57070

2016
JDRXXX10.1177/0022034516657070Journal of Dental ResearchCentralized Pain in Temporomandibular Disorders

Clinical Review
Journal of Dental Research
2016, Vol. 95(10) 1102­–1108
Pain Mechanisms and Centralized Pain © International & American Associations
for Dental Research 2016

in Temporomandibular Disorders Reprints and permissions:

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DOI: 10.1177/0022034516657070
jdr.sagepub.com

D.E. Harper1, A. Schrepf1, and D.J. Clauw1

Abstract
Until recently, most clinicians and scientists believed that the experience of pain is perceptually proportional to the amount of incoming
peripheral nociceptive drive due to injury or inflammation in the area perceived to be painful. However, many cases of chronic pain have
defied this logic, leaving clinicians perplexed as to how patients are experiencing pain with no obvious signs of injury in the periphery.
Conversely, there are patients who have a peripheral injury and/or inflammation but little or no pain. What makes some individuals
experience intense pain with minimal peripheral nociceptive stimulation and others experience minimal pain with serious injury? It
is increasingly well accepted in the scientific community that pain can be generated and maintained or, through other mechanisms,
suppressed by changes in the central nervous system, creating a complete mismatch between peripheral nociceptive drive and perceived
pain. In fact, there is no known chronic pain condition where the observed extent of peripheral damage reproducibly engenders the
same level of pain across individuals. Temporomandibular disorders (TMDs) are no exception. This review focuses on the idea that TMD
patients range on a continuum—from those whose pain is generated peripherally to those whose pain is centralized (i.e., generated,
exacerbated, and/or maintained by central nervous system mechanisms). This article uses other centralized chronic pain conditions as
a guide, and it suggests that the mechanistic variability in TMD pain etiology has prevented us from adequately treating many individuals
who are diagnosed with the condition. As the field moves forward, it will be imperative to understand each person’s pain from its own
mechanistic standpoint, which will enable clinicians to deliver personalized medicine to TMD patients and eventually provide relief in
even the most recalcitrant cases.

Keywords: orofacial pain/TMD, treatment planning, psychosocial factors, neuroscience/ neurobiology, evidence-based dentistry/health
care, multisensory perception

Introduction fibromyalgia (FM) versus 41% for irritable bowel syndrome

(Yunus 2012). In aggregate, TMD patients tend to display
The idea that chronic pain should be treated according to its hyperalgesia (i.e., increased pain sensitivity) and other sensory
underlying mechanisms, which can differ across individuals anomalies as compared with healthy subjects on experimental
with the same diagnosis, was first proposed around the turn of measures, but some studies have failed to find significant dif-
the century (Max 2000). At that time, the author stated that this ferences on these measures. One explanation for the discrepant
would be possible in the future, but due to the scientific prog- results that have been obtained in the TMD literature is that
ress in understanding the mechanisms behind chronic pain different mechanisms produce symptoms that meet the criteria
over the last 2 decades, mechanism-based treatments are now for TMD diagnosis and many previous studies have failed to
possible, at least to some extent. parse them out. Over the last decade, Maixner and colleagues
Temporomandibular disorder (TMD) refers to a family of (2011) have begun to uncover the heterogeneity within TMD in
symptoms characterized chiefly by pain in the temporoman- the large study Orofacial Pain: Prospective Evaluation and Risk
dibular joint and/or surrounding muscle. Many clinicians con- Assessment (OPPERA), including variations in pain sensitivity,
sider persistent pain in the general orofacial region not clearly genetic haplotypes related to pain, immunologic factors, and
identifiable as headache to be TMD. However, it is quite clear
that in many patients diagnosed with TMD, the pain and other
symptoms involve much more than pathology of the temporo- 1
Chronic Pain and Fatigue Research Center, Department of
mandibular joint disorders (TMJ) and/or surrounding struc- Anesthesiology, School of Medicine, University of Michigan, Ann Arbor,
tures. Comorbid (i.e., non-TMD) pain is extremely common, MI, USA
with >50% of TMD patients reporting headache/migraine, A supplemental appendix to this article is published electronically only at
neck pain, joint pain, and low back pain, while only 17% report http://jdr.sagepub.com/supplemental.
pain isolated in the face and jaw (Plesh et al. 2011). Nonetheless,
Corresponding Author:
TMD patients do not necessarily exhibit widespread pain, and D.E. Harper, Chronic Pain and Fatigue Research Center, Department
they tend to have somewhat lower rates of comorbid syn- of Anesthesiology, School of Medicine, University of Michigan, 24 Frank
dromes than do other idiopathic pain conditions. For example, Lloyd Wright Dr, PO Box 385, Lobby M, Ann Arbor, MI 48106 USA.
approximately 24% of TMD patients meet criteria for Email: [email protected]
Centralized Pain in Temporomandibular Disorders 1103

