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 Dent Clin N Am 51 (2007) xi–xii

Preface

Henry A. Gremillion, DDS

Guest Editor

Since the last issue on temporomandibular (TMD) disorders and orofa-

cial pain presented in the Dental Clinics of North America (April 1997), there
has been an explosion of scientific, technologic, and procedural advances in
this complex field. The amalgamation of the science with the art of dentistry
has resulted from an enhanced appreciation for and the ability to provide
evidence-based diagnosis and care.
Pain and compromised function are the most common reasons for which
people seek health care. Historically, dentistry has been most effective re-
garding the diagnosis and management of acute pain conditions. However,
more than one in four Americans, approximately 75 million people, live in
chronic pain. Many of these individuals experience pain in the orofacial
region. Our role as diagnosticians, becoming physicians of the masticatory
system and orofacial area, is more important than ever. We must develop
an increased clinical awareness of pain and its many facets. For example,
we now appreciate that diagnosis of painful conditions involving the head
and neck is frequently complicated by referred pain or co-existing condi-
tions that may lead the practitioner down a path of well-intentioned but
misdirected care.
Our profession is at the forefront in the establishment of a new and
expanded mind-set reflected in the clinician/scientist model. Dentistry must
assume the role of leader in the field of diagnosis and management of pain
and dysfunction in the most complexly innervated area of the human body,
the stomatognathic system and its contiguous structures.

0011-8532/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.cden.2006.10.004 dental.theclinics.com
xii PREFACE

As guest editor, I wanted to provide a forum in which the many facets of

orofacial pain would be presented. The broad scope and depth of informa-
tion contained in this issue is testimony to the rapidly and ever-expanding
body of clinically relevant information in the field of TMD and orofacial
pain. I wish to thank the authors for their excellent effort and cooperation
in putting this volume together. I am especially grateful to John Vassallo,
editor of the Dental Clinics of North America, for his patience, support,
and guidance.

Henry A. Gremillion, DDS

Department of Orthodontics
Parker E. Mahan Facial Pain Center
University of Florida College of Dentistry
PO Box 100437
Gainesville, FL 32610-0437, USA
E-mail address: [email protected]fl.edu
 TEMPOROMANDIBULAR DISORDERS AND OROFACIAL PAIN

CONTENTS

Preface xi
Henry A. Gremillion

Overview of Orofacial Pain: Epidemiology and Gender

Differences in Orofacial Pain 1
René M. Shinal and Roger B. Fillingim
Chronic orofacial pain is a prevalent problem that encompasses
numerous disorders with diverse causes and presenting symp-
toms. Compared with men, women of reproductive age seek treat-
ment for orofacial pain conditions, as well as other chronic pain
disorders more frequently. Important issues have been raised
regarding gender and sex differences in genetic, neurophysiologic,
and psychosocial aspects of pain sensitivity and analgesia. Efforts
to improve our understanding of qualitative sex differences in pain
modulation signify a promising step toward developing more
tailored approaches to pain management.

Peripheral Mechanisms of Odontogenic Pain 19

Michael A. Henry and Kenneth M. Hargreaves
In this article, we review the key basic mechanisms associated with
this phenomena and more recently identified mechanisms that are
current areas of interest. Although many of these pain mechanisms
apply throughout the body, we attempt to describe these mechan-
isms in the context of trigeminal pain.

Central Mechanisms of Orofacial Pain 45

Robert L. Merrill
The orofacial pain clinician must understand the difference
between peripheral and central mechanisms of pain. Particularly,
one has to understand the process of central sensitization as it
relates to the various orofacial pain conditions to understand
orofacial pain. Understanding leads to more effective treatment.

VOLUME 51 Æ NUMBER 1 Æ JANUARY 2007 v

Myogenous Temporomandibular Disorders: Diagnostic
and Management Considerations 61
James Fricton
Myogenous temporomandibular disorders (or masticatory myal-
gia) are characterized by pain and dysfunction that arise from
pathologic and functional processes in the masticatory muscles.
There are several distinct muscle disorder subtypes in the mastica-
tory system, including myofascial pain, myositis, muscle spasm,
and muscle contracture. The major characteristics of masticatory
myalgia include pain, muscle tenderness, limited range of motion,
and other symptoms (eg, fatigability, stiffness, subjective weak-
ness). Comorbid conditions and complicating factors also are
common and are discussed. Management follows with stretching,
posture, and relaxation exercises, physical therapy, reduction of con-
tributing factors, and as necessary, muscle injections.

Joint Intracapsular Disorders: Diagnostic and Nonsurgical

Management Considerations 85
Jeffrey P. Okeson
This article reviews common intracapsular temporomandibular
disorders encountered in the dental practice. It begins with a brief
review of normal temporomandibular joint anatomy and function
followed by a description of the common types of disorders known
as internal derangements. The etiology, history, and clinical presen-
tation of each are reviewed. Nonsurgical management is presented
based on current long-term scientific evidence.

