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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
Facult de mdecine dentaire Faculty of Dentistry
Universit Laval McGill University
Qubec Department of Dentistry of Jewish
Canada General Hospital
Montral, Qubec
Canada

ISBN 978-3-662-53992-7ISBN 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


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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 Iguau 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 sufferers 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 patients 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 patients 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
Jskelinen (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.

Qubec, Canada Jean-PaulGoulet


 AnaMiriamVelly
Contents

Part I Clinical and Epidemiological Aspects of Orofacial Pain


1 Orofacial Pain: Classification andRoad Map toClinical
Phenotypes 3
Jean-Paul Goulet and Alain Woda
2 Comorbidities inIndividuals withOrofacial Pain and
Their Impact onBiomarkers 21
Ana Miriam Velly and James Fricton

Part II Mechanisms of Chronic Orofacial Pain

3 Neurobiological Mechanisms ofChronic Orofacial Pain  35


Barry J. Sessle
4 Oral andCraniofacial 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 ofNeuropathic Orofacial Pain 65


Satu K. Jskelinen
6 Masticatory Muscle Pain Biomarkers 79
Malin Ernberg
7 Molecular Temporomandibular Joint Pain Biomarkers 95
Per Alstergren
8 Genetic Biomarkers ofOrofacial Pain Disorders  107
Zeev Seltzer and Scott R. Diehl
9 Serum, Synovial, andSalivary Biomarkers for
Orofacial Pain Conditions  119
Stergios Katsiougiannis, Varun R. Mallela,
Christopher A. Schafer, and David T. W. Wong

ix
x Contents

Part IVStudy Designs and Statistical Analysis for the Identification


of Biomarkers, and Future Direction

10 Biomarkers inEpidemiologic Research: Definition,


Classification, andImplication  135
Ana Miriam Velly, Shrisha Mohit, Hyman M. Schipper,
and Mervyn Gornitsky
11 Statistical Analysis intheIdentification ofPain
Biomarkers  141
Russell Steele
12 Future Direction andConclusion  147
Jean-Paul Goulet and Ana Miriam Velly
Index 151
Part I
Clinical and Epidemiological
Aspects of Orofacial Pain
Orofacial Pain: Classification
andRoad Map toClinical
1
Phenotypes

Jean-PaulGoulet andAlainWoda

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, Universit Laval, rate of self-reported orofacial pain ranges from
2420 Rue de la Terrasse, G1V 0A6, QC, Qubec, 19% to 26% [1, 2]. In most instances sudden pain
Canada in the orofacial region has a clear somatic cause
e-mail: jean-paul.goulet@fmd.ulaval.ca
with overt clinical manifestations generally asso-
A. Woda, DDS, PhD ciated to recognizable pathophysiological pro-
Faculty of Odontology, Universit dAuvergne,
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, DOI10.1007/978-3-662-53994-1_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 asaUnique 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.
patients 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 andRoad Map toClinical 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 [1315].
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 [911]. 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 ofOrofacial 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 andOrofacial
C
5). Neurovascular pain is unique to the head and Pain: AnEvolving 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 andRoad Map toClinical 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 patients 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, 2735]. 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 andOrofacial
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 etal. [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 andRoad Map toClinical 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 etal. [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 etal. [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 ofOperational
C The strengths and weaknesses of existing meth-
Classification Systems ods for taxonomic research and classification pur-
forOrofacial 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 andRoad Map toClinical 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
11.111.9: Headache and facial pain attributed to differences, for everyones 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 (Raeders)
(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 andRoad Map toClinical 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 andClinical pain is not better accounted for by another pain
Phenotypes forBiomarker 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, 4951]. 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 1kg of pres-
known etiology, a poorly understood pathophysi- sure for 5s 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 etal. [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 [5456]. 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 0.5kg
of overload, overuse, or prolonged contraction of pressure for 5s 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 1kg for 5s 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 patients 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 [6063]. exist by itself with no other joint disorder;
1 Orofacial Pain: Classification andRoad Map toClinical 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 A
 typical Odontalgia (AO) or 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 etal. [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 etal. [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 >2h per day for >3months 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 >2h/day for >3months 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 andRoad Map toClinical Phenotypes 17

1.7.5 Persistent Idiopathic sensory abnormality profiles may indeed be


FacialPain 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- patients 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 2h over biomarkers.
at least 3months, 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
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Comorbidities inIndividuals
withOrofacial Pain andTheir
2
Impact onBiomarkers
Orofacial Pain Comorbidities and Their
Impact on Biomarkers

AnaMiriamVelly andJamesFricton

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 5years 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 [26]
which the diagnosis and management are not and its persistence [1, 710], 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
Montral, 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 Cte Ste-Catherine, Suite A-017,
H3T 1E2 Montral, Qubec, Canada in the identification of biomarkers for orofacial
e-mail: ana.velly@mcgill.ca 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, DOI10.1007/978-3-662-53994-1_2
22 A.M. Velly and J. Fricton

2.2 Epidemiology of 2.3.1 Headaches


OrofacialPain
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, 5052]. More specifically, the fre-
26% among adults [6, 13, 14]. Among orofacial quency of headaches in TMD subjects ranges
pain groups, toothache (1214%) [15, 16] and from 9 to 97% in adults [34, 4042, 47, 5355]
TMD-related pain (512%) [15, 1721] 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 = 1.58.8) 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 3.86.5% [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%) [2527]. 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: 1.64.4) [2] and adults
pain 5years later [1] and 16% are worse [28]. (OR = 2.1, 95% CI: 1.23.7) [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: 3.820.1) [55] or with a headache once a
week or more (OR = 3.7; 95% CI: 1.68.4) [6].
Headaches were also implicated in the aggrava-
2.3 Comorbidities Related tion of TMD signs [54] and in the emotional
toOrofacial Pain functioning of subjects [58].

Comorbidities are common among individuals


with chronic orofacial pain [1, 7, 10, 2947], 2.3.2 Widespread Pain
with higher prevalence among women [34, 48] andFibromyalgia 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 (1654%) [7, 9, 10]. The prev-
1.4, 95% confidence intervals [CI] 1.31.6) 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: 1.31.8) and Hispanics (odds exhibit painful TMD [61], showing again that
ratio [OR] = 1.6, 95% CI: 1.21.6) 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 2.27.4) [3] and adolescents (OR = 3.2, 95% CI:
with orofacial pain but that also increase its onset 1.76.1) [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 inIndividuals withOrofacial Pain andTheir 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 inIndividuals withOrofacial Pain andTheir Impact on Biomarkers 25

CI: 1.42.8) [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 andBack Pain CI: 1.45.1) [55].

Neck and back pains are also common symptoms


reported by adults with orofacial pain (1693%) 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 = 2.65) to associated with chronic pain [6365] 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: 3.74.3) are greater among adults with [68, 70], depression [6, 63, 7073], somatic
TMD-related pain than among those without [34]. awareness [2, 13, 63, 7072, 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 = 4.07.9) [34, individuals with chronic orofacial pain.
57]. Back (OR = 1.2; 95% CI: 1.21.3) and neck Furthermore, affective disturbance (RR = 1.6,
pains (OR = 1.5; 95% CI: 1.41.8) are also more 95% CI: 1,12.2) [9], irritability (RR = 1.5, 95%
likely to occur among females with TMD-related CI: 1.12.1) [9], anxiety (RR = 2.8, 95% CI 1.3
pain than males [34]. 6.2) [3], depression (OR = 2.2, 95% CI: 1.24.0),
Moreover, a prospective-cohort study found and perceived stress (OR = 2.2, 95% CI: 1.24.0)
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: 2.26.8) [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: 1.56.7) [73] (hazard
than for adults since the OR found among adults ratio [HR]= 1.31, 95% CI: 1.191.42)] [77], per-
was close to 3 [(OR = 2.7; 95% CI: 1.17.0) [6] ceived stress [(IDR = 2.6, 95% CI: 1.25.5) [73]
and 2.9 (95% CI: 2.04.3)] [55]. HR = 1.31, 95% CI: 1.16, 1.48)] [77], mood
(IDR = 3.7, 95% CI: 1.78.1) [73], somatization
[(OR = 1.8, 95% CI = 1.12.8) [2], HR = 1.38,
2.3.4 V
 isceral Comorbid Pain 95% CI: 1.271.49)] [77], and life dissatisfaction
Conditions (OR = 4.1, 95% C = 1.99.0) [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; 916%),
interstitial cystitis (17%), and stomach pain 2.4 Implications
(34%) are noted among individuals with TMD [2, ofComorbidities
53, 55]. The neural and sensory conditions onBiomarkers 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: 1.02.1) comorbidities. For example, NGF is elevated in
[25] to 90% (OR = 1.9, 95% CI: 1.23.1) [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, 98102],
[81], visceral pain [8284], 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 [9092], back pain [93], neck pain [94, 95], [105]. Elevated levels of CGRP were noted
2 Comorbidities inIndividuals withOrofacial Pain andTheir 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 [26] 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, 810].
[112115].
Therefore, comorbidities probably can con-
found and/or modify the relationship between a 2.5 Clinical Implications
candidate biomarker and orofacial pain. Hence, ofComorbidities
the studies assessing the putative biomarkers inOrofacialPain
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-1, IL-6, TNF-, IL-8 [84] Interstitial cystitis Serum
IL-6, IL-8, IL-1 (Pike etal. 2015) [100] Irritable bowel syndrome Serum
IL-10, IL-12, TGF- [101] Irritable bowel syndrome Plasma
IL-6, IL-10, IL-13, IL-17, TNF-, TGF- [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 etal. 2010) [114] Irritable bowel syndrome Serum
8-iso-prostaglandin F2 [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
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46, 59] but also have an effect on the persistence
6. Macfarlane TV, Kenealy P, Kingdon HA, Mohlin B,
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All interventions need to be tailored to the adults and associated childhood and adulthood factors:
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dibular muscle and joint pain disordersa prospective
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18-month cohort study. JPain. 2010;11(11):115564.
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Part II
Mechanisms of Chronic Orofacial Pain
Neurobiological Mechanisms
ofChronic Orofacial Pain
3
BarryJ.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 [35]. 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: barry.sessle@dentistry.utoronto.ca processes involved in chronic orofacial pain.

Springer-Verlag GmbH Germany 2017 35


J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI10.1007/978-3-662-53994-1_3
36 B.J. Sessle

3.2  verview ofOrofacial


O with some of the small-diameter, slow-conducting
Nociceptive Pathways primary afferent fibers that are either myelinated
andMechanisms (e.g., A- 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 [68]. 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 (A 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- afferents, some A- 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 [1113]. 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 ofChronic 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 -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 ones 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.
andProcesses 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-) and small-diameter (A- 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 ofChronic Orofacial Pain 39

inputs from A- 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-
andInfluences 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 ofChronic 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 [2934]; 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 [3739] 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 ofChronic 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
44 B.J. Sessle

features that, along with peripheral sensitization spread, and referral of pain from these deep tis-
(see above), can explain the spontaneous pain, sues. Nonetheless, the pain referral mechanisms
hyperalgesia, and allodynia that characterize sev- may depend not only on the convergent afferent
eral orofacial chronic pain conditions and may input patterns to the nociceptive neurons but also
through quantitative sensory testing (QST) reflect on the neuroplastic changes expressed as central
biomarkers for some of these conditions (see sensitization generated in the neurons by these
Chap. 5). An example is the pain of a chronic inputs as a result of injury or inflammation. There
arthritic condition, which may involve central is evidence suggesting that some of the wide-
sensitization of nociceptive neurons as well as spread afferent inputs to the nociceptive neurons
peripheral sensitization of the afferents in the are normally weak and held in check by inhibi-
inflamed region. Another example is TMD, since tory processes but become unmasked in patho-
these central and peripheral processes can explain physiological situations and are more effective in
the ongoing pain, increased pain sensitivity (i.e., exciting the nociceptive neurons that have
hyperalgesia), and the lowered threshold for become hyperexcitable through the central sensi-
evoking pain (i.e., allodynia). The diffuse charac- tization process and a decrease of the inhibitory
ter of TMD pain can also be explained by involve- processes.
ment of adjacent afferents as part of the peripheral Also clinically relevant is evidence that central
sensitization process, but also by central sensiti- sensitization depends on nociceptive afferent inputs
zation since neuronal receptive field expansion is for its initiation and perhaps also for its mainte-
a major feature of trigeminal central sensitization nance. This underpins the now standard incorpora-
in chronic as well as acute orofacial pain models. tion into dental restorative and surgical procedures
As a consequence of the expansion of its recep- of approaches such as local anesthesia and pre- and
tive field, the centrally sensitized nociceptive postoperative analgesic drugs that reduce nocicep-
neuron starts sending signals to higher brain cen- tive afferent inputs into the CNS and thus reduce
ters from more widespread parts of the orofacial the risk for the development of central sensitization
region and thereby contributes to the perception and a persistent pain state. It also emphasizes again
of a diffuse pain. On a related point, central sen- the point made above of the importance of timely
sitization also appears to be important in the and appropriate treatment of an acute pain state to
referral of pain, which is a common feature of reduce the possibility that it could lead to persistent
TMD and some other types of chronic orofacial sensitization processes and a chronic pain condi-
pain states (e.g., headaches). Trigeminal nocicep- tion. Moreover, caudalis central sensitization and
tive afferent inputs relayed to many caudalis the accompanying nociceptive behavior that occur
nociceptive neurons appear to derive exclusively in animal models of orofacial inflammatory or neu-
from cutaneous (and oral mucosal) tissues and ropathic pain can be prevented from developing, or
endow these neurons with coding properties attenuated once developed, by analgesic drugs
important for the detection and discrimination of (e.g., morphine, pregabalin) used clinically in
superficial orofacial pain, which is usually well chronic orofacial pain patients [2, 13, 45, 46].
localized. In contrast, nociceptive information These findings emphasize the crucial role that cen-
from deeper tissues (e.g., tooth pulp, TMJ, mus- tral sensitization plays in the development and
cle, meninges) is predominantly processed by maintenance of chronic orofacial pain states.
other subsets of caudalis nociceptive neurons
(both NS and WDR) receiving extensive conver-
gent afferent inputs from these tissues as well as
cutaneous afferent inputs [2, 25]. These conver- Summary
gence patterns are also a feature of analogous Several mechanisms accounting for chronic oro-
nociceptive neurons in the thalamus and cortex facial pain have been identified in orofacial tis-
and reflect processes contributing to deep pain sues and trigeminal nociceptive pathways inthe
and also to the poor localization, extraterritorial CNS.These include peripheral sensitizationand
3 Neurobiological Mechanisms ofChronic Orofacial Pain 45

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gesia: novel approaches to pain management.
AcknowledgmentsThe cited research studies by the NewYork: Wiley; 2009. p.541.
author have been supported by the US National Institutes 14.
Kopp S.Neuroendocrine, immune, and local
of Health, the Canadian Institutes for Health Research, the responses related to temporomandibular disorders.
Canadian Foundation for Innovation, the Ontario Ministry JOrofac Pain. 2001;15:928.
of Research and Innovation, Pfizer Canada, and The 15. Dostrovsky JO, Craig AD.Ascending projection sys-
Canada Research Chair program tems. In: McMahon SB, Koltzenburg M, Tracey I,
Turk DC, editors. Textbook of pain. 6th ed.
Philadelphia: Elsevier; 2013. p.18297.
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Oral andCraniofacial Pain:
Contribution ofEndogenous,
4
Central Modulation Mechanisms

LaurenceBourgeais Rambur, Charles-DanielArreto,


ClaudeRobert, andLuisVillanueva

Abstract
In this chapter, we will describe the main endogenous, central modulation
and related maladaptive mechanisms involved in processing oral and cra-
niofacial pain. In particular, we will explain how the functional anatomy
and pathophysiology of brainstem, hypothalamic, and corticofugal net-
works may alter the excitability of the trigeminal system. We will describe
our recent findings showing a direct anatomo-functional relationship
between cortical, hypothalamic excitability disturbances and dysfunctions
of medullary trigeminovascular regions. We will analyze the impact of
such dysfunctions as putative biomarkers of central sensitization phenom-
ena at the origin of sustained trigeminal pain.

4.1 Introduction similar to those throughout the rest of the body.


The specific features of trigeminal pain experience
The trigeminal system is involved in processing probably result from activities generated by endog-
nociceptive information from oral, facial, and cra- enous central modulation mechanisms involved in
nial territories. The inputs from tissue-damaging the processing of pain sensations and reactions.
events transduced by trigeminal nociceptors are The sensory pathways that convey craniofacial
nociceptive inputs to higher levels of the brain
originate in trigeminal ganglion nociceptors and
L.B. Rambur, PhD (*)
their associated nuclei within the trigeminal brain-
INSERM / Universit Paris Descartes - UFR des
Sciences Fondamentales et Biomdicales, stem sensory complex (Sp5) and upper cervical
UMR 894, Centre de Psychiatrie et spinal cord (see Chap. 3). These structures are
Neurosciences, Paris, France simultaneously collecting basic somesthetic activ-
e-mail: laurence.bourgeais@inserm.fr
ities from many sources that are not only relevant
C.-D. Arreto, DDS, PhD C. Robert, PhD for pain but that could also have a role in the con-
INSERM / Universit Paris Descartes - Facult de
tinual transmission of crucial information to main-
Chirurgie Dentaire, UMR 894, Centre de Psychiatrie
et Neurosciences, Paris, France tain the integrity of oral and craniofacial regions.
This information is constantly being selected and
L.Villanueva, DDS, PhD
INSERM, UMR 894, Centre de Psychiatrie et modulated in the context of an appropriate
Neurosciences, Paris, France response by endogenous modulation networks

Springer-Verlag GmbH Germany 2017 47


J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI10.1007/978-3-662-53994-1_4
48 L.B. Rambur et al.

originating from several central nervous system nuclei could contribute to the amplification of
(CNS) structures. These regulation circuits can act nociceptive outputs to supramedullary structures
at many levels to specifically discriminate the via the interpolar, oral, and principal subdivi-
incoming messages. Some of the particular fea- sions, since these regions convey orofacial inputs
tures of trigeminal nociception could thus result to brainstem and thalamic areas [5, 6].
not only from the unique anatomo-functional As in spinal nociceptive processing, glutama-
organization of trigeminal brainstem nuclei but tergic transmission is very important in the Sp5C
also from the interaction between bottom-up and since the local application of glutamate activates
top-down central mechanisms located upstream. nociceptive neurons [7]. In addition, systemic or
This chapter outlines the more relevant fea- local application of NMDA antagonists in the
tures of central regulation mechanisms of trigemi- Sp5C inhibits c-fos expression following corneal
nal nociception, on the basis of animal studies thatstimulation [8]. There is also strong evidence that
provide valuable models in our understanding of rostral trigeminal nuclei, especially Sp5O, con-
human oral and craniofacial pain disorders. vey both extra- and intraoral nociceptive inputs,
which are dependent on glutamatergic inputs
from Sp5C (see also Chap. 3) [1, 9]. The excit-
4.2 Endogenous Modulation atory receptive fields of wide dynamic range
Mechanisms (WDR) Sp5C trigeminal neurons that convey
noxious messages to upper CNS structures show
4.2.1 Segmental Modulation: a gradient of responsiveness, with the center
AMedullary Locus forCentral responding to both innocuous and noxious stim-
Sensitization andAnalgesia uli and the remaining area responding only to
strong stimuli. This phenomenon can be inter-
A number of clinical and preclinical findings preted as if an innocuous stimulus would excite
support the involvement of Sp5 neurons in oral only few neurons, whereas a noxious one applied
and craniofacial nociceptive processing. In the on the same somatic area would excite all the
last century, neurosurgical procedures showed neurons showing an overlapping of their recep-
that transection of the trigeminal descending tract tive fields. Based on this view, one could argue
at the level of the rostral pole of the trigeminal that the multiplication of innocuous stimuli
nucleus caudalis (Sp5C) produced thermo- applied over a large area, including a sufficient
analgesia of the face, without affecting signifi- number of centers of receptive fields, would
cantly tactile sensations. However, painful induce pain. However, since WDR neurons also
sensations from the oral cavity were partially pre- have an adjacent inhibitory receptive field dis-
served following tractotomy, suggesting that cra- tinct from the excitatory one, innocuous mechan-
niofacial noxious inputs are conveyed also by ical stimuli applied to this inhibitory field are able
neurons located more rostrally. As detailed in to inhibit WDR activity. These observations led
Chap. 3, animal studies have confirmed that the to the formulation of the gate-control theory of
orofacial tissues have multiple representations in pain, which proposed that segmental inhibitions
the Sp5C, in the transition zone between Sp5C/ are elicited by activity in large-diameter, A cuta-
interpolaris (Sp5I) and oralis (Sp5O). The Sp5C neous afferent fibers and can be activated natu-
projects also to the ipsilateral junction of Sp5C/ rally by innocuous mechanical stimuli [10, 11].
Sp5I, Sp5O, and principalis (Pr5) nuclei over The great majority of nociceptive primary affer-
their whole caudalrostral extent [13]. Such ents terminate in superficial layers (laminae I and
intratrigeminal connections are somatotopically II), but some A-fibers also terminate in lamina V
organized, as observed both in animals [4]; how- of the Sp5C (Fig. 4.1). Recent studies have shown
ever, the functional significance of these topo- the existence of a different distribution of two
graphically organized, intratrigeminal subsets of fine primary afferents: (1) A and C
connections is not fully elucidated. Ipsilateral peptidergic fibers contacting lamina I neurons at
inputs from Sp5C neurons to rostral trigeminal the origin of ascending projections and local
4 Oral andCraniofacial Pain: Contribution ofEndogenous, Central Modulation Mechanisms 49

interneurons in outer lamina II and (2) non-pepti-


dergic nociceptive primary afferents that termi-
nate in the inner part of lamina II.In contrast,
Sp5c
large myelinated A fibers that convey innocuous
inputs contact lamina V projection neurons and
local protein kinase C gamma, (PKC), interneu-
rons in inner lamina II [12]. Recent studies
showed that following intense noxious stimula-
tion or nerve injury, fine primary afferents release
glutamate and several other peptides and neuro-
modulators onto lamina I neurons. Normally
silent NMDA receptors become activated leading
to a cascade of calcium-dependent and second
messenger signaling that increases the excitabil- Lamina V

ity of lamina I neurons and thus facilitates the


transmission of noxious messages to the brain. Lamina III-IV
GABA
Under such circumstances, lamina I nociceptive Gly

neurons could be activated also by A non-noci- Lamina II


ceptive primary afferents that usually drive inhib-
itory interneurons. Following injury, A-fibers Lamina I
could activate PKC-expressing interneurons in
inner lamina II which become disinhibited and in
turn activate lamina I neurons (Fig. 4.1) [1214].
The activation of A- and C-fibers not only
elicits pain but also both segmental and heterose-
gmental inhibitory mechanisms that must have a Ad fibers
Ab fibers
functional basis beyond the dorsal horn scope of
the original gate-control hypothesis. Accordingly,
several studies have shown the importance of
small fiber activation in the production of analge- C fibers

sia by somatic electrical stimulation [15, 16]. In


fact, percutaneous electrical stimuli can elicit
both segmental and extrasegmental postsynaptic Fig. 4.1 Simplified representation of segmental modula-
tory influences onto cervicomedullary trigeminal neurons
inhibitory processes that affect trigeminal WDR (Sp5C). After entering the trigeminal tract, most nociceptive
neurons, which are triggered exclusively by A (A and C) afferents pass caudally while giving off collaterals
or both A- and C-fibers [17]. Although transcu- that terminate in the subdivisions of the spinal trigeminal
taneous electrical nerve stimulation (TENS) can nucleus and upper cervical cord. Second-order nociceptive
neurons located in laminae I and V are activated by A and
be effective when applied at frequencies and C primary afferents. These fibers terminate mostly in lamina
intensities that activate mainly A-fibers, the I, while a proportion of A and A non-nociceptive fibers
resulting pain relief is localized and often limited contact also deep, lamina V neurons. Under normal circum-
to the stimulated segment [18]. It has also been stances, lamina V nociceptive neurons have a center (excit-
atory) surrounded by inhibitory receptive fields driven by
shown that stronger analgesic effects can be A fibers, via deep inhibitory interneurons. Following
obtained with TENS by using a stimulation inten- intense noxious stimulation or nerve injury, this inhibition
sity that produces an unpleasant, but not quite could be lost, and lamina I nociceptive-specific neurons
painful, sensation [18, 19]. In summary, a sub- which are unresponsive to innocuous stimuli could be in
turn activated also by A non-nociceptive primary afferents.
stantial amount of data has implicated the activa- This activation could be partly mediated via PKC-
tion of fine-diameter fibers in analgesic procedures expressing interneurons in inner lamina II, which become
based on segmental, percutaneous electrical stim- disinhibited. Abbreviations: GABA gamma-aminobutyric
ulation. This conclusion is supported by studies acid, Gly glycine, PKC protein kinase C gamma
50 L.B. Rambur et al.

showing that the intensity of stimulation is a criti- summation and DNIC were recently reported
cal parameter for obtaining greater analgesia [30]. In addition, DNIC also inhibits lamina I
using segmental TENS [20, 21]. neurons, suggesting that a broader modulatory
role is exerted by DNIC, probably via additional
networks located in the rostral brainstem, such
4.3 Descending Modulation as the periaqueductal gray (PAG) matter and the
fromtheBrainstem rostral ventromedial medulla (RVM, see below).
Thus, noxious inputs can modulate spinal out-
4.3.1 D
 iffuse Noxious Inhibitory flow via these brainstem structures, in a bidirec-
Controls (DNIC) tional fashion [31].

In contrast to segmental controls, heteroseg-


mental controls are elicited mainly by noxious 4.3.2 D
 NIC andCounter-
stimuli. These inhibitions are mediated by stimulation-Induced
descending brainstem-mediated mechanisms, Analgesia
such as diffuse noxious inhibitory controls
(DNIC). Since the pioneering work of Le Bars Further studies also suggested that DNIC medi-
and colleagues [22] which demonstrated that ates the pain-inhibits-pain or counter-
DNIC could induce widespread inhibitory con- stimulation phenomenon, whereby there is a
trols on rat dorsal horn and medullary trigemi- mutual inhibition between the pathways that gen-
nal neurons [23, 24], a number of studies showed erate sensations elicited concomitantly by two
that these controls have common anatomical separate painful foci. DNIC reduce both spinal
and functional features in animals and humans. [32], trigeminal reflexes [33] and the perception
The supraspinal structures responsible for DNIC of experimental, acute pain following heterotopic
include the rat subnucleus reticularis dorsalis noxious stimulation in man [34]. In addition to
(SRD) in the caudaldorsal medulla, which con- spino-bulbospinal loops involved in the DNIC
tains a homogeneous population of neurons circuitry, human brain imaging studies combined
whose properties mirror the functional charac- with psychophysics and electrophysiology have
teristics of DNIC, viz., they are activated exclu- shown an important contribution of cortical
sively by noxious stimuli applied to any region regions belonging to the so-called pain matrix in
of the body and precisely encode the intensity of the regulation of DNIC networks located down-
these stimuli [25, 26]. Moreover, lesions of the stream, during the analgesia produced by counter-
caudal medulla reduce DNIC in both animals stimulation [35, 36].
[27] and humans [28]. These caudal medullary Chronic pain patient studies suggest that sev-
networks have been proposed to facilitate the eral mechanisms other than DNIC could also be
extraction of nociceptive information by implicated in counter-stimulation phenomena.
increasing the signal-to-noise ratio between a For example, the effects of counter-stimulation
pool of deep dorsal horn neurons that are acti- are altered in neuropathic pain patients, thus
vated from a painful focus and the remaining showing that DNIC mechanisms differ in health
population of such neurons, which are simulta- and disease [37]. Light pressure applied to an
neously inhibited. Accordingly, the spatial sum- allodynic area induced inhibitions of both the spi-
mation of nociceptive peripheral inputs results nal RIII reflex and the concomitant painful sensa-
in an initial increase in the number of activated tion, whereas brushing on the same allodynic
neurons, which beyond a critical level of surface area, eliciting a similar level of pain, induced a
covered by the stimulus, is followed by a reduction of the painful sensation but not a modi-
decrease in the responses of these WDR neu- fication of the RIII reflex. One can conclude that
rons [29]. In humans, similar antagonistic pro- in this latter situation, dynamicmechano-allo-
cesses elicited by interactions of spatial dynia elicited a counter-stimulation effect
4 Oral andCraniofacial Pain: Contribution ofEndogenous, Central Modulation Mechanisms 51

involving supraspinal rather than spinal circuitry. neurons integrate activities from the somatomotor
Furthermore, DNIC effects against temporally and autonomic systems in response to different
and spatially summated pain are reduced in fibro- bodily needs. They could contribute not only to
myalgia patients [38]. Also, significant reductions the modulation of pain but also to arousal reac-
in the strength of DNIC are detected in some tions and homeostatic regulations such as changes
chronic, trigeminal painful conditions such as in vasomotor, temperature, and sexual function in
temporomandibular disorder and atypical trigemi- a manner appropriate to the behavioral status of
nal neuralgia [39, 40]. These observations suggest the body [47, 48].
that the reduced ability to inhibit pain in patients Electrophysiological studies in anesthetized
with chronic pain is probably mediated by a dys- rats have suggested a role of RVM neurons in a
function of endogenous pain inhibitory systems. bidirectional, descending control of nocicep-
Moreover, some studies suggest that such distur- tion. There are three classes of RVM neuron: off
bances could also contribute to head pain process- cells, which pause just prior to withdrawal
ing as illustrated by a reduction of DNIC in reflexes; on cells, which show a burst of activity
chronic tension-type headache patients [41, 42] prior to such reflexes; and neutral cells which
and a loss of DNIC acting on trigeminovascular have no reflex-related activity. On and off cells
Sp5C neurons in an animal model of medication- project directly to dorsal horn laminae I, II, and
overuse headache [43]. V.Off cells are activated by local infusions of
mu opioid agonists or GABAA antagonists, and
their activity is correlated with inhibition of
4.3.3 The Rostral Ventromedial nociceptive transmission. In contrast, on cells,
Medulla (RVM) whose activity correlates with enhanced noci-
ceptive transmission, are inhibited by local or
Early systematic studies of what was originally systemic opioids [49].
termed stimulation-produced analgesia in ani- Electrophysiological studies in unanesthe-
mals showed that localized microstimulation of tized rats are also illuminating in this regard
the ventral periaqueductal gray (PAG) matter and because they demonstrate powerful state-
rostral ventromedial medulla (RVM) effectively dependent changes in RVM neurons. For
elicited strong behavioral antinociceptive effects example, RVM off cells are only intermittently
as shown by the inhibition of jaw-opening reflexes active during waking but become continuously
elicited by tooth pulp stimulation [44]. Since the active when animals transition to slow-wave
PAG projects minimally to the spinal and trigemi- sleep [50] or when they are given barbiturate
nal dorsal horns but densely to the RVM, RVM anesthesia [51] or morphine [52]. On cells
neurons constitute a direct link for the descending show a reciprocal pattern, becoming much less
modulation observed in these early studies. The active during slow-wave sleep. Interestingly,
RVM sends dense descending projections to compared to the anesthetized and sleeping
superficial dorsal horn neurons, and these neu- state, in awake rats, both on and off cells are
rons, in turn, modulate the activity of deep dorsal more responsive to a variety of innocuous
horn cells at the origin of spinal ascending noci- stimuli. Accordingly, unanesthetized rats dis-
ceptive pathways [45]. In contrast to the caudal play robust pro-nociceptive effects while being
SRD-medullary systems that preferentially mod- manipulated or submitted to stressful, threat-
ulate deep dorsal horn neurons, RVM cells modu- ening situations such as inescapable noxious
late not only deep dorsal horn but also lamina I stimuli, the presence of a predator, or contex-
neurons, a key relay for nociceptive inputs to CNS tual cues associated with intense or prolonged
areas that process signals relevant to homeostasis noxious stimuli [53]. In many of these situa-
[46], suggesting a broader modulatory role by the tions, the behavioral pro-nociceptive effect
RVM.In this respect, it was proposed that under probably involves the PAG-RVM network (see
appropriate environmental circumstances, RVM also Chap. 3).
52 L.B. Rambur et al.

