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Traditional classification and prognostic approaches for chronic pain conditions focus primarily on anatomically based clinical characteristics not based on underlying biopsychosocial factors contributing to perception of clinical pain and future pain trajectories. Using a supervised clustering approach in a cohort of temporomandibular disorder cases and controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment study, we recently developed and validated a rapid algorithm (ROPA) to pragmatically classify chronic pain patients into 3 groups that differed in clinical pain report, biopsychosocial profiles, functional limitations, and comorbid conditions. The present aim was to examine the generalizability of this clustering procedure in 2 additional cohorts: a cohort of patients with chronic overlapping pain conditions (Complex Persistent Pain Conditions study) and a real-world clinical population of patients seeking treatment at duke innovative pain therapies. In each cohort, we applied a ROPA for cluster prediction, which requires only 4 input variables: pressure pain threshold and anxiety, depression, and somatization scales. In both complex persistent pain condition and duke innovative pain therapies, we distinguished 3 clusters, including one with more severe clinical characteristics and psychological distress. We observed strong concordance with observed cluster solutions, indicating the ROPA method allows for reliable subtyping of clinical populations with minimal patient burden. The ROPA clustering algorithm represents a rapid and valid stratification tool independent of anatomic diagnosis. ROPA holds promise in classifying patients based on pathophysiological mechanisms rather than structural or anatomical diagnoses. As such, this method of classifying patients will facilitate personalized pain medicine for patients with chronic pain.

Cross-sectional studies confirm, as expected, a positive association between jaw injury and painful temporomandibular disorders (TMDs), but prospective evaluations are lacking. We prospectively assessed incident jaw injury, injury type, and development of TMD in adults aged 18 to 44 years. Data were collected from 3258 individuals from communities surrounding 4 US academic institutes between 2006 and 2008. At enrollment, participants reported no TMD history and no facial injuries in the previous 6 months. Quarterly, follow-up questionnaires assessed incident jaw injury, which was classified as intrinsic (attributed to yawning or prolonged mouth opening) or extrinsic (attributed to other causes). Examiners classified incident TMD during a median follow-up period of 2.8 years (range 0.2-5.2 years). Cox regression models used jaw injury as a time-dependent covariate to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association with incident TMD. Among 1729 participants with complete data, 175 developed TMD. Eighty percent of injuries were intrinsic. Temporomandibular disorder annual incidence was nearly twice as high in those experiencing jaw injury (5.37%) compared with those who did not (3.44%). In the Cox model that accounted for timing of injury, the corresponding HR was 3.94 (95% CI = 2.82-5.50) after adjusting for study site, age, race, and sex. Hazard ratios did not differ (P = 0.91) for extrinsic injuries (HR = 4.03, 95% CI = 2.00-8.12) and intrinsic injuries (HR = 3.85, 95% CI = 2.70-5.49). Jaw injury was strongly associated with incident TMD. If surveillance and intervention after jaw injury is to be effective in preventing TMD, they should focus on both intrinsic and extrinsic injuries.

BACKGROUND Multiple risk factors predict temporomandibular disorders (TMD) onset, but temporal changes in risk factors and their contribution to risk of TMD have not been evaluated. The study aims were to (a) describe changes occurring in premorbid TMD risk factors when re-measured at TMD onset and 6 months later, and (b) determine if measures of change improve accuracy in predicting TMD incidence compared to premorbid measures alone. METHODS In this observational prospective cohort study at four university research clinics, 3,258 community-based, 18- to 44-year-olds without TMD were enrolled. During the 3-year median follow-up, 260 incident cases of first-onset TMD were identified, and 196 TMD-free subjects were selected as matched controls. Six-months later, 147 of 260 incident cases (56.6%) were re-examined revealing 72 (49%) with 'persistent TMD' and 75 (51%) whose condition had resolved ('transient TMD'). Virtually all (126) of the 127 re-examined controls remained without TMD. Questionnaires and clinical measurements evaluated risk factors from clinical, health, psychological and behavioural and neurosensory domains. RESULTS Most risk factors across all four domains increased with TMD onset, remained elevated in the persistent group and declined in the transient group (i.e., significant ANOVA interactions, p

There is good evidence that poor sleep quality increases risk of painful temporomandibular disorder (TMD). However, little is known about the course of sleep quality in the months preceding TMD onset, and whether the relationship is mediated by heightened sensitivity to pain. The Pittsburgh Sleep Quality Index was administered at enrollment into the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study. Thereafter the Sleep Quality Numeric Rating Scale was administered every 3 months to 2,453 participants. Sensitivity to experimental pressure pain and pinprick pain stimuli was measured at baseline and repeated during follow-up of incident TMD cases (n = 220) and matched TMD-free controls (n = 193). Subjective sleep quality deteriorated progressively, but only in those who subsequently developed TMD. A Cox proportional hazards model showed that risk of TMD was greater among participants whose sleep quality worsened during follow-up (adjusted hazard ratio = 1.73, 95% confidence limits = 1.29, 2.32). This association was independent of baseline measures of sleep quality, psychological stress, somatic awareness, comorbid conditions, nonpain facial symptoms, and demographic characteristics. Poor baseline sleep quality was not significantly associated with baseline pain sensitivity or with subsequent change in pain sensitivity. Furthermore the relationship between sleep quality and TMD incidence was not mediated via baseline pain sensitivity or change in pain sensitivity. Perspective Subjective sleep quality deteriorates progressively before the onset of painful TMD, but sensitivity to experimental pain does not mediate this relationship. Furthermore, the relationship is independent of potential confounders such as psychological stress, somatic awareness, comorbid conditions, nonpain facial symptoms, and various demographic factors.

Catecholamine-O-methyltransferase (COMT) is a polymorphic gene whose variants affect enzymatic activity and pain sensitivity via adrenergic pathways. Although COMT represents one of the most studied genes in human pain genetics, findings regarding its association with pain phenotypes are not always replicated. Here, we investigated if interactions among functional COMT haplotypes, stress, and sex can modify the effect of COMT genetic variants on pain sensitivity. We tested these interactions in a cross-sectional study, including 2 cohorts, one of 2972 subjects tested for thermal pain sensitivity (Orofacial Pain: Prospective Evaluation and Risk Assessment) and one of 948 subjects with clinical acute pain after motor vehicle collision (post-motor vehicle collision). In both cohorts, the COMT high-pain sensitivity (HPS) haplotype showed robust interaction with stress and number of copies of the HPS haplotype was positively associated with pain sensitivity in nonstressed individuals, but not in stressed individuals. In the post-motor vehicle collision cohort, there was additional modification by sex: the HPS-stress interaction was apparent in males, but not in females. In summary, our findings indicate that stress and sex should be evaluated in association studies aiming to investigate the effect of COMT genetic variants on pain sensitivity.

In identifying subgroups of a heterogeneous disease or condition, it is often desirable to identify both the observations and the features which differ between subgroups. For instance, it may be that there is a subgroup of individuals with a certain disease who differ from the rest of the population based on the expression profile for only a subset of genes. Identifying the subgroup of patients and subset of genes could lead to better-targeted therapy. We can represent the subgroup of individuals and genes as a bicluster, a submatrix, U , of a larger data matrix, X , such that the features and observations in U differ from those not contained in U . We present a novel two-step method, SC-Biclust, for identifying U . In the first step, the observations in the bicluster are identified to maximize the sum of the weighted between-cluster feature differences. In the second step, features in the bicluster are identified based on their contribution to the clustering of the observations. This versatile method can be used to identify biclusters that differ on the basis of feature means, feature variances, or more general differences. The bicluster identification accuracy of SC-Biclust is illustrated through several simulated studies. Application of SC-Biclust to pain research illustrates its ability to identify biologically meaningful subgroups.

