Canadian Journal of Pain

Revue canadienne de la douleur

ISSN: (Print) 2474-0527 (Online) Journal homepage: https://www.tandfonline.com/loi/ucjp20

Biomarkers in Temporomandibular Disorder and

Trigeminal Neuralgia: A Conceptual Framework for
Understanding Chronic Pain

Tina L. Doshi, Donald R. Nixdorf, Claudia M. Campbell & Srinivasa N. Raja

To cite this article: Tina L. Doshi, Donald R. Nixdorf, Claudia M. Campbell & Srinivasa
N. Raja (2020): Biomarkers in Temporomandibular Disorder and Trigeminal Neuralgia: A
Conceptual Framework for Understanding Chronic Pain, Canadian Journal of Pain, DOI:
10.1080/24740527.2019.1709163

To link to this article: https://doi.org/10.1080/24740527.2019.1709163

© 2019 The Author(s). Published with

license by Taylor & Francis Group, LLC.

Accepted author version posted online: 03

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Publisher: Taylor & Francis & The Author(s). Published with license by Taylor &
Francis Group, LLC.

Journal: Canadian Journal of Pain

DOI: 10.1080/24740527.2019.1709163

Biomarkers in Temporomandibular Disorder and Trigeminal

Neuralgia: A Conceptual Framework for Understanding Chronic Pain

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Tina L. Doshia*, Donald R. Nixdorfb, Claudia M. Campbellc, and Srinivasa

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N. Rajaa

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a
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University,

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Baltimore, MD, USAbDepartment of Diagnostic and Biological Sciences, University of
Minnesota School of Dentistry, Minneapolis, MN, USA
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c
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University,
Baltimore, MD, USA
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550 N. Broadway, Suite 301A

Baltimore, MD 21205
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E-mail: [email protected]
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Disclosures: This work was not supported by any grants. Dr. Doshi is supported by a
research grant from the Foundation for Anesthesia Education and Research. Dr.
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Campbell consults for PainCare and Adynxx, Inc. Dr. Raja has received research grants
from Medtronic Inc., and has served as an advisory board member for Aptinyx and
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Lexicon Pharma.

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Biomarkers in Temporomandibular Disorder and Trigeminal
Neuralgia: A Conceptual Framework for Understanding Chronic Pain

In this review, we will explore the use of biomarkers in chronic pain, using the
examples of two prototypical facial pain conditions: trigeminal neuralgia and
temporomandibular disorder. We will discuss the main categories of biomarkers
and identify various genetic/genomic, molecular, neuroradiological, and
psychophysical biomarkers in both facial pain conditions, using them to compare

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and contrast features of neuropathic, non-neuropathic, and mixed pain. By using
two distinct model facial pain conditions to explore pain biomarkers, we aim to

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familiarize readers with different types of biomarkers currently being studied in
chronic pain, and explore how these biomarkers may be used to develop new

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precision medicine approaches to pain diagnosis, prognosis, and management.

Keywords: facial pain; trigeminal neuralgia; temporomandibular disorder;

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biomarkers; chronic pain; precision medicine

The spectrum of facial pain

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Facial pain encompasses a broad range of disorders, often presenting significant

diagnostic and therapeutic challenges to healthcare professionals. The estimated lifetime

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prevalence of facial pain is 26%,1 but misdiagnosis and delayed or ineffective treatment

of facial pain are exceedingly common. Patients suffering from facial pain may seek
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consultation from a wide array of specialists, such as dentistry, neurology,

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otolaryngology, ophthalmology, dermatology, neurosurgery, plastic surgery, oral

surgery, pain medicine, sleep medicine, rehabilitation medicine, psychology, psychiatry,

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physical therapy, and primary care. However, around the world, many of these

professionals have little formal training or experience in managing pain—particularly

chronic facial pain.2–6 Furthermore, a single facial pain condition can present itself in

multiple ways. Features common in one facial pain condition can occasionally present

in another, and multiple facial pain conditions may appear in a single patient. Such

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difficulties in the precise diagnosis and treatment of facial pain can be agonizing, both

for the patient and for the clinician, and are illustrative of the challenges of treating

chronic pain in general.

The broad spectrum of facial pain disorders is exemplified in two prototypical

conditions: temporomandibular disorders (TMD) and trigeminal neuralgia (TN). TMD

includes a common group of musculoskeletal and neuromuscular conditions that present

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as pain or dysfunction related to the temporomandibular joint(s), the muscles of

mastication, and/or the associated tissues.7 TN is a less common neuropathic pain

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condition affecting the fifth cranial (trigeminal) nerve. TMD pain encompasses not one

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pain disorder, but several conditions associated with temporomandibular dysfunction,

and may include difficulties with chewing, speaking, and other orofacial functions.7,8
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According to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD),

history must be positive for “pain in the jaw, temple, in the ear, or in front of the ear,”
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and “must be modified with jaw movement, function, or parafunction.”8 The specific
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diagnosis of pain-related TMD, such as myalgia, myofascial pain, or arthralgia, depends

on physical examination of the patient.8 Patient-reported location and examiner

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provocation of the pain are therefore key components in the diagnosis of TMD pain. By

contrast, the diagnosis of TN relies heavily on patient description of symptoms.

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Diagnostic criteria for TN vary slightly across the different guidelines commonly used,
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but generally define TN as severe, unilateral, paroxysmal pain in the trigeminal

distribution that is precipitated by innocuous stimuli.9–11 Pain may come and go in an

unpredictable fashion, and sensory examination is often normal.10,11

Although the underlying pathologies of TMD and TN are distinct, both

conditions are clinical diagnoses, and it is not uncommon to misdiagnose one as the

other. Both conditions cause facial pain that is often intermittent (but sometimes

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continuous), usually unilateral (but sometimes bilateral), and frequently precipitated or

exacerbated by touch, talking or eating (but sometimes by nothing at all). TMD pain

tends to be described as dull, aching, and may radiate to the ears, temporal, periorbital,

mandibular, and posterior neck regions.12 In contrast, TN is reported as lancinating,

electric, and shooting in the distribution of the trigeminal nerve.13 However, symptoms

in both conditions can be variable and may change over time.14 It is increasingly

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recognized that a high proportion of patients with TMD and headaches suffer

simultaneously from multiple other pain conditions, and the term “chronic overlapping

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pain conditions” has been introduced to suggest possible shared etiology and disease

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mechanisms.15 By contrast, TN is limited to the trigeminal nerve, and while other pain

conditions may also occur concurrently, it is not as common as in TMD. In addition,

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the prognosis of TMD pain is fairly good, with only 5-10% of those with symptoms

requiring treatment and a spontaneous resolution rate of up to 40%,12 whereas TN can

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be unpredictable, with periods of remission and recurrence lasting weeks to years over

the course of a lifetime.13

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The subjective nature of pain, combined with the evolving, overlapping, and
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often complex features of both types of pain, highlight the need for objective markers of

chronic pain. Such biological markers, or biomarkers, can aid in the correct diagnosis,
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treatment selection, and prognosis of chronic pain disorders. In this review, we will
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familiarize the reader with potential biomarkers in TMD and TN It is not intended to be

comprehensive list of all biomarkers in facial pain. (For a more in-depth exploration of

this topic, we recommend an excellent textbook from Goulet et al.16) Through the two

distinct, prototypical facial pain disorders of TMD and TN, we are provided with a

useful context in which to understand the promise and pitfalls of biomarkers in chronic

pain.

