Who is the patient with resistant myofascial temporomandibular disorders pain? A somatosensory, psychosocial, and genetic characterization

Who is the patient with resistant myofascial temporomandibular disorders pain? 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A somatosensory, psychosocial, and genetic characterization Giancarlo De la Torre Canales, Rodrigo Lorenzi Poluha, Flávia Fonseca Carvalho Soares, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6261328/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 May, 2025 Read the published version in The Journal of Headache and Pain → Version 1 posted 14 You are reading this latest preprint version Abstract Background Resistance to treatments have been assessed in chronic conditions such as migraine, but not in temporomandibular disorders (TMD). This study aimed to identify factors that influence treatment outcome in patients with myofascial TMD pain. Methods Seventy-two females were divided into three groups: TMD successful to treatment (TMD-S, n=24), TMD resistant to treatment (TMD-R, n=24) and Controls without TMD (n=24). Criteria for resistance included: less than 30% pain reduction after three months of conservative treatment and an average pain intensity >50 mm (VAS) during the last month. Quantitative sensory testing (QST), psychosocial status and genetic polymorphisms were examined. ANOVA on ranks (psychosocial variables) with Dunn’s test as post-hoc or ANOVA (age and somatosensory variables) with Tukey test as post-hoc test, and Dwass-Steel-Critchlow-Fligner test (genetic variables) were used for univariate groups comparisons. Multivariate statistics were used to identify outcomes that separated the groups. Results QST assessment revealed lower baseline pressure pain threshold and higher wind-up ratio in the trigeminal and spinal areas in the TMD-R group compared with the other groups (p=0.01). Also, the TMD-R group presented higher values in all assessed psychosocial variables (p<0.01) and higher prevalence of the HTR1A polymorphism rs6295 (p=0.02) compared with the other groups at baseline. Multivariate analysis showed that the three strongest separators between TMD-R and TMD-S were sleeping quality, central sensitization, and depressive symptoms. Conclusion Psychosocial, somatosensory, and genetic alterations are related to unsuccessful treatment response in myofascial TMD patients. Temporomandibular disorders Myofascial pain Refractory pain Chronic pain Phenotype Figures Figure 1 1. INTRODUCTION Chronic primary pain is characterized by persistent or recurring pain lasting more than 3 months in one or more body areas. This pain is accompanied by notable emotional distress or functional impairment, and the symptoms are not attributable to any other diagnosis [ 1 ]. Its underlying mechanisms involve a spectrum of peripheral and central processes, with some of them potentially elucidated through the concept of nociplastic pain [ 2 ]. Therefore, chronic pain is an overarching category including the most prevalent and clinically significant chronic pain conditions, such as chronic primary headache and orofacial pain (eg, temporomandibular disorders, TMD)[ 3 ]. Furthermore, the prevalence of chronic pain is approximately 20% [ 4 , 5 ]. Due to this prevalence, the economic costs to treat this condition are substantial, and could potentially reach as much as US $ 635 billion per year in medical cost and loss of productivity [ 6 ]. Even though several treatment guidelines have been published for chronic pain, treating this condition is challenging [ 7 ]. Treatment is symptom-based and multimodal, and customized to enhance quality of life and diminish pain levels [ 8 ]. However, sometimes treatment is not successful. The Pain Study Tracking Responses for a Year (PainSTORY) reported that among chronic pain patients dissatisfied with their pain management, 67% experienced no change and 11% had increased pain levels over 12 months [ 9 ]. Chronic pain that resists relief from multiple therapeutic interventions has been denominated as “refractory/resistant”. In a broader proposed definition, pain is refractory/resistant when multiple evidence-based therapies used in a clinically appropriate fashion failed to reach treatment goals and when psychiatric disorders and psychosocial factors that could influence pain outcomes have been assessed and addressed [ 10 ]. “Refractory/Resistant pain” in TMD has not been properly addressed, mainly because the prevalence of patients needing significant clinical treatment is low (10%-15%) [ 11 ], and to the high percentage of positive responders to conservative (biopsychosocial) treatments [ 12 ]. However, treating chronic orofacial pain disorders like TMD is challenging because the trigeminal system involves complex neural networks connected to the sympathetic, parasympathetic, and cervical nervous systems [ 13 , 14 ]. Moreover, one-half to two-thirds of TMD patients, still experience pain upon reevaluation after 6 months [ 15 , 16 ]. This pinpoints the heightened risk of developing chronic pain, and the importance of selecting the most appropriate treatment at the beginning to avoid resistant/refractory pain. Treatment difficulties augment when one considers the biopsychosocial nature of TMDs [ 17 – 19 ] and the genetic relation with chronic TMD [ 20 ]. Pain amplification, psychological profile as well as global symptoms are key factors in the etiology of painful TMDs [ 21 , 22 ]. Additionally, the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study, reported single-nucleotide polymorphisms (SNPs) that suggest a contribution of the hypothalamic-pituitary-adrenal system and the nociceptive and affective pathways to chronic TMD [ 20 ]. Considering all these factors may help to identified profiles (phenotype and genotype) of patients that respond or not to TMD treatment and will add valuable clinical insights, allowing clinicians to understand which factors influence successful TMD treatment outcomes. This study investigated the prevalence of resistant myofascial TMD pain and identified somatosensory, psychosocial, and genetic factors affecting treatment outcomes. 2. METHODS 2.1 Settings and Study design This observational cross-sectional study was conducted at the orofacial pain clinic at the Bauru School of Dentistry from October 2019 to May 2021. The study was approved by the Research Ethics Committee of the Bauru School of Dentistry, University of Sao Paulo, Brazil (CAAE # 79079917.6.0000.5417/CAAE # 82201818.3.0000.5417) and was conducted following the Helsinki Declaration. All subjects were informed about the research aims and voluntarily signed an informed consent form to participate in this study. Reporting of the data followed the recommendations of the Strengthening the Reporting of Observational Studies in Epidemiology (Strobe) guidelines. 2.2 Subjects The sample of this study was composed of 72 Brazilian females including TMD cases and healthy controls (n = 24). TMD cases were divided in two groups according to treatment response, after a three-months treatment protocol in: TMD cases with successful treatment (TMD-S, n = 24), TMD cases resistant to treatments (TMD-R, n = 24). For the TMD cases, patients with TMD of muscular origin treated at or referred to the orofacial pain clinic of the Bauru School of Dentistry, University of Sao Paulo were recruited. The general inclusion criteria for the TMD cases were females, aged over 18 years, with a diagnosis of myofascial pain (MFP) and MFP with referral, according to the Brazilian Portuguese version of the Diagnostic Criteria for TMD (DC/TMD) [ 23 ]. Patients in the TMD-S group, should have reported a pain reduction of more than 30% after three months of conservative treatment. Patients in the TMD-R group should have reported a pain reduction of less than 30% and an average pain intensity > 50 mm on a 0–100 mm Visual Analogue Scale (VAS) during the last month of the 3 months treatment period. Mandatory treatments for all patients included counselling, oral appliance, which were applied for three months and pharmacotherapy (acting peripherally or centrally like, NSAIDs/10 days, muscle relaxants/1month and antidepressive/2months), while dry or wet needling, acupuncture, and physiotherapy were used as additional treatments. All patients received the mandatory treatments, but regarding pharmacotherapy, the doses were tailored for each patient accordingly to symptoms. The inclusion criteria for the control group were females, aged over 18 years and good general health. The exclusion criteria for the three groups were presence of dental and neuropathic pain, traumas to the face and neck, uncontrolled systemic disorders, (e.g., diabetes), hypertension, or endocrine disorders; neurological disorders, systemic inflammatory diseases (e.g., arthritis) presence of congenital or developmental changes, (e.g., aplasia, hyperplasia, dysplasia, or neoplasms), and ongoing orthodontic treatment. For the control group the exclusion criteria included presence of primary headache, TMD and fibromyalgia. 2.3 Outcomes 2.3.1. Pain variables The characteristic pain intensity (CPI) was used to compare the participants pain intensity at baseline. This is composed of three 0–10 numerical rating scales (NRS) where 0 represent no pain and 10 represents the worst pain imaginable assessing the current pain intensity and the worst and average pain intensities during the last month. The CPI is the average of the three scores multiplied with 10, giving a score 0-100. For other pain assessments (see below) a 0-100 VAS with the same descriptors for 0 and 100 as for the NRS, was used. 2.3.1 Somatosensory Profile Three tests of the quantitative sensory test (QST) battery for mechanical somatosensory assessment were considered: (a) mechanical pain threshold (MPT), (b) wind up ratio (WUR), and (c) pressure pain threshold (PPT). In the TMD-S and TMD-R groups, measurements in the trigeminal area were performed in the masseter muscle on the side that the patient reported more severe pain, and in the control group on the dominant side (masseter insertion region). In the spinal area, the same tests were performed at the hand on the same side as the most painful masseter in the TMD-S and TMD-R groups and at the dominant hand for the control group. Conditioned pain modulation (CPM) was used to assess endogenous pain inhibition. Mechanical pain threshold For this test, a standardized set of Semmes-Weinstein monofilaments (Touch-Test TM Sensory Evaluators; North Coast Medical Inc, California, USA), which applies forces between 0.008 g/mm 2 and 300 g/mm 2 were used. The monofilaments were applied perpendicularly to the examination sites and a light pressure was applied until the filament curved. Participants were instructed to verbally report when feeling a “prick, pinprick, or slightly painful sting” sensation in the contact area of the monofilaments. The limit method was used to determine the threshold using a series of five ascending and five descending stimuli. The MPT was considered as the geometric mean of these repetitions [ 24 , 25 ]. Wind-up ratio To measure WUR, the smallest Von Frey filament that caused a sensation of mild pain (30 to 50 on VAS) was used. The filament was placed on the skin over the assessed regions and pressure was applied until the filament curved. This test was performed in a continuous sequence where the intensity of a single painful stimulus was compared with that of a series of 10 consecutive stimuli with the same filament and with the same intensity of force (1 per second applied within an area 1 cm 2 ). Single pinprick stimuli were alternated with a train of 10 stimuli until both were done three times. Pain intensity values were quantified (VAS) after the single stimulus and at the end of the series of 10 consecutive stimuli. The wind-up ratio was calculated as the mean score of the three series of 10 stimuli divided by the mean score of the three single stimuli [ 24 , 25 ]. Pressure pain threshold Pressure pain threshold measurements were performed using a digital pressure algometer (model Kratos DDK-20, Sao Paulo, Brazil), with a flat circular tip of 1 cm 2 , through which a constant and increasing pressure of approximately 0.5 kg/cm2/s was applied. Participants were instructed to press a button connected to the algometer when the sensation of pressure turned into a slightly painful sensation to interrupt the exerted pressure. The recordings were repeated three times at 1-min intervals The arithmetic mean of the three measurements in the sequence was calculated and used in analyses [ 24 , 25 ]. Conditioned Pain Modulation To assess the CPM paradigm, as test stimulus (TS), PPT was first obtained in the masseter and thenar muscle, as explained above. As conditioning stimulus (CS), participants were asked to immerse the non-dominant hand in a container with water at 10°C for 60 seconds. Then, a second assessment of PPT was immediately done at the end of CS in the same sites. In each evaluation, PPT was determined as the arithmetic mean of three measurements. The absolute (kgf/cm 2 ) and percent (%) differences between PPT values (‘TS before CS’ and ‘TS after CS’) were considered as the CPM values. Negative values indicate an increase in pain threshold [ 26 , 27 ]. 