Figure.  Mechanistic characterization of pain. Pain mechanisms can be categorized as peripheral nociceptive, peripheral neuropathic, and centralized.
While this classification scheme overly simplifies the vast array of possible mechanisms within each category, it does provide a framework through
which clinicians can narrow down treatment options based on each patient’s most prevalent signs and symptoms. Although some chronic pain
diagnoses are thought to be more centralized (e.g., fibromyalgia) and others more peripheral (e.g., osteoarthritis), on average, the reality is that
no chronic pain state falls neatly into a single mechanistic category. NSAID, nonsteroidal anti-inflammatory drugs; SNRI, serotonin-norepinephrine
reuptake inhibitor; TMD, temporomandibular disorder.

psychosocial variables. Based on supervised cluster analysis, stroke or a lesion, an example being thalamic pain syndrome.
OPPERA has recently identified 3 clusters of TMD patients: More recently, the term central sensitization has been used to
the first characterized by low experimental pain sensitivity and describe the amplification of pain signals that can occur in
low psychological distress, the second by higher pain sensitiv- chronic pain. However, its use in this context is debated since
ity, and the third by higher pain sensitivity and psychological the term was coined to describe a specific mechanistic process
distress (Bair et al. 2016). The differences among these clusters in spinal cord neurons (Woolf and Thompson 1991), and this is
point to mechanistic, etiologic factors that vary across patients but one of many processes that could be causing central pain
in ways that are more meaningful than the distinctions often amplification in patients. Because of the specificity of these
made in diagnosis (e.g., arthralgia vs. myalgia). terms and the myriad ways that one’s pain could be augmented
Although TMD treatments are not yet personalized in the via central means, our group uses the term centralized pain to
clinic in many cases, there is good evidence that some treat- more broadly refer to any condition in which pain is chroni-
ments are more appropriate for some patients than others. This cally perceived because of central nervous system adaptations
review examines an important dimension on which TMD and that 1) abnormally amplify ascending peripheral input or 2)
other types of chronic pain patients can differ, which we generate and maintain the perception of pain despite little or no
believe will be crucial to consider as the field moves toward peripheral nociceptive drive. The distinction between centralized
the personalized treatment of TMD pain—the degree to which and peripheral pain is important, since the mechanism of pain
each individual’s pain has been centralized. will ultimately affect its prognosis and treatment (see Fig.).
Centralized pain is often found in a set of idiopathic chronic
pain conditions, including FM, chronic fatigue syndrome (CFS),
Centralized Pain irritable bowel syndrome, headache, TMD, and interstitial cys-
Classically, the term central pain was used to describe the con- titis (Clauw 2014), which have moderate to high degrees of
dition of patients who experienced chronic pain as a result of a heritability and comorbidity (Diatchenko et al. 2006; Williams
large-scale injury to the central nervous system, such as a and Clauw 2009). The symptomatology of these conditions has
1104 Journal of Dental Research 95(10)

