most trials of FGIDs have been conducted in academic sponse to therapy should be assessed.
centers specifically interested in the FGIDs, creating
concerns of selection bias that favor inclusion of patients
with more severe symptoms and/or with psychosocial Clinical Trial Design
issues.8 Two large trials showed significant differences in Clinical trials differ from usual practice in several
treatment response between primary and referred pa- ways, including the application of strict eligibility cri-
tients with FD.9 Thus, researchers should consider re- teria, use of a placebo, a standardized intervention, fre-
cruiting broadly, noting if subjects are from primary, quent follow-up visits with extensive data recording, and
secondary, or tertiary care. Differences in baseline sever- the use of study coordinators. Nonetheless, standard
ity and treatment response by site or type of recruitment aspects of diagnosis and management, especially an ad-
should be examined. equate explanation and reassurance about the disease, are
Patient characteristics should be documented sufficiently to part of standard care and should be provided to all
examine the comparability of patients among centers and allow patients in the trial. Novel interventions must show
comparisons with other populations. promise of a benefit over standard care.
1540 IRVINE ET AL GASTROENTEROLOGY Vol. 130, No. 5

Table 1. Major Sources of Bias or drug trials in which the active drug causes predictable
Bias Type Comments side effects or rapid symptom change, are difficult to
1. Investigator bias Conscious or unconscious bias, usually mask from patients or investigators, but possible solu-
expressed through decisions about tions to maintain an investigator-masked outcome assess-
eligibility ment include using independent assessors who are un-
2. Patient expectancy Especially a problem where end points
(placebo) are subjective
aware of the intervention, using a standardized
3. Ascertainment bias interviewer or self-administered questionnaire, or per-
Self-selection for Patients are more likely to respond forming laboratory tests (eg, anal manometry in fecal
treatment positively to treatments they prefer
incontinence) that are interpreted by individuals not
and seek out
Changes in subject Publicity or other factors may influence interacting with the patients.
pool the subject pool over time It is mandatory to undertake the maximum masking possible,
4. Nonspecific effects determined by the type of intervention and study design.
Doctor–patient Especially important in psychological
relationship interventions Randomization. Randomization is a process (equiv-
Regression to mean Patients are usually enrolled when alent to the flip of a coin) used to assign patients to
most symptomatic and inevitably treatment arms in an unbiased fashion. The allocation se-
“improve”
5. Publication bias Authors are more likely to submit
quence should be concealed from investigators and research
positive results and journals more personnel should be unaware of the treatment to which a
likely to publish them patient will be assigned until after the patient has been
deemed eligible and has consented to participate.22 Stratified
randomization, whereby the most important prognostic fac-
Every trial should incorporate the principles of good clinical tors (eg, gender and usual bowel habit) are identified be-
practice to ensure that the study results are relevant to real forehand, uses a separate randomization sequence for each
practice situations. stratum (eg, male versus female or constipation-predomi-
nant versus diarrhea-predominant IBS) to balance these
Unique Challenges for the Design of factors among treatment groups.23 Stratification should be
Treatment Trials in FGIDs limited to 1 or 2 factors.22,24 Particularly in multicenter
Study designs for treatment trials in FGID face trials, in which sites may enroll only a few subjects, ran-
several important challenges: (1) a high placebo response domization can be performed in blocks. A block refers to the
rate13,14; (2) fluctuating symptoms15; (3) possible need number of subjects within which the group assignments
for multimodal therapy owing to weak effects of available have to be balanced. A permutated block design (variable block
treatments or multiple etiologic mechanisms interacting size) ensures that the sequence of assignments is unpredict-
in the disease process16; (4) difficulty of masking (blind- able to the investigator. When reporting the trial, the
ing) patients and investigators, particularly in trials of randomization procedure should be explicitly described be-
behavioral interventions17; (5) contamination from over- cause it is a potential source of bias.
the-counter treatments or drugs taken for other condi- Investigators must include a detailed description of their
tions (eg, antidepressants); and (6) avoidance of harms in randomization scheme in the report of the study.
treating non–life-threatening conditions.18,19 Selecting the control group. A placebo control
Bias, defined as systematic error that leads to a devi- group is essential to establish the efficacy of a new
ation of the estimated treatment effect from its true treatment. When a proven efficacious treatment exists,
value, may enter a clinical trial at any stage from patient comparison against this active treatment may be consid-
enrollment to publication of the results. The major ered,25 but inclusion of a placebo is still recommended to
sources of bias are listed in Table 1.20 avoid an inconclusive trial, in which the active treat-
Masking. Double masking (of both patients and ments are of similar efficacy.
researchers) to the intervention ensures the validity of the Behavioral therapy trials17 pose particular challenges
outcome assessment. “Triple masking” is desirable and to identify inactive comparison treatments that generate
extends masking to all investigators, including data expectancy comparable to the active intervention. Un-
managers and statisticians.21 In drug trials, investigators treated patients are poor control subjects because they
are encouraged to ask both the patient and the interven- can experience a “negative expectancy,”26 which may
tionist who interacts with the patient at the end of the result in an overestimate of the impact of the interven-
trial whether they believe the active treatment was ad- tion. Options to assess the integrity of behavioral trials
ministered and to report these data. Certain interven- include (1) testing the credibility of both active and
tions, such as psychotherapy, hypnosis, sphincterotomy, control interventions after initial exposure (eg, by using
April 2006 DESIGN OF TREATMENT TRIALS 1541

the Credibility Scale27),28 or (2) using a process measure The placebo response rate in treatment trials of FGIDs is
to ensure that the active treatment is producing the substantial and largely unavoidable.
intended effects on physiology or cognitions while the Baseline observation versus placebo run-in. A
control treatment does not (eg, does biofeedback for fecal period of prospective baseline measurement before treat-
incontinence change anal sphincter squeeze pressure ment is useful to evaluate patient eligibility. This also
more than the control condition, or does cognitive– limits recall and reporting biases by ensuring that pa-
behavioral therapy alter the patients dysfunctional atti- tients are currently symptomatic. It allows comparison of
tudes to a greater extent than an education control patients in the active and placebo groups, as well as
treatment?).17 Investigators should discuss residual evaluation of a clinically important change in health
sources of bias and their potential impact on study status.
findings in the discussion section of the report. Older studies have used a placebo run-in period where
A placebo control group is essential. In behavioral treatment all patients received placebo for a specified period and
trials, confirming that the control condition produces a similar their response was assessed, using the study outcome
expectation of benefit, but does not act on the same physiologic or measures. Patients who significantly improved were ex-
psychological principles, is recommended. cluded from further participation to reduce the propor-
tion of placebo responders and to exclude patients with
Placebo Interventions poor adherence. This has been used in several trials of
A placebo is an intervention believed to lack any allergic rhinitis and, although acceptable to regulatory
specific effect to change a particular disorder.29 Placebo agencies, may underestimate the overall effect size.32,33 It
effects range from 10% to 70% for FD14 and 0% to 84% is also difficult to predict whether (1) the placebo re-
for IBS.13 This substantial placebo response rate makes it sponse increases, plateaus, or decays after the run-in
more difficult to demonstrate superior efficacy of new phase,34 (2) a differential dropout occurs, and (3) patients
treatments. Of note, a placebo administered by a physi- removed from a trial have a different response to those
cian appears to be more powerful than one given by other who continue. Exclusion of patients for placebo response
health professionals.29 Some treatments also demonstrate may also disrupt the doctor–patient relationship for fu-
an order effect, in which an effective drug has a lesser ture management.
benefit when given after a placebo. This is especially The disadvantages of a placebo run-in appear to outweigh the
important if a placebo run-in period is implemented to benefits and it is best avoided. However, baseline observations
exclude placebo responders or in studies with a crossover are recommended.
design, because approximately half of patients in a cross-
over study receive placebo first. Choice of Study Design
External factors may also contribute to changes in The double-masked, randomized, placebo-con-
health status making it difficult to detect a treatment trolled trial is the gold standard method to test the
effect, including (1) a natural variation in symptoms, (2) efficacy of a new treatment. A parallel group study
regression toward the mean, and (3) unidentified or design requires that patients be randomized to receive
unintended cointerventions. Regression to the mean is the only one treatment assignment throughout the trial (af-
likelihood that patients consult when symptoms are par- ter a period of baseline assessment without treatment).
ticularly severe and improve with time owing to the Dose-ranging studies (different groups receive different
natural variation in symptom severity and irrespective of doses) and multiple control treatments, with a baseline
trial participation.30 Important cointerventions such as observation of no treatment or a washout period after
changes in diet or using over-the-counter remedies could treatment, are different variants of a parallel group de-
also lead to a false interpretation that an intervention was sign.
effective, as could the extra attention given patients by Crossover designs, in which subjects receive both treat-
researchers during clinical trials (Hawthorn effect).20 The ments during distinct time periods, separated by a wash-
magnitude of the placebo response may also be influ- out phase have been popular in some FGIDs.14 Theoret-
enced by the wording of the question used to define ically, lesser variability in outcomes within subjects
treatment response or by the use of a compound ques- could require a smaller sample size for the desired sta-
tion; a recently published meta-analysis31 suggests that tistical power. However, patient dropout rates and miss-
the placebo response rate is larger when a responder is ing data have a greater impact than in a parallel design,
defined by a global improvement in IBS symptoms com- because patients are omitted from both study arms when
pared to defining a responder by reduction in abdominal data are missing. The greatest disadvantages of crossover
pain (average placebo responses of 36% versus 28%). designs are (1) the carry-over (period-by-treatment) ef-
1542 IRVINE ET AL GASTROENTEROLOGY Vol. 130, No. 5