Temporomandibular Disorders: Associated Features 105

Ronald C. Auvenshine
Temporomandibular disorder (TMD) encompasses a number of
clinical problems involving the masticatory muscles or the tempor-
omandibular joints. These disorders are a major cause of nondental
pain in the orofacial region, and are considered to be a subclassifi-
cation of musculoskeletal disorders. Orofacial pain and TMD can
be associated with pathologic conditions or disorders related to
somatic and neurologic structures. When patients present to the
dental office with a chief complaint of pain or headaches, it is vital
for the practitioner to understand the cause of the complaint and to
perform a thorough examination that will lead to the correct diag-
nosis and appropriate treatment. A complete understanding of the
associated medical conditions with symptomology common to
TMD and orofacial pain is necessary for a proper diagnosis.

Temporomandibular Disorders and Headache 129

Steven B. Graff-Radford
Headache is a common symptom, but when severe, it may be
extremely disabling. It is assumed that patients who present to

vi CONTENTS
 dentists with headache often are diagnosed with a temporomandib-
ular disorder (TMD), although many may have migraine. TMD as
a collective term may include several clinical entities, including
myogenous and arthrogenous components. Because headache and
TMD are so common they may be integrated or separate entities.
Nevertheless, the temporomandibular joint (TMJ) and associated
orofacial structures should be considered as triggering or perpetuat-
ing factors for migraine. This article discusses the relationship be-
tween the TMJ, muscles, or other orofacial structures and headache.

Psychological Factors Associated with Orofacial Pains 145

Charles R. Carlson
This article develops the case for why trigeminal pain is a unique
and challenging problem for clinicians and patients alike, and
provides the reader with insights for effective trigeminal pain
management based on an understanding of the interplay between
psychologic and physiologic systems. There is no greater sensory
experience for the brain to manage than unremitting pain in
trigeminally mediated areas. Such pain overwhelms conscious
experience and focuses the suffering individual like few other
sensory events. Trigeminal pain often motivates a search for relief
that can drain financial and emotional resources. In some instances,
the search is rewarded by a treatment that immediately addresses
an identifiable source of pain; in other cases, it can stimulate never-
ending pilgrimages from one health provider to another.

Temporomandibular Disorders, Head and Orofacial Pain:

Cervical Spine Considerations 161
Steve Kraus
Head and orofacial pain originates from dental, neurologic, muscu-
loskeletal, otolaryngologic, vascular, metaplastic, or infectious
disease. It is treated by many health care practitioners, such as
dentists, oral surgeons, and physicians. The article focuses on the
nonpathologic involvement of the musculoskeletal system as a
source of head and orofacial pain. The areas of the musculoskeletal
system that are reviewed include the temporomandibular joint and
muscles of mastication—collectively referred to as temporoman-
dibular disorders (TMDs) and cervical spine disorders. The first
part of the article highlights the role of physical therapy in the
treatment of TMDs. The second part discusses cervical spine con-
siderations in the management of TMDs and head and orofacial
symptoms. It concludes with an overview of the evaluation and
treatment of the cervical spine.

Temporomandibular Joint Surgery for Internal

Derangement 195
M. Franklin Dolwick
Surgery of the temporomandibular joint (TMJ) plays a small,
but important, role in the management of patients who have

CONTENTS vii
 temporomandibular disorders (TMDs). There is a spectrum of sur-
gical procedures for the treatment of TMD that ranges from simple
arthrocentesis and lavage to more complex open joint surgical
procedures. It is important to recognize that surgical treatment
rarely is performed alone; generally, it is supported by nonsurgical
treatment before and after surgery. Each surgical procedure should
have strict criteria for which cases are most appropriate. Recogniz-
ing that scientifically proven criteria are lacking, this article
discusses the suggested criteria for each procedure, ranging from
arthrocentesis to complex open joint surgery. The discussion in-
cludes indications, brief descriptions of techniques, outcomes, and
complications for each procedure.

Neuropathic Orofacial Pain: Proposed Mechanisms,

Diagnosis, and Treatment Considerations 209
Christopher J. Spencer and Henry A. Gremillion
The most common reason patients seek medical or dental care in
the United States is due to pain or dysfunction. The orofacial region
is plagued by a number of acute, chronic, and recurrent painful
maladies. Pain involving the teeth and the periodontium is the
most common presenting concern in dental practice. Non-odonto-
genic pain conditions also occur frequently. Recent scientific inves-
tigation has provided an explosion of knowledge regarding pain
mechanisms and pathways and an enhanced understanding of
the complexities of the many ramifications of the total pain experi-
ence. Therefore, it is mandatory for the dental professional to
develop the necessary clinical and scientific expertise on which
he/she may base diagnostic and management approaches. Opti-
mum management can be achieved only by determining an
accurate and complete diagnosis and identifying all of the factors
associated with the underlying pathosis on a case-specific basis.
A thorough understanding of the epidemiologic and etiologic
aspects of dental, musculoskeletal, neurovascular, and neuropathic
orofacial pain conditions is essential to the practice of evidence-
based dentistry/medicine.

