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 Jean-Paul Goulet
Ana Miriam Velly
Editors

Orofacial
Pain Biomarkers

123
Orofacial Pain Biomarkers
Jean-Paul Goulet • Ana Miriam Velly
Editors

Orofacial Pain
Biomarkers
Editors
Jean-Paul Goulet Ana Miriam Velly
Faculté de médecine dentaire Faculty of Dentistry
Université Laval McGill University
Québec Department of Dentistry of Jewish
Canada General Hospital
Montréal, Québec
Canada

ISBN 978-3-662-53992-7    ISBN 978-3-662-53994-1 (eBook)

DOI 10.1007/978-3-662-53994-1

Library of Congress Control Number: 2017936195

© Springer-Verlag GmbH Germany 2017

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or
part of the material is concerned, specifically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way,
and transmission or information storage and retrieval, electronic adaptation, computer software,
or by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specific statement, that such names are
exempt from the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in
this book are believed to be true and accurate at the date of publication. Neither the publisher nor
the authors or the editors give a warranty, express or implied, with respect to the material
contained herein or for any errors or omissions that may have been made.

Printed on acid-free paper

This Springer imprint is published by Springer Nature

The registered company is Springer-Verlag GmbH Germany
The registered company address is: Heidelberger Platz 3, 14197 Berlin, Germany
Preface

The thread that led to the edition of this volume was a Neuroscience Group
Symposium held in 2012 during the 90th General Session and Exhibition of
the International Association for Dental Research in Iguaçu Falls, Brazil,
entitled “Orofacial pain biomarkers: Implication on pain prevention, manage-
ment and research.” Things have continued to evolve, and within a limited
space, our intent with this book is to cover some of the many different aspects
of pain biomarkers in the context of orofacial pain hoping it can contribute to
improve our understanding and management strategies through better and
more targeted research.
It is not an overstatement to say that, over an entire life span, everyone will
experience orofacial pain at least on few if not several occasions. We may not
recall but for most of us the first occurrence is at an early age with the erup-
tion of our deciduous teeth. At least we must all remember the pain associ-
ated with the loss of one of those teeth, and while growing up, we learned the
important role that pain plays in the presence of a threat or tissue damage that
impairs our well-being. Clearly, being able to give a meaning to an orofacial
pain serves to dissipate the anguish that accompanies such a personal and
unpleasant sensory experience. No wonder that early iteration of the classic
paradigm of pain disappearing with things returning to what they were after
a normal healing timeline becomes expected. However, a much more com-
plex pain experience will emerge in a scenario where the sufferer’s cognitive
construct offers no reasonable explanation for an orofacial pain condition that
is refractory or has a recurrent timeline. Unfortunately, this is not uncommon
considering that chronic orofacial pain conditions that are mostly inexplica-
ble and mainly characterized by nonspecific physical findings have an esti-
mated prevalence in the range of 10% in the general population. Hence, this
brings into play all the emotional and psychosocial factors that contribute to
the multidimensional aspect of the patient’s condition.
As a whole, our understanding of chronic orofacial pain conditions is still
very limited though the progress made during recent decades has contributed
to better diagnosis, classification, and identification of risk and prognostic
factors. However, most patients with chronic orofacial pain are facing uncer-
tainty due to the lack of clear organic causes that could explain the symptoms,
and though we may be better at labeling a patient’s condition so it can legiti-
mate the symptoms, still psychological disturbances and a lower quality of
life are commonalities among those afflicted. Adding to this burden, a return
to normal functioning and previous levels of health is unlikely for many.

v
vi Preface

Despite considerable advancements, we still need to improve treatment

strategies for common chronic orofacial pain conditions so patients can have
more predictable therapeutic benefits. Early diagnosis and better understand-
ing of the underlying pain mechanisms become imperative. A problem in
orofacial pain studies aimed to diagnose, classify, and identify the risk fac-
tors, as well as establish better treatments, is that pain is fundamentally a
multifaceted subjective phenomenon. This is well depicted in the definition
given by the International Association for the Study of Pain (IASP) (1986),
“pain is an unpleasant sensory and emotional experience associated with
actual or potential tissue damage or described in terms of such damage.”
Therefore, identification of biomarkers as measures for ensuring the pres-
ence of chronic orofacial pain conditions could contribute to a more objec-
tive, valid, and reliable multiaxial diagnosis. Biomarkers could also help to
the identification of putative risk factors, elucidate mechanisms associated
with chronic orofacial pain, and aid in the identification of the most appropri-
ate pain management approaches.
The subject of this book is about recent advances in orofacial pain studies
and biomarkers. The content is divided into four thematically distinct parts
that include 12 chapters. In the first part, “Clinical and Epidemiological
Aspects of Orofacial Pain,” Goulet and Woda (Chap. 1) explain what makes
pain in the orofacial region so unique, address classification issues and clini-
cal phenotypes, and describe the features of the most common chronic orofa-
cial pain conditions. In their chapter, Velly and Fricton (Chap. 2) review the
prevalence of painful and non-painful comorbidities among individuals with
orofacial pain and discuss the implication of comorbidities in the identifica-
tion of biomarkers for chronic orofacial pain, which is largely unknown.
In the second part, “Mechanisms of Chronic Orofacial Pain,” Barry
J. Sessle (Chap. 3) reviews relevant orofacial pain mechanisms and trigemi-
nal nociceptive pathways before focusing on peripheral and central processes
involved in chronic orofacial pain. Bourgeais and colleagues (Chap. 4) out-
line the anatomo-functional relationship between cortical regions; address
central regulation mechanisms, hypothalamic excitability disturbances, and
dysfunctions of medullary trigeminovascular regions; and analyze the impact
of such dysfunctions as putative biomarkers of central sensitization phenom-
ena on the origin of sustained trigeminal pain.
Part III, “Biomarkers in Orofacial Pain,” comprises five chapters. Satu
Jääskeläinen (Chap. 5) addresses the neurophysiologic markers of neuro-
pathic orofacial pain and demonstrates how neurophysiologic and psycho-
physical examination provides sensitive and specific information about
trigeminal neuropathy in patients presenting orofacial pain symptoms. After
a brief description of the sampling methods, Malin Ernberg (Chap. 6) pres-
ents the main categories of muscle biomarkers and describes potential bio-
markers for masticatory muscle pain. Per Alstergren (Chap. 7) addresses
immunological biomarkers for inflammatory types of temporomandibular
joint pain focusing on candidate for early diagnosis, prognosis, and monitor-
ing of disease activity. Seltzer and Diehl (Chap. 8) review genes that are can-
didate biomarkers for the major persistent orofacial pain disorders and
potential key elements for the development of “precision medicine”. After an
Preface vii

overview of the different biofluids, Katsiougiannis and colleagues (Chap. 9)

focus on saliva, serum, and synovial fluid as reservoirs of biochemical infor-
mation and discuss their respective utilization and value in the identification
of disease states associated with chronic orofacial pain.
In Part IV, “Study Designs and Statistical Analysis for the Identification of
Biomarkers, and Future Direction,” Velly and colleagues (Chap. 10) provide
a generic-case definition and classification of biomarkers, and propose guide-
lines for the assessement of biomarkers before adressing factors that may
influence the discovery and validation of pain biomarkers. In chapter 11
Russell Steele addresses the complexity of data analysis in pain biomarkers
research and the impact of relying on surrogate measures relevant to the pain
experience. Finally in Chapter 12, the editors present their closing remarks
and future direction.
It is our hope that this book will benefit not only to researchers in the field
of orofacial pain and biomarkers but also clinicians, educators, and students
who are part of the whole community that are instrumental in the develop-
ment of new knowledge. This work has been possible only because all the
authors were willing to invest time and energy on top of their usual duties and
we want to express our sincere gratitude to each of them. Finally, we want to
thank the publisher and more specifically Elektra McDermott and her staff
who supported us all along this endeavor.

Québec, Canada Jean-Paul Goulet

 Ana Miriam Velly
Contents

Part I Clinical and Epidemiological Aspects of Orofacial Pain

1 Orofacial Pain: Classification and Road Map to Clinical
Phenotypes������������������������������������������������������������������������������������������ 3
Jean-Paul Goulet and Alain Woda
2 Comorbidities in Individuals with Orofacial Pain and
Their Impact on Biomarkers���������������������������������������������������������� 21
Ana Miriam Velly and James Fricton

Part II Mechanisms of Chronic Orofacial Pain

3 Neurobiological Mechanisms of Chronic Orofacial Pain ������������ 35

Barry J. Sessle
4 Oral and Craniofacial Pain: Contribution of
Endogenous, Central Modulation Mechanisms���������������������������� 47
Laurence Bourgeais Rambur, Charles-Daniel Arreto, Claude Robert,
and Luis Villanueva

Part III Biomarkers in Orofacial Pain

5 Neurophysiologic Markers of Neuropathic Orofacial Pain���������� 65

Satu K. Jääskeläinen
6 Masticatory Muscle Pain Biomarkers�������������������������������������������� 79
Malin Ernberg
7 Molecular Temporomandibular Joint Pain Biomarkers�������������� 95
Per Alstergren
8 Genetic Biomarkers of Orofacial Pain Disorders ���������������������� 107
Ze’ev Seltzer and Scott R. Diehl
9 Serum, Synovial, and Salivary Biomarkers for
Orofacial Pain Conditions ������������������������������������������������������������ 119
Stergios Katsiougiannis, Varun R. Mallela,
Christopher A. Schafer, and David T. W. Wong

ix
x Contents

Part IV Study Designs and Statistical Analysis for the Identification

of Biomarkers, and Future Direction

10 Biomarkers in Epidemiologic Research: Definition,

Classification, and Implication ���������������������������������������������������� 135
Ana Miriam Velly, Shrisha Mohit, Hyman M. Schipper,
and Mervyn Gornitsky
11 Statistical Analysis in the Identification of Pain
Biomarkers ������������������������������������������������������������������������������������ 141
Russell Steele
12 Future Direction and Conclusion ������������������������������������������������ 147
Jean-Paul Goulet and Ana Miriam Velly
Index�������������������������������������������������������������������������������������������������������� 151
 Part I
Clinical and Epidemiological
Aspects of Orofacial Pain
 Orofacial Pain: Classification
and Road Map to Clinical
1
Phenotypes

Jean-Paul Goulet and Alain Woda

Abstract
The orofacial region consists of heterogeneous tissues that make diagnosing
and treating pain conditions a challenging task. Vital to these processes are
well-structured classification systems that cover the breadth of chronic oro-
facial pain conditions and provide diagnostic criteria to enhance our ability
to properly identify and categorize clinical events in an agreed pattern. A
revision of the classification systems for orofacial pain disorders developed
respectively by the International Association for the Study of Pain, the
International Headache Society, the American Academy of Orofacial Pain,
and the American Academy of Craniofacial Pain reveals a number of defi-
ciencies and inconsistencies ranging from terminology to the structure itself
and the set of diagnostic criteria. To improve communication and enable
effective collaborative work, we are at the crossroads for the development of
a new multiaxial classification system using ontological principles to build a
realistic and comprehensive representation of orofacial pain disorders. With
research focusing on pain biomarkers, optimizing the systematization of
data collection may contribute to identifying clinical phenotypes of chronic
orofacial pain conditions that have the most impact on patient life.

1.1 Introduction damage and pathobiological cause. What makes

it even more challenging for clinicians is the
Pain in the orofacial region is a puzzling health number and diversity of conditions for which
concern, particularly when the pain is persistent orofacial pain is a prominent symptom that makes
and devoid of any explanation in terms of tissue it difficult to distinguish many of these disorders
clinically. Population-based cross-sectional
J.-P. Goulet, DDS, MSD, FRCD (*) ­surveys have shown that a 1-month prevalence
Faculty of Dental Medicine, Université Laval, rate of self-reported orofacial pain ranges from
2420 Rue de la Terrasse, G1V 0A6, QC, Québec, 19% to 26% [1, 2]. In most instances sudden pain
Canada in the orofacial region has a clear somatic cause
e-mail: [email protected]
with overt clinical manifestations generally asso-
A. Woda, DDS, PhD ciated to recognizable pathophysiological pro-
Faculty of Odontology, Université d’Auvergne,
Clermont-Ferrand, France cesses. The diagnosis may not always be

© Springer-Verlag GmbH Germany 2017 3

J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI 10.1007/978-3-662-53994-1_1
4 J.-P. Goulet and A. Woda

straightforward; however, established treatment This chapter first presents what makes pain
modalities through dental procedures and phar- occurring in the orofacial region so intricate by
macological methods normally lead to complete evoking the various source and categories of per-
resolution of the pain with no major or prolonged sistent pain conditions while addressing issues
inconveniences. regarding the concept of chronicity. This is fol-
On the other hand, between 5% and 14% of lowed by an appraisal of the current classification
adults suffer from recurrent or persistent orofa- systems for orofacial pain disorders before focus-
cial pain with an onset going back months or ing finally on the most common clinical pheno-
even years before consulting [3, 4]. The inci- types of persistent orofacial pain which represent
dence of a new onset of chronic orofacial pain is target conditions for biomarker research.
estimated at 4.6% over a 2-year time span [3].
Middle-aged adults are more likely to be afflicted,
and the proportion of women outnumbers men by 1.2  he Orofacial Region
T
a ratio of 2:1. Chronic orofacial pain conditions as a Unique Body Part
are not uncommon, and yet effective treatments
are often limited by inaccurate diagnosis and Before going any further, it is important to recall
poorly understood mechanisms of the pain sig- that the anatomical confinement of pain in the
naling system when overt pathobiological pro- orofacial area corresponds to the region below
cesses remain elusive. In such a scenario, the orbitomeatal line, above the neck and ante-
treatment response is more generic than specific rior to the ears, including pain within the oral
and is greatly influenced by personal and envi- cavity [1]. Of significance is that this topograph-
ronmental factors if not by any chance. ical definition refers to the location of the pain
The study of biomarkers is one of many strate- whatever the source. For example, brain tumors
gies to reveal what can be singular about a disor- and neck problems represent potential source of
der or disease and to uncover mechanisms that orofacial pain that lies outside the anatomical
can contribute to better patient care. What we boundaries defined above. Such heterotopic
currently call biomarkers are characteristics that pains are commonly qualified “referred” or “pro-
can be objectively measured and evaluated as jected” orofacial pain conditions and must at
indicators of normal biological or pathogenic some point be considered in the differential
processes or pharmacological responses to a ther- diagnosis. While referred pain to the orofacial
apeutic intervention [5] (see Chap. 10). Common region can occur, the opposite also happens
chronic orofacial pain conditions with equivocal when the pain spreads outside the orofacial area
treatment response and a clear impact on the and becomes more “diffuse.”
patient’s quality of life are thus likely candidates What also makes the orofacial region unique
for biomarker research, bearing in mind the mul- are the highly specialized structures that lay in
tidimensional aspect of chronic pain which close proximity and receive complex sensory and
broadens the scope beyond the sole biological autonomic supply from the cranial and upper cer-
continuum to include the clinical pathway and, vical nerves to support a variety of specialized
more specifically, psychological and behavioral functions (taste, feeding, swallowing, speech,
domains. Current investigative paths and meth- smell, breathing, hearing, vision) that contribute
ods should focus on combinations of biomarkers to the general well-being of patients. Having
for a given condition rather than looking for an good knowledges of the various face and neck
answer through a single one. Hence, the scope of tissues and structures, such as the salivary glands,
measures for orofacial pain biomarkers goes muscles, nerves, major blood vessels, lymph
from clinic to genetic and includes physiological nodes, bones, teeth, mucosa, and sinuses, helps to
parameters, psychological or behavioral charac- address the arduous task of uncovering the source
teristics, imaging modalities, molecular and pro- of orofacial pain. Moreover, one must be aware
tein gradients, and genomics [6]. that activation of the parasympathetic nervous
1 Orofacial Pain: Classification and Road Map to Clinical Phenotypes 5

system (which results in swelling, flushing, lacri- nociceptive peripheral inputs, the opposite is also
mation, and rhinorrhea) is a prominent feature of true. Creating a mind state of tissue damage
a number of orofacial pain conditions [7]. The under hypnosis is enough to induce pain sensa-
fact that these manifestations may be confined to tions in the absence of nociceptive peripheral
the oral mucosa and not the skin increases the dif- inputs [13–15].
ference with similar conditions affecting other When orofacial pain is induced through the
parts of the body. For example, parasympatheti- activation of peripheral nociceptors, it signals the
cally induced redness is less visible in the mouth brain of the presence of stimuli that may result in
than on a limb. tissue damage, and as such the pain is self-­
From a neurophysiological and psychophysi- protective and possesses a biologic role. This sce-
cal perspective, studies show both similarities nario depicts a stimulus-dependent pain, namely,
and differences in the dynamic and specific “nociceptive pain,” which is usually short lasting.
responsiveness of the trigeminal system to tissue Common examples are sharp tooth pain elicited
injury and inflammation, as compared to the spi- when biting inadvertently on something hard or
nal system [8]. The many distinct orofacial tissue when drinking cold water. We learn by experi-
constituents that are candidate causes of acute ence to avoid orofacial pain linked to noxious
pain states can lead to hyperalgesic priming of mechanical and thermal stimuli. Another type of
the trigeminal pain system through cellular sig- protective pain driven by the activity of the
naling pathways at the primary nociceptor level, immune system follows tissue injuries or infec-
with subsequent changes in brain stem activity. tions, or is induced by autoimmune disorders.
Preclinical studies have clearly demonstrated that This gives rise to “inflammatory pain” which is
plastic changes at one or more levels of the pain better qualified as being adaptive [16, 17]. This
signaling pathways are likely to contribute to the pain has also a biologic role by promoting heal-
transition from acute to chronic pain [9–11]. ing and a functional role by signaling inappropri-
ate action to prevent further damage or discomfort
during the recovery process. Inflammatory pain
1.3 Type of Orofacial Pain can be acute, such as dental pain induced by pul-
pitis or apical infection, or chronic, as seen with
Orofacial pain is a sensory experience within a temporomandibular joint arthralgia associated
specific anatomical region, and as in any other with degenerative joint disease or rheumatoid
part of the body, it is perceived as a symptom that arthritis. As a general rule, “inflammatory pain”
is mostly tied to the belief that something is has a readily identifiable etiology and pathophys-
wrong. However, pain is not simply what goes on iological processes.
in the body part that is hurting but depends also There are instances when pain has no protec-
on brain activity. The International Association tive role and therefore no real purpose. The pain
for the Study of Pain (IASP) thus avoids linking is then disserviceable and represents a disease of
pain to a noxious stimulus by defining it as “an its own. This pain is labeled as being maladaptive
unpleasant sensory and emotional experience and may follow an injury to the nervous system
associated with actual or potential tissue damage, or result from a dysfunction caused by an
or described in terms of such damage” [12]. What impaired regulation of one or more components
best depicts pain as primarily a “brain activity” is of the neurobiological apparatus [18, 19].
the classic example of a patient who undergoes Maladaptive pain in the trigeminal region can be
minor surgery under hypnosis without receiving broadly categorized as being either neuropathic,
any local anesthesia. Although peripheral inputs dysfunctional, or neurovascular in nature.
still reach the brain, hypnosis enables the patient Neuropathic pain occurs when the pain is the
to exert some type of control on brain activity so consequence of injuries or damage to the nervous
they feel no pain [13]. While inhibition of pain system. This may occur following ­dentoalveolar
sensation can take place with no blockage of nerve encroachment during the placement of a
6 J.-P. Goulet and A. Woda

dental implant or following ­orthognathic surgery. better understanding of the etiology from a
Dysfunctional pain is the result of a malfunction ­biological, psychological, and behavioral perspec-
of the pain signaling, modulating, or analyzing tive that considers the impact of comorbid condi-
system in the absence of nerve injury. It is not a tions, as well as the role of personal beliefs and
stimulus-dependent pain and is often in no way emotional status as moderators or mediators of the
related to peripheral inflammation [20]. pain experience.
Conditions displaying features of dysfunctional
orofacial pain include burning mouth syndrome
and persistent idiopathic facial pain (see Chap. 1.4  hronicity and Orofacial
C
5). Neurovascular pain is unique to the head and Pain: An Evolving Concept
face region. Unlike the other pain types, it per-
tains to abnormal brain stem sensory processing Categorizing pain conditions as acute or chronic
following aberrant cortical activity or poorly is routine in clinical settings. Although this is a
understood mechanisms that activate the poste- widely accepted notion, new insights raise con-
rior hypothalamus [21]. Neurovascular orofacial cerns regarding the practice of resorting on tem-
pain is likely the consequence of episodic neuro- poral cutoffs to distinguish acute from chronic.
logic conditions that share clinical features with Not surprisingly, the definition of chronicity var-
migraine and trigeminal autonomic cephalalgia. ies among clinicians, researchers, patients, and
As opposed to the classical migraine and cluster healthcare administrators. In most instances the
headache, the epicenter of neurovascular pain in different viewpoints concern the time elapsed
the face regards the distribution of the maxillary since the onset of the pain and less often the fre-
or mandibular branch of the trigeminal nerve. quency and severity of pain that persists and the
Furthermore, the classical autonomic signs and number of pain days over a predefined period.
symptoms that usually accompany these condi- Generally speaking, most endorse the IASP
tions are not as prominent [22]. definition that “chronic” denotes the “persistence
Better understanding and reliable means to of pain beyond the normal time of healing” [12].
identify pain mechanisms are key approaches to For clinical practicality, the IASP states that for
improve treatment strategies. Animal and human nonmalignant pain, a duration exceeding 3
studies have shown that chronic pain can be months is a reasonable time period, but for
induced or maintained by disturbed functions of research purposes, a duration of 6 months is
the nervous system [23]. Upregulation of neuronal deemed a more convenient point at which a pain
proteins through the selective alteration of gene state can be declared as being chronic. The notion
transcription can alter the excitability of second- of healing generally ties pain to tissue injury and
order brain stem neurons. Chronic pain can also the activation of pain pathways. It is well estab-
stem from a disturbance of the conditioned pain lished, however, that a malfunction of pain sig-
modulation system, or an alteration of brain pro- naling systems also occurs in the absence of
cesses through the hypothalamic-­pituitary-­adrenal tissue injury [20]. On the other hand, the
axis. Still, a degree of uncertainty remains as to International Headache Society (HIS) makes a
whether these pain mechanisms represent a true distinction between pain that is episodic and that
intrinsic malfunctioning of the pain pathways or which is chronic by adding a notion of frequency.
are the result of a subclinical biological process In headache terminology, the qualifier “chronic”
that escapes detection with existing test methods. applies to primary headache disorders, when
Assessing chronic pain mechanisms with minimal attacks occur repeatedly for more than 3 months
accuracy in the clinical setting is a difficult task, on more days than not. The only exception per-
and little is known regarding the reliability and tains to trigeminal autonomic cephalalgias, where
validity of clinical features potentially associated “chronic” is used only when the disorder has
with m ­ alfunction at the peripheral and central been unremitting for more than 1 year. It is clear
­nervous system levels. Parallel efforts to improve that how we currently define chronicity by a
patient management will be successful through a range of calendar-based periods is largely
1 Orofacial Pain: Classification and Road Map to Clinical Phenotypes 7