Cluster analysis methods are used to identify homogeneous subgroups in a data set. In biomedical applications, one frequently applies cluster analysis in order to identify biologically interesting subgroups. In particular, one may wish to identify subgroups that are associated with a particular outcome of interest. Conventional clustering methods generally do not identify such subgroups, particularly when there are a large number of high-variance features in the data set. Conventional methods may identify clusters associated with these high-variance features when one wishes to obtain secondary clusters that are more interesting biologically or more strongly associated with a particular outcome of interest. A modification of sparse clustering can be used to identify such secondary clusters or clusters associated with an outcome of interest. This method correctly identifies such clusters of interest in several simulation scenarios. The method is also applied to a large prospective cohort study of temporomandibular disorders and a leukemia microarray data set.

OBJECTIVES We evaluated the stability of the comorbidity between vulvodynia and orofacial pain (OFP) and its associated clinical characteristics over a 2-year follow-up period. MATERIALS AND METHODS In an earlier study of vestibulodynia patients, we administered questionnaires assessing demographic data, self-reported pain, anxiety, somatic awareness, and presence of signs and symptoms suggestive of clinical and subclinical OFP. The present study readministered the same surveys to a subset of the original cohort after a 2-year follow-up period. RESULTS Of the 138 women in the previous study, 71 (51%) agreed to participate in the present study. We confirmed our earlier findings that (1) OFP is a highly prevalent (66%) condition among women with vestibulodynia, and (2) compared with women with no OFP symptoms, those with OFP symptoms experience higher levels of anxiety (P=0.005) and somatic awareness (P

MicroRNAs (miRs) are a family of noncoding RNAs that regulate gene expression. They are ubiquitous among multicellular eukaryotes and are also encoded by some viruses. Upon infection, viral miRs (vmiRs) can potentially target gene expression in the host and alter the immune response. Although prior studies have reported viral infections in human pulp, the role of vmiRs in pulpal disease is yet to be explored. The purpose of this study was to examine the expression of vmiRs in normal and diseased pulps and to identify potential target genes.Total RNA was extracted and quantified from normal and inflamed human pulps (N = 28). Expression profiles of vmiRs were then interrogated using miRNA microarrays (V3) and the miRNA Complete Labeling and Hyb Kit (Agilent Technologies, Santa Clara, CA). To identify vmiRs that were differentially expressed, we applied a permutation test.Of the 12 vmiRs detected in the pulp, 4 vmiRs (including those from herpesvirus and human cytomegalovirus) were differentially expressed in inflamed pulp compared with normal pulp (P .05). Using bioinformatics, we identified potential target genes for the differentially expressed vmiRs. They included key mediators involved in the detection of microbial ligands, chemotaxis, proteolysis, cytokines, and signal transduction molecules.These data suggest that miRs may play a role in interspecies regulation of pulpal health and disease. Further research is needed to elucidate the mechanisms by which vmiRs can potentially modulate the host response in pulpal disease.

Apical periodontitis is an inflammatory disease of the periradicular tissues caused by the host's immune response to infection of the root canal system. MicroRNAs (miRNAs) have been shown to play an important role in the regulation of inflammation and the immune response; however, their role in the pathogenesis of endodontic periapical disease has not been explored. The purpose of this study was to examine the differential expression of miRNAs in diseased periapical tissues as compared with healthy controls.We first compared miRNA profiles in diseased periapical tissues collected from patients undergoing endodontic surgery with those of healthy pulps by using microarray analyses. The target genes of the differentially expressed miRNAs were identified by using miRWalk and PubMed. Selected miRNAs linked to inflammation and the immune response were then confirmed in a separate cohort of diseased and healthy tissues by using quantitative reverse transcription-polymerase chain reaction. Healthy pulps and periodontal ligaments were used as controls. Data were normalized to the level of SNORD 44, which served as an endogenous control.Of the 381 miRNAs identified by using microarray, 24 miRNAs were down-regulated in diseased periapical tissues compared with controls (n = 13) (P.003). The down-regulation of 7 miRNAs was confirmed from 9 selected miRNAs by using quantitative real-time polymerase chain reaction (n = 19) (P .05). Target genes of these miRNAs include key mediators in the immune and inflammatory response such as interleukin-6, matrix metalloproteinase-9, and transforming growth factor-β.These findings offer new insight into the pathogenesis of endodontic disease and have the potential to impact the development of new methods for prevention, diagnosis, and treatment of apical periodontitis.

Case-control studies have documented clinical manifestations of chronic temporomandibular disorder (TMD), whereas clinical predictors of TMD development are largely unknown. We evaluated 41 clinical orofacial characteristics thought to predict first-onset TMD in a prospective cohort study of U.S. adults aged 18 to 44 years. During the median 2.8-year follow-up period, 2,737 people completed quarterly screening questionnaires. Those reporting symptoms were examined and 260 people were identified with first-onset TMD. Univariate and multivariable Cox regression models quantified associations between baseline clinical orofacial measures and TMD incidence. Significant predictors from baseline self-report instruments included oral parafunctions, prior facial pain and its life-impact, temporomandibular joint noises and jaw locking, and nonspecific orofacial symptoms. Significant predictors from the baseline clinical examination were pain on jaw opening and pain from palpation of masticatory, neck, and body muscles. Examiner assessments of temporomandibular joint noise and tooth wear facets did not predict incidence. In multivariable analysis, nonspecific orofacial symptoms, pain from jaw opening, and oral parafunctions predicted TMD incidence. The results indicate that only a few orofacial examination findings influenced TMD incidence, and only to a modest degree. More pronounced influences were found for self-reported symptoms, particularly those that appeared to reflect alterations to systems beyond the masticatory tissues. Perspective OPPERA's prospective cohort study identifies predictors of first-onset TMD comprising self-reported orofacial symptoms and examination findings. The results suggest a complex pattern of TMD etiology that is influenced by disorders locally, in masticatory tissues, and systemically, in pain-regulatory systems.

Case-control studies have consistently associated psychological factors with chronic pain in general and with temporomandibular disorder (TMD) specifically. However, only a handful of prospective studies have explored whether preexisting psychological characteristics represent risk factors for first-onset TMD. The current findings derive from the prospective cohort study of the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) cooperative agreement. For this study, 3,263 TMD-free participants completed a battery of psychological instruments assessing general psychological adjustment and personality, affective distress, psychosocial stress, somatic symptoms, and pain coping and catastrophizing. Study participants were then followed prospectively for an average of 2.8 years to ascertain cases of first-onset of TMD, and 2,737 provided follow-up data and were considered in the analyses of TMD onset. In bivariate and demographically adjusted analyses, several psychological variables predicted increased risk of first-onset TMD, including reported somatic symptoms, psychosocial stress, and affective distress. Principal component analysis of 26 psychological scores was used to identify latent constructs, revealing 4 components: stress and negative affectivity, global psychological and somatic symptoms, passive pain coping, and active pain coping. In multivariable analyses, global psychological and somatic symptoms emerged as the most robust risk factor for incident TMD. These findings provide evidence that measures of psychological functioning can predict first onset of TMD. Future analyses in the OPPERA cohort will determine whether these psychological factors interact with other variables to increase risk for TMD onset and persistence. Perspective This article reports that several premorbid psychological variables predict first-onset TMD in the OPPERA study, a large prospective cohort study designed to discover causal determinants of TMD pain. Measures of somatic symptoms were most strongly associated with TMD onset, but perceived stress, previous life events, and negative affect also predicted TMD incidence.

