COMT Genotype and Efficacy of Propranolol for TMD Pain: A Randomized Trial.

Propranolol is a nonselective ß-adrenergic receptor antagonist that is efficacious in reducing facial pain. There is evidence that its analgesic efficacy might be modified by variants of the catechol-O-methyltransferase (COMT) gene. We tested the hypothesis in a subset of 143 non-Hispanic Whites from a randomized controlled trial of patients with painful temporomandibular disorder (TMD). Patients were genotyped for rs4680, a single nucleotide polymorphism of COMT, and randomly allocated to either propranolol 60 mg twice daily or placebo. During the 9-wk follow-up period, patients recorded daily ratings of facial pain intensity and duration; the product was computed as an index of facial pain. Postbaseline change in the index at week 9 (the primary endpoint) was analyzed as a continuous variable and dichotomized at thresholds of ≥30% and ≥50% reduction. Mixed models for repeated measures tested for the genotype × treatment group interaction and estimated means, odds ratios (ORs), and 95% confidence limits (95% CLs) of efficacy within COMT genotypes assuming an additive genetic model. In secondary analysis, the cumulative response curves were plotted for dichotomized reductions ranging from ≥20% to ≥70%, and genotype differences in area under the curve percentages (%AUC) were calculated to signify efficacy. Mean index reduction did not differ significantly (P = 0.277) according to genotype, whereas the dichotomized ≥30% reduction revealed greater efficacy among G:G homozygotes (OR = 10.9, 95%CL = 2.4, 50.7) than among A:A homozygotes (OR = 0.8, 95%CL = 0.2, 3.2) with statistically significant interaction (P = 0.035). Cumulative response curves confirmed greater (P = 0.003) efficacy for G:G homozygotes (%AUC difference = 43.7, 95%CL = 15.4, 72.1) than for A:A homozygotes (%AUC difference = 6.5, 95%CL = -30.2, 43.2). The observed antagonistic effect of the A allele on propranolol's efficacy was opposite the synergistic effect hypothesized a priori. This unexpected result highlights the need for better knowledge of COMT's role in pain pathogenesis if the gene is to be used for precision-medicine treatment of TMD (ClinicalTrials.gov NCT02437383).

Pain Sensitivity Modifies Risk of Injury-Related Temporomandibular Disorder.

This study evaluates contributions of jaw injury and experimental pain sensitivity to risk of developing painful temporomandibular disorder (TMD). Data were from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) nested case-control study of incident painful TMD. Injury and subsequent onset of painful TMD were monitored prospectively for ≤5 y in a community-based sample of 409 US adults who did not have TMD when enrolled. At baseline, thermal-pressure and pinprick pain sensitivity, as potential effect modifiers, were measured using quantitative sensory testing. During follow-up, jaw injury from any of 9 types of potentially traumatic events was determined using quarterly (3-monthly) health update questionnaires. Study examiners classified incident painful TMD, yielding 233 incident cases and 176 matched controls. Logistic regression models, estimated incidence odds ratios (IORs), and 95% confidence limits (CLs) were used for the association between injury and subsequent onset of painful TMD. During follow-up, 38.2% of incident cases and 13.1% of controls reported 1 or more injuries that were 4 times as likely to be intrinsic (i.e., sustained mouth opening or yawning) as extrinsic (e.g., dental visits, whiplash). Injuries due to extrinsic events (IOR = 7.6; 95% CL, 1.6-36.2), sustained opening (IOR = 5.4; 95% CL, 2.4-12.2), and yawning (IOR = 3.4; 95% CL, 1.6-7.3) were associated with increased TMD incidence. Both a single injury (IOR = 6.0; 95% CL, 2.9-12.4) and multiple injuries (IOR = 9.4; 95% CL, 3.4,25.6) predicted greater incidence of painful TMD than events perceived as noninjurious (IOR = 1.9; 95% CL, 1.1-3.4). Injury-associated risk of painful TMD was elevated in people with high sensitivity to heat pain (IOR = 7.4; 95% CL, 3.1-18.0) compared to people with low sensitivity to heat pain (IOR = 3.9; 95% CL, 1.7-8.4). Jaw injury was strongly associated with elevated painful TMD risk, and the risk was amplified in subjects who had enhanced sensitivity to heat pain at enrollment. Commonly occurring but seemingly innocuous events, such as yawning injury, should not be overlooked when judging prognostic importance of jaw injury.