r­eminiscent of heuristic views and there is no developed by mandated committees and groups
­universally accepted operational definition to sat- of experts. Although everyone aims to be as close
isfy everyone. to the truth as it can be, the reality that is depicted
Aside from the intrinsic nature of what we tradi- in a classification system depends on the pur-
tionally call chronic pain, it has been suggested that poses and mission of a group or organization.
the lack of significant improvement to render a pain When comparing classification systems, one can
condition more endurable has prognostic relevancy see that similar terms are not utilized following
and may indeed require consideration [24]. A defi- the same reasoning, similar entities are given dif-
nition of chronic based solely on duration (number ferent names or case definitions, and not uncom-
of pain days) is far from being optimal, because it monly distinctive entities may share the same
is difficult to apply to intermittent, recurring pains name. Various views are also expressed by the
and provides no clues as to the clinical significance way classes that regroup the different entities
of long-lasting pain. A reappraisal of what chronic belonging to a classification system are labeled
pain is should better capture the multidimensional and structured.
experience that goes beyond the severity and dura- A common pitfall seen in clinical and research
tion of the pain and also includes the behavioral setting is the misuse of terms such as “temporo-
and psychological aspects that influence the course mandibular disorder” (TMD) and “neuropathic
and the patient’s well-being. pain” which gives the false impression of dealing
New knowledge on the plasticity of the nervous with a specific diagnosis. In fact these terms des-
system has shifted our focus toward the transition ignate a number of clinical entities that must be
between acute and chronic pain and the possibility distinguished from one another for appropriate
that certain pain conditions may be chronic from prognosis appraisal and treatment decisions.
the onset. For example, it has been shown that Such misuse is counterproductive as it perpetu-
acute inflammatory insults and environmental ates ambiguity in the message one wants to con-
stressors produce a long-lasting hypersensitivity of vey regarding the true diagnosis. Not all the
peripheral nociceptors to pro-inflammatory cyto- organizations committed to the relief of temporo-
kines and that this hypersensitivity is later respon- mandibular pain and dysfunction agree on a com-
sible for a dramatically enhanced hyperalgesic mon list of clinical entities, and once again it
response to subclinical traumatic events [11]. The emphasizes that how one sees the reality is
clinical course of burning mouth syndrome that is greatly influenced by its own background and
described later may represent one among other beliefs.
similar conditions that does not show a transition As illustrated in Table 1.1, the list of mastica-
from acute to chronic. Broadening the case defini- tory muscle-related pain entities from different
tion of chronic pain beyond pain duration and fre- sources has undergone a significant number of
quency may thus provide new avenues for clinical changes over the years [25, 27–35]. Only myo-
phenotyping of orofacial pain conditions. It can be fascial pain and muscle spasm remain common to
noted, however, that the occurrence of a pain con- current classification systems. This supports the
dition that is dysfunctional from the onset has little different conceptual views experts have regard-
chance of being immediately diagnosed because no ing the etiology, pathogenesis, and mechanisms
somatic cause is uncovered by the patient or the of masticatory muscle pain disorders. With a
doctor. greater concerted effort, however, we may get
closer to a more consensual taxonomy. For exam-
ple, “protective co-­ contraction” and “muscle
1.5  erminology and Orofacial
T splinting” are probably different names given to
Pain Entities the same phenomenon observed in a number of
pain-related muscle conditions [36]. While this
We learn about the breadth of conditions respon- phenomenon may indeed exist physiologically,
sible for pain in the trigeminal region through its recognition as being a distinct clinical entity is
taxonomy and classification systems that are questionable.
8 J.-P. Goulet and A. Woda

Table 1.1 Past and current terminology for masticatory muscle disorders
W. E. Bell
(1982) (1986)
Protective co-contraction Protective muscle splinting
Myospasm Muscle spasm
Myositis Muscle inflammation
American Academy of Orofacial Pain
(1990) (1993) (1996) (2008) (2014)
Myofascial pain Myofascial pain Local myalgia Local myalgia See DC/TMD
Myositis Myositis Myofascial pain Myofascial pain
Sprain Myospasm Myospasm Centrally mediated
Reflex splinting Protective muscle Myositis myalgia
spasm Myospasm
Myositis
Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD)
(RDC/TMD 1992) (DC/TMD 2014)
Myofascial pain Myalgia
Myofascial pain with limited opening  Local myalgia
 Myofascial pain
 Myofascial pain with referral
Tendonitis
Spasm
Myositis
American Academy of Craniofacial Pain [25]
(Extracapsular TMDs) (Adapted from Pertes and Gross [26])
Myalgia Acute
Muscle splinting  Myositis
Muscle spasm  Reflex muscle splinting
Myositis  Muscle spasm
Trismus Chronic
Myofascial pain syndrome  Myofascial pain
Temporal tendonitis  Muscle contracture
Ernest syndrome  Hypertrophy
 Myalgia secondary to systemic disease
Okeson (2014, [27])
Protective co-contraction Myofascial pain
Local muscle soreness Myospasm
Centrally mediated myalgia Systemic chronic myalgia
Bell [28]; de Leeuw [29]; de Leeuw and Klasser [30]; Dworkin and LeResche [31]; McNeill [32, 33]; Okeson [27, 34];
American Academy of Craniofacial Pain [25]; Pertes and Gross [26]; Schiffman et al. [35]

On the other hand, consensus and standardiza- c­ ondition. The fact that the American Academy
tion go beyond the sole denomination of specific of Orofacial Pain (AAOP) and the International
clinical entities and extend to the case definition, RDC/TMD Consortium Network are now endors-
key clinical features, and diagnostic criteria. ing the recently published expanded taxonomy for
“Myofascial pain” is a clinical entity listed in TMD and the new validated diagnostic criteria for
most classification systems, yet the diagnostic cri- the most common disorders is a move in the right
teria vary substantially across organizations; some direction, and hopefully other organizations will
clearly refer to the presence of an active muscle follow suit [30, 35, 37].
trigger point, whereas for others, it remains a non- Another important aspect is the impact that new
issue [25, 27, 35]. Comparing research data is knowledge and understanding have on current ter-
therefore compromised, which unfortunately minology. At the 2011 World Workshop on Oral
hinders progress in our u­nderstanding of the
­ Medicine, a committee of international experts was
1 Orofacial Pain: Classification and Road Map to Clinical Phenotypes 9

given the task of conducting a systematic review of Before the emergence of multivariate analysis
the pathophysiology of chronic myalgia of the mas- and ontology principles, taxonomic entities were
ticatory system [38]. Although the committee rec- empirically classified by groups of experts using
ognized that the existing terminology “myofascial preconceived theoretical approaches based on
pain” was widely accepted, they expressed concern distinguishing features that best fitted the pur-
regarding the accuracy of the denomination, which pose of the classification system. For practicality
implies that the pain arises from muscle and fascia. in the clinical setting, signs and symptoms, body
The committee suggested a name change for the region, and structures are thus frequently used.
descriptive term “Persistent Orofacial Muscle Pain” The reality of orofacial pain disorders is unique
(POMP), terminology reminiscent of ontological but not everyone sees it the same way; conceptual
principles. Whether POMP is a “particular,” there- differences are therefore responsible for diver-
fore singular, entity or designates rather a wider gent views of how entities are defined, labeled,
“type” of orofacial muscle pain is not really clear and organized. With data that best reflects the
and remains a legitimate question [39]. Obviously, reality, cluster analysis is regarded as the most
any change in terminology must be exercised with appropriate first step to establish an evidence-­
great caution, as it risks adding confusion for based classification system [41]. Clinical entities
researchers and even more so for nonspecialized making up each cluster are likely to show more
practitioners. It should at least not be undertaken homogeneity, and a better hierarchical order of
without revisiting the other entities belonging to the the taxonomy is thus expected. Except for the
same taxonomic cluster, thereby enabling everyone taxonomy proposed by Woda et al. [42] for
to understand what it really means and how it chronic orofacial pain and by Pimenta e Sylva
relates to the other entities. In short, unless research Machado et al. [43] for TMD patients, all of the
brings forth decisive new data, knowledge, or treat- classification systems elaborated by professional
ment, avoiding a change of denomination or tax- organizations are empirical and expert-driven
onomy may represent the best option. [42, 43]. Moreover, entities are defined according
to theoretical concepts, and the diagnostic criteria
are subsequently validated [31, 35, 44].
1.6  urrent State of Operational
C The strengths and weaknesses of existing meth-
Classification Systems ods for taxonomic research and classification pur-
for Orofacial Pain Disorders poses are described in detail elsewhere [41].
Obviously, all have limitations, yet it is possible to
A carefully reasoned classification system depicts use them in a complementary way. Briefly, cluster
the reality and the many faces of a domain and analysis (multivariate analysis) enables us to iden-
how it is organized. It shows the array and diver- tify which entities actually exist in a breadth of
sity of diagnoses, assists in treatment decision orofacial pain characterized by a broad continuum
making, and provides insight regarding progno- containing a combination of signs and symptoms
sis. It is a communication tool as well as an with largely overlapping clinical depictions.
invaluable source of information for research. On Although this analysis should be used first, this
the other hand, a classification system is also requires a large representative sample of patients.
dynamic and is exposed to changes as progress is Even when this condition is satisfied, entities with
made through the accumulation of new data. low prevalence rates cannot be extracted easily
Development and updating, however, have more and or not at all if very rare. The method of clas-
to do with coherence and pragmatism than with sifying subjects according to diagnostic criteria
the absolute truth. The inherent guiding princi- should follow the cluster analysis, when an entity
ples include biological plausibility, exhaustive- has already been singled out. Thus far, the major
ness, mutual exclusivity of items, reliability, and issue in all studies is that groups of subjects with a
simplicity of use for anyone within or gravitating presumed condition are already preselected prior
around a specialized field [39, 40]. to their characterization by diagnostic criteria.
10 J.-P. Goulet and A. Woda

When testing the sensitivity and specificity of a set syndromes of the head and neck” and are classi-
of diagnostic criteria for a given entity, subjects are fied into five subcategories, each listing orofacial
chosen based on preexisting inclusion criteria; pain conditions specific to an organ system or
clearly, this approach is suggestive of circular rea- body structure regardless of pathobiological pro-
soning. As seen with cluster analysis, a number of cesses (Table 1.2).
cases will be left unclassified by diagnostic crite- Each pain condition can be coded according to
ria, particularly clinical entities that have a broad five axes referring respectively to anatomical
spectrum of clinical presentations. The advantage region, system involved, temporal characteristic,
of using diagnostic criteria is undeniable, as it intensity, and etiology. The IHS classification
allows for the standardized inclusion of subjects in system (ICHD-3) pertains to primary and sec-
clinical studies. Thus, an ideal classification ondary headaches (Part I and Part II) as well as
should rely on the association of the two methods painful cranial neuropathies and other facial
described above. Existing entities should be ini- pains not causing secondary headaches (Part III)
tially identified through cluster analyses, followed (Table 1.3).
by a definition of their diagnostic criteria. That Despite the progress in recent decades in the
said, however, these two methods would still leave clinical diagnosis of chronic orofacial pain, we
many entities with a low prevalence rate without a have seen very few changes to the IASP and IHS
label or description. There is therefore an unavoid- classification systems. While more similarities
able need for a more subjective approach in which than differences would generally be expected,
expert opinion (another name for authority-based both taxonomies differ in several regards. First,
consensus) plays the primary role. Expert opinion each classification system includes a number of
makes it possible to propose a more exhaustive conditions that are exclusive to them; second, the
classification, yet it cannot rely on science only. In number of conditions listed under similar subcat-
addition, authority-­based consensus is not auto- egories differs; and finally, similar clinical enti-
matically less subjective when carried out by a ties have different denominations. Except for
committee than when proposed by an individual. osteoarthritis and rheumatoid arthritis, the IASP
Finally, recognizing ontology as the basis for a continues to enclose all temporomandibular pain
coherent description of a clinically and scientifi- disorders under the generic diagnosis
cally established reality has given rise to new rules “Temporomandibular Pain and Dysfunction
and recommendations regarding the classification Syndrome,” thereby failing to acknowledge other
and denomination of orofacial pain disorders. A distinctive entities. For neuropathic pain of the
detailed description of the ontology concept lies head and neck, the IASP has a list of 16 condi-
beyond the scope of this chapter and is covered in tions, whereas 21 are included in the IHS/ICHD-3
a recent publication [39]. and only six denominations are common to both
Owing to their respective missions, two inter-
national organizations include orofacial pain dis- Table 1.2 Classification structure of orofacial pain syn-
orders in their classification systems, namely, the dromes by the International Association for the Study of
International Association for the Study of Pain Pain (IASP) (Merskey and Bugduk [12])
(IASP), with its multiaxial classification and cod- Relatively localized syndromes of the Number of
ing system (http://www.iasp-pain.org/files/ head and neck entities
C o n t e n t / C o n t e n t Fo l d e r s / P u b l i c a t i o n s 2 / 1. Neuralgia of the head and neck 16
FreeBooks/Classification-of-Chronic-Pain.pdf), 2. Craniofacial pain of musculoskeletal 7
origin
and the International Headache Society (IHS),
3. Lesions of the ear, nose, and oral cavity 13
with its classification of headache disorders 4. Primary headache syndromes, vascular 16
(ICHD-3) [12, 45]. The IASP categorizes pain disorders, and cerebrospinal fluid
syndromes into generalized or localized condi- syndromes
tions. Disorders giving rise to orofacial pain 5. Pain of psychological origin in the 3
appear under the heading “Relatively localized head, face, and neck
1 Orofacial Pain: Classification and Road Map to Clinical Phenotypes 11

Table 1.3 Classification structure of orofacial pain enti- gory. For example, “Glossodynia and sore
ties by the International Headache Society (ICHD-­ 3)
mouth” listed by the IASP under “Lesions of the
(International Headache Society Classification Committee
[45]) ear, nose, and oral cavity” refers to “Burning
mouth syndrome” found in the ICHD-3 under
CATEGORY 11: Headache or facial pain attributed to
disorder of the cranium, neck, eyes, ears, nose “Painful cranial neuropathy and other facial
sinuses, teeth, mouth, or other facial or cervical pain.” Additional joint efforts between organiza-
structure tions could easily resolve many of these existing
11.1–11.9: Headache and facial pain attributed to differences, for everyone’s benefit.
disorder from the sources above or to other disorder
The IASP and IHS taxonomies are falling
CATEGORY 13: Painful cranial neuropathies and
other facial pains
short of fulfilling the needs of clinicians and
13.1 Trigeminal neuralgia researchers in the field of orofacial pain [46]. The
Classical trigeminal neuralgia diagnostic criteria they propose are mostly
 Classical trigeminal neuralgia, purely paroxysmal derived from empirical data, and although they
 Classical trigeminal neuralgia with concomitant may indeed have face and content validity, their
persistent facial pain validation awaits prospective field studies. The
Painful trigeminal neuropathy usefulness of these classification systems in the
 Painful trigeminal neuropathy attributed to acute diagnosis of chronic orofacial pain has been
Herpes zoster
recently studied. When the ICHD classification
 Post-herpetic trigeminal neuropathy
system was tested in a neurological tertiary care
 Painful posttraumatic trigeminal neuropathy
(PPTTN) center, up to 29% of patients with facial pain
 Painful trigeminal neuropathy attributed to multiple could not be classified [47]. Used in a dental
sclerosis (MS) plaque clinic for orofacial pain, the ICHD classification
 Painful trigeminal neuropathy attributed to a system yielded a definitive diagnosis for only
space-occupying lesion 56% of patients; not surprisingly, the major
 Painful trigeminal neuropathy attributed to other ­limitation regarded the diagnosis of pain-related
disorder
temporomandibular disorders [48]. Obviously, a
13.2 Glossopharyngeal neuralgia
referral to the expanded taxonomy for temporo-
13.3 Nervus intermedius (facial nerve) neuralgia
Classical nervus intermedius neuralgia
mandibular disorders codeveloped by the
Nervus intermedius neuropathy attributed to Herpes International RDC/TMD Consortium Network
zoster (http://www.rdc-tmdinternational.org) and the
13.4 Occipital neuralgia American Academy of Orofacial Pain could eas-
13.5 Optic neuritis ily fill this gap [35, 37]. The expanded TMD tax-
13.6 Headache attributed to ischaemic ocular motor onomy stems from a multisite project that
nerve palsy addressed the validity of the Research Diagnostic
13.7 Tolosa-Hunt syndrome Criteria for Temporomandibular Disorders
13.8 Paratrigeminal oculosympathetic (Raeder’s)
(RDC/TMD) published by Dworkin and
syndrome
13.9 Recurrent painful ophthalmoplegic neuropathy
LeResche in 1992 [31, 44].
13.10 Burning mouth syndrome (BMS) Briefly, the RDC/TMD is an empirically
13.11 Persistent idiopathic facial pain (PIFP) derived dual-axis classification system for the
13.12 Central neuropathic pain most common TMDs that is based on the bio-
Central neuropathic pain attributed to multiple sclerosis psychosocial model of pain. Although primar-
(MS) ily intended for research purposes, the RDC/
Central post-stroke pain (CPSP) TMD gained acceptance among clinician who
started using them in clinical setting. Axis I
classification systems. These discrepancies led allows to yield a physical diagnosis for the most
the IASP to edit a crosswalk to the classification common pain and non-pain-related TMDs by
of the IHS for conditions that have a different applying diagnostic criteria derived from the
name or are classified under a different subcate- history and clinical examination. Axis II on the
12 J.-P. Goulet and A. Woda

other hand enables to assess and grade TMD AACP regroups craniofacial pain conditions
pain-related disability. The multisite Validation under six headings (Table 1.4). The AACP clas-
Project that assessed the criterion validity of sification of TMDs is adapted from Pertes and
the original Axis I RDC/TMD led to what is Gross [26]; however, a different list of muscle
now known as the Diagnostic Criteria for disorders appears under “Extracapsular TMDs”
Temporomandibular Disorders (DC/TMD) that (Table 1.1) [26]. All of the TMDs included in the
were recently implemented for use in clinical expanded TMD taxonomy do not appear in the
and research setting [35]. The newly validated AACP classification, and a number of conditions
Axis I diagnostic criteria for the most common bear a different name. Moreover, for common
temporomandibular disorders are now part of TMDs, none of the diagnostic criteria have been
the expanded TMD taxonomy that also includes field-tested, and those listed for myalgia repre-
less common disorders. sent potential causes rather than key elements
The American Academy of Orofacial Pain specifically linked to the nature of the condition.
(AAOP) and the American Academy of For headache disorders and neuralgias of the
Craniofacial Pain (AACP) are professional orga- head and neck, the AACP refers to the IHS clas-
nizations that provide a scheme for classifying sification system and the IASP taxonomy,
orofacial pain through their official publications respectively.
[25, 30]. The AAOP assorts orofacial pain condi- Finally, the classification system developed by
tions to six major categories and 15 subcategories Okeson integrates both a physical and a psycho-
referring primarily to pain source (Table 1.4) [30]. logical axis [27]. The structure for the physical
For temporomandibular disorders, the AAOP axis uses a dichotomous approach that defines at
follows the expanded TMD taxonomy and refers the outset orofacial pain as being either “somatic”
to the ICHD-3 classification system for head- or “neuropathic,” with the former being further
ache disorders and painful cranial neuropathies, categorized into “superficial or deep pain” and
thus avoiding the pitfall of inconsistencies. The the latter into “episodic or continuous pain.” The

Table 1.4 Classification structure of the American Academy of Orofacial Pain (AAOP) and the American Academy of
Craniofacial Pain (AACP) (de Leeuw and Klasser [5]; American Academy of Craniofacial Pain [19])
AAOP AACP
1. Intraoral pain disorders 1. Extracapsular temporomandibular disorders
Odontogenic pain Muscles disorders
Non-odontogenic pain Ligament/tendon disorders
Oral mucosal pain
2. Temporomandibular disorders (expanded taxonomy) 2. Headache pain
Temporomandibular joint disorders Primary headache (ICHD list)
Masticatory muscle disorders Secondary headache (ICHD list)
3. Extracranial causes of orofacial pain and headaches 3. Neuralgia of the head and face
Pain stemming from tissues or organs in the head and neck (IASP list)
Pain stemming from systemic disease
4. Neuropathic pain (ICHD list) 4. Temporomandibular disorders
Episodic neuropathic pain Adapted from Pertes and Gross [26]
Continuous neuropathic pain
Dysesthesia
5. Primary headache disorders (ICHD list) 5. Additional structures that can cause
Migraine craniofacial pain
Tension-type headache Eye pain
Cluster headache and other trigeminal autonomic cephalalgias Ear pain
6. Vascular and nonvascular intracranial cause of orofacial 6. Non-odontogenic intraoral pain disorders
pain (ICHD list) Cutaneous and mucogingival pain
Headache associated with vascular intracranial disorders BMS
Headache associated with nonvascular intracranial disorders Glossodynia
1 Orofacial Pain: Classification and Road Map to Clinical Phenotypes 13

next levels regroup orofacial pain conditions orofacial region. As defined by the DC/TMD,
under one of several categories based on tissue or myalgia is a clinical entity characterized by
system involved. pain of masticatory muscle origin affected by
jaw movement, function, or parafunction, and
replication of this pain occurs with provocation
1.7  ommon Chronic Orofacial
C testing of the masticatory muscles. When this
Pain Entities and Clinical pain is not better accounted for by another pain
Phenotypes for Biomarker diagnosis, the recently validated diagnostic
Research criteria show false-positive and false-­negative
rates of 1% and 10% respectively [35]. Other
The starting point for the study of pain biomark- denominations found in the literature for
ers is selecting an entity from every potential dis- “myalgia” as per the DC/TMD include local
order. Empirical data from cross-sectional studies muscle soreness, chronic myalgia, masticatory
show that only a limited number of entities myofascial pain, and persistent orofacial mus-
account for the most common chronic orofacial cle pain [22, 27, 38, 42]. Patients with mastica-
pain conditions and these can be regrouped under tory muscle myalgia complain mostly of a
either temporomandibular disorders or neuro- unilateral dull aching pain in the cheek area,
pathic pain disorders [1, 4, 49–51]. TMD myal- body, and angle of the mandible which may
gia and TMD arthralgia are conditions that extend to the ear and forehead. Headache is a
frequently coexist and present overlapping mani- frequent associated complaint with the involve-
festations. On the other hand, atypical odontalgia ment of the temporalis muscle. Duration,
(persistent dentoalveolar pain disorder), burning severity, and fluctuation of the pain during the
mouth syndrome, and persistent idiopathic facial day tend to vary, as some patients report their
pain pertain to the category of neuropathic pain worse pain upon awakening in the morning,
disorders. What these five conditions have in while others claim the pain builds up as the day
common are the increased odds in females rela- goes on [22, 38, 42].
tive to males, the poor correlation between physi- The systematic palpation of the masseter and
cal findings and the level of pain reported, no temporalis muscles with at least 1 kg of pres-
known etiology, a poorly understood pathophysi- sure for 5 s makes it possible to identify three
ology, and the significant psychosocial and psy- subtypes of myalgia patients [35]. Whether the
chological impact on patient life. Many will lump pain evoked by palpation remains localized
these conditions under the label “Idiopathic under the finger pad, spreads inside the muscle,
chronic orofacial pain syndromes”; however, or is referred outside the confinement of the
enough distinguishing features exist between muscle boundaries, the diagnostic subtypes are
them when the location, character, temporal pat- respectively local myalgia, myofascial pain,
tern, and modifying factors of the pain are com- and myofascial pain with referral (Table 1.5).
pared [22, 42]. A brief description of these Only myalgia, as an umbrella disorder, and
conditions is of particular interest to highlight myofascial pain with referral have validated
potential clinical phenotypes that may help the diagnostic criteria with a respective sensitivity
planning and selection processes of patients for of 0.90 and 0.86 and specificity of 0.99 and
research purposes. 0.98. The likelihood of different pain mecha-
nisms and response to treatment are among the
reasons to support the study of the three myal-
1.7.1 TMD Myalgia gia subtypes. Despite the fact that it remains a
highly controversial subject, more attention
Temporomandibular myalgia represents the should be paid to muscle trigger points, as
most common diagnosis among all of the defined for myofascial pain syndrome occur-
chronic p­ain-­
related disorders affecting the ring in other body parts [52, 53]. The “active”
14 J.-P. Goulet and A. Woda