4.3.4 T
 he Cortex asaWidespread either the visual stimulus or the motor response
Source ofTop-Down (hand movement) indicates that the mechanism
Modulation of the behavioral modulation is mediated by dis-
tinct networks involved in either sensory or motor
Powerful endogenous control of nociception preparation. Interestingly, neither the detection of
probably originates from the cortex since most the visual stimulus nor the movement of the hand
nociceptive relays within the CNS are under cor- was related to the functions normally ascribed to
ticofugal modulation, including downstream net- trigeminal nucleus caudalis. This indicates that
works involved in segmental and heterosegmental relevant information regarding the environment
modulation of medullary trigeminal neurons (see is disseminated to parts of the nervous system
above, also Figs. 4.2 and 4.3). In contrast to that may be involved directly or indirectly in the
bulbo-trigeminal descending controls, corticofu- animals ongoing behavior. Thus, neuronal
gal modulation often occurs in the absence of a responsiveness may bear no relationship to the
painful stimulus. For example, the insular cortex features of stimuli that a sensory nucleus is capa-
contributes to the processing of paradoxical pain ble of processing and may be dependent entirely
elicited by the concurrent application of innocu- on the behavioral context within which a sensory
ous cold and warm stimuli [54], whereas frontal signal is received. As similar task-related
and primary somatosensory cortical areas may responses have been demonstrated in several cor-
selectively alter the unpleasantness of pain per- tical areas, the task-related changes in trigeminal
ception following manipulation of attention, neuronal activity could represent a corticofugal
expectation, empathy, or the analgesia produced reiteration of the paradigm instructions.
by placebo or hypnotic suggestions (for reviews,
see 5557). However, the mechanisms underly- 4.3.4.2 Corticofugal Modulation,
ing these modulations remain poorly Maladaptive Changes,
understood. andImpaired Orofacial
Functions
4.3.4.1 Corticofugal Modulation Based on a number of preclinical and clinical
ofTrigeminal, Medullary Dorsal studies, Avivi-Arber and colleagues [61] pro-
Horn Activities posed that face primary motor (M1) and primary
Early electrophysiological studies showed that somatosensory (S1) cortices undergo plastic
stimulation of the primary somatosensory cortex changes that can be induced by either peripheral
inhibited the evoked responses of a proportion of or central inputs. In everyday life, such influ-
medullary nociceptive neurons in the Sp5C [58]. ences are produced by sensory stimulation and
Although the mediating pathways have not been are involved in training and the learning of new
identified, corticofugal controls are likely motor skills. However, under pathological cir-
involved in the modulation, by behaviorally sig- cumstances, maladaptive changes are produced
nificant stimuli, of neurons in the trigeminal not only by peripheral injury but also following
nucleus caudalis of trained monkeys. This type of progressive changes both in the chemistry and
modulation, termed task related, may produce morphology of the human brain [62, 63].
a greater neuronal response than that produced Cortical plasticity must be highly dependent
by equivalent stimuli in the absence of the rele- on reciprocal interactions with thalamic relays,
vant behavioral state [59]. In this regard, ther- since there are nearly ten times as many fibers
mally responsive cells in the Sp5C exhibit an projecting back from the cortex to the thalamus
additional task-related response to visual or as there are in the forward direction from the
motor cues involved in the behavioral task, but thalamus to the cortex [64]. The function of this
not to similar stimuli presented outside the task massive feedback network from S1 on the organi-
[60]. The fact that many of these task-related zation of whisker-barrel receptive fields in the
responses exhibit a preferential association with ventroposteromedial thalamic nucleus (VPM)
4 Oral andCraniofacial Pain: Contribution ofEndogenous, Central Modulation Mechanisms 53

Fig. 4.2Schematic representation of the main CNS The most important, widespread source of top-down mod-
descending networks of trigeminal pain modulation. A ulation arises from the cortex since both thalamic and pre-
noxious stimulus carried by the trigeminal nerves acti- thalamic nociceptive relays are under corticofugal
vates segmental, bulbospinal, hypothalamic, and corti- modulation (see text). Sp5C spinal trigeminal nucleus,
cofugal modulatory mechanisms by which nociceptive caudalis part, V1 ophthalmic, V2 maxillary, V3 mandibu-
signals may attenuate or increase their own magnitudes. lar divisions of the trigeminal nerve
54

KCl A-fiber dura


a b
C-fiber dura
S1 Brush periocular
cortex
140 KCl S1
S1 120

100

80

60
Sp5C 40

Total spikes (%)


20

0
S1
-30 -20 -10 5 10 20 30 40
Ins Time (min)
S2
C

Cortico-trigeminal S1 180 KCl Ins


KCl
Tract 160
S2 Insular 140
Sp5C cortex
120
V3
V2 100
Ins
() V1 (+) 80

60
Total spikes (%)

40
Sp5C
20

0
-30 -20 -10 5 10 20 30 40
Time (min)

Fig. 4.3 Direct, corticofugal modulation of cervicomedullary trigeminovascular neurons (Sp5C), which convey nociceptive signals from meningeal nociceptors to CNS regions
implicated in headache pain processing. (a) Corticofugal projections to Sp5C originate from the contralateral primary somatosensory (S1) and insular (Ins) cortices. S1 and Ins
cortices innervate both deep and superficial layers of the Sp5C, respectively. (b) Cortical spreading depression (CSD) initiated in S1 cortex induces inhibition of cutaneous and
meningeal-evoked responses of Sp5C neurons. (c) CSD initiated in Ins cortex induces a selective activation of meningeal-evoked responses of Sp5C neurons
L.B. Rambur et al.
4 Oral andCraniofacial Pain: Contribution ofEndogenous, Central Modulation Mechanisms 55

and on the organization of limb tactile receptive s timulation of either the motor or the dorsolateral
fields in the ventroposterolateral nucleus (VPL) prefrontal cortex. Such effects are not topograph-
has been clearly established. The rat ventrobasal ically distributed and probably occur at supraspi-
thalamus contains only excitatory neurons that nal levels, since rTMS does not affect spinal
project mainly to layer IV of the S1 cortex. nociceptive processing as assessed with the RIII
Descending projections in the thalamocortical reflex [68]. The relevance of cortical plasticity in
loop originate primarily in layer VI of the S1 cor- the changes of orofacial somatosensory percep-
tex. Distal dendrites are densely innervated by tion is further underlined by the maladaptive
these projections, which activate both ionotropic changes that may occur following deafferenta-
and metabotropic glutamate receptors. As in the tion. As shown by Ramachandran [69], light
visual and auditory systems, cortical feedback touch on an amputees face referred sensations
from S1 serves to amplify the effects of sensory from the face to a precise area on the phantom
stimulation to the classical center-surround hand. He suggested that these changes could be
receptive fields and helps to sharpen and adjust due to modifications in cortical topography and
the profile of thalamic receptive fields (the ego- thus when the region of the somatosensory cortex
centric selection) [65]. Attempts to address this formerly receiving inputs from the hand becomes
question by Krupa and colleagues [66] have silent, synapses from neighboring regions which
shown that inactivation of the S1 cortex resulted had previously been subliminal become active a
not only in rapid changes in the receptive field process that can be reinforced later by sprouting
properties of VPM cells driven by facial whisker of neurites. This idea is supported by the fact that
pads but also in a significant reduction of their a facial map of the phantom hand may be present
ability to reorganize their receptive fields follow- immediately after surgery [70] and by psycho-
ing reversible deafferentation of trigeminal pri- physical studies showing that, in healthy sub-
mary afferents. jects, complete local anesthesia of the thumb did
Anatomo-functional studies also indicate that not affect the perception of the adjacent finger or
the capability to discriminate noxious inputs by digits on the contralateral side, whereas the per-
S1 cannot be explained only by the projections or ceived size of the unanesthetized lips increased
the response properties of ventrobasal thalamo- by approximately 50% [71].
cortical afferents. Simultaneous thalamic and
cortical recordings and pharmacological manipu- 4.3.4.3 Corticotrigeminal Modulation
lation of corticothalamic feedback have shown andMigraine
that stimulus-driven, modality-specific influ- Several lines of evidence from animal and human
ences from the S1 cortex are required to discrimi- studies indicate that cortical spreading depres-
nate between innocuous and noxious cutaneous sion (CSD) is the pathophysiological substrate of
inputs. Corticothalamic feedback consists of migraine aura [72, 73] and migraine may thus be
either an enhancement of innocuous- or a reduc- a result of maladaptive plasticity of corticofugal
tion of noxious-evoked cutaneous responses. S1 modulation [74]. CSD, which in animals can be
produces such a selective, top-down modulation induced by focal stimulation of the cerebral cor-
of thalamic ventrobasal responses to somatosen- tex, is a slowly propagating wave of neuronal
sory inputs by engaging specific, GABAergic- depolarization and glial activation, whose
mediated, corticothalamic modulation [67]. mechanisms of initiation and propagation remain
S1 neuronal activity can be related to a spe- unclear. There are essentially no biomarkers of
cific movement and may be suppressed during migraine progression, and although numerous
that movement by M1 modulatory influences findings indicate a substantial influence of CSD
[61]. It is tempting to speculate that such mecha- on peripheral, meningeal nociceptors [75], this
nisms could be involved in pain relief following issue is still subject of strong controversy [76].
electrical or repetitive transcranial magnetic Moreover, the existence of a direct relationship
stimulation (rTMS) of the motor cortex. Selective between cortical excitability changes and modifi-
analgesia can be elicited following rTMS cations of central, trigeminovascular neuronal
56 L.B. Rambur et al.

activities was also established. Our findings showed cular pathway (the peripheral trigeminal nerve
that restricted, lateralized regions within the rat S1 innervations of the meningeal vessels and its cen-
and insular (Ins) cortices send descending projec- tral projections that form the trigeminothalamic
tions confined to the Sp5C area innervated by the tract), particularly its central components.
ophthalmic branch of the trigeminal nerve (Sp5C). Imaging studies showed that during the headache
CSD-elicited corticofugal influences from Ins and phase, there is consistent brainstem, pons, tha-
S1 evoked, respectively, an enhancement and an lamic, and cortical activation. Recent studies have
inhibition of activities of Sp5C neurons induced by identified hypothalamic activation during the pre-
the activation of meningeal nociceptors. It is pos- monitory phase that can occur hours before the
sible that such corticofugal influences could con- onset of the actual migraine headache [79].
tribute to the development of migraine pain both in Premonitory symptoms preceding a migraine
terms of topographic localization and pain tuning attack, such as sleep disturbances, excessive
during an attack. We observed also that CSD trig- yawning, changes in mood, alertness, appetite,
gered in the primary visual cortex selectively and thirst, are all functions regulated by the hypo-
affects interoceptive (meningeal) over exterocep- thalamus. Additionally, the episodic nature of
tive (cutaneous) nociceptive inputs onto Sp5C neu- migraine attacks, the circadian rhythmicity, endo-
rons [77]. More recently, by assessing cortical crine fluctuations, common triggers of migraine
excitability and hemodynamic changes induced by such as stress, and female hormonal fluctuations
somatosensory stimulation of the corresponding further implicate a hypothalamic involvement in
peripheral receptive fields, Theriot etal. [78] dem- the initiation of migraine. Importantly, these find-
onstrated that CSD induces a reduction of both ings prompted the successful use of hypothalamic
electrophysiological and hemodynamic maps in stimulation to treat cluster headache [80]. PET
the somatosensory cortex. Electrophysiological studies detected an activation of the ipsilateral
responses to somatosensory inputs were enhanced posterior inferior hypothalamic gray matter dur-
at the receptive field center but suppressed in sur- ing CH attacks, and voxel-based morphometric
round regions. Because such sharpening can be MRI showed alteration of the same area [79].
seen on chronic time scales as a marker of sensory Cranial autonomic manifestations, including red-
plasticity, these observations suggest that such pro- dening of the eye, tearing, rhinorrhea, and eyelid
found alterations of sensory processing after CSD edema, that accompany CH and also to a lesser
could contribute to chronic migraine-related sensi- extent occur in migraine could be produced by
tization. These findings shed new light on the role changes in the activity of hypothalamic structures
of corticofugal mechanisms as a direct link for that integrate signals which drive autonomic
topographically organized, differential, top- responses. Although migraine and TACs are dif-
down processing mechanisms that modulate spe- ferent types of headache disorders, they both
cifically trigeminovascular activities at the origin appear to have hypothalamic involvement in their
of headache pain (Fig. 4.3). pathogenic mechanisms.

4.3.4.4 Hypothalamic Regulation 4.3.4.5 The Paraventricular


inHeadaches: Main or Hypothalamic Nucleus
Supporting Actor asaMajor Source ofTop-Down,
inthePathogenesis? Trigeminovascular Modulation
Although significant advances have been made We recently identified the paraventricular hypo-
over the past decade in understanding primary thalamic nucleus (PVN), a region implicated
headaches, such as migraine and trigeminal auto- both in neurohormonal and autonomic integra-
nomic cephalalgias (TACs), the discovery of tion of stress responses (hypothalamicpituitary
effective treatments for patients has been ham- adrenal, HPA axis), as a likely hub that coordinates
pered by the fact that their pathogenesis remains and integrates pain/anxiety comorbidity mecha-
largely unknown. The migraine attacks are nisms involved in several primary headaches
believed to involve activation of the trigeminovas- (Fig. 4.4) [81]. PVN descending projections are
4 Oral andCraniofacial Pain: Contribution ofEndogenous, Central Modulation Mechanisms 57

a Dural blood vessel


PVN

PPG

Sp5O
3V
SSN opt

Sp5C
V3
V2
V1

b
3000
Drugs microinjections
** *
within PVN
after Muscimol injection
Decrease of activity

Meningeal 2000
(AUc 0-53 min)

electrical
stimulation

Extracellular 1000
recordings
in Sp5C

0
Controls stress Controls stress
Meningeal-evoked Basal activity
responses

Fig. 4.4 Direct, hypothalamic modulation of cervicome- sympathetic outflow via the pterygopalatine ganglion
dullary trigeminovascular neurons (Sp5C), which convey (PPG). (b) Acute stress (red bars) reduces the depressive
nociceptive signals from meningeal nociceptors to CNS effects of PVN microinjections of the GABAA agonist
regions implicated in headache pain processing. (a) muscimol (blue bars), on both basal and meningeal-
Hypothalamic projections to Sp5C originate from the ipsi- evoked responses of neurons simultaneously recorded in
lateral paraventricular nucleus (PVN), a key link of the the Sp5C.Abbreviations: 3V third ventricle; 7 facial nerve
hypothalamicpituitaryadrenal axis. PVN innervates nucleus; opt optical tract; Sp5O spinal trigeminal nucleus,
both the superficial layers of the Sp5C and the superior oralis part; V1 ophthalmic; V2 maxillary; V3 mandibular
salivatory nucleus (SSN) which regulates cranial para- divisions of the trigeminal nerve

confined to laminae I and II of the Sp5C and the and elicited cranial autonomic reactions, which
superior salivatory nucleus (SSN). PVN cells can were inhibited by drugs currently effective in tri-
elicit, via SSN influences onto postganglionic geminal autonomic TACs treatments [82].
parasympathetic neurons in the sphenopalatine Interestingly, the same clusters of parvocellular
ganglion, vasodilation and local release of inflam- PVN-Sp5C projecting cells are also densely
matory molecules that activate meningeal noci- labeled with corticotropin-releasing hormone
ceptors. In this respect, a recent study has shown (CRH) [83] and project to sympathetic and
that SSN stimulation activates both Sp5C n eurons parasympathetic preganglionic neurons in the

58 L.B. Rambur et al.

b rainstem and spinal cord implicated in the auto- maps downstream and consequently altering
nomic aspect of the stress responses [84]. all the modulatory mechanisms as a result of
Our recent findings showed that depression of sensory experiences. Disturbances in normal
PVN cells by the GABAA agonist muscimol sensory processing within these sensorimotor
inhibited both basal and nociceptive, meningeal- loops could lead to maladaptive changes,
evoked activities of Sp5C neurons. A parallel impaired oral and craniofacial functions, and
processing of both HPA and trigeminovascular consequent modifications in pain perception.
activities at the PVN level is further supported by Such ideas will help to bring together bot-
our data indicating that GABAA-mediated inhibi- tom-up and top-down mechanisms of tri-
tion of the excitatory output of PVN cells onto geminal nociception and should be taken into
Sp5C neurons is significantly reduced in a model account in future developments of therapeutic
of acute restrained stress [81]. As previously strategies aimed at improving life quality of
shown [85] acute stress reduces the properties of patients suffering from impaired oral and cra-
GABAA inhibitory synapses impinging on parvo- niofacial functions related to chronic pain.
cellular PVN neurons by downregulating the
transmembrane anion transporter KCC2, which Acknowledgments The authors are very grateful to Pr.
maintains low intracellular Cl concentration, a Yves Boucher for his valuable advice in the preparation of
this manuscript. This work was supported by INSERM,
prerequisite for the generation of Cl hyperpolar- Universit Paris Descartes, Institut UPSA de la Douleur,
izing GABAA-mediated responses. Such a loss of and Association Gliaxone.
inhibition mediated by changes in the expression
of KCC2 could thus constitute one of the mecha-
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Part III
Biomarkers in Orofacial Pain
Neurophysiologic Markers
ofNeuropathic Orofacial Pain
5
SatuK.Jskelinen

Abstract
Comprehensive neurophysiologic and psychophysical examination pro-
vides unique, sensitive, and specific information about an underlying neu-
ropathy in patients presenting with orofacial pain symptoms. These tests
consist of special electroneuromyography techniques, brainstem reflex
examinations, sensory and motor evoked potential recordings, as well as
quantitative sensory testing of different sensory modalities (tactile, ther-
mal, vibratory). The neurophysiologic diagnostic biomarkers for large and
small nerve fiber systems can confirm definite diagnosis of neuropathic
pain, also within the trigeminal distribution with up to 95100% accuracy.
They thus provide valuable differential diagnostic markers of neuropathic
vs. musculoskeletal pain within the orofacial area. When used in appropri-
ate combinations, these neurophysiologic markers allow accurate
topographic-level diagnosis along the neuraxis from peripheral nerves to
the cortex and help in guiding further imaging studies to the most likely
region of underlying pathology. These tests have already elucidated neural
mechanisms of various orofacial pain conditions including trigeminal neu-
ropathic pain, trigeminal neuralgia, persistent idiopathic orofacial pain,
primary burning mouth syndrome, and atypical odontalgia (or persistent
dentoalveolar pain). In the future, neurophysiologic markers will hope-
fully open a way for individually tailored, mechanism-based treatment
approaches. In addition, recent research indicates that neurophysiologic
and psychophysical markers can provide invaluable prognostic informa-
tion as regards, e.g., recovery and individual risk for persistent pain after
nerve injury.

S.K. Jskelinen, MD, PhD


Departments of Clinical Neurophysiology, Turku
University Hospital and University of Turku,
Postal box 52, Turku 20521, Finland
e-mail: Satu.jaaskelainen@tyks.fi

Springer-Verlag GmbH Germany 2017 65


J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI10.1007/978-3-662-53994-1_5
66 S.K. Jskelinen

5.1 Introduction orofacial region, in addition to electroneuro-


toNeurophysiologic myography (ENMG) and evoked potential (EP)


Diagnostics inPain Patients techniques, recording of brainstem reflexes pro-
vides invaluable information of the function of
The diagnosis of neuropathic pain requires objec- the trigeminal and facial nerves, their central
tive verification of a lesion or disease of the connections, and top-down control of the brain-
somatosensory system [1]. Neurological deficits, stem circuits [3, 11]. Unlike neurophysiologic
the hallmark of neuropathy and neuropathic pain, recordings, QST is a psychophysical measure-
result from reduced signaling within the neuraxis ment that requires good cooperation and is influ-
after injury. However, negative sensory signs are enced by several other factors than capacity for
difficult to confirm in clinical examination, espe- sensory discrimination. Alterations in vigilance
cially in case of subtle or old injuries, or when or motor reaction time as well as the inner sub-
positive symptoms and signs complicate the jective criterion or even malingering may have an
examination [2, 3]. False normal findings in clini- effect on the results of QST [3, 1215], and find-
cal examination may occur in up to 94% of intra- ings may thus need further confirmation with
operatively verified iatrogenic nerve injuries at objective neurophysiologic or neuropathological
late recovery [3, 4]. Similarly, clinical symptoms investigations. QST methods and reference val-
and signs alone give only modest to weak evi- ues have been published for several trigeminal
dence for peripheral neuropathy [5]. In addition, distributions and for all sensory modalities
pure small fiber damage may be difficult to verify including tactile, vibratory, and thermal sensa-
in clinical examination with rough suprathresh- tions [3, 11, 14, 16, 17]. The tests can be per-
old stimuli. As regards correct diagnosis and formed either at chairside or, with better quality
classification of pain on individual patient level, control and appropriate reference values, at the
the importance of clinical neurophysiology and departments of clinical neurophysiology in order
quantitative sensory testing (QST) is based on to detect and profile both negative (loss of func-
their ability to detect signs of subtle, even sub- tion) and positive sensory signs (gain of func-
clinical neuropathy from the peripheral receptors tion). In addition to neurophysiologic examination
and nerves to the cerebral cortex [3, 6, 7]. Proper and QST, skin and mucosal biopsies can be done
use of neurophysiologic techniques can also at optimally involved sites showing negative
increase the yield of structural imaging via focus- signs in the preceding neurophysiologic tests to
ing to the neurophysiologic region of interest confirm peripheral small fiber damage by mea-
[8]. For definite diagnosis of neuropathic orofa- suring epithelial nerve fiber density (ENFD) [18].
cial pain, adequate utilization of various combi- Comprehensive reference values for epithelial
nations of these diagnostic techniques is often small fibers and dermal myelinated fibers at all
mandatory. As the trigeminal nerve provides sen- trigeminal skin distributions [19] should facili-
sory innervation for most of the orofacial region, tate application of nerve fiber density measure-
this chapter will focus on neurophysiologic eval- ments in the study of orofacial pain.
uation of the trigeminal system in neuropathic Although small fiber system damage of the
orofacial pain. peripheral small A and C fibers or their central
Clinical neurophysiology offers several sensi- pathways is considered a prerequisite for the
tive and specific diagnostic markers for periph- occurrence of neuropathic pain [1, 2], conven-
eral or central nervous system lesions and tional neurophysiologic tests for large fibers con-
diseases, enabling detailed testing of both the stitute the first step in the differential diagnostic
large and small fiber sensory systems [1, 3, 6, 7, workout of possible neuropathic pain [1, 3, 7, 10,
911]. It provides objective and quantitative data 11]. As all peripheral nerves include both large
that do not depend on patients subjective report and small fibers, both fiber types are injured to
or cooperation. Neurophysiologic techniques are various extents in most neuropathic processes.
especially capable to reveal loss of function, and Thus, recordings investigating the large fibers
the cause for negative signs can be accurately can be used to detect, quantify, and locate poten-
localized along the neuraxis [7, 11]. Within tial underlying nerve lesion in orofacial pain
5 Neurophysiologic Markers ofNeuropathic Orofacial Pain 67

patients. They also enable assessment of progno- masseter nerve [35, 36]. Sensory recording tech-
sis and recovery. Specific neurophysiologic niques have been described for the mandibular
recordings or psychophysical tests for small fiber [37] and maxillary [38] distributions, with high
function are the next step in the diagnostic pro- diagnostic accuracy for iatrogenic inferior alveo-
cess [3, 7]. However, most of the small fiber tests lar lesions and posttraumatic neuropathic orofa-
do not allow topographic-level diagnosis; a lesion cial pain [11, 22, 39]. Needle EMG can easily be
anywhere within the pathway from the skin to the performed at almost all cranial nerve motor dis-
somatosensory cortex will give rise to an abnor- tributions, including the laryngeal muscles.
mal result in thermal QST and laser (LEP) or Large fiber-mediated brainstem reflexes are
contact heat evoked potential (CHEP) testing. useful diagnostic markers of neuropathic orofa-
Skin or mucosal biopsy for ENFD is needed to cial pain. Blink reflex (BR) can be elicited from
confirm or exclude peripheral small fiber neu- eye closing muscles bilaterally after unilateral
ropathy in case of abnormal QST or EP results tactile or electrical stimulation of the trigeminal
[18]. Advanced immunohistochemical analyses distributions (supraorbital, infraorbital, mental,
of the biopsies will allow detection of functional and lingual nerves). The standard electrically
changes in subepithelial fibers related to neuro- elicited BR consists of two components, early
pathic pain such as increased expression of ipsilateral R1 and later bilateral R2, all mediated
TRPV1 ion channels and purinergic receptors in via trigeminal tactile A afferents (with higher
burning mouth syndrome (BMS) [20, 21]. intensities, also A fibers may participate),
Besides their established value as diagnostic brainstem nuclei, and motor fibers of the facial
markers for neuropathic pain, neurophysiologic nerve. Corneal reflex (CR) and its recording
and QST methods have elucidated etiology and resemble BR, but its afferent arc consists solely
pathophysiology of many chronic orofacial pain of nociceptive A fibers that can be activated,
conditions. These include trigeminal neuropathic e.g., with air puffs given to the cornea. Despite
pain after peripheral injury [22] or brainstem its probable usefulness, CR recording has only
lesions [23], classical trigeminal neuralgia (CTN) rarely been applied in the study of chronic orofa-
and atypical or symptomatic trigeminal neuralgia cial pain. Masseter inhibitory reflex (MIR), inhi-
(STN) [24, 25], postherpetic neuralgia [26], BMS bition of ongoing masticatory muscle activity
[6, 27, 28], persistent idiopathic facial pain [PIFP; after tactile stimulation of the infraorbital or
former atypical facial pain (AFP)] [2931], and mental nerve distributions, consists of two com-
atypical odontalgia (AO) [9, 32]. Furthermore, ponents, early silent period or exteroceptive sup-
neurophysiologic methods (somatosensory pression (SP1/ES1) and late SP2/ES2 recorded
evoked potentials (SEP) or somatosensory evoked from masseter muscles bilaterally. The MIR arc
fields (SEF) recorded with electroencephalogra- involves trigeminal afferent and motor efferent
phy or magnetoencephalography and navigated fibers and their circuit within the pons. Jaw jerk
transcranial magnetic stimulation (TMS)) allow reflex (JJR) is a tendon reflex elicited with a chin
the study of cortical reorganization [31, 33] and tap and recorded bilaterally from masseter mus-
alterations of intracortical excitability [34] associ- cles. It is mediated by trigeminal muscle spindle
ated with deafferentation pain. afferents and motor neurons, via trigeminal mes-
encephalic and pontine nuclei. It is often abnor-
mal in extra- axial lesions compressing the
5.2 Neurophysiologic Markers mandibular nerve and causing demyelination. In
oftheOrofacial Large Fiber case of abnormal JJR, needle EMG of the mas-
System seter muscles aids inlocalizing the lesion either
to the rostral brainstem or the trigeminal motor
ENMG of the trigeminal system requires special efferents [3, 10, 11, 40, 41].
techniques for neurography as the main trunks of Revised NeuPSIG guideline on neuropathic
the nerve are located within deep, bony tissues. pain assessment [1] recommends the trigeminal
Motor action potentials can be elicited from mus- reflexes for orofacial pain diagnosis with level
cles of mastication with needle stimulation of the Aevidence. Their diagnostic values in t rigeminal
68 S.K. Jskelinen

neuropathy and pain are shown in Table 5.1. The detecting trigeminal lesions [sensitivity 100%
brainstem reflexes are accurate in revealing etio- and specificity 81% [44] and traumatic brain-
logical lesions in STN and useful inlocalizing it stem injuries [45]]. Similarly, combined use of
within the neuraxis [42]. They aid in differential trigeminal neurography, BR tests, and thermal
diagnostics, as in classical TN, the A-fiber- QST leads to very high diagnostic accuracy (>
mediated BR and MIR responses are normal [1, 95100%) for peripheral trigeminal lesions with
11, 40]. Due to larger between-subject variabil- or without pain [3, 4, 6, 11, 22, 39]. On the
ity in R2 compared to R1 latencies, the R2 com- group level, abnormalities in BR recordings
ponents of the BR are less sensitive although such as high reflex thresholds and prolonged
specific to trigeminal system lesions. Their sen- response latencies have been found in patients
sitivity is best at acute stages, but they mostly with BMS, PIFP [6, 27, 29], and AO [32] giving
normalize by 6months if there are no obstacles support to the neuropathic nature of these pain
to nerve regeneration [3, 11]. In orofacial neuro- states. On individual patient level, abnormal BR
pathic conditions, the various distinct patterns responses compared to reference values can be
of abnormal brainstem reflex components allow found in distinct subgroups of BMS and PIFP
very precise diagnosis and localization of patients [6, 29]. The patterns of reflex abnor-
lesions within the trigeminal system [11, 22, 28, malities indicate that subclinical lesions within
37, 40, 43]. Combined recording of JJR, BR, the trigeminal system either at the peripheral or
and MIR further increases topographic localiz- the brainstem level can give rise to clinically
ing accuracy [11, 23, 40, 4345]. Using brain typical BMS or PIFP symptoms, as similar
MRI as the reference, studies have shown excel- although more severe findings occur in clinically
lent diagnostic precision for a combination of obvious trigeminal neuropathic pain [3, 6,
brainstem reflex recordings (JJR, BR, MIR) in 22,29, 36].