been well characterized, with the most prevalent symptoms distress and somatic complaints were both robust predictors of
being both current and previous incidences of persistent multi- incident TMD (Fillingim et al. 2013).
focal pain, coupled with a host of additional somatic com- Of interest to clinicians treating TMD, axis II dimensions
plaints, including sleep disturbance, memory problems, (i.e., psychosocial characteristics) have generally been found
fatigue, and mood disorders (Williams and Clauw 2009). The to be important predictors of treatment outcomes. For instance,
striking similarity of these conditions, the exception being the levels of depression, catastrophizing, and somatic complaints
region (or regions) where pain is experienced, strongly sug- are strong predictors of a worse response to standard treatment
gests that there are numerous commonalities in their patho- (Fricton and Olsen 1996; Velly et al. 2011; Litt and Porto
physiologic underpinnings. In fact, what is labeled a specific, 2013). Negative affect and psychosocial stress may contribute
new-onset chronic pain condition (e.g., TMD) by the clinician to the symptoms and incidence of TMD directly, by influenc-
who specializes in the area of the body where the pain is expe- ing neural substrates, and/or may indicate common etiologic
rienced can, upon further examination, be identified as a more factors that promote psychological vulnerabilities and chronic
systemic chronic illness that began for the person much earlier pain. For instance, experimental affective priming paradigms
in life, with the perceived pain temporally waxing and waning (e.g., visual cues designed to elicit anxious feelings or positive
at various body locations. affect) modulate pain responses (Tang and Gibson 2005), and
common neuroanatomic vulnerabilities to pain and negative
affect have been identified (Robinson et al. 2009).
Psychosocial Factors While centralized pain and psychological dysfunction
The comorbidity of functional somatic syndromes has been appear to be distinct if overlapping constructs, for purposes of
illustrated by Kato and colleagues (2009). They have shown evaluation and treatment they must be considered in tandem.
that FM, CFS, TMD, and other pain conditions share latent This may be due to common etiologic factors, such as altered
characteristics, such as widespread tenderness, sleep difficul- neurotransmitter function (e.g., monoamines; discussed below)
ties, and memory problems, which are largely distinct from and psychological trauma in early life, which has been linked
“psychological” traits, such as anxiety and depression. For to the development of both psychopathology (MacMillan et al.
example, FM patients who are not depressed have increased 2001) and chronic pain (Paras et al. 2009). Prospective studies
pain-evoked activity in regions of the brain that process the are needed to identify unique and common risk factors for
sensory (i.e., intensive) aspects of pain (e.g., the primary and each, and treatment studies should attempt, where possible, to
secondary somatosensory cortices and the posterior insula), measure both sensory and affective aspects of pain.
while those who are also depressed show enhanced activation
in areas that process the affective (e.g., unpleasant, distressing)
Genetics and Immunology
component, including the amygdala and anterior insula
(Giesecke et al. 2005). Genetic studies also support this idea Currently, it is believed that genetic factors account for about
that there are 2 overlapping sets of traits—those pertaining to half of the variability in sensitivity to experimental pain and
pain and sensory amplification and others concerning mood that these same genes also increase one’s propensity to develop
and affect (Diatchenko et al. 2006). These findings suggest that chronic pain. At least 5 of these sets of genes have been identi-
while both sensory and affective amplifications of pain are fea- fied, including those that affect and/or regulate COMT (an
tures of centralized pain, psychological factors appear to more estrogen-sensitive enzyme that could partially explain sex dif-
strongly influence the affective component. Within TMD ferences in chronic pain), sodium and potassium channel muta-
cohorts, levels of depression and/or somatic complaints are tions, GTP cyclohydrolase, and adrenergic receptors (Diatchenko
associated with chronicity of the disorder (Reiter et al. 2015), et al. 2005; Amaya et al. 2006; Tegeder et al. 2006; Costigan et al.
palpation tenderness in the orofacial area (Sherman et al. 2004), 2010; McLean et al. 2011), but not all studies have confirmed
nonsymptomatic pain tolerance (Koutris et al. 2013), and these findings (Hocking et al. 2010; Nicholl et al. 2010).
comorbid pain conditions (Dahan et al. 2015). These are impor- These genetic predispositions might come into play only
tant outcomes, as pain sensitivity, pain spread, chronicity, and when activated through environmental triggers. For FM and
complex presentation are hallmarks of centralized pain. CFS, potential stressors include early life trauma, physical
More generally, levels of depressive/anxious symptoms in trauma, certain infections, emotional stress, regional pain con-
TMD appear to be elevated as compared with healthy controls ditions, and autoimmune disorders (Clauw and Chrousos 1997;
but comparable to other chronic pain conditions (Dworkin and Ablin et al. 2009). However, only a small number of people
Massoth 1994; Giannakopoulos et al. 2010). The same is true who are exposed to any of the aforementioned conditions (~5%
of nonspecific somatic complaints (i.e., abdominal pain, unre- to 10%) go on to develop FM or CFS; the majority eventually
freshing sleep; Aaron et al. 2000). There is some evidence that return to a normal state of health. The complex interplay between
negative affective symptoms are a risk factor for developing genetic and environmental factors was recently illustrated by a
TMD. The OPPERA study found a number of psychosocial study showing interactions among COMT haplotypes, sex, and
factors that are associated cross sectionally with chronic TMD, psychological stress level, in terms of their effects on pain sen-
including levels of depression, anxiety, and somatization sitivity (Meloto 2016). The current hypothesis is that the vari-
(Fillingim et al. 2011). These results were corroborated by pro- ous factors that are known to be associated with centralized
spective analyses (n = 3,263), as levels of global psychological pain constitute a pain-prone phenotype, which causes people to
Centralized Pain in Temporomandibular Disorders 1105