Table 1.5 DC/TMD for myalgia and its subtypes and arthralgia (Schiffman et al. [35])
Diagnostic criteria for Myalgia
History positive for both: Clinical examination positive for both:
1. Pain in the jaw, temple, in the 1. Confirmation of pain locations(s) in the temporalis or masseter muscle(s);
ear, or in front of ear; 2. Report of familiar pain in the temporalis or masseter muscle(s) with at least
2. Pain modified with jaw one of the following provocation tests:
movement, function or  (a) Palpation of the temporalis or masseter muscle;
parafunction  (b) Maximum unassisted or assisted opening movements(s)
The pain is not better accounted for by another pain diagnosis
Subtypes of myalgia as differentiated by provocation testing with palpation
Local myalgia Myofascial pain Myofascial pain with referral
1. History criteria as for 1. History criteria as for “Myalgia”; 1. History criteria as for “Myalgia”;
“Myalgia”; 2. Clinical examination criteria as for 2. Clinical examination criteria as
2. Clinical examination criteria “Myalgia”; AND for “Myalgia”; AND
as for “Myalgia”; AND (a) Report of pain spreading beyond the (a) Report of pain at a site
(a) Report of pain localized to site of palpation but within the beyond the boundary of the
the site of palpation boundary of the muscle muscle being palpated
The pain is not better accounted for by another pain diagnosis
Diagnostic criteria for arthralgia
History positive for both: Clinical examination positive for both:
1. Pain in the jaw, temple, in the 1. Confirmation of pain locations(s) in the area of the TMJ(s);
ear, or in front of ear; 2. Report of familiar pain in the TMJ with at least one of the following
2. Pain modified with jaw provocation tests:
movement, function or  (a) Palpation of the lateral pole or around the lateral pole;
parafunction  (b) Maximum unassisted or assisted opening, right or left lateral, or protrusive
movements(s)
The pain is not better accounted for by another pain diagnosis

muscle trigger point phenomena appear to be 1.7.2 TMJ Arthralgia

associated with local changes in the ­biochemical
milieu, which may contribute to complex neu- Temporomandibular joint arthralgia corresponds
robiological mechanisms in the peripheral and to joint origin pain felt in front of or inside the ear
central nervous systems [54–56]. These active that is affected by jaw movement, function, or
muscle trigger points have been documented in parafunction, and replication of this pain occurs
the masseter and temporalis muscle of patients with provocation testing of the TMJ. To that end,
with chronic masticatory muscle myalgia and familiar joint pain should be evoked during full
are thought to develop from latent trigger points and assisted mandibular opening or by palpation
in response to altered muscle demand because of the lateral pole of the TMJ with at least 0.5 kg
of overload, overuse, or prolonged contraction of pressure for 5 s while the mandible is in a com-
[57, 58]. Current views regarding other possible fortable position or palpation around the lateral
etiologies include such extrinsic factors as pole with a pressure of 1 kg for 5 s when the man-
trauma, anxiety, and adverse environmental dible is in a forward position. The recently vali-
conditions [59]. dated DC/TMD for TMJ arthralgia has a
Aside from active trigger points that repro- sensitivity of 0.89 and a specificity of 0.98 when
duce the patient’s orofacial pain, potential candi- the pain is not better accounted for by another
dates for clinical phenotype of myalgia subtypes orofacial pain diagnosis (Table 1.5). Contrary to
are concomitant arthralgia and neck pain, level of TMJ arthritis, a diagnosis of arthralgia means no
physical and psychological disabilities, wide- clinical signs of edema, erythema, and/or
spread pain and comorbid conditions, extraterri- increased temperature associated with joint
torial allodynia, and hyperalgesia determined by inflammation or infection. TMJ arthralgia can
quantitative sensory testing [60–63]. exist by itself with no other joint disorder;
1 Orofacial Pain: Classification and Road Map to Clinical Phenotypes 15

h­ owever, the presence of a concomitant disk dis- filling, and despite negative clinical and radio-
placement or joint disease may suggest a differ- graphic findings for apical periodontitis, a series
ent etiology, clinical course, and prognosis. of treatments usually follow because the pain
Moreover, TMJ arthralgia is commonly seen in does not go away. Hence, in many instances, the
conjunction with chronic TMD myalgia [64, 65]. painful tooth shows a technically successful
Hence, for research purposes, different clinical root canal treatment subsequent to several other
phenotypes of TMJ arthralgia may exist, with equally successful ones. Moreover, before a
such possible discriminating factors as (1) pain at diagnosis of AO is finally made, some patients
rest and/or during jaw function, (2) concomitant may elect to undergo apical surgery or an extrac-
diagnosis of another TMD, (3) history of jaw tion because they are convinced that it is a tooth-
injury or trauma, and (4) degree of jaw disability related pain due to an occult odontogenic
and psychosocial impact. These distinctive fea- inflammation [69, 70].
tures may prove to be useful in uncovering more AO may thus have one of three clinical pre-
specific pain biomarkers. sentations and that is pain to (1) a tooth with a
vital pulp whether it has a filling or not, (2) a
devitalized tooth with a technically successful
1.7.3  typical Odontalgia (AO) or
A root canal treatment, or (3) an edentulous site
Persistent Dentoalveolar Pain where the presumed offending tooth was located.
Disorder (PDAP) All too frequently, AO has been a wastebasket
diagnosis for any unexplainable toothache by a
The IASP defines “atypical odontalgia” under the local factor, with no consideration given to vari-
heading “Odontalgia: Toothache 4,” as tooth pain ous forms of heterotopic tooth pain. Conditions
not associated with lesions. According to the besides the one already mentioned above that
IHS, AO represents a more localized intraoral must be excluded by appropriate investigations
subform of “persistent idiopathic facial pain” include referred cardiac pain, cluster headache,
(PIFP) or a subform of “painful posttraumatic tri- and hemicrania continua [71, 72]. Therefore, an
geminal neuropathy” (PPTTN), two nosologic effective diagnosis of AO or more appropriately
entities listed under the heading of “Painful “primary PDAP” signifies that all local and
Cranial Neuropathies and Other Facial Pains.” remote causes have been ruled out and that the
Other terms used to define AO have included tooth pain cannot be explained by another diag-
phantom tooth pain and idiopathic tooth pain. nosis. While there are no universally accepted
More recently and using an ontologically based and validated diagnostic criteria for this subtype
taxonomic approach, persistent dentoalveolar of non-odontogenic toothache, the one proposed
pain disorder (PDAP) was suggested for tooth by Nixdorf et al. [66] for PDAP subtypes repre-
pain of non-odontogenic origin [66]. To differen- sents the best available alternative (Table 1.6).
tiate PDAP caused by nondental factors such as Distinctive phenotypes of primary PDAP (AO)
facial trauma, dental procedures, trigeminal neu- may however exist based on response to local
ralgia, migraine toothache, or post-herpes zoster anesthetic, somatosensory profile determined by
infection from PDAP arising in the absence of intraoral quantitative sensory testing, psychoso-
thereof PDAP is subdivided into primary and sec- cial disability, and the presence of psychiatric
ondary with the former referring to unexplained comorbidity [74, 75].
or idiopathic cases (primary PDAP).
Typically, patients with AO have persistent
pain involving a single tooth or site where a 1.7.4 Burning Mouth Syndrome
tooth has been extracted, and for which clinical
and radiographic investigations reveal no hard According to the International Headache Society
and soft tissue pathologies [67, 68]. At the out- and the International Association for the Study of
set, the presumed offending tooth often has a Pain, burning mouth syndrome (BMS) is a dis-
16 J.-P. Goulet and A. Woda

Table 1.6 Diagnostic criteria for persistent dentoalveo- and sore mouth.” The various denominations
lar pain (PDAP), burning mouth syndrome (BMS), and
given to this condition over the years include sto-
persistent idiopathic face pain (PIFP)
matodynia, stomatopyrosis, glossopyrosis, and
Diagnostic criteria for persistent dentoalveolar pain
primary BMS. Only the ICHD-3 provides a set of
(Atypical odontalgia) (Nixdorf et al. [66])
operationalized diagnostic criteria, although their
A. Persistent pain (including dysesthesia) present at
least 8 h per day, 15 days or more per month for 3 or reliability and validity have yet to be tested in
more months field studies (Table 1.6).
B. Localized in the dentoalveolar region(s), and The burning pain in BMS is usually bilateral
C. Not caused by another disease or disorder
and begins on the anterior third of the dorsal sur-
Primary Secondary
Not in close temporal In close temporal
face of the tongue. It may also involve other intra-
relationship with a causal relationship with a causal oral sites, most likely the labial mucosa and the
event event anterior palate. BMS must be distinguished from
Diagnostic criteria for Burning Mouth Syndrome the symptoms of burning mouth caused by local
International Headache Society Classification and systemic disorders often referred to as “sec-
Committee [73]
ondary burning mouth syndrome” [76, 77]. In such
A. Oral pain fulfilling criteria B and C
B. Recurring daily for >2 h per day for >3 months cases, mucosal changes are usually detected, with
C. Pain has both of the following characteristics: such possible causes as denture-­related mechanical
 1. Burning quality irritation, candida infection, allergic mucosal reac-
 2. Felt superficially in the oral mucosa tions, autoimmune mucosal or salivary gland dis-
D. Oral mucosa is of normal appearance and clinical
examination including sensory testing is normal ease, posttraumatic neuropathy, drug-induced
E. Not better accounted for by another ICHD-3 hyposalivation, anemia, vitamin B12 or folic acid
diagnosis deficiency, diabetes, gastroesophageal reflux disor-
Diagnostic criteria for Persistent Idiopathic Face Pain der, and Parkinson disease [76, 78].
International Headache Society Classification
Of particular interest, BMS predominantly
Committee [73]
A. Facial and/or oral pain fulfilling criteria B and C
affects perimenopausal women, with a spontane-
B. Recurring daily for >2 h/day for >3 months ous onset unrelated to any precipitating events,
C. Pain has both of the following characteristics: and it usually starts from few months before to
 1. Poorly localized, and not following the several years after the beginning of the meno-
distribution of a peripheral nerve
 2. Dull, aching or nagging quality
pause [76, 79]. In addition, a majority of BMS
D. Clinical neurological examination is normal patients complain of dry mouth and altered taste
E. A dental cause has been excluded by appropriate sensation despite normal salivation and somato-
investigation sensory tests [80, 81]. Different temporal pat-
F. Not better accounted for by another ICHD-3
diagnosis
terns of burning pain have been described [82].
With the exception of stress, patients with BMS
usually report no aggravating factors. On the
tinctive nosologic entity characterized by a daily other hand, many will report that the burning sen-
recurring intraoral burning or dysesthetic sensa- sation disappears when they eat, chew gum, or
tion. Occurring on an intact intraoral mucosa, suck candies (personal unpublished data).
BMS is unexplained by local factors, systemic Moreover, disrupted sleep is rarely a problem,
disorders, laboratory abnormalities, or psychiat- and when questioned, BMS patients cannot tell if
ric disorders [76]. BMS is therefore a diagnosis the burning is present when they wake up during
made after excluding all potential causes, and not the night. BMS patients will frequently exhibit
all agree that this condition really fits the defini- considerable distress because of their fear of oral
tion of a true syndrome. This syndrome appears cancer. Finally, there is no significant evidence
under the heading of “Painful cranial neuropa- that anxiety, depression, and somatization prob-
thies” in the ICHD-3 and is listed in the IASP lems cause BMS; however, different psychoso-
classification system under “Group IV: Lesions cial profiles may exist and thus may influence the
of the ear, nose, and oral cavity” as “Glossodynia clinical course and treatment response.
1 Orofacial Pain: Classification and Road Map to Clinical Phenotypes 17

1.7.5 Persistent Idiopathic s­ensory abnormality profiles may indeed be

Facial Pain uncovered by quantitative sensory testing [85]. It
is also possible that PIFP patients with different
Formally called “atypical facial pain,” the IHS levels of psychosocial disability and the pres-
defines persistent idiopathic facial pain (PIFP) as a ence of psychiatric comorbidity represent dis-
distinct entity under the heading “Painful Cranial tinctive phenotypes [84].
Neuropathies and Other Facial Pains,” which is not
to be confused with the same denomination used
by many to qualify the entire group of unexplained Conclusion
chronic orofacial pain conditions. The IASP has The clinical reality of orofacial pain is complex
deleted atypical facial pain from its current taxon- due to the broad continuum of sign and symptom
omy, affirming that it was too often used to desig- combinations arising from heterogeneous tissues
nate a variety of conditions and thus could be better with different anatomical, electrophysiological,
diagnosed under either temporomandibular pain and pharmacological properties. Improving the
syndrome, atypical odontalgia, or pain of psycho- patient’s care flow and clinical pathway goes
logical origin. The IASP decision for not coming through the recognition of the disorder identity,
forth with another denomination and case defini- an understanding of the pain mechanisms, and
tion for “atypical facial pain” is questionable con- the delivery of proper treatment. Classification
sidering the occurrence of chronic orofacial pain in systems can help by giving insight into the
the general population that does not fit the descrip- breadth of orofacial pain conditions that exist but
tion of any existing clinical entity [68, 83, 84]. even more when providing validated diagnostic
Patients with PIFP usually present a dull, poorly criteria for better standardization of the decision
localized facial and/or oral pain that can have sharp process. More advancement will come through
exacerbations and be aggravated by stress. The pain the development of a multidimensional frame-
may be superficial but is most often deep, is uni- or work enabling to classify patient with persistent
bilateral, and does not follow the distribution of a pain by integrating within the biological contin-
peripheral nerve, as does trigeminal neuralgia or uum subsets of clinical phenotypes that take into
painful posttraumatic trigeminal neuropathy. No account the psychosocial and psychological
significant events are associated with the outset, but aspects of the pain experience. A better system-
in many instances, patients may report a history of atization and representation of data linked to
minor injury or trauma to the face, despite no clinical phenotypes can help reduce the blurring
observed deficit during a clinical neurological effect of less than optimal data collection that
examination. Most importantly, the diagnostic cri- results in poor signal-to-­noise ratios when con-
teria listed in the ICHD-3 indicates that the pain ducting research aiming to identify orofacial pain
must have been present daily for more than 2 h over biomarkers.
at least 3 months, that all dental causes have been
excluded, and that the pain cannot be accounted for
by another ICHD-3 diagnosis (Table 1.6). Also not
unusual, patients may report pain following palpa- References
tion of the masticatory muscles or the temporoman-
1. Macfarlane TV, Blinkhorn AS, Davies RM, Kincey J,
dibular joint, but when asked about the evoked
Worthington HV. Oro-facial pain in the community:
pain, they will say that it does not reproduce their prevalence and associated impact. Community Dent
pain. Oral Epidemiol. 2002;30(1):52–60.
Beyond being primarily a diagnosis of exclu- 2. Macfarlane TV, Blinkhorn AS, Craven R, Zakrzewska
JM, Atkin P, Escudier MP, et al. Can one predict the
sion based on the ICHD-3 criteria, it is likely
likely specific orofacial pain syndrome from a self-
that the central sensitization of the nervous completed questionnaire? Pain. 2004;111(3):270–7.
­system and the psychosocial impact of PIFP lead 3. Aggarwal VR, Macfarlane GJ, Farragher TM,
to a specific clinical phenotype. Thus certain McBeth J. Risk factors for onset of chronic oro-facial
18 J.-P. Goulet and A. Woda

pain--results of the North Cheshire oro-facial pain 20. Woda A. A “dysfunctional” pain group in addition to
prospective population study. Pain. 2010;149(2): the “neuropathic” and “nociception/inflammatory”
354–9. groups of orofacial pain entities? J Orofac Pain.
4. Leung WS, McMillan AS, Wong MC. Chronic orofa- 2009;23(2):89–90.
cial pain in southern Chinese people: experience, 21. Robert C, Bourgeais L, Arreto CD, Condes-Lara M,
associated disability, and help-seeking response. J Noseda R, Jay T, et al. Paraventricular hypothalamic
Orofac Pain. 2008;22(4):323–30. regulation of trigeminovascular mechanisms involved
5. Naylor S. Biomarkers: current perspectives and future in headaches. J Neuro Off J Soc Neuro.
prospects. Expert Rev Mol Diagn. 2003;3(5):525–9. 2013;33(20):8827–40.
6. Ceusters W, Nasri-Heir C, Alnaas D, Cairns BE, 22. Benoliel R, Sharav Y. Chronic orofacial pain. Curr
Michelotti A, Ohrbach R. Perspectives on next steps Pain Headache Rep. 2010;14(1):33–40.
in classification of oro-facial pain – part 3: biomarkers 23. Woolf CJ. Central sensitization: implications for the
of chronic oro-facial pain – from research to clinic. J diagnosis and treatment of pain. Pain. 2011;152(3
Oral Rehabil. 2015b; doi:10.1111/joor.12324. Suppl):S2–15.
7. Nixdorf DR, Velly AM, Alonso AA. Neurovascular 24. Von Korff M, Miglioretti DL. A prognostic approach
pains: implications of migraine for the oral and maxil- to defining chronic pain. Pain. 2005;117(3):304–13.
lofacial surgeon. Oral Max Surg Clin N Am. 25. American Academy of Craniofacial Pain. Craniofacial
2008;20(2):221–35, vi–vii. pain: a handbook for assessment, diagnosis and man-
8. Hargreaves KM. Orofacial pain. Pain. 2011;152(3 agement. Chattanooga: Chroma, Inc.; 2009.
Suppl):S25–32. 26. Pertes RA, Gross SG. Clinical management of tem-
9. Ferrari LF, Bogen O, Levine JD. Role of nociceptor poromandibular disorders and orofacial pain. Chicago:
alphaCaMKII in transition from acute to chronic pain Quintessence Books; 1995.
(hyperalgesic priming) in male and female rats. J 27. Okeson JP. Bell’s oral and facial pain. 7th ed. Chicago:
Neuro Off J Soc Neuro. 2013;33(27):11002–11. Quintessence Inc; 2014.
10. Price TJ, Inyang KE. Commonalities between pain 28. Bell WE. Temporomandibular disorders – guidelines
and memory mechanisms and their meaning for for assessment, diagnosis, and management. Chicago:
understanding chronic pain. Prog Mol Biol Transl Sci. Year Book; 1986.
2015;131:409–34. 29. de Leeuw R. Orofacial pain – guidelines for assess-
11. Reichling DB, Levine JD. Critical role of nociceptor ment, diagnosis, and management. 4th ed. Chicago:
plasticity in chronic pain. Trends Neurosci. Quintessence; 2008.
2009;32(12):611–8. 30. de Leeuw R, Klasser GD. Orofacial pain – guidelines
12. Merskey H, Bugduk N. Classification of chronic pain: for assessment, diagnosis, and management. 5th ed.
descriptions of chronic pain syndromes and defini- Chicago: Quintessence; 2013.
tions of pain terms, ASP task force on taxonomy. 31. Dworkin SF, LeResche L. Research diagnostic crite-
2nd ed. IASP: Seattle; 1994. ria for temporomandibular disorders: review, criteria,
13. Del Casale A, Ferracuti S, Rapinesi C, Serata D, examinations and specifications, critique. J Cranio­
Caltagirone SS, Savoja V, et al. Pain perception and mandibular Disord Facial Oral Pain. 1992;6(4):
hypnosis: findings from recent functional neuroimag- 301–55.
ing studies. Int J Clin Exp Hypn. 2015;63(2):144–70. 32. McNeill C. Temporomandibular disorders – guide-
14. Rainville P. Brain mechanisms of pain affect and lines for assessment, diagnosis, and management.
pain modulation. Curr Opin Neurobiol. 2002;12(2): 1st ed. Chicago: Quintessence; 1990.
195–204. 33. McNeill C. Temporomandibular disorders – guide-
15. Rainville P, Hofbauer RK, Bushnell MC, Duncan GH, lines for assessment, diagnosis, and management.
Price DD. Hypnosis modulates activity in brain struc- 2nd ed. Chicago: Quintessence; 1993.
tures involved in the regulation of consciousness. J 34. Okeson JP. Orofacial pain – guidelines for assess-
Cogn Neurosci. 2002;14(6):887–901. ment, diagnosis, and management. 3rd ed. Chicago:
16. Woolf CJ. What is this thing called pain? J Clin Invest. Quintessence; 1996.
2010;120(11):3742–4. 35. Schiffman E, Ohrbach R, Truelove E, Look J,
17. Woolf CJ, American College of P, American Anderson G, Goulet JP, et al. Diagnostic criteria for
Physiological S. Pain: moving from symptom control temporomandibular disorders (DC/TMD) for clinical
toward mechanism-specific pharmacologic manage- and research applications: recommendations of the
ment. Ann Intern Med. 2004;140(6):441–51. international RDC/TMD consortium network* and
18. Gustin SM, Peck CC, Wilcox SL, Nash PG, Murray orofacial pain special interest groupdagger. J Oral
GM, Henderson LA. Different pain, different brain: Facial Pain Headache. 2014;28(1):6–27.
thalamic anatomy in neuropathic and non-neuropathic 36. Lund JP, Donga R, Widmer CG, Stohler CS. The pain-
chronic pain syndromes. J Neuro Off J Soc Neuro. adaptation model: a discussion of the relationship
2011;31(16):5956–64. between chronic musculoskeletal pain and motor activ-
19. von Hehn CA, Baron R, Woolf CJ. Deconstructing the ity. Can J Physiol Pharmacol. 1991;69(5):683–94.
neuropathic pain phenotype to reveal neural mecha- 37. Peck CC, Goulet JP, Lobbezoo F, Schiffman EL,
nisms. Neuron. 2012;73(4):638–52. Alstergren P, Anderson GC, et al. Expanding the
1 Orofacial Pain: Classification and Road Map to Clinical Phenotypes 19