2.4 Psychosocial Profile The psychosocial profile was assessed using the validated Brazilian Portuguese translations of the following self-report questionnaires: Hospital Anxiety and Depression Scale (HADS) [ 28 ]; Central Sensitization Inventory (CSI) [ 29 ]; Perceived Stress Scale (PSS) [ 30 ]; Pittsburgh Sleep Quality Index (PSQI) [ 31 ], and Pain Catastrophizing Scale (PCS) [ 32 ]. Hospital Anxiety and Depression Scale This questionnaire is composed of 14 multiple-choice questions (each scored 0–3), divided into two interleaved subscales, one for anxiety (7 questions) and another for depression (7 questions). The scores range from 0 to 21 points; the higher the value, the greater the symptoms of anxiety (A-HADS) and/or depression (D-HADS) [ 28 ]. Central Sensitization Inventory This questionnaire is designed as an easy-to-administer screener for patients who are at high risk of having Central Sensitization or to assess Central Sensitization-related symptoms. It is divided in two parts: part A with 25 statements about current health symptoms and part B assessing previously diagnosed central sensitivity syndromes and related conditions. For part A, subjects mark the frequency in a scale ranging from 0–4 (0 = never and 5 = always) and after summing all the items, they are classified into five severity levels (subclinical, mild, moderate, severe, extreme) [ 29 ]. Perceived Stress Scale This questionnaire consists of 14 items that measures the degree of perceived stress in the last month considering the individual's global context. The scale total is the sum of the scores (0–4) for these 14 items and the scores can range from 0 to 56 [ 30 ]. Pittsburgh Sleep Quality Index This questionnaire consists of 19 self-report questions that assess various factors related to sleep quality, distinguishing individuals who sleep “well” or “poorly” and providing clinical information about different sleep disorders that can influence the sleep quality. The score ranges from 0 to > 10, and the higher the score, the worse the quality of sleep [ 31 ]. Pain Catastrophizing Scale This questionnaire measures catastrophic thoughts about pain. The subjects indicate the frequency of catastrophic thoughts when pain is severe. It consists of 13 statements in total in which the subjects mark the frequency in a scale ranging from 0–5 (0 = hardly ever and 4 = almost always). The total score is the sum of all the items ranging from 0 to 52 points. The higher the value, the more the degree of catastrophizing [ 32 ]. 2.5 DNA collection and single-nucleotide polymorphism analysis Samples of 5 ml of unstimulated total saliva were collected in a 50 ml Falcon tube. Genomic DNA was extracted from epithelial buccal cells present in saliva using QIAmp DNA Mini Kit (Qiagen, Hilden, Germany), according to the manufacturer's instructions. The analysis of the genotypes of the selected polymorphisms HTR1B rs6296, HTR1A rs6295, OPRM1 rs1799971, COMT rs4680, rs4633, and rs4818, and SCN9A rs6746030) was performed using the Real-Time Polymerase Chain Reaction technique. The reactions were performed on the Viia 7 thermal cycler (Applied Biosystems, Massachusetts. USA), using the TaqMan method using TaqMan SNP genotyping assays (Applied Biosystems, Massachusetts. USA) pre-standardized and experimentally validated, following the manufacturer's instructions. All data collection was performed at baseline (before treatments). 2.6 Statistical Analysis The sample size calculation was performed using G*Power 3.1.9.2 software and was based on calculated effect sizes. The following parameters were considered within a one-way ANOVA analysis: α error probability = 0.05, power (1-β error probability) = 0.8, number of groups = 3, and effect size values for PPT, CPM, MPT, and WUR of ≥ 0.4. The total sample size was calculated to be 66 subjects equally divided into three groups. However, considering an assumed withdrawal or dropout rate, 24 subjects were included in each group. Univariate data were analyzed with SPSS. Data were assessed for distribution normality using the Shapiro-Wilk test. Normal distributions were found for age and somatosensory variables (MPT, WUR, PPT and CPM) why comparisons between groups were done using ANOVA with Tukey test as post-hoc test. As the psychosocial variables (anxiety, depression, central sensitization, stress, sleep, and pain catastrophizing) are composed of scores obtained from individual ordinal scales, the sum scores cannot be regarded as continuous. Therefore, ANOVA on ranks (Kruskall-Wallis test) with Dunn’s test as post-hoc test was used to test for group differences. For the number of other painful TMD diagnosis (arthralgia and headache attributed to TMD) the Chi Square test was used. The Dwass-Steel-Critchlow-Fligner test was used to compare the proportion of polymorphisms between groups. Since many of the outcomes are more or less interrelated, multivariate statistics were used to identify outcomes that separated the groups using SIMCA-P + v.17.0 (Sartorius Stedim Biotech, Umeå, Sweden) as earlier described [ 33 ]. Principle component analysis (PCA) was first used to investigate the correlation patterns for the investigated variables and to detect moderate or strong outliers among the observations using Hotelling’s T2 and DMod. No outliers were detected. Thereafter orthogonal partial least squares discriminant analysis (OPLS-DA) was used to regress group membership, i.e. multivariate correlations between variables and group membership. R2 describes the goodness of fit, i.e., the fraction of sum of squares of all the variables explained by a principal component whereas Q2 describes the goodness of prediction, i.e., the fraction of the total variation of the variables that can be predicted by a principal component using cross validation methods. R2 should not be considerably higher than Q2; if substantially higher (> 0.3) the robustness of the model is poor [ 34 ]. To validate the model, an obtained CV-ANOVA was used to test the significance of the model. The OPLS-DA model was considered significant if the CV-ANOVA had a p-value < 0.05. The variable influence on projection (VIP) value indicates the relevance of each X-variable pooled over all dimensions and the Y-variables indicate the group of variables that best explain Y. P(corr) was used to note the direction of the relationship (positive or negative). VIP > 1.0 and an absolute p(corr) > 0.4 was considered significant. 3. RESULTS Out of the 226 myofascial pain patients who sought treatment at the orofacial pain clinic of the Bauru School of Dentistry during the study period, 10.6% (24) did not respond to the treatment protocols after three months, were considered resistant to treatment and allocated to the TMD-R group. The number of patients included in the other groups were matched and chosen randomly according to the number of patients included in the TMD-R. All patients were women of Latino ethnicity. The mean age (± standard deviation, SD) of the TMD-R group (44 ± 7 yrs) was significantly higher compared with TMD-S (38 ± 10 yrs) and control (32.2 ± 8.7 yrs) groups (p = 0.01). No other major differences in demographic characteristics were found across groups. No significant differences were found regarding the CPI of the TMD-R (7.4 ± 1.3) compared with the TMD-S (7.0 ± 1.5) (p > 0.05) at baseline, and no significant differences were found regarding pain duration between both groups (p > 0.05). The TMD-S group presented a higher presence of other painful TMD diagnoses (arthralgia and headache attributed to TMD) compared to the TMD-R group (p = 0.03). 3.1 Somatosensory variables The TMD-R group had lower PPTs and higher WURs values compared with the other groups (p = 0.01) in both the trigeminal and spinal areas. The patient groups had lower MPTs than the controls in both the trigeminal and spinal areas (p = 0.01), but there were no significant differences between the TMD-S and TMD-R groups. For CPM, no significant differences were found between groups for the trigeminal or spinal areas (p > 0.05) (Table 1 ). Table 1 Baseline somatosensory and conditioned pain modulation data assessed at the masseter and thenar muscles in patients with temporomandibular disorders pain resistant (TMD-R) or successful (TMD-S) to treatment, and in healthy controls. Data are presented as mean (± sd). TMD-R TMD-S Control n = 24 n = 24 n = 24 Masseter Thenar Masseter Thenar Masseter Thenar PPT (kgf/cm 2 ) 1.0 (± 0.4) 2.5 (± 1.2) 1.7 (± 1.0) 4.5 (± 1.5) 1.9 (± 0.9)* 4.1 (± 1.0)* MPT (0-100 VAS) 10.6 (± 12.5) 53.2 (± 53.8) 8.0 (± 15.9) 15.6 (± 39.3) 123.6 (± 147.8)* 149.4 (± 169.4)* WUR (0-100 VAS) 2.3 (± 1.2) 2.2 (± 1.6) 1.9 (± 0.7) 1.8 (± 0.5) 1.5 (± 0.6)* 1.4 (± 0.4)* CPM (kgf/cm 2 ) -0.1 (± 0.1) -0.3 (± 0.7) -0.3 (± 0.7) -0.3 (± 0.6) -0.4 (0.7) -0.7 (± 1.3) PPT: pressure pain threshold; MPT: mechanical pain threshold; CPM: conditioned pain modulation; WUR: wind-up ratio. ANOVA test: * p < .001 between groups 3.2 Psychosocial variables Scores for all questionnaires are shown in Table 2 . Inter-group comparison showed higher values for the TMD-R group when compared with the other groups for A- HADS and D-HADS (p = 0.01), CSI (p = 0.01), PSS (p = 0.03), PSQI (p = 0.01), PCS (p = 0.01). Furthermore, higher values were also found in the TMD-S group for CSI (p = 0.01) and PCS (p = 0.01) compared with the control group (Table 2 ). Table 2 Baseline psychosocial data in patients with temporomandibular disorders pain resistant (TMD-R) or successful (TMD-S) to treatment, and in healthy controls. Data are presented as median (min–max). TMD-R TMD-S Control p n = 24 n = 24 n = 24 A-HADS (total) 8.0 (3–20) * 4.0 (0–19) 5.0 (1–13) 0.01 D-HADS (total) 8.0 (1–14) * 5.0 (0–10) 3.0 (0–8) 0.01 CSI (total) 50.0 (21–85) * 37.5 (12–80) # 25.0 (7–42) 0.01 PSS (total) 29.5 (13–40) * 21.0 (9–28) 21.50 (6–38) 0.03 PSQI (total) 10.0 (4–17) * 6.0 (0–14) # 4.0 (3–13) 0.01 PCS (total) 26.5 (10–49) * 19.5 (0–46) # 11.0 (0–23) 0.01 HADS: Hospital Anxiety (A) and Depression (D) Scale: CSI: Central Sensitization Inventory; PSS: Perceived Stress Scale; PSQI: Pittsburgh Sleep Quality Index; PCS: Pain Catastrophizing Scale. Kruskall Wallis test ( p ) with Dunn’s test as postdoc: * p < 0.05: significant differences between TMD-R and the other groups. # p < 0.05: significant differences between TMD-S and Control group. 3.3 Genetic Variables The inter-group comparisons showed that the TMD-R group presented a higher prevalence of the polymorphic genotype for HTR1A rs6295 when compared with the other groups group (p = 0.02). Likewise, the TMD-R group presented a higher prevalence of the polymorphic genotype for HTR1B rs6296 compared to the control group (p = 0.01). No significant group differences were found for the other genotypes (Table 3 ). Table 3 Genotype frequency (%) for each SNP in patients with temporomandibular disorders pain resistant (TMD-R) or successful to treatment (TMD-S), and in healthy controls. TMD-R TMD-S Control p n = 24 n = 24 n = 24 Genotype Ancestral Polymorphic Ancestral Polymorphic Ancestral Polymorphic COMT rs4680 GG GA + AA GG GA + AA GG GA + AA n (%) 10 (41.7) 14 (58.3) 12 (50.0) 12 (50.0) 8 (33.3) 16 (66.7) 0.8 COMT rs4818 GG GC + CC GG GC + CC GG GC + CC n (%) 4 (16.7) 20 (83.3) 10 (41.7) 14 (58.3) 3 (12.5) 21 (87.5) 0.9 COMT rs4633 CC CT + TT CC CT + TT CC CT + TT n (%) 10 (41.7) 14 (58.3) 12 (50.0) 12 (50.0) 8 (33.3) 16 (66.7) 0.8 HTR1A rs6295 GG GC + CC GG GC + CC GG GC + CC n (%) 2 (8.3) 22 (91.7) 10 (41.4) 14 (58.3) 11 (45.8) 13 (54.2) 0.02* HTR1B rs6296 CC CG + GG CC CG + GG CC CG + GG n (%) 9 (37.5) 15 (62.5) 14 (58.3) 10 (41.7) 19 (79.2) 5 (20.8) 0.01 # OPRM1 rs1799971 AA AG + GG AA AG + GG AA AG + GG n (%) 18 (75) 6 (25) 20 (83.3) 4 (16.7) 16 (66.7) 8 (33.3) 0.8 SCN9A rs6746030 GG GA + AA GG GA + AA GG GA + AA n (%) 13 (54.2) 11 (45.8) 20 (83.3) 4 (16.7) 18 (75) 6 (25) 0.7 COMT: Catechol-O-Methyltransferase; HTR1A: 5-hydroxytryptamine receptor 1A; HTR1B: 5-hydroxytryptamine receptor 1B; OPRM1: opioid receptor mu 1; SCN9A: sodium voltage-gated channel alpha subunit 9. Dwass-Steel-Critchlow-Fligner test *p < 0.05: Significant differences between TMD-R and the other groups, # p < 0.05: Significant difference between the TMD-R and Control group. 