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The role of biomarkers in chronic pain
The hunt for biomarkers in chronic pain has intensified in recent years, as

interest has grown in personalized/precision medicine techniques, and the global opioid

crisis has underscored the need to accelerate the pace of pain research. In late 2018, the

US National Institutes of Health (NIH) and National Institute of Neurological Disorders

and Stroke (NINDS) convened a workshop of international experts in pain research to

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recommend best practices in pain biomarker discovery and validation, which “would

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help to define pathophysiologic subsets of pain, evaluate target engagement of new

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drugs, and predict analgesic efficacy of new drugs.”17 Their published

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recommendations are forthcoming, but despite the group’s extensive discussions and

enthusiasm for promising avenues of research, there remain no objective, measurable

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biomarkers for the detection and quantification pain. State-of-the-art in pain

management, particularly in facial pain management, continues to rely on patient self-

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report, clinical diagnosis, and clinical decision-making.

The term “biomarker” is often misinterpreted as any variable that can be

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quantified and applied to characterize a disease state. However, demographic data,

patient-reported outcome measures, and environmental exposures are not biomarkers,

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since they do not accurately and reliably correspond to an individual’s health. In 2001,
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the World Health Organization (WHO) defined a biomarker as “any substance, structure

or process that can be measured in the body or its products, and influence or predict the
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incidence or outcome of disease”.18 The BEST (Biomarkers, EndpointS, and other

Tools) Resource developed as a joint effort between the US Food and Drug

Administration (FDA) and the US National Institutes of Health (NIH) defines a

biomarker as “a defined characteristic that is measured as an indicator of normal

biological processes, pathogenic processes, or responses to an exposure or intervention,

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including therapeutic interventions… not an assessment of how an individual feels,

functions, or survives.”19 BEST also classifies biomarkers into several categories, and

they may be detected anywhere along the trajectory of the disease or its management

(Figure 1). Susceptibility/risk biomarkers portend the onset of disease, diagnostic

biomarkers confirm its presence, prognostic biomarkers forecast the course of the

disease, predictive biomarkers relate to the potential response of the disease to

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intervention or exposure, pharmacodynamic/response and safety biomarkers

characterize those interventions or exposures, and monitoring biomarkers track trends in

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these other biomarkers over time.19

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A general framework for the evaluation of potential biomarkers along each step

of the development pathway, placed in the context of chronic pain, is provided in Figure
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2. An ideal biomarker must clearly distinguish between individuals with or without the

condition of interest (good discrimination), and this distinction must be accurate (good
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calibration). The defined threshold values that separate positive from negative
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outcomes must have an appropriate balance of sensitivity and specificity depending on

the biomarker’s intended application (e.g., screening, diagnosis, prediction, or

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prognosis). The ideal biomarker must also be easily and affordably detected and

measured, with consistent, reproducible results across the biological variability of the
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condition of interest. Although there are currently no ideal biomarkers for facial pain
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(or indeed, any type of pain), recent research has focused on potential biomarker

candidates, including genetic/genomic, molecular, neuroradiological, and

psychophysical biomarkers.

Although candidate biomarkers may initially be identified from animal studies,

small observational cohorts, or case-control studies, biomarker validation typically

requires large samples of patients and clinical datasets. Prospective cohort studies are

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valuable because they reduce the risk of recall bias compared to retrospective cohorts

and can be designed to track specific exposures and outcomes of interest, and large

cohorts increase the likelihood of finding a significant association between a putative

biomarker and a relatively rare outcome (e.g., onset of a chronic pain condition).20 The

Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study was the

first and largest prospective study designed to examine and identify biopsychosocial,

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environmental, and genetic factors contributing to the development of TMD.21 Subsets

of other large cohorts assembled around the world have also been used to study TMD,

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including the Study of Health in Pomerania (SHIP) in Germany22, the Hispanic

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Community Health Study/Study of Latinos (HCHS/SOL) in the United States23, and the

United Kingdom Biobank (UKB)24. Such TMD cohorts have allowed researchers to
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pool resources internationally and explore a variety of potential biomarkers, such as

genetic and psychophysical associations in TMD.25,26 For TN, no similar cohorts exist,
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and the relatively low incidence of TN (about 4 in 100,000)27 makes assembling a TN

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cohort much more challenging. Many biomarker studies in TN have relied on miniscule

sample sizes and small retrospective cohorts. However, a recent effort from the Facial
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Pain Research Foundation (https://www.facingfacialpain.org/index.php) is underway to

create a database of TN patients, and biomarker studies may develop from this cohort in
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the future.
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Genetic biomarkers

A person’s genetic code can serve as a pain biomarker in a variety of ways.

Single-nucleotide polymorphisms (SNPs) in a gene can have a profound impact on its

function and its role in the development of chronic pain. Genes may interact with each

other or with the environment, altering gene expression to make an individual more or

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less likely to develop a chronic pain condition. Epigenetic regulation can also modulate

gene expression, altering gene function without disturbing the underlying genetic code.

Each step in the sequence from genetic code to gene expression is a potential source for

biomarkers.