t­axonomy of the diagnostic criteria for temporoman- patients: retrospective investigation over 12 years.
dibular disorders. J Oral Rehabil. 2014;41(1):2–23. Acta Med Okayama. 2014;68(5):269–75.
38. Benoliel R, Svensson P, Heir GM, Sirois D, 52. Fernandez-de-Las-Penas C. Myofascial Head Pain.
Zakrzewska J, Oke-Nwosu J, et al. Persistent orofa- Curr Pain Headache Rep. 2015;19(7):28.
cial muscle pain. Oral Dis. 2011;17(Suppl 1): 53. Quintner JL, Bove GM, Cohen ML. A critical evalua-
23–41. tion of the trigger point phenomenon. Rheumatology.
39. Ceusters W, Michelotti A, Raphael KG, Durham J, 2015;54(3):392–9.
Ohrbach R. Perspectives on next steps in classifica- 54. Moraska AF, Hickner RC, Kohrt WM, Brewer A.
tion of oro-facial pain – part 1: role of ontology. J Oral Changes in blood flow and cellular metabolism at a
Rehabil. 2015a; doi:10.1111/joor.12336. myofascial trigger point with trigger point release
40. Fillingim RB, Bruehl S, Dworkin RH, Dworkin SF, (ischemic compression): a proof-of-principle pilot
Loeser JD, Turk DC, et al. The ACTTION-American study. Arch Phys Med Rehabil. 2013;94(1):196–200.
Pain Society Pain Taxonomy (AAPT): an evidence- 55. Shah JP, Danoff JV, Desai MJ, Parikh S, Nakamura
based and multidimensional approach to classifying LY, Phillips TM, et al. Biochemicals associated with
chronic pain conditions. J Pain Off J Am Pain Soc. pain and inflammation are elevated in sites near to and
2014;15(3):241–9. remote from active myofascial trigger points. Arch
41. Woda A, De Laat A. Classification of orofacial pain. Phys Med Rehabil. 2008;89(1):16–23.
Orofacial pain: recent advances in assessment, man- 56. Xu YM, Ge HY, Arendt-Nielsen L. Sustained noci-
agement and understanding of mechanisms. IASP ceptive mechanical stimulation of latent myofascial
Press. 2014:17–31. trigger point induces central sensitization in healthy
42. Woda A, Tubert-Jeannin S, Bouhassira D, Attal N, subjects. J Pain Off J Am Pain Soc. 2010;11(12):
Fleiter B, Goulet JP, et al. Towards a new taxonomy 1348–55.
of idiopathic orofacial pain. Pain. 2005;116(3): 57. Fernandez-de-Las-Penas C, Galan-Del-Rio F, Alonso-
396–406. Blanco C, Jimenez-Garcia R, Arendt-Nielsen L,
43. Pimenta e Silva Machado L, de Macedo Nery MB, de Svensson P. Referred pain from muscle trigger points
Gois Nery C, Leles CR. Profiling the clinical presen- in the masticatory and neck-shoulder musculature in
tation of diagnostic characteristics of a sample of women with temporomandibular disoders. J Pain Off
symptomatic TMD patients. BMC Oral Health. J Am Pain Soc. 2010;11(12):1295–304.
2012;12:26. 58. Huguenin LK. Myofascial trigger points: the current
44. Schiffman EL, Ohrbach R, Truelove EL, Tai F, evidence. Phys Therapy Sport. 2004;5:2–12.
Anderson GC, Pan W, et al. The research diagnostic 59. Cummings M, Baldry P. Regional myofascial pain:
criteria for temporomandibular disorders. V: methods diagnosis and management. Best Pract Res Clin
used to establish and validate revised axis I diagnostic Rheumatol. 2007;21(2):367–87.
algorithms. J Orofac Pain. 2010;24(1):63–78. 60. da Costa DR, de Lima Ferreira AP, Pereira TA,
45. International Headache Society Classification Porporatti AL, Conti PC, Costa YM, et al. Neck dis-
Committee. The international classification of head- ability is associated with masticatory myofascial pain
ache disorders, 3rd edition (beta version). Cephalalgia and regional muscle sensitivity. Arch Oral Biol.
Inter J Head. 2013a;33(9):629–808. 2015;60(5):745–52.
46. Renton T, Durham J, Aggarwal VR. The classification 61. Koutris M, Visscher CM, Lobbezoo F, Naeije M.
and differential diagnosis of orofacial pain. Expert Comorbidity negatively influences the outcomes of
Rev Neurother. 2012;12(5):569–76. diagnostic tests for musculoskeletal pain in the orofa-
47. Zebenholzer K, Wober C, Vigl M, Wessely P, Wober- cial region. Pain. 2013;154(6):927–32.
Bingol C. Facial pain in a neurological tertiary care 62. Michelotti A, Farella M, Stellato A, Martina R, De
centre – evaluation of the International Classification Laat A. Tactile and pain thresholds in patients with
of Headache Disorders. Cephalalgia Inter J Headache. myofascial pain of the jaw muscles: a case-control
2005;25(9):689–99. study. J Orofac Pain. 2008;22(2):139–45.
48. Benoliel R, Birman N, Eliav E, Sharav Y. The 63. Visscher CM, Lobbezoo F, de Boer W, van der Zaag J,
International Classification of Headache Disorders: Naeije M. Prevalence of cervical spinal pain in cranio-
accurate diagnosis of orofacial pain? Cephalalgia mandibular pain patients. Eur J Oral Sci. 2001;109(2):
Inter J Headache. 2008;28(7):752–62. 76–80.
49. Aggarwal VR, McBeth J, Zakrzewska JM, Lunt M, 64. Manfredini D, Guarda-Nardini L, Winocur E, Piccotti
Macfarlane GJ. The epidemiology of chronic syn- F, Ahlberg J, Lobbezoo F. Research diagnostic criteria
dromes that are frequently unexplained: do they have for temporomandibular disorders: a systematic review
common associated factors? Int J Epidemiol. of axis I epidemiologic findings. Oral Surg Oral Med
2006;35(2):468–76. Oral Pathol Oral Radiol Endodontics. 2011;112(4):
50. Shinal RM, Fillingim RB. Overview of orofacial pain: 453–62.
epidemiology and gender differences in orofacial 65. Slade GD, Ohrbach R, Greenspan JD, Fillingim RB,
pain. Dent Clin N Am. 2007;51(1):1–18. Bair E, Sanders AE, et al. Painful temporomandibular
51. Tomoyasu Y, Higuchi H, Mori M, Takaya K, Honda Y, disorder: decade of discovery from OPPERA studies.
Yamane A, et al. Chronic orofacial pain in dental J Dent Res. 2016; doi:10.1177/0022034516653743.
20 J.-P. Goulet and A. Woda

66. Nixdorf DR, Drangsholt MT, Ettlin DA, Gaul C, De Oral Biol Med Off Pub Am Asso Oral Biologists.
Leeuw R, Svensson P, et al. Classifying orofacial 2003;14(4):275–91.
pains: a new proposal of taxonomy based on ontology. 77. Klasser GD, Epstein JB. Oral burning and burning
J Oral Rehabil. 2012;39(3):161–9. mouth syndrome. J Am Dent Assoc. 2012;143(12):
67. Melis M, Lobo SL, Ceneviz C, Zawawi K, Al-Badawi 1317–9.
E, Maloney G, et al. Atypical odontalgia: a review of 78. Nasri C, Teixeira MJ, Okada M, Formigoni G, Heir G,
the literature. Headache. 2003;43(10):1060–74. Siqueira JT. Burning mouth complaints: clinical char-
68. Woda A, Pionchon P. A unified concept of idiopathic acteristics of a Brazilian sample. Clinics. 2007;62(5):
orofacial pain: clinical features. J Orofac Pain. 561–6.
1999;13(3):172–84; discussion 85–95. 79. Coculescu EC, Tovaru S, Coculescu BI. Epidemio­
69. Durham J, Exley C, John MT, Nixdorf DR. Persistent logical and etiological aspects of burning mouth syn-
dentoalveolar pain: the patient’s experience. J Orofac drome. J Med Life. 2014;7(3):305–9.
Pain. 2013;27(1):6–13. 80. Borelli V, Marchioli A, Di Taranto R, Romano M,
70. Pigg M, Svensson P, Drangsholt M, List T. Seven-year Chiandussi S, Di Lenarda R, et al. Neuropeptides in
follow-up of patients diagnosed with atypical odontal- saliva of subjects with burning mouth syndrome: a
gia: a prospective study. J Orofac Pain. pilot study. Oral Dis. 2010;16(4):365–74.
2013;27(2):151–64. 81. Just T, Steiner S, Pau HW. Oral pain perception and
71. Alonso AA, Nixdorf DR. Case series of four different taste in burning mouth syndrome. J Oral Pathol Med
headache types presenting as tooth pain. J Endod. Off Pub Inter Asso Oral Patholog Am Acad Oral
2006;32(11):1110–3. Pathol. 2010;39(1):22–7.
72. Kreiner M, Falace D, Michelis V, Okeson JP, Isberg A. 82. Lamey PJ, Lamb AB, Hughes A, Milligan KA,
Quality difference in craniofacial pain of cardiac vs. Forsyth A. Type 3 burning mouth syndrome: psycho-
dental origin. J Dent Res. 2010;89(9):965–9. logical and allergic aspects. J Oral Pathol Med Off
73. International Headache Society Classification Pub Inter Assoc Oral Pathol Am Acad Oral Pathol.
Committee. The international classification of head- 1994;23(5):216–9.
ache disorders 3rd edition (beta version). Cephalalgia 83. Aggarwal VR, McBeth J, Lunt M, Zakrzewska JM,
Inter J Headache. 2013b;33(9):774–82. Macfarlane GJ. Development and validation of
74. Baad-Hansen L, Pigg M, Ivanovic SE, Faris H, List T, classification criteria for idiopathic orofacial pain
Drangsholt M, et al. Intraoral somatosensory abnor- for use in population-based studies. J Orofac Pain.
malities in patients with atypical odontalgia – a con- 2007;21(3):203–15.
trolled multicenter quantitative sensory testing study. 84. Sardella A, Demarosi F, Barbieri C, Lodi G. An up-to-
Pain. 2013b;154(8):1287–94. date view on persistent idiopathic facial pain. Minerva
75. List T, Leijon G, Svensson P. Somatosensory abnor- Stomatol. 2009;58(6):289–99.
malities in atypical odontalgia: a case-control study. 85. Baad-Hansen L, Abrahamsen R, Zachariae R, List T,
Pain. 2008;139(2):333–41. Svensson P. Somatosensory sensitivity in patients
76. Scala A, Checchi L, Montevecchi M, Marini I, with persistent idiopathic orofacial pain is associated
Giamberardino MA. Update on burning mouth syn- with pain relief from hypnosis and relaxation. Clin J
drome: overview and patient management. Cr Rev Pain. 2013a;29(6):518–26.
 Comorbidities in Individuals
with Orofacial Pain and Their
2
Impact on Biomarkers
Orofacial Pain Comorbidities and Their
Impact on Biomarkers

Ana Miriam Velly and James Fricton

Abstract
This chapter covers the epidemiology of orofacial pain, the comorbidities
implicated in chronic orofacial pain, as well as their relationship with spe-
cific biomarkers. More specifically, it reviews the prevalence of orofacial
pain and of painful and non-painful comorbidities among individuals with
orofacial pain. It also examines the implication of comorbidities in the
onset and persistence of chronic orofacial pain. This chapter further dis-
cusses the role of comorbidities in the identification of biomarkers for
chronic orofacial pain, which is largely unknown, and the clinical and
research impacts of these findings.

2.1 Introduction disorders (TMD)] still had pain 5 years later [1].
Moreover, the presence of other pain conditions
Orofacial pain is a common condition and one for increases the risk of chronic orofacial pain [2–6]
which the diagnosis and management are not and its persistence [1, 7–10], as well as compli-
simple tasks. It has been noted that 30% of indi- cates the diagnosis and treatment effectiveness
viduals with orofacial pain [temporomandibular [11].
This chapter first reviews the epidemiology of
orofacial pain and comorbidities among individ-
A.M. Velly, DDS, MSc, PhD (*) uals with orofacial pain. It also reviews the impli-
Faculty of Dentistry, McGill University, cation of comorbidities on the onset and
Montréal, Canada
persistence of orofacial pain. This is followed by
Department of Dentistry, Jewish General Hospital, an evaluation of the implication of comorbidities
3755, Chemin de la Côte Ste-Catherine, Suite A-017,
H3T 1E2 Montréal, Québec, Canada in the identification of biomarkers for orofacial
e-mail: [email protected] pain conditions. Comorbidity is defined as the
J. Fricton, DDS, MS “concurrent existence and occurrence of two or
School of Dentistry, University of Minnesota, more medically diagnosed diseases in the same
Minneapolis, MN, USA individual” [12].

© Springer-Verlag GmbH Germany 2017 21

J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI 10.1007/978-3-662-53994-1_2
22 A.M. Velly and J. Fricton

2.2 Epidemiology of 2.3.1 Headaches

Orofacial Pain
Headaches are common in the general population
As described in Chap. 1, the 1-month prevalence [22, 49] and among individuals with orofacial
of orofacial pain is estimated to range from 19 to pain [13, 50–52]. More specifically, the fre-
26% among adults [6, 13, 14]. Among orofacial quency of headaches in TMD subjects ranges
pain groups, toothache (12–14%) [15, 16] and from 9 to 97% in adults [34, 40–42, 47, 53–55]
TMD-related pain (5–12%) [15, 17–21] are more and between 30 and 94% for adolescents [2, 56,
common than oral sores (8%) [15, 22], burning 57]. Studies demonstrated that individuals with
mouth (1%) [15, 22], trigeminal neuralgia (0.3%) painful TMD are more likely (OR = 1.5–8.8) to
[23], and persistent idiopathic facial pain (0.03%) have headaches than individuals without TMD
[23]. The incidence of orofacial pain is 4.6% [3]. (Fig. 2.1) [31, 39, 41, 47, 55, 57]. Females with
The incidence of TMD-related pain ranges from TMD have a greater likelihood of having head-
approximately 3.8–6.5% [20, 24]. Women (4.5%) aches than males [34].
are at greater risk of developing TMD-related Epidemiological studies clearly demonstrated
pain than men (1.3%) [25–27]. that headaches not only co-occur among patients
Fifty to sixty-six percent of people with TMD with orofacial pain but also increased its risk.
will seek treatment. However, it is shocking to Studies also showed that the chance of develop-
note that, regardless of treatment received, 30% ing TMD-related pain was higher among adoles-
of individuals with TMD still reported to have cents (OR = 2.7; 95% CI: 1.6–4.4) [2] and adults
pain 5 years later [1] and 16% are worse [28]. (OR = 2.1, 95% CI: 1.2–3.7) [6] with headaches.
One factor that contributes to the persistence and This risk appears to be higher among those with
lack of improvement is the presence of comor- headaches in the previous year (OR = 8.8; 95%
bidities [1, 7, 8, 11]. CI: 3.8–20.1) [55] or with a headache once a
week or more (OR = 3.7; 95% CI: 1.6–8.4) [6].
Headaches were also implicated in the aggrava-
2.3 Comorbidities Related tion of TMD signs [54] and in the emotional
to Orofacial Pain functioning of subjects [58].

Comorbidities are common among individuals

with chronic orofacial pain [1, 7, 10, 29–47], 2.3.2 Widespread Pain
with higher prevalence among women [34, 48] and Fibromyalgia Syndrome
and among those with low socioeconomic status
[33]. Widespread pain also frequently co-occurs with
A cross-sectional study showed that females chronic orofacial pain (39%) [59], especially
with painful TMD were 40% (odds ratio [OR] = TMD-related pain (16–54%) [7, 9, 10]. The prev-
1.4, 95% confidence intervals [CI] 1.3–1.6) more alence of fibromyalgia syndrome (FM) among
likely to present two to three comorbid pain con- TMD individuals ranges between 7 and 18%
ditions than males [34]. African-Americans [7, 32, 53, 60], and most individuals with FM
(OR = 1.4, 95% CI: 1.3–1.8) and Hispanics (odds exhibit painful TMD [61], showing again that
ratio [OR] = 1.6, 95% CI: 1.2–1.6) were also fibromyalgia frequently co-occurs with TMD.
more likely than non-Hispanic whites to report Cohort studies demonstrated that widespread
comorbid pain conditions [33]. The following pain also increased the risk of orofacial pain
section describes a number of painful and psy- among adults (risk ratio [RR] = 4.0, 95% CI:
chological comorbidities that not only co-occur 2.2–7.4) [3] and adolescents (OR = 3.2, 95% CI:
with orofacial pain but that also increase its onset 1.7–6.1) [2]. Widespread pain also increases the
or persistence risks (See Figs. 2.1, 2.2). risk of persistent orofacial pain (RR = 2.0, 95%
2 Comorbidities in Individuals with Orofacial Pain and Their Impact on Biomarkers 23

CDH (Goncalvez et al. 2009)

CDH (Goncalvez et al. 2009)

CDH (Goncalvez et al. 2009)

CDH (Goncalvez et al. 2011)

CDH (Goncalvez et al. 2011)

ETTH (Goncalvez et al. 2009)

ETTH (Goncalvez et al. 2009)

ETTH (Goncalvez et al. 2009)

TTH (Goncalvez et al. 2011)

TTH (Goncalvez et al. 2011)

Any headache in last year

(Ohrbach et al. 2011)

Frequent headache
(MacFarlane et al 2001)

Headache once a week or

more (Nilsson et al. 2013)

Headache (Plesh et al. 2011)

0 5 10 15 20
OR=1

Fig. 2.1 Odds ratio and 95% confidence intervals headache, TTH tension-type headache, OR odds ratio.
illustrating the magnitude of the association between The horizontal line represents the 95% confidence
headache and orofacial pain. Abbreviations: CDH intervals. The line crossing the confidence interval rep-
chronic daily headache, ETTH episodic tension-type resents the OR
24 A.M. Velly and J. Fricton

FM (Velly et al. 2010)

FM (Velly et al. 2010)

WP (Velly et al. 2010)

WP (John et al. 2003)

WP (Velly et al. 2010)

Number of body pain sites

(Rammelsberg et al. 2003)

0 OR=1 5 10

Fig. 2.2 Odds ratio and 95% confidence intervals show- horizontal line represents the 95% confidence intervals.
ing the relationship between comorbid pain conditions The line crossing the confidence interval represents the
and the persistence of orofacial pain. Abbreviations: FM OR
fibromyalgia, WP widespread pain, OR odds ratio. The
2 Comorbidities in Individuals with Orofacial Pain and Their Impact on Biomarkers 25

CI: 1.4–2.8) [9], including painful TMD (Fig. 2.2) more likely to have painful TMD than those with-
[1, 7]. out stomach pain. Another study found an
increased risk of painful TMD among adults with
IBS compared to those without (OR = 2.7, 95%
2.3.3 Neck and Back Pain CI: 1.4–5.1) [55].

Neck and back pains are also common symptoms

reported by adults with orofacial pain (16–93%) 2.3.5 Psychological Factors
[6, 34, 52, 53, 55, 62]. Previous epidemiological
studies demonstrated that individuals with TMD-­ There is evidence that psychological factors are
related pain were more likely (OR = 2.6–5) to associated with chronic pain [63–65] and, in par-
have low back pain than individuals without (Fig. ticular, with chronic painful TMD [66, 67].
2.3) [34, 55, 57]. The odds of joint pain (OR = 4.0, Higher levels of stress [6, 63, 68, 69], anxiety
95% CI: 3.7–4.3) are greater among adults with [68, 70], depression [6, 63, 70–73], somatic
TMD-related pain than among those without [34]. awareness [2, 13, 63, 70–72, 74], and pain cata-
Individuals with TMD-related pain are also more strophizing [63, 75, 76] have been noted among
likely to experience neck pain (OR = 4.0–7.9) [34, individuals with chronic orofacial pain.
57]. Back (OR = 1.2; 95% CI: 1.2–1.3) and neck Furthermore, affective disturbance (RR = 1.6,
pains (OR = 1.5; 95% CI: 1.4–1.8) are also more 95% CI: 1,1–2.2) [9], irritability (RR = 1.5, 95%
likely to occur among females with TMD-related CI: 1.1–2.1) [9], anxiety (RR = 2.8, 95% CI 1.3–
pain than males [34]. 6.2) [3], depression (OR = 2.2, 95% CI: 1.2–4.0),
Moreover, a prospective-cohort study found and perceived stress (OR = 2.2, 95% CI: 1.2–4.0)
an increased risk of painful TMD among adoles- increase the risk of orofacial pain [6]. A higher
cents with back pain compared to those without risk is also related to painful TMD when individ-
(OR = 3.9, 95% CI: 2.2–6.8) [2]. The risk increase uals are exposed to depression (incidence density
among adolescents appears to be a little higher ratio [IDR] = 3.2, 95% CI: 1.5–6.7) [73] (hazard
than for adults since the OR found among adults ratio [HR]= 1.31, 95% CI: 1.19–1.42)] [77], per-
was close to 3 [(OR = 2.7; 95% CI: 1.1–7.0) [6] ceived stress [(IDR = 2.6, 95% CI: 1.2–5.5) [73]
and 2.9 (95% CI: 2.0–4.3)] [55]. HR = 1.31, 95% CI: 1.16, 1.48)] [77], mood
(IDR = 3.7, 95% CI: 1.7–8.1) [73], somatization
[(OR = 1.8, 95% CI = 1.1–2.8) [2], HR = 1.38,
2.3.4  isceral Comorbid Pain
V 95% CI: 1.27–1.49)] [77], and life dissatisfaction
Conditions (OR = 4.1, 95% C = 1.9–9.0) [2]. Psychological
comorbidities also contribute to the persistence
Individuals with orofacial pain such as TMD and of TMD-related pain, regardless of the presence
burning mouth syndrome [52] frequently report of painful comorbidities [7, 8].
abdominal pain. For example, chronic pelvic pain
(8%), irritable bowel syndrome (IBS; 9–16%),
interstitial cystitis (17%), and stomach pain 2.4 Implications
(34%) are noted among individuals with TMD [2, of Comorbidities
53, 55]. The neural and sensory conditions on Biomarkers Identification
include earache or ringing in the ear, hearing loss,
fainting, or dizzy spells; respiratory conditions A number of candidate biomarkers cited in
include sinusitis, allergies or hives, asthma, or Chaps. 6, 7, 8, and 9 are associated with orofa-
breathing difficulties [55]. cial pain. It is important to note that these bio-
Furthermore, adolescents with painful stom- markers are also associated with orofacial pain
ach pain are 50% (OR = 1.5; 95% CI: 1.0–2.1) comorbidities. For example, NGF is elevated in
[25] to 90% (OR = 1.9, 95% CI: 1.2–3.1) [2] many clinical pain conditions, such as headaches
26 A.M. Velly and J. Fricton

Neck pain (Plesh et al.