3.4 Predictors of Resistance The OPLS-DA showed one predictive component that was strongly significant (R2 = 0.302, Q2 = 0.418, CV-ANOVA p-value = 1.65e-12) (Fig. 1 ). The figure clearly shows the separation between the patients and controls, but also a separation between the TMD-R and TMD-S groups. There were nine variables that differed between the groups, i.e., had a VIP > 1.0 and a p(corr) > 0.4. Pain intensity was the strongest separator, followed by CSI and D-HADS. All intercorrelations p(corr) were negative and thus, lower in controls compared to the other groups (Table 4 ). As can be seen in the loading plot (Fig. 1 ) the psychosocial variables were more related to the TMD-R group, whereas the somatosensory variables were more related to the controls. Table 4 OPLS-DA model of variables discriminating healthy controls from patients with temporomandibular disorders myofascial pain resistant to treatment (TMD-R) and with a successful treatment outcome (TMD-S). Nine variables discriminated between groups and had a VIP-value > 1.0 and a p(corr) > 0.4. Three variables (MPT Masseter and hand, PPT Masseter) had a positive p(corr) and were higher in controls, all other variables were lower in controls. VIP p(corr) Pain intensity 1.76 -0.85 CSI 1.56 -0.67 D-HADS 1.37 -0.47 PCS 1.35 -0.58 MPT Masseter 1.31 0.63 PSQI 1.19 -0.40 Age 1.13 -0.55 MPT Hand 1.05 0.51 PPT Masseter 1.05 0.50 CSI: Central Sensitization Index; D-HADS: Hospital Anxiety and Depression Scale, depression subscale; PCS: Pain Catastrophizing Scale; MPT: mechanical pain threshold; PSQI: Pittsburg Sleep Quality Index; PPT: pressure pain threshold; VIP: variable influence on projection; p(corr): correlation coefficient in multivariate analyses. Table 5 OPLS-DA model of variables discriminating temporomandibular disorders myofascial pain patients resistant to treatment (TMD-R) from patients with a successful treatment outcome (TMD-S). Twelve variables significantly discriminated between groups and had a VIP-value > 1.0 and a p(corr) > 0.4. WUR and PPT had a negative p(corr) and were lower in TMD-R. VIP p(corr) PSQI 1.69 0.76 CSI 1.67 0.76 D-HADS 1.49 0.67 A-HADS 1.44 0.65 PSS 1.40 0.63 WUR Masseter 1.28 -0.58 PPT Hand 1.21 -0.54 AGE 1.13 0.51 PCS 1.12 0.51 HTR1A rs6295 1.12 0.51 WUR Hand 1.12 -0.50 COMT rs4818 1.01 0.45 PSQI: Pittsburg Sleep Quality Index; CSI: Central Sensitization Index; D-HADS: Hospital Anxiety and Depression Scale, depression subscale; A-HADS, anxiety subscale; PSS: Perceived Stress Scale; WUR: wind-up ratio; PPT: pressure pain threshold; PCS: Pain Catastrophizing Scale; HTR1A: serotonin type 1 receptor gene; COMT: catecholamine-O-methyltransferase gene; VIP: variable influence on projection; p(corr): correlation coefficient in multivariate analyses. As there was a separation also between the patient groups, we did a separate OPLS-DA to test which variables differed between TMD-R and TMD-S (Fig. 1 ). We found a highly significant predictive component (R2 = 0.204, Q2 = 0.456, CV-ANOVA p-value = 1.11e-6). Twelve of the variables had a VIP > 1 and p(corr) > 0.4 (Table 5 ). The three strongest separators between TMD-R and TMD-S were PSQI, CSI and D-HADS, but also some genetic variables, HTR1A rs6295 and COMT rs4818 differed. 4. DISCUSSION To the best of our knowledge this is the first study phenotyping myofascial TMD patients considered as non-responders to conservative treatments. The main findings were 1) a low prevalence of resistance to treatment among myofascial TMD pain patients, 2) increased pain sensibility (PPT), decreased pain modulation (WUR), higher levels of psychosocial distress, and a higher presence of the HTR1A rs6295 polymorphism in the resistant TMD group compared with the other groups, and 3) that pain intensity, central sensitization, and depression were the strongest predictive variables for myofascial TMD pain, whereas sleep quality, central sensitization, depression, anxiety and stress were the strongest predictive variables for resistance to treatment, followed by somatosensory variables (WUR and PPT) and genetic variables (HTR1A rs6295 and COMT rs4818). Multifaceted treatment strategies in which reversible non-pharmacological therapies are considered the first option, followed by pharmacological options are recommended for TMD [ 35 , 36 ]. Our resistant inclusion criteria followed these recommendations. Unsuccessful treatment with oral appliance, cognitive behavioral and pharmacotherapy, besides other treatments, were used as part of our criteria to classify myofascial TMD pain patients as resistant to treatments. Additionally, as the Initiative of Measurement, Methods, and Pain assessment in Clinical Trials (IMMPACT) recommendations consider treatments with a 30% pain reduction as effective [ 37 , 38 ] and as this percentage is equivalent to “much improved” on the Patient Global Impression of Change Scale [ 39 ], we also included a pain reduction of less than 30% despite treatment as a criterion of resistance. Furthermore, the stablished three-month timeframe for unsuccessful treatment response, was based on responder definitions from other chronic pain conditions (such as fibromyalgia and low back pain) [ 40 , 41 ], and on the resistant migraine criteria proposed by the European Headache Federation consensus [ 42 ], as these parameters have not yet been established for myogenous TMD patients. Validation of our criteria is necessary, as modifying any variable will undoubtedly impact the results, especially regarding the proposed time frame regarding resistance to treatment and the average pain intensity > 50. However, our criteria could be the first step in creating a responder definition that combines multiple significant outcomes into one metric, usable as a primary outcome in clinical trials. This unified metric could also guide clinical decision-making, replacing reliance on group averages for individual patient assessments [ 40 ]. Based on these criteria, our study found a low prevalence of resistant myofascial TMD pain patients. This finding was anticipated, primarily due to the low prevalence of TMD patients requiring treatment and the high response rate of this population to conservative treatments [ 11 , 12 ]. However, since these patients were recruited from an orofacial pain specialist clinic, prevalence may be lower in general dentistry practices. This aligns reports on resistant migraines, with a higher prevalence (75%) in headache specialist centers than in primary care settings (13%) [ 43 ]. Regarding the somatosensory profile, patients of the TMD-R group presented a significant somatosensory gain of function (more sensitive), in the trigeminal and spinal area, when WUR, and PPT were addressed. Taken together, these findings could indicate a generalized hypersensitivity of the central nervous system, inadequate functioning of the endogenous pain modulation system, and central sensitization [ 43 – 46 ]. The lower PPT values found in the TMD-R group compared with the other groups and the non-significant differences between TMD-R and TMD-S for the MPT, could be more related to central hyperexcitability in both the trigeminal and spinal systems which are known to produce hyperalgesia, than to a higher proportion of sensitized primary nociceptive afferents [ 47 ]. Our multivariate analyses support this, demonstrating that lower MPT in both trigeminal and spinal areas, as well as PPT in the trigeminal area, serve as predictors for myofascial TMD pain and lower PPT in the spinal area is identified as a predictor of resistant myofascial TMD pain. In addition, myofascial TMD pain patients are more likely to present generalized mechanical hyperalgesia in the trigeminal and spinal regions than controls [ 48 ], which is in line with our findings. Additionally, a widespread lowering of PPT as showed in our study and in the literature, could reflect a deficit of the endogenous pain inhibitory mechanism [ 48 , 49 ]. Our study demonstrated that the significant deficit in endogenous pain modulation observed in the TMD-R group was primarily due to increased pain facilitation [ 50 ], with a smaller contribution from decreased pain inhibition, since the TMD-R group presented significant higher values in WUR and lower non- significant values in CPM compared with the other groups. These results supports findings from one study [ 51 ] but contradicts another [ 52 ]. Painful TMD subjects often show moderate to severe somatization (28.5%-76.6%) and depression (21.4%-60.1%), and higher stress, catastrophization, and hypervigilance compared to controls [ 53 – 57 ]. In line with these findings, our study revealed that the TMD-R group exhibited higher scores in all psychosocial assessments compared to the other groups; while the TMD-S group only showed worse outcomes for the CSI, PSQI and PCS compared with controls. It is important to note that studies have demonstrated that psychosocial factors (e.g. depression and stress), are significant predictors of new onset-TMD [ 58 ]. Longitudinal designs have also shown that these factors pose a risk for prolonged chronic pain in TMD patients [ 59 – 62 ]. This aligns with our multivariate analysis, which indicates that among the variables distinguishing patients from controls, four are related with psychosocial impairment (CSI, D-HADS, PCS and PSQI). Interestingly, among the 12 variables that differentiate resistant and non-resistant patients, the strongest predictors of belonging to the TMD-R group (PSQI, CSI, D/A-HADS and PSS) were also related with psychosocial impairment. These findings underscore the necessity of assessing psychosocial factors in TMD patients, as they appear to influence their response to treatment. Moreover, the Axis II of the short version of the DC/TMD (bDC/TMD) [ 63 ] can aid non-specialist clinicians in assessing psychosocial factors in a simpler and more interpretable manner. While psychological interventions such as cognitive behavioral therapy and counseling have shown a clinically relevant pain reducing effect in painful TMD patients [ 64 ], our findings highlight the need to include additional psychological treatments and to more effectively apply current treatments, given that counselling was used in our study. Also, our study reinforces the need of a multidisciplinary approach including psychologist specialized treatment. We recommend focusing on assessing central sensitization, depression, catastrophization, and sleep quality, as these factors differentiated patients from controls and treatment responders from resistant patients. The OPPERA study highlighted a significant genetic influence from single nucleotide polymorphisms (SNPs) in key biological pathways related to processing noxious stimuli and perceiving pain. These include genes related to serotonin receptor and catecho-O-methyltransferase (COMT) in relation to chronic TMD [ 65 ]. Our findings revealed that the TMD-R group showed a higher prevalence of the HTR1A polymorphism (rs6295) compared to other groups, and the HTR1B polymorphism (rs6296) compared to the control group. This partially aligns with previous findings [ 65 ], as we assessed other serotonin receptor-related genes. Our study did not identify any genetic predictor for patients, which could be attributed to the small sample size. However, the HTR1A rs6295 polymorphism and COMT rs4818 were found to be predictors for TMD-R patients. Serotonin, which can be considered both a neurotransmitter and a neuromodulator, is present in the peripheral and central nervous systems and affects pain amplification and inhibition within the serotonergic system [ 66 , 67 ]. Clinical results suggest an increased peripheral release of serotonin in patients with chronic myalgia of the masseter and trapezius muscles [ 68 , 69 ], and a relationship with allodynia of orofacial muscles [ 68 ]. However, a meta-analysis found no differences between local and generalized chronic musculoskeletal pain [ 70 ]. We can speculate that in our study serotonin may have affected peripheral and central sensitization in the TMD-R group. Similarly, studies have indicated that reductions in COMT activity can influence pain perception by indirectly regulating u-opioid receptor function [ 71 ] and decreasing the metabolism of epinephrine, thereby potentiating pain signaling through beta-adrenergic receptors [ 72 , 73 ]. Thus, genetic polymorphisms that decrease COMT activity can contribute to the etiology of TMD and may have increased risk of developing persistent pain conditions like in our TMD-R group [ 74 ]. In summary, resistant myofascial TMD pain is not highly prevalent. The phenotype of these patients is primarily influenced by psychosocial impairment, followed by somatossensorial alterations, and distinctive genotype. Interestingly, the somatosensorial and psychosocial characteristics of the TMD-R group are similar to the “global symptoms cluster” identified in the OPPERA study, which exhibited increased pain sensitivity, higher psychological distress and widespread clinical symptoms, suggesting a higher prevalence of central sensitization [ 22 ]. The authors suggested that due to the impairments observed in pain processing, individuals in this cluster may be less responsive to treatments as in our study. Moreover, it is reasonable to consider that treatment resistance may be also influenced by factors related to the physician/dentist, particularly their knowledge of diagnosis and treatment [ 75 ]. Additionally, establishing the correct treatment plan from the initial appointment is crucial to preventing chronic pain [ 22 ]. Since the studied sample was treated by experienced orofacial pain specialists; these factors were minimized as much as possible. Furthermore, since compliance to the proposed treatments could have influenced the results, we recommend that future studies assess this variable in an objective manner, and not only on patient´s self-report. It is also recommended to assess demographic and social factors, medical comorbidities, sleep disorders, nutrition, sunshine and vitamin D, and microbiome as these have been identified as factors that may increase resistancve to treatments [ 14 ]. Yet, labeling some as resistant, opens a window to irreversible therapies which is highly undesirable in non-lethal conditions as TMD. Finally, these findings hold potential for more individualized diagnosis and treatment. 