develop a number of chronic pain conditions and which can Pain Perception and Processing
predict who will transition from acute to chronic pain follow-
ing an injury or environmental stressor. Quantitative sensory testing (QST) and neuroimaging have
The OPPERA study is the largest and most rigorous inves- helped us make significant advances in our understanding of
tigation of genetic risk factors for TMD and related conditions chronic pain pathogenesis. There is a wide bell-shaped range
(Maixner et al. 2011). OPPERA contained a prospective analy- of experimental pain sensitivity across the general population,
sis of >2,700 individuals designed to identify single-nucleotide with chronic pain patients more often found shifted to the right,
polymorphisms (SNPs) of common genes associated with pain hyperalgesic side of the curve (Diatchenko et al. 2005; Ablin
perception, affective processes, and inflammation that confer and Clauw 2009). Centralized pain patients with regional pain
risk for TMD (Smith et al. 2013). While no SNP was associ- (e.g., TMD) often exhibit hyperalgesia to pressure and thermal
ated with first-onset TMD, several emerged as predictors of stimulation, even remote from where the ongoing pain is expe-
intermediate phenotypes likely to be related to centralized rienced, suggesting that the central gain control for pain is set
pain. These included associations among: higher for the entire body (Maixner et al. 1995; Kashima et al.
1999; Giesecke et al. 2004; Slade et al. 2014). There is also
1. nonspecific orofacial pain with SNPs of the SCN1A evidence that nonpainful sensory signals are perceptually
gene, which is implicated in the initiation and propaga- amplified. For example, TMD patients have heightened sensi-
tion of action potentials in afferent nerves and may tivity to innocuous pressure and auditory stimuli, though not to
impair gamma-aminobutyric acid (GABA)ergic inter- the extent of FM patients (Hollins et al. 2009).
neuron function in the central nervous system, altering QST is an excellent tool for determining the potential
inhibitory tone (Martin et al. 2010); underlying mechanisms that may be leading to hyperalgesia
2. general psychological symptoms and 1 SNP of the and increased pain-evoked brain activity. The measurement of
COX1 gene, a strong regulator of central neuroinflam- pressure thresholds at the site of an injury could indicate
mation (Choi et al. 2009); and peripheral sensitization, but this mechanism cannot explain the
3. temporal summation of heat pain sensation with an widespread tenderness and hyperalgesia observed in central-
SNP of the MPDZ gene, which encodes proteins related ized pain patients. Conditioned pain modulation, a QST para-
to G protein–coupled receptors for neurotransmitters, digm in which 2 experimental pain stimuli are applied
including GABA (Balasubramanian et al. 2007). simultaneously, has also provided evidence for central pain–
processing abnormalities in chronic pain. When most healthy
Case-control genetic analyses were also conducted in individuals are tested for conditioned pain modulation, the
OPPERA for chronic TMD, which is most likely maintained in stronger, more tonic (conditioning) pain will inhibit the weaker,
part by centralized pain processes, and they revealed several phasic (test) pain. This form of endogenous analgesia is
SNPs associated with monoamine pathways as well as regulation impaired in FM (Kosek and Hansson 1997), but in TMD the
of inflammation—namely, interleukin 10 (IL-10; an anti-inflam- results have been mixed (King et al. 2009; Garrett 2013), pos-
matory cytokine) and 1 type of glucocorticoid receptor where the sibly due to differences among the samples in the proportion of
anti-inflammatory endogenous hormone cortisol binds (Smith TMD patients with highly centralized pain. If TMD subjects
et al. 2011). Another recent study indicated monoamine involve- are separated out according to their degree of centralized pain,
ment in TMD, as 1 SNP of the dopamine receptor 4 gene confers we expect that differences from controls would be observed in
additional TMD risk (Aneiros-Guerrero et al. 2011). the TMD patients with more centralized pain.
Another large-scale study of TMD compared subjects with- Functional magnetic resonance imaging studies have pro-
out widespread palpation tenderness (i.e., less centralized pain) vided a neurologic basis for hyperalgesia by revealing increased
with subjects with widespread tenderness (i.e., more central- pain-evoked brain activity in centralized pain (Gracely et al.
ized pain). The latter group was found to be characterized by 2002; Cook et al. 2004; Giesecke et al. 2004). The regions of
high levels of IL-8, a proinflammatory cytokine; this pheno- activation by experimental pain vary slightly depending on the
typic relationship was confirmed by experimental pain testing, parameters of stimulation but, for the most part, are activated
as higher levels of IL-8 were associated with reduced pressure reliably in both pain patients and controls. The most common
pain thresholds in the whole TMD sample (Slade et al. 2011). areas of activation are the thalamus, primary and secondary
An earlier study found a positive correlation between levels of somatosensory cortices, and insular cortex, as well as the ante-
circulating IL-6 and ischemic pain intensity (Costello et al. rior, mid-, and posterior cingulate cortex—meaning that pain
2002). Higher plasma levels of acute-phase proinflammatory generates a complex network of activity in sensory, limbic, and
cytokines IL-6, IL-1β, and tumor necrosis factor α, as well as associative brain regions. In general, for any given noxious
IL-10, were recently reported in TMD and were associated stimulus intensity, individuals with centralized chronic pain will
with more dysregulated sleep (Park and Chung 2016). These show greater amounts of pain-evoked activity in these brain regions.
findings are important because circulating levels of proinflam- Neuroimaging may hold one of the important keys for
matory cytokines have been linked to brain inflammation via detecting, diagnosing, and treating centralized pain mecha-
positron emission tomography (Loggia et al. 2015). nisms. There is a growing literature on the structural, functional,
Together these findings suggest that for some TMD patients, and neurochemical alterations that are present in the brains of
centralization of their pain might be due to a number of genetic TMD patients. While the neuroimaging literature on other
and/or inflammatory alterations in neurotransmitter systems. chronic pain conditions (e.g., FM) has begun to tell a consistent
1106 Journal of Dental Research 95(10)