One of the most widely-studied genetic biomarker in facial pain is catechol-O-

methyltransferase (COMT) in TMD. COMT encodes a ubiquitous enzyme responsible

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for the metabolism of catecholamines, which include the neurotransmitters dopamine,

epinephrine, and norepinephrine. Several SNPs in the COMT gene have been identified

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in individuals with TMD, with varying combinations of these SNPs comprising

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haplotypes that fall into one of three categories: low pain sensitivity (LPS), average pain

sensitivity (APS), and high pain sensitivity (HPS).28 Individuals with the LPS
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haplotype have higher levels of COMT enzymatic activity, which is in turn associated

with a 2.3-times decreased probability of developing TMD. In a prospective cohort

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study, Slade et al. found that women with APS or HPS haplotypes had a 2.7-fold
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increased relative risk of developing TMD following orthodontic treatment compared to

those with “pain-resistant” LPS haplotypes.29 Although recent studies have since found
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little to no evidence that orthodontic treatment is a risk factor for TMD,30,31 the Slade et

al. study did demonstrate that genotype may be associated with development of TMD
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following orthodontic treatment. Subsequent studies have provided further evidence

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that certain COMT genotypes may be significant risk or protective factors in the

development of TMD.32–36 However, research has also indicated that no single gene is

responsible for TMD. A systematic review of family and genetic association studies in

TMD concluded that TMD heritability is multifaceted, with the most evidence for

contributions from genes encoding proteins involved in the serotonergic and

catecholaminergic systems.37 The OPPERA study identified associations between

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TMD and SNPs in COMT, the serotonin receptor HTR2A, and the glucocorticoid

receptor NR3C1 (the binding site for cortisol), among others, but notably, the

researchers needed to combine the OPPERA data with those from a separate cohort

including 182 TMD cases and 170 healthy controls in order for any of the identified

associations to reach statistical significance.38 More recently, the OPPERA researchers

pooled two separate cohorts of TMD patients and controls, and found a 2.9 times

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increased odds of TMD in men (but not women) possessing a SNP in chromosome 3

that decreases expression of the muscle RAS oncogene homolog (MRAS) gene, which

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is involved in cell growth and differentiation processes.25 These findings were

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nominally replicated in the researchers’ meta-analysis of seven other TMD cohorts, but

were not statistically significant.25

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Genome-wide association studies suggest that genetic and epigenetic factors

may be implicated in chronic widespread pain conditions, such as fibromyalgia, that

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often overlap with TMD. Potential candidate genes identified include SLC64A4,

TRPV2, MYT1L, and NRXN3.39 Environmental factors and early life experiences may
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also modulate genome function through epigenetic mechanisms. Epigenetic changes in

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women with fibromyalgia have been identified, using genome-wide methylation pattern

analysis.40 It is also important to note that comorbid conditions may confound or

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modify the relationship between candidate biomarkers and orofacial pain; biomarker
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identification therefore requires careful patient selection and/or appropriately adjusted

statistical analyses.41 Further studies are also needed to examine if similar changes are

observed in patients with TMD without widespread pain conditions.

The challenges of genetic biomarker validation are compounded many times

over for a rare disease like TN, but a unique subtype of TN suggests that there may be a

stronger link between genes and TN than between genes and TMD. Although most TN

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cases occur sporadically, familial trigeminal neuralgia is a well-documented

phenomenon. No single genetic locus has been identified in all cases of familial TN,

and analyses of various familial TN lineages have reported both autosomal recessive42

and autosomal dominant43 inheritance patterns. These observations strongly suggest

that TN may be associated with genetic factors in some patients.44 One study of 244 TN

patients found that a SNP in the promoter region of the serotonin transporter (5-HTT)

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resulted in decreased levels of 5-HTT expression, and corresponded with increased risk

of having TN, higher pain severity, and poorer response to carbamazepine.45 In another

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study, researchers identified a gain-of-function mutation in the sodium channel Nav1.6

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in one individual with TN.46

As in TMD, there is some evidence relating the genetics of the descending pain-
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modulatory pathways of the central nervous system to the development of TN.

However, the handful of animal studies exploring trigeminal pain in knockout mice
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suggest that TN may be associated with mutations in genes encoding voltage-gated ion
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channels and regulators of cellular signaling and neuroinflammation—hardly surprising

in a neuropathic pain condition.44 Unfortunately, none of these animal studies have

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translated to human genetic associations. A 2009 Brazilian study reported findings that

Nav1.7 was downregulated and Nav1.3 was upregulated in TN patients compared to

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healthy controls.47 This study was considerably underpowered, with only 13 patients in
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each group, and even though a genetic polymorphism mechanism was proposed, no

specific SNPs were identified. A more recent study of 48 TN patients and 48 controls,

also in Brazil, did not find any association between polymorphisms in Nav1.7 and the

nerve growth factor receptor TrkA.48 As more research emerges in selective sodium

channel blockers for the treatment of TN,49 genetic variants of sodium channels may

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also be identified that could serve as predictive biomarkers for this potential TN

therapy.

Perhaps the most significant genetic biomarkers in TN are related not to its

development, diagnosis, or prognosis, but to the safety of its treatment. The HLA-

B*1502 allele, most commonly found in individuals of East Asian descent, predicts up

to a tenfold increased risk of severe or fatal skin reactions (e.g., Stevens-Johns

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syndrome (SJS), toxic epidermal necrolysis (TEN)) following exposure to the

anticonvulsant carbamazepine.50 Similarly, the HLA-A*3101 allele, found in most

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populations worldwide, is associated with SJS/TEN and other serious carbamazepine-

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induced drug reactions.51 Carbamazepine is considered first-line therapy for TN, and

the only medication approved by the US FDA for the treatment of trigeminal neuralgia.
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However, drug safety organizations around the world, including the US FDA, the Royal

Dutch Association for the Advancement of Pharmacy (KNMP), the Clinical

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Pharmacogenetics Implementation Consortium (CPIC), and the Canadian

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Pharmacogenomics Network for Drug Safety (CPNDS), have all published prescribing

and dosing guidelines for carbamazepine based on genotype.52 In general, genetic

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testing prior to initiation of carbamazepine is recommended for all patients from

populations in which the frequency of these genotypes is common or unknown, or if a

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previously untested patient develops a serious drug reaction after starting on the drug.
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For patients who test positive for a high-risk genotype, alternative medications are

strongly recommended.

Molecular biomarkers

Molecular biomarkers are attractive research targets. Depending on a study’s

particular aims and methodology, a single assay from a simple cheek swab, blood test,

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or biopsy could provide diagnostic, prognostic, predictive, or monitoring information.

In addition, unlike genetic, psychophysical, or radiological biomarkers, which are

typically observed rather than manipulated, many molecular biomarkers are also

enticing pharmacologic targets. However, the complex, heterogeneous, and often

nebulous mechanisms underlying chronic pain conditions make it much more difficult

to find good molecular biomarkers for pain, whereas diseases associated with more

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concrete entities (e.g., single-gene mutations, viruses, nutritional deficiencies) offer

more obvious targets as potential biomarkers. Nevertheless, understanding the

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pathophysiology of disease in TN and TMD is a logical starting point in the search for

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molecular biomarkers in facial pain.