5. CONCLUSION This is the first study presenting criteria to classify myofascial TMD pain patients as resistant to conventional treatments. Resistant myofascial TMD pain is not highly prevalent. Nevertheless, the phenotype of these patients includes psychosocial, somatosensory, and genetic factors, which may be considered risk factors for developing resistance to conservative myofascial TMD pain treatment. These results could help clinicians in identifying myofascial TMD pain patients resistant to treatments, in order to propose a more tailored treatment plan. Declarations Ethics approval and consent to participate The study was approved by the Research Ethics Committee of the Bauru School of Dentistry, University of Sao Paulo, Brazil (CAAE # 79079917.6.0000.5417/CAAE # 82201818.3.0000.5417) All subjects were informed about the research aims and voluntarily signed an informed consent form to participate in this study. Data availability The datasets generated during and/or analyzed during the current study, are not publicly available but are available from the corresponding author upon reasonable request and completion of an institutional data transfer agreement. Competing interests The authors declare that they have no competing interests. Funding No funding was received for this study. Acknowledgments The Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Finance Code 001 for the Ph.D. scholarship of R. Lorenzi Poluha and the Sao Paulo Research Foundation (FAPESP) for the post-doctoral scholarship of G. De la Torre Canales (process 2017/21674-0). These institutions were not involved in study design, collection, analysis and interpretation of data, decision to publish, or preparation of the manuscript. Authors contributions This study was designed by G.D.C., L.R.B., R.L.P., and P.C.R.C. The data collection was performed by G.D.C., R.L.P., D.M.A.O.F., and F.F.C.S. The data were analyzed by G.D.C., A.S.A., and M.E. The results were critically examined by all authors. G.D.C. had a primary role in preparing the manuscript, which was edited by M.E., and P.C.R.C. 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Cite Share Download PDF Status: Published Journal Publication published 06 May, 2025 Read the published version in The Journal of Headache and Pain → Version 1 posted Editorial decision: Revision requested 15 Apr, 2025 Reviews received at journal 14 Apr, 2025 Reviewers agreed at journal 10 Apr, 2025 Reviews received at journal 10 Apr, 2025 Reviewers agreed at journal 10 Apr, 2025 Reviews received at journal 08 Apr, 2025 Reviewers agreed at journal 08 Apr, 2025 Reviewers agreed at journal 08 Apr, 2025 Reviewers agreed at journal 30 Mar, 2025 Reviewers agreed at journal 20 Mar, 2025 Reviewers invited by journal 20 Mar, 2025 Editor assigned by journal 19 Mar, 2025 Submission checks completed at journal 19 Mar, 2025 First submitted to journal 19 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6261328","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":434964526,"identity":"7bd6f095-04ac-4f28-9b43-dbe5594729d5","order_by":0,"name":"Giancarlo De la Torre Canales","email":"data:image/png;base64,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","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":true,"prefix":"","firstName":"Giancarlo","middleName":"De la Torre","lastName":"Canales","suffix":""},{"id":434964527,"identity":"a4425741-4e61-4de3-803e-0b217350c4e9","order_by":1,"name":"Rodrigo Lorenzi Poluha","email":"","orcid":"","institution":"State University of Maringá","correspondingAuthor":false,"prefix":"","firstName":"Rodrigo","middleName":"Lorenzi","lastName":"Poluha","suffix":""},{"id":434964528,"identity":"1c71a8e1-ef02-458e-bf82-a4239495f768","order_by":2,"name":"Flávia Fonseca Carvalho Soares","email":"","orcid":"","institution":"University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Flávia","middleName":"Fonseca Carvalho","lastName":"Soares","suffix":""},{"id":434964529,"identity":"cc8433c6-bbc5-4879-8cb7-027adbc97417","order_by":3,"name":"Dyna Mara Araújo Oliveira Ferreira","email":"","orcid":"","institution":"University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Dyna","middleName":"Mara Araújo Oliveira","lastName":"Ferreira","suffix":""},{"id":434964530,"identity":"5dd27213-8bc9-480d-8b5e-132ccb167589","order_by":4,"name":"Alfonso Sánchez-Ayala","email":"","orcid":"","institution":"University of Ponta Grossa","correspondingAuthor":false,"prefix":"","firstName":"Alfonso","middleName":"","lastName":"Sánchez-Ayala","suffix":""},{"id":434964531,"identity":"d9dd8110-6a3a-465e-9840-cf8af572d13d","order_by":5,"name":"Leonardo Rigoldi Bonjardim","email":"","orcid":"","institution":"University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Leonardo","middleName":"Rigoldi","lastName":"Bonjardim","suffix":""},{"id":434964533,"identity":"71cdc061-7841-4c7a-b555-8f8a6f000cc7","order_by":6,"name":"Malin Ernberg","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Malin","middleName":"","lastName":"Ernberg","suffix":""},{"id":434964534,"identity":"4d4b5977-144a-4283-9d7d-87e2a4f6b029","order_by":7,"name":"Paulo César Rodrigues Conti","email":"","orcid":"","institution":"University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Paulo","middleName":"César Rodrigues","lastName":"Conti","suffix":""}],"badges":[],"createdAt":"2025-03-19 11:53:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6261328/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6261328/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s10194-025-02055-7","type":"published","date":"2025-05-06T15:57:28+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79578369,"identity":"3f07f4ff-8b9e-4c5b-a58d-9a46409cd042","added_by":"auto","created_at":"2025-03-31 11:33:14","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":169824,"visible":true,"origin":"","legend":"\u003cp\u003eOrthogonal partial least square discriminant analysis (OPLS-DA) of patients with myogenous temporomandibular disorders (TMD) resistant to treatment (TMD-R), successful to treatment (TMD-S) and healthy control subjects (CON). (A) Score plots showing the separation between each observation in the TMD-R, TMD-NR, and CON and B) the separation between the TMD-R and TMD-S. C) and D) Loading plots showing the variables and their loadings with a VIP-value \u0026gt;1.0 and p(corr) \u0026gt; 0.4 (red boxes). Green boxes are non-significant variables. Significant variables correspond to those in Tables 4 and 5.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6261328/v1/79e839a06f1d51cab85df1cc.jpg"},{"id":82537718,"identity":"28733241-041b-4024-abcc-9714f587a128","added_by":"auto","created_at":"2025-05-12 16:10:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1131079,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6261328/v1/b37a2826-b117-4af2-ae10-1d4ee0c09ecf.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Who is the patient with resistant myofascial temporomandibular disorders pain? A somatosensory, psychosocial, and genetic characterization","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eChronic primary pain is characterized by persistent or recurring pain lasting more than 3 months in one or more body areas. This pain is accompanied by notable emotional distress or functional impairment, and the symptoms are not attributable to any other diagnosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Its underlying mechanisms involve a spectrum of peripheral and central processes, with some of them potentially elucidated through the concept of nociplastic pain [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Therefore, chronic pain is an overarching category including the most prevalent and clinically significant chronic pain conditions, such as chronic primary headache and orofacial pain (eg, temporomandibular disorders, TMD)[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Furthermore, the prevalence of chronic pain is approximately 20% [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Due to this prevalence, the economic costs to treat this condition are substantial, and could potentially reach as much as US\u003cspan\u003e$\u003c/span\u003e635\u0026nbsp;billion per year in medical cost and loss of productivity [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEven though several treatment guidelines have been published for chronic pain, treating this condition is challenging [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Treatment is symptom-based and multimodal, and customized to enhance quality of life and diminish pain levels [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, sometimes treatment is not successful. The Pain Study Tracking Responses for a Year (PainSTORY) reported that among chronic pain patients dissatisfied with their pain management, 67% experienced no change and 11% had increased pain levels over 12 months [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Chronic pain that resists relief from multiple therapeutic interventions has been denominated as \u0026ldquo;refractory/resistant\u0026rdquo;. In a broader proposed definition, pain is refractory/resistant when multiple evidence-based therapies used in a clinically appropriate fashion failed to reach treatment goals and when psychiatric disorders and psychosocial factors that could influence pain outcomes have been assessed and addressed [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e\u0026ldquo;Refractory/Resistant pain\u0026rdquo; in TMD has not been properly addressed, mainly because the prevalence of patients needing significant clinical treatment is low (10%-15%) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and to the high percentage of positive responders to conservative (biopsychosocial) treatments [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, treating chronic orofacial pain disorders like TMD is challenging because the trigeminal system involves complex neural networks connected to the sympathetic, parasympathetic, and cervical nervous systems [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Moreover, one-half to two-thirds of TMD patients, still experience pain upon reevaluation after 6 months [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This pinpoints the heightened risk of developing chronic pain, and the importance of selecting the most appropriate treatment at the beginning to avoid resistant/refractory pain.\u003c/p\u003e \u003cp\u003eTreatment difficulties augment when one considers the biopsychosocial nature of TMDs [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and the genetic relation with chronic TMD [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Pain amplification, psychological profile as well as global symptoms are key factors in the etiology of painful TMDs [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Additionally, the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study, reported single-nucleotide polymorphisms (SNPs) that suggest a contribution of the hypothalamic-pituitary-adrenal system and the nociceptive and affective pathways to chronic TMD [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Considering all these factors may help to identified profiles (phenotype and genotype) of patients that respond or not to TMD treatment and will add valuable clinical insights, allowing clinicians to understand which factors influence successful TMD treatment outcomes.