fects that occur when the first treatment influences the There is a growing interest in developing drugs for
response to the second treatment or when symptoms intermittent treatment (short-course administration for a
change with time,35 and (2) the high likelihood of un- predetermined time period after symptom recurrence) or
masking owing to side effects.35 The European Agency on-demand treatment (medication is taken only during
for the Evaluation of Medicinal Products (EMEA) may symptoms). These issues have been addressed in gastro-
accept a crossover design for a Phase III trial, yet has esophageal reflux disease.40 IBS and FD trials have fo-
highlighted problems that could invalidate study re- cused on continuous administration of drugs to moderate
sults36 and does not provide guidance for analysis. If or prevent attacks.4,5 However, most patients with
period and sequence effects occur, only the first treat- FGIDs experience episodic “attacks,”15,41 and experts
ment period data should be used to determine efficacy. believe that patients often take medications only as
Although crossover designs are not recommended for needed. Trial designs and outcome measures required for
treatment trials with subjective end points, they may be testing the efficacy of intermittent therapy differ from
used in physiologic studies, where the end points are those used to test continuously administered treatments.
objectively measured. After establishing efficacy during continuous administra-
A factorial design can be undertaken to evaluate com- tion, intermittent or on-demand studies can be con-
bined treatments.37 For example, to test the effects of ducted. Guidelines for intermittent treatment of mi-
combining two treatments, A and B, subjects are ran- graine42 or gastroesophageal reflux disease43 may provide
domly assigned to 4 groups: no A and no B; A and no B; a model for FGIDs.
B and no A; or both A and B. Investigators might The parallel group design is the accepted standard for
consider such a design either (1) to save money by testing evaluation of efficacy for most treatments and is applicable to
2 treatments at once with fewer subjects overall, or (2) to most experimental situations. The crossover design is best
test for synergistic effects of combined treatments. Im- avoided.
portantly, the 2 treatments should have distinct mecha- Types of trials. The strongest case supporting the
nisms of action to be able to interpret the simple effects efficacy of a new medication is made by demonstrating
(ie, the comparison of all patients receiving treatment A clinical and statistical superiority to placebo or an active
to all patients not receiving treatment A, and the com- control treatment. An equivalence study or noninferior-
parison of all patients receiving treatment B to all pa- ity trial can also be considered if (1) a known, effective
tients not receiving treatment B), or to detect whether treatment is available and it would be unethical to
there is added benefit from combining treatments. Also, administer a placebo (eg, cancer or inflammatory bowel
a control is required for each intervention. Potential cost disease, not FGID), or (2) a new treatment might be less
savings are frequently offset by the complexity of inter- costly, safer, or just as good as standard therapy.25 Such
preting the data, except when testing for synergistic trials are usually more costly than superiority trials,
treatment effects. because much larger sample sizes are required. Investi-
The withdrawal trial is an enrichment design, in which gators must first estimate the expected difference be-
all subjects receive the active treatment. At a predefined tween standard treatment and placebo from a meta-
time point, they are classed as responders or nonre- analysis or systematic review25,44 and then define
sponders and the latter are excluded. Responders are then “equivalence margins” that are smaller than the expected
randomly assigned to receive active treatment or placebo difference. The trial is judged to be positive only if the
and efficacy is based on the second part of the trial. 95% confidence interval for the observed difference be-
Potential carry-over effects from the first treatment, how- tween the new and standard treatments falls within the
ever, can prevent an accurate estimate of the drug benefit. equivalence margins. For a noninferiority trial, only the
The EMEA guidelines38 support this design for testing lower 95% confidence limit must fall within the
drugs for short-term efficacy in IBS, and require 2 or margins.
more treatment cycles to demonstrate efficacy. The In trials that compare the investigational treatment to
EMEA recommends38 that masked withdrawal (switch to a different active treatment, the investigator is obliged to
placebo at an unpredictable time) be undertaken after show that the treatment arms are in equipoise; it is
active drug, but does not address how to perform the unethical, for example, to compare the investigational
complex statistical analysis. Like the placebo run-in, this drug to an ineffective dose of an alternative compound.
design can overestimate the effect size.39 One completed Superiority trials (not equivalence or non-inferiority trials)
study39 followed the EMEA guidelines (with minor vari- are recommended for FGIDs.
ations) and provided data supporting the efficacy of Duration of treatment. Treatment duration for
tegaserod for IBS on repeated dosing cycles. specific FGIDs should be based on natural history data
April 2006 DESIGN OF TREATMENT TRIALS 1543

describing the frequency and duration of episodes. For Symptom Diaries

IBS, this is highly variable,15 but for the majority of Diaries have been used to measure primary or
patients both flares and remissions appear to last less than secondary end points and minimize recall bias. Relatively
1 week15,45; for dyspepsia, there is a high symptom few symptoms are recorded and ratings can be performed
turnover in the general population.46 Prior recommen- at a fixed time (eg, bedtime) or when symptoms actually
dations for trials of 8 –12 weeks were based on experience occur. The former method is simpler for data analysis. A
and on concerns for cost and ability to retain patients. major problem of diaries50 is poor adherence; patients
EMEA guidelines38 differentiate trials of short-term ef- often complete them retrospectively or just before a
ficacy, for which they would accept 4-week trials, from visit.51 Hand-held electronic devices with reminder
long-term efficacy trials, for which 6-month trials are alarms51 or collecting information by telephone52 have
required. Although both types of trials require patients been shown to improve adherence to 80%–90%, and
with active symptoms at randomization, long term-stud- patient satisfaction is good.51,52 Diary symptoms can also
ies could include patients with intermittent symptoms. be recorded on secure Web sites, which can accurately
Further research on the natural history of individual record the time of completion.
FGIDs should be a high priority, to allow clearer recom- Retrospective questionnaires are an acceptable method for
mendations for trial duration. Extended follow-up assessing symptoms provided the recall interval is limited to 3
should be considered to determine treatment durability months. Patients should receive clear instructions on the use of a
and should relate to symptom periodicity and presumed diary, including the directive to leave it blank if they forget to
treatment mechanism. record information. Electronic diaries are preferred over paper
A minimum treatment duration of 4 weeks that reflects the diaries. Methods to ensure adherence to recording methods should
symptom periodicity and anticipated treatment mechanism is be implemented.
recommended. If chronic use is anticipated, trials of at least 6
months should be undertaken to establish long-term efficacy. Outcome Measures
Adherence to treatment and study protocol. Stan- The primary outcome variable(s) provides the ba-
dard methods to assess adherence include interviewing sis for judging the success or failure of an intervention.
patients, counting unused medication,47 or measuring Only 1 or at most 2 variables should be selected and this
blood levels of metabolites28 and may be especially im- should be done before the trial begins. The Food and
portant when interpreting studies of long duration. The Drug Administration and EMEA have recommended
frequency of missed or late appointments and missing that investigators provide rules, a priori, that allow clas-
data from diaries or questionnaires should be reported for sification of each participant as a responder or nonre-
all trials. sponder for the primary outcome.38 Most trials also
Adherence to the protocol and treatment should be measured. include secondary outcome variables to (1) strengthen
the results by showing concordance between individual
symptoms and the primary outcome measure, (2) address
Methods for Collecting Symptoms the mechanism of the intervention, (3) assess the safety or
and Outcome Data (4) cost effectiveness of the treatment, and (5) identify
Accuracy of Symptom Recall variables that predict which patients are most or least
likely to benefit.
Efficient symptom assessment can be achieved by
The definition of a responder should reflect a clinically
having patients complete questionnaires before treat- meaningful symptom improvement for each patient. For
ment and at follow-up visits. However, concerns about IBS and other FGIDs, there is no consensus on what
the accuracy of retrospective questionnaires include constitutes a clinically meaningful improvement. Some
whether (1) symptoms present on the day they complete studies accept as little as a 10% reduction in a visual
the questionnaire influence reporting; (2) poor recall analog scale rating of symptom severity53 or 1 step on a
affects the accuracy of a retrospective report; and (3) 7-step ordinal scale39 as clinically meaningful, whereas
patients feel pressured to give a more positive report if other studies require a 50% reduction in an aggregate
questionnaires are completed in the presence of the in- symptom severity index54 or questionnaire.55 However,
vestigator. Although data support the presence of these the most commonly employed definition of clinically
biases, they do not appear to be substantial.48 Recall of meaningful improvement in IBS has been a patient’s
health-related events appears to be reasonably accurate report (yes or no) of “adequate relief of abdominal pain
for up to 3 months.49 and discomfort”4,56 –58 or “satisfactory relief of IBS symp-
1544 IRVINE ET AL GASTROENTEROLOGY Vol. 130, No. 5

toms.”59,60 These definitions are assumed to have face Adequate relief or satisfactory relief as a primary
validity. However, empirical data are needed for each outcome measure. Since 1999, most published pharma-
outcome measure to assess the clinical significance of ceutical trials for IBS have used “adequate relief of ab-
different degrees of change from both the patient’s and dominal pain and discomfort”4,56 –58 or ”satisfactory relief
the physician’s perspectives. of IBS symptoms”59,60 as their primary outcome measure.
One or at most 2 primary outcome measures should be specified Responders were defined as patients who reported “yes”
in advance. Investigators should list criteria to classify each to adequate relief or satisfactory relief on at least half of
patient as a responder or nonresponder based on a clinically the weeks in the treatment trial. These studies demon-
meaningful change in symptoms. strated statistically significantly higher responder rates
for active drug relative to placebo and led to approvals
Choosing a Primary Outcome Variable
for alosetron and tegaserod by the Food and Drug
In selecting a primary outcome, investigators Administration.
should examine the trial objectives, population, and Mangel et al64 assessed the validity of the adequate
mechanism of action of the proposed treatment and relief measure in diarrhea-predominant IBS patients and
should choose either a global measure, which integrates showed that responders differed significantly from non-
the symptoms into a single numerical index, or the responders regarding pain-free days, pain severity, ur-
summary score of a validated symptom severity and/or gency, stool frequency, and 6 of 8 SF-36 quality of life
frequency questionnaire. subscales plus 8 of 9 scales on a disease-specific quality of
Attention should be paid to the suitability of the life measure. However, correlations among measure-
measurement scale used for each outcome measure. A ments (convergent validity), test–retest reliability, and
detailed discussion of measurement scales and their prop- internal consistency were not reported. Similar validation
erties is beyond the scope of this report, but is more data have been reported for satisfactory relief.55,65
thoroughly addressed in the Rome III book and else-
Integrative symptom questionnaires. An alterna-
where.2,61
tive method for defining a responder in an IBS treatment
Physician-reported assessments have been accepted in
trial is to ask patients to report the frequency or severity
some studies,14 but are subject to greater measurement
of all (or a representative group) of IBS symptoms prior
error than patient reports.62 Therefore, patient-reported
to and again following treatment, and to define a re-
measures are endorsed. Only fully validated instruments
sponder as a patient who reports at least a 50% decrease
are recommended as primary outcome assessment tools,
in IBS symptom severity.54,55,66 There are several ques-
and secondary outcome measures should also be assessed
for robustness. Psychometric validation requires that (1) tionnaires that examine the severity of IBS, such as the
the assessment instrument includes symptoms relevant Gastrointestinal Symptom Rating Scale for IBS67 and the
to and fully representative of the disorder (face validity); Functional Bowel Disorder Severity Index.68 However,
(2) it show a predictable relationship with other measures the Irritable Bowel Syndrome Symptom Severity Scale69
(construct validity); (3) the assessment produces similar is the only IBS symptom severity scale that has been
results when readministered to patients whose health shown to be responsive to treatment effects.17,69,70
status has not changed (reliability); (4) it can detect Whitehead et al55 compared different outcome mea-
clinically meaningful change in health status when such sures including satisfactory relief and a 50% reduction in
a change has occurred (responsive); and (5) changes in score the Irritable Bowel Syndrome Symptom Severity Scale
can be related to clinical indicators that are meaningful questionnaire, in an observational study of patients’ re-
to clinicians (criterion validity). sponse to usual medical care for IBS. They reported that
Validation of a new outcome measure is best estab- the response rate on satisfactory relief was influenced by
lished in a separate study.63 The frequency of data re- pretreatment symptom severity: patients with initially
cording for each outcome should also be specified before mild IBS symptoms showed the highest responder rate
the trial begins, as should the time frame defining the but the smallest change in symptom severity, whereas
patient response (whether at the end of the trial, during patients with initially severe IBS symptoms showed the
a prespecified proportion of weeks or months that re- lowest responder rate but the largest decrease in severity.
sponder criteria have been fulfilled, or for all time points In contrast, when defining a responder as a patient who
assessed during the trial). reported at least a 50% decrease in symptom severity,
A patient-reported outcome assessment is recommended. Psy- pretreatment symptom severity had no impact on the
chometric validation of each outcome measure is recommended responder rate. Defining a responder based on a 50%
before it is used in clinical trials. reduction in symptoms has been used in several stud-
April 2006 DESIGN OF TREATMENT TRIALS 1545