TN pain arises from dysfunction of the trigeminal nerve. Vascular compression

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of the trigeminal nerve is present in approximately 95% of TN patients, and most

evidence suggests that compression of the nerve root leads to focal demyelination
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and/or hyperexcitability of the nerve, causing the distinctive features of TN.13 Most
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other cases of TN without vascular compression occur in neurodegenerative lesions,

such as multiple sclerosis plaques or lacunar infarcts of the trigeminal nerve root, which
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are also associated with demyelination and hyperexcitability.13 Central mechanisms

may also play a role: neurophysiologic studies have found impaired inhibition of central
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nociceptive pathways in TN patients with concomitant chronic facial pain, a substantial

population of TN patients who are particularly refractory to treatment.53

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TMD does not have a single anatomic origin; broadly speaking, it may arise

from degeneration of the temporomandibular joint (TMJ), painful TMJ disc

displacement, and pain within the muscles of mastication. TMJ degeneration may occur

through various pathologies, such as osteoarthritis, degenerative joint disease, or

autoimmune arthritis, as well as exacerbation by mechanical stressors.54 Mechanical

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stimulation of nociceptors results in increased levels of neuropeptides and inflammatory

mediators, and local hypoxia; these changes can lead to pain and dysfunction,

potentially exacerbating degeneration and mechanical stress on the joint,54 but also for

the muscles of mastication.55,56 Thus, TMD encompasses joint-related pain as well as

associated myalgia, myofascial pain, tendonitis, spasm, and myositis.8 Furthermore, as

with many other chronic pain conditions, prolonged peripheral stimulation of

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nociceptive pathways can lead to central sensitization of temporomandibular pain;

consequently, TMD patients fall along a continuum from peripherally-generated to

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centralized pain.57 In addition, as discussed earlier, a substantial proportion of

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individuals with TMD also present with other chronic overlapping pain conditions, such

as irritable bowel syndrome, migraine headaches, fibromyalgia and pelvic pain. A

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common characteristic in these patients is sensory hypersensitivity and pain

amplification, suggesting a central sensitization mechanism.58

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The simplistic perspective that TMD is a problem of inflammation and

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sensitization, while TN is a problem of nerve dysfunction, would suggest very different

areas of biomarker research for the two conditions. However, chronic pain is never that
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simple, and some evidence suggests that inflammation could contribute to TN pain,59,60

while nerve dysfunction may play a role in TMD61,62. Moreover, the same nerves can
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be involved in both conditions. Sensory innervation of the temporomandibular joint is

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supplied by the V3 branch of the trigeminal nerve, so in cases of TMD involving facial

or joint pain, the trigeminal nerve is necessarily involved in pain transmission. The

branches of the trigeminal also supply motor innervation to the muscles of mastication

(masseter, temporalis, medial and lateral pterygoids, and anterior digastric); therefore,

dysfunction of the trigeminal nerve may also lead to dysfunction of musculoskeletal

structures involved in TMD. Identifying areas of overlap and dissimilarity in

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biomarkers for the two conditions has important implications for understanding which

molecules may better serve as screening or diagnostic biomarkers, and which are better

suited as predictive biomarkers.

Cytokines and other inflammatory mediators

Although both TMD and TN may cause pain extending beyond the pathological

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anatomic structure, they are also both characterized by pain that is localized to the

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craniofacial region. As such, researchers intuitively seek biomarkers that are also

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localized to the specific area of interest. As a superficial structure, the

temporomandibular joint is significantly more accessible than the trigeminal nerve. The

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prospect of obtaining salivary, synovial, or even muscle biopsy samples for TMD
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biomarker research is more appealing (and less daunting) than the analogous collection

of cerebrospinal fluid (CSF) or nerve biopsy from the trigeminal nerve. Consequently,
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molecular biomarker research in TMD covers a wide range of bodily tissues, from

blood to biopsy, whereas relatively few TN studies have analyzed more than blood, and
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occasionally CSF.

Research on inflammatory mediators in facial pain provides an excellent

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illustration of this challenge. The strongest evidence of differences in inflammatory

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profiles in patients with TMD pain compared to controls has been in synovial fluid

rather than plasma. Increased levels of the pro-inflammatory cytokine tumor necrosis
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factor (TNF) have been found in the synovial fluid of patients with TMD,63–66 and

higher levels of synovial TNF-α are associated with increased TMD pain.67 Synovial

TNF-α levels have also been found to be predictive of treatment response to intra-

articular glucocorticoid injection68 and temporomandibular joint surgery,69 with degree

of pain relief corresponding to concomitant decreases in TNF-α levels after the

procedure. Other cytokines studied in TMD include the pro-inflammatory cytokine

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interleukin-1β (IL-1β) and the mixed-effect cytokine interleukin-6 (IL-6). Like TNF-α,

IL-1β is increased in the synovial fluid of TMD patients,66,70 and increased synovial

fluid IL-1β is associated with increased TMD pain.64,71 Similarly, IL-6 is found more

frequently in the synovial joints of patients with TMD compared to healthy controls,

and higher levels are correlated with increased pain and TMD symptoms.66,70,72–74

Beyond synovial fluid, intramuscular cytokines and salivary biomarkers have also been

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studied in TMD. For example, elevated levels of IL-6, IL-7, IL-8 and IL-13 have been

found in the masseter muscles of patients with TMD myalgia,56 and salivary levels of

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oxidative stress biomarkers 8-hydroxydeoxyguanosine, malondialdehyde and total

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antioxidant status have been found to be significantly different between TMD patients

and controls.75
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A growing body of evidence indicates that inflammation may play a role in the

development of neuropathic pain,76 but there are few studies of cytokines in TN. A
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recent study collected venous blood from patients with TN and hemifacial spasm (a
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similar pathological condition affecting the facial nerve) and found increased

concentrations of IL-1β, IL-6, IL-8, and TNF-α compared to healthy volunteers.60

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However, all samples were collected during microvascular decompression surgery, and

it is unclear how the environmental stress of the perioperative setting may have affected
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cytokine levels. Cytokine analysis of the CSF surrounding the trigeminal nerve may be
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less influenced by environmental factors, but only one study reporting on a technique to

measure cytokines in the CSF of TN patients has been published.77 Although cytokines

were detected, mediator levels varied depending on where the sample was collected

along the trigeminal nerve root, and no comparisons could be made to a control

population.