\u003c/p\u003e \u003cp\u003eThis study investigated the prevalence of resistant myofascial TMD pain and identified somatosensory, psychosocial, and genetic factors affecting treatment outcomes.\u003c/p\u003e"},{"header":"2. METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Settings and Study design\u003c/h2\u003e \u003cp\u003eThis observational cross-sectional study was conducted at the orofacial pain clinic at the Bauru School of Dentistry from October 2019 to May 2021. The study was approved by the Research Ethics Committee of the Bauru School of Dentistry, University of Sao Paulo, Brazil (CAAE # 79079917.6.0000.5417/CAAE # 82201818.3.0000.5417) and was conducted following the Helsinki Declaration. All subjects were informed about the research aims and voluntarily signed an informed consent form to participate in this study. Reporting of the data followed the recommendations of the Strengthening the Reporting of Observational Studies in Epidemiology (Strobe) guidelines.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Subjects\u003c/h2\u003e \u003cp\u003eThe sample of this study was composed of 72 Brazilian females including TMD cases and healthy controls (n\u0026thinsp;=\u0026thinsp;24). TMD cases were divided in two groups according to treatment response, after a three-months treatment protocol in: TMD cases with successful treatment (TMD-S, n\u0026thinsp;=\u0026thinsp;24), TMD cases resistant to treatments (TMD-R, n\u0026thinsp;=\u0026thinsp;24). For the TMD cases, patients with TMD of muscular origin treated at or referred to the orofacial pain clinic of the Bauru School of Dentistry, University of Sao Paulo were recruited. The general inclusion criteria for the TMD cases were females, aged over 18 years, with a diagnosis of myofascial pain (MFP) and MFP with referral, according to the Brazilian Portuguese version of the Diagnostic Criteria for TMD (DC/TMD) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Patients in the TMD-S group, should have reported a pain reduction of more than 30% after three months of conservative treatment. Patients in the TMD-R group should have reported a pain reduction of less than 30% and an average pain intensity\u0026thinsp;\u0026gt;\u0026thinsp;50 mm on a 0\u0026ndash;100 mm Visual Analogue Scale (VAS) during the last month of the 3 months treatment period. Mandatory treatments for all patients included counselling, oral appliance, which were applied for three months and pharmacotherapy (acting peripherally or centrally like, NSAIDs/10 days, muscle relaxants/1month and antidepressive/2months), while dry or wet needling, acupuncture, and physiotherapy were used as additional treatments. All patients received the mandatory treatments, but regarding pharmacotherapy, the doses were tailored for each patient accordingly to symptoms. The inclusion criteria for the control group were females, aged over 18 years and good general health.\u003c/p\u003e \u003cp\u003eThe exclusion criteria for the three groups were presence of dental and neuropathic pain, traumas to the face and neck, uncontrolled systemic disorders, (e.g., diabetes), hypertension, or endocrine disorders; neurological disorders, systemic inflammatory diseases (e.g., arthritis) presence of congenital or developmental changes, (e.g., aplasia, hyperplasia, dysplasia, or neoplasms), and ongoing orthodontic treatment. For the control group the exclusion criteria included presence of primary headache, TMD and fibromyalgia.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Outcomes\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003e2.3.1. Pain variables\u003c/h2\u003e \u003cp\u003eThe characteristic pain intensity (CPI) was used to compare the participants pain intensity at baseline. This is composed of three 0\u0026ndash;10 numerical rating scales (NRS) where 0 represent no pain and 10 represents the worst pain imaginable assessing the current pain intensity and the worst and average pain intensities during the last month. The CPI is the average of the three scores multiplied with 10, giving a score 0-100. For other pain assessments (see below) a 0-100 VAS with the same descriptors for 0 and 100 as for the NRS, was used.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e2.3.1 Somatosensory Profile\u003c/h2\u003e \u003cp\u003eThree tests of the quantitative sensory test (QST) battery for mechanical somatosensory assessment were considered: (a) mechanical pain threshold (MPT), (b) wind up ratio (WUR), and (c) pressure pain threshold (PPT). In the TMD-S and TMD-R groups, measurements in the trigeminal area were performed in the masseter muscle on the side that the patient reported more severe pain, and in the control group on the dominant side (masseter insertion region). In the spinal area, the same tests were performed at the hand on the same side as the most painful masseter in the TMD-S and TMD-R groups and at the dominant hand for the control group. Conditioned pain modulation (CPM) was used to assess endogenous pain inhibition.\u003c/p\u003e \u003cp\u003eMechanical pain threshold\u003c/p\u003e \u003cp\u003eFor this test, a standardized set of Semmes-Weinstein monofilaments (Touch-Test TM Sensory Evaluators; North Coast Medical Inc, California, USA), which applies forces between 0.008 g/mm\u003csup\u003e2\u003c/sup\u003e and 300 g/mm\u003csup\u003e2\u003c/sup\u003e were used. The monofilaments were applied perpendicularly to the examination sites and a light pressure was applied until the filament curved. Participants were instructed to verbally report when feeling a \u0026ldquo;prick, pinprick, or slightly painful sting\u0026rdquo; sensation in the contact area of the monofilaments. The limit method was used to determine the threshold using a series of five ascending and five descending stimuli. The MPT was considered as the geometric mean of these repetitions [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWind-up ratio\u003c/p\u003e \u003cp\u003eTo measure WUR, the smallest Von Frey filament that caused a sensation of mild pain (30 to 50 on VAS) was used. The filament was placed on the skin over the assessed regions and pressure was applied until the filament curved. This test was performed in a continuous sequence where the intensity of a single painful stimulus was compared with that of a series of 10 consecutive stimuli with the same filament and with the same intensity of force (1 per second applied within an area 1 cm\u003csup\u003e2\u003c/sup\u003e). Single pinprick stimuli were alternated with a train of 10 stimuli until both were done three times. Pain intensity values were quantified (VAS) after the single stimulus and at the end of the series of 10 consecutive stimuli. The wind-up ratio was calculated as the mean score of the three series of 10 stimuli divided by the mean score of the three single stimuli [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePressure pain threshold\u003c/p\u003e \u003cp\u003ePressure pain threshold measurements were performed using a digital pressure algometer (model Kratos DDK-20, Sao Paulo, Brazil), with a flat circular tip of 1 cm\u003csup\u003e2\u003c/sup\u003e, through which a constant and increasing pressure of approximately 0.5 kg/cm2/s was applied. Participants were instructed to press a button connected to the algometer when the sensation of pressure turned into a slightly painful sensation to interrupt the exerted pressure. The recordings were repeated three times at 1-min intervals The arithmetic mean of the three measurements in the sequence was calculated and used in analyses [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eConditioned Pain Modulation\u003c/p\u003e \u003cp\u003eTo assess the CPM paradigm, as test stimulus (TS), PPT was first obtained in the masseter and thenar muscle, as explained above. As conditioning stimulus (CS), participants were asked to immerse the non-dominant hand in a container with water at 10\u0026deg;C for 60 seconds. Then, a second assessment of PPT was immediately done at the end of CS in the same sites. In each evaluation, PPT was determined as the arithmetic mean of three measurements. The absolute (kgf/cm\u003csup\u003e2\u003c/sup\u003e) and percent (%) differences between PPT values (\u0026lsquo;TS before CS\u0026rsquo; and \u0026lsquo;TS after CS\u0026rsquo;) were considered as the CPM values. Negative values indicate an increase in pain threshold [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Psychosocial Profile\u003c/h2\u003e \u003cp\u003eThe psychosocial profile was assessed using the validated Brazilian Portuguese translations of the following self-report questionnaires: Hospital Anxiety and Depression Scale (HADS) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]; Central Sensitization Inventory (CSI) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]; Perceived Stress Scale (PSS) [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]; Pittsburgh Sleep Quality Index (PSQI) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], and Pain Catastrophizing Scale (PCS) [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHospital Anxiety and Depression Scale\u003c/p\u003e \u003cp\u003eThis questionnaire is composed of 14 multiple-choice questions (each scored 0\u0026ndash;3), divided into two interleaved subscales, one for anxiety (7 questions) and another for depression (7 questions). The scores range from 0 to 21 points; the higher the value, the greater the symptoms of anxiety (A-HADS) and/or depression (D-HADS) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCentral Sensitization Inventory\u003c/p\u003e \u003cp\u003eThis questionnaire is designed as an easy-to-administer screener for patients who are at high risk of having Central Sensitization or to assess Central Sensitization-related symptoms. It is divided in two parts: part A with 25 statements about current health symptoms and part B assessing previously diagnosed central sensitivity syndromes and related conditions. For part A, subjects mark the frequency in a scale ranging from 0\u0026ndash;4 (0\u0026thinsp;=\u0026thinsp;never and 5\u0026thinsp;=\u0026thinsp;always) and after summing all the items, they are classified into five severity levels (subclinical, mild, moderate, severe, extreme) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePerceived Stress Scale\u003c/p\u003e \u003cp\u003eThis questionnaire consists of 14 items that measures the degree of perceived stress in the last month considering the individual's global context. The scale total is the sum of the scores (0\u0026ndash;4) for these 14 items and the scores can range from 0 to 56 [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePittsburgh Sleep Quality Index\u003c/p\u003e \u003cp\u003eThis questionnaire consists of 19 self-report questions that assess various factors related to sleep quality, distinguishing individuals who sleep \u0026ldquo;well\u0026rdquo; or \u0026ldquo;poorly\u0026rdquo; and providing clinical information about different sleep disorders that can influence the sleep quality. The score ranges from 0 to \u0026gt;\u0026thinsp;10, and the higher the score, the worse the quality of sleep [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePain Catastrophizing Scale\u003c/p\u003e \u003cp\u003eThis questionnaire measures catastrophic thoughts about pain. The subjects indicate the frequency of catastrophic thoughts when pain is severe. It consists of 13 statements in total in which the subjects mark the frequency in a scale ranging from 0\u0026ndash;5 (0\u0026thinsp;=\u0026thinsp;hardly ever and 4\u0026thinsp;=\u0026thinsp;almost always). The total score is the sum of all the items ranging from 0 to 52 points. The higher the value, the more the degree of catastrophizing [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.5 DNA collection and single-nucleotide polymorphism analysis\u003c/h2\u003e \u003cp\u003eSamples of 5 ml of unstimulated total saliva were collected in a 50 ml Falcon tube. Genomic DNA was extracted from epithelial buccal cells present in saliva using QIAmp DNA Mini Kit (Qiagen, Hilden, Germany), according to the manufacturer's instructions. The analysis of the genotypes of the selected polymorphisms HTR1B rs6296, HTR1A rs6295, OPRM1 rs1799971, COMT rs4680, rs4633, and rs4818, and SCN9A rs6746030) was performed using the Real-Time Polymerase Chain Reaction technique. The reactions were performed on the Viia 7 thermal cycler (Applied Biosystems, Massachusetts. USA), using the TaqMan method using TaqMan SNP genotyping assays (Applied Biosystems, Massachusetts. USA) pre-standardized and experimentally validated, following the manufacturer's instructions.