story regarding centralized pain, small sample sizes and incon- most often undertaken (Wieckiewicz 2015). When the results
sistent findings across studies currently make solid conclusions are broken down by disease entity, no clear pattern of specific
about TMD difficult to come by (Lin 2014; Walitt et al. 2016). treatments targeted to specific pathologies emerges. For exam-
ple, occlusal splints were often utilized for treating myofascial
TMD, disk displacements, and bruxism.
Central Neurotransmission: The Common Although occlusal splints are often used to treat TMD, there is
Denominator no definitive answer on whether they are more effective than pla-
Given the high degree of comorbidity with other disorders and cebo. This discrepancy could be easily explained if occlusal
the frequency of certain symptoms, the most parsimonious splints are an effective treatment option for particular TMD
pathologic theory for centralized pain is thus: imbalances in pathologies but not others; the failure of many studies to separate
the neurotransmitters known to play a role in causing the pain TMD patients out based on etiology has likely masked the obser-
of the disorder are contributing to the comorbid pain condi- vance of treatment effectiveness beyond placebo in some sam-
tions and to disturbances with sleep, affect, memory, and other ples. For example, Raphael and Marbach (2001) conducted an
realms of function. The persistent pain could be due to 1) oral splint treatment study in 63 women with myofascial TMD.
increased neurotransmission in pronociceptive systems, 2) Some women received an active splint and others a sham or pla-
decreased neurotransmission in antinociceptive pathways, or cebo splint, and pain was measured at a 6-wk follow-up. Overall,
3) some combination thereof. If there is increased glutamater- there was no difference between the groups (i.e., no additional
gic tone, for example, this could lead to 1) an increase in the benefit of the active splint beyond placebo). However, when the
volume control for pain and other sensory stimuli because of researchers separated individuals out according to whether they
its actions in ≥1 sensory brain regions and 2) a dysregulation of had tenderness localized to the TMJ region or widespread tender-
sleep due to its action in sleep-related brain areas. There is ness, the active splint was shown to be significantly more effec-
ample evidence that neurotransmitter levels are altered in FM tive than the sham in the people who had localized TMD pain
and some evidence in TMD (Gerstner et al. 2012). Optimal (Raphael and Marbach 2001). It appears that this peripherally
treatment of centralized pain, including TMD, will likely entail targeted treatment was effective in individuals whose pain was
a determination of which neurotransmitter systems are dis- not centralized. In contrast, for centralized pain, this peripheral
rupted and the administration of the proper exogenous drug to treatment did not target the source and was therefore ineffective.
rectify the imbalance. Still, nondrug therapies (e.g., cognitive The move from the sophisticated neuroimaging, genetic,
behavioral therapy) will have a place in treatment, since they and QST methods that have been used to uncover centralized
too are capable of altering neurotransmission. Also, because of pain features to the clinic may seem complicated, but much of
the overlap in the brain’s use of neurotransmitter classes for the information about a patient’s degree of pain centralization
different functions, drugs that might be good candidates for can be obtained, albeit less precisely, through methods cur-
reducing pain will not be recommended due to side effects via rently available to clinicians.
interactions with other nonpain systems. By taking a thorough history and conducting a physical
examination, clinicians can gain insight into the amount of sen-
sory amplification (and, thus, pain centralization) present in a
Mixed Pain States patient. Centralized pain often entails a ramping up of the vol-
ume control for not only pain but also touch, heat, sounds, and light
There are both central and peripheral contributions to chronic
(Geisser et al. 2008). In addition, these patients have signifi-
pain in most patients—meaning that pain is mechanistically
cantly higher somatic awareness, or hypervigilance—meaning
mixed, but central factors are more relevant in some cases and
that they are much more aware of sensations associated with
peripheral factors in others (possibly nociceptive and/or periph-
their own bodies (e.g., indigestion, urinary urgency, eyelids
eral neuropathic). For further discussion of this topic, consult
twitching; Hollins et al. 2009). Discussing these factors with
Appendix A.
patients can be illuminating. Although experimental pain test-
ing is not yet routine and standardized in clinical practice, one
can gain insight into the degree of centralization in a patient by
Implications for the Treatment of TMD assessing pressure pain thresholds at asymptomatic locations,
Past lessons of failed TMJ implants, the often observed mis- such as the arms or hands. By applying firm pressure over 1)
match between peripheral pathology and pain level, and the several interphalangeal joints of each hand, 2) the adjacent
fact that for many individuals TMD pain is self-limiting have phalanges, and 3) the forearm muscles (including the lateral
brought the field to a point where conservative, reversible epicondyle region), one can assess overall pain sensitivity and
treatments are recommended. While this is an improvement gain other potentially valuable information. If the patient is
from the most common standards of care decades ago, it is still tender in most or all areas or just the forearm, they are likely a
the case that TMD treatment is not often personalized based on pain-sensitive individual, making the chances that their pain is
each patient’s underlying pain mechanism. centralized to some degree greater. If the patient is tender in
A recent review of 66 TMD treatment papers published only the fingers, this might indicate other pathologies (e.g.,
between 1994 and 2014 concluded that conservative treat- rheumatoid arthritis, lupus, metabolic bone disease).
ments—including counseling, occlusal splint therapy, physio- The degree of pain centralization for each patient can be taken
therapeutic techniques (e.g., massage), and drug therapy—are into account when determining the appropriate pharmacologic
Centralized Pain in Temporomandibular Disorders 1107