Human association studies of common genetic polymorphisms have identified many loci that are associated with risk of complex diseases, although individual loci typically have small effects. However, by envisaging genetic associations in terms of cellular pathways, rather than any specific polymorphism, combined effects of many biologically relevant alleles can be detected. The effects are likely to be most apparent in investigations of phenotypically homogenous subtypes of complex diseases. We report findings from a case-control, genetic association study of relationships between 2925 single nucleotide polymorphisms (SNPs) and 2 subtypes of a commonly occurring chronic facial pain condition, temporomandibular disorder (TMD): 1) localized TMD and 2) TMD with widespread pain. When compared to healthy controls, cases with localized TMD differed in allelic frequency of SNPs that mapped to a serotonergic receptor pathway (P=0.0012), while cases of TMD with widespread pain differed in allelic frequency of SNPs that mapped to a T-cell receptor pathway (P=0.0014). A risk index representing combined effects of 6 SNPs from the serotonergic pathway was associated with greater odds of localized TMD (odds ratio 2.7, P=1.3 E-09), and the result was reproduced in a replication case-control cohort study of 639 people (odds ratio 1.6, P=0.014). A risk index representing combined effects of 8 SNPs from the T-cell receptor pathway was associated with greater odds of TMD with widespread pain (P=1.9 E-08), although the result was not significant in the replication cohort. These findings illustrate potential for clinical classification of chronic pain based on distinct molecular profiles and genetic background.

The enzyme catechol-O-methyltransferase (COMT) metabolizes catecholamine neurotransmitters involved in a number of physiological functions including pain perception. Both human and mouse COMT genes possess functional polymorphisms contributing to inter-individual variability in pain phenotypes such as sensitivity to noxious stimuli, severity of clinical pain and response to pain treatment. In this study, we found that the effects of Comt functional variation in mice are modality-specific. Spontaneous inflammatory nociception and thermal nociception behaviors were correlated the most with the presence of the B2 SINE transposon insertion residing in the 3’UTR mRNA region. Similarly, in humans, COMT functional haplotypes were associated with thermal pain perception and with capsaicin-induced pain. Furthermore, COMT genetic variations contributed to pain behaviors in mice and pain ratings in humans in a sex-specific manner. The ancestral Comt variant, without a B2 SINE insertion, was more strongly associated with sensitivity to capsaicin in female versus male mice. In humans, the haplotype coding for low COMT activity increased capsaicin-induced pain perception in women, but not men. These findings reemphasize the fundamental contribution of COMT to pain processes, and provide a fine-grained resolution of this contribution at the genetic level that can be used to guide future studies in the area of pain genetics.

A fluorescent peptide substrate was used to measure dephosphorylation by protein tyrosine phosphatases (PTP) in cell lysates and single cells and to investigate the effect of environmental toxins on PTP activity in these systems. Dephosphorylation of the substrate by PTPN1 and PTPN2 obeyed Michaelis-Menten kinetics, with KM values of 770 ± 250 and 290 ± 54 nM, respectively. Dose-response curves and IC50 values were determined for the inhibition of these two enzymes by the environmental toxins Zn(2+) and 1,2-naphthoquinone, as well as pervanadate. In A431 cell lysates, the reporter was a poor substrate for peptidases (degradation rate of 100 ± 8.2 fmol min(-1) mg(-1)) but an excellent substrate for phosphatases (dephosphorylation rate of 1.4 ± 0.3 nmol min(-1) mg(-1)). Zn(2+), 1,2-naphthoquinone, and pervanadate inhibited dephosphorylation of the reporter in cell lysates with IC50 values of 470 nM, 35 μM, and 100 nM, respectively. Dephosphorylation of the reporter, following loading into living single cells, occurred at rates of at least 2 pmol min(-1) mg(-1). When single cells were exposed to 1,2-naphthoquinone (50 μM), Zn(2+) (100 μM), and pervandate (1 mM), dephosphorylation was inhibited with median values and first and third quartile values of 41 (Q1 = 0%, Q3 = 96%), 50 (Q1 = 46%, Q3 = 74%), and 53% (Q1 = 36%, Q3 = 77%), respectively, demonstrating both the impact of these toxic exposures on cell signaling and the heterogeneity of response between cells. This approach will provide a valuable tool for the study of PTP dynamics, particularly in small, heterogeneous populations such as human biopsy specimens.

We explored causal mediation of sleep quality and perceived stress in development of painful temporomandibular disorder (TMD). Sleep quality and perceived stress were assessed at baseline and quarterly intervals thereafter in 2,737 initially TMD-free adults in the Orofacial Pain Prospective Evaluation and Risk Assessment study (OPPERA) prospective cohort study. During follow-up, incident TMD cases were classified using research diagnostic criteria. Mediation analysis was conducted using a weighted Cox proportional hazards regression model that estimated hazard ratios (HRs) and 95% confidence limits (CL) of first-onset TMD. Models determined whether: 1) poor sleep quality during follow-up mediated the effect of baseline perceived stress on first-onset TMD, and 2) perceived stress during follow-up mediated the effect of baseline poor sleep quality on first-onset TMD. In both analyses, the total effect was decomposed into natural direct and indirect effects. Poor baseline sleep quality led to heightened perceived stress that then contributed to TMD development. When the total effect of poor sleep quality (HR = 2.10, CL = 1.76, 2.50) was decomposed, 34% of its effect was mediated by perceived stress (indirect effect HR = 1.29, CL = 1.06, 1.58). The effect of perceived stress on first-onset TMD was not mediated by sleep quality. Improving sleep may avert escalation of stress, limiting effects of both factors on TMD development. Perspective Causal mediation analysis highlights mechanisms by which poor sleep quality promotes development of TMD. First, poor sleep quality exerts a direct effect on pain. Second, it triggers a heightened perception of stress, which acts as an intermediate factor in the causal pathway between poor sleep quality and first-onset TMD pain.

The demographic factors of sex, age, and race/ethnicity are well recognized as relevant to pain sensitivity and clinical pain expression. Of these, sex differences have been the most frequently studied, and most of the literature describes greater pain sensitivity for women. The other 2 factors have been less frequently evaluated, and current literature is not definitive. Taking advantage of the large Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study cohort, we evaluated the association of sex, age, and self-reported race with 34 measures of pressure, mechanical, and thermal pain sensitivity encompassing threshold and suprathreshold perception. Women were significantly more pain-sensitive than men for 29 of 34 measures. Age effects were small, and only significant for 7 of 34 measures, however, the age range was limited (18–44 years of age). Race/ethnicity differences varied across groups and pain assessment type. Non-Hispanic white individuals were less pain-sensitive than African-American (for 21 of 34 measures), Hispanic (19 of 34), and Asian (6 of 34) individuals. No pain threshold measure showed significant racial differences, whereas several suprathreshold pain measures did. This suggests that racial differences are not related to tissue characteristics or inherent nociceptor sensitivity. Rather, the differences observed for suprathreshold pain ratings or tolerance are more likely related to differences in central nociceptive processing, including modulation imposed by cognitive, psychological, and/or affective factors. Perspective The influence of sex, age, and race/ethnicity on various aspects of pain sensitivity, encompassing threshold and suprathreshold measures and multiple stimulus modalities, allows for a more complete evaluation of the relevance of these demographic factors to acute pain perception.