ies54,71 and has been endorsed by 1 expert panel.72 How- how they were measured. Investigators should attempt to
ever, like satisfactory relief and adequate relief, it re- place benefits and harms for any intervention into
quires further validation. perspective.
Subjects can be classed as responders and nonre- Anticipated and unanticipated adverse events should be
sponders at different time points during a trial. In pub- reported.
lished trials, patients were classified as responders if they
reported adequate relief or satisfactory relief on at least Choosing Secondary Outcome Variables
50% of weeks over a 1- to 3-month period.4,39,53,57,59,60 The reasons for including each secondary outcome
However, this loses important information; the most and the plan for analysis should clearly be identified
persuasive evidence for efficacy would be to show that before the trial begins. Health economic outcomes are
patients in the active treatment had a sustained response becoming an important class of secondary outcomes.83,84
once they reported satisfactory or adequate relief. Inves- Secondary outcomes should be selected based on the study
tigators are encouraged to use more sophisticated statis- question and should be validated measures that support or
tical models that address the longitudinal trajectory of explain the results. Integrating health economic outcomes is
responder status.73,74 At a minimum, studies should recommended when feasible.
report the proportion of patients responding at each time Quality of life assessment. FGIDs significantly
point and throughout the trial. impact quality of life.85,86 Generic and disease-specific
Several well-validated outcome measures have been quality of life instruments are available.63 Generic in-
used in FD trials.75 These use a single global outcome of struments can assess quality of life in large populations
a specific symptom (eg, Glasgow Dyspepsia Severity and across a wide spectrum of disorders, but may not
Score76), a global overall assessment of dyspepsia symp- reflect all important aspects of health status for specific
toms (eg, the Canadian Dyspepsia Score77), the LEEDS disorders. They may be less sensitive to detect important
Dyspepsia Questionnaire,78 or several questions covering treatment effects, but they permit comparisons with
important dyspepsia and quality of life outcomes (eg, the other diseases and help to detect unexpected changes in
Severity of Dyspepsia Assessment,79 the Dyspepsia health status after treatment. Examples of validated in-
Symptom Questionnaire,67 the Quality of Life in Reflux struments include the Sickness Impact Profile,87 the
and Dyspepsia Questionnaire,67 and the Nepean Dyspep- Nottingham Health Profile, the SF-36 (Short Form of
sia Questionnaire80). For some FGIDs, such established General Health Questionnaire),88 and the Psychological
outcome measures are yet to be developed. General Well-Being Index.89 Disease-specific quality of
Pain or discomfort is a key feature of many FGIDs and life instruments75,90,91 examine problems specific to the
is typically either the primary outcome variable or an FGID (eg, the fear of fecal incontinence in IBS). Theo-
important secondary outcome variable in clinical trials. retically, they can detect smaller and more specifically
Pain has 3 dimensions—intensity, duration, and fre- relevant changes in health status, which may be missed
quency—that can be considered separately or integrated by generic instruments. Quality of life measures have not
in a global assessment of pain or can be incorporated into been used as the primary outcomes in pharmaceutical
a quality of life measure. Different rating scales can be clinical trials because they were believed to be insuffi-
used that are reproducible and sensitive to change.81 If ciently responsive to treatment, but have been strongly
pain is chosen as the primary outcome, a meaningful recommended as secondary outcome variables. One re-
clinical response should be defined beforehand, and the port focusing on the health-related quality of life data
proportion of patients reaching this end point reported. from two previously reported trials of alosetron found a
Adequate relief and satisfactory relief are the current stan- significantly greater improvement on active drug com-
dards for primary outcome assessment in treatment trials in pared to placebo,92 challenging the belief that these
FGIDs. Alternative outcome measures such as integrative symp- measures are not responsive enough to be employed as
tom questionnaires are also acceptable. All of these measures primary outcome variables.
require additional validation. Quality of life assessments are important secondary outcomes.
Safety issues and absence of harms. Every trial Investigators are encouraged to include both a baseline generic
should document and report adverse events. Recent at- and a pre–post disease-specific quality of life instrument.
tention has focused on the appropriate reporting of
harms-related issues in randomized clinical trials.82
When collecting harms data is a trial objective, it should Analysis and Data Reporting
be reflected in the manuscript reporting the study results The type of statistical analysis is determined by
and the report should clearly define adverse events and the particular study design and primary outcome mea-
1546 IRVINE ET AL GASTROENTEROLOGY Vol. 130, No. 5

sure(s). The Consolidated Standards for Reporting Trials efficacy trial, can also allow computation of the number
(CONSORT) statement was developed by scientists and of patients who need to be treated (NNT) to encounter a
editors to improve the quality of reporting parallel patient who will experience a clinical benefit. Although
group, randomized, controlled trials.93 It emphasizes the the NNT is reported infrequently in randomized, con-
importance of transparently reporting the study objective trolled trials, its inclusion can convey the clinical impor-
and how the study was conducted and analyzed. Evidence tance of a study result.98 Similarly, harms data can be
supports improved quality of methodology and data used to estimate the number of patients that would need
reporting93 when CONSORT guidelines are used. Many to be treated with a drug to see an adverse event (number
journals now require that manuscripts describing clinical needed to harm [NNH]). Calculation of the NNT and
trials conform to the CONSORT guidelines, found on NNH allows the researcher or clinician to more quanti-
the web at www.consort-statement.org. Recent publica- tatively assess the benefits and risks of any given therapy.
tions have made similar recommendations for studies When reporting P values, actual values and not thresholds
evaluating diagnostic testing (Standards for Reporting of should be provided. An NNH can be calculated based on the
Diagnostic Accuracy initiative94) and reporting meta- risk of adverse effects and can be weighed against the NNT.
analyses (Quality of Reports of Meta-Analyses state- The statistical analysis should be based on an inten-
ment95). tion-to-treat (ITT) principle99 with a plan for handling
Investigators should adhere to the CONSORT statement on dropouts. The trial can either be analyzed as the propor-
reporting of clinical trials. tion of responders in each group, treating all dropouts as
The main analysis for FGID trials should focus on the nonresponders, or by carrying forward the last observa-
primary outcome measure(s) to determine whether or not tion available for the primary outcome. A dual analysis,
the study results support a new treatment. Although the examining for differences in results using the 2 different
main outcome often compares the end of treatment and methods should be performed. Many studies also report
baseline observations, data should also describe how pa- a per protocol (all patients who followed the protocol) or
tients changed during the study; the results of a trial are an all-patients-treated (all patients who received treat-
far more compelling if patients have had a sustained ment following randomization) analysis. These analyses
response to the intervention. When 2 primary outcome may provide insight as to whether a treatment works
variables are included in a trial, investigators should under optimal conditions, but cannot replace the ITT
specify in advance whether the trial will be considered analysis. When there is a discrepancy between the ITT
positive if only 1 outcome measure is significant, or if (negative) and per protocol (positive) analyses, the results
both are required. If significance on any primary outcome should be interpreted as inconclusive. The effect of po-
suffices, the analysis should adjust for multiple compar- tential modifiers such as gender, age, duration or severity
isons, for example, using the Bonferroni correction.96 of disease, and presence of psychological stress can be
The committee suggests that the EMEA recommenda- assessed using a logistic regression analysis, where the
tion requiring 2 positive primary outcomes for trials in binary dependent variable represents the a priori speci-
IBS may be overly conservative. The primary outcome fied definition of a responder.100 Such covariates should
results should be stated in absolute numbers to include also be prespecified.
both a numerator and denominator; it is not sufficient to The primary analysis should be the ITT analysis and must
list only percentages of (non)-responders (eg, not 20% include all patients randomized.
but rather 10/50, 20%). For all outcome measures, the
estimated effect of the intervention (difference between
Secondary Outcome Measures and
active and placebo treatment) and a 95% 2-sided confi-
dence interval should also be included.97 Subgroups
The main result of the study must be based on the evaluation Results should be reported for all prespecified
of the primary outcome measure as stated in the protocol before outcomes. Score changes should be reported for each
the study begins. The primary outcome should be stated in cardinal symptom of the entry criteria. Secondary
absolute numbers and should include a 95% confidence interval. outcomes that are used to support or refute the pri-
Statistically significant differences between study mary analysis should be analyzed by ITT and not per
groups can also be expressed using a P value. Actual protocol. Adjustment for multiple comparisons is gen-
values and not thresholds (ie, not P ⬍ .05) should be erally unnecessary when analyzing secondary outcome
provided and should be complementary to confidence measures because the efficacy of the treatment is
intervals. The reciprocal of the absolute risk reduction, in judged on the basis of the analysis of the primary
a risk reduction trial, or therapeutic gain, in a treatment outcome variable, not the secondary outcomes. Sec-
April 2006 DESIGN OF TREATMENT TRIALS 1547