Table 5.1. Clinical and research indications of clinical neurophysiologic and psychophysical tests for orofacial neuro-
pathic conditions and their diagnostic accuracy as appropriate or available
Application in the orofacial
Test Sensitivityb Specificityb region Abnormal findings
Electromyography 8090% > 90% Needle EMG of muscles Loss of function: signs of
(EMG) innervated by cranial nerves denervation in case of loss of
V, VII, IX, X, XI, XII motoneurons; signs of collateral
cranial neuropathy and and axonal reinnervation;
neuropathic pain localization, activity and age of
the lesion
Neurography 8090% 60100% Infraorbital, inferior alveolar Loss of function: small or
(nerve conduction (mental), lingual, and major absent responses, slow
velocity and auricular sensory nerves, and conduction velocity, conduction
response masseteric motor nerve; blocks, type of injury (axonal or
amplitude) neuropathic pain related to demyelinating), extent of axonal
their peripheral lesions injury, level of injury
Transcranial Trigeminal, facial, and Loss of function: small or
magnetic accessory spinal nerves absent responses, slow central
stimulation: motor (pyramidal tract and or peripheral motor conduction
evoked potential motoneurons) lesions
within the pyramidal tract
and peripheral nerves
Transcranial Mapping of the Quantification of maladaptive
magnetic representation of hand and cortical plasticity: shrinkage of
stimulation: facial or masticatory muscles representation area in pain,
mapping of the within the M1 cortex study recovery after successful
motor cortex of cortical reorganization treatment
5 Neurophysiologic Markers ofNeuropathic Orofacial Pain 69

Table 5.1.(continued)

Application in the orofacial


Test Sensitivityb Specificityb region Abnormal findings
Transcranial Study of intracortical Gain of function: decrease in
magnetic inhibition and facilitation cortical inhibition in neuropathic
stimulation: changes in cortical pain; differential diagnostics of
paired-pulse excitability in neuropathic neuropathic and musculoskeletal
techniques pain pain
Blink reflex with R1 59100% R1 93100% Trigeminal sensory divisions Loss of function: delayed,
electrical R2 2759% R2 60100% (A afferents in SON, ION, small, or absent responses;
stimulation MN, LN), pontine and accurate topographic-level
medullary brainstem, facial diagnostics in orofacial
nerve peripheral and central pain and peripheral or
nervous system lesions and brainstem lesions
neuropathic pain within the trigeminofacial
system
Habituation of the Dopaminergic nigrostriatal Gain of function: deficient
blink reflex, and serotonergic habituation of the R2
paired-pulse striatoreticular inhibitory component due to decreased
techniques control of the brainstem top-down inhibition; defects in
increased excitability/ the nigrostriatal dopamine
decreased inhibition in system function in BMS and
neuropathic orofacial pain PIFP, verified with PETa
Blink reflex with Trigeminal small fiber Loss of function: small or
laser or system: nociceptive A absent or delayed
nociceptive afferents and their CNS responses in trigeminal system
electrical pathways neuropathic pain lesions and neuropathic
stimulation orofacial pain
Corneal reflex Corneal A afferents, Loss of function: absent or
brainstem, facial nerve delayed responses
Jaw jerk (masseter Muscle spindle Ia afferents Loss of function: absent or
reflex) from masticatory muscles, delayed responses
mandibular nerve,
mesencephalic and pontine
nuclei of the trigeminal nerve
Masseter SP1 59100% SP1 93100% Trigeminal sensory afferents Loss of function: absent or
inhibitory reflex (ION, MN), pontine delayed responses
trigeminal motor nucleus, and
motoneurons
Trigeminal Needle stimulation of the Loss of function: small or
somatosensory SON, ION, and MN early absent or delayed responses in
evoked potential waves (up to 10ms) useful in trigeminal system lesions and
(TSEP) demonstrating trigeminal neuropathic orofacial pain,
A-fiber dysfunction and subtle abnormalities in classical
brainstem pathology trigeminal neuralgia, level
diagnosis
Laser evoked 64% 83% Trigeminal A (heat pain) Loss of function: small or
potential (LEP) and C (warm) small fibers; absent or delayed responses in
peripheral and central trigeminal system lesions and
pathways; cortical sources neuropathic orofacial pain,
within anterior cingulum and abnormalities even in classical
insular cortex trigeminal neuralgia, no level
diagnosis
Gain of function: abnormal
habituation in migraine
(continued)
70 S.K. Jskelinen

Table 5.1.(continued)
Application in the orofacial
Test Sensitivityb Specificityb region Abnormal findings
Contact heat Same as LEP Same as LEP Same as LEP, but also A Loss of function: small or
evoked potential (cool) fibers can be studied absent or delayed responses in
(CHEP) trigeminal system lesions and
neuropathic orofacial pain, no
level diagnosis
Quantitative 4060% 80100% Small fiber system for Both loss (hypoesthesia,
sensory testing innocuous warming (C anesthesia) and gain of function
(QST): warm fibers), from the periphery to (hyperesthesia, allodynia), no
detection threshold the cerebral cortex level diagnosis
QST: cool 4065% 80100% Small fiber system for Both loss (hypoesthesia,
detection threshold innocuous cooling (A anesthesia) and gain of function
fibers), from the periphery to (hyperesthesia, allodynia), no
the cerebral cortex level
QST: heat pain 1040% 90100% Small fiber system for Both loss (hypoalgesia,
detection threshold noxious heat (A fibers), analgesia) and gain of function
from the periphery to the (hyperalgesia, allodynia), no
cerebral cortex level
QST: cold pain Small fiber system for Both loss (hypoalgesia,
detection threshold noxious cold (A fibers), analgesia) and gain of function
from the periphery to the (hyperalgesia, allodynia), no
cerebral cortex level
QST: tactile 3060% 5090% Large fiber system (A Both loss (hypoesthesia,
detection threshold afferents), from the periphery anesthesia) and gain of function
to the cerebral cortex (hyperesthesia, allodynia), no
level
SON supraorbital nerve, ION infraorbital nerve, MN mental nerve, LN lingual nerve, dx diagnosis, R1 early blink reflex
component, R2 late BR components, SP1 early component of masseter inhibitory reflex, BMS primary burning mouth
syndrome, PIFP persistent idiopathic orofacial pain
a
Neurotransmitter positron emission tomography (PET)
b
Diagnostic values gathered from: [1, 3, 4, 7, 11, 39, 42, 44, 45, 57] all figures not exclusively for orofacial region

While brainstem reflexes are convincingly stimulation and unreliable analysis of the vari-
useful markers for neuropathic orofacial pain, able middle or long latency TSEP components or
they do not provide reliable positive diagnostic muscle and reflex activity contaminating the
markers for temporomandibular pain [41, 46]. recording (for detailed discussion, see [10, 47,
Regarding musculoskeletal or nociceptive orofa- 48]). Nevertheless, appropriately performed
cial pain, neurophysiologic methods are currently TSEP recordings are able to reveal subtle abnor-
useful only in their differential diagnosis from malities in large fiber function, such as focal
neuropathic pain. demyelination in CTN patients [48]. Transcranial
Somatosensory EPs to electrical stimuli may magnetic stimulation (TMS) is used to elicit
be applied to study trigeminal A afferent fibers motor evoked potentials (MEP) for the investiga-
(TSEP), but this requires special needle stimula- tion of central and peripheral motor pathways,
tion technique at low intensities for reliable also within the cranial nerve distributions. While
recording of the early potentials arising from the abnormal MEP may aid inlocalizing neuropathic
brainstem, thalamocortical radiation, and the S1 lesions of the trigeminal and facial systems [35],
cortex and occurring within the first 10ms of the results are normal in TMD [46]. So far, the
stimulation [10, 47]. Most studies reporting on TMS method has only rarely been applied to
TSEP findings in orofacial patients with study orofacial pain. Yet, new navigated TMS
neuropathy or pain have used imprecise surface devices hold promising potential for the study of
5 Neurophysiologic Markers ofNeuropathic Orofacial Pain 71

central mechanisms of neuropathic pain, and A recent study [51] using both laser and nocicep-
repetitive TMS can even be used to treat intrac- tive electrical stimulation to evoke pain-related
table trigeminal pain. evoked potentials (PREP) showed that electrical
stimulation might offer a safer and better toler-
ated means than LEP to study small fiber system.
5.3 Neurophysiologic Markers However, unlike laser and contact heat stimuli,
oftheSmall Fiber System electrical stimuli always simultaneously activate
the large A afferents in addition to small A
Neurophysiologic markers of small fiber dys- pain fibers, and thus, PREP is not a pure measure
function include brainstem reflex recordings of small fiber function.
(BR and MIR) and EP recordings with painful Table 5.1 summarizes the indications and
electrical, laser, or contact heat stimuli [7, 26, diagnostic values of LEP and CHEP recordings
4851]. The possibility to directly measure the in verifying loss of function within the A- and
small fiber system, the lesions of which are con- C-fiber-mediated small fiber systems in neuro-
sidered responsible for most of the sensory phe- pathic pain and trigeminal system damage [26,
nomena related to neuropathic pain, has raised 49]. Specifically, A-fiber-mediated LEP and
considerable interest during the last decade. CHEP recordings are helpful in detecting sensory
Neuropathic orofacial pain offers an optimal tar- neuropathy and, consequently, recommended for
get for the application of these techniques as the diagnosis of neuropathic pain with level A
contact heat and laser stimuli to the trigeminal evidence [1, 7]. The use of specific nociceptive
distributions elicit the largest and most stable stimuli increases the diagnostic sensitivity for an
CHEP and LEP responses at the central EEG underlying neuropathy, as LEP recordings have
derivations. After stimulation of the epithelial demonstrated abnormal small fiber function in up
small A-fiber endings, the main nociceptive to 100% of STN patients and even in half of the
N2-P2 complex arises from the anterior cingu- CTN patients irrespective of the findings in clini-
lum, with preceding small bilateral early compo- cal examination [24]. In addition, PREP record-
nents of insular origin [7, 26, 52]. ings have shown that patients with CTN (only
With specific settings, laser stimulators allow paroxysmal pain) have delayed nociceptive EPs
separate analysis of the function of the A- and and BR and reduced amplitudes, whereas the
C-fiber tracts [26, 48, 53]. C-fiber stimulation PREP responses are larger and have shorter laten-
seems to be technically more demanding with cies in patients with atypical TN [25]. These
contact heat stimulator [26] that may, however, large pain-related EPs probably reflect deficient
allow recording of cold evoked potentials. The habituation of single consecutive EP responses in
price of the new laser stimulators (neodymium- atypical TN, similar to the phenomena found in
or thulium-YAG/YAP) able to give short stimuli LEP studies on headache [54] and BR studies on
with a rise time of 1000C/s that is optimal for BMS and PIFP [3, 6, 27, 29, 31]. Furthermore, in
A LEP recordings is rather high. In addition, trigeminal neuropathy with persistent burning
laser stimulators bear a risk for burn injuries as pain, multimodal EP recordings have demon-
well as for retinal damage. These facts currently strated specific sparing of C-fiber responses in
limit the availability of neurophysiologic tech- the absence of A and A responses [10], indi-
niques utilizing laser stimulation although they cating that the remaining C fibers are responsible
have been suggested to be the most useful diag- for mediating the ongoing burning pain sensa-
nostic markers of neuropathic pain [1, 7]. Contact tion. In line, abnormalities in A- and C-fiber
heat stimulators have the advantage that the skin LEPs are associated with ongoing burning pain in
temperature is always controlled, and burn inju- postherpetic neuralgia, whereas abnormal
ries do not occur. In CHEP recording, the stimu- A-fiber-mediated BR responses occur in those
lus risetime is slower (70C/s), and the responses PHN patients who have paroxysmal pain symp-
therefore are more dispersed and latencies longer. toms [26]. Clinical neurophysiologic techniques
72 S.K. Jskelinen

are evidently able to elucidate distinct pathophys- 4, 22, 27, 29, 39]. In the majority of neuropathic
iological mechanisms of chronic trigeminal and pain patients, loss of function can be confirmed
orofacial pain and their association with subjec- with QST.Thermal hypoesthesia first indicated
tive symptoms. However, there are still scarce small fiber system hypofunction in BMS [27].
data on LEP findings in different orofacial pain This finding was later verified with ENFD to be
conditions and even less on CHEP or PREP due to focal small fiber neuropathy of the tongue
techniques. mucosa [18]. Similar thermal hypoesthesia has
On group-level comparisons, BR responses to been reported to occur in PIFP and neuropathic
nociceptive-specific electrical stimulation [50] of facial pain due to trigeminal injuries [22, 29].
the supraorbital, infraorbital, or mental nerves However, QST is only moderately sensitive com-
have been found to be smaller and have longer pared to objective and more accurate neurophysi-
latencies both in CTN [25] and AO patients [32], ologic methods [3, 4, 39] or ENFD measurements
which may indicate neuropathic etiology at least [55]. Best diagnostic accuracy for neuropathy
in part of the AO patients. It remains to be inves- and neuropathic pain is reached when neurophys-
tigated whether nociceptive-specific BR or MIR iologic recordings are combined with thermal
can be utilized for individual patient diagnostics QST or ENFD measurements, all complementing
in orofacial pain conditions. In AO, this would each other [3, 4, 7, 27, 29, 39, 56, 57].
probably require very focal stimulation of the The sensitivity of orofacial QST in neuropa-
distal alveolar nerve branches that may be dam- thy diagnosis varies according to sensory modal-
aged after dental procedures. ity tested, type of change (loss or gain of
function), and time of testing. As shown in
Tables5.1 and 5.2, elevation of tactile and innoc-
5.4 Psychophysical Markers uous thermal detection thresholds (hypoesthesia)
inOrofacial Pain offers better diagnostic yield for trigeminal neu-
ropathic pain than heat pain detection thresholds
QST, with appropriately gathered and applied (HPT) or cold pain detection thresholds (CPT)
reference values, improves diagnostic accuracy that, due to large between-subject variation (in
for trigeminal neuropathy compared to standard- the order of 1030C), have wide reference
ized clinical sensory examination (Table 5.2) [3, limits and, thus, are insensitive diagnostic tools.

Table 5.2. Comparison of diagnostic values (%) of intraoperative neurophysiological monitoring (at
qualitative clinical sensory tests, quantitative sensory 2weeks) combined with subjective report of sensory
testing, and neurophysiologic recordings in the diagnosis alteration (at 1year) were used as the gold standard of
of inferior alveolar nerve (IAN) neuropathy: results of nerve injury
Test Sensitivity at 2weeks/1year Specificity at 2weeks/1year
Brush stroke direction 40/0 89/100
Sharp/blunt discrimination 40/0 89/100
Warm/cold discrimination 44/7 100/100
Grating orientation discrimination 59/27 73/88
Tactile detection threshold 58/33 56/88
Cool detection threshold 64/40 100/88
Warm detection threshold 50/47 100/92
Heat pain detection threshold 43/13 100/96
Blink reflex of the mental nerve 59/27 60/100
Neurography of the IAN 88/82 55/100
Source: Modified from [3, 4, 39]. Normality of all QST and clinical neurophysiologic (CN) test results was determined
according to own reference values gathered in the same CN laboratory (with a quality-control system accredited since
2003 according to the ISO/IEC 17025:2005 standard) with exactly same equipment, device settings, and instructions in
healthy subjects
5 Neurophysiologic Markers ofNeuropathic Orofacial Pain 73

At individual patient level, thermal pain detection p ronounced tendency to contralateral and
most often remains normal, especially in subtle extrasegmental spread both in musculoskeletal
or old injuries (>6months), whereas tactile detec- [63] and neuropathic pain. The use of peripheral
tion thresholds (TDT), cool detection thresholds anesthetic blocks may aid in differentiating
(CDT), and warm detection thresholds (WDT) peripheral from central nervous system pathology
may help in confirming the diagnosis even at late [64], but neurophysiologic recordings, ENFD, or
stages of recovery [3, 4, 22]. Similarly, hypo- radiological imaging is crucial for exact localiza-
function in thermal QST (loss of function in tion of the cause of pain [3, 6, 7, 11].
innocuous modalities) most often occurs in Hypoesthesia to innocuous thermal stimuli is
patients with neuropathic pain as recently rather specific for neuropathic pain [2, 3, 58, 65],
reported in a large multicenter study [58]. whereas tactile hypoesthesia may occur in chronic
Appropriate reference values are extremely musculoskeletal and inflammatory pain [1]. QST
important in diagnostic use of QST.Due to spatial offers a unique possibility to measure and quan-
summation effect, thermode size has significant tify positive sensory phenomena (hyperesthesia,
influence on pain and warm detection thresholds hyperalgesia, allodynia) in humans. None of these
that are higher with smaller thermode [3, 11, 59]. are specific to neuropathic conditions, though
Furthermore, thermode size should always be occurring also in musculoskeletal and inflamma-
appropriate to the nerve distributions under study in tory pain [2, 3]. Thus, gain of function does not
order not to stimulate the neighboring intact territo- differentiate neuropathic and nociceptive pain,
ries [3, 11, 14, 60]. Density of small fiber endings although cold allodynia is mostly found in neuro-
varies between body sites, being highest in the fin- pathic pain [1, 2, 15]. However, thermal allodynia
gertips and the lips and lowest on the trunk and seems to be very rarely present in trigeminal neu-
proximal parts of the extremities this variation is ropathic pain [22, 27, 29, 60, 65].
reflected in QST detection thresholds that are low- QST findings can provide clues to the type
est on the palmar skin of the hands and near midline and severity of trigeminal nerve injury and,
of the face [16, 61]. Consequently, reference values hence, prognostic information about recovery
gathered, e.g., laterally at the cheek with large ther- and risk of neuropathic pain. Hypoesthesia in
mode cannot be applied to the small mental nerve thermal QST indicates small fiber injury and
distribution near midline [11, 16]. Inappropriate moderate to severe axonal nerve lesion [4, 11,
thermode size or reference site may blur diagnostic 65], whereas tactile hypoesthesia occurs both in
accuracy of QST; abnormalities in QST profiles demyelinating and axonal nerve damage [4, 36].
were reported in 41% of healthy subjects with a At the acute stage, loss of function in thermal
recently launched protocol [58] in which reference QST reflects axonal injury and small fiber deaf-
values gathered at distal legs or hands may be ferentation, which predicts later development of
applied to investigate proximal symptoms. chronic neuropathic pain [36, 65]. Initially severe
A major limitation of QST method is the lack loss of thermal sensibility (i.e., severe axonal
of topographic-level diagnostic efficacy. A lesion damage) predicts poor overall recovery from
anywhere along the neuraxis from the skin to the peripheral nerve injury [36, 65]. Furthermore, in
cortex may cause abnormalities in QST, and spe- line with observations on inferior alveolar nerve
cific diagnosis requires additional investigations injuries with neurography [22] and experimental
[3, 7, 15, 56, 57]. Similar to the spread of pain evidence from spinal cord injuries [66], QST
symptoms, thermal hypoesthesia is liable to findings have demonstrated that less severe, par-
extend beyond the original neuroanatomical bor- tial nerve injury may be more frequently associ-
ders both extrasegmentally and across the midline ated with the occurrence of neuropathic pain than
especially in neuropathic pain [22, 62], which severe or total loss of function [65]. Less exten-
makes the use of homologous contralateral site an sive axonal injury may also cause gain, instead of
unreliable reference in QST.The same applies to loss, of function in distinct subgroups of AO [60],
positive sensory signs in QST showing a BMS [27], and PIFP [29] patients, since very
74 S.K. Jskelinen

minor nerve injuries seem to induce mainly posi- Conclusions


tive signs [22]. In addition, originally low HPT, Neurophysiologic and psychophysical tests
i.e., high thermal pain sensitivity, is considered provide useful and accurate diagnostic,
an independent risk factor for development of mechanism-related, and prognostic functional
persistent postsurgical [67] and TMD pain [65]. markers for neuropathic pain, but their full
Pain measures in QST vary widely between potential has not yet been explored in orofa-
subjects due to differences in subjective criterion cial pain states. The diagnostic sensitivity of
[13] but are rather stable within a subject between the tests is best at the acute stage after nerve
repeated tests [59]. The within-subject consis- damage, but they are superior to clinical
tency forms the basis for the use of QST and gain examination also in chronic conditions and at
of function profiles in the follow-up of treatment late stages of recovery. Reports on deficient
effects and disease progression or recovery [1, habituation of EPs to multimodal stimuli in
15]. This potential of QST still mainly waits for migraine patients [54] raise the quest for stud-
future application to orofacial pain. ies on habituation of EPs, utilizing single-trial
analyses and multimodal salient stimuli, also
in different orofacial pain entities.
5.5  arkers ofAltered
M Neurophysiologic demonstration of deficient
Excitability central inhibition or increased excitability
WithintheNeuraxis could serve as a marker for increased risk of
chronic neuropathic pain after injury. It might
Brainstem reflex recordings have provided mark- also provide a marker for patient selection to
ers to study increased excitability within the tri- pain treatment with new noninvasive neuro-
geminal system in neuropathic orofacial pain. modulation techniques such as repetitive
Normally, the BR responses habituate, i.e., the TMS, known to release endogenous dopa-
area under R2 response decreases with steady mine. For future work, there are additional
repetition of stimuli at 1Hz frequency. exciting neurophysiologic markers that can
Habituation of BR is under nigrostriatal dopami- evaluate phenomena occurring in neuropathic
nergic inhibitory control [6]. Deficient habitua- pain such as cortical reorganization measured
tion of the BR has been found in patients with with source analysis of SEF or SEP responses
trigeminal neuropathic pain[29], BMS [27, 28], [31, 33], as well as specific tests for cortical
and PIFP [29, 31], suggesting deficient inhibitory excitability and intracortical inhibition,
control of the brainstem. Subsequent neurotrans- assessed in detail with paired-pulse TMS tech-
mitter PET studies have shown defects in nigros- niques [34]. With a few exceptions [31], these
triatal dopamine system reminiscent of early have not been explored in chronic orofacial
Parkinsons disease in both BMS and PIFP pain yet. TMS can also be used to assess
patients [6, 68]. This increased trigeminal excit- training-induced plasticity within the primary
ability extrasegmental to the distribution of motor cortex, as has been shown, e.g., for
peripheral neuropathy may represent a marker of tongue musculature in healthy subjects [14].
deficient top-down inhibition that in turn might With the recently introduced neuronavigated
be a risk trait for the development of neuropathic TMS devices, cortical mapping of the motor
pain. Similarly, reduced habituation of pain- representation areas with an accuracy of a few
related LEPs has been interpreted to indicate millimeters [69] offers a precision tool for the
increased excitability of the somatosensory cor- study of injury or disease as well as plasticity-
tex in migraine [54]. Excitability of the trigemi- and treatment-related changes in cortical
nal system may also be evaluated with motor maps. These novel neurophysiologic
paired-pulse stimulation and brainstem reflex markers of neuropathic pain-related brain
recordings, as has been done for the study of level alterations still mostly wait for applica-
TMD patients with normal results [46]. tion to the study of chronic orofacial pain. In
5 Neurophysiologic Markers ofNeuropathic Orofacial Pain 75

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iologic, psychophysical, and neuropathologi-
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Masticatory Muscle Pain
Biomarkers
6
MalinErnberg

Abstract
This chapter focuses on the potential role of biomarkers for masticatory mus-
cle pain, i.e., myalgia. To date, no biomarkers have been identified that can be
used clinically for diagnosis or treatment of myalgia of jaw muscles. There is
evidence from microdialysis studies that intramuscular levels of glutamate
and serotonin are elevated in patients with chronic myalgia, including myal-
gia of jaw muscles. High muscle levels of glutamate and serotonin correlate
to pain intensity and mechanical allodynia, and both glutamate and serotonin
have been shown to induce pain and mechanical hyperalgesia when injected
into jaw muscles. This pain, consequently, can be blocked with specific
receptor antagonists, indicating that glutamate and serotonin may be promis-
ing biomarker candidates. However, muscle levels of glutamate and serotonin
do not correlate to plasma levels, which is a disadvantage since measuring
intramuscular biomarker levels with currently available techniques is too
complicated to be clinically useful. Nerve growth factor (NGF) has also been
shown to cause long-lasting hyperalgesia, albeit with no pain, when injected
into jaw muscles, but muscle biopsies did not show any differences in NGF
levels between patients with jaw myalgia and pain-free controls. Additionally,
muscle levels of prostaglandins, bradykinin, or substance P, commonly char-
acterized pain mediators, do not seem to be elevated in myalgic jaw muscles.
Because pain mediation and peripheral sensitization are complex events that
involve many substances, future research should focus on investigating intra-
muscular profiles of multiple biomarkers. This, in turn, is possible with newly
developed methods, such as proteomics and metabolomics.

The author declares no conflict of interest.

6.1 Introduction
M. Ernberg, DDS, PhD
Karolinska Institutet, Department of Dental
Medicine, Section of Orofacial Pain and Jaw Chronic masticatory muscle pain, i.e., myalgia, is a
Function and Scandinavian Center for Orofacial disorder affecting approximately 10% of the popu-
Neurosciences (SCON), Box 4064, lation and of which two thirds are women [1]. It is
SE14104Huddinge, Sweden
e-mail: malin.ernberg@ki.se therefore a commonly treated disorder among

Springer-Verlag GmbH Germany 2017 79


J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI10.1007/978-3-662-53994-1_6
80 M. Ernberg

clinicians, and although extensive research has Thus, the ideal biomarker could be measured in
focused on the pathogenesis of chronic muscle pain body fluids that are easily sampled at a low cost
in the last decades, the nociceptive mechanisms that such as blood, urine, or saliva (see Chaps. 9 and
underlie the pain are still largely unknown [2]. This, 10).
in turn, requires that clinicians rely on patient Conversely, since the events leading to pain
reports, questionnaires, and semi-objective findings may occur within the muscle itself, any change in
for diagnostics. For example, in the recently pub- intramuscular biomarker levels may not signifi-
lished Diagnostic Criteria for Temporomandibular cantly alter systemic levels. Therefore, tech-
Disorders (DC/TMD), there are three subclasses of niques that could measure biomarker levels in the
myalgia; local myalgia, myofascial pain, and myo- muscle, such as muscle biopsies, may be useful.
fascial pain with referral [1]. The same main criteria The disadvantages of biopsies, however, are both
are used for all diagnoses, and they differ only the tissue trauma induced and the difficulty of
regarding the presence of pain spread with palpa- accessing certain muscle groups.
tion and if the pain spreads within or beyond the Microbiopsy techniques, which are used, for
boundary of the muscle. However, the pathogenesis example, in cancer diagnosis, may reduce tissue
underlying these diagnoses may not be the same trauma and thus be more useful but have not been
and may also differ between patients with the same adopted in muscle pain research until recently
diagnosis. Pain is always a subjective experience, and need to be validated (Fig. 6.1).
and semi-objective clinical methods like muscle Another technique of potential use is microdi-
palpation or assessment of pressure pain thresholds alysis. This technique allows for continuous
(PPT) have limited sensitivity and correlate only monitoring of biomarkers in tissues invivo,
weakly with ongoing pain ratings [3]. There is which is the major advantage over biopsies. By
therefore a need for more objective and sensitive inserting a hollow microdialysis catheter with a
tools, which has led to an increasing research inter- dialysis membrane at its tip into the tissue and
est in biomarkers for pain. Biomarkers are specific very slowly perfuse it with a saline buffer, mole-
biochemicals in the body with a well-defined
molecular feature that may be used in disease diag-
nosis and disease progress and to evaluate treatment
effects [4] (see Chap. 10).
Biomarkers in muscle pain can be divided into
three main categories; algesic biomarkers, tissue
metabolites, and inflammatory mediators [5].
Algesic biomarkers are substances that can
directly activate muscle nociceptors, such as glu-
tamate and protons, whereas tissue metabolites
are important substances in the cell metabolism,
such as lactate and pyruvate. Inflammatory bio-
markers are substances released in the tissue dur-
ing inflammation, such as prostaglandins and
cytokines (see further below).

6.2  ethods forSampling


M
andAnalyzing Muscle Fig. 6.1 A representative confocal image showing the
Biomarkers expression of 5-HT3 receptors on sensory nerve fibers sur-
rounding myocytes in the human masseter muscle. The
To be clinically useful, potential biomarkers have biopsy was taken from a pain-free volunteer with microbi-
opsy technique. The fluorescent intense green color
to be easily and reliably measured and also need marked by arrows represents 5-HT3 receptor expression
to correlate to pain variables (e.g., pain intensity). (Courtesy of Dr. Nikolaos Christidis)
6 Masticatory Muscle Pain Biomarkers 81

cules may diffuse passively across the dialysis conditions, peripheral input is needed to drive
membrane and be sampled for later analysis. pain. There is good evidence from animal studies
Using different techniques, the true tissue con- that muscle trauma and ischemia may cause neu-
centration of the biomarkers may be calculated. rogenic inflammation, which is a normal response
The major disadvantages of microdialysis are that promotes healing [2]. During this process,
that the technique is time-consuming, compli- peripheral sensory afferent nerves are activated
cated, and expensive and that it requires sensitive which leads to antidromic release of neuropep-
analyses due to the limited volumes of fluid that tides, such as substance P (SP), calcitonin gene-
can be collected. related peptide (CGRP), neurokinin A (NKA),
A problem with all the sampling methods out- and vasoactive intestinal peptide (VIP). These
lined is potential diurnal variations in biomarker substances promote the release of other chemi-
levels, which either must be ruled out or con- cals, e.g., prostaglandins, nerve growth factor
trolled for by sampling at the same time of the (NGF), bradykinin, and serotonin (5-HT) that
day (see Chap. 10). Tissue fluid levels of bio- activate and sensitize the neuron by binding to
markers may also be influenced by, e.g., age, gen- specific receptors on the peripheral nerve termi-
der, and body mass, which must also be nal (Table 6.1) [2, 7]. Another important mole-
considered. Furthermore, in most commercial cule is the vanilloid receptor (TRPV1) that seems
kits, only single biomarkers can be analyzed, to have a key role in initiating the neurochemical
which makes analyses expensive and time- cascade associated with neurogenic inflamma-
consuming if multiple biomarkers are to be tion [2, 7]. There is also evidence of a role for
assessed. More recent analyses that can combine
several biomarkers have been developed. Bio- Table 6.1 Potential biomarkers for muscle pain and their
Plex, for example, uses color-coated polystyrene peripheral receptors
beads that allow analyses of up to 100 biomark- Endogenous ligand Peripheral receptor
ers in one sample using as little as 25L sample. Glutamate NMDA, AMPA, mGlu
The rapid development of proteomics and metab- Serotonin 5-HT1, 5-TH2, 5-HT3,
olomics with multi-panel analyses using protein 5-HT7
Nerve growth factor TrkA, p75
or DNA microarrays, additionally, is also a prom-
Protons TRPV1, ASIC
ising tool for biomarker analyses.
Bradykinin BK1, BK2
Eicosanoids
PGE2 EP1, EP2, EP3, EP4
6.3 Muscle Pain LTB4 LTB41, LTB42
Pathophysiology Neuropeptides
SP NK1
Myalgia is characterized by spontaneous pain CGRP CGRP1
that is aggravated by function and muscle sore- NPY Y1, Y2, Y4
ness (hyperalgesia); pain referral is also fre- Cytokines
quently noted. It was previously believed that IL-1beta IL1RI, IL1RII
myalgia was caused by muscle inflammation, but TNF TNFRI, TNFRII
in most myalgic pain conditions, there are no IL-6 IL-6R
gross signs of inflammation or tissue trauma [6]. IL-8 IL-8R alpha, IL-8R beta
However, inflammation may still be present on a PGE2 prostaglandin E2, LTB4 leukotriene B4, SP sub-
molecular level (neurogenic inflammation). stance P, CGRP calcitonin gene-related peptide, NPY neu-
ropeptide Y, IL interleukin, TNF tumor necrosis factor,
There seems to be agreement about both periph- NMDA N-methyl-D-aspartate, AMPA -amino-3-
eral and central mechanisms participating in hydroxy-5-methyl-4-isoxazolepropionic acid, mGlu
muscle pain development and that the longer pain metabotropic glutamate receptor, 5-HT 5 hydroxytrypta-
persists, the role of the central mechanisms mine, TrKA tyrosine kinase A, p75 p75 neurotrophin
receptor, EP E-prostanoid, TRPV1 transient receptor
becomes more pronounced. However, many potential vanilloid 1, ASIC acid-sensing ion channel, BK
researchers believe that even in chronic myalgic bradykinin receptor, NK neurokinin 1
82 M. Ernberg

peripheral glutamate receptors in this peripheral are increased and that ionotropic GluRs are
sensitization. If peripheral sensitization contin- upregulated during inflammation. By activation
ues for a prolonged period, central sensitization of peripheral GluRs (AMPA, NMDA), glutamate
develops during which sensitization of second excites peripheral sensory afferents and sensi-
order N-methyl-D-aspartate (NMDA) glutamate tizes them to thermal and mechanical stimuli [8].
receptors seems to play an important role [2, 7]. Additionally, in human tissue, levels of gluta-
Besides these pain biomarkers, of which many mate are elevated in inflammatory conditions,
have been of interest as candidates for muscle such as rheumatoid arthritis [8], and glutamate
biomarkers, there are also inflammatory media- injection evokes pain, mechanical sensitization,
tors, such as cytokines, that may also serve as and increased blood flow [8]. In addition, inges-
biomarkers in jaw myalgia. Most cytokines are tion of glutamate increased muscle glutamate
released from circulating immune cells, e.g., neu- levels more in patients with jaw myalgia than
trophils, monocytes, and mast cells during controls. However, thus far no specific GluR
inflammation, but some may also participate in antagonist for clinical use has been developed
neurogenic inflammation. Other potential bio- and local administration of the noncompetitive
markers include metabolites, such as lactate, NMDA antagonist ketamine shows contradictory
pyruvate, glucose, and glycerol. To date, no sin- results.
gle biomarkers have been identified for jaw myal-
gia, but there are a few promising candidates. The
following section of this chapter will deal with 6.4.2 Serotonin
substances that have been a target for research as
potential biomarkers for jaw myalgia. Serotonin, or 5-hydroxytryptamine (5-HT), is a
small molecule of the monoamine family that
exerts a range of biological effects in the human
6.4  otential Biomarkers inJaw
P body and modulates physiological processes in
Myalgia both the central and peripheral nervous systems.
5-HT is synthesized both peripherally and in the
6.4.1 Glutamate CNS from the essential amino acid tryptophan,
which is derived from the diet. Peripherally, the
Glutamate is an excitatory amino acid present in major sources of 5-HT are the enterochromaffin
afferent sensory nerves where it acts as the main cells of the small intestines and enteric neurons,
neurotransmitter for conveying sensory informa- but 5-HT is also present in platelets and mast
tion to the central nervous system (CNS). It is cells, and a small fraction of 5-HT is also unbound
present both in the trigeminal ganglion and in the in the blood. In the CNS, 5-HT is found in sero-
central and peripheral nerve terminals and tonergic neurons, including those in the nucleus
released in response to intense noxious stimula- raphe magnus [9].
tion or inflammation [8]. Immunohistochemistry In response to tissue trauma and inflamma-
has shown that glutamate receptors (GluRs) are tion, 5-HT is released and, by activating recep-
present on peripheral nerve terminals, which tors on peripheral sensory nerves, may activate
makes it likely that glutamate would interact with and sensitize these peripheral neurons. Of special
these receptors. Three types of ionotropic GluR importance is the 5-HT3 receptor, which seems to
subtypes have been identified, all of which are be important for mediating pain from the periph-
present on peripheral nerve terminals: NMDA, ery [9]. Recent data shows that 5-HT3 receptors
- a m i n o - 3 - h y d r o x y - 5 - m e t h y l - 4 - are present on sensory nerves in the human mas-
isoxazolepropionic acid (AMPA), and kainate seter muscle (Fig. 6.1), and in patients with jaw
(Table 6.1). There are also metabotropic GluR myalgia more nerve fibers in the masseter muscle
present on peripheral nerve terminals. Animal express 5-HT3 receptors compared to controls.
studies have shown that tissue glutamate levels This suggests a potential role of 5-HT in myalgia.
6 Masticatory Muscle Pain Biomarkers 83

Indeed, tender point injection with the 5-HT3 by three kinases, among them angiotensin-
receptor antagonist granisetron into the masseter converting enzyme (ACE). Bradykinin is a potent
muscle alleviate jaw myalgia. 5-HT also sensi- vasodilator and bronchoconstrictor that increases
tizes peripheral mechanoreceptive afferent fibers vascular permeability and facilitates pain trans-
to other chemicals, e.g., glutamate, SP, and mission. Additionally, bradykinin further pro-
CGRP, by enhancing the efficiency of motes the release of glutamate from astrocytes.
tetrodotoxin-resistant sodium channels and low- During ischemic contractions, bradykinin is
ering the threshold of TRPV1 receptors, which released in muscle tissue and numerous animal
results in primary hyperalgesia [9]. studies have shown that it has a role in muscle
nociception and sensitization [11].