2011)

Recurrent pain in neck

(Nilsson et al. 2013)

Back pain
(Nilsson et al. 2013)

Current low back pain

(Ohrbach et al. 2011)

Low back pain

(Plesh et al. 2011)

0 5 10
OR=1

Fig. 2.3 Odds ratio and 95% confidence intervals illus- represents the 95% confidence intervals. The line crossing
trating the magnitude of the association between back the confidence interval represents the OR
pain or neck pain and orofacial pain. The horizontal line

[78, 79], rheumatoid arthritis [80], fibromyalgia headaches [96, 97], visceral pain [84, 98–102],
[81], visceral pain [82–84], and psychological and psychological comorbidities [103].
comorbities [85, 86]. Elevated glutamate levels Individuals with headaches [104] and neck pain
were also noted among patients with fibromyal- [94] also presented higher levels of serotonin.
gia [87], back pain [88], and headaches [89]. Substance P levels were found to be positively
High levels of pro-inflammatory cytokines (e.g., related to neck pain [94], headaches [78, 105],
IL-8, TNF, IL-6) are correlated with fibromyal- visceral pain [106], and rheumatoid arthritis
gia [90–92], back pain [93], neck pain [94, 95], [105]. Elevated levels of CGRP were noted
2 Comorbidities in Individuals with Orofacial Pain and Their Impact on Biomarkers 27

among individuals with headaches [78, 107– based on cohort studies, comorbidities contribute
109]. High levels of prostaglandins were identi- to the onset [2–6] and the persistence of chronic
fied among headaches [110], fibromyalgia [111], orofacial pain over and beyond the expected heal-
visceral pain [110], and depression cases ing time (Table 2.1) [1, 8–10].
[112–115].
Therefore, comorbidities probably can con-
found and/or modify the relationship between a 2.5 Clinical Implications
candidate biomarker and orofacial pain. Hence, of Comorbidities
the studies assessing the putative biomarkers in Orofacial Pain
need to recruit a specific population and/or per-
form suitable statistical analysis to assess the In the treatment of orofacial pain, health-care
impact of comorbidities on the relationship providers need to identify the comorbidities and
between a biomarker and orofacial pain (see address them within a well-designed, multi-
Chaps. 10 and 11). modal, interdisciplinary integrative treatment
The identification of biomarkers for orofacial plan that may involve dentists, physicians, physi-
pain or comorbidities are very relevant since, cal therapists, and psychologists [116] since

Table 2.1 Examples of candidate biomarker of orofacial pain associated with orofacial pain comorbidities
Candidate biomarker Comorbidity Biofluid
Nerve growth factor [78, 79] Migraine Plasma
Nerve growth factor [84] Interstitial cystitis Serum
Nerve growth factor [82, 83] Interstitial cystitis Urine
Nerve growth factor [80] Rheumatoid arthritis and psoriatic Synovial fluid
arthritis
Nerve growth factor [85] Psychological stress Saliva
Nerve growth factor [86] Depression Serum
Glutamate [89] Headache Plasma
IL-8 [92] Fibromyalgia Serum
IL-5 and IL-4 [96] Migraine Plasma
IL-6 and IL-10 [97] Migraine Serum
IL-17 [99] Chronic pelvic pain syndrome Urine
IL-1β, IL-6, TNF-α, IL-8 [84] Interstitial cystitis Serum
IL-6, IL-8, IL-1β (Pike et al. 2015) [100] Irritable bowel syndrome Serum
IL-10, IL-12, TGF-β [101] Irritable bowel syndrome Plasma
IL-6, IL-10, IL-13, IL-17, TNF-α, TGF-β [102] Ulcerative colitis Serum
IL-6 [103] Depression Serum
Serotonin higher [104] Headache attack Serum
Serotonin [94] Neck pain Microdialysis
Substance P [94] Neck pain Microdialysis
Substance P [106] Interstitial cystitis Urine
Substance P [105] Migraine Plasma
Substance P [78] Migraine Plasma and saliva
Substance P [105] Rheumatoid arthritis Synovial fluid and serum
Calcitonin gene-related peptide [78, 107, 108] Migraine Plasma
Calcitonin gene-related peptide [78, 109] Migraine, cluster headache Saliva
Prostaglandin E2 (Clarke et al. 2010) [114] Irritable bowel syndrome Serum
8-iso-prostaglandin F2α [110] Headache Urine
Prostaglandin E2 [111] Fibromyalgia Serum
Prostaglandin D2, prostaglandin E2 [115] Major depression Saliva
28 A.M. Velly and J. Fricton

comorbidities not only contribute to the onset [2, s­ymptoms of temporomandibular disorders. Acta
Odontol Scand. 2010;68(5):289–99.
4–6, 59] but also have an effect on the persistence
6. Macfarlane TV, Kenealy P, Kingdon HA, Mohlin B,
of pain [1, 7, 9, 10]. Pilley JR, Mwangi CW, et al. Orofacial pain in young
All interventions need to be tailored to the adults and associated childhood and adulthood factors:
patient’s unique characteristics and focus on treat- results of the population study, Wales, United Kingdom.
Community Dent Oral Epidemiol. 2009;37(5):438–50.
ing the primary condition while addressing rele-
doi:10.1111/j.1600-0528.2009.00482.x.
vant risk factors and enhancing protective factors 7. Velly AM, Look JO, Schiffman E, Lenton PA, Kang W,
[116]. The ultimate goal of this strategy is to pre- Messner RP, et al. The effect of fibromyalgia and wide-
vent the transition from acute to chronic orofacial spread pain on the clinically significant temporoman-
dibular muscle and joint pain disorders–a prospective
pain as well as to promote tertiary prevention.
18-month cohort study. J Pain. 2010;11(11):1155–64.
doi:10.1016/j.jpain.2010.02.009.
Conclusions 8. Velly AM, Look JO, Carlson C, Lenton PA, Kang W,
The findings presented in this chapter establish Holcroft CA, et al. The effect of catastrophizing and
depression on chronic pain–a prospective cohort
that a number of painful and non-painful comor-
study of temporomandibular muscle and joint pain
bidities are common among patients with orofa- disorders. Pain. 2011;152(10):2377–83. doi:10.1016/j.
cial pain and, more specifically, painful pain.2011.07.004.
TMD. Furthermore, epidemiological studies 9. Macfarlane TV, Blinkhorn AS, Davies RM, Kincey
J, Worthington HV. Predictors of outcome for orofa-
show that these comorbidities not only co-occur
cial pain in the general population: a four-year fol-
with orofacial pain but also contribute to the low-­up study. J Dent Res. 2004;83(9):712–7.
onset and persistence of orofacial pain. In addi- 10. John MT, Miglioretti DL, LeResche L, Von Korff M,
tion, studies demonstrated that a series of candi- Critchlow CW. Widespread pain as a risk factor for
dysfunctional temporomandibular disorder pain.
date biomarkers for orofacial pain were also
Pain. 2003;102(3):257–63.
associated with the comorbidities of orofacial 11. Raphael KG, Marbach JJ. Widespread pain and the
pain. It is therefore vital that researchers iden- effectiveness of oral splints in myofascial face pain.
tify comorbid conditions and assess how these J Am Dent Assoc. 2001;132(3):305–16.
12. Nardi R, Scanelli G, Corrao S, Iori I, Mathieu G,
comorbidities affect the relationship between a
Cataldi AR. Co-morbidity does not reflect complexity
candidate biomarker and orofacial pain. in internal medicine patients. Eur J Intern Med.
2007;18(5):359–68. doi:10.1016/j.ejim.2007.05.002.
13. Macfarlane TV, Blinkhorn AS, Davies RM, Ryan P,
Worthington HV, Macfarlane GJ. Orofacial pain:
References just another chronic pain? Results from a population-­
based survey. Pain. 2002;99(3):453–8.
1. Rammelsberg P, LeResche L, Dworkin S, Mancl 14. Macfarlane TV, Blinkhorn AS, Craven R,
L. Longitudinal outcome of temporomandibular disor- Zakrzewska JM, Atkin P, Escudier MP, et al. Can
ders: a 5-year epidemiologic study of muscle disorders one predict the likely specific orofacial pain syn-
defined by research diagnostic criteria for temporo- drome from a self-completed questionnaire? Pain.
mandibular disorders. J Orofac Pain. 2003;17(1):9–20. 2004;111(3):270–7. doi:10.1016/j.pain.2004.07.002.
2. LeResche L, Mancl LA, Drangsholt MT, Huang G, 15. Lipton JA, Ship JA, Larach-Robinson D. Estimated
Von Korff M. Predictors of onset of facial pain and prevalence and distribution of reported orofacial
temporomandibular disorders in early adolescence. pain in the United States. J Am Dent Assoc.
Pain. 2007;129(3):269–78. 1993;124(10):115–21.
3. Aggarwal VR, Macfarlane GJ, Farragher TM, 16. Locker D, Grushka M. Prevalence of oral and facial
McBeth J. Risk factors for onset of chronic oro-­ pain and discomfort: preliminary results of a mail
facial pain–results of the North Cheshire oro-facial survey. Community Dent Oral Epidemiol.
pain prospective population study. Pain. 1987;15(3):169–72.
2010;149(2):354–9. 17. National Institute of Dental and Craniofacial
4. Lim PF, Smith S, Bhalang K, Slade GD, Maixner Research. Facial pain. 2014. http://www.nidcr.nih.
W. Development of temporomandibular disorders is gov/DataStatistics/FindDataByTopic/FacialPain.
associated with greater bodily pain experience. Clin 18. Isong U, Gansky SA, Plesh O. Temporomandibular
J Pain. 2010;26(2):116–20. joint and muscle disorder-type pain in U.S. adults:
5. Marklund S, Wanman A. Risk factors associated the National Health Interview Survey. J Orofac Pain.
with incidence and persistence of signs and 2008;22(4):317–22.
2 Comorbidities in Individuals with Orofacial Pain and Their Impact on Biomarkers 29

19. Sanders AE, Slade GD. Gender modifies effect of 33. Plesh O, Adams SH, Gansky SA. Racial/Ethnic and
perceived stress on orofacial pain symptoms: gender prevalences in reported common pains in a
National Survey of Adult Oral Health. J Orofac Pain. national sample. J Orofac Pain. 2011;25(1):25–31.
2011;25(4):317–26. 34. Plesh O, Adams SH, Gansky SA. Temporomandibular
20. Von Korff M, Dworkin SF, Le Resche L, Kruger joint and muscle disorder-type pain and comorbid
A. An epidemiologic comparison of pain complaints. pains in a national US sample. J Orofac Pain.
Pain. 1988;32(2):173–83. 2011;25(3):190–8.
21. Matsuka Y, Yatani H, Kuboki T, Yamashita 35. Leblebici B, Pektas ZO, Ortancil O, Hurcan EC,
A. Temporomandibular disorders in the adult popu- Bagis S, Akman MN. Coexistence of fibromyalgia,
lation of Okayama City, Japan. Cranio. temporomandibular disorder, and masticatory myo-
1996;14(2):158–62. fascial pain syndromes. Rheumatol Int.
22. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed 2007;27(6):541–4.
ML, Stewart WF. Migraine prevalence, disease bur- 36. Korszun A, Papadopoulos E, Demitrack M,
den, and the need for preventive therapy. Neurology. Engleberg C, Crofford L. The relationship between
2007;68(5):343–9. temporomandibular disorders and stress-associated
23. Mueller D, Obermann M, Yoon MS, Poitz F, Hansen syndromes. Oral Surg Oral Med Oral Pathol Oral
N, Slomke MA, et al. Prevalence of trigeminal neural- Radiol Endod. 1998;86(4):416–20.
gia and persistent idiopathic facial pain: a population-­ 37. Wiesinger B, Malker H, Englund E, Wanman
based study. Cephalalgia. 2011;31(15):1542–8. A. Back pain in relation to musculoskeletal disorders
doi:10.1177/0333102411424619. in the jaw-face: a matched case-control study. Pain.
24. Slade GD, Fillingim RB, Sanders AE, Bair E, 2007;131(3):311–9.
Greenspan JD, Ohrbach R, et al. Summary of find- 38. Hagberg C. General musculoskeletal complaints in a
ings from the OPPERA prospective cohort study of group of patients with craniomandibular disorders
incidence of first-onset temporomandibular disorder: (CMD). A case control study. Swed Dent
implications and future directions. J Pain. 2013;14(12 J. 1991;15(4):179–85.
Suppl):T116–24. doi:10.1016/j.jpain.2013.09.010. 39. Goncalves DA, Bigal ME, Jales LC, Camparis CM,
25. Nilsson IM, List T, Drangsholt M. Prevalence of Speciali JG. Headache and symptoms of temporo-
temporomandibular pain and subsequent dental mandibular disorder: an epidemiological study.
treatment in Swedish adolescents. J Orofac Pain. Headache. 2009;50:231–41.
2005;19(2):144–50. 40. Goncalves DA, Speciali JG, Jales LC, Camparis
26. Nilsson IM, List T, Drangsholt M. Incidence and CM, Bigal ME. Temporomandibular symptoms,
temporal patterns of temporomandibular disorder migraine, and chronic daily headaches in the popula-
pain among Swedish adolescents. J Orofac Pain. tion. Neurology. 2009;73(8):645–6.
2007;21(2):127–32. 41. Goncalves DA, Camparis CM, Speciali JG, Franco AL,
27. LeResche L. Epidemiology of temporomandibular Castanharo SM, Bigal ME. Temporomandibular disor-
disorders: implications for the investigation of etio- ders are differentially associated with headache diagno-
logic factors. Crit Rev Oral Biol Med. ses: a controlled study. Clin J Pain. 2011;27(7):611–5.
1997;8:291–305. doi:10.1097/AJP.0b013e31820e12f5.
28. Ohrbach R, Dworkin SF. Five-year outcomes in 42. Graff-Radford SB. Temporomandibular disorders
TMD: relationship of changes in pain to changes in and headache. Dent Clin N Am. 2007;51(1):129–44,
physical and psychological variables. Pain. vi–vii.
1998;74(2–3):315–26. 43. Ballegaard V, Thede-Schmidt-Hansen P, Svensson P,
29. Aaron LA, Buchwald D. A review of the evi- Jensen R. Are headache and temporomandibular
dence for overlap among unexplained clinical disorders related? A blinded study. Cephalalgia.
­
conditions. Ann Intern Med. 2001;134(9 Pt 2008;28(8):832–41. doi:10.1111/j.1468-2982.2008.​
2):868–81. 01597.x.
30. Aaron LA, Buchwald D. Chronic diffuse musculo- 44. De Laat AMH, Stevens A, Verbeke G. Correlation
skeletal pain, fibromyalgia and co-morbid unex- between cervical spine and temporomandibular dis-
plained clinical conditions. Best Pract Res Clin orders. Clin Oral Investig. 1998;2:54–7.
Rheumatol. 2003;17(4):563–74. 45. Glaros AG. Patients with acute painful TMD at high
31. Yunus MB. Central sensitivity syndromes: a new risk for developing a chronic condition report less
paradigm and group nosology for fibromyalgia and pain, emotional distress, and health care use after a
overlapping conditions, and the related issue of dis- psychological intervention using cognitive-­
ease versus illness. Semin Arthritis Rheum. behavioral skills training and biofeedback. J Evid
2008;37(6):339–52. Based Dent Pract. 2007;7(1):14–6. doi:10.1016/j.
32. Plesh O, Wolfe F, Lane N. The relationship between jebdp.2006.12.007.
fibromyalgia and temporomandibular disorders: 46. Sipila K, Suominen AL, Alanen P, Heliovaara M,
prevalence and symptom severity. J Rheumatol. Tiittanen P, Kononen M. Association of clinical findings
1996;23(11):1948–52. of temporomandibular disorders (TMD) with self-
30 A.M. Velly and J. Fricton

reported musculoskeletal pains. Eur J Pain. tioning in subjects with temporomandibular disorder
2011;15(10):1061–7. doi:10.1016/j.ejpain.2011.05.001. pain. J Orofac Pain. 2012;26(2):83–90.
47. Macfarlane TV, Gray RJM, Kincey J, Worthington HV. 59. Aggarwal VR, Lovell K, Peters S, Javidi H, Joughin A,
Factors associated with the temporomandibular disor- Goldthorpe J. Psychosocial interventions for the man-
der, pain dysfunction syndrome (PDS): Manchester agement of chronic orofacial pain. Cochrane Database
case-control study. Oral Dis. 2001;7(6):321–30. Syst Rev. 2011;11:1–57. doi:10.1002/14651858.
48. Dominick CH, BFM. Epidemiology of pain and CD008456.pub2.
non-pain comorbidities. In: Giamberardino MA, 60. Burris JL, Evans DR, Carlson CR. Psychological
Jensen TS, editors. Pain comorbidities: understand- correlates of medical comorbidities in patients with
ing and treating the complex patient. Seattle: IASP temporomandibular disorders. J Am Dent Assoc.
Press; 2012. p. 21–35. 2010;141(1):22–31.
49. Stovner L, Hagen K, Jensen R, Katsarava Z, Lipton 61. Balasubramaniam R, de Leeuw R, Zhu H,
R, Scher A, et al. The global burden of headache: a Nickerson RB, Okeson JP, Carlson CR. Prevalence
documentation of headache prevalence and disabil- of temporomandibular disorders in fibromyalgia
ity worldwide. Cephalalgia. 2007;27(3):193–210. and failed back syndrome patients: a blinded
doi:10.1111/j.1468-2982.2007.01288.x. prospective comparison study. Oral Surg Oral
­
50. de Siqueira SR, Vilela TT, Florindo AA. Prevalence Med Oral Pathol Oral Radiol Endod.
of headache and orofacial pain in adults and elders in 2007;104(2):204–16.
a Brazilian community: an epidemiological study. 62. Hagberg C, Hagberg M, Kopp S. Musculoskeletal
Gerodontology. 2015;32(2):123–31. doi:10.1111/ symptoms and psychosocial factors among patients
ger.12063. with craniomandibular disorders. Acta Odontol
51. Baad-Hansen L, Leijon G, Svensson P, List Scand. 1994;52(3):170–7.
T. Comparison of clinical findings and psychosocial 63. Fillingim RB, Ohrbach R, Greenspan JD, Knott C,
factors in patients with atypical odontalgia and tem- Dubner R, Bair E, et al. Potential psychosocial risk
poromandibular disorders. J Orofac Pain. factors for chronic TMD: descriptive data and
2008;22(1):7–14. empirically identified domains from the OPPERA
52. Mignogna MD, Pollio A, Fortuna G, Leuci S, case-­control study. J Pain. 2011;12(11
Ruoppo E, Adamo D, et al. Unexplained somatic Suppl):T46–60. doi:10.1016/j.jpain.2011.08.007.
comorbidities in patients with burning mouth syn- 64. Gatchel RJ, Peng YB, Peters ML, Fuchs PN, Turk
drome: a controlled clinical study. J Orofac Pain. DC. The biopsychosocial approach to chronic pain:
2011;25(2):131–40. scientific advances and future directions. Psychol
53. Aaron LA, Burke MM, Buchwald D. Overlapping Bull. 2007;133(4):581–624.
conditions among patients with chronic fatigue syn- 65. Keefe FJ, Rumble ME, Scipio CD, Giordano LA,
drome, fibromyalgia, and temporomandibular disor- Perri LM. Psychological aspects of persistent pain:
der. Arch Intern Med. 2000;160(2):221–7. current state of the science. J Pain. 2004;5(4):195–
54. Anderson GC, John MT, Ohrbach R, Nixdorf DR, 211. doi:10.1016/j.jpain.2004.02.576.
Schiffman EL, Truelove ES, et al. Influence of head- 66. Rollman GB, Gillespie JM. The role of psychosocial
ache frequency on clinical signs and symptoms of factors in temporomandibular disorders. Curr Rev
TMD in subjects with temple headache and TMD Pain. 2000;4(1):71–81.
pain. Pain. 2011;152(4):765–71. doi:10.1016/j. 67. Rollman GB, Abdel-Shaheed J, Gillespie JM, Jones
pain.2010.11.007. KS. Does past pain influence current pain: biological
55. Ohrbach R, Fillingim RB, Mulkey F, Gonzalez Y, and psychosocial models of sex differences. Eur
Gordon S, Gremillion H, et al. Clinical findings and J Pain. 2004;8(5):427–33.
pain symptoms as potential risk factors for chronic 68. Carlson CR, Okeson JP, Falace DA, Nitz AJ, Curran
TMD: descriptive data and empirically identified SL, Anderson D. Comparison of psychologic and
domains from the OPPERA case-control study. physiologic functioning between patients with mas-
J Pain. 2011;12(11 Suppl):T27–45. doi:10.1016/j. ticatory muscle pain and matched controls. J Orofac
jpain.2011.09.001. Pain. 1993;7(1):15–22.
56. List T, Wahlund K, Wenneberg B, Dworkin SF. TMD 69. Wirz S, Ellerkmann RK, Buecheler M, Putensen C,
in children and adolescents: prevalence of pain, gen- Nadstawek J, Wartenberg HC. Management of chronic
der differences, and perceived treatment need. orofacial pain: a survey of general dentists in german
J Orofac Pain. 1999;13(1):9–20. university hospitals. Pain Med. 2010;11(3):416–24.
57. Nilsson IM, List T, Drangsholt M. Headache and doi:10.1111/j.1526-4637.2010.00805.x.
Co-morbid Pains Associated with TMD Pain in 70. Velly AM, Gornitsky M, Philippe P. Contributing
Adolescents. J Dent Res. 2013;92(9):802–7. doi: factors to chronic myofascial pain: a case-control
10.1177/0022034513496255. study. Pain. 2003;104(3):491–9.
58. List T, John MT, Ohrbach R, Schiffman EL, Truelove 71. Manfredini D, Winocur E, Ahlberg J, Guarda-­
EL, Anderson GC. Influence of temple headache fre- Nardini L, Lobbezoo F. Psychosocial impairment in
quency on physical functioning and emotional func- temporomandibular disorders patients. RDC/TMD
2 Comorbidities in Individuals with Orofacial Pain and Their Impact on Biomarkers 31