ondary outcome measures are examined to support the Interim Analysis and Stopping Rules
primary outcome analysis. When many secondary vari- There is no compelling reason to incorporate in-
ables are included to identify predictors of response or terim analyses in trials to determine efficacy because
explore for other benefits, the type I error rate may be FGIDs are not life threatening. Moreover, because the
inflated and can be adjusted.96 However, the Bonfer- incidence of serious adverse events is expected to be low,
roni correction may be too conservative96 and can any occurrence of a serious adverse event is likely to
increase the likelihood of a type II statistical error, prompt the safety committee to reevaluate the trial with-
rendering truly important differences nonsignificant. out carrying out an interim analysis. Thus, interim anal-
Using descriptive rather than inferential statistics (eg, yses in trials of FGIDs are normally only done to assess
means and confidence intervals) or reporting actual P the futility of continuing the trial. Plans for interim
values is a possible solution. analyses should be clearly prespecified in the study pro-
Specific plans to present and analyze harms data tocol and appropriate statistical methods to adjust for
should be clearly described and withdrawals from each multiple comparisons are necessary.101,102 The most com-
arm of the trial should be detailed. ITT is the preferred mon method is to partition the ␣ level for the trial by
analysis for harms data.82 subtracting the ␣ level for the interim analysis from the
Exploratory subgroup analyses are commonly per- ␣ level intended for the final analysis. Consequently,
formed in trials of FGIDs, although their validity is most investigators use a conservative ␣ level, such as
controversial.101 The recommended test of interaction101 .001, for the interim analysis so that sufficient power is
evaluates for differences in treatment effects between reserved for the final analysis. If an interim analysis is
complementary subgroups (eg, older and younger sub- preplanned, ␣ sharing can be incorporated when calcu-
jects), rather than simply comparing P values for each lating the sample size. Unplanned preliminary analyses
subgroup, thereby maintaining statistical power. should be avoided; premature presentation of results may
affect the further conduct of the trial and can lead to the
Secondary analyses used to support an efficacy claim should be
reporting of inaccurate observations.
ITT analyses. Harms data should be analyzed by ITT when
There are few guidelines for conducting interim anal-
possible, but absolute incidence rates and 95% confidence inter-
yses to assess the futility of continuing a trial. However,
vals should also be provided.
to preserve the credibility of the investigators (a) such
analyses should be overseen by a Data and Safety Moni-
Sample Size and Power
toring Board that is independent from the investigators,
The protocol should present and clearly specify (b) the analysis should test for equivalence rather than
the assumptions underlying the sample size calculation. superiority of 1 treatment relative to the other, and (c)
These elements include the minimum effect size (differ- liberal equivalence margins for the effect size should be
ence in primary outcome between groups) that the trial defined a priori and will likely be wider than those
is designed to detect, the ␣ (type I) error level, the applied to serious harms.
statistical power or ␤ (type II) error level, and when Interim analyses are not recommended because they may
evaluating continuous outcomes (eg, difference in sever- jeopardize the trial integrity unless there is reason to believe
ity scores), the standard deviation of the difference. Re- participation in the trial (either in the active treatment or
cent trials have been powered to detect differences as control group) places the patient at risk.
small as 10%,58 12%,59,60 or 15%.4,57 Often, a power of
80% is used (␤ error or type II error of 20%) and ␣ (type Ethical Issues
I) error of 5% using a 2-sided test. An allowance for The main result of a trial must be presented
dropouts should also be made in determining the appro- according to the predetermined primary outcome mea-
priate sample size, but efforts should be made to keep the sure(s). Selecting a primary outcome measure after the
dropout rate below 10%–20%. It is inappropriate for an trial is concluded inflates the type I error rate and is
investigator to conclude, from an inadequately powered misleading. Unexpected results that were not part of the
study that fails to find a statistically significant difference original hypothesis103 should be considered as purely
between interventions, that the 2 interventions are exploratory, for testing in future studies. Adherence to
equivalent.44 study goals is strengthened when an independent advi-
A sample size calculation should be routinely performed and sory group is assembled.
should be based on the expected behavior of the primary outcome Changing the primary outcome measure(s) in the analysis
measure. phase of a study should not be done; it invalidates the statistical
1548 IRVINE ET AL GASTROENTEROLOGY Vol. 130, No. 5

Table 2. Recommendations for Future Research 2. Veldhuyzen van Zanten SJ, Talley NJ, Bytzer P, Klein KB, Whor-
well PJ, Zinsmeister AR. Design of treatment trials for functional
1. Examine the periodicity and severity of symptoms in natural gastrointestinal disorders. Gut 1999;45(Suppl 2):II69 –II77.
history studies.
3. Talley NJ, Nyren O, Drossman DA, Heaton KW, Veldhuyzen van
2. Evaluate the multidimensional construct of symptom severity
Zanten SJO, Koch MM, Ransohoff DF. The irritable bowel syn-
(eg, frequency, number present, clustering, severity,
drome: toward optimal design of controlled treatment trials.
contribution to “global severity,” and changes in primary
Gastroenterology International 1993;189 –211.
symptoms over time).
4. Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D,
3. Examine the influence of disease modifiers (predictors) such as
Mangel AW. Efficacy and safety of alosetron in women with
disease duration, baseline severity, psychological status,
irritable bowel syndrome: a randomised, placebo-controlled trial.
comorbidity, surgeries, and response to prior treatments.
Lancet 2000;355:1035–1040.
4. Investigate what contributes to the placebo response in
different FGIDs and how to minimize its impact on efficacy 5. Muller-Lissner SA, Fumagalli I, Bardhan KD, Pace F, Pecher E,
assessment. Nault B, Ruegg P. Tegaserod, a 5-HT(4) receptor partial agonist,
5. Evaluate the impact of baseline observations and diagnostic relieves symptoms in irritable bowel syndrome patients with
testing on symptoms, data quality, and treatment response. abdominal pain, bloating and constipation. Aliment Pharmacol
6. Further validate adequate and satisfactory relief during clinical Ther 2001;15:1655–1666.
trials. 6. Fass R, Longstreth GF, Pimentel M, Fullerton S, Russak SM,
7. Develop, validate fully, and determine minimal clinically Chiou CF, Reyes E, Crane P, Eisen G, McCarberg B, Ofman J.
important differences for new outcome measures and disease- Evidence- and consensus-based practice guidelines for the di-
specific quality of life instruments. Catalog and critically agnosis of irritable bowel syndrome. Arch Intern Med 2001;161:
appraise them. 2081–2088.
8. Further evaluate and validate definitions of the treatment 7. Cash BD, Schoenfeld P, Chey WD. The utility of diagnostic tests
responder measure(s) including a 50% reduction in symptom in irritable bowel syndrome patients: a systematic review. Am J
severity and ensure that the definitions are clinically relevant. Gastroenterol 2002;97:2812–2819.
9. Develop and validate trial designs for testing on-demand 8. Jones R. Likely impacts of recruitment site and methodology on
treatments for intermittent symptoms. characteristics of enrolled patient population: irritable bowel
10. Examine the impact of CONSORT, EMEA, and Food and Drug syndrome clinical trial design. Am J Med 1999;107:85S–90S.
Administration guidelines on study quality. 9. Talley NJ, Meineche-Schmidt V, Pare P, Duckworth M, Raisanen
P, Pap A, Kordecki H, Schmid V. Efficacy of omeprazole in
functional dyspepsia: double-blind, randomized, placebo-con-
trolled trials (the Bond and Opera studies). Aliment Pharmacol
analysis and renders the conclusions of uncertain value by Ther 1998;12:1055–1065.
inflating the chances of a type I error. 10. Longstreth GF, Hawkey CJ, Mayer EA, Jones RH, Naesdal J,
Wilson IK, Peacock RA, Wiklund IK. Characteristics of patients
Concern has been raised that several negative FGID with irritable bowel syndrome recruited from three sources:
treatment trials have not been published, overestimating implications for clinical trials. Aliment Pharmacol Ther 2001;15:
the efficacy of some treatments and/or diminishing safety 959 –964.
concerns. Investigators are ethically obliged to publish 11. Camilleri M, Atanasova E, Carlson PJ, Ahmad U, Kim HJ, Vi-
ramontes BE, McKinzie S, Urrutia R. Serotonin-transporter poly-
the results of all completed studies, and journal editors morphism pharmacogenetics in diarrhea-predominant irritable
should publish methodologically sound studies, whether bowel syndrome. Gastroenterology 2002;123:425– 432.
results are negative or positive. Some journals now re- 12. Guthrie E, Barlow J, Fernandes L, Ratcliffe J, Read N, Thompson
DG, Tomenson B, Creed F. Changes in tolerance to rectal dis-
quire investigators to register clinical trials before initi- tension correlate with changes in psychological state in patients
ation, and failure to do so bars their publication by with severe irritable bowel syndrome. Psychosom Med 2004;
subscribing journals.104 The Cochrane Collaboration sys- 66:578 –582.
tematic reviews also underscore the need for publication 13. Spiller RC. Problems and challenges in the design of irritable
bowel syndrome clinical trials: experience from published trials.
of all relevant studies.105 Am J Med 1999;107:91S–97S.
It is unethical to withhold publishing the results of a 14. Veldhuyzen van Zanten SJ, Cleary C, Talley NJ, Peterson TC,
completed trial. Nyren O, Bradley LA, Verlinden M, Tytgat GN. Drug treatment of
In reviewing the relevant literature for this report, the functional dyspepsia: a systematic analysis of trial methodology
with recommendations for design of future trials. Am J Gastro-
committee identified a number of areas that require enterol 1996;91:660 – 673.
additional evaluation. These recommendations for future 15. Hahn B, Watson M, Yan S, Gunput D, Heuijerjans J. Irritable
research are listed in Table 2. bowel syndrome symptom patterns: frequency, duration, and
severity. Dig Dis Sci 1998;43:2715–2718.
16. Drossman DA, Thompson WG. The irritable bowel syndrome:
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 GASTROENTEROLOGY 2006;130:1552–1556

The Road to Rome

W. GRANT THOMPSON
University of Ottawa, Ottawa, Canada

he traditional medical diagnosis of disease requires some cases form the basis of regulatory approval of drugs
T observed anatomical or physiological abnormalities.
Description of the disease’s symptoms and signs follows
that remain on national formularies. Most of these re-
ports implied that the diagnosis of their subjects rested
naturally. Clinicians can then predict the anatomic di- solely on the exclusion of structural disease. The trials
agnosis by recognizing these symptoms and signs in their shown in Table 1 include IBS or irritable colon syndrome
patients. In the case of the functional disorders, such a (ICS) in their titles, yet they describe very different trial
process is impossible. Since there are no observed patho- subjects. The listed trimebutine trials were the basis of
physiological defects, we only know of the existence of regulatory approval in France, Canada, and elsewhere, yet
the disorders through the words of our patients. The the entered patients in these “IBS trials” were dissimilar.
movement to define these disorders of unknown pathol- The trial reports in Table 1 fail to state entry criteria that
ogy represents a substantial change in thinking for doc- would permit doctors to judge which patients should
tors whose training concentrates on basic science and receive the tested treatments. This lack of definition was
palpable “evidence.” Since more than half of gut disor- similar for dyspepsia and constipation. It was time to
ders encountered by gastroenterologists and primary care define and establish criteria for the functional gastroin-
doctors are functional, we must face the reality that no testinal disorders.
current scientific evidence explains these disorders, and There are many references to gut dysfunction in the
develop alternate methods to identify them. ancient and early European literature. However, the first
For too long, functional diseases were described by credible English language descriptions of irritable bowel
what they are not, rather than as real entities. Yet they syndrome (IBS) appeared in the early nineteenth century.
are real enough to patients. Not only does such an One such description of the IBS in 18182 drew attention
exclusive approach fail to provide the patient with the to three cardinal symptoms of IBS: abdominal pain,
dignity of a diagnosis, but it also generates needless tests “derangement ofѧ digestion,” and “flatulence.” A few
and consultations. The fruitless pursuit of an anatomical years later, Howship3 described a “spasmodic stricture”
cause renders functional disorders “diagnoses of exclu- of the colon reflecting the enduring, but unsubstantiated
sion.” Their very numbers and cost demand a more belief that functional gut disorders are somehow the
positive approach. product of gut spasm. Mid-century brought more sophis-
More seriously, there was a disconnect between the ticated treatises (and very unsophisticated cures such as
subjects chosen for randomized clinical trials (RCTs) and purging and “electrogalvanism”). In 1849, Cumming4
the labels used in clinical practice. Because clinical sci- exclaims incredulously, “the bowels are at one time con-
entists failed to describe their subjects accurately, the stipated and at another lax in the same person ѧ how the
results of their RCTs are of uncertain applicability to the disease has two such different symptoms I do not propose
patients encountered by practicing doctors. In a 1988 to explain.” Were he to return to a modern IBS consensus
critique of 43 clinical trials of irritable bowel syndrome meeting, he would discover that this enigma remains!
(IBS) treatments, Klein1 observed that 58% of them Cumming’s treatise contained one other comment in line
reported “absolutely nothing about the criteria by which with modern thinking about IBS. “One can tell, without
IBS patients were selected.” There were important dif- more minute examination what the nature of the com-
ferences among the remainder, some not requiring ab- plaint is.” The authors of this book agree with Cum-
dominal pain, and others not even requiring a bowel ming’s notion of a positive diagnosis, even though many
habit abnormality. Klein concludes, “Not a single IBS doctors persist in recognizing IBS and the other func-
treatment trial reported to date [1988], used an adequate
operational definition of IBS.”
© 2006 by the American Gastroenterological Association Institute
Table 1 further illustrates this point. Many of these 0016-5085/06/$32.00
reports were published in prestigious journals and in doi:10.1053/j.gastro.2006.03.011
April 2006 THE ROAD TO ROME 1553