6.4.3 Nerve Growth Factor


6.4.5 TRPV1
Nerve growth factor (NGF) belongs to the family
of neurotrophins. NGF binds both to the low- TRPV1 is a nonselective cation channel that is
affinity transmembrane receptor p75 and also to activated by a variety of exogenous and endoge-
the high-affinity tyrosine kinase receptor A nous stimuli, for example, noxious heat (43
(TrkA), both of which are expressed on sensory 52C), chemical compounds, and protons [12].
neurons. It has been shown that the expression of Polymodal C-fibers normally express TRPV1
these receptors in the trigeminal system is higher receptors, and during inflammation TRPV1
than in the spinal system [10]. Activation of TrkA receptors are upregulated. Interestingly, TRPV1
receptors by NGF results in a cascade of intracel- receptors are not present on A fibers under nor-
lular and extracellular events leading to periph- mal conditions but are expressed during inflam-
eral sensitization. mation. The pungent ingredient of chili pepper,
Animal research has shown an increase of capsaicin, but also mechanical stimuli activates
endogenous levels of NGF after tissue injury and TRPV1 receptors on sensory afferents that con-
that inflammation and intramuscular administra- tain various pro-inflammatory neuropeptides.
tion of NGF in rodents is associated with mechan- This causes the antidromic release of neuropep-
ical and thermal hyperalgesia and nociceptive tides from the nerve endings that induce vasodi-
processing within the CNS [10]. lation and sensitize the neuron to other nociceptive
Furthermore, levels of NGF are elevated in chemicals, e.g., prostaglandins, NGF, bradyki-
many clinical pain conditions, such as rheuma- nin, and 5-HT.
toid arthritis, cancer pain, and degenerative disc
disease. TrkA receptors are co-localized with
TRPV1 receptors, and NGF increases TRPV1 6.4.6 Neuropeptides
and NMDA expression and induces the release of
other pain mediators, for example, prostaglan- Since the cloning of the first neuropeptide recep-
dins [10]. In addition, via a positive feedback tors in the late 1980s, neuropeptides have been a
loop, NGF also induces the release of NGF itself target for extensive research, especially in the
that may sensitize adjacent nociceptors [10]. pharmaceutical industry in search for new drug
targets [13]. As the name implies, neuropeptides
are small peptides that are released from neuronal
6.4.4 Bradykinin cells and are commonly used by neurons to com-
municate with each other. Many neuropeptides
Bradykinin is a peptide involved in the inflamma- are co-released with other neurotransmitters, such
tory response. Bradykinin is synthesized in the as glutamate, acetylcholine, and norepinephrine.
kinin-kallikrein system from the kininogen pre- Aside from their functions as neurotransmitters,
cursor by the enzyme kallikrein and metabolized neuropeptides have a variety of other functions,
84 M. Ernberg

for example, as neurohormones and growth fac- peripheral release of prostaglandins and leukotri-
tors. Some neuropeptides are released peripher- enes could be part of the pathogenesis of jaw
ally and have a key role in neurogenic myalgia. However, the dose of PGE2 needed for
inflammation, such as SP, CGRP, NKA, and VIP, excitation of muscle nociceptors is so high that it
whereas others are released in central brain is unlikely that it exerts a nociceptive effect dur-
regions, such as galanin, cholecystokinin, and ing pathologic conditions. Therefore it is more
neurotensin. Many neuropeptides affect vessel likely that PGE2 is involved in sensitization of
tone. For example, SP, CGRP, and VIP act as nociceptors [16].
vasodilators, and neuropeptide Y (NPY), which is
co-released with norepinephrine, is a strong vaso-
constrictor. Several animal studies have shown 6.4.8 Cytokines
that SP and CGRP relay nociceptive information
and that sensitized peripheral neurons release SP Cytokines are small peptides that are produced by
and CGRP in response to innocuous stimulation. most nucleated cells and released during inflam-
It is also believed that SP and CGRP act synergis- mation but are also involved in many physiologi-
tically in inflammation and nociception [13]. cal processes. Cytokines may have both pro- and
anti-inflammatory effects. Normally there is a
balance between these two effects to maintain
6.4.7 Eicosanoids homeostasis, but during inflammation there is
typically a shift in cytokine production so that the
During inflammation, eicosanoids play an essen- normal balance is disrupted in favor of pro-
tial role. Eicosanoids are substances produced in inflammatory signaling. Interleukin 1 beta (IL-
various cell types, e.g., endothelial cells, fibro- 1), TNF, IL-6, and IL-8 are pro-inflammatory
blasts, and leukocytes, by the breakdown of ara- cytokines that are implicated in the illness
chidonic acid in the cell membrane in response to response (fever, fatigue, etc.) and produce hyper-
tissue trauma, leading to the formation of prosta- algesia upon peripheral administration [14].
glandins, thromboxanes, and leukotrienes. The These pro-inflammatory cytokines are all pro-
formation of prostaglandins and thromboxanes duced in muscle tissue and released in response to
from arachidonic acid depends on cyclooxygen- exercise and tissue trauma. If overproduction of
ase enzymes that catalyze the conversion. pro-inflammatory cytokines is part of the patho-
However, while prostaglandins may sensitize genesis of jaw myalgia, one might assume that
nociceptors, induce vasodilation, and inhibit intramuscular levels of these cytokines would be
trombocyte aggregation, thromboxanes have the increased as muscle levels of IL-6 are increased in
opposite effect in that they facilitate trombocyte delayed onset muscle soreness, i.e., myalgia that
aggregation and induce vasoconstriction. may develop after eccentric exercises [15].
Leukotrienes, conversely, depend on the
enzyme lipoxygenase for their production.
Leukotrienes are strong vasoconstrictors, 6.4.9 Metabolites
increase blood vessel permeability, induce che-
motaxis, but also sensitize nociceptors [14]. Pyruvate and lactate are important end-products
The prostaglandin PGE2 has been of particular of glucose metabolism. Pyruvate is a key metabo-
interest in inflammatory pain studies and is an lite in many metabolic pathways and is involved
important biomarker in delayed onset muscle in both aerobic and anaerobic metabolism.
soreness [15]. Nonsteroidal anti-inflammatory During aerobic metabolism, glucose is cleaved to
drugs (NSAIDs), such as aspirin, reduce inflam- pyruvate, which enters the Krebs cycle to pro-
matory pain at a peripheral level by inhibiting duce additional energy. As part of anaerobic
cyclooxygenases and, hence, the synthesis of metabolism, pyruvate is converted by fermenta-
prostaglandins. Thus, one may speculate that tion to lactate following glycolysis. This process
6 Masticatory Muscle Pain Biomarkers 85

is reversible; when oxygen is present, lactate is (10mmol/l) with glutamate in pain-free volun-
reconverted to pyruvate, and through gluconeo- teers attenuated pain with a better effect in men
genesis, pyruvate can be converted back to glu- [28], whereas co-injection of ketamine at higher
cose. Pyruvate can also be converted to fatty dose (20mmol/l) had similar effects in men and
acids and to the amino acid alanine. women [20]. However, injection of ketamine
It is well known that heavy exercise leads to (10mmol/l) did not alter pain and mechanical
metabolic changes within the muscle as lactate allodynia in jaw myalgia patients [29]. The
accumulates in the muscle and blood plasma. It results also suggest that local treatment with ket-
has also been speculated that continuous low amine may not be clinically useful in jaw
force exercise could alter local muscle metabo- myalgia.
lism since the same low-threshold motor units are Injection of serotonin into human jaw muscles
activated during a longer time and with time may of healthy volunteers evoked pain and mechani-
become overloaded. This, in turn, may alter the cal allodynia [30]. Similarly, injection of sero-
muscle pressure around the muscle fibers and tonin into the anterior tibialis muscle evoked pain
impede blood flow, oxygen delivery, and removal but did not induce mechanical allodynia [31].
of metabolites as ischemia develops [17]. Lactate The lower dose of serotonin and the larger size of
itself does not seem to induce pain, but ischemia the muscle may explain these differences.
may cause the release of pain biomarkers and Additionally, serotonin seems to enhance the
thus lead to pain. effect of bradykinin, as combined injection of
serotonin and bradykinin into the anterior tibialis
and temporalis muscles increased pain responses
6.5 Pain Evoked and produced long-lasting secondary allodynia
byIntramuscular Injection [32, 33]. Co-injection of serotonin and the 5-HT3
ofBiomarkers inHumans receptor antagonist granisetron (1mg/ml) attenu-
ated the pain and hyperalgesia induced by sero-
Intramuscular injection of glutamate into the jaw tonin [34]. Pretreatment with granisetron
muscles of pain-free human volunteers was effectively attenuated hypertonic saline and
shown to evoke pain, pain referral, and mechani- acidic saline-induced masseter muscle pain [35,
cal allodynia, with stronger pain effects in women 36] with a greater increase of PPT in men [35].
[1821]. Both pain intensity and pain drawing Local and oral administration of granisetron
area were greater in the temporalis muscle com- increased muscle PPTs in pain-free subjects, with
pared to the masseter [19]. Sensory-discriminative a greater effect in men [37, 38], indicating that
and affective-unpleasantness components to glu- serotonin may decrease the sensitivity of muscle
tamate injections are similar to jaw myalgia, but mechanoreceptors. Moreover, local and systemic
the psychosocial features differ [21, 22]. Injection granisetron and other 5-HT3 antagonists attenu-
of glutamate into other muscles (splenius mus- ate jaw myalgia [37] and chronic low back and
cles, forearm) induces similar responses [23, 24]. trapezius muscle pain [39] and also have a posi-
Thus glutamate-evoked pain seems to be a valid tive effect on widespread pain in patients with
model for myalgia. Pretreatment with NGF fibromyalgia [40]. Thus, there is evidence from
before glutamate injection increased masseter human studies that serotonin may activate and
pain area and reduced PPTs [25], and pretreat- sensitize muscle nociceptors and that substances
ment with glutamate before capsaicin injection that block 5-HT3 receptors may be of therapeutic
enhanced pain variables [26]. However, pretreat- value in jaw myalgia. However, more research is
ment with capsaicin before glutamate injection needed to establish this.
diminished glutamate-induced pain [26, 27], NGF injected into the masseter muscle of pain-
which indicates that desensitization by capsaicin free volunteers provoked mechanical allodynia
blocks the release of glutamate. Co-injection of that lasted up to 7days with similar effects in men
the NMDA receptor antagonist ketamine and women and pain upon chewing and yawning
86 M. Ernberg

[41, 42]. The injection also affected motor func- glutamate level compared to pain-free controls.
tion. Injection of NGF into the tibialis anterior Regarding urine, one study reported that the total
muscle induced long-lasting allodynia that also amino acid excretion was positively correlated
spread distally and proximally and was also appar- with pain intensity and that the urine levels of glu-
ent over the finger 1 day after injection, indicating tamine/glutamate correlated to pain duration in
signs of central sensitization [43]. Injection of patients with jaw myalgia, which they interpreted
hypertonic saline 1 day after NGF injection into as a depletion of metabolic reserves [51].
the tibialis anterior muscle induced more pain in Studies employing intramuscular microdialy-
men than after isotonic saline injection on day 1. sis to sample glutamate in female patients with
These results indicate that NGF injection may be a jaw myalgia show contradictory results. One
useful model for mechanical muscle allodynia. study did not show any difference in masseter glu-
Intramuscular injection of capsaicin into the tamate levels between patients and controls [52],
masseter muscle of pain-free volunteers caused and another reported increased levels in female
pain that lasted for 20min and was described as patients compared to age-matched pain-free con-
pressing and taut and also pain referral, pre- trols [53]. Both studies found similar masseter
dominantly to the molar teeth as well as mechani- levels of glutamate in the patients, but the controls
cal allodynia [44, 45]. It also decreased the in the latter study had lower glutamate levels,
electromyographic activity in the masseter mus- which may explain the contradictory results. The
cle but increased the jaw stretch reflex amplitude glutamate levels did not correlate with pain levels
[45, 46]. Experimental tooth grinding before cap- in either study. Muscle glutamate levels in the lat-
saicin injection induced more long-lasting ter study were higher compared to plasma levels
mechanical allodynia and reduced jaw opening in the patients, but plasma levels did not differ
compared to capsaicin alone [44]. Furthermore, between patients and controls [53]. The results
capsaicin injection into the masseter increased from the latter study are corroborated by studies
local blood flow but also skin blood flow, which in patients with localized trapezius myalgia,
might indicate that it induces neurogenic inflam- which reported elevated glutamate levels in the
mation [47]. trapezius muscle in patients with work-related tra-
Additionally, injections of a few other bio- pezius myalgia and chronic widespread pain [54
markers have been investigated for potential 56]. In the trapezius, high glutamate levels
effects on muscle pain. Injection of SP or NKA, correlated to low PPT and high pain levels [54,
or a combination of both, into the temporalis 55]. However, other studies did not find any dif-
muscle of healthy subjects did not induce pain or ferences in trapezius levels of glutamate between
mechanical hyperalgesia [48], while injection of patients with chronic trapezius myalgia (not spec-
potassium into the temporalis muscle did [49]. ified), fibromyalgia, whiplash- associated disor-
Injection of a combination of serotonin, hista- ders (WAD), and pain-free controls [5759]. This
mine, bradykinin, PGE2, and ATP into the trape- might be due to methodological differences
zius muscle of healthy subjects and patients with between studies, such as different flow-rates and a
tension-type headache induced prolonged pain low number of subjects in certain studies. Neither
and mechanical allodynia [50], but the combina- did the levels of glutamate in trapezius tender
tion has not been tested for jaw myalgia. points of chronic tension-type headache patients
differ from pain-free controls [60].
Serum levels of serotonin did not differ
6.6  issue Levels ofBiomarkers
T between jaw myalgia and healthy controls [61].
inPatients withMuscle Pain However, the release of serotonin in the masseter,
measured with microdialysis, was increased in
So far few studies have investigated saliva or urine patients with jaw myalgia [52, 62]. Additionally,
levels of pain biomarkers in patients with jaw the levels of serotonin correlated with pain and
myalgia. One study found no differences in saliva mechanical pain thresholds [62]. Similar results
6 Masticatory Muscle Pain Biomarkers 87

are reported from the trapezius muscle, where IL-6, and IL-8in the trapezius muscle [64], but
levels of serotonin were elevated in patients with also in the pain-free gastrocnemius muscle [69],
localized trapezius myalgia (work-related and were reported to be increased when compared to
WAD) as well as in fibromyalgia [5456, 58, 63, pain-free controls. Patients with WAD had
64]. These results also correlated with pain levels increased levels of IL-6in the trapezius muscle
[54, 58]. Furthermore, recent results indicate that [58], but normal levels of IL-6 were found in
the frequency of sensory nerve fibers that express patients with work-related trapezius myalgia
5-HT3 receptors in the masseter muscle is upreg- [70]. Elevated blood levels of the pro-
ulated in female patients with jaw myalgia, when inflammatory cytokine monocyte chemotactic
compared to pain-free matched controls [65]. protein (MCP-1) and anti-inflammatory cytokine
However, the data need to be confirmed with a IL-1ra were recently reported in TMD patients
larger patient sample before any firm conclusions [71], whereas increased blood and cerebrospinal
can be drawn. These results strengthen a role for fluid levels of pro-inflammatory (IL-8, TNF) and
serotonin in jaw myalgia. reduced blood levels of anti-inflammatory cyto-
Studies investigating tissue levels of other kines (IL-4, IL-10) were found in fibromyalgia
pain molecules in jaw myalgia are scarce. One patients [72]. Finally a recent study using posi-
study showed that the masseter levels of leukotri- tron emission tomography (PET) reported
ene B4 (LTB4), but not PGE2, were higher in increased uptake of D-deprenyl, a marker of
patients with masseter myalgia than in healthy inflammation, in painful neck muscles in WAD
controls. However, PGE2 levels were positively [73]. Whether D-deprenyl uptake can be visual-
correlated to pain intensity [66]. No differences ized in jaw myalgia patients is unknown but
were found between patients with jaw myalgia would be an interesting area for future research.
and controls in levels of PGE2, LTB4, NGF, SP, or
bradykinin in open biopsies obtained from the
masseter muscle. However, the level of F(2) iso- 6.7  uscle Biomarkers Tissue
M
prostane, a marker of oxidative stress, was lower Levels AfterExercise
in patients than in controls and correlated to mus-
cle pain intensity and PPT [67]. In concordance Some studies have investigated the effect of
with these studies, trapezius levels of PGE2 in muscle exercise on biomarker levels using
patients with chronic trapezius myalgia, and in microdialysis, but very few have been per-
tender points of patients with chronic tension- formed in the orofacial region. There were no
type headache, did not differ from healthy con- alterations in masseter muscle levels of NPY in
trols [57, 60], indicating that there is no detectable response to experimental tooth clenching in
inflammation in myalgic/tender muscles. pain-free volunteers [74], and there were also no
Increased levels of protons, bradykinin, SP, changes in the levels of serotonin, glutamate
CGRP, and norepinephrine have been reported in lactate, or pyruvate in patients with jaw myal-
active trigger points of the trapezius muscle [64]. gia, although clenching induced low levels of
A recent study reported no differences in mas- pain [52]. Similarly, serotonin levels did not
seter lactate or pyruvate levels in jaw myalgia as change in the trapezius muscle of patients with
compared to healthy controls [52]. Muscle pyru- work-related trapezius myalgia, WAD, and
vate and lactate levels in the trapezius muscle of fibromyalgia or in pain-free controls after exer-
patients with trapezius myalgia show varying cise (peg board) [56, 58, 63]. With regard to glu-
results; most studies report increased levels [17, tamate, lactate, and pyruvate, however, the
55, 59, 68], but one found no differences to pain- results from the masseter muscle differ from
free controls [58]. those of the trapezius muscle, in which levels of
No study has investigated cytokines in myal- these metabolites increased after exercise both
gic jaw muscles. In patients with active trapezius in patients with work-related trapezius myalgia,
muscle trigger points, the levels of IL-1, TNF, WAD, fibromyalgia, and in pain-free controls
88 M. Ernberg

[17, 58, 75]. The difference between regions channels that are thought to be the major chan-
may be due to differences in exercise protocol: nels involved in acid-induced pain [78].
in the masseter muscle, a resting period of 1min Injection of acidic saline into the human ante-
was alternated with clenching for 30s, whereas rior tibialis muscle evoked low-levels of pain
in the trapezius, continuous repetitive arm and short-lasting mechanical allodynia [78].
movements were used. Glutamate and lactate However, mechanical allodynia in the masseter
levels, as well as the levels of PGE2 and SP, muscle was not induced with this model,
were also increased in the calf muscle after although very low levels of pain were evoked
eccentric exercise, which caused delayed-onset [79]. The release of serotonin, glutamate, lac-
muscle soreness [16]. Pilot data from our group tate, or pyruvate was not found to change in
indicate that IL-6 and IL-8 levels in the masseter response to acidic saline-injection [80]. These
muscle of healthy subjects increase in response results combined imply that the acidic saline
to tooth clenching (J. Goerlach etal., personal model does not seem to be a useful experimental
communication). Additionally, IL-6 levels in model of orofacial myalgia. Intramuscular infu-
the trapezius muscle increased after exercise in sion of a chemical mixture consisting of brady-
patients with trapezius myalgia and healthy con- kinin, PGE2, histamine, and serotonin into the
trols [58, 70]. trapezius muscle did not cause the release of
glutamate, lactate, glucose, glycerol, pyruvate,
and urea even as it evoked local pain and
6.8  uscle Biomarker Levels
M mechanical allodynia [81]. Collectively, these
inExperimental Myalgia results show that only the hypertonic saline
model seems to be a valid experimental model
Human experimental pain models are important of clinical myalgia.
tools to bridge the gap between animal studies
and the clinic. An often-used model to induce Summary
myalgia that mimics clinical situations is intra- Table 6.2 summarizes the findings from
muscular injection of hypertonic saline. Recent human studies regarding the evidence for a
studies show that hypertonic saline injection role of potential biomarkers for jaw myalgia.
into the masseter cause the release of serotonin, Although there is evidence that glutamate and
glutamate, and glycerol but not lactate or pyru- serotonin play a role in jaw myalgia, evidence
vate [76]. Similarly, hypertonic saline injection for the role of other potential biomarkers in
into the biceps muscle induced the release of human muscle pain is scarce. To be useful to a
glutamate but had no effect on lactate, PGE2, or clinician, a biomarker should be easily col-
nitric oxide levels [15]. This indicates that, even lected. This explains why blood or saliva sam-
as an acute pain model, injection of hypertonic ples would be preferable. Because of the lack
saline shows similar clinical and molecular pain of correlation between muscle and plasma lev-
manifestations as clinical myalgia. Another els of serotonin and glutamate, their useful-
experimental pain model that recently has ness as biomarkers for jaw myalgia is limited.
gained attraction in human studies is intramus- In conclusion, no substance at present fulfills
cular injections of acidic saline. In animals, two the role of a useful biomarker for jaw myalgia.
repeated injections of acidic saline 25days Future studies with new and highly sensitive
apart induce long-lasting mechanical allodynia methods that can combine analyses of several
[77]. During ischemia, pH drops, and the biomarkers are therefore warranted to further
released protons may activate acid-sensing ion advance the field.
Table 6.2 Summary of the effects of potential biomarkers for muscle pain in humans
Muscle levels Muscle levels: other muscles Muscle level Receptor Effect of injection
correlation to pain expression into masticatory Effect of receptor
Substance MMP After exercise MP After exercise variables MMP muscles antagonist in MMP
Glutamate Increased No change Increased Increased Pain level, ? Pain, pain referral, Reduced pain and
hyperalgesia hyperalgesia hyperalgesia
Serotonin Increased No change Increased Increased Pain level, Increased (?) Pain and Reduced pain and
6 Masticatory Muscle Pain Biomarkers

hyperalgesia hyperalgesia hyperalgesia


NGF ? ? ? ? ? Normal Hyperalgesia ?
Protons ? ? Increased ? ? ? Pain, hyperalgesia ?
(capsaicin)
Bradykinin ? ? Increased ? ? Normal Pain, hyperalgesia ?
PGE2 Normal ? ? Increased Pain level Normal No effect ?
LTB4 Increased ? Increased ? No Normal ? ?
SP ? ? Increased ? ? Normal No effect ?
CGRP ? ? ? ? ? ? ? ?
NPY ? No change Increased Increased No ? ? ?
IL-1beta ? No change Increased ? ? ? ? ?
TNF-alpha ? No change Increased ? ? ? ? ?
IL-6 ? Increased Increased ? ? ? ? ?
IL-8 ? Increased Increased ? ? ? ? ?
Lactate Normal No change Increased Increased No ? ? ?
Pyruvate Normal No change Increased Increased No ? ? ?
MMP masticatory muscle pain, MP muscle pain other regions (trapezius myalgia, fibromyalgia), NGF nerve growth factor, PGE2 prostaglandin E2, LTB4 leukotriene B4, SP
substance P, CGRP calcitonin gene-related peptide, NPY neuropeptide Y, IL interleukin, TNF tumor necrosis factor, ? no information available. See text for more information and
references
89
90 M. Ernberg

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receptor targets for analgesia. Hoboken: John Wiley and TTX insensitive sodium channels (NaV1.8) by
& Sons, Inc.; 2009. p.15374. masseter muscle nerve fibers in healthy subjects com-
79. Castrillon EE, Cairns B, List T, Svensson P, Ernberg pared to patients with local myalgia. JHeadache Pain.
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substances. Eur JPain. 2013;17(4):53950. P.Increased pain and muscle glutamate concentration
81. Ashina M, Jorgensen M, Stallknecht B, Mork H,
after single ingestion of monosodium glutamate by
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K.TRPV1 channel-mediated bilateral allodynia induced
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Additional Reading Wong H, Kang I, Dong XD, Christidis N, Ernberg M,
Svensson P, Cairns BE.NGF-induced mechanical sen-
Christidis N, Omrani S, Fredriksson L, Gjelset M, Louca sitization of the masseter muscle is mediated through
S, Hedenberg-Magnusson B, Ernberg M.Repeated peripheral NMDA receptors. Neuroscience.
tender point injections of granisetron alleviate chronic 2014;269:23244.
myofascial pain a randomized, controlled, double- Xu XX, Cao Y, Ding TT, Fu KY, Li Y, Xie QF.Role of
blinded trial. JHeadache Pain 2015;16(1):104. TRPV1 and ASIC3 channels in experimental occlusal
Christidis N, Cairns BE, Kumar U, Dong X, Rosn A, interference-induced hyperalgesia in rat masseter
Kopp S, Ernberg M.Expression of 5-HT3 receptors muscle. Eur JPain. 2016;20(4):55263.
Molecular Temporomandibular
Joint Pain Biomarkers
7
PerAlstergren

Abstract
This chapter covers immunological markers for inflammatory types of
temporomandibular joint (TMJ) pain. The specific biological relevance or
clinical value of biomarkers in TMJ pain is, however, so far insufficiently
investigated. There are studies that indicate candidate biomarkers for
diagnostic or prognostic purposes in diseases like rheumatoid arthritis
and psoriatic arthritis. This chapter discusses available knowledge regard-
ing cytokines, cytokine receptors, serotonin, prostaglandin E2, and gluta-
mate in relation to diagnosis, prognosis, and treatment of TMJ
inflammatory pain.

7.1 Introduction diagnostic or prognostic purposes or to assess


or monitor disease activity, especially in dis-
Much of the recent research regarding TMJ eases like rheumatoid arthritis (RA) and psori-
arthritis and molecular diagnostics aims to atic arthritis (PsA).
identify patients at risk for disease develop- Inflammation of articular tissues, i.e., arthri-
ment and to enable early treatment to prevent tis, frequently shows chronic pain as a major
chronification of the pain and tissue damage. symptom. Chronic arthritis may also result in
The specific biological relevance or clinical articular cartilage and bone tissue destruction.
value of biomarkers in temporomandibular This is commonly seen, especially in systemic
joint (TMJ) pain is, however, so far insuffi- arthritides like RA and PsA.In these conditions,
ciently investigated. At the same time, there pain is the major factor for impaired daily activi-
are numerous studies available that indicate ties and quality of life. Indeed, TMJ pain has a
highly interesting candidate biomarkers for substantial negative impact on activities of daily
living in RA [1].
The peripheral contribution to TMJ pain as
P. Alstergren, DDS, PhD, Med Dr well as cartilage and bone tissue destruction is
Orofacial Pain Unit, Faculty of Odontology, locally and systemically modulated by a huge
Department of Orofacial Pain and Jaw Function,
Malm University, Malm, Sweden number of mediators, among them cytokines,
e-mail: per.alstergren@mah.se serotonin, prostaglandins, and glutamate.

Springer-Verlag GmbH Germany 2017 95


J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI10.1007/978-3-662-53994-1_7
96 P. Alstergren

7.2 Cytokines Cytokines have been extensively studied in


immune reactions and inflammation but less so
Cytokines are small peptides with redundant effects regarding their specific and distinct roles in pain.
that mediate potent stimulatory or inhibitory effects The relation between cytokines and pain is prob-
in immunity and inflammation. All nucleated cells ably better understood by placing it in a broader
are capable of synthesizing cytokines, produced de context as a part of an immune reaction or
novo in response to immune stimuli, and most cell inflammation. In fact, most, if not all, experi-
types respond to them. Cytokines generally act at mental models to study hyperalgesia or pain
very low concentrations during short periods of facilitation induce release of proinflammatory
time in an autocrine or paracrine manner although cytokines [10].
additional endocrine effects have been described
for some cytokines [2, 3].
It is now apparent that cytokines are involved in 7.2.1 Peripheral Cytokine
most physiological processes, including modula- Modulation ofPain
tion of repair and remodeling of damaged tissue.
For the most part, however, cytokines are produced Locally released cytokines are believed to influ-
and released during inflammation. Cytokines are ence or modulate pain in a complex manner on
often produced in a cascade, as one cytokine stim- several levels:
ulates its target cells to make additional cytokines.
The complex interconnectivity and dynamics of 1. Direct effects on nociceptors via cell-surface
cytokine biology might better be visualized as a receptors
network within a cascade where cytokines can act 2. Indirect effects on nociceptors via stimulation
independently, additively, or synergistically [3]. of local production of other cytokines and
The central role of the cytokines tumor necrosis mediators with nociceptive effects
factor (TNF), interleukin-1 (IL-1), and IL-6 3. Pain/hyperalgesia as a part of the illness

within the proinflammatory cytokine network is response
now conclusively established [4]. 4. The cholinergic anti-inflammatory pathway
Cytokine-mediated inflammation induces
gene products usually not produced during a 7.2.1.1 Direct Effects onNociceptive
healthy state, i.e., other cytokines, phospholipase Fibers viaCell-Surface
A2, and cyclooxygenase-2 (COX-2). TNF and Receptors
IL-1 are particularly effective in initiating and Peripheral nociceptive neurons express receptors
stimulating the expression of these genes [5]. for various cytokines. When stimulated, these
There is, on the other hand, a simultaneous pro- receptors may influence nerve fiber depolariza-
duction and release of anti-inflammatory cyto- tion and conductivity as well as apoptosis and
kines like IL-4 and IL-10 and soluble cytokine gene expression of factors important for nocicep-
receptors that block or suppress the intensity of tive signaling in the neuron [6]. There is also evi-
this cascade as an endogenous control of the net dence for a role of proinflammatory cytokines not
cytokine effects [6]. In inflammatory conditions, only in inflammatory pain but also in neuropathic
a dramatic increase in cytokine production can be pain [11, 12].
seen at the same time as the balance between the
cytokine production and its control is disturbed 7.2.1.2 Indirect Effects onNociceptors
[7]. Indeed, it appears that the balance of proin- viaStimulation ofLocal
flammatory cytokines and their endogenous con- Production ofOther Cytokines
trol mediators (anti-inflammatory cytokines, andMediators withNociceptive
soluble or decoy receptors, and antagonists) is at Effects
least as important as the absolute levels of indi- In inflammation, release of hyperalgesic media-
vidual cytokines [8, 9]. tors seems to be secondary to the release of
7 Molecular Temporomandibular Joint Pain Biomarkers 97

proinflammatory cytokines. TNF and IL-1 rap-

7.2.2 C
 ytokines asClinical
idly induce synthesis and release of other noci- Biomarkers
ceptive mediators such as IL-1, IL-6, bradykinin, ofTemporomandibular Joint
serotonin, and prostaglandins as well as them- Pain?
selves. This has to be taken into account when
discussing the contribution of these cytokines to With relevance to cytokines, TMJ pain seems to
pain, i.e., these cytokines exert both direct effects be modulated by both local and systemic factors,
and indirect effects [11]. as described above. For example, pressure-pain
threshold over the TMJ in RA seems to be mainly
7.2.1.3 Pain/Hyperalgesia asaPart modulated by systemic factors, whereas TMJ
oftheIllness Response movement pain is mainly modulated by local
Besides local effects, cytokines also cause or inflammatory factors [16].
modulate a wide array of changes called the ill-
ness response, which follow immune activation 7.2.2.1 Tumor Necrosis Factor
by inflammation, injury, or infection. The illness Ligands The main physiological role of TNF is
response includes physiological, behavioral, activation of the first-line reaction to microbial,
endocrine, and neural changes like fever, viral, and mechanical stress. TNF exists in both a
increased sleep, decreased activity, social inter- soluble (17 kD) and a cell-bound, transmembrane
action, etc., changes that also form a part of form (tmTNF, 26 kD), and it is primarily pro-
chronic pain phenotype. Generalized reduction duced in response to various inflammatory stim-
of pain thresholds and exaggerated pain uli [17]. TNF is synthesized by a variety of cell
responses, i.e., hyperalgesia, are also aspects of types like macrophages and monocytes, T cells,
the illness response [9, 11, 13]. B cells, and fibroblasts. Interestingly, about 45%
The illness response occurs due to periph- of small dorsal root ganglion neurons also express
eral release of proinflammatory cytokines, TNF, suggesting it may be released by peripheral
especially TNF, IL-1, and IL-6, that spills afferent fibers as well [18].
over to the blood and stimulates the afferent Almost all stressful and inflammatory stimuli
portion of the vagus nerve in the liver. Once have been shown to induce TNF production and
activated, the vagus nerve communicates with release. TNF can also upregulate its own synthe-
the brain to induce and maintain the illness sis. Several agents downregulate TNF expres-
response, including changes in the central pain sion, for example, inhibitors of prostaglandin
processing resulting in pain and generalized synthesis (salicylate), glucocorticoids, and
sensitization[14]. endogenous immunosuppressive cytokines like
IL-4 and IL-10 [17]. TNF rapidly induces synthe-
7.2.1.4 The Cholinergic Anti- sis of other mediators such as IL-1, IL-6, and
inflammatory Pathway prostaglandins.
A neuronal cholinergic anti-inflammatory path-
way exerting peripheral cytokine control has Receptors Biological responses to TNF are
recently been demonstrated [5]. This pathway mediated by ligand-binding via two structurally
functions as a fast, reflex-like anti-inflammatory distinct transmembrane receptors; the type I and
mechanism controlled by brain networks [5] and II receptors (TNFRI; TNFRII). The TNFRI is
seems to be mediated by the vagus nerve but per- present on all cell types except erythrocytes,
haps also by other parasympathetic efferents. whereas the TNFRII is mainly expressed by
Activation of this pathway reduces peripheral cells of the immune system [18]. The receptors
cytokine production by leukocytes in the reticu- primarily modulate activation of the transcrip-
loendothelial system (e.g., liver and spleen) and tion factor nuclear factor kappa B (NF-kB),
redirection of leukocyte trafficking away from which controls a large number of inflammatory
the periphery [15]. genes [19].
98 P. Alstergren