Development and preliminary evaluation of a new screening instrument for atypical odontalgia and persistent dentoalveolar pain disorder.

AIM: To develop and preliminarily evaluate a new screening instrument for atypical odontalgia (AO) or persistent dentoalveolar pain disorder (PDAP). To evaluate the instrument's performance in detecting AO/PDAP amongst a heterogeneous group of orofacial pain conditions and pain-free controls and empirically compare its performance with an established neuropathic screening instrument (S-LANSS), which is the best available standard. METHODS: The study design was cross-sectional; subjects recruited included a convenience sample of pain-free controls (n = 21) and four groups of orofacial pain conditions: AO/PDAP (n = 22); trigeminal neuralgia (n = 21); temporomandibular disorder (n = 41); and acute dental pain (n = 41). The instrument's internal reliability and factor structure were examined alongside its sensitivity and specificity and ROC-determined threshold score. RESULTS: The 9 AO/PDAP-specific items were found to moderately correlate with the S-LANSS (r = 0.58; P < 0.01). The 14-items of the full instrument were examined using exploratory factor analysis and reduced to ten items in a two-factor structure that explained 96% of the variance. This 10-item final instrument had a ROC area of 0.77 (95% CI: 0.67; 0.88), sensitivity of 77% (95% CI: 55; 92%), and specificity of 69% (95% CI: 60; 77%) with an intentionally higher false-positive rate than false-negative rate. In contrast, the S-LANSS exhibited sensitivity of 32% (95% CI: 14;55%) and specificity of 78% (95% CI: 70;85%) with less optimal false-positive versus false-negative rates. CONCLUSION: This preliminary study confirms the new screening instrument for AO/PDAP merits progression to field testing.

Influence of culture on pain comorbidity in women with and without temporomandibular disorder-pain.

Evidence on cultural differences in prevalence and impact of common chronic pain conditions, comparing individuals with temporomandibular disorders (TMD) versus individuals without TMD, is limited. The aim was to assess cross-cultural comorbid pain conditions in women with chronic TMD pain. Consecutive women patients (n = 122) with the index condition of chronic TMD pain diagnosed per the research diagnostic criteria for TMD and TMD-free controls (n = 121) matched for age were recruited in Saudi Arabia, Italy and Sweden. Self-report questionnaires assessed back, chest, stomach and head pain for prevalence, pain intensity and interference with daily activities. Logistic regression was used for binary variables, and ancova was used for parametric data analysis, adjusting for age and education. Back pain was the only comorbid condition with a different prevalence across cultures; Swedes reported a lower prevalence compared to Saudis (P < 0·01). Saudis reported higher prevalence of work reduced >50% due to back pain compared to Italians or Swedes (P < 0·01). Headache was the most common comorbid condition in all three cultures. The total number of comorbid conditions did not differ cross-culturally but were reported more by TMD-pain cases than TMD-free controls (P < 0·01). For both back and head pain, higher average pain intensities (P < 0·01) and interference with daily activities (P < 0·01) were reported by TMD-pain cases, compared to TMD-free controls. Among TMD-pain cases, Italians reported the highest pain-related disability (P < 0·01). Culture influences the associated comorbidity of common pain conditions. The cultural influence on pain expression is reflected in different patterns of physical representation.

GWAS Identifies New Loci for Painful Temporomandibular Disorder: Hispanic Community Health Study/Study of Latinos.