Table 1. Irritable Bowel Syndrome Entry Criteria for Randomized, Controlled Trials Prior to 1988
Author Year Journal Drug Entry criteria
Kasich24 1959 AJ Gastro tricyclanol irritable colon syndrome (ICS)
Connell25 1965 BMJ mebeverine ICS
Tasmen-Jones26 1973 N Z J Med mebeverine abdominal pain & altered bowel habit
Greenbaum27 1973 NEJM diphenylhydrate compatible history of irritable bowel syndrome (IBS)
Piai28 1979 Gastroenterology profinium compatible history of IBS
Moshal29 1979 J Int Med Res trimebutine constipation—10% had pain
Fielding30 1980 Irish Med J trimebutine diagnosed as suffering from IBS
Luttecke31 1980 Curr Med Res Opin trimebutine IBS on the basis of their symptoms
Fielding32 1981 Digestion timolol IBS
Cann33 1983 Gut domperidone abdominal pain and bowel disturbance suggestive of IBS
Dew34 1984 Br J Clin Pract peppermint oil typical symptoms of IBS
Flexinos35 1985 Eur J Clin Pharm trimebutine constipation or diarrhea or both
Pidgeon36 1985 Ir J Med Sci cimetidine IBS patients with excessive muscle spasm on sigmoidoscopy
Narducci37 1985 Am J Gastro nifedipine abdominal pain relieved by defecation and either constipation or diarrhea
Perez-Mateo38 1986 Int J Clin Pharm Res Diltiazam compatible clinical history, physical exploration
Prior39 1988 Aliment Pharm Ther lidamadine abdominal pain and distress with abnormal bowel habit
Dobrilla40 1990 Gut cimetropium abdominal pain “after all other organic causes . . . excluded”

NOTE. Data for 2005 were collected on January 31, 2006 and are therefore incomplete.

tional gut disorders only after the patient has undergone reported results obtained by questionnaire administered
exhaustive investigation. to Bristol outpatients with abdominal pain and disor-
Medicine’s understanding of IBS progressed little dur- dered bowel habit.11 The 6 of 15 symptoms we found
ing the next 120 years. Indeed, it may have lost ground! more common in IBS than organic gut disease (diagnosis
Edwardian physicians considered functional disorders to determined by a chart review a year later) became the
be diseases of the wealthy. In fact, only the affluent could Manning Criteria. In 1984, Kruis et al from Germany
afford to be the patients of those Harley Street doctors reported a similar study.12 Their report recalls the 3
who published their observations in the medical litera- cardinal IBS symptoms of pain, bowel dysfunction, and
ture.5 Constipation became associated with uncleanness.6 flatulence mentioned by Powell in 1818. If all 3 were
The notion of “autointoxication” due to retained colon present, IBS was highly likely. Kruis et al stressed chro-
contents prompted an urge to purge that persists to this nicity and other symptoms as well, but their major
day. In the 1920s and 1930s, pejorative descriptors such contribution was to record “alarm” symptoms that
as “psychogenic,” “neurogenic,” and “The Abdominal should alert the physician to organic disease. These two
Woman”7 did little to help patients with functional gut
disorders. Proctalgia fugax was long thought to be a
disease of young professional males, because only doctors
had the temerity to describe their symptoms in letters to
the editor of the Lancet.8 Use of terms such as “spastic
colitis” and “hyperacidity” inferred now-discredited eti-
ologies for these disorders.6
The first systematic attempt to bring discipline to this
area was a 1962 retrospective review of IBS patients at
Oxford by Chaudhary and Truelove.9 The authors re-
ported symptoms that we recognize to be those of IBS (or
ICS as they termed it). They even separated IBS from
what we now call functional diarrhea, and noted that one
quarter of their patients’ complaints began with an en-
teric infection. Their report ushered a new era, and
scientific publications on functional disorders increased Figure 1. Annual results of PubMed literature searches for irritable
rapidly thereafter (Figure 1). bowel syndrome (IBS) and irritable colon syndrome (ICS) between the
The table of contents of my book The Irritable Gut 1962 Chaudhary and Truelove report and December 2005. Note the
rapid rise in publications during that period. While half the publica-
(1979) contained the first classification of the functional tions in the 1960s had ICS in their titles, only 1 or 2 do so now–
gastrointestinal disorders.10 In 1978, Ken Heaton et al exclusively in the non-English literature.
1554 W. GRANT THOMPSON GASTROENTEROLOGY Vol. 130, No. 5

Table 2. History of the Rome Diagnostic Criteria iary,19 bowel,20 and anorectal21) and discussed topics
The Manning Criteria for IBS (1978)11 related to functional gut disorders. In 1994, their col-
The Kruis Criteria for IBS (1984)12 lective work was updated and published in The Functional
The Rome Guidelines for IBS (1989)15 (Rome-2 IBS Criteria)
The Rome Classification System for FGIDs (1990)16 (Rome-1)
Gastrointestinal Disorders: Diagnosis, Pathophysiology and
The Rome I Criteria for IBS (1992)20 and the FGIDs (1994)22 Treatment; a multinational consensus.22
The Rome II Criteria for IBS (1999)41 and the FGIDs (1999)23 While this work is now known as Rome I, it includes
The Rome III Criteria (2006)
the third rendition of the Rome IBS criteria.20 From
1988 to 1992, three IBS working teams added duration
parameters, and pain went from being unnecessary for
discriminate function studies in addition to epidemio- the diagnosis of IBS,15 to being a suggested symptom,16
logic data provided by Drossman13 and Whitehead14 are to eventually a requisite.20
the basis of the Rome criteria for IBS. The Rome II process included 4 years of delibera-
The inspiration for the Rome process was an IBS tions by over 50 investigators from 13 Western coun-
symposium at the 12th International Congress of Gas- tries organized into 10 committees. The result was the
troenterology held in Lisbon in 1984. Despite being second edition of Gastrointestinal Disorders: Diagnosis,
perhaps the earliest international symposium on IBS, the Pathophysiology and Treatment; a multinational consensus.
symposium attracted an audience that far outstripped the This iteration encompassed several important innova-
capacity of the assigned room. One panel member, Pro- tions. George Degnon became the Rome organiza-
fessor Aldo Torsoli, was an organizer of the next inter- tion’s executive director in 1994 and provided logistic
national congress planned for Rome in 1988. Over coffee and management support for a greatly expanded pro-
in Portugal, we discussed the need for guidelines for the cess generously funded by several pharmaceutical com-
management and study of IBS. A working team was set panies. Carlar Blackman became the administrative
up to produce such guidelines for the next congress.
coordinator for the Coordinating Committee and the
As chair, I collaborated with Doug Drossman (USA),
working teams. The organization became separated
Ken Heaton (UK), Gerhard Dotteval (Sweden), and
into an operational component (fundraising, meeting
Wolfgang Kruis (Germany) for 2 years. In 1987, we met
planning, book publishing) managed by Degnon As-
in Rome to debate a draft proposal and reach consensus.
sociates, and an academic component coordinated by
We sent the penultimate draft to 16 expert colleagues in
Ms. Blackman and the Coordinating Committee. To
7 countries. The working team considered their com-
ensure that the Rome process remained at arm’s length
ments and suggestions and presented the first Rome
criteria at the 13th Congress in Rome in 1988. The from the sponsors, the Industry Research Council
guidelines were published the following year.15 Guide- (IRC) was created with Dr. Bill Whitehead as chair.
lines were this report’s objectives, and diagnostic criteria The IRC meets annually to allow Rome committee
were subordinate. They might be known as the Rome-2 members, representatives of the sponsoring compa-
IBS Criteria, and attracted much interest among re- nies, and regulatory authorities to discuss progress and
searchers and pharmaceutical companies (Table 2). mutual concerns. Working team members do not
Following that Rome meeting, Professor Torsoli and communicate directly with the sponsors, and partici-
Dr. Enrico Corrazziari invited Dr. Doug Drossman to set pating individuals must report their industry relation-
up another committee to consider subgroups of IBS. ships. Rather than meeting independently, the work-
After discussion, the project expanded to include all the ing teams met together in Rome in 1998. This
functional gastrointestinal disorders. This working team, permitted interaction and harmonization among the
which included most of the this book’s editors, met in committees. The Rome II criteria and essential sup-
Rome to classify the functional gastrointestinal disorders porting information were published in a Gut supple-
into 21 entities in 5 anatomical regions of the gut.16 This ment in 1999.23 In addition to the anatomically de-
was the first time that diagnostic criteria were proposed termined criteria and clinical trials working teams,
for all the functional gut disorders and included the first new teams addressed basic science, neurogastroenter-
revision of the 1988 IBS criteria and could be considered ology, psychosocial issues, and pediatric functional
Rome-1. gut disorders. The second edition of the book, also
With sponsorship organized by Professor Torsoli, published in 1999, included a glossary, proposed
Doug Drossman organized a succession of working teams questionnaires, and the results of a Vienna symposium
over 4 years that further developed these criteria in the 5 on the Definition of a Responder involving academics,
anatomical regions (esophageal,17 gastroduodenal,18 bil- regulators, and the pharmaceutical industry.
April 2006 THE ROAD TO ROME 1555