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 The two examples of cytokine profiles in TMD and TN illustrates some of the

difficulties in using cytokines as biomarkers. First, it is worth noting that cytokine

studies typically evaluate levels of multiple cytokines, but in many of the studies

referenced above, only one or two cytokines were found to be significantly different

between patients and controls. Alstergren et al. have recently proposed clinical

diagnostic criteria for temporomandibular joint arthritis by measuring synovial fluid

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levels of seven different inflammatory mediators; a concentration above normal for any

one of these inflammatory mediators was considered diagnostic of arthritis.78 However,

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it is unclear how the specific mediators chosen are any more or less reflective of TMD

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pathology than any of the dozens of other mediators that have been studied, and the

high cost of multiplex cytokine assays may limit the use of this approach. Second,
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cytokine levels are known to vary widely within individuals. Basi et al. assayed venous

blood, biopsied masseter muscle, and synovial fluid from TMD patients and healthy
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controls for levels of the inflammatory mediators bradykinin, F2-isoprostane,

leukotriene B4, nerve growth factor, prostaglandin E2, and substance P.79 Although
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muscle levels of F2-isoprostane were negatively correlated with muscle pain intensity
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and pressure pain threshold, no other biomarkers were correlated with pain intensity.

Furthermore, only plasma bradykinin was correlated with synovial bradykinin levels,
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and there were no significant correlations among the tissue types for any of the other
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mediators. Thus it appears that inflammatory mediator levels are highly dependent on

sample location, particularly in localized disease states such as TMD. In addition,

levels of cytokines and inflammatory mediators may fluctuate according to time of day,

fasting status, physical activity, and stress.80 Taken together, these findings suggest that

although cytokines and other inflammatory mediators may provide insights into the

mechanisms of pain in TMD and TN, and perhaps a broad sense of inflammation in

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TMD and TN patients, they may be too variable and unpredictable to serve as practical

biomarkers in facial pain.

Neuronal signaling molecules: neurotransmitters and neuropeptides

Whether pain is neuropathic or nociceptive, all pain signals must be conducted

through the nervous system. Neuronal signaling molecules therefore play a key role in

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pain processing and have been explored as potential molecular biomarkers in a variety

of chronic pain conditions. In chronic facial pain, most of this research has focused on

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the monoamine neurotransmitters and neuropeptides. The monoamine

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neurotransmitters include serotonin (5-HT), dopamine, and norepinephrine, whose roles

in the descending inhibition and affective components of chronic pain have been studied
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extensively yet are not completely understood. Neuropeptides, which are often co-

secreted with neurotransmitters, are released by neuronal cells to facilitate intercellular

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communication. These small molecules, such as calcitonin gene-related peptide

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(CGRP), substance P (SP), nerve growth factor (NGF), are vital to the initiation and

amplification of a variety of inflammatory, nociceptive, and vasoactive processes,

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including neurogenic inflammation. The best example of a validated biomarker in

craniofacial pain is CGRP in migraine, the levels of which are elevated in blood and
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saliva during migraine attacks.81 The prospective utility of these signaling molecules as
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biomarkers is further enhanced by the availability of targeted pharmacological therapies

that are already in clinical use, including 5-HT modulators, norepinephrine reuptake

inhibitors, α2-agonists, and CGRP receptor antagonists. CGRP receptor antagonists

have been recently approved for the prevention of migraine episodes and are an

excellent illustration of how biomarker research can have a profound impact in our

understanding of pain and its treatment.

17
 In TMD, elevated synovial 5-HT has been associated with increased pain,82 and

both local and systemic levels of 5-HT predict response to intra-articular glucocorticoid

injection.83 A small study found that the masseter muscles of women with myofascial

TMD had more nerve fibers expressing 5-HT3A receptors compared to healthy controls,

and that these fibers more frequently exhibited increased co-expression of 5-HT3A

receptors with Nav1.8 channels, a marker of small, thinly myelinated nociceptive

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fibers.84 A more recent study found no difference in plasma levels of 5-HT between

patients with myofascial TMD and healthy controls, but that plasma dopamine levels

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were significantly increased in TMD patients.85 These findings suggest a complex

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relationship between the peripheral and central actions of these neurotransmitters in

TMD pain.
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Neuropeptides may also contribute to TMD pathophysiology. Both CGRP86 and

SP87,88 have been found to be increased in synovial samples from TMD pain patients,
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but only CGRP levels are positively correlated with pain. These observations suggest
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that SP levels may reflect joint injury or pathology, whereas CGRP levels may be more

reflective of joint pain. However, it not clear whether these associations reflect
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increased expression in response to mechanical joint injury, or whether these

neuropeptides, which are both potent vasodilators, are secreted in response local tissue
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hypoxia that may occur in TMD.54,89

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As previously noted, due to the challenges of studying the local milieu of the

trigeminal nerve, biomarker studies in TN are relatively rare. The few available studies

create a slightly different picture of our understanding of TN pain as compared to TMD.

Whereas in TMD, 5-HT was found to be elevated and associated with increased pain,

rodent models of TN have found that agonism of 5-HT1A and 5-HT2C receptors

attenuate pain behaviors.90,91 Serotonin (5-HT) has a complex role in pain. Outside of

18
the central nervous system, 5-HT acts as an inflammatory mediator and sensitizes

afferent nerve fibers to induce hyperalgesia.92 Inside the central nervous system, it can

have analgesic or hyperalgesic effects in the brainstem and spinal cord, inhibit

neurotransmitter release in the trigeminal system, or modulate descending pain

inhibition pathways.92 Thus, the particular effects of serotonin will depend on where it

is located in the body, the relative concentrations, and available receptor subtypes,

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meaning that serotonin modulators may have very different effects in TMD versus TN,

depending on route of administration, dosing, and receptor selectivity.

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Only a handful of other neuronal signaling molecules have been studied in TN

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patients. A study of CSF samples from 16 TN patients found that the concentrations of

norepinephrine and its metabolite vanillylmandelic acid, the dopamine metabolite

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homovanillic acid, the serotonin metabolite 5-hydroxyindoleacetic acid, and

somatostatin were all significantly decreased compared to controls, while substance P

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was increased.93 The authors suggested that elevated SP might indicate neurogenic
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inflammation, whereas changes in the monoaminergic systems might reflect central

dysfunction in TN. Consistent with this hypothesis, a subsequent study comparing the
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CSF of 20 TN patients with that of 20 controls with nervous system or gynaecological

disease found that the neuropeptides CGRP, SP, and vasoactive intestinal peptide were
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significantly elevated in patients versus controls, while β-endorphin was significantly

decreased.94
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“Omics” profiling
Recently, exploration of the human genome, epigenome, transcriptome,

proteome, and metabolome has become possible with the availability of reliable high-

throughput technologies, sparking increased interest in so-called “omics” biomarkers.