therapy. For patients with peripheral/nociceptive noninflam- Pfizer and serves as a consultant for Tonix, Theravance, Cerephex,
matory pain, acetaminophen and nonsteroidal anti-inflammatory Pfizer, Abbott, Merck, Eli Lilly, UCB, Johnson & Johnson, Forest
drugs work well. The former is now thought to be safer but less Laboratories, and Purdue Pharma. The authors declare no poten-
effective than the latter. Although opioids can be effective in tial conflicts of interest with respect to the authorship and/or pub-
certain situations, they are known to be ineffective (and some- lication of this article.
times counterproductive) for chronic pain and are no longer
recommended for it. Both inflammatory and noninflammatory References
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Bair E, Baraian C, Mack N, Slade GD, et al. 2013. Psychological factors
D.E. Harper and A. Schrepf, contributed to conception and design, associated with development of TMD: the OPPERA prospective cohort
drafted and critically revised the manuscript; D.J. Clauw, contrib- study. J Pain. 14(12 Suppl):T75–T90.
uted to conception and design, critically revised the manuscript. Fillingim RB, Ohrbach R, Greenspan JD, Knott C, Dubner R, Bair E, Baraian
C, Slade GD, Maixner W. 2011. Potential psychosocial risk factors for
All authors gave final approval and agree to be accountable for all
chronic TMD: descriptive data and empirically identified domains from the
aspects of the work. OPPERA case-control study. J Pain. 12(11 Suppl):T46–T60.
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Acknowledgments Garrett PH, Sarlani E, Grace EG, Greenspan JD. 2013. Chronic temporoman-
Drs. Harper and Schrepf are supported by National Institutes of dibular disorders are not necessarily associated with a compromised endog-
enous analgesic system. J Orofac Pain. 27(2):142–150.
Health (K12-DE023574; D.J.C., principal investigator). Dr. Clauw Geisser ME, Strader DC, Petzke F, Gracely RH, Clauw DJ, Williams DA.
has received research funding from Cerephex, Forest, Merck, and 2008. Comorbid somatic symptoms and functional status in patients with
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