By 2000, there was great interest in the Rome process functional. How much physiological or structural evi-
as more researchers and interest groups entered the field, dence is necessary for an entity to cease being functional?
and the pharmaceutical companies and regulators became How long, how often, and how severe must symptoms
concerned how to define and test treatments for the become before they constitute a functional gastrointesti-
functional gastrointestinal disorders. Thus, plans for nal disorder? Tradition and the lack of viable alternatives
Rome III began promptly. Dr. Robin Spiller and Dr. make change difficult. Those interested in the functional
Michel Delvaux joined the now 7-member Coordinating disorders express disparate views on these and other
Committee. The organization registered as a non-profit issues— epidemiologists, primary care physicians, con-
educational foundation, and the Coordinating Commit- sultants, researchers, psychologists, physiologists, phar-
tee became known as the Rome Board. The Board held a maceuticals, regulators, third party payers and, of course,
retreat in London in February 2002 to plan its future. the patients themselves. In Rome III, these voices were
The Board agreed upon a Rome III format and addressed prominent in the background and in the reviews of the
a wide range of operational topics including relationships chapter manuscripts.
with industry; projects such as validation that went Despite the controversies, the criteria have gained
beyond publication of diagnostic criteria; the promotion such currency that they are the basis for entry into most
of evidence as the basis of criteria change; and the research studies of functional gut disorders and have
encouragement of “developing world” participation. The compelled an accurate description of entered patients in
Board also initiated an ongoing project to develop an the remainder. They are the industry standard for entry
educational slide program for the functional gastrointes- into clinical drug trials, although they are sometimes
tinal disorders. modified to suit the characteristics of the product to be
For Rome III, the Board selected 87 participants from tested. They have given these disorders, particularly IBS,
18 countries in 14 committees and briefed the chairper- a profile. Patients can now be reassured they suffer from
sons in 2003, 2004, and 2005. Members were added
a legitimate disorder, not symptoms rendered imaginary
from developing countries including China, Brazil,
by a negative test. The criteria have created a language
Chile, Venezuela, Hungary, and Romania. New working
with which the above-mentioned groups can communi-
teams were created for gender, society, patient, and social
cate. The coming together of such disparate constituen-
issues; and pharmacology and pharmacokinetics. Func-
cies in a common effort is a major achievement, due in no
tional abdominal pain was split from functional bowel
small way to Rome’s systematic recognition of the func-
disease and 2 committees (neonate/toddler and child/
tional gut disorders.
adolescent), rather than 1, served pediatrics. A subcom-
mittee of the board consisting of myself (chair), Doug This Rome III publication culminates a new 6-year
Drossman, Nick Talley, Lynn Walker, and William effort to update the Rome criteria and, like Rome I
Whitehead designed the adult and pediatric question- and II, owes much to the energy and drive of Doug
naires as the criteria were developed. Rome III culmi- Drossman who describes the mechanics of this process
nated in a meeting in Rome in November/December in Chapter 1. The Rome II and Rome III processes
2004. As the final drafts of the chapters were being were generously supported by industry, and attracted
prepared, Dr. Whitehead conducted a validation study of the interest and participation of many people in sev-
the criteria and the questionnaire designed by the ques- eral disciplines from around the world. There can be
tionnaire subcommittee, the results of which are in- no better testimony to the stature that the Rome
cluded in this publication. Following peer review, the criteria have achieved. However, Rome III is neither
results of the process are now published as articles in the end, nor even the beginning of the end. It is
GASTROENTEROLOGY, and in full as the third edition of perhaps the end of the beginning of an ongoing pro-
Rome III, The Functional Gastrointestinal Disorders in the cess that will last as long as understanding the patho-
summer of 2006. In addition, Board members reported physiology of functional gut disorders eludes us.
the Rome III process to the 2005 World Congress of Meanwhile, here is a great need to generate data that
Gastroenterology in Montreal, and the criteria them- will sharpen the criteria and validate their use. Pre-
selves to the 2006 American Gastrointestinal Association liminary discussions have begun for Rome IV, but we
meeting in Los Angeles. must allow sufficient time for the accumulation of
The Rome criteria generate much energy and contro- evidence to justify meaningful changes. The Delphi
versy. They are imperfect. Validation studies are difficult approach may be less useful now, but the need remains
and rare. There is much debate within the Rome pro- for consensus as to the meaning of the slowly accu-
cesses about terminology, notably the use of the term mulating, fragmented, and controversial evidence.
1556 W. GRANT THOMPSON GASTROENTEROLOGY Vol. 130, No. 5

References 22. Drossman DA, Richter JE, Talley NJ, Corazziari E, Thompson WG,
Whitehead WE. Functional gastrointestinal disorders. Boston:
1. Klein KB. Controlled treatment trials in the irritable bowel syn- Little, Brown, 1994.
drome: a critique. Gastroenterology 1988;95:232–241. 23. Drossman DA, Corazziari E, Talley NJ, Thompson WG, Whitehead
2. Powell R. On certain painful afflictions of the intestinal canal. Med WE. Rome II: a multinational consensus document on functional
Trans Royal Coll Phys 1818;6:106 –117. gastrointestinal disorders. 45 ed. 1999.
3. Howship J. Practical remarks on the discrimination and success- 24. Kasich A, Rafsky JC. Clinical evaluation of an anticholinergic in
ful treatment of spasmodic stricture of the colon. London: Bur- the irritable colon syndrome. Am J Gastroenterol 1959;4:229 –
gess and Hill, 1830. 234.
4. Cumming W. Electro-galvanism in a peculiar affliction of the mu- 25. Connell AM. Physiological and clinical assessment of the effect
cous membrane of the bowels. London Med Gazette 1849;NS9: of the musculotropic agent mebeverine on the human colon. BMJ
969 –973. 1965;2:848 – 851.
5. Hale-White W. Colitis. Lancet 1895;1:537. 26. Tasman-Jones C. Mebeverine in patients with the irritable colon
6. Thompson WG. Gut reactions. New York: Plenum, 1989. syndrome: double blind study. N Z Med J 1973;1:232–235.
7. Hutchison R. Lectures on dyspepsia. London: Edward Arnold, 27. Greenbaum DS, Ferguson RK, Kater LA, et al. A controlled ther-
1927. apeutic study of the irritable bowel syndrome. N Engl J Med
8. Thompson WG. Proctalgia fugax. Dig Dis Sci 1981;26:1121– 1973;288:612– 616.
1124. 28. Piai G, Mazzacca G. Profinium Bromide in the treatment of the
9. Chaudhary NA, Truelove SC. The irritable colon syndrome. Q irritable bowel syndrome. Gastroenterology 1979;77:500 –502.
J Med 1962;31:307–322. 29. Moshal MG, Herron M. A clinical trial of trimebutine in spastic
10. Thompson WG. The irritable gut. Baltimore: University Park Press, colon. J Int Med Res 1979;7:231–234.
1979. 30. Fielding JF. Double blind trial of trimebutine in the irritable bowel
11. Manning AP, Thompson WG, Heaton KW, Morris AF. Towards syndrome. Ir Med J 1980;73:377–379.
positive diagnosis of the irritable bowel. Br Med J 1978;2:653– 31. Luttecke K. A trial of trimebutine in spastic colon. J Int Med Res
654. 1978;6:86 – 88.
12. Kruis W, Thieme CH, Weinzierl M, Schussler P, Hall J, Paulus W. 32. Fielding JF. Timolol treatment in the irritable bowel syndrome.
A diagnostic score for the irritable bowel syndrome. Its value in Digestion 1982;22:155–158.
the exclusion of organic disease. Gastroenterology 1984;87: 33. Cann PA, Read NW, Holdsworth CC. Oral domperidone: double
1–7. blind comparison with placebo in irritable bowel syndrome. Gut
13. Drossman DA, Sandler RS, McKee DC, Lovitz AJ. Bowel patterns 1983;24:1135–1140.
among subjects not seeking health care. Use of a questionnaire 34. Dew MJ, Evans BK, Rhodes J. Peppermint oil for the irritable
to identify a population with bowel dysfunction. Gastroenterology bowel syndrome. Br J Clin Pract 1984;38:394 –398.
1982;83:529 –534. 35. Flexinos J, Fioramonti J, Bueno L. Effect of trimebutine on colonic
14. Whitehead WE, Winget C, Fedoravicius AS, Wooley S, Blackwell myoelectric activity in IBS patients. Eur J Clin Pharmacol 1985;
B. Learned illness behavior in patients with irritable bowel syn- 28:181–185.
drome and peptic ulcer. Dig Dis Sci 1982;27:202–208. 36. Pidgeon F, Craig F, Fielding JF. Lack of effect of cimetidine in the
15. Thompson WG, Dotevall G, Drossman DA, Heaton KW, Kruis W. irritable bowel syndrome. Ir J Med Sci 1985;154:33–34.
Irritable bowel syndrome: guidelines for the diagnosis. Gastroen- 37. Narducci F, Bassotti G, Gaburri M. Nifedipine reduces the colonic
terol Int 1989;2:92–95. motor response to eating in patients with the irritable colon
16. Drossman DA, Funch-Jensen P, Janssens J, Talley NJ, Thompson syndrome. Am J Gastroenterol 1985;80:317–319.
WG, Whitehead WE. Identification of subgroups of functional 38. Perez-Mateo M, Sillero C, Cuesta A, Vazquez N, Berbegel J.
bowel disorders. Gastroenterol Int 1990;3:159 –172. Diltiazem in the treatment of irritable bowel syndrome. Int J Clin
17. Richter JE, Baldi F, Clouse RE, Diamant NE, Janssens J, Stiano A. Pharmacol Res 1986;5:425– 427.
Functional oesophageal disorders. Gastroenterol Int 1992;5:3– 39. Prior A, Wilson KM, Whorwell PJ. Double-blind study of an ␣2
17. agonist in the treatment of irritable bowel syndrome. Aliment
18. Talley NJ, Colin-Jones D, Koch KL, Koch M, Nyren O, Stanghellini Pharmacol Ther 1988;2:535–539.
V. Functional dyspepsia: a classification with guidelines for diag- 40. Dobrilla G, Imbimbo BP, Piazzi L, Bensi G. Longterm treatment of
nosis and management. Gastroenterol Int 1991;4:145–160. IBS with cimetropium bromide: a double blind placebo-controlled
19. Corazziari E, Funch-Jensen P, Hogan W, Tanaka J, Toouli J. Work- clinical trail. Gut 1990;31:355–358.
ing team report on functional biliary disorders. Gastroenterol Int 41. Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine
1993;6:129 –144. EJ, Muller-Lissner SA. Functional bowel disease and functional
20. Thompson WG, Creed FH, Drossman DA, Heaton KW, Mazzacca abdominal pain. Gut 1999;45:43– 47.
G. Functional bowel disorders and functional abdominal pain.
Gastroenterol Int 1992;5:75–91.
21. Whitehead WE, Devroede G, Habib FI, Meunier P, Wald A. Report Address requests for reprints to: W. Grant Thompson, MD, FRCPC,
of an international workshop on functional disorders of the ano- University of Ottawa, 7 Nesbitt Street, University of Ottawa, Ottawa,
rectum. Gastroenterol Int 1992;5:92–108. Canada K2H 8C4. e-mail: [email protected].
 Forthcoming Articles

RAPID COMMUNICATION

Gastric Bypass Surgery Improves Metabolic and Hepatic Abnormalities Associated With
Nonalcoholic Fatty Liver Disease
S. Klein, B. Mittendorfer, J. C. Eagon, B. Patterson, L. Grant, N. Feirt, E. Seki, D. Brenner, K. Korenblat, and
J. McCrea

CLINICAL–ALIMENTARY TRACT

Gastrointestinal Stromal Tumors With KIT Exon 11 Deletions Are Associated With Poor
Prognosis
J. Andersson, P. Bümming, J. M. Meis–Kindblom, H. Sihto, N. Nupponen, H. Joensuu, A. Odén, B. Gustavsson,
L.– G. Kindblom, and B. Nilsson