Temporomandibular disorder (TMD) is a musculoskeletal condition characterized by pain and reduced function in the temporomandibular joint and/or associated masticatory musculature. Prevalence in the United States is 5% and twice as high among women as men. We conducted a discovery genome-wide association study (GWAS) of TMD in 10,153 participants (769 cases, 9,384 controls) of the US Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The most promising single-nucleotide polymorphisms (SNPs) were tested in meta-analysis of 4 independent cohorts. One replication cohort was from the United States, and the others were from Germany, Finland, and Brazil, totaling 1,911 TMD cases and 6,903 controls. A locus near the sarcoglycan alpha ( SGCA), rs4794106, was suggestive in the discovery analysis ( P = 2.6 × 106) and replicated (i.e., 1-tailed P = 0.016) in the Brazilian cohort. In the discovery cohort, sex-stratified analysis identified 2 additional genome-wide significant loci in females. One lying upstream of the relaxin/insulin-like family peptide receptor 2 ( RXP2) (chromosome 13, rs60249166, odds ratio [OR] = 0.65, P = 3.6 × 10-8) was replicated among females in the meta-analysis (1-tailed P = 0.052). The other (chromosome 17, rs1531554, OR = 0.68, P = 2.9 × 10-8) was replicated among females (1-tailed P = 0.002), as well as replicated in meta-analysis of both sexes (1-tailed P = 0.021). A novel locus at genome-wide level of significance (rs73460075, OR = 0.56, P = 3.8 × 10-8) in the intron of the dystrophin gene DMD (X chromosome), and a suggestive locus on chromosome 7 (rs73271865, P = 2.9 × 10-7) upstream of the Sp4 Transcription Factor ( SP4) gene were identified in the discovery cohort, but neither of these was replicated. The SGCA gene encodes SGCA, which is involved in the cellular structure of muscle fibers and, along with DMD, forms part of the dystrophin-glycoprotein complex. Functional annotation suggested that several of these variants reside in loci that regulate processes relevant to TMD pathobiologic processes.

Longitudinal Stability of Common TMJ Structural Disorders.

The longitudinal course of temporomandibular joint (TMJ) disc displacement (DD) and degenerative joint disease (DJD) has never been conclusively described with magnetic resonance imaging and computed tomography, respectively. This 8-y observational study's objective was to assess the longitudinal stability of DD and DJD among 401 subjects. The Validation Project provided baseline measures; follow-up was performed in the TMJ Impact Project. With magnetic resonance imaging, 2 radiologists rendered a consensus diagnosis of normal/indeterminate, DD with reduction, or DD without reduction. Computed tomography consensus diagnoses included normal/indeterminate, grade 1 DJD, or grade 2 DJD. Radiologist reliability was assessed by kappa; a Hui-Walter model was used to estimate, after accounting for diagnostic disagreement, the frequency of diagnostic progression and reversal. Permutation tests were used to test the statistical influence of concurrent baseline diagnoses on diagnostic changes at follow-up. Of 789 baseline joint-specific soft tissue diagnoses of DD, 598 (76%) joints showed no change; 109 (14%) demonstrated progression; and 82 (10%) had reversal. Of 794 joints with baseline joint-specific hard tissue diagnoses of DJD, progression was observed in 122 (15%) joints, no change in 564 (71%), and reversal in 108 (14%). Radiologist reliability (kappa) was 0.73 (95% CI, 0.64 to 0.83) for DD and 0.76 (95% CI, 0.68 to 0.83) for DJD. After accounting for the influence of diagnostic disagreement, progression of hard tissue diagnoses in the right TMJ occurred in 15.2% of subjects (95% CI, 10.5% to 20.8%) and reversal in 8.3% (95% CI, 4.9% to 12.3%); results were similar for soft tissue diagnoses and the left TMJ. Concurrent baseline soft tissue diagnoses were associated with hard tissue diagnostic changes at follow-up ( P < 0.0001). Baseline hard tissue diagnoses showed no statistical association with soft tissue changes at follow-up ( P = 0.11). Longitudinally, 76% of baseline TMJ soft tissue diagnoses and 71% of the baseline hard tissue diagnoses remained stable. Diagnostic reversal and progression were confirmed for both soft and hard tissues.

Self-management programmes in temporomandibular disorders: results from an international Delphi process.