axis II findings from a multicentre study. J Dent. nerve growth factor expressions in serum of patients
2010;38(10):765–72. with interstitial cystitis/bladder pain syndrome.
72. Agarwal R, Gupta D, Ray P, Aggarwal AN, Jindal PLoS One. 2013;8(10):e76779. doi:10.1371/journal.
SK. Epidemiology, risk factors and outcome of nos- pone.0076779.
ocomial infections in a Respiratory Intensive Care 85. Laurent HK, Laurent SM, Granger DA. Salivary
Unit in North India. J Infect. 2006;53(2):98–105. nerve growth factor reactivity to acute psychosocial
doi:10.1016/j.jinf.2005.10.021. stress: a new frontier for stress research.
73. Slade GD, Diatchenko L, Bhalang K, Sigurdsson A, Psychosom Med. 2013;75(8):744–50. doi:10.1097/
Fillingim RB, Belfer I, et al. Influence of psycho- PSY.0b013e3182a85ffd.
logical factors on risk of temporomandibular disor- 86. Martino M, Rocchi G, Escelsior A, Contini P,
ders. J Dent Res. 2007;86(11):1120–5. Colicchio S, de Berardis D, et al. NGF serum levels
74. Huang GJ, LeResche L, Critchlow CW, Martin MD, variations in major depressed patients receiving dulox-
Drangsholt MT. Risk factors for diagnostic sub- etine. Psychoneuroendocrinology. 2013;38(9):1824–
groups of painful temporomandibular disorders 8. doi:10.1016/j.psyneuen.2013.02.009.
(TMD). J Dent Res. 2002;81(4):284–8. 87. Harris RE, Sundgren PC, Craig AD, Kirshenbaum E,
75. Campbell CM, Witmer K, Simango M, Carteret A, Sen A, Napadow V, et al. Elevated insular glutamate
Loggia ML, Campbell JN, et al. Catastrophizing in fibromyalgia is associated with experimental pain.
delays the analgesic effect of distraction. Pain. Arthritis Rheum. 2009;60(10):3146–52.
2010;149(2):202–7. doi:10.1016/j.pain.2009.11.012. doi:10.1002/art.24849.
76. Quartana PJ, Buenaver LF, Edwards RR, Klick B, 88. Harrington JF, Messier AA, Bereiter D, Barnes B,
Haythornthwaite JA, Smith MT. Pain catastrophiz- Epstein MH. Herniated lumbar disc material as a
ing and salivary cortisol responses to laboratory pain source of free glutamate available to affect pain sig-
testing in temporomandibular disorder and healthy nals through the dorsal root ganglion. Spine (Phila
participants. J Pain. 2010;11(2):186–94. Pa 1976). 2000;25(8):929–36.
77. Fillingim RB, Ohrbach R, Greenspan JD, Knott C, 89. D'Andrea G, Cananzi AR, Joseph R, Morra M,
Diatchenko L, Dubner R, et al. Psychological factors Zamberlan F, Ferro Milone F, et al. Platelet glycine,
associated with development of TMD: the OPPERA glutamate and aspartate in primary headache.
prospective cohort study. J Pain. 2013;14(12 Cephalalgia. 1991;11(4):197–200.
Suppl):T75–90. doi:10.1016/j.jpain.2013.06.009. 90. Rodriguez-Pinto I, Agmon-Levin N, Howard A,
78. Jang MU, Park JW, Kho HS, Chung SC, Chung Shoenfeld Y. Fibromyalgia and cytokines.
JW. Plasma and saliva levels of nerve growth factor Immunol Lett. 2014;161(2):200–3. doi:10.1016/j.
and neuropeptides in chronic migraine patients. Oral imlet.2014.01.009.
Dis. 2011;17(2):187–93. 91. Kadetoff D, Lampa J, Westman M, Andersson M,
79. Blandini F, Rinaldi L, Tassorelli C, Sances G, Motta Kosek E. Evidence of central inflammation in
M, Samuele A, et al. Peripheral levels of BDNF and fibromyalgia-­increased cerebrospinal fluid interleu-
NGF in primary headaches. Cephalalgia. 2006;26(2): kin-­8 levels. J Neuroimmunol. 2012;242(1–2):33–8.
136–42. doi:10.1111/j.1468-2982.2005.01006.x. doi:10.1016/j.jneuroim.2011.10.013.
80. Raychaudhuri SP, Raychaudhuri SK, Atkuri KR, 92. Wallace D, Linker-Israeli M, Hallegua D, Silverman
Herzenberg LA, Herzenberg LA. Nerve growth fac- S, Silver D, Weisman M. Cytokines play an aetio-
tor: a key local regulator in the pathogenesis of pathogenetic role in fibromyalgia: a hypothesis and
inflammatory arthritis. Arthritis Rheum. pilot study. Rheumatology (Oxford).
2011;63(11):3243–52. doi:10.1002/art.30564. 2001;40(7):743–9.
81. Giovengo SL, Russell IJ, Larson AA. Increased con- 93. Burke JG, Watson RW, McCormack D, Dowling FE,
centrations of nerve growth factor in cerebrospinal Walsh MG, Fitzpatrick JM. Intervertebral discs
fluid of patients with fibromyalgia. J Rheumatol. which cause low back pain secrete high levels of
1999;26(7):1564–9. proinflammatory mediators. J Bone Joint Surg.
82. Qu HC, Zhang W, Yan S, Liu YL, Wang P. Urinary 2002;84(2):196–201.
nerve growth factor could be a biomarker for inter- 94. Gerdle B, Kristiansen J, Larsson B, Saltin B, Sogaard
stitial cystitis/painful bladder syndrome: a meta-­ K, Sjogaard G. Algogenic substances and metabolic
analysis. PLoS One. 2014;9(9):e106321. status in work-related Trapezius Myalgia: a multivariate
doi:10.1371/journal.pone.0106321. explorative study. BMC Musculoskelet Disord.
83. Kim SW, Im YJ, Choi HC, Kang HJ, Kim JY, Kim 2014;15:357. doi:10.1186/1471-2474-15-357.
JH. Urinary nerve growth factor correlates 95. Gerdle B, Lemming D, Kristiansen J, Larsson B,
with the severity of urgency and pain. Int Peolsson M, Rosendal L. Biochemical alterations in
Urogynecol J. 2014;25(11):1561–7. doi:10.1007/ the trapezius muscle of patients with chronic whip-
s00192-014-2424-8. lash associated disorders (WAD)–a microdialysis
84. Jiang YH, Peng CH, Liu HT, Kuo HC. Increased study. Eur J Pain. 2008;12(1):82–93. doi:10.1016/j.
pro-inflammatory cytokines, C-reactive protein and ejpain.2007.03.009.
32 A.M. Velly and J. Fricton

96. Munno I, Centonze V, Marinaro M, Bassi A, Lacedra 106. Burkman RT. Chronic pelvic pain of bladder origin:
G, Causarano V, et al. Cytokines and migraine: epidemiology, pathogenesis and quality of life.
increase of IL-5 and IL-4 plasma levels. Headache. J Reprod Med. 2004;49(3 Suppl):225–9.
1998;38(6):465–7. 107. Cernuda-Morollon E, Larrosa D, Ramon C, Vega J,
97. Fidan I, Yuksel S, Ymir T, Irkec C, Aksakal FN. Martinez-Camblor P, Pascual J. Interictal increase of
The importance of cytokines, chemokines CGRP levels in peripheral blood as a biomarker for
and nitric oxide in pathophysiology of chronic migraine. Neurology. 2013;81(14):1191–6.
migraine.  J Neuroimmunol. 2006;171(1–2):184–8. doi:10.1212/WNL.0b013e3182a6cb72.
doi:10.1016/j.jneuroim.2005.10.005. 108. Messlinger K, Fischer MJ, Lennerz JK. Neuropeptide
98. Neziri AY, Bersinger NA, Andersen OK, Arendt-­ effects in the trigeminal system: pathophysiology
Nielsen L, Mueller MD, Curatolo M. Correlation and clinical relevance in migraine. Keio J Med.
between altered central pain processing and concen- 2011;60(3):82–9.
tration of peritoneal fluid inflammatory cytokines in 109. Fischer HP, Eich W, Russell IJ. A possible role for
endometriosis patients with chronic pelvic pain. Reg saliva as a diagnostic fluid in patients with chronic
Anesth Pain Med. 2014;39(3):181–4. doi:10.1097/ pain. Semin Arthritis Rheum. 1998;27(6):348–59.
AAP.0000000000000068. 110. Chen SP, Chung YT, Liu TY, Wang YF, Fuh JL,
99. Murphy SF, Schaeffer AJ, Done J, Wong L, Bell-­ Wang SJ. Oxidative stress and increased formation
Cohn A, Roman K, et al. IL17 mediates pelvic pain of vasoconstricting F2-isoprostanes in patients with
in Experimental Autoimmune Prostatitis (EAP). reversible cerebral vasoconstriction syndrome. Free
PLoS One. 2015;10(5):e0125623. doi:10.1371/jour- Radic Biol Med. 2013;61:243–8. doi:10.1016/j.
nal.pone.0125623. freeradbiomed.2013.04.022.
100. Pike BL, Paden KA, Alcala AN, Jaep KM, Gormley 111. Ardic F, Ozgen M, Aybek H, Rota S, Cubukcu D,
RP, Maue AC, et al. Immunological Biomarkers in Gokgoz A. Effects of balneotherapy on serum IL-1,
Postinfectious Irritable Bowel Syndrome. J Travel PGE2 and LTB4 levels in fibromyalgia patients.
Med. 2015;22(4):242–50. doi: 10.1111/jtm.12218. Rheumatol Int. 2007;27(5):441–6. ­ doi:10.1007/
Epub 2015 Jun 8. s00296-006-0237-x.
101. Vazquez-Frias R, Gutierrez-Reyes G, Urban-Reyes 112. Sinreih M, Anko M, Kene NH, Kocbek V, Rizner
M, Velazquez-Guadarrama N, Fortoul-van der Goes TL. Expression of AKR1B1, AKR1C3 and other
TI, Reyes-Lopez A, et al. Proinflammatory and anti-­ genes of prostaglandin F2alpha biosynthesis and
inflammatory cytokine profile in pediatric patients action in ovarian endometriosis tissue and in model
with irritable bowel syndrome. Revista de gastroen- cell lines. Chem Biol Interact. 2015;234:320–31.
terologia de Mexico. 2015;80(1):6–12. doi:10.1016/j. doi:10.1016/j.cbi.2014.11.009.
rgmx.2014.11.001. 113. Ray K, Fahrmann J, Mitchell B, Paul D, King H, Crain
102. Feng JS, Yang Z, Zhu YZ, Liu Z, Guo CC, Zheng C, et al. Oxidation-sensitive nociception involved in
XB. Serum IL-17 and IL-6 increased accompany endometriosis-associated pain. Pain. 2015;156(3):
with TGF-beta and IL-13 respectively in ulcerative 528–39. doi:10.1097/01.j.pain.0000460321.72396.88.
colitis patients. Int J Clin Exp Med. 114. Clarke G, Fitzgerald P, Hennessy AA, Cassidy EM,
2014;7(12):5498–504. Quigley EM, Ross P, et al. Marked elevations in pro-­
103. Tavakoli-Ardakani M, Mehrpooya M, Mehdizadeh inflammatory polyunsaturated fatty acid metabolites
M, Hajifathali A, Abdolahi A. Association between in females with irritable bowel syndrome. J Lipid
Interlukin-6 (IL-6), Interlukin-10 (IL-10) and Res. 2010;51(5):1186–92. doi:10.1194/jlr.P000695.
depression in patients undergoing Hematopoietic 115. Ohishi K, Ueno R, Nishino S, Sakai T, Hayaishi
stem cell transplantation. Int J Hematol Oncol Stem O. Increased level of salivary prostaglandins in
Cell Res. 2015;9(2):80–7. patients with major depression. Biol Psychiatry.
104. Kalaycioglu E, Gokdeniz T, Aykan AC, Gursoy MO, 1988;23(4):326–34.
Gul I, Ayhan N, et al. Evaluation of right ventricle 116. Fricton J, Schiffman EL. Management of mastica-
functions and serotonin levels during headache tory myalgia and arthralgia. In: Sessle BJ, Lavigne
attacks in migraine patients with aura. Int GJ, Lund JP, Dubner R, editors. Orofacial pain from
J Cardiovasc Imaging. 2014;30(7):1255–63. basic science to clinical management. Chicago:
doi:10.1007/s10554-014-0456-2. Quintessence Publishing Co, Inc; 2008. p. 179–85.
105. Munoz M, Covenas R. Involvement of substance P and
the NK-1 receptor in human pathology. Amino Acids.
2014;46(7):1727–50. doi:10.1007/s00726-014-1736-9.
 Part II
Mechanisms of Chronic Orofacial Pain
 Neurobiological Mechanisms
of Chronic Orofacial Pain
3
Barry J. Sessle

Abstract
This chapter reviews the several mechanisms in orofacial tissues and
trigeminal nociceptive pathways in the brain that may account for
chronic orofacial pain. Peripheral sensitization and central sensitization
are particularly emphasized since they have characteristics that can
explain the spontaneous nature, hyperalgesia, allodynia, and spread and
referral of pain resulting from injury or inflammation of orofacial tissues
and nerves. The chapter also notes several neural and non-neural modu-
latory factors influencing these mechanisms and their clinical
implications.

3.1 Introduction pain conditions in particular can present diagnos-

tic and management challenges to the clinician.
Pain is a multidimensional experience encom- This is because of (i) the complex, even bizarre,
passing sensory-discriminative, cognitive, affec- nature of some of these pains; (ii) the multidi-
tive, and motivational dimensions, the expression mensional experience of pain itself that reflects a
of which can vary from one individual to another host of biopsychosocial influences; (iii) the spe-
[1, 2]. The face, mouth, and jaws represent some cial biological, emotional, and psychological
of the most common areas of pain in the body, meaning that the face and mouth have to humans;
and epidemiological studies have documented and (iv) the limited knowledge of the etiology,
the high prevalence of several acute or chronic pathogenesis, and mechanisms underlying the
orofacial pain conditions [3–5]. These chronic initiation and progression of these pain condi-
tions. This chapter reviews recent advances in our
understanding of the mechanisms underlying
orofacial pain, and chronic orofacial pain in par-
B.J. Sessle, MDS, PhD, DSc (hc), FRSC, FCAHS
Faculties of Dentistry and Medicine, University of
ticular, in order to assist clinicians in their man-
Toronto, Toronto, Canada agement of the various chronic orofacial pain
Faculty of Dentistry, University of Toronto,
conditions. It first outlines relevant orofacial
124 Edward Street, Toronto, ON, M5G 1G6, Canada pathways and mechanisms and then focusses on
e-mail: [email protected] processes involved in chronic orofacial pain.

© Springer-Verlag GmbH Germany 2017 35

J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI 10.1007/978-3-662-53994-1_3
36 B.J. Sessle

3.2  verview of Orofacial

O with some of the small-diameter, slow-­conducting
Nociceptive Pathways primary afferent fibers that are either myelinated
and Mechanisms (e.g., A-δ afferents) or unmyelinated (C-fiber
afferents), and these thermoreceptive primary
3.2.1 Peripheral Processes afferents provide the CNS with accurate informa-
tion on the location, magnitude, and rate of the
The fifth cranial nerve, the trigeminal nerve, pro- temperature change. There are of course also
vides the major sensory innervation of the face, chemoreceptors in the oral cavity and nose that
mouth, and jaws. These tissues are densely inner- through other cranial nerves provide the CNS
vated by trigeminal primary afferent (i.e., sen- with information related to taste and smell.
sory) nerve fibers, each of which terminates Many of the free nerve endings in the orofa-
peripherally as nerve endings termed receptors cial tissues function as receptors (nociceptors)
that “sense” stimuli applied to the face, mouth, that sense the occurrence of a noxious stimulus
and jaws. As a result of these stimuli, action [6–8]. They are the endings of primary afferents
potentials may be generated by these receptors in that are small diameter and slowly conducting
their associated afferent fibers, which conduct the (Aδ and C fibers). Several chemical mediators
action potentials into the brainstem. The orofa- and cellular changes occur following the noxious
cial receptors can be broadly categorized into two stimulus, resulting in the activation of the noci-
types: specialized or corpuscular receptors, of ceptive endings and their associated nociceptive
which several anatomically distinct types exist, afferents, which conduct the nociceptive signals
and free nerve endings. into the CNS and thus may lead to the experience
Many of the receptors associated primarily of pain. A prolonged increase in their excitability
with large-diameter, fast-conducting myelinated (so-called nociceptor or peripheral sensitization)
primary afferent fibers (A-β afferents, some A-δ may also occur, to such an extent that they
afferents) function as low-threshold mechanore- become more responsive to subsequent noxious
ceptors since they respond to innocuous mechan- stimuli or even start responding to stimuli that
ical stimuli applied to the localized orofacial area normally are innocuous; they may also develop
supplied by the afferent (i.e., the receptive field of spontaneous (background) activity. In addition,
the afferent). There are mechanoreceptors in the some mechanically or thermally insensitive end-
facial skin, oral mucosa, periodontal tissues, peri- ings (“silent nociceptors”) may be activated or
osteum, jaw muscles, and temporomandibular sensitized by noxious chemical stimuli and then
joint (TMJ), and their mechanoreceptive primary become responsive to noxious stimuli.
afferents provide sensory inputs into the central It has become apparent over the past two
nervous system (CNS) that reflect detailed infor- decades that the mechanisms involved in the acti-
mation of the quality, location, intensity, dura- vation or peripheral sensitization of orofacial
tion, and rate of movement of an orofacial nociceptive endings are very complex [7, 9, 10].
mechanical stimulus [6, 7]. Mechanoreceptors Ion channels or membrane receptors occur on the
located in the periodontal tissues, TMJ, and jaw nociceptive afferent endings and include seroto-
muscles also account for our ability to detect and nergic, cholinergic, opioid, purinergic, bradyki-
discriminate the size of small objects placed nin, histamine, prostaglandin, anandamide,
between the teeth, their hardness and texture, and excitatory amino acid and acid-sensitive recep-
bite force. Receptors in the TMJ and jaw muscles tors, adrenoreceptors, and vanilloid receptors
also underlie our conscious perception of jaw [11–13]. Some of these ion channels and mem-
position (mandibular kinesthesia). The orofacial brane receptors are activated, or their afferent
region also has thermoreceptors that are specifi- endings are sensitized relatively directly by sev-
cally activated by a small thermal change in eral types of noxious mechanical, chemical, and
either a cooling (cold receptors) or warming thermal stimuli (e.g., some vanilloid receptors
(warm receptors) direction. They are associated [TRPVI] respond to protons (H+), heat, and alge-
3 Neurobiological Mechanisms of Chronic Orofacial Pain 37

sic chemicals such as capsaicin), whereas others cially of nerve fibers, can also cause changes in
are acted upon by intermediary chemical media- the properties of trigeminal ganglion cell bodies
tors that are released in the peripheral tissues as a that may contribute to an abnormal sensory input
result of the noxious stimulus causing injury to into the brainstem (see Sect. 3.3).
the tissues. In addition, noxious stimuli produc- There are several clinically relevant aspects of
ing tissue damage may cause the release of neu- these peripheral processes. Peripheral sensitiza-
rochemicals that are synthesized in the trigeminal tion of the nociceptive afferents is an important
ganglion cell bodies of the primary afferents process contributing to the increased sensitivity
themselves and released from their afferent end- that is usually a feature of a peripheral injury or
ings; these include substance P, calcitonin gene- inflammation site, e.g., as in the pain of a sun-
related peptide (CGRP), somatostatin, glutamate, burn, arthritis, myositis, and pulpitis. The
and nerve growth factors. Some of these neuro- increased sensitivity may be reflected as an exag-
chemicals act on platelets, macrophages, mast gerated perceptual response to a noxious stimu-
cells, and other cells of the immune system to lus (“hyperalgesia) or as a pain response to a
cause them to release inflammatory mediators stimulus (e.g., tactile) that is normally innocuous
such as serotonin (5-HT), histamine, bradyki- (“allodynia”) or as an ongoing spontaneous pain;
nins, and cytokines. The resulting redness, the sensitization of adjacent afferent endings
edema, and local temperature increases reflect beyond the initial injury site is a peripheral pro-
what has been termed neurogenic inflammation cess contributing to the spread of pain in these
since the inflammation may be initiated from tissues. Furthermore, the identification of sub-
these chemical mediators released from the nerve stances released in painful tissues (e.g., gluta-
fibers themselves. Many of the chemical media- mate, 5-HT, etc.) suggests that they may prove
tors also spread through the tissues and act on the useful as biomarkers for certain types of pain
ion channels and membrane receptors of adjacent states [13, 14], and other chapters in this book
nociceptive afferent endings and contribute to discuss this further (Chaps. 6, 7, 8, and 9). Also,
their peripheral sensitization. Glutamate, for the physiologically based sex differences noted
example, is synthesized in the primary afferent above in the sensitivity of jaw muscle and TMJ
cell bodies in the trigeminal ganglion and is nociceptive afferents to glutamate and opiate-­
released from not only the central endings of the related substances (i.e., morphine) may also con-
primary afferents in the CNS (i.e., brainstem) but tribute, along with the sex differences documented
also from their endings in the orofacial tissues. in environmental and psychosocial influences
Some afferent endings in peripheral tissues have and the sex differences in CNS nociceptive
glutamatergic receptors (N-methyl-D-aspartate mechanisms [4], to the sex differences in many
[NMDA] and non-­NMDA receptors) by which orofacial pain conditions involving these tissues.
glutamate may excite or sensitize the nociceptive Another clinically significant point is that
afferents. Some other chemical mediators (e.g., some drugs that are commonly used to relieve
opioids and δ-amino butyric acid [GABA]) in orofacial pain may exert their analgesic action by
contrast may decrease afferent excitability by interfering with some of these peripheral mecha-
acting on GABA and opiate receptors on the nisms. Indeed, many common nonsteroidal anti-­
afferent endings. Interestingly, there is a sex dif- inflammatory drugs (NSAIDs) as well as several
ference in the peripheral action of glutamate and recently developed analgesics (e.g., cyclooxy-
the opiate-­related drug morphine; e.g., jaw or genase-­2 [COX-2] inhibitors) have their principal
TMJ muscle nociceptive afferents show a greater analgesic action by their influence on processes
sensitivity in females than in males to the appli- that enhance the excitability of nociceptive affer-
cation of glutamate, but females are less sensitive ent endings. Furthermore, local anesthetics are
than males to the peripheral application of mor- effective for nerve blocks in eliminating pain
phine [7, 8]. There is also increasing evidence resulting from peripheral tissue injury because
that orofacial tissue inflammation or injury, espe- they interfere with the ionic channels and c­ urrents
38 B.J. Sessle