During inflammatory conditions, the con- TNFRI on primary afferent neurons to produce
centrations of both receptors increase dramati- hyperalgesia [26]. Indeed, TNFRI-neutralizing
cally. The TNF receptors are upregulated by a antibodies as well as antisense RNA against
number of factors including glucocorticoids TNFRI, but not antibodies toward TNFRII, can
and IL-6 [19]. reduce experimentally induced hyperalgesia [25].
Both TNF receptors are subject to proteolytic TNFRI and TNFRII immunoreactivity has
cleavage by matrix metalloproteases. This cleav- been found in the dorsal root ganglion [26]. The
age is increased in response to inflammatory sig- expression of TNFRI RNA in rat dorsal root gan-
nals. These soluble receptors have been found in glion seems to not be restricted to presumed
blood, urine, cerebrospinal fluid, and synovial nociceptive neurons in the dorsal root ganglion,
fluid in patients, and the levels of these receptors which actually implies a broader role of TNF in
increase during inflammation [20]. The soluble primary sensory functions than nociception
forms of both receptors, TNFsRI and TNFsRII, alone [26].
are primarily believed to be endogenous inhibi-
tors of TNF bioactivity by binding to TNF and Clinical Findings TNF has been detected in the
removing TNF from the site of its release [9, 20]. synovium and synovial fluid from patients with
Indeed, a dimer of TNFsRII is today an approved RA [27] and in patients with other inflammatory
pharmaceutical drug (etanercept, Enbrel) in diseases such as PsA, pelvospondylitis, and reac-
many countries for treatment of chronic and gen- tive arthritis [28, 29]. TNF has also been found in
eral inflammatory diseases like RA and psoriatic the synovial fluid of patients with RA, PsA, and
arthritis [21]. internal derangement of the TMJ [30] as well as
in patients with unspecified TMJ disorders [31].
Experimental Findings Peripheral TNF signal- Synovial fluid TNF levels have been shown to
ing is involved in nociceptive responses includ- be significantly higher in individuals with TMJ
ing hyperalgesia [11, 22]. Local TNF pain upon mandibular movement than in those
administration evokes spontaneous activity in without such pain [29]. In addition synovial fluid
afferent C and A nerve fibers that results in low- TNF levels were associated with tenderness to
grade nociceptive input, contributing to central palpation of the TMJ, which corresponds to sen-
sensitization [22]. Indeed, peripheral TNF sitization of afferent nerves in the synovial tis-
induces a mechanical hyperalgesia with rapid sues and tissues surrounding the TMJ.As then
onset (< 30min) when administered subcutane- can be expected, TNF levels in synovial fluid and
ously. It appears to result from sensitization of plasma appear to be predictive for the treatment
cutaneous C-fibers and to be associated with response to intra-articular administration of glu-
signs of local inflammation and increased levels cocorticoid into the TMJ.A high pretreatment
of inflammatory mediators, e.g., prostaglandins level of TNF in the TMJ synovial fluid was found
[18]. For example, intraplantar injection of TNF to be a positive predictor for TMJ pain relief after
in rats reduced mechanical nociceptive thresh- intra-articular administration of glucocorticoid
olds in a prostaglandin-dependent process [23]. [27]. The pain relief after treatment was associ-
TNF is involved in several animal models of ated with reduction of synovial fluid TNF.It is
arthritis [23]. Subcutaneous administration of the thus quite likely that TNF is involved in the mod-
TNF inhibitor etanercept decreased mechanical ulation of joint pain.
hyperalgesia when administered prior to induc- Patients with RA have circulating levels of
tion of arthritis by injection of complete Freunds soluble TNF receptors that are higher than those
adjuvant into the rat knee joint [24]. observed in patients with osteoarthritis or non-
The effects of TNF associated with experi- RA inflammatory arthritis [32]. Insufficient sys-
mental hyperalgesia have been shown to be temic endogenous control of TNF, as estimated
dependent on TNFRI [25], and it has been shown by the plasma level of the soluble receptor
that non-neurally derived TNF directly acts via TNFsRII, contributes to TMJ pain in RA [9, 20].
7 Molecular Temporomandibular Joint Pain Biomarkers 99

7.2.2.2 Interleukin-1 There is also a soluble form of this receptor,


Ligands IL-1 has a molecular weight of 17kDa IL-1sRI, which is released from the cell surface
and is mainly derived from macrophages and T by proteolytic cleavage. It has anti-inflammatory
cells. So far, three subtypes of IL-1 have been effects by binding to and thereby blocking IL-1
identified: two agonists with strong proinflamma- from reaching cell-bound IL-1RI receptors.
tory effects, IL-1 and IL-1, as well as an endog- IL-1RII is primarily expressed on monocytes,
enous IL-1 receptor antagonist, IL-1ra. Most of macrophages, neutrophils, and B lymphocytes.
the IL-1 remains intracellularly or on the surface The IL-1sRII is a decoy receptor in that it lacks a
of the cell membrane where it functions as an cytoplasmic portion capable of signaling, and its
autocrine messenger, while most IL-1 is trans- primary ligand IL-1 binds to this receptor
ported out of the cell where it acts locally or enters rather than to IL-1RI.Binding of IL-1 to IL-1RII
the blood circulation [6]. Indeed, both have been is nearly irreversible [37, 38].
shown to be involved in inflammatory reactions Similar to soluble receptors for TNF and
but only IL-1 has been found in synovial fluid IL-1RI, IL-1sRII has been demonstrated in the
from patients with RA [33]. IL-1ra competes with circulation and urine of healthy subjects and in
IL-1 and IL-1 for receptor binding and is pro- inflammatory synovial and other pathologic body
duced in substantially higher concentrations than fluids [37, 39, 40]. The induction of release of the
IL-1 during inflammation. IL-1ra does not elicit IL-1sRII decoy receptor is probably an early
a biological response when coupled to an IL-1 event in inflammation to limit the cascade [2].
receptor and has therefore an anti-inflammatory
character [2]. Inflammation causes an increased Experimental Findings IL-1 is capable of
local IL-1ra release but during active inflamma- decreasing nociceptive thresholds in peripheral
tion probably in insufficient amounts to inhibit the tissues by direct excitatory and sensitizing action
strong proinflammatory effects of IL-1 [2]. on nociceptive fibers [41]. Injection of IL-1 into
IL-1 induces several inflammatory events, i.e., one paw in rats evokes a dose-dependent hyperal-
activation of lymphocytes and stimulation of gesia in both the ipsilateral and the contralateral
cytokine and prostaglandin and collagenase paws, except for very low doses that solely pro-
release from connective tissue cells, but it is also duce hyperalgesia in the injected paw. This shows
involved in hyperalgesia and pain. In addition, it that IL-1 influences hyperalgesia both by local
has systemic effects by stimulating the produc- effect in the paw and by systemic effects. The
tion and release of C-reactive protein, eliciting hyperalgesia in the injected paw could be attenu-
fever and the illness response [34]. ated by COX inhibitors, suggesting that IL-1
evokes local hyperalgesia via stimulation of COX
Receptors There are two IL-1 receptors identi- products as prostaglandins [42]. Intraperitoneal
fied: IL-1RI with low/high affinity for IL-1/ injection of IL-1 induces a generalized hyperal-
IL-1ra and IL-1RII with high/low affinity for gesia via actions on the hepatic vagus nerve that
IL-1/IL-1ra. When stimulated, IL-1RI elicits a elicits afferent signaling to the brain [11, 42].
biological response in the cell, whereas IL-1RII In mice overexpressing TNF, a rheumatoid
causes no signal transduction and is therefore arthritis-like disease develops. Treatment with
considered as a decoy receptor [6]. Lacking a blocking antibodies to IL-1RI prevents the onset
second binding site, IL-1ra binds primarily to of disease [43], indicating a pathophysiologcal
IL-1RI but does not trigger a biological response. role for IL-1RI in an inflammatory disease with
Stimulation of IL1-RI leads to activation of the pain as one of its hallmarks.
transcription factor NF-kB, among others [35, 36].
In turn, genes encoding pro- and anti-inflammatory Clinical Findings IL-1 is undetectable in TMJ
cytokines as well as enzymes involved in inflam- synovial fluid from healthy individuals while
mation like COX-2, phospholipase A2, and nitric patients with polyarthritides have significantly
oxide synthase are upregulated [2]. higher such concentrations [44]. The IL-1 found in
100 P. Alstergren

the synovial fluid of the TMJ from patients with n ucleated cells, but the main sources are macro-
inflammatory disorder seems to originate from local phages, fibroblasts, and endothelial cells [48]. IL-6
production since the correlation between plasma plays a pivotal role in chronic disease where it regu-
and synovial fluid levels is poor and the synovial lates both local inflammatory events and associated
fluid level is substantially higher than the plasma systemic symptoms such as fever, illness response,
level. The synovial fluid level of IL-1 in human and induction of acute-phase reactants [49].
knees also shows a poor correlation to the plasma
level and has accordingly been found to correlate Receptor The IL-6 receptor (IL-6R) consists of
more with local disease activity, for example, as two subunits: the extracellular portion, which
measured by the Ritchie score (joint tenderness), binds IL-6 with low affinity, and the gp130, a
than with systemic disease activity [45]. transmembrane glycoprotein [48]. On target
High level of IL-1 in the synovial fluid from cells, IL-6 first binds to the IL-6R.The complex
the arthritic TMJ is associated with resting pain, of IL-6 and IL-6R then associates with the gp130,
tenderness to digital palpation, and a decreased thereby inducing signaling. gp130 is expressed
pressure-pain tolerance [46]. Patients with high by all cells in the body, whereas IL-6R is mainly
synovial fluid IL-1ra and low IL-1 concentra- expressed by hepatocytes, neutrophils, mono-
tions show a more rapid resolution of arthritis, cytes/macrophages, and some lymphocytes [50].
including pain variables, and the balance between A naturally occurring soluble form of the
synovial fluid IL-1 and IL-1ra concentrations IL-6R (IL-6sR) has been found in various body
seems to determine the progression of the inflam- fluids. Besides IL-6 binding to cell-bound IL-6R
matory process [47]. Indeed, high TMJ synovial to cause biological responses in target cells, an
fluid level of IL-1ra in TMJ synovial fluid has additional model of IL-6-IL-6R modulation of
been found to be associated with few or no painful cell function has been described.
mandibular movements [40]. High level of IL-1ra In addition, the IL-6- IL-6sR complex may in
in TMJ synovial fluid was associated with few or fact bind to the cell-bound gp130 and thereby
no painful mandibular movements, perhaps due to stimulate cells that express gp130 but not the
receptor binding and inhibition of IL-1 [40]. cell-bound IL-6R.This mechanism is named
IL-1sRI and IL-1sRII are present in the extra- IL-6 trans-signaling [48]. T cells, many neural
cellular matrix and blood both in healthy indi- cells, smooth muscle cells, and endothelial cells,
viduals and in patients with inflammatory among others, do not express cell-bound IL-6R,
disorders. Elevated levels of especially IL-1sRII but they are remarkably responsive to IL-6 but
are found in plasma and synovial fluid of patients only in the presence of IL-6sR [48, 50].
with inflammatory joint disease [9, 37]. However, The agonistic properties of the sIL-6R are
RA patients seropositive for the rheumatoid fac- counteracted by a soluble form of gp130
tor seem to have lower plasma concentrations of (sgp130), which circulates at relatively high lev-
IL-1sRII than seronegative patients, indicating a els (100300ng/mL) in human sera [48, 50].
deficient systemic control of the effects of IL-1
[40]. Upregulation of these soluble receptors has Experimental Findings Sensory neurons
anti-inflammatory effects per se [2], but these express receptors for cytokines including IL-6,
anti-inflammatory effects are often insufficient to and nociceptive effects of peripheral cytokines
completely inhibit the very strong proinflamma- have been reported in behavioral studies [51].
tory effects of elevated IL-1 levels, especially IL-6 influences responses of unmyelinated knee
during high inflammatory activity. joint afferents to mechanical stimulation invivo.
In the inflamed knee, local application of IL-6sR
7.2.2.3 Interleukin-6 causes an increase in responses to mechanical
Ligand IL-6 is a protein of 186 amino acids with a stimuli. Thus, IL-6 and its receptor signaling are
molecular weight of 2128kDa. IL-6 can be important factors in the generation of mechanical
produced and released by nearly all, if not all,
hypersensitivity under arthritic conditions [52].
7 Molecular Temporomandibular Joint Pain Biomarkers 101

Clinical Findings IL-6 is found more frequently change in pressure-pain threshold over the TMJ is
in the synovial fluid from patients with TMJ pain influenced by systemic serotonin [60].
than in healthy controls, and high IL-6 levels are
associated with pain [53]. IL-6 is significantly
raised in RA, and the plasma level of IL-6 was 7.4 Prostaglandin E2
reduced after systemic administration of inflix-
imab in parallel with a reduction of global joint Prostaglandin E2 (PGE2) is locally synthesized
pain intensity [54]. In an arthroscopic study of and released during inflammation. The synthesis
TMJ internal derangements, IL-6 showed the clos- of prostaglandins is inhibited by glucocorticoids
est correlation with the degree of synovitis [30]. and by nonsteroidal anti-inflammatory drugs
(NSAIDs) [61]. PGE2 acts as a potent proinflam-
matory, immunoregulatory molecule via EP
7.3 Serotonin receptors and stimulates bone resorption, pro-
motes sensitization of peripheral nociceptors,
Serotonin (5-HT) is peripherally a mediator and elicits erythema as well as edema [62].
released during inflammation from platelets and
perhaps also serotonergic neurons. For example, Ligands Prostaglandins are synthesized de novo
platelets activated by the rheumatoid factor in RA from membrane-released arachidonic acid by
release serotonin and other mediators. Serotonin most cells when these are activated by mechanical
produces hyperalgesia by a direct action on the trauma or by specific cytokine, growth factor, and
5-HT3 receptors of the primary afferent sensory other stimuli. Prostaglandins exert their actions on
neurons [55]. The 5-HT3 receptor is peripherally target cells in close proximity, both as an inflam-
located only on neurons [56]. Activation of 5-HT3 matory mediator released at the site of tissue
receptors causes a long-lasting sensitization of inflammation and neuromodulator that alters neu-
high-threshold mechanosensitive afferents as ronal excitability and synaptic processing [63].
well as a brief excitation of chemo- and mecha-
nosensitive afferents in joints [57]. Receptors There are at least nine known prosta-
glandin receptor forms in mouse and man, and
some of these can be found in splice variants
7.3.1 S
 erotonin asClinical [64]. Most of the prostaglandin receptors are
Biomarker of localized at the plasma membrane although some
Temporomandibular Joint are situated at the nuclear envelope [65].
Pain?
Clinical Findings PGE2 has been found in TMJ
Serotonin is undetectable in TMJ synovial fluid synovial fluid from patients with internal derange-
from healthy individuals [58], which is important ment [66] and chronic TMJ inflammatory disor-
from a diagnostic point of view. Elevated sero- ders but not in healthy individuals [67]. Alstergren
tonin levels in the TMJ synovial fluid has been and Kopp detected PGE2 in 20 out of 30 TMJ in
strongly associated with TMJ pain provoked dur- patients with chronic inflammatory joint disease,
ing mandibular movements and reduced maxi- and the levels were found to be related to TMJ
mum voluntary mouth opening capacity [59]. Pain pain on mandibular movement [67].
localized to the TMJ as a response to mandibular
movement might thus be a useful clinical parame-
ter for verification of inflammatory articular pain 7.5 Glutamate
conditions of the TMJ [59]. Local and systemic
serotonin predicts the effect of intra-articular glu- Peripheral glutamate, which is a mediator not
cocorticoid treatment on TMJ pain in patients with primarily associated with inflammation, and its
chronic TMJ arthritis of systemic nature, while receptors have been found to possess modulatory
102 P. Alstergren

roles in peripheral nociception and sensitization profiles, including reduction of pain, for inflix-
and are elevated in synovial fluid from joints imab, etanercept, and adalimumab have been
with active arthritis [68]. Synovial tissue gluta- extensively reviewed in detail elsewhere (see,
mate originates from inflammatory cells or nerve e.g., [72]).
fibers in the inflamed synovial membrane but Despite the revolutionary improvements in
also from plasma extravasation into the synovial RA treatment with the introduction of anti-
tissues [69]. cytokine therapy, about a third of the patients do
Injection of glutamate activates the peripheral not respond to anti-cytokine treatment or still
N-methyl-D-aspartate (NMDA) receptor. experience symptoms from a single or a few
Glutamate injected in the healthy human TMJ joints [73]. This suggests, in turn, a significant
evokes immediate pain that is partly mediated by influence by non-TNF-modulated inflammatory
peripheral NMDA receptors in the synovial tis- mechanisms in the nonresponders. Accordingly,
sues [70]. Peripheral block of the NMDA recep- more than a third of patients with TMJ pain did
tor reduces glutamate-induced TMJ resting pain not respond to systemic infliximab treatment
but also reduces glutamate-induced palpation within 24weeks, and treatment failure was
pain in women. However, peripheral NMDA associated with high circulating levels of IL-1
receptors may play a minor role in the pathophys- or rheumatoid factor [74]. Since the major
iology of TMJ arthralgia because ketamine, an pathology takes place in the synovial tissues,
NMDA antagonist, had little effect on TMJ pain intra-articular administration of cytokine block-
in these patients [70]. The relevance of synovial ers could be a future possibility to obtain remis-
fluid glutamate is thus still unclear and warrants sion of affected single joints. Indeed, there are
further investigation. some recent positive reports with single intra-
articular infliximab injections in patients with
RA or ankylosing spondylitis [75, 76]. There is
7.6  urrent or Potential
C also one case report of the use of multiple intra-
Treatments articular infliximab injections. In that report, the
ofTemporomandibular clinical and radiographic course TMJ involve-
JointPain ment in a patient with severe TMJ symptoms
from psoriatic arthritis resistant to both systemic
Targeting cytokine, serotonin, or prostaglandin infliximab and intra- articular glucocorticoid
receptors for specific treatment of TMJ pain is was presented. The patient received multiple
promising. However, this approach is not clini- intra-articular infliximab injections every sixth
cally available today and seems to require sub- week for 36weeks, and the TMJ symptoms
stantial development and trial before it may be improved already after the first bilateral intra-
considered an option. articular infliximab injections but even more so
after the second set of injections. A considerable
improvement remained for the 36weeks studied
7.6.1 Cytokine Receptors [16].

There is today only one approved treatment with


a specific cytokine receptor antagonist for clini- 7.6.2 Serotonin Antagonists
cal use: anakinra (IL-1ra). However, anakinra is
approved for treatment of RA and not for spe- Intra-articular TMJ injections of the serotonin
cific treatment of pain, although pain is certainly 5-HT3 receptor antagonist granisetron have been
an important aspect of RA.On the other hand, used in patients with RA.The injections caused a
several anti-TNF drugs such as infliximab, etan- short-time reduction of TMJ movement pain, a
ercept, and adalimumab are now available for reduction that was greater in patients with high
the treatment of RA [71]. The clinical efficacy serotonin levels in plasma [77].
7 Molecular Temporomandibular Joint Pain Biomarkers 103

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Genetic Biomarkers ofOrofacial
Pain Disorders
8
ZeevSeltzer andScottR.Diehl

Abstract
Despite major advances in basic and translational research, pain medicine
still offers no cure for persistent orofacial pain disorders, nor effective
strategies for preventing their development. There is growing hope that
knowledge garnered in pain genetics will identify novel target molecules
for more effective drug treatments and precision medicine approaches
that best fit each patients genome. Combined with nongenetic informa-
tion, knowledge of inherited variation may lead to development of algo-
rithms that yield more precise biologically based diagnoses and prognoses
for orofacial pain conditions. This chapter reviews the current status of
pain genetics with a focus on persistent orofacial pain.

8.1 Introduction (PNS, CNS, respectively) nodes of the pain net-


work, involving specific mechanisms and unique
Chronic pain conditions impact many aspects of neuronal and glial types and their cell-specific
life that can be dissected into spatiotemporal, neurochemicals. Each pain disorder and func-
emotive-aversive, and cognitive-evaluative tional parameter are likely to be encoded by a
parameters as well as an impact on functionality unique combination of genes, upregulated or
and participation at work, domestic, and social downregulated at specific times following the
life. Each of these parameters is processed in etiological event in the different parts of the pain
dedicated peripheral and central nervous system network in the PNS and CNS.A multitude of
genes and sequence variants within them and
Z. Seltzer, DMD (*) throughout the large regions of the genome
Faculty of Dentistry, University of Toronto Pain between the genes that we now know are impor-
Centre, 124 Edward Street, Toronto,
ON, M5G 1G6, Canada
tant for gene regulation mean that persistent oro-
e-mail: zeev.seltzer@utoronto.ca facial pain disorders (POPDs) are complex traits.
S.R. Diehl, PhD
In most cases, the overall heritable risk is the sum
Department of Oral Biology, Rutgers School of of the contributions of many genetic variants,
Dental Medicine, Newark, NJ, USA each contributing a small effect size [1]. In addi-
Health Informatics, School of Health Professions, tion to single nucleotide polymorphism (SNP)
Rutgers University, Newark, NJ, USA sequence variation, there are copy number

Springer-Verlag GmbH Germany 2017 107


J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI10.1007/978-3-662-53994-1_8
108 Z. Seltzer and S.R. Diehl

p olymorphisms, gene-environment interactions, gene has been the focus of a wide range of studies
epistatic (gene-gene) interactions, and epigenetic of diverse acute, inflammatory, and chronic pain
variation caused by factors other than changes in conditions both in humans and rodent models [5].
the DNA sequence. A POPD occurs when indi- As early as 1976, reduced COMT activity was
viduals, who inherited variations that increase reported in red blood cells with increased levels
risk for development of a certain type of pain dis- of catecholamine metabolites in the urine of
order, are exposed to one or more environmental POPD patients [6]. The past decade has seen a
factors, often (though not always) comprising an surge in research, reviewed in the following sec-
acute injury. As described below, some pain dis- tion, that provides an example of how genetic
orders may develop spontaneously in carriers of knowledge can be translated from mechanism to
genetic risk factors in genes such as SCN9A that clinical applications using pharmacogenomic
encode the voltage-gated sodium channel NaV1.7 strategies.
[24]. These genetic variants cause a specific COMT is located in chromosome 22 (at band
POPD and/or its maintenance over time by pro- q11.21). COMT has two alternative exon splicing
ducing certain peptides or proteins that are the patterns: one codes a soluble protein (S-COMT)
building blocks of the orofacial pain network and and the other membrane-bound (MB-COMT)
structures that may be unique to the orofacial form is expressed more abundantly in the nervous
region or are shared with other parts of the body. system [7]. These two alternative transcripts are
Unfortunately, the identity of most POPD genes, formed by differential mRNA splicing from the
their biologically important mutations, and the same DNA sequence on each of the two copies of
gene-gene, gene-environment, and epigenetic each autosomal gene that every cell normally car-
interactions at play are not yet known. This chap- ries. Both forms of COMT methylate catechol
ter provides an update on the limited number of neurotransmitters, and this inactivates them. But
confirmed or strongly suggested genes important while S-COMT operates in the cytoplasm and the
for POPD and explores their potential utility as nucleus, the MB-COMT isoform is located in the
predictive biomarkers and as drug treatment endoplasmic reticulum and the outer membrane
targets. of the soma, axons, and dendrites of neurons and
some glia cells. As the C-terminal catalytic
domain of MB-COMT is located extracellularly,
8.2  enetics oftheMajor
G it is positioned to inactivate catechols in synaptic
Persistent Orofacial Pain clefts and outside the synapse.
Disorders TMD is the most prevalent orofacial pain con-
dition affecting mainly women, typically between
8.2.1 Temporomandibular 20 and 50years of age. Based on a comparison of
Disorder (TMD) the prevalence of TMD in 1236 monozygotic
(identical) versus 570 dizygotic (fraternal) female
The COMT gene encodes the enzyme twin pairs, Plesh etal. estimated that TMD is
catecholamine- O-methyltransferase that inacti- 27% heritable [8], a value relatively low com-
vates and catabolizes the neurotransmitters dopa- pared to other chronic pain conditions [9]. COMT
mine, norepinephrine (NE), and epinephrine, as has been assayed for six common SNPs through-
well as caffeine and estrogens. Not surprisingly, out the gene, searching for association with TMD
COMT affects many neural functions including symptoms. These SNPs included rs2097903
reward-motivated behavior, cognition, psychiat- (located in the promoter of MB-COMT); rs6269
ric disorders, arousal, motor control, and stress (located in the promoter of S-COMT); rs4633,
reactivity. It is expressed in several types of neu- rs4818, and rs4680 (located in exons shared by
rons and glia cells throughout the CNS and both isoforms); and rs165599 (located in the 3
PNS.Since these neurotransmitters play impor- untranslated region of COMT) [5, 10, 11].
tant roles in processing nociceptive inputs, this Polymorphisms in rs4633 and rs4818 do not
8 Genetic Biomarkers ofOrofacial Pain Disorders 109

change the protein sequence as they are synony- makes sense if considering the reciprocal role
mous SNPs, but were included as markers for that epinephrine and norepinephrine play in some
other nearby potentially causative SNPs. rs4680 types of neuropathic pain, operating in the CNS
is a non-synonymous SNP, where a nucleotide versus the PNS.Following nerve injury an abnor-
substitution between G--> A results in an amino mal excitatory link forms at the site of injury
acid change from valine (Val) to methionine between postganglionic sympathetic efferents
(Met) at codon 158 (Val158Met). The A (or met) and some primary afferents. Persistence of pain
allele is associated with lower enzymatic activity, in certain peripheral neuropathies is explained in
due to thermal instability of the molecule at body part by ongoing and/or evoked sympathetic activ-
core temperature. Thus, at normal body tempera- ity. This abnormal link is the product of upregu-
ture, the enzyme becomes less catalytically effec- lated expression of adrenoreceptor proteins in
tive, resulting in extended presence of catechol somata of injured afferents in dorsal root ganglia
neurotransmitters in the synapse. Based on com- associated with the injured nerve. These proteins
binations of the genotypes of these SNPs, three are shipped distally by axonal transport and
haplotypes were identified: LPS, associated with assembled in the membrane of axonal sprouts of
low pain sensitivity to a diverse array of experi- injured afferents in nerve end neuromas or neuro-
mental noxious stimuli; APS, associated with mas in continuity [14]. NE, released from post-
average pain sensitivity; and HPS, associated ganglionic sympathetic efferents, binds to
with high pain sensitivity. Carriers of LPS had adrenoreceptors on afferents causing supra-
high COMT enzymatic activity, associated with threshold depolarization and discharges of action
rapid clearance of catechol neurotransmitters potentials that contribute neuropathic pain [15].
from synapses in pain pathways. Carriers of the COMT knockout mice and human carriers of the
APS haplotype had an average COMT enzymatic low enzymatic activity variant of MB-COMT are
activity and average pain sensitivity to the same expected to have more NE present in neuromas,
noxious stimuli, whereas carriers of the HPS hap- enhanced ectopic afferent firing, and sympatheti-
lotype had high pain sensitivity and low COMT cally maintained neuropathic pain. This shows
enzymatic activity. Moreover, Diatchenko etal. that COMT may have pleiotropic effects in some
(and others later on) showed that symptoms of types of neuropathic pain, where the same gene
TMD depended on the number of copies of these may play two contrasting effects in two different
genotypes: carriers of LPS diplotypes (i.e., two targets along the same pain neuroaxis [16]. Thus,
copies of the LPS haplotype) had less TMD pain if confirmed by research, the impact of COMT
scores than the heterozygotes, and the latter had will depend on the genotypes an individual car-
lower TMD pain score than those carrying no ries and on the type of chronic pain.
LPS haplotypes, suggesting that the LPS haplo- Exogenous inhibitors of COMT have addi-
type was associated with significant protection tional documented properties, including scaveng-
against TMD [5, 10, 11]. ing oxygen and nitrogen radicals, and these may
Inhibition of COMT activity in rats and mice also explain the antiallodynic effects found in
has been found to be associated with increased some neuropathic pain models. Also, increased
nociception in several models of acute and number of -opioid receptors in certain brain
inflammatory pain [12]. Compatible with this areas following nerve injury may be responsible
observation, COMT knockout mice were more for the enhanced opioid effects associated with
sensitive to nociceptive stimuli and had reduced low COMT activity. A low COMT activity also
analgesic responses to opioids and stress, whereas increases the availability of opioid receptors and
mice overexpressing COMT showed decreased may enhance opioid analgesia [17].
nociceptive sensitivity in such models. However, Gene-by-environment interaction between
inhibition of COMT in rat models of neuropathic COMT haplotypes and orthodontic treatment was
pain by nitecapone caused the unexpected anti- examined in view of the fact that this treatment is
nociception and antiallodynia [13]. This finding a risk factor in developing TMD.Carriers of the
110 Z. Seltzer and S.R. Diehl