Four Oral Motor Disorders: Bruxism, Dystonia,

Dyskinesia and Drug-Induced Dystonic
Extrapyramidal Reactions 225
Glenn T. Clark and Saravanan Ram
This article reviews four of the involuntary hyperkinetic motor
disorders that affect the orofacial region: bruxism, orofacial
dystonia, oromandibular dyskinesia, and medication-induced
extrapyramidal syndrome–dystonic reactions. It discusses and
contrasts the clinical features and management strategies for spon-
taneous, primary, and drug-induced motor disorders in the oro-
facial region. The article provides a list of medications that have
been reported to cause drug-related extrapyramidal motor activity,
and discusses briefly the genetic and traumatic events that are
associated with spontaneous dystonia. Finally, it presents an

viii CONTENTS
 approach for management of the orofacial motor disorders. The
contraindications, side effects, and usual approach for medications
and injections are covered. An overview of the indications, con-
traindications, and complications of using botulinum toxin as a
therapeutic modality is discussed briefly.

A Critical Review of the Use of Botulinum Toxin

in Orofacial Pain Disorders 245
Glenn T. Clark, Alan Stiles, Larry Z. Lockerman,
and Sheldon G. Gross
This article reviews the appropriate use, cautions, and contraindi-
cation for botulinum neurotoxin (BoNT) and reviews the peer-
reviewed literature that describes its efficacy for treatment of
various chronic orofacial pain disorders. The literature has long
suggested that BoNT is of value for orofacial hyperactivity and
more recently for some orofacial pain disorders; however, the
results are not as promising for orofacial pain. The available data
from randomized, double-blind, placebo-controlled trials (RBCTs)
do not support the use of BoNT as a substantially better therapy
than what is being used already. The one exception is that BoNT
has reasonable RBCT data to support its use as a migraine prophy-
laxis therapy. The major caveat is that the use of BoNT in chronic
orofacial pain is ‘‘off-label’’.

Complementary and Alternative Medicine for Persistent

Facial Pain 263
Cynthia D. Myers
This article discusses complementary and alternative medicine
(CAM), reviews literature on the prevalence of use of CAM by
the general adult population in the United States and by patients
with persistent facial pain, and summarizes published, peer-
reviewed reports of clinical trials assessing the effects of CAM
therapies for persistent facial pain. Results indicate that many
patients use CAM for musculoskeletal pain, including persistent
facial pain. Preliminary work on selected complementary therapies
such as biofeedback, relaxation, and acupuncture seems promising;
however, there are more unanswered than answered questions
about cost-effectiveness, efficacy, and mechanisms of action of
CAM for persistent facial pain.

Index 275

CONTENTS ix
 Dent Clin N Am 51 (2007) 1–18

Overview of Orofacial Pain:

Epidemiology and Gender Differences
in Orofacial Pain
René M. Shinal, PhDa, Roger B. Fillingim, PhDa,b,*
a
Department of Community Dentistry and Behavioral Science, College of Dentistry, University
of Florida, P.O. Box 103628 Gainesville, FL 32610-3628, USA
b
North Florida/South Georgia Veterans Health System, Malcolm Randall VA Medical
Center, 1601 SW Archer Road, Gainesville, FL 32608-1197, USA

Pain is the number one reason people seek health care; it is deemed the
‘‘fifth vital sign,’’ to mark its importance as health status indicator [1].
The most widely used definition of pain is an ‘‘unpleasant sensory and
emotional experience associated with actual or potential tissue damage, or
described in terms of such damage’’ [2]. Pain is a personal experience that
reflects the totality of genetic, physiologic, and psychosocial contributions.
An area that is receiving considerable attention is the influence of biologic
sex and gender role identity on the experience of pain. This article provides
an overview of current findings regarding sex and gender differences in clin-
ical and experimental pain responses, with particular attention to findings
pertaining to orofacial pain. Evidence is presented from human and nonhu-
man animal studies that address sex differences in pain sensitivity, pain tol-
erance, and analgesia. The potential mechanisms involved, as well as
implications for future research and clinical practice, are discussed.

Epidemiology of orofacial pain

Orofacial pain refers to a large group of disorders, including temporo-
mandibular disorders (TMDs), headaches, neuralgia, pain arising from
dental or mucosal origins, and idiopathic pain [3,4]. The classification and
epidemiology of orofacial pain presents challenges because of the many
anatomic structures involved, diverse causes, unpredictable pain referral

* Corresponding author. Department of Community Dentistry and Behavioral Science,

College of Dentistry, University of Florida, P.O. Box 103628 Gainesville, FL 32610-3628.
E-mail address: [email protected] (R.B. Fillingim).

0011-8532/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.cden.2006.09.004 dental.theclinics.com
2 SHINAL & FILLINGIM