involved in the initiation and conduction of action Such modulatory mechanisms may explain how
potentials along the nociceptive afferents into the distraction or focusing one’s attention on a par-
CNS [12, 13]. ticular task at hand can depress our awareness,
for example, of the extensive mechanosensory
inputs into the CNS from the mechanoreceptors
3.2.2 Central Pathways that are being activated by our clothing.
and Processes In the case of orofacial thermosensation, the
main brainstem relay site of the signals carried in
The primary afferent nerve fibers in the trigemi- the orofacial thermoreceptive primary afferent
nal nerve project via the trigeminal ganglion and fibers is the trigeminal subnucleus caudalis.
the trigeminal sensory nerve root into the trigem- Some caudalis neurons appear to be exclusively
inal brainstem sensory nuclear complex, which activated by thermal stimulation of localized
can be subdivided into a main sensory nucleus parts of the face and mouth and relay this thermal-­
and a spinal tract nucleus; the latter is subdivided related information to the contralateral thalamus
further into the subnuclei oralis, interpolaris, and and then to the somatosensory cerebral cortex.
caudalis. The neural signals evoked by a light Subnucleus caudalis also is the major brainstem
mechanical stimulus (e.g., tactile) of an orofacial relay site of orofacial pain-related information, as
tissue are transferred (via synaptic transmission) noted below.
from the brainstem endings of the mechanore- The vast majority of the nociceptive primary
ceptive primary afferents to low-threshold mech- afferent fibers supplying the face and mouth proj-
anosensitive (LTM) neurons at all levels of the ect via the trigeminal ganglion to the trigeminal
trigeminal brainstem sensory nuclear complex brainstem sensory nuclear complex, especially to
[2, 6, 10]. These second-order neurons conduct the subnucleus caudalis where they release the
the signals onward to local brainstem regions, chemical mediators that are synthesized in the
including those responsible for activating or sup- primary afferent trigeminal ganglion cell bodies
pressing muscles, and thereby serve as interneu- (see above). These include glutamate and the
rons involved in reflexes or more complex neuropeptide substance P which activate neurons
sensorimotor behaviors. Another major projec- in the trigeminal brainstem complex by acting,
tion from the LTM neurons in the trigeminal spi- respectively, on glutamatergic receptors
nal tract nucleus and especially the main sensory (N-methyl-D-aspartate [NMDA] and non-­
nucleus is to LTM neurons in the ventroposterior NMDA receptor subtypes) and neurokin recep-
thalamus (termed the ventrobasal thalamus in tors on the neurons. Many caudalis neurons
subprimates), principally on the contralateral receive the signals from these orofacial nocicep-
side of the brain [2, 15]. Many of these thalamic tive primary afferents and thus can be excited by
LTM neurons project to parts of the overlying noxious stimulation of the face and mouth, TMJ,
cerebral cortex, including the so-called somato- masticatory muscles, or meninges [6, 10]. These
sensory cortex involved in the perception of an caudalis nociceptive neurons have been catego-
orofacial touch stimulus. It has an extensive and rized as either wide dynamic range (WDR) neu-
disproportionate representation of the face and rons or nociceptive-specific (NS) neurons, and
mouth relative to other body regions, reflecting analogous neurons exist in the spinal dorsal horn
the importance of sensory information from oro- of the spinal nociceptive pathways. The WDR
facial tissues compared to most other body neurons are activated by non-noxious (e.g., tac-
regions. It is also noteworthy that the complex tile) stimuli as well as by noxious stimuli applied
ultrastructure and regulatory processes that exist to an orofacial receptive field and receive large-­
at each of the brainstem, thalamus, and cortical diameter (A-β) and small-diameter (A-δ and C
relay sites underlie the considerable modification fiber) afferent inputs. In contrast, NS neurons
of the synaptic transmission of the tactile-related normally respond only to noxious stimuli (e.g.,
signals that can occur at each of these CNS l­ evels. pinch, heat) and receive small-diameter afferent
3 Neurobiological Mechanisms of Chronic Orofacial Pain 39

inputs from A-δ and/or C fibers. Both types of transmission. Some of these processes are
neurons relay nociceptive information to other involved in modifying touch, as noted above, but
brainstem regions and also to the contralateral modulation of nociceptive transmission in the tri-
thalamus from where it is then relayed from anal- geminal system can also occur. For example, the
ogous WDR or NS neurons to the overlying cere- responses of caudalis nociceptive neurons to
bral cortex or other thalamic regions [2, 6, 10, 15] small-fiber nociceptive afferent inputs can be
where the information is processed and expressed markedly suppressed by large-fiber afferent
as one or more of the many dimensions of the inputs to caudalis that are activated by tactile
pain experience (see Sect. 3.1). stimulation of orofacial tissues (so-called sensory
Although some differences between the two interaction); in some situations, even small-fiber
structures do exist, there is a close structural and nociceptive afferent inputs from other parts of the
functional homology between subnucleus cauda- body may also suppress their activity. Their activ-
lis and the spinal dorsal horn, and so subnucleus ity can also be suppressed by intrinsic inputs to
caudalis has become known also as the medullary caudalis from the spinal cord, brainstem, and
dorsal horn [6, 16]. Nonetheless, subnucleus cau- higher CNS centers, such as the reticular forma-
dalis is not the only or essential brainstem ele- tion, the periaqueductal gray, rostroventral
ment in orofacial nociceptive transmission since medial medulla, and sensorimotor cortex. These
there is evidence that some of the more rostral modulatory influences result from endogenous
subdivisions of the trigeminal brainstem com- neurochemicals, such as opioids, 5-HT, norepi-
plex, especially subnuclei interpolaris and oralis, nephrine, and GABA, being released from these
may also play an important role [2, 17]. For inputs and acting on the caudalis nociceptive
example, afferent fibers from the tooth pulp, gen- neurons. Modulatory influences on trigeminal
erally assumed to represent a nociceptive input, nociceptive transmission may also occur at tha-
synapse with neurons present not only in subnu- lamic and cortical levels [2, 10, 18].
cleus caudalis but also in the more rostral compo- There are several clinically relevant points
nents of the complex, and the transitional zone about these modulatory influences. The influ-
between subnuclei caudalis and interpolaris has ences on the nociceptive neurons of state of alert-
recently been shown to be important in muscle, ness, sleep, distraction and attention, and cognitive
autonomic, and endocrine responses to noxious behavioral therapy are examples of behavioral
orofacial stimuli and in intrinsic CNS modula- factors whereby descending influences emanating
tory influences on orofacial nociceptive from CNS regions involved in these behavioral
transmission. functions and operating at the trigeminal brain-
stem complex and at higher brain levels may
3.2.2.1 Modulatory Processes affect orofacial pain [2, 10, 19]. Placebo analge-
and Influences sia, which contributes to the effect of most pain-
At each relay in the trigeminal somatosensory relieving procedures, also involves some of these
pathways, the transmission process may vary systems [10, 20, 21]. Descending influences also
depending on such diverse factors as matura- have been implicated as intrinsic mechanisms
tional stage, age and sex, and behavioral state of contributing to the analgesic effects of several
the individual, plus genetic, nutritional, and other procedures used to control pain. Morphine,
immunological influences [2, 10, 18]. The intri- for example, suppresses the activity of the noci-
cate organization of the trigeminal brainstem ceptive neurons by mimicking the action of the
complex, especially subnucleus caudalis, as well endogenous opioid chemical enkephalin which is
as the numerous afferent inputs to the trigeminal a peptide that is pharmacologically similar to the
brainstem complex from peripheral tissues and opiate drugs such as morphine and which acts on
from several CNS regions, provides the neural opiate receptors existing on the nociceptive neu-
circuitry for the several interactions between rons and on neurons in some of the intrinsic mod-
these many inputs that influence somatosensory ulatory pathways. Other p­ ain-­relieving drugs act
40 B.J. Sessle

on other receptor processes to suppress the neu- caudalis and especially involves the release from
rons, for example, amitriptyline on 5-HT receptor the caudalis endings of trigeminal nociceptive
processes and pregabalin on voltage-gated cal- afferents of excitatory amino acids (e.g., gluta-
cium channels [22, 23]. The analgesic effects of mate) that act via NMDA receptor mechanisms
some physical procedures (such as acupuncture or to induce a cascade of intracellular events in cau-
transcutaneous electrical nerve stimulation) dalis nociceptive neurons [2, 10, 24, 25]. A num-
appear also to involve some of these endogenous ber of other brain chemicals such as those
neurochemical processes and intrinsic pain-mod- operating through neurokinin, opioid, GABA,
ulatory circuits [2, 10]. and 5-HT receptor mechanisms contribute to or
On the other hand, some modulatory CNS modulate these central neuroplastic changes
pathways have the opposite effect, i.e., facilita- induced by peripheral injury or inflammation.
tion of the nociceptive neurons, and contribute to Other factors that influence these changes include
the enhancement of pain, as might occur, for genetic and environmental factors as well as non-­
example, in the development and persistence of a neural (e.g., glial) cells, as noted below.
chronic pain state or in the enhanced pain levels
associated with fear, anxiety, and catastrophizing
(Chap. 2). Facilitatory interactions also occur 3.3  hronic Orofacial Pain
C
between various convergent afferent inputs to tri- Mechanisms
geminal nociceptive neurons in the CNS and con-
tribute to the so-called referral of pain that may With this background in processes underlying
sometimes occur following tissue injury or orofacial nociceptive transmission and its modu-
inflammation (see Sect. 3.3.2 below). An espe- lation, we can now focus on the peripheral and
cially noteworthy facilitatory effect may be initi- CNS mechanisms contributing to chronic orofa-
ated by injury or inflammation of peripheral cial pain states.
tissues and can result in a prolonged increase in As Chap. 2 notes, chronic orofacial pain may
excitability of nociceptive neurons in the accompany several types of painful and non-­
CNS. This so-called central sensitization is painful comorbidities. Chronic orofacial pain
thought to be an important process contributing also can arise following injury or inflammation of
to the hyperalgesia, allodynia, and pain referral orofacial tissues, including that associated with
that characterize pain resulting from an orofacial dental treatments (e.g., following endodontic
injury or inflammation [2, 10, 24]. Furthermore, treatment, dental implant placement, orthogna-
the development and maintenance of a central thic surgery, tooth extraction), emphasizing the
sensitization state appears to underlie most importance of trying to provide appropriate and
chronic pain conditions. Central sensitization timely management of acute pain so as to reduce
reflects a neuroplasticity of the nociceptive path- the likelihood that it will transition into a chronic
ways in the CNS and emphasizes that the noci- pain state (see Chap. 2). But for several chronic
ceptive system is not hard wired but is dynamic orofacial pain conditions (e.g., temporomandibu-
and plastic, such that its excitability can change lar disorders [TMD], burning mouth syndrome,
from one moment to another depending on the trigeminal neuralgia, so-called atypical odontal-
signals that its constituent WDR and NS neurons gia or persistent idiopathic facial pain), the etiol-
receive from peripheral tissues and on the CNS ogy and pathogenesis are still unclear. The
state of the individual. Central sensitization is following sections on peripheral processes and
manifested as an increase in excitability (e.g., central processes outline what is known of the
spontaneous activity, increased receptive field peripheral and CNS processes that are associated
size and responses to noxious stimuli, decreased with chronic inflammatory or neuropathic pain
activation threshold) of WDR and NS neurons. states and how they may explain chronic ­orofacial
In the trigeminal nociceptive system, central pain conditions. It is noteworthy that while many
sensitization has been most studied in subnucleus of these conditions may involve processes similar
3 Neurobiological Mechanisms of Chronic Orofacial Pain 41

to those in the spinal nociceptive system, there channels on the endings and contribute, for
are some differences between trigeminal and spi- example, to spontaneous or ectopic discharges
nal systems [6, 16]. For example, recovery from that are conducted along the afferents into the
injury or inflammation may be faster in the tri- brainstem; such changes have been implicated in
geminal system, autonomic responses differ (e.g., the development of many types of neuropathic
no sprouting of sympathetic terminals on trigem- pain including those manifested in the orofacial
inal ganglion cells following peripheral nerve region [9, 24, 26]. On the other hand, if the nerve
injury), and the specific patterns of up- and injury transects afferent nerve fibers, there may
downregulation of some ion channels and neuro- be loss of sensation in the peripheral area sup-
chemicals in primary afferents appear to be dif- plied by the transected afferents, but the neuropa-
ferent between the two systems following chronic thology may still produce a neuropathic pain
inflammation or injury. Thus, it cannot be state because of the central consequences of the
assumed that processes involved in chronic nerve injury (see below). Nociceptive afferents
inflammatory or neuropathic pain states in the may also become sensitive to sympathetic modu-
spinal system can be automatically applied to the lation following nerve injury, and this is thought
trigeminal system. to contribute to some pain conditions, e.g., some
types of complex regional pain syndrome [9, 27].
It is important to note that changes are not lim-
3.3.1 Peripheral Processes ited to the peripheral endings of the primary affer-
ents. Injury or inflammation of orofacial tissues,
It was noted earlier in the peripheral processes including primary afferent nerve fibers, can also
section that peripheral sensitization is reflected in be associated with persistent physiological and
enhanced spontaneous firing, an increase in neurochemical changes in the neuronal cell bod-
responsiveness to noxious stimuli, and a decrease ies of the primary afferents in the trigeminal gan-
in activation threshold of nociceptive primary glion and involve modulatory influences on the
afferents, features that may contribute to the ganglion neuronal cell bodies from non-­neural
spontaneous pain, hyperalgesia, and allodynia (satellite glial cells) that are closely associated
that characterize many pain states, such as the with the cell bodies [24, 28]. The injury or inflam-
increased sensitivity of the temporomandibular mation can send signals via the involved afferent
tissues in TMD, and the thermal sensitivity and nerve fibers to the trigeminal ganglion and pro-
spontaneous pain of an inflamed tooth [7, 9, 10, duce alterations in gene expression, intracellular
13]. In addition, the spread of pain that occurs signaling (e.g., ERK, p38MAPK, phosphatases),
following tissue injury or inflammation may be and excitability of the ganglion neurons. The sat-
explained by the chemical mediators released as ellite glial cells may also show intracellular
part of the peripheral sensitization process that changes and themselves can be acted upon by
may spread through the tissues to act upon adja- chemical mediators (e.g., substance P, CGRP,
cent nociceptive afferent endings. Peripheral sen- ATP) released from the affected neurons. The
sitization is normally reversible and gradually existence of gap junctions between these cells,
dissipates as the injured or inflamed tissue heals. and between them and the neurons, provides an
But persistence of a peripheral inflammatory additional process by which the satellite glial cells
state and the continual sensitizing effect of chem- and neurons may communicate and contribute to
ical mediators on nociceptive afferent endings the spread of excitation in the trigeminal gan-
(e.g., as in an arthritic joint) can lead to accompa- glion. These forms of communication between
nying CNS changes (see below) and thereby to a them may explain recent findings that injury to
chronic pain state. Likewise, nerve injury may sensory nerves or inflammation of one trigeminal
affect the nociceptive endings by producing pro- division (e.g., V3) can lead to excitability changes
longed changes in the expression and activity of in trigeminal ganglion neurons subserving another
voltage-gated calcium, sodium, or potassium ion division (e.g., V2) [24, 25]. It is however not yet
42 B.J. Sessle

clear if the neurons involved in these changes are abnormal afferent inputs in the production of an
nociceptive and/or non-nociceptive neurons. altered CNS state that, as the following section
Nonetheless, these cellular events in the trigemi- indicates, underpins the development and main-
nal ganglion likely are important processes tenance of a chronic orofacial pain condition.
involved in the generation of increased or abnor-
mal trigeminal afferent inputs to the brainstem
that can influence neuronal and glial cell func- 3.3.2 Central Processes
tions in the central trigeminal nociceptive pro-
cesses underlying orofacial chronic pain As noted above, a number of alterations can
mechanisms. occur in the CNS in association with tissue injury
The clinical implications of these events in or inflammation and contribute to the develop-
peripheral orofacial tissues and trigeminal gan- ment and maintenance of a chronic orofacial pain
glion are several. As noted above, the alterations condition. Central sensitization appears to be the
in the properties of trigeminal nociceptive affer- dominant central neural change associated with
ents as part of the peripheral sensitization process these pain states.
may contribute to spontaneous pain, hyperalge- Central sensitization reflected in a hyperexcit-
sia, allodynia, and pain spread in chronic pain ability of brainstem nociceptive neurons in tri-
states. In addition, it was noted earlier (Sect. geminal subnucleus caudalis has been well
3.3.1) that the several chemical mediators and documented in several chronic as well as acute
cellular processes involved in the activation or inflammatory or neuropathic pain models [10,
sensitization of the nociceptive afferents repre- 24, 25]. Central sensitization also occurs in other
sent potential or realized targets of peripherally components of the trigeminal brainstem complex
acting analgesic (e.g., COX-2 inhibitors, local (e.g., subnucleus oralis and the interpolaris/cau-
anesthetics). Nonetheless, the multiplicity of pro- dalis transitional zone) as well as at higher levels
cesses, often acting in parallel, implies that tar- of the trigeminal nociceptive system (e.g., thala-
geting only one or a few of them is unlikely to mus) although it appears to depend on the func-
have a significant analgesic impact [12]. The tional integrity of subnucleus caudalis for its
recent findings of spread of excitation to other expression since it can be abolished in these CNS
trigeminal division(s) within the ganglion follow- sites by experimentally blocking the synaptic
ing inflammation or injury within another trigem- function of subnucleus caudalis [36]. It is also
inal division also have clinical relevance since noteworthy that excitability changes following
such a process could conceivably be important in trigeminal nerve injury are not limited to the tri-
the extraterritorial sensory changes reported in geminal somatosensory system but may also
some clinical cases of chronic pain [29–34]; as occur in CNS regions involved in the psychoso-
noted below, central processes may also contrib- cial functioning of the individual or in motor
ute to such extraterritorial spread. Also of clinical functions such as motor cortex pathways project-
relevance are recent findings in animal models ing to trigeminal motoneurons [37–39] and thus
mimicking the compression of the trigeminal contribute to comorbid psychosocial and motor
ganglion or trigeminal sensory root that has been disruptions that are frequently associated with
reported to occur in many trigeminal neuralgia chronic pain states.
patients and to be of etiological significance. Like peripheral sensitization (see above), cen-
Such compression produces nociceptive behavior tral sensitization appears to be normal physiolog-
in the animals and trigeminal brainstem cellular ical reaction to sustained noxious stimulation,
changes apparently reflecting the consequences and in most situations it is reversible and the pain
of the abnormal afferent inputs to the brainstem state resolves. However, if central sensitization
produced by the compression [35]. These find- becomes maintained, chronic or persistent pain
ings further emphasize the importance of trigem- may develop [2, 10, 24, 25]. Unfortunately, the
inal ganglion changes and the generation of factors that predispose to the prolongation of
3 Neurobiological Mechanisms of Chronic Orofacial Pain 43

these reactions to tissue injury or inflammation chemical, and behavioral studies in animal
are not yet well understood, but there is emerging models of chronic orofacial inflammatory or neu-
evidence that they include genetic as well as ropathic pain have documented a role for both
environmental, immunological, and psychophys- astrocytes and microglia in trigeminal central
iological factors [10, 40]. For example, different sensitization. For example, interfering with glial
rodent strains may express different levels of tri- cell function in the medulla can prevent the
geminal central sensitization and nociceptive development of trigeminal central sensitization
orofacial behavior, and environmental influences in caudalis nociceptive neurons and the associ-
related to stress may also modify the behavior ated nociceptive behavior of the animal and can
[41, 42]. Recent findings also point to changes in also reverse the sustained central sensitization
the inhibitory or facilitatory intrinsic modulatory and nociceptive behavior that are a feature of
processes that were noted earlier to influence tri- chronic orofacial pain models [10, 24, 25, 28].
geminal nociceptive processing in the CNS. An The normal or baseline nociceptive processing,
increase in descending facilitatory influences or a in caudalis neurons, for example, is not affected
decrease in inhibitory influences can enhance tri- by blockade of glial cells; only the hyperexcit-
geminal neuronal excitability. Another related able state of the sensitized nociceptive neurons is
mechanism is that in some circumstances, the affected.
normal inhibitory action of the neurotransmitter These recent findings are of clinical impor-
GABA is switched in chronic pain models to an tance from several perspectives. The documenta-
action that facilitates neuronal excitability lead- tion of the critical role in trigeminal central
ing to a centrally sensitized state [43]. sensitization of glial cells offers the possibility of
Recent findings also point to another factor new therapeutic targets for pain control, which
important in the development and maintenance of pharmacologically in the past has been domi-
a centrally sensitized state. Like the involvement nated by drugs targeting neuronal mechanisms.
of non-neural cells in peripheral tissues and the In addition, central sensitization reflects a neuro-
trigeminal ganglion in chronic inflammatory and plasticity of the trigeminal nociceptive system,
neuropathic pain states (see above), central sensi- and more and more evidence is emerging from
tization in subnucleus caudalis nociceptive neu- brain imaging and other approaches in humans
rons also involves non-neural cells. Indeed it is that such neuroplasticity in certain CNS regions
dependent on the functional integrity of glial is associated with a chronic pain state such as
cells in the brainstem. There are two types of TMD, trigeminal neuralgia, or other neuropathic
CNS glial cells that are particularly involved, pain conditions [44] and may prove useful as a
namely, astrocytes and microglia. Glial cells are pain biomarker.
even more numerous than neurons in most CNS The recent findings in chronic pain states of
areas, and they normally serve to nurture neu- changes in excitability occurring in orofacial
rons, maintaining the chemical environment motor pathways (e.g., motor cortex) and the
around them and protecting and assisting in their changes that may occur in CNS regions involved
repair and regeneration following injury, infec- in psychosocial functions are also clinically rele-
tion, or inflammation. In the brainstem and spinal vant. Such alterations may contribute to the
cord, they are in close proximity to neurons and motor limitations and psychosocial problems that
the afferent inputs to the neurons and so are are often seen in chronic orofacial pain
uniquely placed to interact with them. Indeed, conditions.
following injury or inflammation of orofacial tis- Also of clinical relevance are the features of
sues, those in subnucleus caudalis and adjacent central sensitization of nociceptive neurons in tri-
regions become “activated” and release inflam- geminal nociceptive pathways in chronic orofa-
matory cytokines and other substances that can cial pain models, namely, spontaneous activity,
influence the excitability of the nociceptive neu- hyperexcitable responses to noxious stimuli, and
rons. Recent electrophysiological, immunocyto- decreased activation threshold, which also reflect
 Another Random Document on
Scribd Without Any Related Topics
 As in the case of my Civic Ritual “The New Citizenship”[7] this
Masque can only have its completely adequate production on a large
and elaborate scale. Like the Civic Ritual, however, which—originally
designed for the New York stadium—is being performed on an
adapted scale in many parts of the country, in schools and
elsewhere, this Masque may perhaps serve some good purpose in
being made available for performance in a smaller, simpler manner,
adapted to the purposes of festivals during this year of
Shakespeare’s Tercentenary. At the invitation, therefore, of Mr.
Percival Chubb, President of the Drama League of America, who first
suggested to me the writing of a Memorial Masque to Shakespeare,
the publishers have made arrangements with officers of the Drama
League for making known its availability as stated in their
announcement printed at the back of this volume.
The accompanying stage-designs are the work of Mr. Joseph
Urban, the eminent Viennese artist and producer [who has recently
become an American], and of Mr. Robert Edmond Jones, designer of
the scenes and costumes for Mr. Granville Barker’s production of
“The Man Who Married a Dumb Wife.”
At the date of this preface, Mr. Arthur Farwell has nearly
completed his compositions for the lyric choruses and incidental
music of the Masque. The choruses will shortly be made available,
published by G. Schirmer, New York.
With all three of these artists I am fortunate in being associated
in preparations for the Masque’s New York production next May.
These preparations have met with many complex difficulties of
launching and organization; the time remaining is very brief to
accomplish the many-sided community task for which the Masque is
designed; only the merest beginnings of so vast a movement can be
attempted; but, with coöperation and support from those who
believe in that task, the producers look forward hopefully to serving,
in some pioneering degree, the great cause of community
expression through the art of the theatre.
 Percy MacKaye.
New York, February 22, 1916.
 MASQUE STRUCTURE
The Action
The action takes place, symbolically, on three planes: (1) in the
cave of Setebos (before and after its transformation into the theatre
of Prospero); (2) in the mind of Prospero (behind the Cloudy
Curtains of the inner stage); and (3) on the ground-circle of “the
Yellow Sands” (the place of historic time).