Researchers can now extract prodigious quantities of information from a single patient,

19
or even a single cell, to develop a comprehensive, personalized biomarker profile. This

approach allows many potential biomarkers to be studied at the same time from very

small sample quantities. Data from these RNAs, proteins, or metabolites provide

information about the function and functionality of entire pathways, giving investigators

a perspective on disease that is both broad and detailed. However, the information

obtained is only as valid as the source of the information; poor patient selection, poor

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sample selection, and poor sample collection may all yield misleading results.

Researchers must also guard against the trap of equating statistical significance with

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clinical significance. Analyzing the sheer volume of data produced from these assays

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requires advanced statistical and computational skills, but even an excellent statistical

analysis can fail to produce useful biomarkers. Consequently, the identification of

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valid, practical biomarkers requires an approach that balances statistical rigor with

expert knowledge about the scientific underpinnings of disease.95

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Although omics profiling is now more readily available than ever before, assays
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are still quite expensive, time- and labor-intensive, and computationally complex. As a

result, there are few published studies evaluating these biomarker profiles in TMD or
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TN. MicroRNA (miRNA) profiling of synovial fibroblasts from patients with TMD

found decreased expression of the miRNA221-3p.96 miRNAs are small, non-coding

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RNA molecules that act as regulators of gene expression. The researchers found that
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miRNA221-3p inhibits transcription of Ets-1, which is itself a transcription factor for

matrix metalloproteinases (MMP). MMPs comprise a large family of enzymes

responsible for tissue degradation and remodelling, particularly in joint cartilage. IL-1β

reduces miRNA221-3p, upregulating Ets-1 and its downstream MMP products. This

example provides a good illustration of how omics profiling may lead to insights in the

mechanisms of joint degeneration in TMD. Recently, a rapid biomarker-based method

20
has been reported, using vibrational spectroscopy for metabolomic analysis of blood

smears, which could serve as a metabolic fingerprint to differentiate patients with

fibromyalgia from those with other rheumatologic disorders.97 Whether such tools can

be used for the diagnosis of craniofacial pain states remains to be determined.

In TN, a preliminary study examined the plasma proteome of patients before and

after microvascular decompression surgery, a neurosurgical procedure used to treat TN,

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and compared patients to healthy volunteers.98 Patients had significantly altered levels

of several proteins, including transthyretin, retinol binding protein, and alpha-1-acid

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glycoprotein 2, proteins that may play a role in oxidative stress and peripheral nerve

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regeneration. In addition, the investigators found alterations in plasma levels of CGRP,

nitric oxide, glycine, and vitamin D before versus after surgery, suggesting that these
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molecules may play a role in pain sensitization. To our knowledge, no other published

studies have examined “omics” biomarkers in TN. However, as these technologies

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become more accessible over time, more studies in TMD and TN will undoubtedly
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emerge.

Neuroradiological biomarkers
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Neuroradiological imaging is another promising area of pain biomarker

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research. Advances in imaging techniques over the past several decades have allowed

better quantification of the structural, chemical, cognitive, and psychological changes

Ac

that occur in chronic pain. Neuroimaging in chronic pain has many potential benefits,

including: non-invasive characterization of brain structure and function (e.g., magnetic

resonance imaging (MRI)); assessment of changes that occur in response to various

stimuli, tasks, cognitive and behavioural states (e.g., functional MRI (fMRI));

evaluation of pharmacologic function (e.g., positron emission tomography (PET)); and

21
evaluation of neurotransmitter and metabolite concentrations (e.g., magnetic resonance

spectroscopy (MRS)).99 However, these techniques require a substantial investment of

equipment, expense, participant burden, and image interpretation and analysis, and

studies can be limited by artifacts, low resolution, risks of the imaging techniques (e.g.,

use of radiotracers in PET, contraindications to MRI), and challenges in making causal

inferences based on observed group differences.99 Nevertheless, neuroimaging remains

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a powerful potential tool in pain research, with new discoveries forward translating pain

mechanisms into potential diagnostics or treatments, or reverse translating clinical

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observations to refine preclinical models of chronic pain.100

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Numerous studies have investigated neuroimaging in TMD. Structural MRI

studies have found evidence of white matter abnormalities in the trigeminal nerve and
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corpus callosum of TMD patients compared to controls, suggesting that increased

nociceptive activity in TMD may cause microstructural changes in the trigeminal nerve
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and be associated with changes in sensory, motor, cognitive, and pain pathways.61
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Similarly, TMD patients have been found to have abnormalities in gray matter in brain

areas associated with pain, modulation, and sensorimotor functioning, and these
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changes are correlated to pain duration, intensity, and unpleasantness.101

In a comprehensive literature review of neuroimaging in several “central

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sensitivity” syndromes, including TMD, Wallitt et al. concluded that there were
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inconsistent and conflicting data regarding basal neuronal activity patterns (n = 3

studies), gray matter volume (n = 3), and white matter volume (n = 2) in structural MRI

studies of TMD patients.102 All TMD studies included in the review examined fewer

than 20 (and in some cases, fewer than 10) TMD, and it may be that the observed

inconsistencies derive from small sample sizes and the clinical heterogeneity of TMD.

Functional MRI studies have provided some evidence demonstrating that TMD patients

22
have changes in cortical processing that manifest as increased sensitivity to non-painful

tactile stimuli.103,104 In addition, the only molecular measurement study published at the

time of the review demonstrated increased glutamine in the right posterior insula and

increased N-acetylaspartate and choline in the left posterior insula in MRS of TMD

patients.105 A more recent MRS study found increased total creatine in the posterior

insula of TMD patients, and furthermore, that increased choline and glutamate

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concentrations in the posterior insular cortex were correlated with clinical

characteristics of TMD pain, including generalized pain.106

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Since MRI is a standard diagnostic tool in TN and is critical to evaluation for

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surgical treatments of TN, almost all TN patients have neuroimaging. However,

research MRIs often use specialized protocols and post-processing techniques not
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typically used in clinical practice. In TN research, high-resolution anatomical imaging

(e.g., variations of T1- and T2-weighted images) assesses anatomical characteristics and
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patterns of neurovascular contact, brain grey matter volume, and cortical thickness,
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while diffusion imaging (e.g., diffusion-weighted images (DWI), diffusion tensor

images (DTI)) assesses brain white matter and trigeminal nerve microstructure.107
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These advances in neuroimaging have already had significant practical implications in

TN. Until recently, a central debate in our understanding of TN pathophysiology has

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been the degree to which neurovascular contact explains TN symptoms. Although