patterns and presenting symptoms, and a lack of consensus regarding differ-

ential diagnostic criteria [5,6]. Despite these obstacles, several investigators
and professional associations have made progress in developing diagnostic
criteria [7–9]. For example, the International Association for the Study of
Pain and the International Headache Society have developed widely used
orofacial pain diagnostic criteria [10,11]. Similarly, Dworkin and LeResche
[12] have proposed Research Diagnostic Criteria for TMD, including a dual
axis system for classifying patients according to the predominant pain
source (eg, muscle pain, disk displacement, joint condition) and any associ-
ated psychosocial features (eg, disability, depression, somatization). The
often weak association between pain and observable tissue pathology has
prompted researchers and clinicians to use a multidimensional approach
for studying this widespread problem [13].
Chronic orofacial pain affects approximately 10% of adults and up to 50%
of the elderly [4]. There is evidence that sex differences in masticatory muscle
pain and tenderness emerge as early as 19 years of age [14]. Women of repro-
ductive age, with a concentration of women in their 40s, seek treatment for
orofacial pain more frequently compared to men by a 2:1 ratio [15–17]. More-
over, a greater proportion of women seek treatment for other pain con-
ditions, such as migraine and tension-type headaches, fibromyalgia,
autoimmune rheumatic disorders, chronic fatigue, orthopedic problems,
and irritable bowel syndrome [16,18,19]. Women are more likely to seek med-
ical care for pain; however, they also report more pain for which they do not
seek treatment [20,21]. This holds true for all bodily symptoms, and for those
with unknown etiology [22–24]. Women also experience more symptom re-
currences and more intense pain. These differences persist when apparent
confounding factors, such as sex differences in the prevalence rates of medical
conditions and gynecologic pain, are controlled statistically [22].
Kohlmann [17] noted that, among patients who presented with orofacial
pain lasting at least a week, more than 90% complained of pain in other
body areas as well. Patients who have orofacial pain share many similarities
with other patients who have chronic pain, such as a moderate correlation
between reported symptoms and objective pathologic findings, maladaptive
behaviors (eg, parafunctions), social and psychologic distress, impairment of
daily activities, occupational disability, and higher rates of health care use
[16,25,26]. The result is a diminished quality of life that is constrained by
pain experiences.
Numerous factors with varying degrees of empiric support have been pos-
ited to explain sex differences in pain prevalence. These include differences in
descending central nervous system pathways that modulate pain signal trans-
mission [27–29], genetics [30], and the effects of gonadal hormones [31–34].
Also, a vast literature addresses psychosocial sex differences in symptom ap-
praisal, socialization and gender roles, abuse and trauma, depression and
anxiety, gender bias in research and clinical practice, and race and ethnicity
[22,35].
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 EPIDEMIOLOGY & GENDER DIFFERENCES IN OROFACIAL PAIN 3

Sex differences in responses to experimental pain

Although numerous factors inevitably contribute to sex differences in the
prevalence and severity of clinical pain, the senior author and colleague [28]
previously suggested that sex differences in the processing of pain-related
information could play an important role. That is, a higher level of pain
sensitivity among women may serve as a risk factor for developing certain
pain disorders, including chronic orofacial pain. A robust and expanding
literature that addresses sex differences in experimental pain sensitivity
is available, and these findings are discussed below.

Nonhuman animal research

Considerable research with nonhuman animals (primarily rodents) has
examined whether males and females differ regarding responses to noxious
stimuli [24,28,36] and analgesia [37–39]. Rodent studies have yielded mixed
information concerning sex differences in pain perception and analgesia
(called ‘‘nociception’’ and ‘‘antinociception,’’ respectively, when referring
to nonhuman animals). A comprehensive meta-analysis by Mogil and col-
leagues [39] found that female rats were more sensitive to electrical shock
and chemically-induced inflammatory nociception (eg, abdominal constric-
tion, formalin tests) in most studies; however, results using thermal assays
were equivocal. Of the 23 studies reviewed, 17 reported no significant sex
differences; in the remainder, females exhibited more sensitivity to the hot
plate test than did males. With regard to radiant heat and hot water immer-
sion, most studies reported no sex differences, with 8 reporting increased
sensitivity in male rats and 2 reporting increased sensitivity in female
mice. To clarify discrepancies, the investigators conducted additional noci-
ceptive testing and morphine antinociception experiments using a variety
of outbred mice and rats. Regarding nociception and morphine antinocicep-
tion, there was a significant interaction between sex and genotype (ie, strain)
of rodents. To complicate matters, strain differences can be relevant for one
sex, but not the other, and vary according to the pain assay. Female noci-
ception and antinociception also change across the estrous cycle; however,
when female mice were tested as a randomly mixed group (ie, estrous and
diestrus), sex differences tended to diminish. The investigators noted that
males and females might use qualitatively distinct neurochemical mecha-
nisms to modulate nociception. They also suggested that the organizing ef-
fects of early hormone exposure during development might have more
impact than do adult gonadal hormone fluctuations.

Human research
Laboratory pain research in humans suggests that women are more sen-
sitive to several forms of laboratory pain compared with men. Consistent
with rodent research, there is considerable variability in the magnitude
4 SHINAL & FILLINGIM