The classification of most chronic pain disorders gives emphasis to anatomical location of the pain to distinguish one disorder from the other (eg, back pain vs temporomandibular disorder [TMD]) or to define subtypes (eg, TMD myalgia vs arthralgia). However, anatomical criteria overlook etiology, potentially hampering treatment decisions. This study identified clusters of individuals using a comprehensive array of biopsychosocial measures. Data were collected from a case-control study of 1031 chronic TMD cases and 3247 TMD-free controls. Three subgroups were identified using supervised cluster analysis (referred to as the adaptive, pain-sensitive, and global symptoms clusters). Compared with the adaptive cluster, participants in the pain-sensitive cluster showed heightened sensitivity to experimental pain, and participants in the global symptoms cluster showed both greater pain sensitivity and greater psychological distress. Cluster membership was strongly associated with chronic TMD: 91.5% of TMD cases belonged to the pain-sensitive and global symptoms clusters, whereas 41.2% of controls belonged to the adaptive cluster. Temporomandibular disorder cases in the pain-sensitive and global symptoms clusters also showed greater pain intensity, jaw functional limitation, and more comorbid pain conditions. Similar results were obtained when the same methodology was applied to a smaller case-control study consisting of 199 chronic TMD cases and 201 TMD-free controls. During a median 3-year follow-up period of TMD-free individuals, participants in the global symptoms cluster had greater risk of developing first-onset TMD (hazard ratio = 2.8) compared with participants in the other 2 clusters. Cross-cohort predictive modeling was used to demonstrate the reliability of the clusters.

Vestibulodynia, the most common type of chronic vulvovaginal pain, impairs the psychological, physical health of nearly 10% of women at some point in their lifetime. The aim of this investigation was to establish reliable standardized methodologies for assessment of pain sensitivity in vulvar mucosa and pelvic musculature. We enrolled 34 women with vestibulodynia and 21 pain-free controls. The participants underwent a nuanced exam that consisted of palpation of precisely located vulvar mucosal and pelvic muscle sites. These measurements remained highly stable when participants were reexamined after 2 weeks, with high within-examiner correlation. Vestibulodynia patients reported greater sensitivity than pain-free controls at the majority of examination sites, particularly at mucosal sites on the lower vestibule. The pain threshold measures at the lower mucosal sites were also associated with the participants’ self-reported pain levels during intercourse. These mucosal pain threshold measurements were used to discriminate between vestibulodynia cases and controls with high sensitivity and specificity. This data supports the feasibility of contemporaneous assessment of vulvar mucosa and underlying musculature in the pelvic region, offering the hope of a more precise case definition for vestibulodynia and related disorders. Perspective This study describes performance characteristics of novel methodologies for assessing pelvic muscle and mucosal sensitivity. These pain sensitivity measures were reproducible and associated with subjective pain reports and vestibulodynia case status and represent an important step toward a more precise case definition for vestibulodynia and related disorders.

Chronic pain is a significant health care problem, ineffectively treated because of its unclear etiology and heterogeneous clinical presentation. Emerging evidence demonstrates that microRNAs (miRNAs) regulate the expression of pain-relevant genes, yet little is known about their role in chronic pain. Here, we evaluate the relationship among pain, psychological characteristics, plasma cytokines, and whole blood miRNAs in 22 healthy controls (HCs); 33 subjects with chronic pelvic pain (vestibulodynia, VBD); and 23 subjects with VBD and irritable bowel syndrome (VBD + IBS). VBD subjects were similar to HCs in self-reported pain, psychological profiles, and remote bodily pain. VBD + IBS subjects reported decreased health and function; and an increase in headaches, somatization, and remote bodily pain. Furthermore, VBD subjects exhibited a balance in proinflammatory and anti-inflammatory cytokines, whereas VBD + IBS subjects failed to exhibit a compensatory increase in anti-inflammatory cytokines. VBD subjects differed from controls in expression of 10 miRNAs of predicted importance for pain and estrogen signaling. VBD + IBS subjects differed from controls in expression of 11 miRNAs of predicted importance for pain, cell physiology, and insulin signaling. miRNA expression was correlated with pain-relevant phenotypes and cytokine levels. These results suggest that miRNAs represent a valuable tool for differentiating VBD subtypes (localized pain with apparent peripheral neurosensory disruption vs widespread pain with a central sensory contribution) that may require different treatment approaches.

Purpose We assessed a novel Food and Drug Administration–approved hydrogel, synthesized as absorbable iodinated particles, in gynecologic-cancer patients undergoing computed tomography (CT) or magnetic resonance (MR) based brachytherapy after external beam radiation. Methods and Materials Nineteen patients underwent CT-guided (n = 13) or MR-guided (n = 6) brachytherapy for gynecologic cancers. Seventy-seven hydrogel injections were placed. The hydrogel material was injected into gross residual disease and/or key anatomic landmarks in amounts ranging from 0.1 to 0.4 mL. The visibility of the tracer was scored on CT and on MR images using a 5-point scoring scale. A Cohen's kappa statistic was calculated to assess interobserver agreement. To assess the unadjusted effects of baseline parameters on hydrogel visibility, we modeled visibility using a linear mixed-effect model. Results Injections were without complication. The kappa statistic was 0.77 (95% confidence interval [CI], 0.68–0.87). The volume of hydrogel injected was significantly associated with visibility on both CT ( p = 0.032) and magnetic resonance imaging ( p = 0.016). We analyzed visibility by location, controlling for amount. A 0.1-cc increase in volume injected was associated with increases of 0.54 (95% CI = 0.05–1.03) in the CT visibility score and 0.83 (95% CI = 0.17–1.49) in the MR visibility score. Injection of 0.4 cc or more was required for unequivocal visibility on CT or MR. No statistically significant correlation was found between tumor type, tumor location, or anatomical location of injection and visibility on either CT or magnetic resonance imaging. Conclusions In this first report of an injectable radiopaque hydrogel, targets were visualized to assist with three-dimensional–based brachytherapy in gynecologic malignancies. This marker has potential for several applications, is easy to inject and visualize, and caused no acute complications.

Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs) have a well-established analgesic efficacy for inflammatory pain. These drugs exert their effect by inhibiting the enzyme cyclooxygenase (COX) and are commonly used for the management of pain after endodontic treatment. There are 2 distinct isoforms of COX: COX-1, which is constitutively expressed, and COX-2, which is primarily induced by inflammation. Previous studies have shown that functional human genetic variants of the COX-2 gene may explain individual variations in acute pain. The present study extends this work by examining the potential contribution of the 2 COX isoforms to pain after endodontic treatment. Methods Ninety-four patients treated by endodontic residents at the University of North Carolina School of Dentistry were enrolled into a prospective cohort study. Data on potential predictors of post-treatment pain were collected, and all patients submitted saliva samples for genetic analysis. Nonsurgical root canal therapy was performed, and participants recorded pain levels for 5 days after. Results In this study, 63% of patients experienced at least mild pain after root canal therapy, and 24% experienced moderate to severe pain. The presence of pretreatment pain was correlated with higher post-treatment pain (P = .01). Elevated heart rate (P = .02) and higher diastolic blood pressure (P = .024) were also correlated with decreased post-treatment pain. Finally, we identified genetic variants in COX-2 (haplotype composed of rs2383515 G, rs5277 G, rs5275 T, and rs2206593 A) associated with post-treatment pain after endodontic treatment (P = .025). Conclusions Understanding the genetic basis of pain after endodontic treatment will advance its prevention and management.