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contact of the trigeminal nerve by an overlying blood vessel is one of the most common

explanations for pain in TN, it has also been observed that neurovascular contact is not

always present in patients diagnosed with TN.107 Furthermore, contact of vessels with

the trigeminal nerve can often be seen on routine biopsy and conventional MRI of

asymptomatic individuals.107 However, advanced imaging techniques have provided

better resolution of the trigeminal nerve, demonstrating that although neurovascular

23
contact may occur in asymptomatic trigeminal nerves, symptomatic trigeminal nerves

are frequently dislocated or distorted by compressive vascular structures; furthermore,

those changes correlate with TN symptom severity.108–110 Neuroradiological

biomarkers have also been used to predict treatment response to TN treatments. DTI

uses the restricted diffusion of water in tissues to provide detailed information about

trigeminal nerve microstructures. Pre-treatment DTI metrics have been correlated with

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treatment response of patients following TN surgery, such as MVD,111 stereotactic

radiosurgery111 and radiofrequency lesioning.112,113

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The utility of DWI and DTI go beyond TN and have also been used to study

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other chronic orofacial pain conditions, including TMD, yielding a better understanding

about the neural mechanisms underlying trigeminally-mediated pain.114 In a study of

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using high-resolution MRI and DTI, Wilcox et al. found that TN patients had a

significant decrease in nerve volume compared to controls, neuropathy patients had a

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significant increase in nerve volume, and TMD patients displayed no difference in

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volume, while none of the patient groups demonstrated significant changes in DTI

values.115 A review of brain signatures in chronic orofacial pain examined

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neuroimaging studies in TMD and trigeminal neuropathic pain (TNP), which includes

TN, post-traumatic trigeminal neuropathy, and post-herpetic neuropathy.116 TNP

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disorders have different underlying etiologies, but all involve dysfunction of the
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trigeminal nerve and have very similar clinical features. Summarizing the available

studies, the author concluded that both TMD and TNP patients demonstrated consistent

structural and functional changes in the thalamus and the primary somatosensory cortex,

as well as the prefrontal cortex and the basal ganglia, indicating the importance of the

thalamocortical pathway, cognitive modulation, and reward processing in chronic

orofacial pain. However, it also appeared that TNP patients had greater alterations to

24
the thalamocortical pathway, and furthermore, the two conditions displayed different

patterns of thalamic and insular connectivity.116 Subsequent studies have supported

these differences. Youssef et al. examined cerebral blood flow using fMRI in patients

with TMD (non-neuropathic pain) and TNP (neuropathic pain).117 Neuropathic pain

was associated with decreased cerebral blood flow in the thalamus, primary

somatosensory, and cerebellar cortices. Non-neuropathic pain was associated with

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significant increases in cerebral blood flow to the anterior cingulate cortex, the

dorsolateral prefrontal cortex, and the precuneus—regions generally associated with

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higher-order cognition and emotion—as well as motor-related regions and the spinal

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trigeminal nucleus.117 Although this report suggests that neuroradiological biomarkers

may help distinguish between neuropathic and non-neuropathic pain, these observations
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should be interpreted with caution. Differences in neuroradiological biomarkers may

demonstrate different changes associated with each condition, but they are not
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necessarily reflective of differences in underlying mechanisms of pain. As we will

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discuss next, quantitative sensory studies of TMD patients suggest that sensory

amplification occurs in many patients, indicating central sensitization (a hallmark of

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neuropathic pain) as a mechanism of pain in TMD.

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Psychophysical biomarkers

Quantitative sensory testing (QST) is a non-invasive, psychophysical method

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using calibrated, objective stimuli (e.g., heat, touch, pressure, vibration) to elicit

subjective patient responses (e.g., detection of sensation or pain). Depending on the

stimulus used, QST can evaluate loss and gain of function along large (Aβ) or small

(Aδ, C) fiber pathways from various peripheral body sites to the somatosensory cortex.

Although frequently used in pain research, QST is rarely used in clinical practice, in

25
part due to equipment costs and time involved in conducting the tests. Performing QST

also requires specialized training, and wide variations between subjects, QST protocols,

and examiners make it difficult to interpret results. In recent years, standardized QST

protocols have been developed, along with age-, gender-, and site-associated reference

values in healthy volunteers.118–120 The International Association for the Study of Pain

(IASP) Neuropathic Pain Special Interest Group (NeuPSIG) released a consensus

t
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statement in 2013 recommending QST for screening for small and large fiber

neuropathies, monitoring somatosensory deficits, and monitoring of evoked pain,

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allodynia, and hyperalgesia; QST was not recommended as a stand-alone test for the

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diagnosis of neuropathic pain, but it was considered valuable when taken in clinical

context to provide information about the functional status of the somatosensory

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system.121

Overall, QST studies of TMD patients have found that enhanced pain sensitivity
M

is associated with subsequent development of TMD,122 and that TMD is associated with

various abnormalities in somatosensory profiles compared to controls,123,124 although

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the specific QST parameters found to be abnormal are inconsistent across studies.
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Although various QST measures have been correlated with subjective pain report, QST

is known to be highly variable even among healthy individuals, and even wider
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interindividual variability has been observed within TMD patients.125 In addition,

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sensory abnormalities have also been observed in TMD patients at body sites outside

the painful facial region.123,126 These findings may be reflective of centralized pain

phenomena,127 which can be present in multiple chronic overlapping pain conditions.

From the OPPERA cohort, pressure pain thresholds (PPTs) were found to be weak

predictors of TMD onset, but were found to be significantly decreased at the time of

TMD onset; in addition, PPTs were persistently lower in patients with ongoing TMD

26
symptoms, but tended to normalize in cases of symptom resolution.128 A more recent

study of the OPPERA cohort showed that individuals who transition from control to

TMD show the greatest reductions in PPT over a period of 5 to 7 years.129 Thus, it

seems the sensitivity and specificity of QST are rather poor for it to be useful as a

diagnostic tool in TMD, but it could be more valuable as a monitoring biomarker to

track the development or maintenance of sensory abnormalities over time.

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In TN, routine neurological evaluation is often normal. QST has identified

subtle, subclinical sensory abnormalities in TN patients using comprehensive QST

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panels,130–134 but as with TMD, the specific abnormalities within those panels vary

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across studies. Although QST is generally considered more useful in the assessment of

neuropathic pain conditions (e.g., TN), somatosensory deficits still occur in non-
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neuropathic pain conditions (e.g., TMD). Therefore, the diagnostic resolution of QST

in distinguishing between neuropathic and non-neuropathic pain is low. As noted

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above, QST may be more practical as a monitoring biomarker, particularly in the

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context of assessing somatosensory function before and after treatment. A study of TN

patients before and after decompression surgery found that although pain and
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masticatory function improved after surgery, QST identified the development of subtle

new sensory deficits following surgery.135 QST could also serve as a predictive
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biomarker, forecasting potential efficacy to various treatment options.