and direction of sex differences [24,28,36]. A meta-analysis conducted by

Riley and colleagues [40] found that women generally show lower pain
thresholds and tolerances than do men to a variety of noxious laboratory
stimuli. Effect sizes for pain threshold and tolerance ranged from large to
moderate, and varied according to pain assay. Pressure pain and electrical
stimulation demonstrated the largest effects for the 22 studies reviewed,
whereas thermal pain yielded inconsistent results. The investigators con-
cluded that small sample sizes contributed to inadequate statistical power
and inconsistent results. Regarding cold pressor stimulation, studies show
that men generally display higher pain thresholds and tolerance, and lower
pain ratings than do women [41]; however, Logan & Gedney [42] noted a sig-
nificant sex-by-session interaction such that women anticipated and re-
ported more pain than did men after a second session of forehead cold
pressor testing. There were no sex differences during the initial cold pressor
session, however. This indicates that previous experience with pain can af-
fect subsequent pain perception and modulation in a sex-dependent fashion.
Several studies have examined laboratory models of orofacial pain. For
example, Karibe and colleagues [43] noted that healthy female controls ex-
perienced more masticatory muscle pain during 6 minutes of gum chewing
than did men, and had more pain (compared with pretest measures) an
hour after chewing. Similarly, Plesh and colleagues [44] assessed jaw pain
tolerance in healthy subjects during and after bite force tasks. Both sexes
had increased pain during bite tasks; however, postclenching pain lasted
longer for women. Notably, women reported significantly more baseline
pain upon jaw movement on the second day of testing, whereas men did
not report an increase in baseline pain 24 hours later. The investigators
ruled out muscular microtrauma because there were no significant differ-
ences in postexertion pressure pain tolerance or threshold. Instead, they
suggested that neuronal hypersensitivity might play a role in postexertion
hyperalgesia.
Injection of algesic substances into the facial and cervical muscles also
has been used as an experimental model that mimics head and neck pain
of muscular origin [45]. Injections of hypertonic saline or glutamate solu-
tions into the trapezius muscle produced significantly more pain among
women relative to men [46,47]. Similarly, pain induced by glutamate injec-
tions into the masseter muscle was more intense, larger in area, and longer
lasting in women [48]. Thus, sex differences in pain perception extend to ex-
perimental models of particular relevance for clinical orofacial pain.
Another experimental pain model that may be of significant clinical rel-
evance is temporal summation of pain. Temporal summation refers to a per-
ceived increase in pain that is generated by rapidly repeated noxious
stimulation [49]. This phenomenon is believed to be the perceptual correlate
that occurs when high-frequency stimulation of C-fibers (C polymodal no-
ciceptive afferents) amplifies second-order neuronal activity in the spinal
cord dorsal horn (ie, windup). This series of events involves N-methyl-D-
 EPIDEMIOLOGY & GENDER DIFFERENCES IN OROFACIAL PAIN 5

aspartate [NMDA] glutamate receptors [50,51]. Temporal summation is

thought to reflect central neural mechanisms similar to those that are re-
sponsible for the hyperalgesia and allodynia that characterize many forms
of clinical pain [51–57]. Healthy women exhibit more robust temporal sum-
mation than do men in response to thermal, electrical, and mechanical stim-
ulation [29,58,59]. Staud and colleagues [60] showed that patients who had
fibromyalgia exhibited greater temporal summation of heat pain and height-
ened after-sensations compared with healthy controls. Similarly, patients
who had TMDs showed greater temporal summation of thermal and me-
chanical pain compared with pain-free controls [61,62]. Such findings invite
speculation that individuals who display exaggerated temporal summation
of pain might be at greater risk for developing central sensitization of
pain pathways, which may reflect a predisposition for developing chronic
pain syndromes [29]. There is a need for prospective longitudinal studies
to determine whether enhanced temporal summation of pain precedes
chronic pain, or is a consequence thereof.

Brain imaging studies

A rapidly expanding body of research uses functional brain imaging in an
attempt to identify cerebral responses that are associated with the experience
of pain [27,63–66]. Several brain regions have emerged consistently as areas
that are activated during acute exposure to noxious stimuli. Acute painful
events often elicit activity in the primary and secondary somatosensory cor-
tices, insular cortex, anterior cingulate, and prefrontal cortices [27]. Bilateral
thalamic and brain stem activation have been associated with general
arousal (eg, attention) in response to noxious stimuli [65], whereas limbic
system components (eg, anterior cingulate, medial prefrontal, insular corti-
ces) are believed to reflect emotional aspects of pain anticipation and
processing [27,65,67]. The periaqueductal gray, regions of the anterior cingu-
late, and the orbitofrontal cortex are implicated in endogenous pain modula-
tion [27].
A small body of evidence addresses sex differences in brain activation
patterns in the contralateral insula, thalamus, and prefrontal cortex in re-
sponse to experimentally evoked pain. For example, in response to a painful
thermal stimulus, patterns of pain-related brain activation showed similarity
between the sexes; however, women showed greater activation in the contra-
lateral prefrontal cortex, contralateral insular and anterior cingulate cortex,
and cerebellar vermis compared with men [68]. In contrast, Derbyshire and
colleagues [69] reported greater heat pain–related activation among men
versus women in bilateral parietal cortex, and in contralateral primary
and secondary somatosensory, prefrontal, and insular cortices. Women
showed greater activation in ipsilateral perigenual cortex. This conflicting
pattern of results likely reflects differences in stimulus characteristics. Specif-
ically, Paulson and colleagues [68] used an identical (50 C) contact heat
6 SHINAL & FILLINGIM

stimulus, which was rated as more painful by women, whereas Derbyshire

and colleagues [69] adjusted the intensity of their laser stimulus to be equally
painful across sexes.
Several studies have examined sex differences in cerebral responses to
stimuli delivered to deep abdominal body tissues (ie, visceral stimulation).
Berman and colleagues [70] found that, compared with women who had
irritable bowel syndrome (IBS), men who had IBS showed greater bilateral
insular cortex activation to rectal pressure. These investigators subsequently
showed that rectal distention produces greater activation in ventromedial
prefrontal and right anterior cingulate cortex, and left amygdala among
women who had IBS, whereas men who had IBS showed greater activation
in right dorsolateral prefrontal cortex, insula, and periaqueductal gray [71].
In contrast, Hobson and colleagues [72] found no sex differences in cortical
activity evoked from esophageal stimuli in healthy subjects.
Thus, these findings involving somatic and visceral stimuli indicate sub-
stantial overlap in brain areas that are involved in acute pain processing be-
tween men and women. The variable sex differences that have emerged
across studies likely depend upon the stimulus properties and population
characteristics.