Self-management (SM) programmes are commonly used for initial treatment of patients with temporomandibular disorders (TMD). The programmes described in the literature, however, vary widely with no consistency in terminology used, components of care or their definitions. The aims of this study were therefore to construct an operationalised definition of self-management appropriate for the treatment of patients with TMD, identify the components of that self-management currently being used and create sufficiently clear and non-overlapping standardised definitions for each of those components. A four-round Delphi process with eleven international experts in the field of TMD was conducted to achieve these aims. In the first round, the participants agreed upon six principal concepts of self-management. In the remaining three rounds, consensus was achieved upon the definition and the six components of self-management. The main components identified and agreed upon by the participants to constitute the core of a SM programme for TMD were as follows: education; jaw exercises; massage; thermal therapy; dietary advice and nutrition; and parafunctional behaviour identification, monitoring and avoidance. This Delphi process has established the principal concepts of self-management, and a standardised definition has been agreed with the following components for use in clinical practice: education; self-exercise; self-massage; thermal therapy; dietary advice and nutrition; and parafunctional behaviour identification, monitoring and avoidance. The consensus-derived concepts, definitions and components of SM offer a starting point for further research to advance the evidence base for, and clinical utility of, TMD SM.

The Evolution of TMD Diagnosis: Past, Present, Future.

This review explores the principles and process associated with the diagnosis of temporomandibular disorders (TMDs). TMD diagnosis has evolved substantially over the past 25 y. Previously, diagnosis focused solely on aberrations in oral structures, largely without empirical evidence. The Research Diagnostic Criteria for TMD (RDC/TMD) were developed on core principles of 1) a dual-axis system reflecting the biopsychosocial model, 2) a clear operationalization for reliability, and 3) the allowance of multiple diagnoses. These principles were retained in the subsequent validation research of the RDC/TMD, and the current diagnostic system-the Diagnostic Criteria for TMD (DC/TMD)-has improved on those principles as well as on diagnostic validity and protocols for assessing the psychosocial domain. Further investigations into etiology and its potential contribution to taxonomy revision are described, particularly within the context of complex disease. The review concludes with an outline of major research areas already underway that will support future revisions of the DC/TMD.

Painful Temporomandibular Disorder: Decade of Discovery from OPPERA Studies.

In 2006, the OPPERA project (Orofacial Pain: Prospective Evaluation and Risk Assessment) set out to identify risk factors for development of painful temporomandibular disorder (TMD). A decade later, this review summarizes its key findings. At 4 US study sites, OPPERA recruited and examined 3,258 community-based TMD-free adults assessing genetic and phenotypic measures of biological, psychosocial, clinical, and health status characteristics. During follow-up, 4% of participants per annum developed clinically verified TMD, although that was a "symptom iceberg" when compared with the 19% annual rate of facial pain symptoms. The most influential predictors of clinical TMD were simple checklists of comorbid health conditions and nonpainful orofacial symptoms. Self-reports of jaw parafunction were markedly stronger predictors than corresponding examiner assessments. The strongest psychosocial predictor was frequency of somatic symptoms, although not somatic reactivity. Pressure pain thresholds measured at cranial sites only weakly predicted incident TMD yet were strongly associated with chronic TMD, cross-sectionally, in OPPERA's separate case-control study. The puzzle was resolved in OPPERA's nested case-control study where repeated measures of pressure pain thresholds revealed fluctuation that coincided with TMD's onset, persistence, and recovery but did not predict its incidence. The nested case-control study likewise furnished novel evidence that deteriorating sleep quality predicted TMD incidence. Three hundred genes were investigated, implicating 6 single-nucleotide polymorphisms (SNPs) as risk factors for chronic TMD, while another 6 SNPs were associated with intermediate phenotypes for TMD. One study identified a serotonergic pathway in which multiple SNPs influenced risk of chronic TMD. Two other studies investigating gene-environment interactions found that effects of stress on pain were modified by variation in the gene encoding catechol O-methyltransferase. Lessons learned from OPPERA have verified some implicated risk factors for TMD and refuted others, redirecting our thinking. Now it is time to apply those lessons to studies investigating treatment and prevention of TMD.

Directed Acyclic Graphs for Oral Disease Research.