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Conclusions
As the demand for precision medicine techniques and personalized pain

management grows, the field of pain biomarker research will continue to expand. The

spectrum of chronic pain conditions typified by TMD and TN demonstrate the various

challenges and exciting opportunities in pain biomarkers. Although there are currently

no validated, established biomarkers for pain, promising genetic, molecular,

27
neuroradiological, and psychophysical strategies are currently being explored in both

TMD and TN. Most of the potential biomarkers in these conditions are still in the early

stages of biomarker discovery and verification. An incomplete, evolving knowledge of

the mechanisms of chronic facial pain and imperfect (or, in the case of “omics”,

previously unavailable) measurement techniques have been barriers in the earlier stages

of biomarker development. As we have seen in the examples above, the clinical

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heterogeneity of pain patient populations, small sample sizes, and insufficiently

characterized clinical cohorts in both TMD and TN can present challenges to successful

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biomarker verification and validation. Furthermore, it remains to be seen whether these

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potential biomarkers can fulfill considerations of reliability and practicality (e.g., cost

and speed) to bridge the gap from biomarker validation to implementation. However, as
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researchers learn more about facial pain pathophysiology, refine assay techniques and

technologies, and assemble larger, well-defined clinical cohorts, we may soon have not
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one, but several, new facial pain biomarkers. The same framework of biomarker
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development may also be applied and tailored to assess potential biomarkers in other

chronic pain states, as well. These tools could provide us with valuable insights into the
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mechanisms of chronic pain, forecast disease trajectories, predict treatment response, or

identify suitable targets for personalized therapies and rational drug design.
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Summarizing the evidence for sensory testing, skin biopsy, and functional brain
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imaging as biomarkers, the Initiative on Methods, Measurement, and Pain Assessment

in Clinical Trials (IMMPACT) noted their potential utility as diagnostic, prognostic,

predictive, and pharmacodynamic biomarkers, but also called for further standardization

and demonstrations of validity and reliability.136 Identifying the most useful and

successful future biomarkers will require systematic approaches that capitalize on

innovative techniques and build on existing knowledge. Despite the trendy appeal of

28
the term “biomarker discovery,” this area of research is not merely a passing trend.

Biomarker discovery is a vital goal in pain research, and the results of these efforts will

undoubtedly transform the way we approach pain and pain treatment in the future.

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cr
doi:10.1016/j.jpain.2017.02.429

us
an
M
ed
pt
ce
Ac

47
 • Susceptibility/riskk
Pre-
Diiagnosis

• Diagnosstic
• Prognosstic
Onset

• Monittoring

t
ip
• Predictive
• Pharma acodynamic/response

cr
Treeatment • Safety

us
Figu
an
ure 1. Typess of biomarrkers alongg the diseasse trajectorry.
M
ed
pt
ce
Ac

48
Figu
ure 2. Fram
mework for assessmentt of potentiial biomark
kers in chroonic pain.

Discovery T
Target id
dentificaation
• Purpose: What
W is thee intended use u of the bio omarker, annd what is th
he
appropriaate outcome measure (ee.g., pain sco ores, sympttom severity
y)?
• Knowledg ge: Does thee target hav
ve a role in pain
p pathopphysiology?
• Feasibility
y: Can the ttarget be detected and quantified?
q Can the
i t l b bt i d ( ti l ll i i )?

t
ip
cr
T
Target co
onfirmattion and
d assay develop
d pment
Verification

us
• Discrimination: Is thee target diffferentially expressed
e inn individuals with
and withoout pain?
• Calibratio
on: Does thee assay accu urately distiinguish betwween individuals
with and without paiin?
an
• Methods:: How shou ld samples be collected d processeed and analyzed?
M

A
Assay peerformannce and prospecctive cliinical stu
udies
Validation

ed

• Performan nce: Is the ttarget assay

y appropriateely sensitivee and speciffic in a
prospectivve cohort?
• Consisten
ncy: Is the taarget assay reproduciblle?
pt

• Cohort: Iss the prospeective cohorrt sufficiently large, adeequately

h t i d d th i t t l?
ce Implementation

C
Clinical and
a labooratory use
u
Ac

• Practicality: Are the required tecchnologies accessible tto the targett

population?
• Affordabiility: Is the assay cost-eeffective?
• Speed: Arre results avvailable within a time frame
f suitabble for the pain
p
diti d t fi t t?

49
 Temporomandibular
Biomarker Type Trigeminal Neuralgia (TN)
Disorder (TMD)

COMT, 5-HT receptor, 5-HT transporter, Nav1.6

glucocorticoid receptor, channel,
Genetic
muscle RAS oncogene HLA-B*1502 and HLA-
homolog A*3101 (treatment)

Molecular
IL-1β, IL-6, IL-8, TNF-α
Cytokines and other
IL-1β, IL-6, TNF-α, F2-
inflammatory mediators
isoprostane 5-HT, dopamine,
norepinephrine, CGRP, SP,

t
Neuronal signaling
5-HT, dopamine, CGRP, SP vasoactive intestinal peptide,

ip
molecules
β-endorphin

miRNA221-3p Transthyretin, retinol binding

cr
“Omics” profiling
protein, alpha-1-acid
glycoprotein 2

us
fMRI changes in cortical
processing
MRS changes in posterior High-resolution anatomical
an
insula neurotransmitters and imaging correlation between
metabolites neurovascular compression
and pain
Structural and functional
changes in thalamus, DTI metrics correlated with
M
Neuroradiological somatosensory cortex, treatment response
prefrontal cortex, and basal Structural and functional
ganglia changes in thalamus,
somatosensory cortex,
ed

Changes in blood flow to

regions of higher-order prefrontal cortex, and basal
cognition, emotion, motor- ganglia
related regions, and spinal
pt

trigeminal nucleus

Specific sensory abnormalities

ce

inconsistent across studies Specific sensory abnormalities

Enhanced pain sensitivity inconsistent across studies
Psychophysical
(risk factor) Subclinical abnormalities in
Ac

Sensory abnormalities often the facial region

observed outside facial region
Table 1. Summary of potential biomarkers discussed in this review. COMT =
catechol-O-methyltransferase; 5-HT = serotonin; CGRP = calcitonin gene-related
peptide; SP = substance P; fMRI = functional magnetic resonance imaging; MRS =
magnetic resonance spectroscopy; DTI = diffusion tensor imaging

50