The Time
The Masque Proper is concerned, symbolically, with no literal
period of time, but with the waxing and waning of the life of
dramatic art (and its concomitant, civilization) from primitive
barbaric times to the verge of the living present.
The Interludes are concerned with ritualistic glimpses of the art
of the theatre (in its widest, communal scope) during three historical
periods: (1) Antiquity, (2) the Middle Ages, and (3) Elizabethan
England.
The Epilogue is concerned with the creative forces of dramatic art
from antiquity to the present, and—by suggestion—with the future
of those forces.

The Setting
The setting of the entire Masque is architectural and scenic, not a
background of natural landscape as in the case of most outdoor
pageants. Being constructed technically for performance, on a large
scale, by night only, its basic appeals are to the eye, through expert
illusions of light and darkness, architectural and plastic line, the
dance, color, and pageantry of group movements; to the ear,
through invisible choirs and orchestra, stage instrumental music and
voices of visible mass-choruses [in the Interludes only].
As indicated by the accompanying diagram [Time Chart][8] of its
Inner Structure, the Masque Proper is enacted by a comparatively
few [about thirty] professional actors, who use the spoken word to
motivate the large-scale pantomime of their action; the Interludes
[which use no spoken word, but only dance, pageantry, miming, and
choruses] are performed by community participants [to the number
of thousands]; the Epilogue utilizes both kinds of performers.
Corresponding to this Inner Structure, the Outer Structure
consists of three architectural planes or acting stages [all
interdependent]: a modified form of Elizabethan stage, [here called
“the Middle Stage—B”] consisting of a raised platform [to which
steps lead up from a ground-circle, eight feet below] provided with a
smaller, curtained Inner Stage [A—under a balcony, on which the
upper visions appear, and above which the concealed orchestra and
choirs are located]. This Inner Stage is two feet higher than the
Middle Stage, from which ramps lead up to it. Shutting it off from
the other, its “Cloudy Curtains,” when closed, meet at the centre;
when they are open, the inner Shakespearean scenes [visions in the
mind of Prospero] are then revealed within.
Between the raised Middle Stage and the audience lies the
Ground-Circle—in form like the “orchestra” of a Greek theatre. Here
the community Interludes take place around a low central Altar, from
which rises a great hour-glass, flowing with luminous sands. This
ground-circle is the place of the Yellow Sands, the outer wave-lines
of which are bordered by the deep blue of the space beyond. The
circle itself, representing the magic isle of Prospero [the temporal
place of his art], is mottled with shadowy contours of the continents
of the world.
Beneath the middle stage, and between the broad spaces of the
steps which lead up to it from the ground-circle, is situated, at
centre, the mouth of Caliban’s cell, which thus opens directly upon
the Yellow Sands.
All of these features of the setting, however, are invisible when
the Masque begins, and are only revealed as the lightings of the
action disclose them.
 GROUND·PLAN
FOR·AUDITORIUM·AND·STAGE
OF·SHAKESPEARE·MASQUE
A·INNER·STAGE·SHAKESPEARE·SCENES
B·MIDDLE·STAGE·ACTION·OF·MASQUE·PROPER·
C·OUTER·STAGE·(ON·THE·YELLOW·SANDS)·ACTION·OF·INTERLUD
ES·
 PERSONS AND PRESENCES
I. OF THE MASQUE PROPER[9]
Speaking Persons
ARIEL
SYCORAX[10]
CALIBAN
PROSPERO
MIRANDA
Lust
Death
War
Caligula [Impersonated by Lust]
One in Gray [Impersonated by Death]
Another in Gray [Impersonated by Caliban]
Mute Presences
SETEBOS[11]
Choral Presences
SPIRITS OF ARIEL
POWERS OF
SETEBOS
Pantomime Groups
Lust Group ┐
Death Group │
Impersonated by the Powers of
War Group ├
Setebos
Roman Group │
The Ones in Gray ┘
Transformation Choir ┐
Gregorian Choir ├ Impersonated by the Spirits of Ariel
The Ones in Green ┘
The Nine Muses
Renaissance Fauns

II. OF THE TEN INNER-STAGE SCENES

[Enacted by the Spirits of Ariel.]
See Appendix: Pages 159-161.
Of these scenes eight are spoken scenes taken from plays of
Shakespeare; one (the sixth) is a pantomime devised from a
descriptive speech in “Henry the Eighth,” Act I, Scene I; one (the
fourth) is a tableau scene symbolic of the early Christian Church.
Those taken from Shakespeare are printed in black-faced type.

III. OF THE INTERLUDES

See Appendix: Pages 162, 166, 172, 184, 187, 190, 195.

IV. OF THE EPILOGUE

Speaking Persons
The Spirit of Time
Shakespeare [as Prospero]
Pantomime Groups[12]
Theatres [with Musicians, Dancers, Designers, Producers,
Inventors, etc.: Creators of the art of the theatre]
Actors
Dramatists
Spirit Trumpeters [Announcers of the Groups]
STAGE·FOR·SHAKESPEARE·MASQUE
·
BEHIND THE CLOUDY CURTAINS IS STAGE A OF INNER SCENES (SEE GROUND
PLAN)
IN FRONT OF THE CURTAINS IS STAGE B OF MASQUE PROPER (SEE GROUND
PLAN)
AT CENTRE, CALIBAN’S CELL OPENS UPON STAGE C OF INTERLUDES (SEE
GROUND PLAN)
CALIBAN
 PROLOGUE
The action begins in semi-darkness, out of which
sound invisible choirs.
The scene is the cave of SETEBOS, whose stark-
colored idol—half tiger and half toad—colossal and
primitive—rises at centre above a stone altar.
On the right, the cave leads inward to the abode of
SYCORAX; on the left, it leads outward to the sea, a blue-
green glimpse of which is vaguely visible.
High in the tiger-jaws of the idol, ARIEL—a slim,
winged figure, half nude—is held fettered.
In the dimness, he listens to deep-bellowing choirs
from below, answered by a chorus of sweet shrill voices
from within.
 THE VOICES FROM BELOW
[Sing.]
Setebos! Setebos!

THE VOICES FROM WITHIN

[Sing.]
Ariel!

ARIEL
[Calls aloud.]
O, my brave spirits!

THE VOICES FROM BELOW

Setebos! Setebos!
Over us which art, and under:
Fang of fire
From mouth of thunder!
Hungering goad
From belly of mire!
Tiger and toad—
Setebos!
Blood which art on the jungle bloom,
Sloth and slumber and seed in the womb:
Which art wondrous
Over and under us,
Setebos! Setebos! Thou art Setebos!

THE VOICES FROM WITHIN

Sealèd in a starless cell,
We are shut from dawn and sky.
Ariel!—Ariel!
Why?

ARIEL
Setebos knows, but his jaws
Fetter me fast: he is dumb—
Answering never.

THE VOICES FROM WITHIN

We, who parch for dew and star—
Ariel!—Ariel!—
Must we perish where we are?
Tell!

ARIEL
Sycorax knows, but she sits
There in the cave with her son—
Mocking us ever.

THE VOICES FROM WITHIN

Ariel!

ARIEL
Call me no more,
Lest they torment us. I hear them
Coming now.

THE VOICE OF SYCORAX

Caliban!

ARIEL
Hush!

[Gigantic, the twisted form of SYCORAX looms from

within the rock.]

SYCORAX
[Calling toward the sea.]
Come, fish-fowl! Leave thy flapping in the mud
And keep thy father’s temple. Call his priests.
Thy father Toad’s a god, hath double teeth
In his two heads. The Tiger loins of him
Begot thee in my belly for a cub
T li k hi d l h i h th
To lick his paws and purr, else he may pinch thee
Behind an eye-tooth, like yon flitter mouse
That hangs there wriggling.

THE VOICE OF CALIBAN

So, so Sycorax!—
Coming!

SYCORAX
Aye, so so: crawling still!

[Malformed and hissing, CALIBAN enters on his belly

and arms.]

CALIBAN
Syc-Syco-
Sycorax! See!

SYCORAX
What hast thou got thee?

CALIBAN
[Laughs, half rising, and holds up a wriggling creature.]
Got
A little god—a little Caliban.
Ha!—make him out of mud. See: Squeezed it round
And slipped him through my fist-hole. Am a god:
[Rising.]
See Sycorax—her grandchild!

SYCORAX
’Tis an eel-worm.
Fling him to the white bat yonder.

[Her form vanishes in the rock.]

CALIBAN
[Approaching the idol.]
[ pp oac g t e do ]
Ariel,
Here’s food for thee: a wormling for thy beak.
So, my trapped bird:—How sayst, ha?

ARIEL
[Sings.]
“Where the bee sucks there suck I.”

CALIBAN
[Laughing.]
Bee, sayst thou?
Still buzzest of thy wings, and eatest—air!

ARIEL
[Sings.]
“In a cowslip’s bell I lie.”

CALIBAN
My father’s gullet is no cowslip’s bell.
Shalt lie in the belly of Setebos.
[Tossing away the eel.]
—What waitest for?

ARIEL
I am waiting for one who will come.

CALIBAN
Aye? Who will come?

ARIEL
One from the heart of the world; and he shall rise
On tempest of music and in thunder of song.

CALIBAN
[Gaping.]
Thunder and tempest—so!

ARIEL
 ARIEL
[With ecstasy.]
I see him now.

CALIBAN
[Crouching back.]
See him! Where, now?

ARIEL
In my dream:—He bears
A star-wrought staff and hooded cloak of blue,
And on his right hand bums the sun, and on
His left, the moon; and these he makes his masks
Of joy and sorrow.

CALIBAN
Where? Mine eye seeth naught.

ARIEL
Before him comes a maid—a child, all wonder—
And leads, him to this blighted isle.

CALIBAN
What for, here?

ARIEL
To set me free, and all my air-born spirits
Whom Setebos holds prisoned in this earth.

CALIBAN
Free? What’s that—free?

ARIEL
What thou canst never be
Who never shalt dance with us by yellow sands.

SPIRITS OF ARIEL
[Sing within.]
[S g t ]
“Come unto these yellow sands,
And then take hands:
Courtsied when you have and kiss’d
The wild waves whist.
Foot it featly here and there”—

CALIBAN
Ho, blast their noises! Stop thy spirits’ squealing.
Their piping itcheth me like hornets’ stings.

SPIRITS OF ARIEL
[Sing on, within.]
“And, sweet sprites, the burthen bear”—

CALIBAN
[Screaming.]
Setebos! Squash ’em!

POWERS OF SETEBOS
[Sing below with strident roarings, drowning the song
of Ariel’s Spirits.]
Setebos! Setebos! Thou art Setebos!

CALIBAN
[Exulting grotesquely.]
Who’ll dance by yellow sands?—Who’s free now, spirit?
Ho, Caliban can squash their music. Free?
Aren’t I a god, bitch-born, the son of Setebos
Can howl all hell up? Worship me, thou wings!
Praise my toad-father in his temple!

ARIEL
The priests
Of Setebos are Lust and Death and War.
Not Ariel—nor Ariel’s Spirits ever—
Shall do them honor. One shall come hereafter
Whom we now worship, waiting.
 o e o o s p, at g

CALIBAN
[Roaring.]
Sycorax!

SYCORAX
[Reappearing.]
Swallow thy croakings, bullfrog. Call the priests,
And fill this spirit’s nostrils with the reek
Of Setebos, his blood-rites.

THE SPIRITS OF ARIEL

[Cry out piercingly.]
Ariel!

ARIEL
Peace, my brave hearts! Be dumb—but still be dreaming!

CALIBAN
Powers of Setebos!—Lust, Death, War,—ho, now!
Hither, and do my father worship!

ARIEL
[Stifling a cry.]
Ah!

[Enter LUST, DEATH, and WAR, arrayed as priests

of Setebos.]

SYCORAX
[To Caliban.]
Come, toad-boy: watch with me, within.

CALIBAN
[Going within the cave, as Sycorax disappears.]
Free, saith?
Will dance by yellow sands?—Now, Spirit, dance!
[As Caliban goes within, the powers of Setebos come forth.
At the altar beneath Ariel, the three Priests lead
them in ceremonial rites of primeval pageantry and
dance—the sacrificial worship of Setebos. Above
them Ariel suffers, with closed eyes. In their
rites, Lust pours his libation, and lights the
altar fire, which—when War has made there his
living sacrifice—Death extinguishes in darkness.
Through the dark, which gradually changes to a glowing
dusky Ariel speaks aloud.]

ARIEL
O Spirits, I have dreamed, but Death has closed
My sight in darkness. Spirits, I have begotten
Sweet Joy, but Lust hath drowned her in his wine.
Yea, I have wove Love wings, but War hath robbed them
And riven his lovely body all alive
To feed the hungering flames of Setebos.
My Spirits, I your master am unmastered.
Speak to me! Comfort me! Is there no joy,
No love, no dream, that shall survive this dark?
Hath this our isle no king but Caliban?
Are there no yellow sands where we shall dance
To greet the master of a timeless dawn?
Or must there break no morning?—Ah, you are dumb
Still to my doubtings. Yet the dark grows pale,
And, paling, pulses now with rosier shadows;
And now the shadows tremble, and draw back
Their trailing glories: hark! All little birds
Wake in the gloaming: look! What young Aurora
Walks in the dusk below, and like a child
Turns her quick face to listen?—Ah!

[Below, against the light from the sea, has entered

the dim Figure he descries.]
 THE FIGURE
Who calls?

ARIEL
Spirits, ’tis she! O, we have dreamed her true
At last—Miranda!

SPIRITS OF ARIEL
[Call, in echoing song.]
Miranda!

MIRANDA
[Searching with her eyes.]
Earth and air
Echo my name. Who calls me?

ARIEL
Ariel.

SPIRITS OF ARIEL
[As before.]
Ariel!

MIRANDA
Light and dark spin webs around me.
What art thou, voice—and where?

ARIEL
Here—and your servant.

MIRANDA
[Beholding him.]
O me!—poor Spirit!—What mouth so terrible
Utters a voice so tender?

ARIEL
Setebos,
God of this isle holds me in ’s fangs
God of this isle, holds me in s fangs.

MIRANDA
But why?

ARIEL
I will not serve him.

MIRANDA
[Naïvely, drawing nearer to the huge idol.]
Setebos, be kind.
Release this Spirit.

ARIEL
He hath nor ears, nor eyes,
Nor any sense to know thee by, but only
These tusks and claws and his toad-belly.

MIRANDA
Dost
Thou suffer, so?

ARIEL
Not now.

MIRANDA
And hath he held thee
Long captive?

ARIEL
Since old ocean’s slime first spawned
Under the moon, I have awaited thee
And him thou bringest here.

MIRANDA
You mean my father,
Prospero.
 ARIEL
[Exultingly.]
Hail him, Spirits!

SPIRITS OF ARIEL
[Sing.]
Prospero!

MIRANDA
Yea, many a starry journey we have made
Searching this isle. At last to-day, at dawn,
I saw its yellow sands, and heard thy voice
Calling for pity. Now my father is come
And shall release thee.

ARIEL
Where? Where is he?

MIRANDA
Here:
His cloak is round us now: he holds us now
In his great art, revealing each to each
Though he be all invisible.

[Reëntering, Caliban comes forward, sniffing and

peering at Miranda.]

CALIBAN
Hath feet
And hair: hath bright hair shineth like a fish’s tail;
Hath mouth, and maketh small, sweet noises.

ARIEL
[Crying out.]
Beast,
Go back!

MIRANDA
 MIRANDA
[Staring, amazed.]
What’s here?

CALIBAN
Ca—Caliban; cometh here
To smell what ’tis.
[He sniffs nearer; then howls strangely.]
Spring in the air: Oho!

MIRANDA
Alas, poor creature! Who hath hurt thee?

CALIBAN
Hurt?
Who hurteth God? Am seed of Setebos:
Am Caliban: the world is all mine isle:
Kill what I please, and play with what I please;
So, yonder, play with him: pull out his wings
And put ’em back to grow.—Where be thy wings,
Spring-i’-the-air?

MIRANDA
O Ariel, is this sight
A true thing, and speaks truly?

ARIEL
What you hear
And see—’tis my master.

MIRANDA
’Tis so wonderful
I know not how to be sad.

CALIBAN
[In puzzled fascination, staring at Miranda.]

The moon hath a face

 e oo at a ace
And smileth on the lily pools, but hath
No lily body withal: thy body is
All lilies and the smell of lily buds,
And thy round face a pool of moonbeams!

MIRANDA
[With smile and laughter.]
Nay,
Then look not in, lest thou eclipse the moon.

CALIBAN
Syc—Sycorax hath no such laughing: soundeth
Like little leaves i’ the rain! Hath no such mouth
Bright-lipp’d with berries ripe to suck i’ the sun—
Sycorax.

MIRANDA
Who is Sycorax?

ARIEL
Ah, pain!

CALIBAN
Ho, she that hath calved Caliban to the bull
Setebos, my blood-sire. [Pauses at a glowing thought,
then cries with sudden exultance:] So shall us twain
Caliban all this world!

[He crouches, then rolls over at her feet.]

—Laugh, Spring-i’-the-air!
Lift so thy lily-pad foot and rub his ear
Where the fur tickleth, and let thy Caliban
Tongue-lick its palm.

[He lies, dog-like, on his back, and laughs loud.]

MIRANDA
 MIRANDA
This wonder grows too wild.

ARIEL
Go, go! O flee away!

CALIBAN
[Leaping up.]
Away?—Aye, so!
[He approaches Miranda, who recoils, half fearful.]
Wist where salt water lappeth warm i’ the noon
And shore-fish breed i’ the shoals.—Wist where the sea-bull
Flap-flappeth his fin and walloweth there his cow
And snoreth the rainbow from his nostrils.

[He begins to dance grotesquely about her.]

Ho,
Spring-i’-the-air! shalt leap, shalt roll in the sun,
Shalt dance with lily-warm limbs, shalt race wi’ the gulls!
Shalt laugh, and call—Come, Come!

Come, come, Caliban!

Catcheth who catcheth can!
Mateth mew, mateth man:
Catch, come, Caliban!

ARIEL
O Setebos, let me go free!

MIRANDA
[To Caliban.]
Peace! Dance no more.
Go hence, and leave me.

CALIBAN
[Staring.]
Hence? Aye both—us twain
 Hence? Aye, both us twain.

MIRANDA
[With simple command.]
Nay, thou alone.

CALIBAN
[With narrowing eyes, draws nearer.]
Saith what?

MIRANDA
[Unafraid.]
Go from me.

CALIBAN
[Stops, with a hissing growl.]
Syc-
Syc-Sycorax! Sycorax!

SYCORAX
[Reappearing.]
Mole in the mire, wilt squeak
When thou art trod on?—Bite! Bite, Setebos’ son!
Let the brave wonder breed of thee.

CALIBAN
Aye, mother.
[With rising passion—to Miranda.]
A child! Shalt bear me such as thou, with head
Of Caliban: no eel-worm, nay—a wonder,
With lily feet, that walk. Ho, Setebos!

SYCORAX
Setebos! Mate them at thine altar.

MIRANDA
[Fleeing from Caliban, pauses in terror of Sycorax.]
Save me!
 POWERS OF SETEBOS
[Sing within.]
Setebos! Setebos!

CALIBAN
[Rushing toward Miranda.]
Mine!

MIRANDA
Save me, father!

ARIEL
[Calling shrilly.]
Prospero!

SPIRITS OF ARIEL
[Sing within.]
Prospero! Hail!

[A clap of thunder strikes, rolling, in sudden darkness.

Lightnings burst from the idol of Setebos.
From the flashing gloom, choruses of contending
spirits commingle the roar of their deep bass and
high-pitched choirs.]

SPIRITS OF ARIEL
Prospero! Prospero!
Out of our earth-pain
Raise and array us
In splendor of order!
Pour on our chaos—
Prospero! Prospero!—
Peace to our earth-pain!

POWERS OF SETEBOS

Setebos! Setebos!
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