Directed acyclic graphs (DAGs) are nonparametric graphical tools used to depict causal relations in the epidemiologic assessment of exposure-outcome associations. Although their use in dental research was first advocated in 2002, DAGs have yet to be widely adopted in this field. DAGs help identify threats to causal inference such as confounders, bias due to subject selection, and inappropriate handling of missing data. DAGs can also inform the data analysis strategy based on relations among variables depicted on it. This article uses the example of a study of temporomandibular disorders (TMDs), investigating causal effects of facial injury on subsequent risk of TMD. We illustrate how DAGs can be used to identify 1) potential confounders, 2) mediators and the consequences of attempt to estimate direct causal effects, 3) colliders and the consequences of conditioning on colliders, and 4) variables that are simultaneously mediators and confounders and the consequences of adjustment for such variables. For example, one DAG shows that statistical adjustment for the pressure pain threshold would necessarily bias the causal relation between facial injury and TMD. Finally, we discuss the usefulness of DAGs during study design, subject selection, and choosing variables to be measured in a study.

The effect of culture on pain sensitivity.

Cross-cultural differences in pain sensitivity have been identified in pain-free subjects as well as in chronic pain patients. The aim was to assess the impact of culture on psychophysical measures using mechanical and electrical stimuli in patients with temporomandibular disorder (TMD) pain and pain-free matched controls in three cultures. This case-control study compared 122 female cases of chronic TMD pain (39 Saudis, 41 Swedes and 42 Italians) with equal numbers of age- and gender-matched TMD-free controls. Pressure pain threshold (PPT) and tolerance (PPTo) were measured over one hand and two masticatory muscles. Electrical perception threshold and electrical pain threshold (EPT) and tolerance (EPTo) were recorded between the thumb and index fingers. Italian females reported significantly lower PPT in the masseter muscle than other cultures (P < 0.001) and in the temporalis muscle than Saudis (P = 0.003). Swedes reported significantly higher PPT in the thenar muscle than other cultures (P = 0.017). Italians reported significantly lower PPTo in all muscles than Swedes (P ≤ 0.006) and in the masseter muscle than Saudis (P < 0.001). Italians reported significantly lower EPTo than other cultures (P = 0.01). Temporomandibular disorder cases, compared to TMD-free controls, reported lower PPT and PPTo in all the three muscles (P < 0.001). This study found cultural differences between groups in the PPT, PPTo and EPTo. Overall, Italian females reported the highest sensitivity to both mechanical and electrical stimulation, while Swedes reported the lowest sensitivity. Mechanical pain thresholds differed more across cultures than did electrical pain thresholds. Cultural factors may influence response to type of pain test.

Perspectives on next steps in classification of oro-facial pain - part 2: role of psychosocial factors.

This study was initiated by a symposium, in which the present authors contributed, organised by the International RDC/TMD Consortium Network in March 2013. The purpose of the study was to review the status of biobehavioural research - both quantitative and qualitative - related to oro-facial pain (OFP) with respect to the aetiology, pathophysiology, diagnosis and management of OFP conditions, and how this information can optimally be used for developing a structured OFP classification system for research. In particular, we address representation of psychosocial entities in classification systems, use of qualitative research to identify and understand the full scope of psychosocial entities and their interaction, and the usage of classification system for guiding treatment. We then provide recommendations for addressing these problems, including how ontological principles can inform this process.

Perspectives on next steps in classification of oro-facial pain - part 1: role of ontology.

The purpose of this study was to review existing principles of oro-facial pain classifications and to specify design recommendations for a new system that would reflect recent insights in biomedical classification systems, terminologies and ontologies. The study was initiated by a symposium organised by the International RDC/TMD Consortium Network in March 2013, to which the present authors contributed. The following areas are addressed: problems with current classification approaches, status of the ontological basis of pain disorders, insufficient diagnostic aids and biomarkers for pain disorders, exploratory nature of current pain terminology and classification systems, and problems with prevailing classification methods from an ontological perspective. Four recommendations for addressing these problems are as follows: (i) develop a hypothesis-driven classification structure built on principles that ensure to our best understanding an accurate description of the relations among all entities involved in oro-facial pain disorders; (ii) take into account the physiology and phenomenology of oro-facial pain disorders to adequately represent both domains including psychosocial entities in a classification system; (iii) plan at the beginning for field-testing at strategic development stages; and (iv) consider how the classification system will be implemented. Implications in relation to the specific domains of psychosocial factors and biomarkers for inclusion into an oro-facial pain classification system are described in two separate papers.

Perspectives on next steps in classification of oro-facial pain - Part 3: biomarkers of chronic oro-facial pain - from research to clinic.