\u003c/p\u003e \u003cp\u003eAll data collection was performed at baseline (before treatments).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Statistical Analysis\u003c/h2\u003e \u003cp\u003eThe sample size calculation was performed using G*Power 3.1.9.2 software and was based on calculated effect sizes. The following parameters were considered within a one-way ANOVA analysis: α error probability\u0026thinsp;=\u0026thinsp;0.05, power (1-β error probability)\u0026thinsp;=\u0026thinsp;0.8, number of groups\u0026thinsp;=\u0026thinsp;3, and effect size values for PPT, CPM, MPT, and WUR of \u0026ge; 0.4. The total sample size was calculated to be 66 subjects equally divided into three groups. However, considering an assumed withdrawal or dropout rate, 24 subjects were included in each group.\u003c/p\u003e \u003cp\u003eUnivariate data were analyzed with SPSS. Data were assessed for distribution normality using the Shapiro-Wilk test. Normal distributions were found for age and somatosensory variables (MPT, WUR, PPT and CPM) why comparisons between groups were done using ANOVA with Tukey test as post-hoc test. As the psychosocial variables (anxiety, depression, central sensitization, stress, sleep, and pain catastrophizing) are composed of scores obtained from individual ordinal scales, the sum scores cannot be regarded as continuous. Therefore, ANOVA on ranks (Kruskall-Wallis test) with Dunn\u0026rsquo;s test as post-hoc test was used to test for group differences. For the number of other painful TMD diagnosis (arthralgia and headache attributed to TMD) the Chi Square test was used. The Dwass-Steel-Critchlow-Fligner test was used to compare the proportion of polymorphisms between groups.\u003c/p\u003e \u003cp\u003eSince many of the outcomes are more or less interrelated, multivariate statistics were used to identify outcomes that separated the groups using SIMCA-P\u0026thinsp;+\u0026thinsp;v.17.0 (Sartorius Stedim Biotech, Ume\u0026aring;, Sweden) as earlier described [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Principle component analysis (PCA) was first used to investigate the correlation patterns for the investigated variables and to detect moderate or strong outliers among the observations using Hotelling\u0026rsquo;s T2 and DMod. No outliers were detected. Thereafter orthogonal partial least squares discriminant analysis (OPLS-DA) was used to regress group membership, i.e. multivariate correlations between variables and group membership. R2 describes the goodness of fit, i.e., the fraction of sum of squares of all the variables explained by a principal component whereas Q2 describes the goodness of prediction, i.e., the fraction of the total variation of the variables that can be predicted by a principal component using cross validation methods. R2 should not be considerably higher than Q2; if substantially higher (\u0026gt;\u0026thinsp;0.3) the robustness of the model is poor [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. To validate the model, an obtained CV-ANOVA was used to test the significance of the model. The OPLS-DA model was considered significant if the CV-ANOVA had a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05. The variable influence on projection (VIP) value indicates the relevance of each X-variable pooled over all dimensions and the Y-variables indicate the group of variables that best explain Y. P(corr) was used to note the direction of the relationship (positive or negative). VIP\u0026thinsp;\u0026gt;\u0026thinsp;1.0 and an absolute p(corr)\u0026thinsp;\u0026gt;\u0026thinsp;0.4 was considered significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. RESULTS","content":"\u003cp\u003eOut of the 226 myofascial pain patients who sought treatment at the orofacial pain clinic of the Bauru School of Dentistry during the study period, 10.6% (24) did not respond to the treatment protocols after three months, were considered resistant to treatment and allocated to the TMD-R group. The number of patients included in the other groups were matched and chosen randomly according to the number of patients included in the TMD-R. All patients were women of Latino ethnicity. The mean age (\u0026plusmn; standard deviation, SD) of the TMD-R group (44 \u0026plusmn; 7 yrs) was significantly higher compared with TMD-S (38 \u0026plusmn; 10 yrs) and control (32.2 \u0026plusmn; 8.7 yrs) groups (p\u0026thinsp;=\u0026thinsp;0.01). No other major differences in demographic characteristics were found across groups. No significant differences were found regarding the CPI of the TMD-R (7.4 \u0026plusmn; 1.3) compared with the TMD-S (7.0 \u0026plusmn; 1.5) (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) at baseline, and no significant differences were found regarding pain duration between both groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The TMD-S group presented a higher presence of other painful TMD diagnoses (arthralgia and headache attributed to TMD) compared to the TMD-R group (p\u0026thinsp;=\u0026thinsp;0.03).\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Somatosensory variables\u003c/h2\u003e \u003cp\u003eThe TMD-R group had lower PPTs and higher WURs values compared with the other groups (p\u0026thinsp;=\u0026thinsp;0.01) in both the trigeminal and spinal areas. The patient groups had lower MPTs than the controls in both the trigeminal and spinal areas (p\u0026thinsp;=\u0026thinsp;0.01), but there were no significant differences between the TMD-S and TMD-R groups. For CPM, no significant differences were found between groups for the trigeminal or spinal areas (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline somatosensory and conditioned pain modulation data assessed at the masseter and thenar muscles in patients with temporomandibular disorders pain resistant (TMD-R) or successful (TMD-S) to treatment, and in healthy controls. Data are presented as mean (\u0026plusmn;\u0026thinsp;sd).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eTMD-R\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eTMD-S\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMasseter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThenar\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMasseter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eThenar\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMasseter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eThenar\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePPT (kgf/cm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.0 (\u0026plusmn;\u0026thinsp;0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.5 (\u0026plusmn;\u0026thinsp;1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.7 (\u0026plusmn;\u0026thinsp;1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.5 (\u0026plusmn;\u0026thinsp;1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.9 (\u0026plusmn;\u0026thinsp;0.9)*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4.1 (\u0026plusmn;\u0026thinsp;1.0)*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMPT (0-100 VAS)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.6 (\u0026plusmn;\u0026thinsp;12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.2 (\u0026plusmn;\u0026thinsp;53.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.0 (\u0026plusmn;\u0026thinsp;15.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15.6 (\u0026plusmn;\u0026thinsp;39.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e123.6 (\u0026plusmn;\u0026thinsp;147.8)*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e149.4 (\u0026plusmn;\u0026thinsp;169.4)*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWUR (0-100 VAS)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.3 (\u0026plusmn;\u0026thinsp;1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.2 (\u0026plusmn;\u0026thinsp;1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.9 (\u0026plusmn;\u0026thinsp;0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.8 (\u0026plusmn;\u0026thinsp;0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.5 (\u0026plusmn;\u0026thinsp;0.6)*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.4 (\u0026plusmn;\u0026thinsp;0.4)*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCPM (kgf/cm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.1 (\u0026plusmn;\u0026thinsp;0.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.3 (\u0026plusmn;\u0026thinsp;0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.3 (\u0026plusmn;\u0026thinsp;0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.3 (\u0026plusmn;\u0026thinsp;0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.4 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-0.7 (\u0026plusmn;\u0026thinsp;1.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003ePPT: pressure pain threshold; MPT: mechanical pain threshold; CPM: conditioned pain modulation; WUR: wind-up ratio.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eANOVA test: * p\u0026thinsp;\u0026lt;\u0026thinsp;.001 between groups\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Psychosocial variables\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eScores for all questionnaires are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Inter-group comparison showed higher values for the TMD-R group when compared with the other groups for A- HADS and D-HADS (p\u0026thinsp;=\u0026thinsp;0.01), CSI (p\u0026thinsp;=\u0026thinsp;0.01), PSS (p\u0026thinsp;=\u0026thinsp;0.03), PSQI (p\u0026thinsp;=\u0026thinsp;0.01), PCS (p\u0026thinsp;=\u0026thinsp;0.01). Furthermore, higher values were also found in the TMD-S group for CSI (p\u0026thinsp;=\u0026thinsp;0.01) and PCS (p\u0026thinsp;=\u0026thinsp;0.01) compared with the control group (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline psychosocial data in patients with temporomandibular disorders pain resistant (TMD-R) or successful (TMD-S) to treatment, and in healthy controls. Data are presented as median (min\u0026ndash;max).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTMD-R\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTMD-S\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA-HADS \u003cem\u003e(total)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.0 (3\u0026ndash;20)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.0 (0\u0026ndash;19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.0 (1\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD-HADS \u003cem\u003e(total)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.0 (1\u0026ndash;14)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.0 (0\u0026ndash;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.0 (0\u0026ndash;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSI \u003cem\u003e(total)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.0 (21\u0026ndash;85)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37.5 (12\u0026ndash;80)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25.0 (7\u0026ndash;42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSS \u003cem\u003e(total)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.5 (13\u0026ndash;40)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.0 (9\u0026ndash;28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21.50 (6\u0026ndash;38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSQI \u003cem\u003e(total)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.0 (4\u0026ndash;17)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.0 (0\u0026ndash;14)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.0 (3\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCS \u003cem\u003e(total)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.5 (10\u0026ndash;49)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19.5 (0\u0026ndash;46)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11.0 (0\u0026ndash;23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eHADS: Hospital Anxiety (A) and Depression (D) Scale: CSI: Central Sensitization Inventory; PSS: Perceived Stress Scale; PSQI: Pittsburgh Sleep Quality Index; PCS: Pain Catastrophizing Scale.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eKruskall Wallis test (\u003cem\u003ep\u003c/em\u003e) with Dunn\u0026rsquo;s test as postdoc: \u003csup\u003e*\u003c/sup\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05: significant differences between TMD-R and the other groups. \u003csup\u003e#\u003c/sup\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05: significant differences between TMD-S and Control group.