Sex differences in analgesic systems

Many organisms, including humans, possess natural pain control mech-
anisms (ie, endogenous systems). Nonhuman animal studies have revealed
sex differences for at least one form of endogenous pain modulation:
stress-induced analgesia (SIA). In rodents, mildly stressful events (eg, brief
swims in tepid water) recruit endogenous opiate systems, whereas intensely
stressful events (eg, forced cold-water swims) recruit nonopioid systems (eg,
NMDA glutamate receptors) more heavily [24,73]. Given the same stressor,
female rodents usually have equal or less SIA than do males. Blocking opi-
oid or NMDA receptors reverses SIA in male and ovariectomized female
mice, but not in intact female mice. This suggests that the neurochemical
and hormonal mechanisms that support SIA might differ for female and
male animals [74,75].
Methods for investigating endogenous pain inhibition also are available
in humans. One frequently used method is assessment of diffuse noxious in-
hibitory controls (DNIC). DNIC, or counterirritation, refers to the process
whereby one noxious stimulus inhibits the perception of a second painful
stimulus. This phenomenon is believed to reflect descending inhibition of
pain signals [76,77]. DNIC is presumed to operate through activation of de-
scending supraspinal inhibitory pathways that are initiated by release of en-
dogenous opioids [78–81]. Several studies have investigated sex differences in
the efficacy of DNIC, with mixed results. France and Suchowiecki [82] re-
ported that ischemic arm pain produced equal reductions in the nociceptive
flexion reflex (NFR, a pain-related reflex in the biceps femoris in response to
 EPIDEMIOLOGY & GENDER DIFFERENCES IN OROFACIAL PAIN 7

electrical stimulation of the lower extremity) activity in women and men,

which indicated no differences in DNIC. Serrao and colleagues [29] recorded
the NFR and pain intensity for 36 healthy adults randomized to a baseline,
nonpainful control or a painful cold pressor DNIC condition. As expected,
women, on average, had lower NFR temporal summation thresholds than
did men. The cold pressor produced greater increases in the stimulus inten-
sity at which temporal summation elicited a reflex in men compared with
women, which indicated greater DNIC among men. In contrast, Baad-Han-
sen and colleagues [83] found no sex differences in the ability of an ice-water
DNIC to modulate intraoral pain that was induced by the application of
a topical irritant (ie, capsaicin) in healthy participants.
Responses to analgesic medication (ie, exogenous analgesia) also might
differ as a function of sex, although the findings are far from consistent.
For example, clinical studies have indicated greater morphine analgesia
among women [84], among men [85], and others have reported no sex differ-
ences in morphine analgesia [86,87]. Consistent sex differences have been re-
ported in the analgesic effects of mixed action opioids (eg, pentazocine,
butorphanol, nalbuphine), which produce analgesia, in part, by binding of
k-receptors [88]. This class of medications also has partial agonist action
at d-receptors and antagonist action at m-receptors, which complicates the
side effect profile [89]. Among patients who experienced postoperative
pain after third molar extraction, Gear and colleagues [89] demonstrated
that pentazocine and butorphanol produced greater and longer-lasting anal-
gesia among women versus men. Subsequently, these investigators found
that a 5-mg dose of nalbuphine had paradoxic antianalgesic effects on
men [90]. To obtain analgesia, men required higher doses (20 mg) than
did women (10 mg). This trend persisted when body weight was included
as a covariate. Men also had more pain by the end of the study protocol,
whereas women, on average, did not return to their baseline pain levels.
This study demonstrates that subtle sex differences exist in response to
k-opioids.
Experimental pain models also have been used to explore sex differences
in opioid analgesia. With an electrical pain assay, women have shown
greater analgesic potency but slower onset and offset of morphine analgesia
than did men [91], although these investigators failed to include a placebo
condition and subsequently observed no sex differences in analgesic re-
sponses to morphine-6-glucuronide, an active metabolite of morphine [92].
Zacny [93] reported that m-opioid agonists (eg, morphine, meperidine, hy-
dromorphone) produced greater analgesic responses among women using
cold pressor pain, but no sex differences in analgesia emerged for pressure
pain. The authors’ group [94] found no sex differences in morphine analgesia
using pressure, heat, and ischemic pain. Regarding mixed action opioids,
Zacny and Beckman [95] reported that men experienced slightly, though
not significantly, greater analgesia in response to butorphanol. The authors
and colleagues [96] reported no sex differences in pentazocine analgesia;
8 SHINAL & FILLINGIM