In a prospective cohort study, examining all participants for incidence of the condition of interest may be prohibitively expensive. For example, the “gold standard” for diagnosing temporomandibular disorder (TMD) is a physical examination by a trained clinician. In large studies, examining all participants in this manner is infeasible. Instead, it is common to use questionnaires to screen for incidence of TMD and perform the “gold standard” examination only on participants who screen positively. Unfortunately, some participants may leave the study before receiving the “gold standard” examination. Within the framework of survival analysis, this results in missing failure indicators. Motivated by the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study, a large cohort study of TMD, we propose a method for parameter estimation in survival models with missing failure indicators. We estimate the probability of being an incident case for those lacking a “gold standard” examination using logistic regression. These estimated probabilities are used to generate multiple imputations of case status for each missing examination that are combined with observed data in appropriate regression models. The variance introduced by the procedure is estimated using multiple imputation. The method can be used to estimate both regression coefficients in Cox proportional hazard models as well as incidence rates using Poisson regression. We simulate data with missing failure indicators and show that our method performs as well as or better than competing methods. Finally, we apply the proposed method to data from the OPPERA study.

Cluster analysis methods seek to partition a data set into homogeneous subgroups. It is useful in a wide variety of applications, including document processing and modern genetics. Conventional clustering methods are unsupervised, meaning that there is no outcome variable nor is anything known about the relationship between the observations in the data set. In many situations, however, information about the clusters is available in addition to the values of the features. For example, the cluster labels of some observations may be known, or certain observations may be known to belong to the same cluster. In other cases, one may wish to identify clusters that are associated with a particular outcome variable. This review describes several clustering algorithms (known as “semi-supervised clustering” methods) that can be applied in these situations. The majority of these methods are modifications of the popular k-means clustering method, and several of them will be described in detail. A brief description of some other semi-supervised clustering algorithms is also provided.

Central sensitization elicits pain hypersensitivity and is thought to be causally implicated in painful temporomandibular disorder (TMD). This causal inference is based on cross-sectional evidence that people with TMD have greater sensitivity than controls to noxious stimuli. We tested this inference in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study of 3258 adults with no lifetime history of TMD when enrolled (visit 1). During 5 years of follow-up, 1 group labeled "persistent TMD cases" (n=72) developed first-onset TMD by visit 2 that persisted ⩾ 6 months until visit 3. Another group labeled "transient TMD cases" (n=75) developed first-onset TMD at visit 2, which resolved by visit 3. Randomly sampled "controls" (n=126) remained TMD-free throughout all 3 visits. At each visit, pressure pain thresholds (PPTs) were measured by algometry at 10 cranial and bodily sites. In persistent TMD case patients, mean PPTs reduced 43 kPa (P

We examined the incidence and predictors of peritraumatic distress and dissociation after one of the most common forms of civilian trauma exposure: motor vehicle collision (MVC).In this study, patients presenting to the emergency department after MVCs who were without serious injury and discharged to home after evaluation (n = 935) completed an emergency department interview evaluating sociodemographic, collision-related, and psychological characteristics.The incidence and predictors of distress (Peritraumatic Distress Inventory score ≥23) and dissociation (Michigan Critical Events Perception Scale score3) were assessed. Distress was present in 355 of 935 patients (38%), and dissociation was present in 260 of 942 patients (28%). These outcomes showed only moderate correlation (r = .45) and had both shared and distinct predictors. Female gender, anxiety symptoms prior to the MVC, and vehicle damage severity predicted both distress and dissociation. Higher socioeconomic status (higher education, higher income, full-time employment) had a protective effect against distress but not dissociative symptoms. Better physical health and worse overall mental health were associated with increased risk of dissociation but not distress. Distress but not dissociation was associated with lower patient confidence in recovery and a longer expected duration of recovery.There are unique predictors of peritraumatic distress and dissociation. Further work is needed to better understand the neurobiology of peritraumatic distress and dissociation and the influence of these peritraumatic outcomes on persistent psychological sequelae.

Debate continues regarding the influence of litigation on pain outcomes after motor vehicle collision (MVC). In this study we enrolled European Americans presenting to the emergency department (ED) in the hours after MVC (n = 948). Six weeks later, participants were interviewed regarding pain symptoms and asked about their participation in MVC-related litigation. The incidence and predictors of neck pain and widespread pain six weeks after MVC were compared among those engaged in litigation ("litigants") and those not engaged in litigation ("non-litigants"). Among the 859/948 (91%) participants completing six week follow-up, 711/849 (83%) were non-litigants. Compared to non-litigants, litigants were less educated and had more severe neck pain, overall pain, and a greater extent of pain at the time of ED evaluation. Among individuals not engaged in litigation, persistent pain six weeks after MVC was common: 199/711 (28%) had moderate or severe neck pain, 92/711 (13%) had widespread pain, and 29/711 (4%) had fibromyalgia-like symptoms. Incidence of all three outcomes was significantly higher among litigants. Initial pain severity in the ED predicted pain outcomes among both litigants and non-litigants. Markers of socioeconomic disadvantage predicted worse pain outcomes in litigants but not non-litigants, and individual pain and psychological symptoms were less predictive of pain outcomes among those engaged in litigation. These data demonstrate that persistent pain after MVC is common among those not engaged in litigation, and provide evidence for bidirectional influences between pain outcomes and litigation after MVC.

We describe a novel method for the measurement of protein tyrosine phosphatase (PTP) activity in single human airway epithelial cells (hAECs) using capillary electrophoresis. This technique involved the microinjection of a fluorescent phosphopeptide that is hydrolyzed specifically by PTPs. Analyses in BEAS-2B immortalized bronchial epithelial cells showed rapid PTP-mediated dephosphorylation of the substrate (2.2 pmol min(-1) mg(-1)) that was blocked by pretreatment of the cells with the PTP inhibitors pervanadate, Zn(2+), and 1,2-naphthoquinone (76%, 69%, and 100% inhibition relative to PTP activity in untreated controls, respectively). These studies were then extended to a more physiologically relevant model system: primary hAECs cultured from bronchial brushings of living human subjects. In primary hAECs, dephosphorylation of the substrate occurred at a rate of 2.2 pmol min(-1) mg(-1) and was also effectively inhibited by preincubation of the cells with the inhibitors pervanadate, Zn(2+), and 1,2-naphthoquinone (91%, 88%, and 87% median PTP inhibition, respectively). Reporter proteolysis in single BEAS-2B cells occurred at a median rate of 43 fmol min(-1) mg(-1) resulting in a mean half-life of 20 min. The reporter displayed a similar median half-life of 28 min in these single primary cells. Finally, single viable epithelial cells (which were assayed for PTP activity immediately after collection by bronchial brushing of a human volunteer) showed dephosphorylation rates ranging from 0.34 to 36 pmol min(-1) mg(-1) (n = 6). These results demonstrate the utility and applicability of this technique for the ex vivo quantification of PTP activity in small, heterogeneous, human cells and tissues.