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Genetic Variables\u003c/h2\u003e \u003cp\u003eThe inter-group comparisons showed that the TMD-R group presented a higher prevalence of the polymorphic genotype for HTR1A rs6295 when compared with the other groups group (p\u0026thinsp;=\u0026thinsp;0.02). Likewise, the TMD-R group presented a higher prevalence of the polymorphic genotype for HTR1B rs6296 compared to the control group (p\u0026thinsp;=\u0026thinsp;0.01). No significant group differences were found for the other genotypes (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGenotype frequency (%) for each SNP in patients with temporomandibular disorders pain resistant (TMD-R) or successful to treatment (TMD-S), and in healthy controls.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eTMD-R\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eTMD-S\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAncestral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePolymorphic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAncestral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePolymorphic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAncestral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePolymorphic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOMT rs4680\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGA\u0026thinsp;+\u0026thinsp;AA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGA\u0026thinsp;+\u0026thinsp;AA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eGA\u0026thinsp;+\u0026thinsp;AA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003en (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (58.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e16 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOMT rs4818\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGC\u0026thinsp;+\u0026thinsp;CC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGC\u0026thinsp;+\u0026thinsp;CC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eGC\u0026thinsp;+\u0026thinsp;CC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003en (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14 (58.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e21 (87.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOMT rs4633\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCT\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCT\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCT\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003en (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (58.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e16 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHTR1A rs6295\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGC\u0026thinsp;+\u0026thinsp;CC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGC\u0026thinsp;+\u0026thinsp;CC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eGC\u0026thinsp;+\u0026thinsp;CC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003en (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (91.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 (41.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14 (58.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11 (45.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e13 (54.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.02*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHTR1B rs6296\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCG\u0026thinsp;+\u0026thinsp;GG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCG\u0026thinsp;+\u0026thinsp;GG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCG\u0026thinsp;+\u0026thinsp;GG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003en (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (62.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14 (58.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e19 (79.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5 (20.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.01\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOPRM1 rs1799971\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAG\u0026thinsp;+\u0026thinsp;GG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAG\u0026thinsp;+\u0026thinsp;GG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAG\u0026thinsp;+\u0026thinsp;GG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003en (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSCN9A rs6746030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGA\u0026thinsp;+\u0026thinsp;AA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGA\u0026thinsp;+\u0026thinsp;AA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eGA\u0026thinsp;+\u0026thinsp;AA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003en (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (54.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (45.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e18 (75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003eCOMT: Catechol-O-Methyltransferase; HTR1A: 5-hydroxytryptamine receptor 1A; HTR1B: 5-hydroxytryptamine receptor 1B; OPRM1: opioid receptor mu 1; SCN9A: sodium voltage-gated channel alpha subunit 9.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003eDwass-Steel-Critchlow-Fligner test *p\u0026thinsp;\u0026lt;\u0026thinsp;0.05: Significant differences between TMD-R and the other groups, \u003csup\u003e#\u003c/sup\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05: Significant difference between the TMD-R and Control group.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Predictors of Resistance\u003c/h2\u003e \u003cp\u003eThe OPLS-DA showed one predictive component that was strongly significant (R2\u0026thinsp;=\u0026thinsp;0.302, Q2\u0026thinsp;=\u0026thinsp;0.418, CV-ANOVA p-value\u0026thinsp;=\u0026thinsp;1.65e-12) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The figure clearly shows the separation between the patients and controls, but also a separation between the TMD-R and TMD-S groups. There were nine variables that differed between the groups, i.e., had a VIP\u0026thinsp;\u0026gt;\u0026thinsp;1.0 and a p(corr)\u0026thinsp;\u0026gt;\u0026thinsp;0.4. Pain intensity was the strongest separator, followed by CSI and D-HADS. All intercorrelations p(corr) were negative and thus, lower in controls compared to the other groups (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). As can be seen in the loading plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) the psychosocial variables were more related to the TMD-R group, whereas the somatosensory variables were more related to the controls.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOPLS-DA model of variables discriminating healthy controls from patients with temporomandibular disorders myofascial pain resistant to treatment (TMD-R) and with a successful treatment outcome (TMD-S). Nine variables discriminated between groups and had a VIP-value\u0026thinsp;\u0026gt;\u0026thinsp;1.0 and a p(corr)\u0026thinsp;\u0026gt;\u0026thinsp;0.4. Three variables (MPT Masseter and hand, PPT Masseter) had a positive p(corr) and were higher in controls, all other variables were lower in controls.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep(corr)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePain intensity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD-HADS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMPT Masseter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSQI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMPT Hand\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePPT Masseter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eCSI: Central Sensitization Index; D-HADS: Hospital Anxiety and Depression Scale, depression subscale; PCS: Pain Catastrophizing Scale; MPT: mechanical pain threshold; PSQI: Pittsburg Sleep Quality Index; PPT: pressure pain threshold; VIP: variable influence on projection; p(corr): correlation coefficient in multivariate analyses.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOPLS-DA model of variables discriminating temporomandibular disorders myofascial pain patients resistant to treatment (TMD-R) from patients with a successful treatment outcome (TMD-S). Twelve variables significantly discriminated between groups and had a VIP-value\u0026thinsp;\u0026gt;\u0026thinsp;1.0 and a p(corr)\u0026thinsp;\u0026gt;\u0026thinsp;0.4. WUR and PPT had a negative p(corr) and were lower in TMD-R.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep(corr)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSQI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD-HADS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA-HADS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWUR Masseter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePPT Hand\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAGE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHTR1A rs6295\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWUR Hand\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOMT rs4818\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003ePSQI: Pittsburg Sleep Quality Index; CSI: Central Sensitization Index; D-HADS: Hospital Anxiety and Depression Scale, depression subscale; A-HADS, anxiety subscale; PSS: Perceived Stress Scale; WUR: wind-up ratio; PPT: pressure pain threshold; PCS: Pain Catastrophizing Scale; HTR1A: serotonin type 1 receptor gene; COMT: catecholamine-O-methyltransferase gene; VIP: variable influence on projection; p(corr): correlation coefficient in multivariate analyses.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAs there was a separation also between the patient groups, we did a separate OPLS-DA to test which variables differed between TMD-R and TMD-S (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). We found a highly significant predictive component (R2\u0026thinsp;=\u0026thinsp;0.204, Q2\u0026thinsp;=\u0026thinsp;0.456, CV-ANOVA p-value\u0026thinsp;=\u0026thinsp;1.11e-6). Twelve of the variables had a VIP\u0026thinsp;\u0026gt;\u0026thinsp;1 and p(corr)\u0026thinsp;\u0026gt;\u0026thinsp;0.4 (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The three strongest separators between TMD-R and TMD-S were PSQI, CSI and D-HADS, but also some genetic variables, HTR1A rs6295 and COMT rs4818 differed.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eTo the best of our knowledge this is the first study phenotyping myofascial TMD patients considered as non-responders to conservative treatments. The main findings were 1) a low prevalence of resistance to treatment among myofascial TMD pain patients, 2) increased pain sensibility (PPT), decreased pain modulation (WUR), higher levels of psychosocial distress, and a higher presence of the HTR1A rs6295 polymorphism in the resistant TMD group compared with the other groups, and 3) that pain intensity, central sensitization, and depression were the strongest predictive variables for myofascial TMD pain, whereas sleep quality, central sensitization, depression, anxiety and stress were the strongest predictive variables for resistance to treatment, followed by somatosensory variables (WUR and PPT) and genetic variables (HTR1A rs6295 and COMT rs4818).