TMD-protective COMT LPS haplotype, who had fibromyalgia [28]. The second gene, SLC6A4,
orthodontic treatment, were partially protected encodes the sodium-dependent serotonin trans-
from developing TMD, whereas carriers of the porter (also known as 5-HTTLPR) that is located
APS and HPS haplotypes had a greater risk for in chromosome 17 (at band q11.1q12). It har-
TMD if undergoing such orthodontic treatment. bors a 44-base pair insertion/deletion indel
This finding supports the model that TMD results variant in the promoter region. Two alleles of
from an interaction between heritable risk (here SLC6A4 are known, a short allele s having a
conferred by the APS and HPS COMT haplotypes) lower transcriptional activity and a long allele
and exposure to an environmental effect [18]. l. Carrying the one allele results in more trans-
Recent experiments in the rat show that acute porter molecules available for a faster clearance
pain sensitivity was reduced when blocking both of serotoninergic synaptic clefts from serotonin
adrenergic transmission and COMT activity [19]. or its clearance from non-synaptic peripheral tar-
This result has motivated an ongoing clinical trial gets of 5-HT on nociceptors. Thus, similar to
where TMD pain patients were stratified by their COMT, the net effect of carrying either allele is
LPS, APS, and HPS COMT haplotypes, address- complex, resulting from contrasting effects of
ing their TMD pain by blocking -adrenergic 5-HT in the CNS and PNS.That net effect
neurotransmission with propranolol [20]. This depends on which allele an individual carries, the
ongoing study is one of the first to show the util- number of such copies (i.e., ss, sl, or ll), and the
ity of pharmacogenetic approaches to the treat- pain phenotype in question: in the periphery,
ment of POPD. serotonin stimulates and sensitizes nociceptors
Several other candidate POPD genes were and sprouts of neuroma afferents, whereas in the
additionally identified in the Orofacial Pain CNS there are pro-nociceptive effects and antino-
Prospective Evaluation and Risk Assessment ciceptive 5-HT effects depending on the type of
(OPPERA) study [21]. The ADRB2 (encoding receptors present on postsynaptic sites of sero-
the 2-adrenergic receptor) gene is located on toninergic synapses. HTR2A also harbors a com-
human chromosome 5 (at band q3132). It com- mon T102C polymorphism. This SNP (rs6313) is a
prises about 5500kb and harbors the following synonymous substitution located in exon 1 where
eight common SNPs that were genotyped to it codes the 34th amino acid as serine. It has been
interrogate their possible association with TMD: interrogated in a small cohort of 200 Brazilian
G-7027A, rs11948840, rs1432612, rs1432613, men and women, of whom 100 were TMD cases.
and rs2400696 are all located in the promoter Carrying the CC genotype is associated with a
region of this gene, whereas rs1042703 higher risk for TMD at odds ratio (OR) of 2.25
(Arg16Gly a non-synonymous polymorphism), (95% CI, 1.134.46) [28, 29]. This finding, how-
rs1042704 (Gln27Glu a non-synonymous poly- ever, did not replicate in a Turkish small cohort of
morphism), and rs1042707 (Leu83Leu a synon- women with fibromyalgia [30].
ymous polymorphism) are in the coding regions. ER (encoding estrogen receptor alpha) is
Three common haplotypes were identified, another gene studied in the OPPERA project for
named H1, H2, and H3 [22], that play a role in an obvious reason: POPDs, including TMD-
TMD onset, somatization scores, and low blood related pain, are significantly more prevalent in
pressure (known covariates of TMD) [2325]. women than men. Moreover, estrogen targets tis-
Two other interrogated TMD genes relate to sues of the temporomandibular joint (TMJ) that
the pivotal role that serotonin (5-HT) plays in are frequently involved in TMD pain disorders
processing nociceptive input. HTR2A, encoding [3133]. This gene is located on chromosome 6
the serotonin 5-HT2A receptor, is located in (at band q25.1), harboring two SNPs that are seen
chromosome 13 (band q1421), harboring a syn- frequently in the population: T396C and A351G.
onymous T102C SNP where the less frequent Carriers of the substituted T396C SNP have a ten-
allele (C) is associated with TMD [26] [24] (but fold increased transcription of ER [34].
not in a Japanese population [27]) and with Brazilian women who carry the CG haplotype
8 Genetic Biomarkers ofOrofacial Pain Disorders 111

had a 3.2-fold risk of developing TMD (95% CI, certain analgesics and of developing adverse
1.66.2) [35], but not in Korean women [36]. reactions to these analgesics.
Another biochemical pathway probed in the About a million individuals in the USA
context of TMD is folate. Genes interrogated develop shingles every year (http://www.cdc.
were SHMT1 (encoding serine hydroxymethyl- gov/shingles/about/overview.html), but only
transferase-1), MTHFD (encoding methylenetet- about a fifth to a tenth will proceed to develop
rahydrofolate dehydrogenase), and MTRR PHN [38]. Race also plays a role, e.g., African
(encoding methionine synthase reductase) har- Americans are 5075% less likely to develop
boring the SNPs rs1979277, rs638416, PHN compared to Caucasians [39]. It is yet to be
rs2236225, and rs1801394. Aneiros-Guerrero determined whether or not the same effect of
etal. [37] reported on finding in a Spanish cohort race/ethnicity exists in TPHN.Age is another
significant associations between alleles of these important covariate, as <10% of people who are
SNPs and risk of developing TMD with ORs younger than 60years of age develop shingles,
ranging from 2.35 to 3.99. However, since these whereas in those who are older than 60years, the
findings reported on a small cohort comprising incidence rises to about 40%. Sex is another
only 89 TMD cases (all women) versus 143 con- covariate, as women are more susceptible to
trols (lower 95% CI from 1.10 to 1.72, higher develop shingles than men [40].
95% CI from 5.00 to 9.25), replication in a larger Pain symptoms in TPHN vary highly across
cohort is needed. This group also reported that individuals, even when the shingles occupied the
carrying the GSTM1-null polymorphism (a dele- same size of skin and were of similar severity,
tion of the GSTM1 gene, encoding glutathione suggesting that the pain symptoms are controlled
S-transferase 1, an enzyme associated with genetically by a pool of genes different from the
inflammatory oxidative stress) was associated pool engaged in the disease itself. The median
with TMD at an OR = 2.21 (95% CI, 1.244.36) heritability value calculated for several chronic
[37]. This finding also needs replication. pain conditions, other than TPHN, is about 0.45,
suggesting that approximately 45% of the vari-
ance in chronic pain levels is due to genetic fac-
8.2.2 Trigeminal Postherpetic tors [41, 42]. As TPHN has a late age of onset, it
Neuralgia (TPHN) is difficult to estimate its heritability because a
twin who did not develop the disease even at an
TPHN results from neural damage caused by advanced age cannot be considered a control
reactivated varicella-zoster virus (VZV) in the because he/she may still be a latent case who
trigeminal ganglion. Thus, genetic polymor- could develop TPHN later.
phisms that influence the immune system and the Three candidate PHN genes were identified to
inflammatory response to viral infections, partic- date, however none as of yet for TPHN.
ularly to VZV, are likely contributors to the heri- Polymorphisms in chromosome 6 (band p23.1)
table risk of TPHN.Likewise, polymorphisms were screened in a Japanese cohort of PHN.This
predisposing trigeminal primary afferent nerve genomic region harbors the human leukocyte
fibers to be sensitive to the damage caused by antigen (HLA) system and, therefore, is impli-
VZV particles are expected to render carriers to cated in the immune response to VZV reinfec-
be more/less susceptible for TPHN, as do poly- tion. This study found a significant association
morphisms in genes associated with the response between PHN and a haplotype comprising the
of CNS pain pathways to peripheral nerve injury. HLA-A*3303, B*4403, and DRB1*1302 alleles,
The extent of nerve injury and type of afferents but not with polymorphisms on the promoter of
injured will determine in part the likelihood of the TNFA gene (encoding tumor necrosis factor
developing TPHN and its characteristics. A sepa- alpha, a cytokine that participates in inflamma-
rate set of genetic polymorphisms determines the tory reactions) or NCR3 (encoding natural cyto-
chances of deriving sufficient pain relief from toxicity triggering receptor 3) also designated as
112 Z. Seltzer and S.R. Diehl

CD337, or cluster of differentiation 337, or time, however, it is not known whether the same
NKp30 [43]. The second candidate gene was genetic polymorphisms confer risk for familial
APOE that is mapped to human chromosome 19 and nonfamilial TN.
[44]. APOE encodes for apolipoprotein E Many, but not all, cases of TN develop follow-
(APOE) that transports lipoproteins, fat-soluble ing abnormal compression of the trigeminal root
vitamins, and cholesterol into the lymph system by an ectopic blood vessel. This implies that pro-
and then into the blood. APOE is mainly synthe- duction, pathophysiology, and treatment of TN
sized in the liver but also in the kidneys and involve three largely independent sets of genetic
spleen as well as in the nervous system. Astroglia variants. The first predisposes carriers to develop
and microglia are its primary producers in the the etiological vascular deformity, which in itself
CNS, whereas neurons express the receptors for is asymptomatic, but when they co-inherit the
APOE [44]. In the brain APOE is mostly known second set of genetic variants, TN occurs. The
for its role in Alzheimer and Parkinson diseases genetic variants causing neurovascular compres-
and cognition, but the rationale for studying sion (NVC) are relatively common, since this
whether polymorphisms in APOE influence PHN condition is seen in about 16% of healthy adults,
was different, presuming that VZV particles bind the vast majority never developing TN or related
to their cellular targets (i.e., afferents and their facial sensory abnormalities [50, 51]. Presumably,
somata in the trigeminal ganglion) and enter the first set of genes encode proteins that com-
them using the same sites in the cell surface to prise the wall of blood vessel and/or neurons,
which APOE molecules bind. Thus, by way of glia, and connective tissue within the trigeminal
competition with APOE, the damage caused by root that interact mechanically and/or chemically
VZV particles could be limited. Another mecha- with the pounding juxtaposed blood vessel or
nism by which APOE could be involved in PHN inflammatory cells responding to this injury.
is via its link to intraneuronal increase in calcium The fact that only one in ~10,000 individuals
ion levels and apoptosis following injury [45]. who have NVC progresses to develop TN sug-
Indeed, fewer females carrying the e4 allele had gests that TN patients carry in addition to the first
PHN whereas carrying the e3 allele conferred set of genetic variants another set of variants that
increased risk [43]. is independent of the first. This second set predis-
poses carriers to develop TN pain symptoms
given the presence of an NVC.These variants are
8.2.3 Trigeminal Neuralgia likely in genes encoding proteins in pain path-
ways of the trigeminal system and/or inflamma-
Trigeminal neuralgia (TN) is said to be the most tory and immune cells that might be attracted to
excruciating pain that humans suffer. It is typi- the site of root injury by NVC.As these genes are
cally triggered by low threshold inputs in the oro- unknown as of yet, it is impossible at this stage to
facial region and manifests as repetitive sharp determine how unique are they to the trigeminal
paroxysmal attacks of pain that are limited to one system or whether they play the same role in pain
or two divisions of the trigeminal nerve, usually pathways elsewhere in the body. The fact that TN
unilaterally [46]. TN is rare, having an incidence is only seen in the face and mouth may be due to
of approximately 70/100,000, usually peaking in the fact that the cause of TN does not occur else-
the fifth decade of life. It is so rare that the where in the body. Nevertheless, if the second set
chances of having more than one individual with of genetic variants is expressed throughout the
TN in the same family make it impractical to somatosensory system, carbamazepine and
study heritability using pedigree analysis or oxcarbazepine, the drugs most often effective for
twins. But several reports of TN cases occurring treatment of TN, should be much more effective
in multiple members of a family indicate that in treating paroxysmal neuropathic pain else-
familial forms are likely to exist that may be where in the body, but this is not the case [52].
caused by genes of major effect [4749]. At this These facts suggest that a preferential expression
8 Genetic Biomarkers ofOrofacial Pain Disorders 113

of specific subtypes or combinations of sodium c hannelopathy of primary afferents, compatible


channels are expressed in the trigeminal system with the clinical experience of successfully treat-
and lead to TN.While it is tempting to think of ing TN patients with certain sodium channel
genes for sodium channels as the most likely can- blockers. Moreover, it would suggest that noci-
didates for TN (in light of the efficacy of carbam- ceptive afferents undergo phenotypic switch to
azepine and oxcarbazepine), this may not become hyperexcitable to low-threshold mechan-
necessarily be so. The electrogenic properties of ical stimuli, which are the typical triggers of TN
nociceptive primary afferents, and neurons in pain paroxysms. But even if this is the case, this
pain pathways in the CNS, depend on other ion explanation is insufficient to explain how a local-
channels as well, including potassium, calcium, ized, occasionally single mechanical stimulus
and chloride, and on nonionic mechanisms, applied to the gums could trigger repetitive TN
including glial properties. attacks and their strong intensity.
The rarity of TN is compatible with it being a In a recent press conference, the British phar-
Mendelian trait governed by a gene of major maceutical company Convergence reported prom-
effect with low penetrance that is expressed ising results with a new drug currently called
exclusively in the trigeminal system, perhaps CNV1014802in a placebo-controlled double-
modified by a few other genes as this would blind clinical trial of TN patients. This molecule
explain changes in TN over the years, variability is a state-dependent sodium channel blocker that
in its type and severity of symptoms among dif- is active against the NaV1.7 sodium channel. The
ferent cases, and differences in response to medi- trial demonstrated a consistent reduction of pain
cations. No less likely, however, TN may be a severity in 58% of patients and a 66% reduction in
polygenic complex heritable trait, with risk deter- the number of paroxysms, at the cost of no serious
mined by multiple rare and common genetic vari- adverse events [http://www.convergencepharma.
ants that only co-occur rarely in an individual com/index.asp?page_id=14].
who also inherits the NVC-causing genetic poly- A large-scale gene mapping study is currently
morphisms. Both scenarios equally well explain underway, carried out by a group that includes
the wide range of phenotypic variation seen in the authors of this chapter and others. It is aimed
TN, manifesting in the frequency, duration, inten- at identifying the genetic underpinnings of TN
sity, and enormity of pain paroxysms, what stim- using a genome-wide approach. Rather than
ulus provokes them, responses to treatments, as interrogating candidate genes, a genome-wide
well as the impacts on functionality, sleep, and approach is free of biases driven by preexisting
other aspects of the quality of life with TN. etiological, mechanistic, or pharmacological
One study analyzed gene expression in TN information. Funded by the Facial Pain Research
using reverse transcription polymerase chain Foundation (FPRF, USA), its goal is to genotype
reaction (RT-PCR) of gingival biopsies from TN in the discovery phase about 500 carefully diag-
pain-affected regions versus the same tissues nosed TN cases and replicate the results in a sec-
from controls to determine the expressed levels ond cohort of 500 TN cases. The study includes a
of transcripts of the voltage-gated sodium chan- SNP array-based exome analysis of the DNA
nel types NaV1.7, NaV1.8, and NaV1. (see below) to identify SNPs segregating in
Regrettably, this study was severely underpow- patients having TN compared to the general pop-
ered, comparing only 10 TN patients versus 13 ulation that serves as a control group. Since TN is
pain-free controls [53]. Patients with TN had so rare, it is safe to use genotypes drawn from the
reduced levels of NaV1.7 but increased levels of normal population as controls. An exome analy-
NaV1.3 (albeit at a weak significance level) and sis can be carried out either by fully sequencing
no significant difference from controls in gingi- the coding regions (i.e., the exons) of all genes
vally expressed NaV1.8 levels. This study must throughout the genome or with microarrays that
be replicated. If confirmed, these findings could carry hundreds of thousands of genetic probes
suggest that, in some cases, TN is a sodium developed to detect the presence of SNPs in these
114 Z. Seltzer and S.R. Diehl

exons. Exonic variants encode the amino acid precision medicine where the most effective
sequence of all peptides and proteins comprising drug can be selected for each patient, clinicians
the trigeminal nervous system, including those have to proceed via a trial-and-error approach
that control the development and maintenance of that for many patients is far from optimal.
TN.However, by focusing exclusively on the
exome, this analysis ignores the introns (i.e.,
nucleotide bases in segments of the DNA that 8.2.4 Burning Mouth
space between exons within genes). Introns har- Syndrome (BMS)
bor SNPs that may influence the transcription
and stability of the mRNA.In addition, exome BMS manifests as spontaneous burning painful
analysis also ignores SNPs in the vast spans of sensation in the mouth, often worsening during
the DNA between the genes. Formerly referred to the day and subsiding at night, typically associ-
as junk DNA, we now know that these regions ated with dysgeusia. BMS is comorbid with gas-
contain innumerable sequence variations influ- trointestinal, urogenital, psychiatric, neurologic,
encing gene expression that we are just now and metabolic disorders, as well as drug reac-
beginning to understand. Therefore, to comple- tions. The estimated prevalence ranges widely
ment the exome analysis, DNA samples of the from 0.7% (a value derived from self-reports of
same TN patients comprising the discovery >45,000 American households [54]) up to 15% in
cohort are also undergoing a genome-wide asso- a Finnish adult cohort (but half of whom had oral
ciation study (GWAS) using an SNP microarray mucosal lesions) [55]. A prevalence of ~1% was
that contains more than 800,000 SNP targets, documented in a retrospective study of >3000
complementing the coverage of the exome array Brazilians who were referred to an oral pathol-
focusing on the coding regions that make up only ogy service clinic [56]. The prevalence of BMS
around 3% of the human genome. The results of increases with age and is 2.57 times more com-
this analysis will undergo validation using the mon in women than men [5658]. The vast
independent replication sample of 500 TN majority of the women with BMS are peri- and
patients currently being recruited using the same postmenopausal [59].
patient selection criteria and pain phenotyping The pathophysiology of BMS is far from
tools [http://www.facingfacialpain.org]. being clear, and no genes have been identified as
A third set of genetic variants may predispose of yet for this condition. However, some abnor-
carriers who are already TN patients to derive mal sensory mechanisms associated with BMS
beneficial analgesic effects from membrane sta- may provide clues about its genetic underpin-
bilizers, anticonvulsants, and antiarrhythmics nings. For example, tongue biopsy from BMS
and other analgesics with minimal adverse side patients showed reduced numbers of unmyelin-
effects. This means that those TN patients who ated fibers associated with taste papillae and
do not carry these genetic variants may not ben- intraepithelial fibers [55, 58], suggesting that
efit from these analgesics or they might be so BMS is a small-fiber sensory neuropathy [60].
sensitive to the medications adverse side effects Increased nerve growth factor (NGF) in the saliva
that preclude their use. It is likely that the analge- of patients with BMS [61] and increased densi-
sic efficacy of each medication type is controlled ties of TRPV1 ion channels and P23 receptors
by unique genetic variants, with some overlap on primary afferents of BMS patients were
that may be related to shared transport mecha- reported as well [62]. These abnormalities were
nisms in the alimentary canal, catabolysis, or previously linked to sensory hypersensitivity and
chaperoning to their targets in the trigeminal ner- neuropathic pain in several conditions of painful
vous system. A TN patient is likely to inherit a neuropathies in humans. CNS changes manifest-
mixture of such genetic variants that reduce or ing as central sensitization of trigeminal pain
enhance the efficacy of treatment outcomes. pathways have been proposed as well [6365].
Until these variants are identified, enabling Likewise, functional magnetic resonance imaging
8 Genetic Biomarkers ofOrofacial Pain Disorders 115

studies showed that, compared to controls, the PEPD.Both of the latter two disorders are inher-
brain of BMS patients abnormally processes nox- ited in an autosomal dominant pattern so that a
ious and thermal stimuli in the thalamus [66]. single copy of the mutated gene, inherited from
Dysregulation of the nigrostriatal dopaminergic one parent, is sufficient to cause them, while con-
system has also been demonstrated in the brain of genital insensitivity to pain is usually recessively
BMS patients [67]. Interestingly, Parkinson transmitted.
patients are 5 more likely to have BMS than SCN9A encodes the alpha subunit of the voltage-
controls [68]. Some relief in BMS symptoms can gated NaV1.7 sodium channel. The point muta-
be accomplished by consumption of alpha lipoic tions in some positions along the alpha subunit
acid, clonazepam, capsaicin, and antidepressants cause nociceptive primary afferents to be hyperex-
as well as psychotherapy [69]. citable by way of delaying the closing time of the
Although no study has yet identified genes NaV1.7 channels when action potentials are turned
directly associated with this enigmatic pain condi- off, leading to the pain attacks. But this mechanism
tion, some research has hinted at a genetic compo- does not explain the regional nature of the pain in
nent based on the increased prevalence of PEPD: why do carriers only express the extreme
supertasters (i.e., persons with enhanced abilities to paroxysms first in the rectal region when they are
detect bitter taste) among patients with BMS [70]. young and what causes the syndrome as patients
age to emerge in the trigeminal region (i.e., around
the eyes and mandible)? [72].
8.2.5 P
 aroxysmal Extreme Pain In some PEPD cases, the duration of a typical
Disorder (PEPD) pain paroxysm is a few seconds, whereas in oth-
ers it may last up to hours at a time. Furthermore,
PEPD is very rare, even less common than in some cases the pain paroxysms are accompa-
TN.Yet readers of this book may find it of inter- nied by epileptic seizures, while in others they
est to learn about this condition because of the may be associated with slow heartbeat or short
genetic architecture that brings this condition epochs of apnea. These variations in pain and
about. Orofacial PEPD manifests as pain mainly non-pain symptoms may suggest that in addition
in the mandibular and submandibular regions as to mutations on SCN9A, carriers may co-inherit
well as around the ocular region, accompanied other genetic variants elsewhere in the genome
with cutaneous reddening, swelling, and that can modify the effect of the causative SCN9A
increased warmth (flushing) [71]. These symp- mutations and/or bring about additional symp-
toms are identical to primary erythromelalgia, toms [72].
but unlike the latter that appears in the extremi-
ties, PEPD is associated with pain that begins at
an early age (perhaps as early as in utero) in the Summary
rectal region and later on in life moves to the Orofacial pain medicine faces major chal-
face. Like erythromelalgia, symptoms of PEPD lenges as available treatments neither cure nor
persist throughout life, manifesting as strong prevent POPD.Current treatment approaches
spontaneous paroxysms or triggered by tempera- utilize the trial-and-error and one-drug-fits-
ture changes (e.g., a cold breeze), emotional dis- all paradigms that are based on population
tress, and consuming spicy foods or drinking average efficacy in treating different types of
cold drinks. pain, ignoring individual variation. As a result,
The special interest in this pain condition the average success of analgesic treatment of
arose when it was found that mutations in the POPD is measured in a reduction of only about
very same gene (SCN9A, encoding the voltage- two points on a 011 numerical rating scale of
gated sodium channel NaV1.7) are associated pain severity. In many cases, even this modest
with extremely contrasting phenotypes: congeni- effect is attained at the cost of unacceptable
tal insensitivity to pain, erythromelalgia, and adverse side effects. Since a significant portion
116 Z. Seltzer and S.R. Diehl

of the phenotypic variation in POPD and other migraine headache in women: a preliminary twin
chronic pain syndromes is heritable, there is study. JOrofac Pain. 2012;26:918.
9. Seltzer Z, Mogil JS.Pain and genetics. In: Sessle B,
growing hope that a better understanding of Lavigne G, Lund J, Dubner R, editors. Orofacial Pain:
human genome variation can lead to the devel- From Basic Science to Clinical Management. 2nd ed.
opment of improved analgesics and precision Hanover Park: Quintessence Publishing Company;
medicine approaches to treatments of POPD. 2007. p.6975.
10. Diatchenko L, Slade GD, Nackley AG, Bhalang K,
Pain genetics is still at an early stage of Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina
development, and much more work lies ahead. SA, Shagin D, Max MB, Makarov SS, Maixner
However, we strongly believe that the prelimi- W.Genetic basis for individual variations in pain per-
ception and the development of a chronic pain condi-
nary discoveries already made highlight the
tion. Hum Mol Genet. 2005;14:13543.
great potential of this approach. Among the 11. Smith SB, Mir E, Bair E, Slade GD, Dubner R,

major benefits of success will include ability Fillingim RB, Greenspan JD, Ohrbach R, Knott C,
to use genetic biomarkers to identify individu- Weir B, Maixner W, Diatchenko L.Genetic variants
associated with development of TMD and its interme-
als at high risk of developing POPD (before
diate phenotypes: the genetic architecture of TMD in
symptoms emerge), thus offering potential for the OPPERA prospective cohort study. JPain.
prevention, and a new era of individualized 2013;14(Suppl 11):T91T101.
(precision medicine) medications for more 12. Kline 4th RH, Exposto FG, OBuckley SC, Westlund
KN, Nackley AG.Catechol-O-methyltransferase inhi-
effective treatment of these pain disorders.
bition alters pain and anxiety-related volitional behav-
iors through activation of -adrenergic receptors in
the rat. Neuroscience. 2015;290:5619.
13. Kambur O, Talka R, Ansah OB, Kontinen VK,

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Serum, Synovial, andSalivary
Biomarkers forOrofacial Pain
9
Conditions

StergiosKatsiougiannis, VarunR.Mallela,
ChristopherA.Schafer, andDavidT.W.Wong

Abstract
Orofacial conditions such as temporomandibular disorders are often asso-
ciated with extended bouts of debilitating chronic pain. Unfortunately,
these and other similar pathologies are characterized by their inherent
complexity and poorly understood etiologies making diagnoses and subse-
quent treatments exceedingly difficult. With a significant proportion of the
population suffering from painful orofacial conditions, the development of
new and accurate diagnostic procedures is essential to improve the current
standard of care. Here, we overview the potential of serum, saliva, and
synovial fluids as reservoirs of biochemical information capable of dis-
cerning specific disorders, including those correlated with orofacial pain.
Determining the worth of these biofluids in the assessment of health status
could expedite diagnoses and enhance pain management strategies while
also enhancing our understanding of disease pathophysiology.

9.1 Introduction

With affected areas including the face, mouth,


ears, eyes, nose, and neck, orofacial discomfort
may result from a diverse range of conditions.
S. Katsiougiannis, PhD Among these are temporomandibular disorders
V.R. Mallela, BDS, DDS
(TMDs), the second most common musculoskele-
C.A. Schafer, BS, MBA, PhD
University of California Los Angeles, tal condition after chronic lower back pain. TMDs
School of Dentistry, are highly prevalent and frequently associated
10833 Le Conte Ave., 73-041 CHS, with debilitating chronic pain, a feature with dev-
Los Angeles, CA, 90095, USA
astating impact on patients quality of life. This
D.T.W. Wong, MD, DMD, DMSc (*) emphasizes the need for developing methodolo-
Department of Dentistry, UCLA,
gies aimed at early diagnosis and effective man-
10833 Le Conte Ave., 73-038 CH,
Los Angeles, CA, 90095, USA agement. However, the diagnosis of pain relies on
e-mail: dtww@ucla.edu patient reports, questionnaires, and semi-objective

Springer-Verlag GmbH Germany 2017 119


J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI10.1007/978-3-662-53994-1_9
120 S. Katsiougiannis et al.

findings for diagnostics (see Chap. 1, 5, 6 and 7). plasma, which results from the forced separation
As described in Chap. 6, the diagnosis of myalgia of blood cells prior to clotting, serum is free of
using the validated Diagnostic Criteria for TMD fibrinogens and is the predominant source of
(DC/TMD], includes three pain subgroups: local blood-based diagnostic analytes.
myalgia, myofascial pain, and myofascial pain
with referral. This current lack of specific vali- 9.2.1.1 Function
dated diagnostic criteria for pain subgroups serves The primary function of blood serum is to facili-
as a major barrier to achieving early diagnosis and tate the transport of nutritive molecules and waste
effective management. Although much effort has products throughout the body. It also plays a key
been placed into establishing novel modes to accu- role in regulating bodily fluids, controlling core
rately diagnose disorders of chronic pain, the most body temperature, maintaining pH, and supporting
efficacious methods have yet to be determined. immunological responses to pathogenic invasion.
One approach involves the evaluation of bioflu-
ids for molecular and microbial clues that may 9.2.1.2 Composition
actually indicate the onset or progression of dis- Although serum is predominantly composed of
ease. While blood is considered the gold standard water (95%), its molecular constituency consists
for these purposes, recent evidence suggests that of proteins and peptides (such as albumins, glob-
saliva and synovial fluids could potentially be uti- ulins, lipoproteins, enzymes, and hormones),
lized as well. We begin our discussion here with an amino acids, lipids, carbohydrates, electrolytes,
overview of these biofluids and go on to describe and numerous additional entities present in min-
each of these as a prospective warehouse of bio- ute concentrations [1]. As an easily accessible
chemical indicators capable of determining indi- body fluid teeming with analytes, blood serum
viduals suffering from chronic oral facial pain. has been extensively investigated for decades.
These efforts have resulted in the publication of
comprehensive reference tables describing its
9.2 Biofluids biochemical composition. As an example,
Psychogios and colleagues [1] developed a
A biofluid is defined as any aqueous solution pro- human serum metabolome database detailing
duced by the body. With functions ranging from over 4000 unique molecules found within blood
digestion to joint lubrication, these fluids may samples (see Table 9.1). Aberrations in the
include serum, sweat, saliva, gastric acid, syno- respective concentrations of these analytes have
vial fluid, tears, etc. Our focus will comprise an routinely been associated with the presence or
overview of serum, synovial, and oral fluids and onset of distinct disease states. To this day, prob-
the possible utilization of their respective molecu- ing an individuals serum remains the most com-
lar constituencies as diagnostic media. Elucidating monly employed technique for the analysis of
disease-indicating entities within these fluids and biofluids and determination of health status.
exploring their etiology may facilitate a greater
understanding of human pathophysiology and
provide new insights regarding the diagnosis and 9.2.2 Synovial Fluid
management of chronic orofacial pain disorders.
We begin our discussion here by detailing the use Similar to serum in appearance, synovial fluid is a
of blood serum as a diagnostic medium. viscous stress-bearing solution occupying the
synovial cavities of highly mobile joints, such as
the temporomandibular joint (TMJ) (see Chap. 7).
9.2.1 Blood Serum
9.2.2.1 Function
Blood serum is the pale yellow liquid remaining While synovial fluid is considered multifunctional,
when coagulated blood samples are centrifuged its primary purpose is to lubricate cartilaginous tis-
at high speeds. Not to be confused with blood sues in regions where proximate bone structures
9 Serum, Synovial, andSalivary Biomarkers forOrofacial Pain Conditions 121

Table 9.1 Chemical classes in the serum metabolome database


Compound class No. Compound class No.
Acyl glycines 10 Inorganic ions and gases 20
Acyl phosphates 10 Keto acids 8
Alcohol phosphates 2 Ketones 6
Alcohols and polyols 40 Leukotrienes 8
Aldehydes 3 Minerals and elements 40
Alkanes and alkenes 10 Miscellaneous 77
Amino acid phosphates 1 Nucleosides 24
Amino acids 114 Nucleotides 24
Amino alcohols 14 Peptides 21
Amino ketones 14 Phospholipids 2177
Aromatic acids 22 Polyamines 11
Bile acids 19 Polyphenols 22
Biotin and derivatives 2 Porphyrins 6
Carbohydrates 35 Prostanoids 23
Carnitines 22 Pterins 14
Catecholamines and derivatives 21 Purines and purine derivatives 11
Cobalamin derivatives 4 Pyridoxals and derivatives 7
Coenzyme A derivatives 1 Pyrimidines and pyrimidine derivatives 2
Cyclic amines 9 Quinones and derivatives 3
Dicarboxylic acids 17 Retinoids 11
Fatty acids 65 Sphingolipids 3
Glucuronides 8 Steroids and steroid derivatives 109
Glycerolipids 1070 Sugar phosphates 9
Glycolipids 15 Tricarboxylic acids 2
Hydroxy acids 129
Indoles and indole derivatives 12
Adapted from [1]

concertedly facilitate skeletal movements. In this by synovial cell populations, are selectively
milieu, synovial fluid serves to support coordinated retained inside the synovial space, while large
physical actions via preserving and protecting adja- blood-based molecules like fibrinogen are pro-
cent bone tissues, thereby safeguarding against fric- hibited access. Consequently, synovial fluid is
tional wear and promoting the longevity of joints. mainly a dialysate of blood plasma supple-
Hence, synovial fluids are essential for the long- mented with locally produced constituents
term utilization of complex skeletal structures. including hyaluronic acid, lubricin, and other
joint-lubricating macromolecules [2].
9.2.2.2 Composition The diverse nature of synovial-based com-
The molecular composition of synovial fluid is pounds in combination with the intimate anatom-
derived from blood plasma as well as chondro- ical environment of the synovial space suggests
cytes and other cell populations lining the syno- the possibility that fluids bore from this region
vial cavity. Interestingly, its biochemical may contain a unique collection of biomarkers
makeup may actually be influenced by the with the potential to reveal key information
synovium, a semipermeable membrane encom- regarding joint health. Examining the molecular
passing the non-cartilaginous surfaces of syno- composition of synovial fluids could lead to the
vial joints. As a size-selective boundary, the discovery of discriminatory factors indicative of
synovium acts to inhibit the passage of high disease pathogenesis with the capacity to
molecular weight compounds. Thus, substances preclude the occurrence of chronic pain (see

such as hyaluronic acid, a compound secreted Chap. 7).
122 S. Katsiougiannis et al.

9.2.3 Saliva 9.2.3.2 Composition


Saliva is a continuously secreted, slightly acidic,
Saliva is produced by a number of salivary glands clear, hypotonic fluid predominantly composed of
located within and around the oral cavity including water (99.5%). The remaining 0.5% is c omprised
the parotid, submandibular, sublingual, and minor of inorganic ions, including sodium, chloride,
salivary glands and posterior deep lingual glands potassium, and calcium, along with organic com-
(von Ebners glands) (Fig. 9.1). Each gland is com- ponents, such as amino acids, proteins, antibod-
prised of clustered acinar cells called acini, which ies, hormones, enzymes, lipids, and cytokines,
concertedly produce about 5001500ml daily [3]. among many others.[4]. In addition, recent stud-
There are two categories of acinar cells: [1] ies have shown that saliva actually contains a vari-
serous cells (most commonly found in the parotid ety of genomic, transcriptomic, proteomic,
gland), which secrete a nonviscous watery prod- microbiologic, and immunologic analytes [58]
uct, and [2] mucous cells (predominant in the that may be capable of identifying both local and
sublingual gland), which secrete a highly viscous systemic disorders in afflicted individuals.
mucous-like product. These cells produce a solu- Consequently, saliva is now the focal point of
tion containing electrolytes, mucins, and multiple investigations aimed at establishing oral
enzymes, which subsequently flow into collect- fluids as the preferred diagnostic medium.
ing tubes, where their composition can be further
altered by the reabsorption of specific molecules
before release into the mouth as saliva. 9.3  erum, Synovial Fluid,
S
andSaliva asDiagnostic
9.2.3.1 Function Media
Saliva lubricates and moistens the oral tissues to
aid in speech, chewing, swallowing, and taste. The orofacial region is anatomically complex and
Saliva also plays a key role in initiating and facil- often presents with exclusive ailments and con-
itating digestion. In addition, salivas cleansing comitant chronic pain not routinely experienced
actions and intrinsic anti-pathogenic characteris- in other regions of the body. These include, but
tics are crucial for maintenance of oral health. are not limited to, masticatory muscle and

Fig. 9.1 Location of


salivary glands: parotid,
submandibular, and
sublingual
9 Serum, Synovial, andSalivary Biomarkers forOrofacial Pain Conditions 123

temporomandibular joint disorders as well as manifest bleeding gums or mouth ulcers all of
burning mouth syndrome. Current diagnostic which can negatively affect the efficacy of the
methodologies directed at the early identification saliva sample. Despite these complications, saliva
of these conditions have thus far proved to be represents the most attractive technique aimed at
invasive and occasionally inaccurate. Developing procuring analyzable biofluids. Noninvasiveness
new procedures designed to discriminate these and overall ease of collection highlight its poten-
and other maladies associated with chronic oro- tial as a diagnostic medium. Establishing the use-
facial pain could help initiate the expeditious fulness of saliva in this capacity could prove to be
onset of corrective therapies and alleviate much immensely useful in the field of molecular
of their associated enduring discomfort. The pro- diagnostics.
ceeding sections will describe the potential utili- In juxtaposing all three biomarker sources,
zation of serum, synovial fluid, and saliva as synovial fluid may be the most limiting in terms of
diagnostic media with the power to discern evaluating our physiologic state because of its
patients suffering from orofacial disorders com- small volume, especially in joints like TMJ.Saline
monly presenting with chronic pain. aspirates from TMJs devised to overcome this bar-
rier may lead to unknown dilution effects on target
biomarkers [9] making it difficult to standardize
9.3.1 B
 iofluids inDisease Detection: measurements, thereby diminishing their diagnos-
Advantages tic utility. Regardless, synovial fluid has the dis-
andDisadvantages tinct advantage of presenting a concurrent portrait
of joint health that may not be available by any
9.3.1.1 Collection other means [10]. This makes synovial fluid espe-
Both serum and synovial samples are collected cially appealing as a tool for the early detection of
via insertion and retraction of hypodermic nee- joint-related conditions including TMDs.
dles into specific anatomical locations. While Serum, while currently the standard in molec-
this technique may allow for real-time analysis of ular diagnostics, is hindered, like synovial fluid,
disease-indicating molecules, its execution is not by the fact that its collection is invasive. Clearly,
a straightforward task and carries a risk of iatro- among these methodologies, saliva is the most
genic infections. Moreover, these approaches favorable, although determining its value as a
require advanced training, a thorough under- diagnostic medium comparable with that of
standing of anatomy, and patients willing to tol- serum is yet to be established.
erate substantial discomfort despite the use of
local anesthetic. Resulting anxiety may compel 9.3.1.2 Availability ofBiomarkers
subjects to avoid or delay voluntary participation, As mentioned previously, blood serum is cur-
leading to a lack of timely diagnosis and thera- rently the gold standard for discriminatory bio-
peutic intervention. marker discovery and validation. Accordingly,
In contrast to serum and synovial fluids, sali- serum has been the focal point of multiple investi-
vary samples are collected painlessly and expedi- gations evaluating its constituents for indications
tiously with patients simply spitting into sterile of chronic pain conditions. For example, studies
tubes. Saliva-based analytes can be stabilized, have shown that patients with TMD can be identi-
stored, and even shipped without the need for fied by a significant rise in serum 2,3-dihydroxy-
specially trained staff or the inclusion of antico- benzoic [11] as well as malondialdehyde and
agulants. In consideration, future measures could 8-hydroxydeoxyguanosine (8-OHdG) [12].
even include the possibility of collecting clini- However, in recent years saliva and synovial flu-
cally invaluable salivary secretions at home. ids have piqued the interest of numerous research-
While presented as simplistic, accumulating ers and clinicians as possible alternatives. Not
saliva is not without intermittent difficulties. For surprisingly, this paradigm shift may be due to the
example, Sjgrens syndrome patients often pres- noninvasiveness of saliva collection and the
ent with dry mouth, while other individuals may apparent tissue specificity of synovial fluid.
124 S. Katsiougiannis et al.