Temporomandibular disorder (TMD) overlaps with other health conditions, but no study has examined which of these conditions increase the risk of developing first-onset TMD. The authors prospectively evaluated the relationship between health status at enrollment and subsequent incidence of TMD in 2,722 men and women. Participants aged 18 to 44 years had no history of TMD and were clinically free of TMD when enrolled in 2006 to 2008 at 4 U.S. study sites in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study. First-onset examiner-classified TMD developed in 260 people over a median 2.8 years of follow-up. Cox regression estimated the association between health conditions and TMD incidence while accounting for potential confounders. Incidence of first-onset TMD was 50% higher for people with low back pain (adjusted hazard ratio [AHR] = 1.50, 95% confidence limits [CLs]: 1.08, 2.10) and 75% higher for people with genital pain symptoms (AHR = 1.75, 95% CLs = 1.04, 2.93) than people without a history of these pain disorders. Digit ratio, a marker of intrauterine exposure to sex hormones, was significantly associated with TMD incidence. Other independent predictors of first-onset TMD were sleep disturbance and cigarette smoking. These findings reveal multiple influences of health status on incidence of first-onset TMD. Perspective This article examines health conditions that commonly overlap with TMD to determine which ones predict first-onset TMD. A history of low back pain and genital pain conditions at baseline were important predictors. Novel findings were that disrupted sleep and conditions in utero may increase incidence of first-onset TMD.

Incidence of temporomandibular disorder (TMD) was predicted with multivariable models that used putative risk factors collected from initially TMD-free individuals in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. The 202 baseline risk factors included sociodemographic and clinical characteristics, measures of general health status, experimental pain sensitivity, autonomic function, and psychological distress. Study participants (n = 2,737) were then followed prospectively for a median of 2.8 years to ascertain cases of first-onset TMD. Lasso regression and random forest models were used to predict incidence of first-onset TMD using all of the aforementioned measures. Variable importance scores identified the most important risk factors, and their relationship with TMD incidence was illustrated graphically using partial dependence plots. Two of the most important risk factors for elevated TMD incidence were greater numbers of comorbid pain conditions and greater extent of nonspecific orofacial symptoms. Other important baseline risk factors were preexisting bodily pain, heightened somatic awareness, and greater extent of pain in response to examiners' palpation of the head, neck, and body. Several demographic variables persisted as risk factors even after adjusting for other OPPERA variables, suggesting that environmental variables not measured in OPPERA may also contribute to first-onset TMD. Perspective Multivariable methods were used to identify the most important predictors of first-onset TMD in the OPPERA study. Important variables included comorbid pain conditions, preexisting pain, and somatic awareness. Demographic characteristics, which probably reflect environmental variables not measured in OPPERA, also appear to play an important role in the etiology of TMD.

DNA microarrays are a relatively new technology that can simultaneously measure the expression level of thousands of genes. They have become an important tool for a wide variety of biological experiments. One of the most common goals of DNA microarray experiments is to identify genes associated with biological processes of interest. Conventional statistical tests often produce poor results when applied to microarray data owing to small sample sizes, noisy data, and correlation among the expression levels of the genes. Thus, novel statistical methods are needed to identify significant genes in DNA microarray experiments. This article discusses the challenges inherent in DNA microarray analysis and describes a series of statistical techniques that can be used to overcome these challenges. The problem of multiple hypothesis testing and its relation to microarray studies are also considered, along with several possible solutions.

Papers in this issue investigate when and how putative risk factors influence development of first-onset, painful temporomandibular disorder (TMD). The results represent first findings from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study that monitored 2,737 men and women aged 18 to 44 years recruited at 4 U.S. study sites. During a median 2.8-year follow-up period, 260 participants developed TMD. The average incidence rate of 4% per annum was influenced by a broad range of phenotypic risk factors including sociodemographic characteristics, health status, clinical orofacial factors, psychological functioning, pain sensitivity, and cardiac autonomic responses. A novel method of multivariable analysis used random forest models to simultaneously evaluate contributions of all 202 phenotypic variables. Variables from the health status domain made the greatest contribution to TMD incidence, followed closely by psychological and clinical orofacial domains. However, only a few measures of pain sensitivity and autonomic function contributed to TMD incidence, and their effects were modest. Meanwhile, age and study site were independent predictors of TMD incidence, even after controlling for other phenotypes. Separate analysis of 358 genes that regulate pain found several novel genetic associations with intermediate phenotypes that, themselves, are risk factors for TMD, suggesting new avenues to investigate biological pathways contributing to TMD. Perspective Collectively, the papers in this issue demonstrate that TMD is a complex disorder with multiple causes consistent with a biopsychosocial model of illness. It is a misnomer and no longer appropriate to regard TMD solely as a localized orofacial pain condition.

The course of preclinical pain symptoms sheds light on the etiology and prognosis of chronic pain. We aimed to quantify rates of developing initial and recurrent symptoms of painful temporomandibular disorder (TMD) and to evaluate associations with health behaviors. In the OPPERA prospective cohort study, 2,719 individuals aged 18 to 44years with lifetime absence of TMD when enrolled completed 25,103 quarterly (3-monthly) questionnaires during a median 2.3-year follow-up period. Questionnaires documented TMD symptom episodes, headache, other body pain, health care attendance, and analgesic use, and. Kaplan-Meier methods for clustered data estimated symptom-free survival time. Multivariable models assessed demographic variation in TMD symptom rates and evaluated associations with health care and analgesic use. One-third of the study subjects developed TMD symptoms and for a quarter of symptomatic episodes, pain intensity was severe. Initial TMD symptoms developed at an annual rate of 18.8 episodes per 100 persons. The annual rate more than doubled for first-recurrence and doubled again for second or subsequent recurrence such that, 1year after first recurrence, 71% of study subjects experienced a second recurrence. The overall rate increased with age and was greater in African Americans and lower in Asians relative to those of white race/ethnicity. The probability of TMD symptoms was strongly associated with concurrent episodes of headache and body pain and with past episodes of TMD symptoms. Episodes of TMD symptoms, headache, and body pain were associated with increases of ∼10% in probability of analgesic use and health care attendance. Yet, even when TMD, headache, and body pain occurred concurrently, 27% of study subjects neither attended health care nor used analgesics.

When studying incidence of pain conditions such as temporomandibular disorder (TMD), repeated monitoring is needed in prospective cohort studies. However, monitoring methods usually have limitations and, over a period of years, some loss to follow-up is inevitable. The OPPERA prospective cohort study of first-onset TMD screened for symptoms using quarterly questionnaires and examined symptomatic participants to definitively ascertain TMD incidence. During the median 2.8-year observation period, 16% of the 3,263 enrollees completed no follow-up questionnaires, others provided incomplete follow-up, and examinations were not conducted for one third of symptomatic episodes. Although screening methods and examinations were found to have excellent reliability and validity, they were not perfect. Loss to follow-up varied according to some putative TMD risk factors, although multiple imputation to correct the problem suggested that bias was minimal. A second method of multiple imputation that evaluated bias associated with omitted and dubious examinations revealed a slight underestimate of incidence and some small biases in hazard ratios used to quantify effects of risk factors. Although “bottom line” statistical conclusions were not affected, multiply-imputed estimates should be considered when evaluating the large number of risk factors under investigation in the OPPERA study. Perspective These findings support the validity of the OPPERA prospective cohort study for the purpose of investigating the etiology of first-onset TMD, providing the foundation for other papers investigating risk factors hypothesized in the OPPERA project.