however, the melanocortin-1-receptor genotype (MC1R) was associated

with pentazocine analgesia in a sex-dependent manner [30]. Specifically,
women with two variant MC1R alleles, associated with red hair and fair
skin, reported significantly greater analgesia with the k-opioid pentazocine
during thermal and ischemic pain testing compared with women with one
or no variant MC1R allele; MC1R genotype was not associated with anal-
gesic responses among men.
In summary, evidence from clinical and experimental pain models present
a mixed picture of sex differences in response to opioids, and the presence of
sex differences likely depends on multiple factors, including the specific opi-
oid agonist and dose used, the pain model tested, and the timing of postdrug
assessments. Moreover, human and nonhuman animal data suggests that
sex-by-genotype interactions may influence the findings of such studies.

Clinical relevance of experimental pain responses

It has not been determined whether common mechanisms underlie sex
differences in the epidemiology of clinical pain and sensitivity to experimen-
tal pain; however, this possibility is supported by increasing evidence that
experimental pain sensitivity predicts clinical pain responses [97]. Indeed,
patients who have certain chronic pain disorders, such as TMD [56,61],
IBS [98], headache pain [99], and fibromyalgia [57], exhibit increased sensi-
tivity to a variety of experimental pain stimuli. Moreover, some evidence
suggests that within populations that have chronic pain, greater experimen-
tal pain sensitivity is associated with greater severity of clinical symptoms
[100–103].
Fillingim and colleagues [104] investigated the relationship between heat
pain tolerance and threshold in healthy adults, and reports of daily pain in
the month preceding pain testing. Consistent with previous studies, women
reported more pain sites (but not more pain episodes) and greater health
care use in the month preceding experimental testing. Women also displayed
increased sensitivity to thermal pain after adjusting for baseline sensitivities
in warmth detection. Women who reported higher levels of clinical pain dur-
ing the month preceding testing exhibited lower thermal pain thresholds and
tolerances than did those who reported less clinical pain; however, men
showed no significant relationship between clinical and experimental pain.
Growing evidence also suggests that experimental pain sensitivity may
predict future pain severity and response to treatment. Indeed, several stud-
ies now indicate that laboratory pain sensitivity that is assessed presurgically
predicts severity of postsurgical pain [105–107]. Also, pretreatment ischemic
pain tolerance predicted pain reductions following multidisciplinary treat-
ment among women, but not among men, who had chronic pain [101].
More recently, pretreatment heat pain thresholds predicted the effectiveness
of opioids for neuropathic pain [108]. Taken together, these findings support
the clinical relevance of experimental pain assessment, which implies that
 EPIDEMIOLOGY & GENDER DIFFERENCES IN OROFACIAL PAIN 9

sex differences in experimental pain sensitivity are related to sex differences

in clinical pain.

Responses to nonpharmacologic treatment

Women and men may respond differently to pharmacologic pain treat-
ment, but little is known about sex differences in the effectiveness of non-
pharmacologic interventions for pain. In a study of orofacial pain, women
who had TMD showed significant decreases in pain 2 years after multidisci-
plinary treatment, whereas pain reports among men who had TMD
remained unchanged [109]. In the experimental setting, a cognitive interven-
tion encouraging a sensory focus aimed at pain reduction significantly atten-
uated pain intensity among men but not women [110]. Also, exercising on
a treadmill reduced cold pressor pain ratings in women but not men,
whereas playing video games decreased pain in men but not women [111].
In the clinical setting, conventional physical therapy was more effective
for men who had back pain, whereas intensive dynamic back exercises pro-
duced greater pain reduction among women [112]. In another study, women
who had back pain showed significant improvements in health-related qual-
ity of life with cognitive behavioral treatment and the combination of cog-
nitive behavioral treatment plus physical therapy, whereas men showed no
benefit [113]. Other recent findings indicate similar treatment gains for
women and men following active rehabilitation for chronic low back pain
[114], and one study reported better outcomes from multidisciplinary treat-
ment among men [115]. Thus, these findings are mixed, but, on balance, they
suggest greater treatment responses for women, especially when treatments
are multimodal.

Mechanisms underlying sex differences in pain perception

Several mechanisms have been proposed to explain gender differences, in-
cluding ‘‘biologic’’ factors, such as genetic and hormonal influences as well
as sex differences in endogenous pain modulation. In addition, ‘‘psychoso-
cial’’ processes have been suggested, including gender roles and other cogni-
tive/affective influences. Before discussing these putative explanatory
mechanisms, it is worth noting that this distinction between ‘‘psychosocial’’
and ‘‘biologic’’ contributions is artificial, because psychosocial variables can
reflect or alter the underlying biologic processes that are involved in the
modulation of pain. In addition, sex differences in pain inevitably are driven
by multiple mechanisms; therefore, reductionistic attempts to identify the
reason for sex differences likely will be unsuccessful.
Gonadal hormones may contribute to sex differences in pain modulation
and opioid analgesia. Experimental pain perception varies across the men-
strual cycle in healthy women, with the greatest pain sensitivity occurring
perimenstrually [116]. The severity of some pain disorders fluctuates with
10 SHINAL & FILLINGIM