Surface Visualization at 3D Endoluminal CT Colonography: Degree of Coverage and

Implications for Polyp Detection
P. J. Pickhardt, A. J. Taylor, and D.V. Gopal

Acute Gastroenteritis Is Followed by an Increased Risk of Inflammatory Bowel Disease

L. A. Garcı́a Rodrı́guez, A. Ruigómez, and J. Panés

The Value of Myenteric Plexitis to Predict Early Postoperative Crohn’s Disease Recurrence
M. Ferrante, G. De Hertogh, T. Hlavaty, G. D’Haens, F. Penninckx, A. D’Hoore, S. Vermeire, P. Rutgeerts,
K. Geboes, and G. Van Assche

CLINICAL–LIVER, PANCREAS, AND BILIARY TRACT

Alcohol Use and Treatment of Hepatitis C Virus: Results of a National Multicenter Study
B. S. Anand, S. Currie, E. Dieperink, E. J. Bini, H. Shen, S. B. Ho, and
T. Wright for the VA-HCV-001 Study Group

The Evolution of Severe Steatosis After Bariatric Surgery Is Related to Insulin Resistance
P. Mathurin, F. Gonzalez, O. Kerdraon, E. Leteurtre, L. Arnalsteen, A. Hollebecque, A. Louvet, S. Dharancy,
P. Cocq, T. Jany, J. Boitard, P. Deltenre, M. Romon, and F. Pattou

Genotypes and Viremia of Hepatitis B and D Viruses Are Associated With Outcomes of Chronic
Hepatitis D Patients
C.– W. Su, Y. H. Huang, T.–I. Huo, H. H. Shih, I.– J. Sheen, S.– W. Chen, P.–C. Lee, S.–D. Lee, and J.– C. Wu

Relationship Between Steatosis, Inflammation and Fibrosis in Chronic Hepatitis C: A Meta-

Analysis of Individual Patient Data
G. Leandro, A. Mangia, J. Hui, P. Fabris, L. Rubbia–Brandt, G. Colloredo, L. E. Adinolfi, T. Asselah, J. R. Jonsson,
A. Smedile, N. Terrault, V. Pazienza, M. T. Giordani, E. Giostra, A. Sonzogni, G. Ruggiero, P. Marcellin,
E. E. Powell, J. George, and F. Negro, for the HCV MAID Study Group

(continued)
 Forthcoming Articles
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Distal Splenorenal Shunt Versus Transjugular Intrahepatic Portal Systematic Shunt for Variceal
Bleeding: A Randomized Trial
J. M. Henderson, T. D. Boyer, M. H. Kutner, J. R. Galloway, L. F. Rikkers, L. M. Jeffers, K. Abu–Elmagd,
J. Connor, and the DIVERT Study Group

Evidence-Based Incorporation of Serum Sodium Concentration Into MELD

S. W. Biggins, W. R. Kim, N. A. Terrault, S. Saab, V. Balan, T. Schiano, J. Benson, T. Therneau, W. Kremers,
R. Wiesner, P. Kamath, and G. Klintmalm

Liver Microsomal Triglyceride Transfer Protein Is Involved in Hepatitis C Liver Steatosis

S. Mirandola, S. Realdon, J. Iqbal, M. Gerotto, F. Dal Pero, G. Bortoletto, M. Marcolongo, A. Vario, C. Datz,
M. M. Hussain, and A. Alberti

Proteomic Classification of Pancreatic Adenocarcinoma Tissue Using Protein Chip Technology

C. J. Scarletti, R. C. Smith, A. Saxby, A. Nielsen, J. S. Samra, S. R. Wilson, and R. C. Baxter

Identification of Two Gene Variants Associated With Risk of Advanced Fibrosis in Patients With
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H. Huang, M. L. Shiffman, R. C. Cheung, T. J. Layden, S. Friedman, O. T. Abar, L. Yee, A. P. Chokkalingam,
S. J. Schrodi, J. Chan, J. J. Catanese, D. U. Leong, D. Ross, X. Hu, A. Monto, L. B. McAllister, S. Broder, T. White,
J. J. Sninsky, and T. L. Wright

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A Recombinant Probiotic for Treatment and Prevention of Cholera

A. Focareta, J. C. Paton, R. Morona, J. Cook, and A.W. Paton

Trefoil Factor Family-1 Mutations Enhance Gastric Cancer Cell Invasion Through Distinct
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X. Yio, M. Diamond, J.–Y. Zhang, H. Weinstein, L.–H. Wang, L. Werther, and S. Itzkowitz

Therapeutic Action of Ghrelin in a Mouse Model of Colitis

E. Gonzalez–Rey, A. Fernandez–Martin, A. Chorny, and M. Delgado

CD4ⴙ T Cell Modulation of Visceral Nociception in Mice

M. Verma–Gandhu, P. Bercik, Y. Motomura, E. F. Verdu, W. I. Khan, P.A. Blennerhassett, L. Wang,
R. T. El–Sharkawy, and S. M. Collins

The Role of Neurokinin 1 Receptors in the Maintenance of Visceral Hyperalgesia Induced by

Repeated Stress in Rats
S. Bradesi, E. Kokkotou, S. Simeonidis, S. Patierno, H. S. Ennes, Y. Mittal, J. A. McRoberts, G. Ohning,
J. C. Marvizon, C. Sternini, C. Pothoulakis, and E. A. Mayer

(continued)
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Antidepressants Attenuate Increased Susceptibility to Colitis in a Murine Model of Depression
A. K. Varghese, E. F. Verdú, P. Bercik, W. I. Khan, P. A. Blennerhassett, H. Szechtman, and S. M. Collins

The Role of Matrix Metalloproteinase (MMP)-7 in Redefining the Gastric Micro-Environment in

Response to Helicobacter pylori
C. McCaig, C. Duval, E. Hemers, I. Steele, D. M. Pritchard, S. Przemeck, R. Dimaline, S. Ahmed, K. Bodger,
D. D. Kerrigan, T. C. Wang, G. J. Dockray, and A. Varro

Candida albicans Is an Immunogen for Anti-Saccharomyces cerevisiae Antibodies (ASCA)

Markers of Crohn’s Disease
A. Standaert–Vitse, T. Jouault, P. Vandewalle, C. Mille, M. Seddik, B. Sendid, J.–M. Mallet, J.–F. Colombel, and
D. Poulain

Diet- and Colonization-Dependent Intestinal Dysfunction Predisposes to Necrotizing

Enterocolitis in Preterm Pigs
P. T. Sangild, R. H. Siggers, M. Schmidt, J. Elnif, C. R. Bjornvad, T. Thymann, M. L. Grondahl, A. K. Hansen,
S. K. Jensen, M. Boye, L. Moelbak, R. K. Buddington, B. Westrom, and D. G. Burrin

BASIC–LIVER, PANCREAS, AND BILIARY TRACT

Drug and Bile Acid Transporters in Rosuvastatin Hepatic Uptake: Function, Expression, and
Pharmacogenetics
R. H. Ho, R. G. Tirona, B. F. Leake, H. Glaeser, W. Lee, C. J. Lemke, Y. Wang, and R. B. Kim

The Bone Marrow Functionally Contributes to Liver Fibrosis

F. P. Russo, M. R. Alison, B. W. Bigger, E. Amofah, A. Florou, F. Amin, G. Bou–Gharios, R. Jeffery, J. P. Iredale,
and S. J. Forbes

The Vagus Nerve and Nicotinic Receptors Modulate Experimental Pancreatitis Severity in Mice
D. J. van Westerloo, I. A. Giebelen, S. Florquin, M. J. Bruno, G. J. LaRosa, L. Ulloa, K. J. Tracey, and
T. van der Poll

Endogenous Opioids Modulate the Growth of the Biliary Tree in the Course of Cholestasis
M. Marzioni, G. Alpini, S. Saccomanno, S. De Minicis, S. Glaser, H. Francis, L. Trozzi, J. Venter, F. Orlando,
G. Fava, C. Candelaresi, G. Macarri, and A. Benedetti

CASE REPORTS

Intestinal Cholesterol Absorption Inhibitor Ezetimibe Added to Cholestyramine for

Sitosterolemia and Xanthomatosis
G. Salen, T. Starc, C. McCrary Sisk, and S. B. Patel

(continued)
 Forthcoming Articles
(continued)
MICROARRAYS AND OTHER NEW TECHNOLOGIES

Diagnosis of Gastric Cancer by Serum Proteomic Fingerprinting

T. C. W. Poon, J. J. Y. Sung, S. Man Chow, E. K.W. Ng, A. C. W. Yu, E. S.H. Chu, A. M. Y. Hui, and W. K. Leung

SPECIAL REPORTS AND REVIEWS

Guidelines for Colonoscopy Surveillance After Cancer Resection: A Consensus Update by the
American Cancer Society and U.S. Multi-Society Task Force on Colorectal Cancer
D. K. Rex, C. J. Kahi, B. Levin, R. A. Smith, J. H. Bond, D. Brooks, R.W. Burt, T. Byers, R. H. Fletcher, N. Hyman,
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Guidelines for Colonoscopy Surveillance After Polypectomy: A Consensus Update by the U.S.
Multi-Society Task Force on Colorectal Cancer and the American Cancer Society
S. J. Winawer, A. G. Zauber, R. H. Fletcher, J. S. Stillman, M. J. O’Brien, B. Levin, R. A. Smith, D. A. Lieberman,
R. W. Burt, T. R. Levin, J. H. Bond, D. Brooks, T. Byers, N. Hyman, L. Kirk, A. Thorson, C. Simmang, D. Johnson,
and D. K. Rex

Toll-Like Receptor Signaling in the Liver

R. F. Schwabe, E. Seki, and D. A. Brenner
STYLE GUIDE
GASTROENTEROLOGY receives manuscripts from authors the world over. These papers are reviewed and read by medical personnel
on every continent. Thus, national, regional, or personal variations in scientific terminology and style can impede the progress
of a manuscript from submission to publication. In order to facilitate the reviewing and editing of manuscripts, we recommend
that authors use the following style guidelines when manuscripts are submitted to or revised for the Journal. Final acceptance
of any paper, however, will be based on its merits and its suitability for the Journal.