Although cross-sectional studies of temporomandibular disorder (TMD) often report elevated prevalence in young women, they do not address the risk of its development. Here we evaluate sociodemographic predictors of TMD incidence in a community-based prospective cohort study of U.S. adults. Symptoms and pain-related disability in TMD cases are also described. People aged 18 to 44 years with no history of TMD were enrolled at 4 study sites when they completed questionnaires about sociodemographic characteristics. During the median 2.8-year follow-up period, 2,737 participants completed quarterly screening questionnaires. Those reporting symptoms were examined clinically and 260 had first-onset TMD. Additional questionnaires asked about severity and impact of their symptoms. Univariate and multivariable Cox regression models quantified associations between sociodemographic characteristics and TMD incidence. First-onset TMD developed in 3.9% of participants per annum, typically producing mild to moderate levels of pain and disability in cases. TMD incidence was positively associated with age, whereas females had only slightly greater incidence than males. Compared to whites, Asians had lower TMD incidence whereas African Americans had greater incidence, although the latter was attenuated somewhat after adjusting for satisfaction with socioeconomic circumstances. Perspective In this study of 18- to 44-year-olds, TMD developed at a higher rate than reported previously for similar age groups. TMD incidence was positively associated with age but weakly associated with gender, thereby differing from demographic patterns of prevalence found in some cross-sectional studies. Experiences related to aging merit investigation as etiologic influences on development of TMD.

Cross-validation is frequently used for model selection in a variety of applications. However, it is difficult to apply cross-validation to mixed effects models (including nonlinear mixed effects models or NLME models) due to the fact that cross-validation requires "out-of-sample" predictions of the outcome variable, which cannot be easily calculated when random effects are present. We describe two novel variants of cross-validation that can be applied to nonlinear mixed effects models. One variant, where out-of-sample predictions are based on post hoc estimates of the random effects, can be used to select the overall structural model. Another variant, where cross-validation seeks to minimize the estimated random effects rather than the estimated residuals, can be used to select covariates to include in the model. We show that these methods produce accurate results in a variety of simulated data sets and apply them to two publicly available population pharmacokinetic data sets., Comment: 38 pages, 15 figures To be published in the Journal of Pharmacokinetics and Pharmacodynamics

Genetic risk factors are believed to combine with environmental exposures and contribute to the risk of developing temporomandibular disorder (TMD). In this prospective cohort study, 2,737 people without TMD were assessed for common genetic variation in 358 genes known to contribute to nociceptive pathways, inflammation, and affective distress. During a median follow-up period of 2.8 years, 260 people developed first-onset TMD. Hazard ratios were computed as measures of association between 2,924 single-nucleotide polymorphisms and TMD incidence. After correction for multiple testing, no single single-nucleotide polymorphism was significantly associated with risk of onset TMD. However, several single-nucleotide polymorphisms exceeded Bonferroni correction for multiple comparison or false discovery rate thresholds (.05, .1, or .2) for association with intermediate phenotypes shown to be predictive of TMD onset. Nonspecific orofacial symptoms were associated with voltage-gated sodium channel, type I, alpha subunit ( SCN1A , rs6432860, P = 2.77 × 10 −5 ) and angiotensin I–converting enzyme 2 ( ACE2 , rs1514280, P = 4.86 × 10 −5 ); global psychological symptoms with prostaglandin-endoperoxide synthase 1 ( PTGS1 , rs3842803, P = 2.79 × 10 −6 ); stress and negative affectivity with amyloid-β (A4) precursor protein ( APP , rs466448, P = 4.29 × 10 −5 ); and heat pain temporal summation with multiple PDZ domain protein ( MPDZ , rs10809907, P = 3.05 × 10 −5 ). The use of intermediate phenotypes for complex pain diseases revealed new genetic pathways influencing risk of TMD. Perspective This article reports the findings of a large candidate gene association study of first-onset TMD and related intermediate phenotypes in the OPPERA Study. Although no genetic markers predicted TMD onset, several genetic risk factors for clinical, psychological, and sensory phenotypes associated with TMD onset were observed.

To evaluate the relationship between preoperative resting arterial blood pressure and postoperative pain in patients undergoing nonsurgical root canal therapy.Written informed consent was obtained from normotensive patients seeking treatment for teeth with a preoperative diagnosis of pulpal necrosis and periradicular periodontitis. Preoperative resting blood pressure was recorded, and nonsurgical root canal therapy was initiated using a standardized protocol. Patients recorded their pre- and postoperative pain intensity on a 100-mm visual analog scale (VAS) for 7 days after the procedure. A linear regression model to predict postoperative VAS intensity used preoperative pain and blood pressure values as covariates. Pearson correlations were calculated to assess the relationship between the measures of preoperative blood pressure and both pre- and postoperative pain.After controlling for preoperative pain, significant correlations were observed between preoperative systolic blood pressure and postoperative pain (P.05), as well as between preoperative pulse pressure and postoperative pain (P.005) on day 1.This study has provided further evidence of a functional interaction between the cardiovascular and trigeminal pain regulatory systems. Understanding this complex relationship may lead to enhanced pain management strategies.

Several case-control studies have been conducted that examine the association between autonomic variables and persistent pain conditions; however, there is a surprising dearth of published studies in this area that have focused on temporomandibular disorders (TMD). The current study presents autonomic findings from the baseline case-control study of the OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) cooperative agreement. Measures of arterial blood pressure, heart rate, heart rate variability, and indirect measures of baroreflex sensitivity were assessed at rest and in response to a physical (orthostatic) and psychological (Stroop) stressors in 1,633 TMD-free controls and 185 TMD cases. In bivariate and demographically adjusted analyses, greater odds of TMD case status were associated with elevated heart rates, reduced heart rate variability, and reduced surrogate measures of baroreflex sensitivity across all experimental procedures. Principal component analysis was undertaken to identify latent constructs revealing 5 components. These findings provide evidence of associations between autonomic factors and TMD. Future prospective analyses in the OPPERA cohort will determine if the presence of these autonomic factors predicts increased risk for developing new onset TMD.This article reports autonomic findings from the OPPERA Study, a large prospective cohort study designed to discover causal determinants of TMD pain. Findings indicate statistically significant differences between TMD cases and controls across multiple autonomic constructs at rest and during both physical and psychologically challenging conditions. Future analyses will determine whether these autonomic factors increase risk for new onset TMD.

Genetic factors play a role in the etiology of persistent pain conditions, putatively by modulating underlying processes such as nociceptive sensitivity, psychological well-being, inflammation, and autonomic response. However, to date, only a few genes have been associated with temporomandibular disorders (TMD). This study evaluated 358 genes involved in pain processes, comparing allelic frequencies between 166 cases with chronic TMD and 1,442 controls enrolled in the OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) study cooperative agreement. To enhance statistical power, 182 TMD cases and 170 controls from a similar study were included in the analysis. Genotyping was performed using the Pain Research Panel, an Affymetrix gene chip representing 3,295 single nucleotide polymorphisms, including ancestry-informative markers that were used to adjust for population stratification. Adjusted associations between genetic markers and TMD case status were evaluated using logistic regression. The OPPERA findings provided evidence supporting previously reported associations between TMD and 2 genes: HTR2A and COMT. Other genes were revealed as potential new genetic risk factors for TMD, including NR3C1, CAMK4, CHRM2, IFRD1, and GRK5. While these findings need to be replicated in independent cohorts, the genes potentially represent important markers of risk for TMD, and they identify potential targets for therapeutic intervention. Perspective Genetic risk factors for TMD pain were explored in the case-control component of the OPPERA cooperative agreement, a large population-based prospective cohort study. Over 350 candidate pain genes were assessed using a candidate gene panel, with several genes displaying preliminary evidence for association with TMD status.