Despite the fact that its molecular community 9.3.2 Comparative Analysis
is partially derived from blood, synovial fluids
are not an exact mirror image of plasma. The overarching goal of molecular diagnosti-
Synovium, the semipermeable boundary lining cians or clinicians is to identify disease prior to
the synovial joint, naturally restricts the passage its genesis or at its earliest developmental stages.
of oversized molecules, thereby preventing select The preponderance of current protocols designed
joint-specific biochemical markers from entering to address these needs utilize invasive blood tests
the bloodstream. Hence, synovial fluid analyses or biopsies to determine the onset or advance-
can uniquely pinpoint local conditions, a task not ment of pathologies, both local and distant.
feasible through the evaluation of serum and Nonetheless, recent research indicates this
saliva. These attributes distinguish the synovia as approach may not remain the status quo as the
an attractive and perhaps optimal medium for the composition of saliva and synovial fluids may
assessment of joint health. more accurately reflect orofacial physiological
Like serum, saliva is currently being pursued anomalies, including those associated with
as a medium for biomarker development and dis- chronic pain [13, 1719]. The following sections
ease detection [4]. Interestingly, most compounds review selected research aimed at elucidating
found in blood are also present in saliva, albeit at orofacial pain biomarkers within the biofluids
a significantly lower concentration [13]. Even so, described thus far.
what is most interesting here is not that saliva-
based molecular entities correspond with those of 9.3.2.1 Saliva Versus Serum
blood but that how this is even possible. In an Both saliva and blood are complex bodily fluids
effort to explain this phenomenon, it has been containing a multitude of molecular and micro-
suggested that blood-borne molecules may act to bial analytes. Similarities in their respective con-
induce salivary biomarkers by interacting with stituencies have led to the idea that saliva may be
salivary glands and subsequently altering the an effective diagnostic alternative to blood, the
molecular composition of oral fluids [14]. most traditional and frequently accessed source
Exosome-like microvesicles are thought to have of biochemical disease indicators.
a key role in this process by encasing, protecting, Regardless, credentialing oral fluids as an
and shuttling RNAs and proteins throughout the acceptable diagnostic medium may be a difficult
vasculature. In doing so, exosomes, shed from hurdle to overcome. Multiple studies suggest that
distant tissues, could deliver viable biochemical while most blood-based analytes are also detected
information to salivary glands, which in turn in saliva, they are substantially diminished or do
could be reflected in oral fluids [1416]. Defining not significantly correlate [13, 2022]. Even so, a
the mechanistic minutia of this long-range inter- growing number of investigations conclude that
action may further our understanding of disease saliva-based biomarkers are not only preferred but
pathogenesis and extracellular communication also accurate in discerning healthy subjects from
while also establishing saliva as a credible diag- those afflicted with periodontal disease or burning
nostic medium. mouth syndrome [2329]. Saliva has also been
Summarily, under certain circumstances, employed as an indicator of stress and chronic
molecular indicators housed within either blood pain. For example, reports state that substance P, a
or saliva may not be as informative as those found neuropeptide associated with inflammation and
in synovial fluids. Nevertheless, blood and saliva pain, the stress hormone cortisol, and markers of
should not be discounted as valuable in identify- oxidative stress can be repeatedly detected within
ing the onset and progression of local and sys- salivary secretions [12, 3032]. Suggesting a
temic disorders. Determining which biofluid to preference for saliva over serum in the detection
assess may highly depend on the pathophysiol- of select markers, researchers go on to describe
ogy of the disease in question as well as its tissue that substance P is actually more readily available
of origin [4]. in oral fluids than patient-matched blood samples.
9 Serum, Synovial, andSalivary Biomarkers forOrofacial Pain Conditions 125

Together, these findings support the idea that sali- Similar to what has been observed in saliva, some
vary secretions could supersede serum as the pre- miRNAs are thought to be transported inside of
ferred biofluid for routine evaluation of our exosomes, but this idea is still in its infancy and
current physiologic state. other mechanisms may also exist. The elucida-
tion of these analytes as biomarkers of joint-
9.3.2.2 Synovial Fluid VersusSerum related disorders substantiates the significance of
andSaliva exploring synovial fluids as a reservoir of molec-
As a size-selective barrier, the synovium facili- ular information regarding the current state of
tates the confinement and concentration of dis- joint health.
tinct biomarkers capable of providing real-time To expand upon the aforementioned, very few
information concerning joint health that may be synovia-derived indicators have corresponding
unavailable in blood. This lack of correspon- concentrations within the blood serum. In a study
dence suggests that the synovial fluids may be evaluating six distinct TMJ biomarkers, only one,
optimal in assessing TMDs. Expanding our bradykinin, was significantly correlated when
understanding of synovial fluids and their poten- comparing synovial fluid and serum [47]. Further
tial role in biomarker development could not only studies support these findings, by determining
enhance our ability to diagnose and treat joint- that elevated synovial tumor necrosis factor alpha
related disorders but also effectively manage (TNF-alpha) was not observed in the serum of
related instances of chronic pain. TMD patients [48]. These outcomes suggest that
In considering the orofacial complex, disor- synovial compartments contain discriminatory
ders of the TMJs are often associated with sub- biomarkers capable of identifying select patholo-
stantial bouts of chronic pain. Identifying gies with greater specificity and sensitivity than
discriminatory biomarkers indicative of early dis- that of blood. Despite the compelling nature of
ease onset may ameliorate patient discomfort by this evidence, synovial fluids may not be an ideal
expediting the delivery of corrective therapies matrix by which to determine the overall condi-
and pain management strategies. While saliva has tion of our joints. As it turns out, a series of inves-
also shown some promise in detecting potential tigations comparing synovial- and serum-derived
temporomandibular biomarkers [12], researchers molecular analytes indicate a contrasting notion.
have also reported that it may be possible to Current data exists suggesting that evaluating
reveal joint-related TMDs by evaluating the serum-derived cell populations, peptides, miR-
molecular content of synovial fluids (Chap. 7). In NAs, and even neurotransmitters [31, 32, 4951]
a recent study, researchers determined that insuf- can distinguish distinct manifestations of chronic
ficient hyaluronic acid [19] and enhanced con- pain disorders. While divisive, these investiga-
centrations of a hyperalgesic eicosanoid acid tions, along with the above statements, indicate
(15-HETE) within synovial fluid were highly that no one biofluid is an ideal diagnostic medium.
correlated with TMD-positive patients [11]. Summarily, determining the most efficacious
Similar efforts describe a number of additional mode for rapid and accurate physiological assess-
markers including nitric oxide [33], serotonin ment may be a function of each individual dis-
[34], aggrecanase [35, 36], chondroitin-4 and ease state.
chondroitin-6 sulfate [37], cytokine receptors,
and proteinases [3845]. Although miRNAs 9.3.2.3 Factors Affecting
(microRNAs), another novel biomarker, have Biomarkers Present
also been identified within the synovial fluids of Although theoretically simplistic, the collection
certain joints, there has been little to no correla- and subsequent evaluation of biofluids is not
tion between their relative concentrations in without difficulty. Some common issues include
either plasma and synovial fluid [46]. subjects age, sleeping patterns [5254], relevant
Furthermore, the mechanism for stability of comorbidities (see Chap. 2), pharmaceutical side
synovial fluid miRNA remains to be determined. effects [25, 55], physical activity [54], and
126 S. Katsiougiannis et al.

method of sample collection and processing [13, Traditionally, blood serum has served as
56] (see Chap. 10). For example, Sjgrens syn- the most commonly accessed biofluid for the
drome patients receiving hydroxychloroquine molecular diagnosis of systemic disease as
treatments are commonly characterized by well as certain orofacial conditions. However,
decreased salivary IL-6 and hyaluronic acid in recent efforts have determined that saliva
comparison to serum [55]. In addition, substan- could supplant blood in this capacity and opti-
tial molecular discrepancies were noted [13, 56] mize the processes by which physicians deter-
in processed (centrifuged upon collection) versus mine the onset of disease and monitor
unprocessed saliva samples, as well as in unstim- therapeutic progress. Employing oral fluids in
ulated drool versus filter paper sampling. Another this context not only utilizes a unique method-
important factor to consider is diurnal variation, a ology of patient assessment; it also introduces
phenomenon defined by fluctuations in the con- the possibility of pain-free medicine, an idea
centrations of biofluid constituents throughout long sought after by scientists, clinicians, and
the day. Although this effect has not been assessed patients alike.
with regard to chronic orofacial pain disorders, it Along with saliva and serum, synovial
has been reported that levels of salivary cortisol fluid, a protective lubricant located in and
and dehydroepiandrosterone (DHEA) can be around complex joints, could also prove to be
influenced by time [52]. Similarly, diurnal con- an invaluable source of biochemical informa-
centrations of serum-based cartilage oligomeric tion. Although acquiring synovial samples is
matrix protein (COMP) levels in arthritic sub- accompanied by a degree of invasiveness, its
jects have been shown to significantly vary with inimitable anatomical locale yields a real-time
physical activity [53, 54]. molecular overview of its immediate milieu.
Concertedly, these findings indicate that bio- Information obtained from evaluating this
marker levels may be influenced by a number of fluid could be used to accurately discern local-
confounding variables. With this in mind, ized physiological alterations, such as TMDs.
researchers and clinicians should be cautious Finally, it can be inferred that at this time
when utilizing biofluids to evaluate their patients there is no one ideal biofluid capable of
health status and pain levels. In any event, further imparting an all-encompassing portrait of our
investigation is required to not only determine current health status. While serum, saliva, and
the effectiveness of a particular biofluid as an synovial fluids all contain biomarkers indica-
indicator of chronic pain but also to establish bio- tive of unique disease states, both local and
marker diagnostics as the preferred mode of systemic, none are considered comprehensive,
patient assessment, monitoring, and prognosis. hence necessitating the ongoing research for
personalized diagnostics and therapeutics. At
this time, determining the appropriate biofluid
Summary by which to appraise health status continues to
Chronic orofacial pain is a substantial medical be a function of the disease condition in ques-
corollary with mixed etiology from TMD to tion. Table 9.2 lists a series of orofacial disor-
burning mouth syndrome. Left undiagnosed ders commonly associated with chronic pain
and without treatment, suffering patients can along with their respective biomarkers and
be subject to ongoing discomfort, loss of biofluid source.
appetite, and lack of sleep. Unfortunately,
most conditions presenting with chronic oro-
facial pain are difficult to differentiate, and 9.4 Future Directions
establishing rapid and accurate methods of
patient evaluation could allay a great deal of The field of molecular diagnostics is an ever-
agony by identifying affected individuals at expanding genre of basic and translational
the earliest stages of pathogenesis. research. Newer methods, techniques, and ideas
9 Serum, Synovial, andSalivary Biomarkers forOrofacial Pain Conditions 127

are routinely introduced and explored as poten- of methylation within a genome and determines
tial platforms for advancing our understanding of its potential as a disease-specific biomarker. More
disease pathophysiology and early identification. specifically, these analyses identify the degree of
One area in particular that is gaining increas- DNA methylation for thousands of genes and
ing popularity is the identification of DNA meth- relate that data to specific disease states, a truly
ylation biomarkers. Termed methylomics, this impactful attribute. Whats more is that these
area of research focuses on evaluating the extent experiments can be performed utilizing extremely

Table 9.2 Orofacial conditions and their potential serum, synovial, and salivary biomarkers
Biofluid Condition Biomarker Reference
Serum Facial 15-HETE Aghabeigi etal. [11]
Arthromyalgia 2,3-dihydroxybenzoic acid
Burning IL-2 Xia etal. [57]
mouth sensation IL-6 Boras etal. [58]
Neurokinin A
TMD (serum and saliva) 8-OHdG Rodriguez de Sotillo etal. [12]
Malondialdehyde Slade etal. [51]
MCP-1 Kopp and Alstergren [49]
IL-1ra Voog etal. [59]
IL-8
Serotonin
P-IL-1sRII
C-reactive protein
Saliva Burning IL-2 Simcic etal. [60]
mouth syndrome IL-6 Zidverc-Trajkovic etal. [29]
CGRP Srinivasan etal. [28]
Chondroitin sulfate Loeb etal. [24]
Kallikrein Pekiner etal. [26]
CD14
TLR-2
Magnesium
Periodontal disease 8-OHdG Su etal. [61]
8-epi-PGF2alpha Mirrielees etal. [25]
Carbonylated proteins Kibayashi etal. [23]
Albumin Nishida etal. [62]
Alkaline phosphatase Horst etal. (2011)
Aspartate aminotransferase Lee etal. [63]
Calprotectin Sexton etal. [64]
Cystatins
Defensins
Histatins
IL-1alpha
IL-1beta
Immunoglobulin
Lactate dehydrogenase
Lactoferrin
Lysozyme
MMP-8
HSP70
Mucins
Prostaglandin E2
Salivary amylase
TMD 8-OHdG Rodriguez de Sotillo etal. [12]
Malondialdehyde
(continued)
128 S. Katsiougiannis et al.

Table 9.2(continued)
Biofluid Condition Biomarker Reference
Synovial TMD Aggrecanase Yoshida etal. [35, 36]
fluid Lubricin Wei etal. [19]
Hyaluronic acid Takahashi etal. [33]
Nitric oxide Alstergren etal. [34]
Serotonin Murakami etal. [37]
Chondroitin-4 Fredriksson etal. [48]
Chondroitin-6 Kubota etal. [39]
TNF-alpha Kaneyama etal. [45]
IL-1beta Tominaga etal. [41]
IL-1ra Shafer etal. [44]
P-IL-1sRII Srinivas etal. [43]
IL-6 Tanaka etal. [42]
MMP-2 Snadler etal. [65]
MMP-8 Guven etal. [66]
MMP-9 Hajati etal. (2010)
PGE2 Herr etal. [67]
Cytokine receptors
EG-VEGF/PK1
Superoxide dismutase
Glutamate
15-HETE 15-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid, 8-OHdG 8-hydroxydeoxyguanosine, CGRP calcitonin
gene-related peptide, EG-VEGF/PK1 endocrine gland-derived vascular endothelial growth factor/prokineticin-1, Hsp70
heat shock protein 70, IL-1alpha interleukin 1 alpha, IL-1beta interleukin 1 beta, IL-1ra IL-1 receptor antagonist, IL-2
interleukin 2, MCP-1 monocyte chemoattractant protein-1, MMP-2 matrix metallopeptidase 2, MMP-8 matrix metal-
lopeptidase 8, MMP-9 matrix metallopeptidase 9, PGE2 prostaglandin E2, P-IL-1sRII interleukin-1 soluble receptor
type II, TLR-2 toll-like receptor-2, 8-epi-PGF2alpha 8-epiprostagladin F2 alpha

small quantities of sample material suggesting ing the initiation of corrective treatments. Serum,
that it may be possible to identify novel gene tar- salivary, and synovial fluids have all been shown
gets using minute volumes of select biofluids. to contain biochemical information that could
In line with this notion, a recent study of rheu- serve to identify specific disease states associ-
matoid arthritis patients distinguished a number ated with orofacial pain. Although substantial
of hypermethylated and downregulated gene tar- efforts have revealed their value as reservoirs of
gets in synovial fibroblasts. The authors of this diagnostic analytes, continued research is neces-
investigation further suggest that these genes sary to establish their efficacy and comprehen-
may play an important role in TGF-beta signal- sive clinical acceptability. Credentialing these
ing, a transduction pathway known to play a role biofluids and their respective biomarkers could
in chronic pain and joint disorders [51]. Overall, not only mitigate a great deal of patient discom-
these findings indicate that methylomic analysis fort but also support the formulation of novel
may have a place in discerning the presence of preventive care, planning of therapeutic strate-
orofacial disorders and therefore could be an gies, and furthering our understanding of the dis-
interesting avenue to pursue in the continually ease processes. However, much remains to be
growing arena of molecular diagnostics. learned and achieved.

Competing Interests David Wong is co-founder


Conclusion of RNAmeTRIX Inc., a molecular diagnostic
The development of discriminatory orofacial company. He holds equity in RNAmeTRIX, and
pain biomarkers could help alleviate a great deal serves as a company Director and Scientific
of patient discomfort by facilitating and expedit- Advisor. The University of California also holds
9 Serum, Synovial, andSalivary Biomarkers forOrofacial Pain Conditions 129

equity in RNAmeTRIX. Intellectual property that 13. Williamson S, Munro C, Pickler R, Grap MJ, Elswick
David Wong invented and which was patented by Jr RK.Comparison of biomarkers in blood and saliva
in healthy adults. Nurs Res Pract. 2012;2012:246178.
the University of California has been licensed to doi:10.1155/2012/246178.
RNAmeTRIX. Additionally, he is a consultant to 14. Lau C, Kim Y, Chia D, Spielmann N, Eibl G,

PeriRx. ElashoffD, etal. Role of pancreatic cancer-derived
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Part IV
Study Designs and Statistical Analysis for
the Identification of Biomarkers,
and Future Direction
Biomarkers inEpidemiologic
Research: Definition, Classification,
10
andImplication

AnaMiriamVelly, ShrishaMohit,
HymanM.Schipper, andMervynGornitsky

Abstract
The aim of this chapter is to give an introduction to biomarkers. It provides
a definition for the term biomarker before describing their classification
and the criteria applicable to each. This chapter also offers a general guide-
line for the development and assessment of biomarkers, including an
insight into the various factors that need to be considered in order to
advance biomarker discovery and validation. Finally, the chapter lists the
possible contributions of biomarkers in clinical research.

10.1 Introduction

Chronic orofacial pain is a common condition and


poses a significant global public health problem
A.M. Velly, DDS, MSc, PhD (*) (Chaps. 1 and 2). Many studies have identified a
Faculty of Dentistry, McGill University,
Montral, QC, Canada
series of risk factors for chronic orofacial pain. For
instance, some of the most relevant and common
Department of Dentistry, Jewish General Hospital,
3755, Chemin de la Cte Ste-Catherine, Suite A-017,
risk factors are psychological and painful comor-
H3T 1E2 Montral, QC, Canada bidities (Chap. 2). Several randomized clinical tri-
e-mail: ana.velly@mcgill.ca als (RCTs) investigated the effect of treatments for
S. Mohit, BSc managing chronic orofacial pain. Two systematic
Department of Dentistry, Jewish General Hospital, reviews show that behavioral therapy [1] and the
3755, Chemin de la Cte Ste-Catherine, Suite A-017, use of appliances [2] are effective in alleviating
H3T 1E2 Montral, QC, Canada
a type of orofacial pain call painful temporo-
H.M. Schipper, MD, PhD, FRCPC mandibular disorders (TMD). However, the evi-
Department of Neurology and Neurosurgery, McGill
University, Montral, QC, Canada dence for effectiveness of the appliances was weak
[2]. These systematic reviews concluded that these
M. Gornitsky, DDS, FRCDC
Faculty of Dentistry, McGill University, treatments would not cure TMD.
Montral, QC, Canada The reasons for unsuccessful treatment out-
Department of Dentistry, Jewish General Hospital, comes are not clear. Ohrbach and Dworkin sug-
3755, Chemin de la Cte Ste-Catherine, Suite A-019, gested that there is a very complex interaction
H3T 1E2 Montral, QC, Canada between changes in physical and psychological

Springer-Verlag GmbH Germany 2017 135


J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI10.1007/978-3-662-53994-1_10
136 A.M. Velly et al.

factors responsible for chronic TMD pain, which evaluate disease severity, and (5) prognostic bio-
could in part explain the weak effectiveness of markers to predict the disease course [9, 10].
the treatments [3]. Biomarkers could indicate a variety of disease
The identification and validation of biomark- characteristics such as pain intensity, duration,
ers that are indicators for pain chronicity and the and classification [11].
effectiveness of pain management will undoubt- In addition, biomarkers are classified as
edly lead to the development of optimal strate- exploratory, probable valid, or known valid bio-
gies for pain prevention and management. The markers. Exploratory are potential biomark-
next section defines and classifies biomarkers ers tested in analytic studies where validity has
and describes the process for their development not been demonstrated. A biomarker is defined
and analysis, as well as their contribution. as probable when it is measured in an analyti-
cal test system with well-established perfor-
mance characteristics and for which there is a
10.2 Biomarkers scientific framework or body of evidence that
appears to elucidate the physiologic, toxicologic,
Hulka and colleagues [4] defined biomarkers as pharmacologic or clinical significance of the test
cellular, biochemical or molecular alterations results. A known biomarker is defined as a
that are measurable in biological media such as biomarker that is measured in analytical test sys-
human tissues, cells, or fluids. As defined by tem with well-established performance charac-
Strimbu and Tavel [5], biomarker is a term teristics and for which there is widespread
derived from biological markers. agreement in the medical or scientific community
The National Institutes of Health Biomarkers about the physiologic, pharmacologic and or
Definitions Working Group defined biomarkers clinical significance of the results [12].
as a characteristic that is objectively measured The following criteria to validate a biomarker
and evaluated as indicator of normal biological have been proposed [13]:
processes, pathogenic processes, or pharmaco-
logical responses to a therapeutic intervention 1. Content validity, assessing how much the bio-
[6]. The International Programme on Chemical marker reflects the study outcome (e.g., orofa-
Safety, under the World Health Organization cial pain, pain intensity). This validity consists
(WHO), added that biomarkers are any sub- of the judgment by experts as to whether the
stance, structure, or process that can be mea- exploratory biomarker seems suitable for the
sured in the body, or its products and influence, intended purpose (e.g., diagnosis, classification,
or predict the incidence of outcome or disease surrogate of a risk factor, pain effectiveness).
[7]. Health Canada provided a specific defini- 2. Construct validity, evaluating the association
tion to genomic biomarker as any measurable between an exploratory biomarker and a spe-
characteristic that is an indicator of normal cific construct (e.g., hypothesis). This
biological processes, pathogenic processes, description can be explained with the example
and/or response to therapeutic or other inter- of studies assessing the hypothesis that indi-
ventions [8]. viduals with orofacial pain have higher levels
of oxidative stress than individuals without this
pain condition. Chapters 6, 7, 8, and 9 described
10.3 Biomarkers Classification numerous studies evaluating this validity.
3. Criterion validation, assessing how well the
Perera and Weinstein [9] classified biomarkers exploratory biomarker is in agreement with a
based on the disease pathway from the etiology specific criterion outcome. To assess this
to the prognosis. Therefore, biomarkers are clas- validity, it is necessary to identify the sensitiv-
sified as (1) antecedent biomarkers to assess the ity, the specificity, and the predictive value of
risk of a disease, (2) screening biomarkers, (3) the exploratory biomarker. [4]. A biomarker
diagnostic biomarkers, (4) staging biomarkers to must also be precise and reproducible [10].
10 Biomarkers inEpidemiologic Research: Definition, Classification, andImplication 137

Biomarkers may also be classified by pain these influence one another in a multivariable
mechanism. For example, Chaps. 6, 7, 8, and 9 analysis. For example, Rodrigues and colleagues
classify biomarkers based on (1) direct activation found higher levels of DNA damage, and lipid
of nociceptors (e.g., glutamate and protons), peroxidation biomarkers were independently
(2)inflammation (e.g., prostaglandins and cyto- related to painful TMD [17]. In addition, investi-
kines), and (3) cell metabolism (e.g., lactate and gators need to assess the best tissue or sample
pyruvate). Currently, none of the possible pain type from which to measure the biomarker: serum,
biomarkers may be classified as validated [14]. plasma, saliva, synovial fluid, or muscle biopsy.
The Rodrigues study [17] further found that DNA
damage and lipid peroxidation biomarkers col-
10.4 Biomarkers Development lected from saliva were more strongly related to
andAnalysis TMD than from serum.

The development of biomarkers depends on the


current knowledge of the biologic mechanism, 10.4.2 Study Population
the outcome, and the exploratory biomarker [15].
The analytical evaluation of the exploratory bio- A blinded investigator without knowledge of any
marker is primordial for success in the identifica- candidate biomarker should perform the recruit-
tion of a biomarker [10, 16]. ment of the study population based on specific
Wagner and Ball [16] describe the following eligibility criteria [18].
questions that should be addressed for a
biomarker:
10.4.3 Instrument toAssess
1. Is the biomarker measurement valid and reli- Exploratory Biomarker
able across instruments, laboratories, and
clinical settings? Valid and reliable instruments to assess explor-
2. Is the biomarker associated with the clinical atory biomarkers must be used to prevent or
endpoint of interest? decrease the chance of misclassification. For
3. What is the specific context of the proposed example, enzyme-linked immunosorbent assays
use? (ELISA) and flow cytometry such as Luminex
have been employed to identify possible pain
The following protocol may assist in advanc- biomarkers in serum, plasma, or saliva. Other
ing the discovery and validation of biomarkers: methods were described in Chaps. 6, 7, 8, and 9.

10.4.1 Rationale 10.4.4 Assessment ofExploratory


Biomarker
It is vital to describe and justify the rationale of
the evaluation of a specific biomarker [6]. We Each sample should be handled, processed, and
need to define the study outcome for which the stored consistently, as per the protocol, to prevent
assessed biomarker will be investigated (e.g., pain bias. A trained researcher should perform the
management, prediction of chronic pain, persis- assessment of the biomarker following the
tence of chronic pain). The rationale for the tested established standardized protocols. One relevant
biomarker should be based on scientific evidence. issue is the time of the sample collection. It is
As there is more than one mechanism and set of important to evaluate if there are considerable
characteristics associated with chronic orofacial variations in the levels and/or concentration of
pain, several biomarkers may be investigated. In possible biomarkers during the day. This is cru-
this case, investigators need to assess the crude cial since some exploratory biomarkers display
effect of each biomarker and then evaluate how this characteristic (e.g., cortisol [19], protein car-
138 A.M. Velly et al.

bonyls [20]). If this evaluation is not possible, the cess of inference at any stage that tends to produce
investigators need to standardize the ideal time results or conclusions that differ from the truth,
frame for sample collection (e.g., only mornings) leading to an incorrect estimate of the association
or to stratify the analysis based on the time when between a putative risk factor and a disease [24].
the sample was collected. All measurement This systematic error may occur when selecting the
assays should be conducted in duplicate or study population and/or collecting the information
triplicate. for the study (e.g., instruments to measure bio-
markers or pain). Confounding is a situation in
which a measure of the effect of an exposure on
10.4.5 Statistical Analysis risk is distorted because of the association of expo-
sure with other factors(s) that influence the out-
Appropriate statistical analyses need to be come under study [22]. For example, gender is a
applied, taking into consideration the study potential confounder in the studies assessing poten-
design, putative confounders, and/or effect modi- tial biomarkers of orofacial pain. External validity
fiers (e.g., age, sex, smoking status) (Chap. 11). of the results need also be appraised. External
validity is met if a study can produce unbiased
inferences regarding a target population [22].
10.4.6 Results It is relevant to recognize that biomarkers
identified should be constantly evaluated, since
The first clinical results should evaluate if the new studies may identify new mechanisms, new
exploratory biomarker is reliable and if it is associ- outcomes, and/or patient characteristics that may
ated with the study outcome [18]. It is important to explain the identified association [5].
understand that a candidate biomarker associated
with a condition (e.g., chronic orofacial pain) does
not obligatorily indicate that it is a cause or part 10.5 U
 se ofValid Biomarkers
of the pathophysiological pathway of the specific inClinical Studies
condition (see [5] for more information). Moreover,
it is important to evaluate not only if there is an The potential contributions of biomarkers are to:
association between the exploratory biomarker and
the study outcome but also the strength and direc- 1. Serve as a diagnostic, screening, or prognostic
tion of this association. It is also relevant to verify tool. It can decrease the chance of misclassifi-
other evidences of the relationship between the cation of orofacial pain classification.
exploratory biomarker and study outcome (e.g., 2. Assess the relationship between exposure and
pain intensity) and which other factors could mod- disease.
ify this association (e.g., sex, age). 3. Evaluate pain mechanisms.
We should assess the internal validity of the 4. Serve as surrogate of risk factors. It can

results [21] and its use in clinical practice [18]. decrease the chance of misclassification of the
Internal validity requires that the index and risk factor.
comparison groups be compared in such a man- 5. Assess the efficacy of pain management in
ner that the observed differences between them clinical trials, as well as dose-response
on the dependent variables under study may, relationships.
apart from sampling error, be attributed only to
the hypothesized effect under investigation [22].
In this process, it is necessary to evaluate if there Conclusion
are already other scientific evidences for the results Biomarkers may assist in improving the
obtained in the study [23], any relationship between screening and diagnosis of orofacial pain as
dose and response, and any bias or confounders well as its classification. They may also con-
that could have influenced the result. Bias is a pro- tribute to our understanding of disease patho-
10 Biomarkers inEpidemiologic Research: Definition, Classification, andImplication 139

genesis and their mechanisms, in addition to


12. US Food and Drug Administration. Guidance for
being used as endpoints for clinical trials industry pharmacogenomic data submissions. U.S.
Food&Drug.2016.http://google2.fda.gov/
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vention of chronic orofacial pain. l r = & p r o x y s t y l e s h e e t = F DA g ov & r e q u i r e d fi e
lds=-archive%3AYes&output=xml_no_dtd&getfields=*
13. Schulte PA, Perera FP.Validation. In: Schulte PAPF,
editor. Molecular epidemiology: principles and
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Statistical Analysis
intheIdentification ofPain
11
Biomarkers

RussellSteele

Abstract
The statistical analysis of data collected from orofacial pain biomarker
studies presents challenges that go far beyond what is typically encoun-
tered in standard epidemiological studies. In this complex scientific con-
text, it is critically important for researchers to properly identify the
scientific question of interest. This chapter primarily focuses on the dif-
ferentiation between finding predictive models for pain outcomes and
identifying causal relationships between biological markers, potential
treatments, and pain (typically measured by patient-reported instru-
ments). The chapter begins by defining the scientific context and identify-
ing two types of scientific questions. Next, I will introduce modern, but
computationally accessible, techniques for biomarker prediction to be
used when one wants simply to identify predictors of pain outcome.
Subsequently, I will contrast predictive methods with approaches that are
generally used to select causal models for quantifying the causal effects
of intervention on pain outcomes. I will introduce the two complementary
approaches that modern epidemiologists and statisticians use to assess
causal relationships. In the next section, I will discuss the complications
that result due to the fact that pain is a latent construct that can only nois-
ily be observed via self-reported instruments. The chapter will end with a
short overview of other statistical issues that often appear in the analysis
of pain data.