the menstrual cycle [117–119]. For example, in patients who have TMD,
peak pain occurs perimenstrually and at the time of ovulation [120]. It is hy-
pothesized that rapidly dropping estrogen levels may be associated with
heightened symptoms in this population. Hormone replacement therapy
also has been associated with an increased risk for developing TMDs
[121] and back pain [122,123], and women who were using exogenous hor-
mones reported more severe orofacial pain compared with women who were
not using hormones [124]. Furthermore, postmenopausal women who were
taking hormone replacement showed lower pain thresholds and tolerances
compared with women who were not taking hormone replacement and
men [125,126]. Thus, endogenous and exogenous hormonal events affect
clinical and experimental pain responses.
Psychosocial factors also contribute to sex differences in responses to
pain. Psychologic distress is common among patients who have orofacial
pain [127]. Several studies indicate that psychologic factors play a larger
role when TMD pain is myogenic (as opposed to arthrogenic), perhaps be-
cause of more parafunctional behaviors in the former group [128–130]. Re-
garding emotion, two dimensions seem to be especially important for pain
modulation: valencedwhether an emotion is positive or negative, and
arousaldhow intensely the emotion is experienced [131]. Although negative
and positive emotions can influence pain, more research has addressed the
effect of negative emotions. For example, fear is a high-intensity negative
emotion that is associated with threat or perception of imminent harm.
The fear response is characterized by autonomic arousal and temporary
pain attenuation (ie, ‘‘fight, flight, or freeze’’). Fear-based analgesia is not
studied readily in humans because of ethical considerations. In comparison,
anxiety is a lower-intensity negative emotion that often heightens pain sen-
sitivity [131]. Thus, an emotional stimulus can attenuate or amplify pain de-
pending upon how it is perceived.
Aggregate findings suggest that, given the same negative stimuli (eg, up-
setting photographs, startling noise), women display more intense affective
reactions compared with men. In addition, women report higher base rates
of depression and anxiety than do men, which often are associated with in-
creased pain and other physical symptoms [132,133]. These negative affec-
tive states generally predict greater sensitivity pain in the laboratory [134].
Thus, higher levels of affective distress might account for some of the in-
creased pain sensitivity among women. Robinson and colleagues [135]
found that sex differences in temporal summation of heat pain became non-
significant after controlling for anxiety, indicating that anxiety mediates
gender differences. Several studies suggest that anxiety more strongly
predicts experimental pain responses in men than in women, however
[136–138]. Similar results have been reported for clinical pain [139]. Thus,
it seems that anxiety more strongly predicts clinical and experimental pain
among men. Clearly, more investigation is warranted concerning the role
of negative emotions during pain processing.
 EPIDEMIOLOGY & GENDER DIFFERENCES IN OROFACIAL PAIN 11

In addition to emotional factors, cognitive variables, such as self-efficacy,

anticipation, expectancies, perceived ability to control pain, and coping
strategies, can contribute to gender differences in pain perception and treat-
ment outcomes [16,140]. Orofacial patients who have positive pretreatment
expectations, and who use adaptive cognitive coping strategies, report better
treatment satisfaction [141,142]. Relative to men, women report more worry
and catastrophizing in laboratory and clinical pain settings [143,144].
Turner and colleagues [145] found that a catastrophizing coping style was
associated with extraoral muscle and joint palpation pain, activity interfer-
ence, and higher health care use in patients who had TMDs. Despite
a greater tendency to catastrophize, Unruh and colleagues [146] found
that women use a broader repertoire of coping strategies. Furthermore,
men and women seem to derive differential benefits from coping skills train-
ing, which highlights the importance of tailoring treatments to meet individ-
ual needs [140].
Stereotypic gender roles also should be considered because traditional
Western feminine roles may enable reporting pain, whereas masculine roles
discourage such complaints. Among men, masculinity has been associated
with higher pain thresholds [147]. One study found that men reported less
pain to an attractive female experimenter than to a male experimenter,
whereas experimenter gender did not influence women’s pain reports
[148]. Two studies that used standardized measures of gender role demon-
strated that gender roles are associated with experimental pain responses,
but gender role measures did not account for sex differences in pain
[147,149]. More recently, a subscale that assesses willingness to report
pain was found to mediate sex differences partially in temporal summation
of heat pain [135]. Also, feminine gender role and threat appraisal mediated
sex differences in cold pressor pain [140,150]. Thus, gender roles seem to
contribute to sex differences in pain sensitivity.

Summary and future directions

Considerable clinical and experimental evidence demonstrates gender and
sex differences in the epidemiology, etiology, and manifestation of orofacial
pain. Experimental studies in humans consistently indicate greater pain sen-
sitivity among women, although the magnitude of the sex difference varies
across studies. Some evidence suggests sex differences in responses to phar-
macologic and nonpharmacologic treatments for pain; however, conflicting
findings abound. The mechanisms that underlie these sex differences in clin-
ical and experimental pain responses are not understood fully; however, sev-
eral biopsychosocial factors are believed to contribute, including gonadal
hormones, genetics, cognitive/affective processes, and stereotypic gender
roles.
A clinically relevant area for future research involves identifying sex-re-
lated markers that distinguish individuals who are at risk for developing
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