The purpose of this study was to review the current status of biomarkers used in oro-facial pain conditions. Specifically, we critically appraise their relative strengths and weaknesses for assessing mechanisms associated with the oro-facial pain conditions and interpret that information in the light of their current value for use in diagnosis. In the third section, we explore biomarkers through the perspective of ontological realism. We discuss ontological problems of biomarkers as currently widely conceptualised and implemented. This leads to recommendations for research practice aimed to a better understanding of the potential contribution that biomarkers might make to oro-facial pain diagnosis and thereby fulfil our goal for an expanded multidimensional framework for oro-facial pain conditions that would include a third axis.

COMT Diplotype Amplifies Effect of Stress on Risk of Temporomandibular Pain.

When measured once, psychological stress predicts development of painful temporomandibular disorder (TMD). However, a single measurement fails to characterize the dynamic nature of stress over time. Moreover, effects of stress on pain likely vary according to biological susceptibility. We hypothesized that temporal escalation in stress exacerbates risk for TMD, and the effect is amplified by allelic variants in a gene, catechol-O-methyltransferase (COMT), regulating catechol neurotransmitter catabolism. We used data from the Orofacial Pain: Prospective Evaluation and Risk Assessment prospective cohort study of 2,707 community-dwelling adults with no lifetime history of TMD on enrollment. At baseline and quarterly periods thereafter, the Perceived Stress Scale (PSS) measured psychological stress. Genotyped DNA from blood samples determined COMT diplotypes. During follow-up of 0.25 to 5.2 y, 248 adults developed examiner-verified incident TMD. PSS scores at baseline were 20% greater (P < 0.001) in adults who developed incident TMD compared with TMD-free controls. Baseline PSS scores increased by 9% (P = 0.003) during follow-up in cases but remained stable in controls. This stress escalation was limited to incident cases with COMT diplotypes coding for low-activity COMT, signifying impaired catabolism of catecholamines. Cox regression models confirmed significant effects on TMD hazard of both baseline PSS (P < 0.001), modeled as a time-constant covariate, and change in PSS (P < 0.001), modeled as a time-varying covariate. Furthermore, a significant (P = 0.04) interaction of COMT diplotype and time-varying stress showed that a postbaseline increase of 1.0 standard deviation in PSS more than doubled risk of TMD incidence in subjects with low-activity COMT diplotypes (hazard ratio = 2.35; 95% confidence limits: 1.66, 3.32), an effect not found in subjects with high-activity COMT diplotypes (hazard ratio = 1.42; 95% confidence limits: 0.96, 2.09). Findings provide novel insights into dynamic effects of psychological stress on TMD pain, highlighting that effects are most pronounced in individuals whose genetic susceptibility increases responsiveness to catecholamine neurotransmitters.

Achieved competences in temporomandibular disorders/orofacial pain: a comparison between two dental schools in Europe.

AIMS: The aim was to study achieved competences in temporomandibular disorders (TMD)/orofacial pain (OP) at two universities by comparing student's knowledge and understanding, satisfaction with their education and confidence in their clinical competences of TMD/OP. METHODS: The study was conducted in collaboration between Malmö University, Sweden­which uses problem-based learning­and the University of Naples Federico II, Italy­which uses traditional educational methods. Final-semester dental students responded to a self-report questionnaire regarding their knowledge and understanding, interpretation of cases histories, clinical experience, satisfaction and confidence in clinical examination, management and treatment evaluation. RESULTS: No significant difference was found between the students regarding knowledge and understanding. Eighty-seven per cent of the Malmö students and 96% of the Naples students met the criterion on achieved competence. Malmö students had a higher per cent of correct diagnoses than Naples students in the interpretation of case histories. Overall, Malmö students reported most clinical experience and higher confidence than Naple students. CONCLUSIONS: The main findings were that students from Malmö and Naples were, similar in knowledge and understanding of TMD/OP and in satisfaction with their clinical competences. However, Malmö students perceived more confidence in clinical management of patients with TMD/OP. This may reflect that, besides the theoretical part of the programme, a sufficient level of clinical exposure to patients with TMD/OP is essential to gain competences in TMD/OP.