Abbreviations, Acronyms, and Short Names IBD inflammatory bowel disease

IC intracisternal(ly)
Listed below are the preferred forms of some common abbreviations, ID inner diameter†
acronyms, and short names. Unless otherwise noted, these short forms IEL intraepithelial leukocyte
should always be written out in full in titles. When introducing these Ig immunoglobulin
abbreviations (or others not listed here), the term should be written IM intramuscular(ly)
out in full and the abbreviation or acronym given in parentheses; IP intraperitoneal(ly)
therafter only the abbreviations need be used. IV intravenous(ly)
ACTH adrenocorticotropic hormone (adrenocorticotropin) Km Michaelis constant
ADP adenosine diphosphate LES lower esophageal sphincter
ADPase adenosine diphosphatase mol wt molecular weight†
ALT alanine aminotransferase mRNA messenger RNA
AMP adenosine monophosphate (adenylic acid) NANB non-A, non-B (hepatitis)
anti-HAV antibody to hepatitis A virus NPY neuropeptide Y
anti-HBc antibody to hepatitis B core antigen NSAID nonsteroidal anti-inflammatory drug
anti-HBe antibody to hepatitis B e antigen OD outer diameter†
anti-HBs antibody to hepatitis B surface antigen PAGE polyacrylamide gel electrophoresis
anti-HCV antibody to hepatitis C virus PBS phosphate-buffered saline
anti-HDV antibody to hepatitis D (delta) virus PD potential difference
AST aspartate aminotransferase PEG polyethylene glycol
ATP adenosine triphosphate PG prostaglandin
ATPase adenosine triphosphatase PGI prostacyclin
BUN blood urea nitrogen PHI peptide histidine isoleucine
CAH chronic active hepatitis PI phosphatidylinositol
cAMP adenosine 3⬘,5⬘-cyclic monophosphate PLC phospholipase C
CCK cholecystokinin PP pancreatic polypeptide
CCK-LI cholecystokinin-like immunoreactivity PYY peptide YY
CD Crohn’s disease RBC red blood cell†
CDAI Crohn’s Disease Activity Index RIA radioimmunoassay
cDNA complementary DNA RNA ribonucleic acid*
cGMP guanosine 3⬘,5⬘-cyclic monophosphate SC subcutaneous(ly)
CGRP calcitonin gene-related peptide SGOT serum glutamic oxaloacetic transaminase
CNS central nervous system SGPT serum glutamic pyruvic transaminase
CoA coenzyme A SI saturation index
con A concanavalin A SP substance P
DEAE diethylaminoethyl sp act specific activity†
DNA deoxyribonucleic acid (deoxyribonucleate)* TLC thin-layer chromatography
EDTA ethylenediaminetetraacetic acid* TPN total parenteral nutrition
FFA free fatty acid(s) Tris tris(hydroxymethyl)aminomethane*
GIP gastric inhibitory polypeptide TXA2 thromboxane A2
GRP gastrin-releasing peptide UC ulcerative colitis
HAV hepatitis A virus UDC ursodeoxycholate
HBcAg hepatitis B core antigen UDCA ursodeoxycholic acid
HBeAg hepatitis B e antigen UDP uridine 5⬘-diphosphate
HBsAg hepatitis B surface antigen VIP vasoactive intestinal polypeptide
HBV hepatitis B virus vol volume†
HCC hepatocellular carcinoma wt weight†
HCV hepatitis C virus
HDV hepatitis D (delta) virus
H&E hematoxylin and eosin stain* *Need not be defined.
HEPES N-2-hydroxyethylpiperazine-N⬘-2-ethanesulfonic acid* †Need not be defined, but use only with numerals, in figures, or in
IA intra-arterial(ly) the body of tables.
STYLE GUIDE (Continued)

Measurements and Units of Measure L liter(s)

mL milliliter(s)
Abbreviate measurements and units of measure only with numerals, ␮L microliter(s)
in figures, or in the body of tables. In measurements using more than m meter(s)
2 units of measure (e.g., 1.5 ␮mol/cm2/s), do not use more than one ␮m micrometers (do not use microns, ␮)
slant line (solidus). Instead, please express the measurement in the ⫻ magnification
following way: mile/h mile(s) per hour (not mph)
1.5 ␮mol · cm⫺2 · s⫺1 mm Hg millimeter(s) of mercury
min minute(s)
Combining Prefixes mol/L molar
T tera- (1012) mo month(s)
G giga- (109) mol mole(s)
M mega- (106) newton(s) newton(s) (do not abbreviate)
k kilo- (103) N normal
h hecto- (102) ⍀ ohm(s)
da deca- (101) osm osmole(s)
d deci- (10⫺1) oz ounces(s)
c centi- (10⫺2) Pa pascal(s)
m milli- (10⫺3) lb pound(s)
␮ micro- (10⫺6) rad(s) rad(s) (do not abbreviate)
n nano- (10⫺9) rpm revolutions per minute
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a atto- (10⫺18) U unit(s)
V volts(s)
Units W watt(s)
wk week(s)
A ampere(s)
yr year(s)
Å angstrom(s)
cal calorie(s)
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Radioisotopes
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Ci Curie(s) are:
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cycle/s cycles per second 1. The symbol for the isotope should be placed in square brackets
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STYLE GUIDE (Continued)

Statistical Terms Drug names. Please use generic names wherever possible. If a trade
name drug was used in the study being reported, please cite the trade
␹2method chi-squared method
name in parentheses, along with the manufacturer’s name and loca-
r correlation coefficient
tion (see Manufacturers).
df degrees of freedom
Greek letters. Current preferred style favors the use of Greek letters
x mean
over their English equivalents. Thus alpha-l-antitrypsin and gamma-
NS not significant
globulin should be styled ␣1-antitrypsin and ␥-globulin, respectively.
n number of observations
Manufacturers. When the use of specific scientific equipment or
P probability
other products is cited in the manuscript, the manufacturer’s full
SD standard deviation
name, city, and state (or country) should be given in parentheses
SEM standard error of the mean
immediately after the citation. If other equipment or products from
Student t test express in full
the same manufacturer are cited later in the paper, the manufacturer’s
F variance ratio
name only should be given in parentheses.
Molecular weight. Molecular weight is a pure number, and is defined
as molecular weight ratio; it is not expressed in daltons. The dalton is
a unit of mass equal to 1⁄12 the mass of one atom of carbon 12.
General Information Trade names. Trade names should be capitalized, and the manufac-
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according to the Merck Index, 10th edition. be written in all capital letters.
MANUSCRIPT DESCRIPTOR FORM

Describe the type of manuscript you are submitting by listing in 1.

order of importance three relevant descriptor numbers here: 2.
3.

AGAI DESCRIPTORS: Gastrointestinal Oncology Hormones and Receptors

Clinical Practice 35 Cell & Molecular Biology/Immunology/ 73 Physiology/Cell Biology/Biochemistry
01 Clinical Management Strategies Genetics 74 Receptor Characterization/Regulation
36 Proliferation/Carcinogenesis 75 Molecular Biology
02 Epidemiology
37 Screening/Diagnosis/Prognosis 76 Biochemistry
03 Health Policy/Technology
38 Prevention/Treatment/Experimental 77 Neurobiology, Neurotransmitters and
Assessment/Health Services
Therapeutics Signaling
Research 39 General Clinical/Epidemiology
04 Practice Management & Quality 78 Biology of Growth/Proliferation/Growth
Assurance Motility and Nerve-Gut Interactions Factors
79 Brain-Gut Axis
40 Receptors/Channels/Intracellular
80 Clinical Disorders
Signals/Contraction/Relaxation
Esophageal, Gastric, and Duodenal 41 Intrinsic & Extrinsic Innervation: 81 Miscellaneous
Disorders Anatomy, Nervous, Physiology, Chemistry
05 Secretion: Mechanisms and 42 Physiology/Pathophysiology/
Regulation Pharmacology: Esophagus
06 Mucosal Repair and Healing 43 Physiology/Pathophysiology/ Nutrition and Obesity
07 Experimental Mucosal Lesions Pharmacology: Stomach 82 Short Gut Syndrome and Intestinal
08 Helicobacter pylori: Epidemiology & 44 Physiology/Pathophysiology/ Transplantation
Pathogenesis Pharmacology: Small Bowel 83 Malabsorption
09 Helicobacter pylori: Diagnosis & 45 Physiology/Pathophysiology/ 84 Nutrients and Gut Function: Clinical
Pharmacology: Colon & Anorectum 85 Nutritional Support and Nutritional
Treatment
46 Functional GI Disorders: Symptoms,
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Physiology, Behavior, Epidemiology,
Epidemiology & Pathogenesis 86 Milk: Human and Non-Human
Treatment
11 Acid/Peptic (Includes NSAIDs): Substitutes
Diagnosis, Complications, Treatment Growth, Development, and Aging 87 Probiotics and Functional Foods
12 Reflux Esophagitis 47 Mucosal Growth Factors and Receptors 88 Vitamins, Minerals and Micronutrients:
13 Clinical Esophageal Disorders 48 Cell Signaling Clinical
(Nonreflux) 49 Intestinal Proliferation, Cell Cycle 89 Intestinal Absorption and Nutrient
Regulation and Apoptosis Transport
50 Biology of Intestinal Growth, Adaptation 90 Nutrient and Gut Function: Basic
Intestinal Disorders and Repair 91 Nutrient Metabolism and Signaling
14 Pathophysiology of Diarrheal Disorders 51 Growth and Development of Liver and 92 Obesity and Eating Disorders: Clinical
15 Malabsorption/Gas Pancreas 93 Obesity and Satiety: Basic
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Transport Physiological and Molecular Mechanisms
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54 Development of Enteric Nerves and Muscle Liver
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55 Transgenic and Knock out Animals
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56 Morphogenesis, Organogenesis and
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Stem Cells
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Interactions 96 Chronic Hepatitis (Nonviral), Primary
Pancreatic Disorders Biliary Cirrhosis, Sclerosing Cholangitis,
58 Gene Structure, Regulation and
21 Acinar Cell Function Expression Immunology
22 Duct Cell Function 59 Pediatric Gastrointestinal Disease 97 Hepatitis
23 Receptors/Receptor Action 60 Pediatric Liver and Pancreatic Disorders 98 Ethanol, Nutrition, Metabolism
24 Neurohormonal Control 61 Aging and Gastrointestinal Function: (Including Genetic Disease)
25 Experimental Pancreatitis Clinical and Basic 99 Complications of Cirrhosis: Portal
26 Acute Pancreatitis 62 Clinical Gastroenterology in the Elderly Hypertension, Portal Circulation
27 Chronic Pancreatitis 100 Complications of Cirrhosis: Ascites,
Immunology, Microbiology, and
28 Exocrine/Endocrine Tumors Encephalopathy
Inflammatory Disorders
101 Hepatic & Biliary Bile Acid and Ion
63 Mucosal Immunity Transport Bile Formation &
Biliary Disorders 64 Host Defense Mechanisms
Cholestasis
65 Inflammation
29 Biliary Stone Disease: Nonsurgical 102 Bile Acids, Bile Acid Synthesis &
66 Inflammatory Bowel Disease: Basic
Therapy Metabolism, Bile Lipids & Proteins,
67 Inflammatory Bowel Disease: Therapy
30 Biliary Stone Disease: Surgical & 68 Inflammatory Bowel Disease: Clinical Lipoproteins
Endoscopic Investigation and Epidemiology 103 Gallstones, Formation & Treatment;
31 Gallstones: Chemical, Physical, 69 Gastrointestinal and Hepatic Infections/ Pathobiology of Gallbladder & Biliary
Mechanical, Radiological Properties Viruses Tree
32 Biliary Tract Imaging: Biliary Tract 70 AIDS (Basic and Clinical) 104 Cell Injury, Hepatoxicity and
Endoscopy 71 Helicobacter pylori (Basic) Pharmacology
33 Biliary Tract Motility; Sphincter of Oddi 72 Microbial and Immune Mediated Injury/ 105 Transplantation and Hepatobiliary
34 Biliary Disease: Other Pathology Surgery
 GASTROENTEROLOGY 2006;130:5
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