To examine long-term reports of pain and psychologic correlates of pain in women after vestibulectomy.In a retrospective cross-sectional exploratory study, 37 women who had undergone vestibulectomy between January 1989 and January 2008 completed questionnaires assessing demographic information, self-reported levels of pain, anxiety, somatization, psychologic distress, and sexual function.Eight women reported being completely pain free after surgery. The remaining 29 women reported various levels of pain during intercourse (as measured by the Gracely pain scale) and decreased sexual function (as measured by a sexual functioning questionnaire). Various measures of psychologic distress were associated with average intercourse-related pain, including brief symptom inventory (P=0.002), Pennebaker inventory of limbic languidness (P=0.002), perceived stress scale (P=0.04), and Spielberger trait-anxiety inventory (P=0.01). These same measures of psychological distress were similarly associated with general, unprovoked vaginal pain.The present data suggest that the pathophysiology of localized vulvodynia may be more complex in some women, leading to a suboptimal response to surgical treatment.

This paper describes methods used in the project “Orofacial Pain Prospective Evaluation and Risk Assessment” (OPPERA) and evaluates sociodemographic characteristics associated with temporomandibular disorders (TMD) in the OPPERA case-control study. Representativeness was investigated by comparing sociodemographic profiles of OPPERA participants with population census profiles of counties near study sites and by comparing age and gender associations with TMD in OPPERA and the 2007 to 2009 US National Health Interview Survey. Volunteers aged 18 to 44 years were recruited at 4 US study sites: 3,263 people without TMD were enrolled into the prospective cohort study; 1,633 of them were selected as controls for the baseline case-control study. Cases were 185 volunteers with examiner-classified TMD. Distributions of some demographic characteristics among OPPERA participants differed from census profiles, although there was less difference in socioeconomic profiles. Odds of TMD was associated with greater age in this 18 to 44 year range; females had 3 times the odds of TMD as males; and relative to non-Hispanic-Whites, other racial groups had one-fifth the odds of TMD. Age and gender associations with chronic TMD were strikingly similar to associations observed in the US population. Assessments of representativeness in this demographically diverse group of community volunteers suggest that OPPERA case-control findings have good internal validity. Perspective Demographic associations with TMD were consistent with population benchmarks and with other studies, suggesting broad applicability of these OPPERA findings. Greater occurrence of TMD in non-Hispanic-Whites than in other racial/ethnic groups and the lack of a socioeconomic gradient contradicts the disparities seen in many other health conditions.

Many studies report that people with temporomandibular disorders (TMD) are more sensitive to experimental pain stimuli than TMD-free controls. Such differences in sensitivity are observed in remote body sites as well as in the orofacial region, suggesting a generalized upregulation of nociceptive processing in TMD cases. This large case-control study of 185 adults with TMD and 1,633 TMD-free controls measured sensitivity to painful pressure, mechanical cutaneous, and heat stimuli, using multiple testing protocols. Based on an unprecedented 36 experimental pain measures, 28 showed statistically significantly greater pain sensitivity in TMD cases than controls. The largest effects were seen for pressure pain thresholds at multiple body sites and cutaneous mechanical pain threshold. The other mechanical cutaneous pain measures and many of the heat pain measures showed significant differences, but with lesser effect sizes. Principal component analysis (PCA) of the pain measures derived from 1,633 controls identified 5 components labeled: 1) heat pain ratings; 2) heat pain aftersensations and tolerance; 3) mechanical cutaneous pain sensitivity; 4) pressure pain thresholds; and 5) heat pain temporal summation. These results demonstrate that compared to TMD-free controls, chronic TMD cases are more sensitive to many experimental noxious stimuli at extracranial body sites, and provide for the first time the ability to directly compare the case-control effect sizes of a wide range of pain sensitivity measures. Perspective This article describes experimental pain sensitivity differences between a large sample of people with chronic TMD and non-TMD controls, using multiple stimulus modalities and measures. Variability in the magnitude and consistency of case-control differences highlight the need to consider multiple testing measures to adequately assess pain processing alterations in chronic pain conditions.

Case-control studies have consistently associated psychosocial factors with chronic pain in general, and with temporomandibular disorders (TMD) specifically. Moreover, a handful of prospective studies suggest that preexisting psychosocial characteristics represent risk factors for new onset TMD. The current study presents psychosocial findings from the baseline case-control study of the Orofacial Pain Prospective Evaluation and Risk Assessment (OPPERA) cooperative agreement. For this study, 1,633 TMD-free controls and 185 TMD cases completed a battery of psychosocial instruments assessing general psychosocial adjustment and personality, affective distress, psychosocial stress, somatic awareness, and pain coping and catastrophizing. In bivariate and demographically adjusted analyses, odds of TMD were associated with higher levels of psychosocial symptoms, affective distress, somatic awareness, and pain catastrophizing. Among controls, significant gender and ethnic group differences in psychosocial measures were observed, consistent with previous findings. Principal component analysis was undertaken to identify latent constructs revealing 4 components: stress and negative affectivity, global psychosocial symptoms, passive pain coping, and active pain coping. These findings provide further evidence of associations between psychosocial factors and TMD. Future prospective analyses in the OPPERA cohort will determine if the premorbid presence of these psychosocial factors predicts increased risk for developing new onset TMD. Perspective This article reports baseline psychosocial findings from the OPPERA Study, a large prospective cohort study designed to discover causal determinants of TMD pain. Findings indicate significant differences between TMD cases and TMD-free controls across multiple psychosocial constructs, and future analyses will determine whether these psychosocial factors increase risk for new onset TMD.

Multiple studies report that individuals with chronic temporomandibular disorder (TMD) have enhanced sensitivity to experimental pain. Additionally, chronic TMD cases show altered autonomic function, including elevated heart rate and reduced heart rate variability. However, causal inferences regarding the association between TMD and pain sensitivity and autonomic function cannot be drawn from these cross-sectional observations. The prospective Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study examines whether measures of pain sensitivity or cardiac autonomic function provide predictive value in TMD incidence. A cohort of 2,737 initially TMD-free participants was followed for up to 5.2 years, during which time 260 developed first-onset TMD. Fourteen of 39 experimental pain measures produced significant hazard ratios, such that greater pain sensitivity was associated with greater TMD incidence. A single autonomic measure—heart rate at rest—was also associated significantly with greater TMD incidence. In contrast, using the same measures of pain sensitivity and cardiac autonomic function, we previously reported a larger group of variables that was significantly associated with chronic TMD in the OPPERA case-control study. Future studies should investigate whether premorbid pain sensitivity or autonomic function more specifically predicts risk of developing chronic TMD than first-onset TMD. Perspective Our previous case-control studies showed that associations with both pain sensitivity and cardiac autonomic function are profound in chronic TMD cases. Here we show that some measures of enhanced pain sensitivity contribute modestly to the risk of developing TMD whereas autonomic dysregulation appears to confer little or no risk for TMD incidence.