R. Steele, PhD 11.1 Introduction


Department of Mathematics and Statistics, McGill
University, Montral, QC, Canada The other chapters in this volume detail several
Centre for Clinical Epidemiology and Community scientific advances in orofacial pain research due
Studies, Jewish General Hospital, to recent advances in biomarker measurement
805 Sherbrooke Ouest, Montral,
H3A 2K6, QC, Canada
and understanding. However, these new scientific
e-mail: steele@mat.mcgill.ca developments in methods of data collection and

Springer-Verlag GmbH Germany 2017 141


J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI10.1007/978-3-662-53994-1_11
142 R. Steele

observation stretch the limits of classical 11.3 A


 xiom 1: TheTrue Model
statistical techniques to extract the greatest pos- That Generates theData Can
sible amount of information from the data Never BeCompletely
collected. Correctly Specified, Even
In this chapter, I will provide an overview of inthePresence ofLarge
how analyses of orofacial pain biomarker data Numbers ofMeasurements
could be conducted in a way to improve clinical
decision-making and to better inform future Axiom 1 holds in general for almost all statistical
decisions. The chapter begins by defining two problems, but recognizing this limitation is very
basic axioms that must be kept in mind during important in pain biomarker research. The biologi-
any statistical analysis. The next section focuses cal systems which cause a subject to experience
on the most critical aspect of the analysis, defini- pain (chronic or otherwise) are complex, and the
tion of the scientific question. Depending on more that is learned, the more complex the system
whether one wants to develop models for predic- descriptions become. It is infeasible to measure
tion or model for causal relationships, different every single aspect of the biological processes
statistical techniques will be appropriate. The underlying patient pain, so at some point there will
next section then details the approaches that are remain unmeasured aspects of the model that cant
generally used for determining appropriate be identified from the observed data alone.
causal models, with a particular focus on how to For example, Slade etal. [1] reported the anal-
properly choose which variables should be yses of levels of 22 cytokines taken from 344
included in the model. We then describe the patient blood serum samples in order to determine
advantages and disadvantages of various meth- associations of these biomarkers with three types
ods of statistical prediction for biomarker data of case status (healthy control and temporoman-
and provide a guide for researchers as to what dibular disorder with [TMD+WPT] and without
might be most appropriate for their problem. The [TMD-WPT] widespread palpation tenderness).
latency of the pain construct aspect is often In the paper, they present two kinds of analyses.
ignored in statistical analyses of pain data from In one analysis, they present multivariate logistic
studies. I will describe how this differentially regression coefficients for three cytokines (IL-8,
impacts analyses when pain is both used as a MCP-1, and IL-1ra) in a model where case status
covariate and when pain is the outcome that is (HC, TMD+WPT, TMD-WPT) is the response,
being measured. Finally, I will briefly discuss where they have also adjusted for age and sex (not
other issues that occur in the analysis of pain shown in the table). Obviously, this model is
data. insufficient for completely describing patient
pain. Rather, the model approximates the true
model that underlies the generation of the data. It
11.2 T
 wo Basic Axioms describes the association between case status and
forModeling Pain cytokine presence conditional on adjustments for
BiomarkerData age and gender. Implicitly, other patient charac-
teristics have been averaged over in the sample or,
The analysis of pain biomarker data is well suited more technically, marginalized in the analysis.
to the idea of a statistical model. In this context, I More particular to pain research, the pain a
will define a statistical model as the probability subject experiences is an inherently unmeasur-
model that defines how the observed data were able (or latent) characteristic. So in addition to
generated. The first key enabling idea for analyz- the previous challenge, pain can never be directly
ing pain data applies to any statistical modeling observed, only through measured surrogates,
problem. which are generally either patient-reported
11 Statistical Analysis intheIdentification ofPain Biomarkers 143

s urrogates or other patient physiological charac- different from the physiological measurements,
teristics (such as behavior or gait) thought to be leading to potentially conflicting interpretations
related to pain. For example, one might choose to of answers to the question: Which cytokines are
use pain instrument such as the McGill Pain associated with pain? The conflicting interpreta-
Questionnaire (MPQ) or the Short Form-36 (SF- tions result from the limitation to conclusions
36) bodily pain scale or perhaps a blood serum from the data regarding a different question, i.e.,
biomarker that has been associated with patient Which cytokines are associated with which
pain in the past. These surrogates will never per- measured surrogates for pain?
fectly correlate with the target pain characteristic
that the researcher is interested in, which again
leads to imprecision in the inference from the sta- 11.5 D
 efining theScientific
tistical model. Therefore, we can state a second Question
axiom of the analysis of pain data as:
The most critical step in any statistical analysis is
a clear definition of the scientific question of
11.4 A
 xiom 2: TheChoice interest. The stated goal of the analysis in Slade
ofSurrogate Measures etal. [1] was to elucidate the contributions of
forPatient Pain Will cytokines to TMD... and other related pheno-
Inevitably Determine types. The authors used standard methods, e.g.,
theScientific Questions That standard linear and multiple logistic regression,
One Can Ask oftheData to analyze their data and were properly careful in
their description of results as associations. I
The impact of the choice of pain surrogate mea- will use their problem to illustrate how modern
sures can often be lost in the interpretation of statistical methods would allow for one to go
pain data results. One possible explanation for beyond just description of associations, but only
conflicting results can be subtle differences in the by carefully stating the research question.
way that patient pain manifests itself differen-
tially in the surrogate measures. For example,
one may find that the most useful predictors of 11.5.1 The Basic Conundrum:
pain using the SF-36 pain scale will be different Prediction or Causation?
from those that predict the MPQ.This choice of
surrogate (or surrogates) for response can impact In introductory statistics education, students are
inference as much or more than the associations taught that regression approaches should be used
that one is trying to assess. to answer questions about prediction and causa-
Returning to Slade etal. [1] the first set of tion similarly and rarely is a distinction drawn. In
analyses use cytokine protein levels as the out- many situations, e.g., in the analysis of clinical tri-
come and case status (control vs. two TMD dis- als, the two kinds of questions produce somewhat
ease groups) as the exposure of interest. However, similar answers. However, although the two axi-
the second set of analyses examines the associa- oms of the last section may seem overly formal,
tions between the cytokine levels and 16 interme- they are critically important for addressing the
diate pain phenotypes, some of which are basic premise of the statistical investigation. We
patient-reported questionnaires (MPQ, SF-12v2) must accept that our models are limited in their
and others are physiological measurements ability to accurately reflect reality, and we also
(quantitative sensory testing). The observed must accept that the surrogates that can be
values and statistical significance of associations measured directly define the statistical reality.

of cytokines with the patient questionnaires are Therefore, our statistical models do not predict
144 R. Steele

patient pain; they predict patient responses to pain the association of circulating cytokine protein
questionnaire items. Our models do not describe levels with case status (TMD-WPT, TMD+WPT,
the exact causal relationships of biomarkers with and control). One could frame the objective of
pain, but instead describe the casual relationship the analysis as one of prediction, i.e., to try to
of biomarkers with pain surrogates, marginalizing predict the case status of the individual on the
over other aspects of the patient that are known to basis of a particular cytokine profile. The inter-
be important for determining pain levels. Such esting clinical question could be to try to build a
distinctions may seem pedantic, but understand- clinical model, which distinguishes TMD WPT-
ing the distinction can help researchers decide positive patients from TMD WPT-negative
which methods should be used. patients. In contrast, one could argue that the
In a 2001 paper, Breiman [2] outlines the two interest lies in identifying the causal mecha-
broad classes of statistical analyses. Although nisms, which underlie widespread palpitation
much of the paper and discussion focus on the tenderness in TMD patients. Both questions are
relative importance of the two classes, generally equally valid and interesting, but the methods
statisticians agree that they are focused on differ- that would be appropriate will differ in both
ent objectives. In one class of statistical analysis, cases. The next two sections will outline the dif-
one assumes an underlying model that generates ferences and give recommendations for analysis.
the data and the focus of estimation and inference
is to estimate and interpret aspects of that model.
In the second class, the actual underlying data- 11.6 I dentifying Causal Data-
generating model is not relevant for decision- Generating Models
making and the focus is instead on prediction.
Neither class should be generally preferred to The notion that correlation does not equal cau-
the other without considering the objective of the sation has gone far beyond statisticians and per-
analysis. If the important scientific question requires meated popular culture. However, asking
knowledge of the underlying data model (or some questions about causal data-generating models
aspect of the model), then it follows that statistical from observational data requires subtle and
methods should be used that can allow one to obtain sometimes nonintuitive choices for researchers.
that knowledge. However, if one is merely inter- It is well understood in epidemiology that stan-
ested in prediction and is content to allow for the dard measures of observed association (e.g.,
data-generating model to be unknown, one can t-statistics, regression coefficients, odds ratios)
choose statistical methods that, by their design, pro- cannot automatically be interpreted as indicating
vide little to no information about how the data a direct causal relationship between two variables
came to be. One way to view this distinction is that due to the possibility of confounding. In its most
requiring knowledge of the data-generating model basic form, we say that an observed association
places a constraint of the kinds of methods that between two variables is confounded if there is at
could be used. In a setting where prediction is the least one common cause of both variables that
primary goal, there is no such constraint and poten- makes the observed association noncausal.
tially better methods for prediction could be found For example, if patient anxiety increases the
outside of the previously restricted class. levels of certain biomarkers and also increases
the values to responses on a pain questionnaire,
we may observe an association in the data
11.5.2 Specifying theQuestion between the biomarkers and pain that is not
forPain Biomarker Research causal. An increase in biomarker level would be
associated with an increase in reported pain, but
I return once again to the Slade etal. [1] analyses changing the levels of the biomarker would not
to illustrate the difference in motivation of the necessarily have an effect on the reported pain, as
analyses. In Sect. 3.2 of the paper, they discuss anxiety provides the real causal mechanism for
11 Statistical Analysis intheIdentification ofPain Biomarkers 145

reported pain. The complexity of the general than repeat the material contained in the other two
problem depends on the data collected, so we papers, this chapter discusses some basic con-
will divide our discussion into two kinds of data cepts that differentiate constructing DAGs for
collection: cross-sectional and longitudinal. biomarker pain research from other clinical areas.

11.6.1 Causal Models forCross-


Sectional Data References
1. Slade GD, Conrad MS, Diatchenko L, Rashid NU,
One way to visualize the relationships among Zhong S, Smith S, etal. Cytokine biomarkers and
covariate and outcome measurements is through chronic pain: association of genes, transcription, and
the use of a directed acyclic graph (or DAG). circulating proteins with temporomandibular disor-
Although DAGs cannot represent all aspects of a ders and widespread palpation tenderness. Pain.
2011;152(12):280212. doi:10.1016/j.pain.2011.09.005.
statistical model [3, 4], they do provide research- 2. Breiman L.Statistical modeling: the two cultures. Stat
ers with a visual tool for organizing their hypoth- Sci. 2001;16(3):199231. doi:10.1214/ss/1009213726.
eses regarding the causal structure of their model 3. Rubin DB.The design versus the analysis of observa-
and their observed and unobserved quantities. tional studies for causal effects: parallels with the
design of randomized trials. Stat Med. 2007;26(1):20
Hernan etal. [5] provide a tutorial on the use of 36. doi:10.1002/sim.2739.
DAGs and their interpretation intended for clini- 4. Richardson TS, Robins JM.Single World
cal researchers. Shrier and Platt [6] describe a Intervention Graphs (SWIGs): A Unification of the
simple six-step process by which one can iden- Counterfactual and Graphical Approaches to
Causality. Working Paper Number 128. Center for
tify the most important potential confounders in Statistics and the Social Sciences. Washington:
an analysis. University of Washington; 2013.
Researchers collecting pain data would most 5. Hernan MA, Hernandez-Diaz S, Werler MM, Mitchell
benefit from following the instructions in Hernan AA.Causal knowledge as a prerequisite for con-
founding evaluation: an application to birth defects
etal. [5] and Shrier and Platt [6] at the study epidemiology. Am JEpidemiol. 2002;155(2):
design stage, which would allow them to priori- 17684.
tize resources to measuring confounders and min- 6. Shrier I, Platt RW.Reducing bias through directed
imize resources allocated to the variables that will acyclic graphs. BMC Med Res Methodol. 2008;8:70.
doi:10.1186/1471-2288-8-70.
not confound the causal effect of interest. Rather
Future Direction andConclusion
12
Jean-PaulGoulet andAnaMiriamVelly

Our understanding of many aspects of chronic The main alleged difference among the most
pain and more specifically of trigeminal pain has common chronic orofacial pain conditions is that
advanced substantially over the past 25 years (see the predominant symptoms and physical mani-
Chap. 3). Among others are the processing of festations arise from distinct anatomical location
afferent inputs along the trigeminal path and at and target organs [2, 3]. For example, the masti-
the brainstem trigeminal sensory complex, the catory muscles, temporomandibular joints, den-
peripheral as well as central mechanisms involved toalveolar process, tongue, and branches of the
in sensitization that can contribute to the transi- trigeminal nerve are all different structures or
tion from acute to chronic pain, and the role systems involved that push patients to seek care.
played by non-neuronal cells and genetic and When we dismiss the body region and target
environmental factors. These progresses in our organ to focus on similarities, the most common
understanding of chronic pain also apply to chronic pain conditions share a number of impor-
chronic orofacial pain conditions even though tant features. For one, clinical examination find-
physiologic studies on trigeminal pain point to ings are less deviant than expected considering
several unique characteristics compared with the the number and extent of reported symptoms and
spinal nociceptive system in terms of differences associated suffering. In addition, the presence of
in response patterns to tissue injury [1]. Despite comorbid conditions is more the norm than the
the accumulation of new knowledge and insights exception, and most notably the etiology and
into orofacial pain mechanisms, the advancement pathogenesis of the pain remain unclear or at best
in management strategies has not kept the pace. speculative. This should make us wonder if we
That is reflected by the lack of significant changes are really dealing with conditions that are unre-
seen in the treatment response for most chronic lated and pain mechanisms that need different
orofacial pain conditions over the past decade. treatment strategies.
As new findings in orofacial pain unfold, our
operationalized concept of chronic orofacial pain
based on specific end organs is more than ever
J.-P. Goulet, DDS, MSD, FRCD (*) challenged [4]. At least for TMDs that feature
Faculty of Dental Medicine, Universit Laval, persistent pain in the absence of organic sub-
2420 Rue de la Terrasse, G1V 0A6, QC, Qubec,
strate, the target organ identified as the source of
Canada
e-mail: jean-paul.goulet@fmd.ulaval.ca the pain might not be where all the answers lie.
While the view that peripheral inputs play a
A.M. Velly, DDS, MSc, PhD
Faculty of Dentistry, McGill University, major role in chronic pain state and ongoing
Montral, QC, Canada pathological processes occur within the end

Springer-Verlag GmbH Germany 2017 147


J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI10.1007/978-3-662-53994-1_12
148 J.-P. Goulet and A.M. Velly

organ is frequently emphasized, the evidence As pointed out in Chap. 8 (Seltzer and Diehl),
remains equivocal for the cluster of chronic oro- a number of genes harboring single nucleotide
facial pain disorders that are commonly seen in polymorphisms (SNPs) can alter regulatory
clinic and more specifically for joint (arthralgia) mechanisms of neurotransmitters involved in
and muscle pain (myalgia and its subtypes) processing nociceptive input and contribute to
related to TMD. the onset or put subjects at risk of developing
Recent studies have greatly advanced our chronic orofacial pain. Of particular interest is
understanding of biomarkers in orofacial pain, the catecholamine-O-methyltransferase (COMT)
and so far, some putative biomarkers have been gene located on chromosome 22 that encodes the
identified. The overview on masticatory muscle enzyme COMT responsible for the inactivation
pain biomarkers in Chap. 6 indicates that and catabolism of neurotransmitters such as
glutamate and serotonin are implicated in jaw dopamine and norepinephrine and the HTR2A
myalgia, although the exact pathological process gene that encodes one of the serotonin receptors
is yet to be elucidated. Chapter 7 on molecular (5-hydroxytryptamine receptor 2A). Dopamine
temporomandibular joint biomarkers underscores and 5-hydroxytryptamine (5-HT) are neurotrans-
that a number of peripheral pain mediators are mitters involved, respectively, in pain perception
indeed elevated in the synovial fluid of TMJ and pain transmission. Altered dopaminergic
arthritis patients with joint pain on mandibular neurotransmission in the central nervous system
movements. Significant correlation is reported has been reported in patients with burning mouth
for higher level of tumor necrosis factor, interleu- syndrome (BMS) and persistent idiopathic face
kin 6, serotonin, and prostaglandin E2. Synovial pain (PIFP) [8, 9]. Moreover, patients with
fluid of arthritic TMJ with high level of chronic masticatory muscle pain have elevated
interleukin-1 is associated with resting joint interstitial concentrations of 5-HT compared to
pain and tenderness to palpation. In addition, healthy controls, and 5-HT levels are correlated
interleukin 6 is more frequently found in synovial with muscle pain and allodynia [10, 11]. More
fluid of patients with TMJ pain associated with recently it has been shown that plasma dopamine
cartilage destruction. These potential biomarkers level was elevated in muscle pain-related TMD
are therefore good candidates for distinguishing and correlated with present pain intensity and
TMJ arthritis from TMJ arthralgia, knowing that perceived mental stress [12].
this distinction impacts on treatment decision and What is emphasized and discussed in Chap. 2
prognosis. about the presence of other painful and non-
Arthralgia with masticatory muscle myalgia painful comorbid symptoms that coexist with a
and its different subtypes are the most common chronic orofacial pain condition is the norm rather
TMDs featuring persistent pain in the absence of than the exception. Other comorbid pain disorders
organic substrate. There is accumulating evi- such as fibromyalgia, low back pain, and irritable
dence that these conditions can be defined and bowel syndrome show similar patterns of clinical
understood through the appraisal of other painful manifestations. This substantial overlap of physi-
symptoms and psychosocial factors as well cal symptoms related and unrelated to the end-
(Chap. 2). This would be in line with the pro- organ conditions among different comorbid pain
posed hypotheses that biopsychosocial risk fac- disorders raises the possibility of a common
tors are appropriate predictors of distinct clusters underlying substrate that needs full attention.
of people with pain-related TMD in the absence Thus, it is legitimate to consider unexplained
of end-organ pathobiological substrate and that chronic orofacial pain conditions as potential
some manifestations result from the interplay of manifestations of general central nervous system
central and peripheral nociceptive mechanisms dysregulation [7, 13]. Knowing the temporal rela-
influenced by genes that regulate biological sys- tionship of these different clinical manifestations
tems relevant to pain perception [57]. could uncover whether nonspecific symptoms
12 Future Direction andConclusion 149

that occur frequently strongly influence and pre- psychosocial factors, represent a serious barrier
dict the onset of pain-related TMD [14]. The com- to the future identification of meaningful orofa-
bined effect of genetic determinants and cial pain biomarkers. Revisiting the conceptual
gene-environment interaction with psychosocial framework of unexplained chronic orofacial pain
stress could represent a pathway giving rise not disorders, and searching for biomarkers of auto-
only to pain-related TMD but also to other chronic nomically mediated dysregulation as a generator
orofacial pain conditions such as burning mouth of nonspecific symptoms in an apparent end-
syndrome (BMS) and persistent idiopathic face organ disorder, may provide answers regarding
pain (PIFP) that are unexplained by pathological the natural history and the possibility of a
processes involving the peripheral end organs. common underlying substrate shared by the most
This is conceivable as evidenced by data pre- common disorders. Therefore, it is crucial to
sented in Chap. 5 on neurophysiologic markers identify a series of biomarkers indicative of diag-
of orofacial pain attributed to a dysregulation or nosis, classification, pain mechanism, prognosis,
dysfunction of the trigeminal sensory system. and orofacial pain management (Chap. 10).
Thermal hypoesthesia, a feature of small fiber
system hypofunction as well as increased excit-
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Index

A exploratory type
Algesic biomarkers, 80 assessment of, 137138
American Academy of Craniofacial Pain (AACP), 12 definition, 136
American Academy of Orofacial Pain (AAOP), 8, 12 instrument to assess, 137
Atypical facial pain. See Persistent idiopathic facial pain masticatory muscle pain (see Masticatory muscle
(PIFP) pain biomarkers)
Atypical odontalgia (AO), 15 validation criteria, 136
Blink reflex (BR)
components, 67
B sensitivity, 68
Back pain, 25 Blood serum, 120, 125
Biofluids Bradykinin, 83
blood serum, 120 Burning mouth syndrome (BMS)
comparative analysis biomarker research, 1516
collection and evaluation, 125 POPDs, 114115
diurnal variation, 126
saliva vs. serum, 124125
synovial fluid vs. serum and saliva, 125 C
definition, 120 Candidate biomarkers, 2527
in disease detection Catecholamine-O-methyltransferase (COMT)
biomarkers availability, 123124 neurotransmitters, 148
collection, 123 POPDs, 108110
saliva, 122 Causal data-generating models
synovial fluid, 120121 confounding, 144
Biomarkers cross-sectional data, 145
algesic, 80 patient anxiety, 144
candidate, 2527 Chronic masticatory muscle pain, 81. See also Myalgia
classification by Chronic orofacial pain
disease pathway, 136 IASP definition, 6
pain mechanism, 137 neurobiological mechanism (see Neurobiological
contributions of, 138 mechanism)
cytokines as (see Cytokines) Comorbidity, orofacial pain
definition, 136 candidate biomarkers, 2527
development and analysis clinical implications, 2728
clinical results, 138 definition, 21
confounding, 138 epidemiology, 22
exploratory biomarker, 137138 FM, 22, 25
external validity, 138 headache, 22
internal validity, 138 neck and back pain, 25
rationale of, 137 odds ratio and confidence intervals, 2324
statistical analysis, 138 psychological factors, 25
study population, 137 visceral comorbid pain conditions, 25
DNA methylation, 127 widespread pain, 22, 25

Springer-Verlag GmbH Germany 2017 151


J.-P. Goulet, A.M. Velly (eds.), Orofacial Pain Biomarkers, DOI10.1007/978-3-662-53994-1
152 Index

Corneal reflex (CR), 67 spinal nociceptive processing, 48


Cortex, top-down modulation transcutaneous electrical nerve stimulation (TENS),
corticofugal modulation 4950
cervicomedullary trigeminovascular neurons, 52, trigeminal nucleus caudalis (Sp5C) neurons, 48
54 Erythromelalgia, 115
cortical plasticity, 52
corticothalamic feedback, 55
repetitive transcranial magnetic stimulation, 55 F
task-related responses, 52 Fibromyalgia syndrome (FM), 22, 25
corticotrigeminal modulation and migraine, 5556
descending networks, 52, 53
hypothalamic regulation, 56 G
trigeminovascular modulation Glutamate
attack generators, 58 jaw myalgia, 82
GABAA-mediated responses, 58 TMJ pain, 101102
PVN, 5658
salivatory nucleus (SSN), 57
Cortical spreading depression (CSD), 5556 H
Corticofugal modulation, 5255 Headache, 22
Corticotrigeminal modulation and migraine, 5556 5-Hydroxytryptamine (5-HT). See Serotonin
Counter-stimulation-induced analgesia, 5051 Hypothalamic regulation, 56
Cytokines
jaw myalgia, 84
receptors, 102 I
TMJ pain Inflammatory mediators, 80
anti-inflammatory cytokines, 96 Inflammatory pain, 5
clinical biomarkers, 97101 International Association for the Study of Pain (IASP)
peripheral cytokine modulation, 9697 classification structure, 10
role of, 96 PIFP, 17
International Headache Society (IHS), with its
classification of headache disorders
D (ICHD-3)
Descending modulation, pain classification structure, 10, 11
cortex PIFP, 17
corticofugal modulation, 5255
corticotrigeminal modulation and migraine, 5556
hypothalamic regulation, 56 J
trigeminovascular modulation, 5658 Jaw jerk reflex (JJR), 67
DNIC and counter-stimulation-induced analgesia, Jaw myalgia
5051 bradykinin, 83
RVM, 51 cytokines, 84
Diagnostic Criteria for Temporomandibular Disorders eicosanoids, 84
(DC/TMD) glutamate, 82
arthralgia, 14, 15 lactate, 8485
masticatory muscle pain biomarkers, 80 nerve growth factor (NGF), 83
myalgia, 14, 15 neuropeptides, 8384
Diffuse noxious inhibitory controls (DNIC) pyruvate, 8485
counter-stimulation-induced analgesia, 5051 serotonin, 8283
supraspinal structures, 50 TRPV1, 83
Directed acyclic graph (DAG), 145
Diurnal variation, 126
DNA methylation biomarkers, 127 L
Dysfunctional pain, 6 Lactate, 8485
Low-threshold mechanosensitive (LTM) neurons, 38

E
Eicosanoids, 84 M
Endogenous modulation mechanism Maladaptive pain
A and A non-nociceptive fibers, 4849 role of, 5
protein kinase C gamma, (PKC), 49 types, 67
Index 153

Masseter inhibitory reflex (MIR), 67 N


Masticatory muscle pain biomarkers Neck pain, 25
algesic biomarkers, 80 Nerve growth factor (NGF), 83
DC/TMD, 80 Neurobiological mechanism
in experimental myalgia, 88 central processes
inflammatory mediators, 80 central sensitization, 42
intramuscular injection, 8586 clinical relevance, 4344
jaw myalgia CNS, 42, 43
bradykinin, 83 QST, 44
cytokines, 84 TMD, 44
eicosanoids, 84 diagnostic and management challenges, 35
glutamate, 82 nociceptive pathways
lactate, 8485 central pathways, 3840
nerve growth factor (NGF), 83 peripheral processes, 3638
neuropeptides, 8384 pain, definition of, 35
pyruvate, 8485 peripheral processes, 4142
serotonin, 8283 Neuropathic pain, 5
TRPV1, 83 Neuropeptides, 8384
pathophysiology, 8182 Neurophysiologic markers
sampling and analyzing methods of altered excitability, 7475
limitation, 81 diagnosis of, 6667
microbiopsy, 80 large fiber system
microdialysis, 8081 blink reflex, 67
tissue levels corneal reflex, 67
after exercise, 8788 jaw jerk reflex, 67
leukotriene B4 (LTB4), 87 masseter inhibitory reflex, 67
muscle glutamate, 86 transcranial magnetic stimulation, 7071
PGE2, 87 trigeminal A afferent fibers, 70
serotonin, 8687 small fiber system, 7172
tissue metabolites, 80 Neurotransmitters, 148
McGill Pain Questionnaire (MPQ), 143 Neurovascular pain, 6
Methylomics, 127 Nociceptive pain, 5
Molecular temporomandibular joint Nociceptive pathways
pain biomarkers central pathways
arthritis, 95 central sensitization, 40
cytokines low-threshold mechanosensitive neurons, 38
clinical biomarkers, 97101 modulatory processes and influences, 3940
peripheral modulation, 9697 N-methyl-D-aspartate, 38
role of, 96 nociceptive-specific neurons, 3839
glutamate, 101102 orofacial thermosensation, 38
prostaglandin E2, 101 subnucleus caudalis and spinal dorsal horn, 39
serotonin, 101 wide dynamic range neurons, 3839
treatment peripheral processes
cytokine receptors, 102 allodynia, 37
serotonin antagonists, 102 -amino butyric acid, 37
Myalgia hyperalgesia, 37
arthralgia with masticatory muscle, 148 mechanoreceptors, 36
DC/TMD, 14, 15 neurogenic inflammation, 37
experimental, 88 peripheral sensitization, 36
jaw specialized/corpuscular receptors, 36
bradykinin, 83 Nociceptive-specific (NS) neurons, 3839
cytokines, 84
eicosanoids, 84
glutamate, 82 O
lactate, 8485 Operational classification systems
nerve growth factor, 83 classification structure
neuropeptides, 8384 AACP, 12
pyruvate, 8485 AAOP, 12
serotonin, 8283 IASP, 10
TRPV1, 83 ICHD-3, 11
154 Index

Operational classification systems (cont.) Q


cluster analysis, 910 Quantitative sensory testing (QST)
diagnostic criteria, 910 central processes, 44
RDC/TMD, 11 diagnosis, 66
Orofacial thermosensation, 38 limitation, 73
pain measures, 74
trigeminal nerve injury, 73
P
Paraventricular hypothalamic nucleus (PVN)
attack generators, 58 R
role of, 56 Rostral ventromedial medulla (RVM ), 51
superior salivatory nucleus, 57
transmembrane anion transporter KCC2, 58
Paroxysmal extreme pain disorder (PEPD), 115 S
Persistent dentoalveolar pain disorder (PDAP), 15 Saliva, 122
Persistent idiopathic facial pain (PIFP), 17 SCN9A, 115
Persistent orofacial pain disorders (POPDs) Segmental modulation
BMS, 114115 A and A non-nociceptive fibers, 4849
genetic variants, 107108 protein kinase C gamma, 49
PEPD, 115 spinal nociceptive processing, 48
TMD transcutaneous electrical nerve stimulation, 4950
average pain sensitivity, 109 trigeminal nucleus caudalis neurons, 48
COMT haplotypes, 108110 Serotonin
ER (encoding estrogen receptor alpha), 110111 antagonists, 102
folate, 111 jaw myalgia, 8283
high pain sensitivity, 109 masticatory muscle pain, 148
HTR2A, 110 tissue levels, 8687
low pain sensitivity, 109 TMJ pain biomarkers, 101
prevalence of, 108 Serum metabolome database, 120, 121
SLC6A4, 110 Short Form-36 (SF-36), 143
SNP, 109 Sjgrens syndrome
TN comparative analysis, 126
analgesic effects, 114 saliva sample collection, 123
electrogenic properties, 113 Statistical model, orofacial pain biomarker
genome-wide approach, 113 causal data-generating models
incidence, 112 confounding, 144
neurovascular compression, 112 cross-sectional data, 145
SNPs, 113114 patient anxiety, 144
voltage-gated sodium channel types, 113 definition, 142
TPHN McGill Pain Questionnaire (MPQ), 143
APOE gene, 112 multivariate logistic regression coefficients, 142
genetic polymorphisms, 111 scientific question, definition of
pain symptoms, 111 pain biomarker research, 144
TNFA gene, 111 prediction/causation, 143144
varicella-zoster virus, 111112 Short Form-36, 143
Probable biomarker, 136 surrogate measures, 143
Prostaglandin E2 (PGE2), 101 Synovial fluid, 120121
Psychophysical markers
quantitative sensory testing
limitation, 73 T
pain measures, 74 Temporomandibular disorders (TMDs)
trigeminal nerve injury, 73 arthralgia with masticatory muscle myalgia, 148
tactile and innocuous thermal detection thresholds, 72 biofluids
thermal hypoesthesia, 72 blood serum, 120
thermode size, 73 comparative analysis, 124126
Pyruvate, 8485 definition, 120
Index 155

in disease detection, 123124 Tissue metabolites, 80


saliva, 122 Trigeminal A afferent fibers (TSEP), 70
synovial fluid, 120121 Trigeminal autonomic cephalalgias (TACs), 56
central process, neurobiological mechanism, 44 Trigeminal nerve injury, 73
clinical manifestations, 148 Trigeminal neuralgia (TN)
diagnosis, 119120 analgesic effects, 114
epidemiology, 22 electrogenic properties, 113
FM, 22, 25 genome-wide approach, 113
headache, 22 incidence, 112
methylomics, 127 neurovascular compression, 112
neck and back pain, 25 SNPs, 113114
odds ratio and confidence intervals, 2324 voltage-gated sodium channel types, 113
orofacial disorders and biomarkers, 126, 127 Trigeminal postherpetic neuralgia (TPHN)
POPDs APOE gene, 112
average pain sensitivity, 109 genetic polymorphisms, 111
COMT haplotypes, 108110 pain symptoms, 111
ER (encoding estrogen receptor alpha), 110111 TNFA gene, 111
folate, 111 varicella-zoster virus, 111112
high pain sensitivity, 109 Trigeminovascular modulation
HTR2A, 110 attack generators, 58
low pain sensitivity, 109 GABAA-mediated responses, 58
prevalence of, 108 PVN, 5658
SLC6A4, 110 superior salivatory nucleus (SSN), 5758
SNP, 109 TRPV1, 83
psychological factors, 25
TGF-beta signaling, 128
visceral comorbid pain conditions, 25 W
widespread pain, 22, 25 Whiplash-associated disorders (WAD), 8788
Temporomandibular joint arthralgia, 1415 Wide dynamic range (WDR) neurons
Temporomandibular myalgia, 1314 nociceptive pathways, 3839
Thermal hypoesthesia, 72 Sp5C, 48