\u003c/p\u003e \u003cp\u003eMultifaceted treatment strategies in which reversible non-pharmacological therapies are considered the first option, followed by pharmacological options are recommended for TMD [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Our resistant inclusion criteria followed these recommendations. Unsuccessful treatment with oral appliance, cognitive behavioral and pharmacotherapy, besides other treatments, were used as part of our criteria to classify myofascial TMD pain patients as resistant to treatments. Additionally, as the Initiative of Measurement, Methods, and Pain assessment in Clinical Trials (IMMPACT) recommendations consider treatments with a 30% pain reduction as effective [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] and as this percentage is equivalent to \u0026ldquo;much improved\u0026rdquo; on the Patient Global Impression of Change Scale [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], we also included a pain reduction of less than 30% despite treatment as a criterion of resistance. Furthermore, the stablished three-month timeframe for unsuccessful treatment response, was based on responder definitions from other chronic pain conditions (such as fibromyalgia and low back pain) [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], and on the resistant migraine criteria proposed by the European Headache Federation consensus [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e], as these parameters have not yet been established for myogenous TMD patients. Validation of our criteria is necessary, as modifying any variable will undoubtedly impact the results, especially regarding the proposed time frame regarding resistance to treatment and the average pain intensity\u0026thinsp;\u0026gt;\u0026thinsp;50. However, our criteria could be the first step in creating a responder definition that combines multiple significant outcomes into one metric, usable as a primary outcome in clinical trials. This unified metric could also guide clinical decision-making, replacing reliance on group averages for individual patient assessments [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBased on these criteria, our study found a low prevalence of resistant myofascial TMD pain patients. This finding was anticipated, primarily due to the low prevalence of TMD patients requiring treatment and the high response rate of this population to conservative treatments [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, since these patients were recruited from an orofacial pain specialist clinic, prevalence may be lower in general dentistry practices. This aligns reports on resistant migraines, with a higher prevalence (75%) in headache specialist centers than in primary care settings (13%) [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRegarding the somatosensory profile, patients of the TMD-R group presented a significant somatosensory gain of function (more sensitive), in the trigeminal and spinal area, when WUR, and PPT were addressed. Taken together, these findings could indicate a generalized hypersensitivity of the central nervous system, inadequate functioning of the endogenous pain modulation system, and central sensitization [\u003cspan additionalcitationids=\"CR44 CR45\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. The lower PPT values found in the TMD-R group compared with the other groups and the non-significant differences between TMD-R and TMD-S for the MPT, could be more related to central hyperexcitability in both the trigeminal and spinal systems which are known to produce hyperalgesia, than to a higher proportion of sensitized primary nociceptive afferents [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Our multivariate analyses support this, demonstrating that lower MPT in both trigeminal and spinal areas, as well as PPT in the trigeminal area, serve as predictors for myofascial TMD pain and lower PPT in the spinal area is identified as a predictor of resistant myofascial TMD pain. In addition, myofascial TMD pain patients are more likely to present generalized mechanical hyperalgesia in the trigeminal and spinal regions than controls [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], which is in line with our findings. Additionally, a widespread lowering of PPT as showed in our study and in the literature, could reflect a deficit of the endogenous pain inhibitory mechanism [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Our study demonstrated that the significant deficit in endogenous pain modulation observed in the TMD-R group was primarily due to increased pain facilitation [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e], with a smaller contribution from decreased pain inhibition, since the TMD-R group presented significant higher values in WUR and lower non- significant values in CPM compared with the other groups. These results supports findings from one study [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] but contradicts another [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePainful TMD subjects often show moderate to severe somatization (28.5%-76.6%) and depression (21.4%-60.1%), and higher stress, catastrophization, and hypervigilance compared to controls [\u003cspan additionalcitationids=\"CR54 CR55 CR56\" citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. In line with these findings, our study revealed that the TMD-R group exhibited higher scores in all psychosocial assessments compared to the other groups; while the TMD-S group only showed worse outcomes for the CSI, PSQI and PCS compared with controls. It is important to note that studies have demonstrated that psychosocial factors (e.g. depression and stress), are significant predictors of new onset-TMD [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. Longitudinal designs have also shown that these factors pose a risk for prolonged chronic pain in TMD patients [\u003cspan additionalcitationids=\"CR60 CR61\" citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. This aligns with our multivariate analysis, which indicates that among the variables distinguishing patients from controls, four are related with psychosocial impairment (CSI, D-HADS, PCS and PSQI). Interestingly, among the 12 variables that differentiate resistant and non-resistant patients, the strongest predictors of belonging to the TMD-R group (PSQI, CSI, D/A-HADS and PSS) were also related with psychosocial impairment. These findings underscore the necessity of assessing psychosocial factors in TMD patients, as they appear to influence their response to treatment. Moreover, the Axis II of the short version of the DC/TMD (bDC/TMD) [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e] can aid non-specialist clinicians in assessing psychosocial factors in a simpler and more interpretable manner. While psychological interventions such as cognitive behavioral therapy and counseling have shown a clinically relevant pain reducing effect in painful TMD patients [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e], our findings highlight the need to include additional psychological treatments and to more effectively apply current treatments, given that counselling was used in our study. Also, our study reinforces the need of a multidisciplinary approach including psychologist specialized treatment. We recommend focusing on assessing central sensitization, depression, catastrophization, and sleep quality, as these factors differentiated patients from controls and treatment responders from resistant patients.\u003c/p\u003e \u003cp\u003eThe OPPERA study highlighted a significant genetic influence from single nucleotide polymorphisms (SNPs) in key biological pathways related to processing noxious stimuli and perceiving pain. These include genes related to serotonin receptor and catecho-O-methyltransferase (COMT) in relation to chronic TMD [\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e]. Our findings revealed that the TMD-R group showed a higher prevalence of the HTR1A polymorphism (rs6295) compared to other groups, and the HTR1B polymorphism (rs6296) compared to the control group. This partially aligns with previous findings [\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e], as we assessed other serotonin receptor-related genes. Our study did not identify any genetic predictor for patients, which could be attributed to the small sample size. However, the HTR1A rs6295 polymorphism and COMT rs4818 were found to be predictors for TMD-R patients. Serotonin, which can be considered both a neurotransmitter and a neuromodulator, is present in the peripheral and central nervous systems and affects pain amplification and inhibition within the serotonergic system [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. Clinical results suggest an increased peripheral release of serotonin in patients with chronic myalgia of the masseter and trapezius muscles [\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e], and a relationship with allodynia of orofacial muscles [\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e]. However, a meta-analysis found no differences between local and generalized chronic musculoskeletal pain [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]. We can speculate that in our study serotonin may have affected peripheral and central sensitization in the TMD-R group. Similarly, studies have indicated that reductions in COMT activity can influence pain perception by indirectly regulating u-opioid receptor function [\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e] and decreasing the metabolism of epinephrine, thereby potentiating pain signaling through beta-adrenergic receptors [\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e]. Thus, genetic polymorphisms that decrease COMT activity can contribute to the etiology of TMD and may have increased risk of developing persistent pain conditions like in our TMD-R group [\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e].\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eIn summary, resistant myofascial TMD pain is not highly prevalent. The phenotype of these patients is primarily influenced by psychosocial impairment, followed by somatossensorial alterations, and distinctive genotype. Interestingly, the somatosensorial and psychosocial characteristics of the TMD-R group are similar to the \u0026ldquo;global symptoms cluster\u0026rdquo; identified in the OPPERA study, which exhibited increased pain sensitivity, higher psychological distress and widespread clinical symptoms, suggesting a higher prevalence of central sensitization [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The authors suggested that due to the impairments observed in pain processing, individuals in this cluster may be less responsive to treatments as in our study. Moreover, it is reasonable to consider that treatment resistance may be also influenced by factors related to the physician/dentist, particularly their knowledge of diagnosis and treatment [\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e]. Additionally, establishing the correct treatment plan from the initial appointment is crucial to preventing chronic pain [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Since the studied sample was treated by experienced orofacial pain specialists; these factors were minimized as much as possible. Furthermore, since compliance to the proposed treatments could have influenced the results, we recommend that future studies assess this variable in an objective manner, and not only on patient\u0026acute;s self-report. It is also recommended to assess demographic and social factors, medical comorbidities, sleep disorders, nutrition, sunshine and vitamin D, and microbiome as these have been identified as factors that may increase resistancve to treatments [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Yet, labeling some as resistant, opens a window to irreversible therapies which is highly undesirable in non-lethal conditions as TMD. Finally, these findings hold potential for more individualized diagnosis and treatment.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"5. CONCLUSION","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThis is the first study presenting criteria to classify myofascial TMD pain patients as resistant to conventional treatments. Resistant myofascial TMD pain is not highly prevalent. Nevertheless, the phenotype of these patients includes psychosocial, somatosensory, and genetic factors, which may be considered risk factors for developing resistance to conservative myofascial TMD pain treatment. These results could help clinicians in identifying myofascial TMD pain patients resistant to treatments, in order to propose a more tailored treatment plan.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Research Ethics Committee of the Bauru School of Dentistry, University of Sao Paulo, Brazil (CAAE # 79079917.6.0000.5417/CAAE # 82201818.3.0000.5417) All subjects were informed about the research aims and voluntarily signed an informed consent form to participate in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study, are not publicly available but are available from the corresponding author upon reasonable request and completion of an institutional data transfer agreement.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Coordena\u0026ccedil;\u0026atilde;o de Aperfei\u0026ccedil;oamento de Pessoal de N\u0026iacute;vel Superior (CAPES) Finance Code 001 for the Ph.D. scholarship of R. Lorenzi Poluha and the Sao Paulo Research Foundation (FAPESP) for the post-doctoral scholarship of G. De la Torre Canales (process 2017/21674-0). These institutions were not involved in study design, collection, analysis and interpretation of data, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was designed by G.D.C., L.R.B., R.L.P., and P.C.R.C. The data collection was performed by G.D.C., R.L.P., D.M.A.O.F., and F.F.C.S. The data were analyzed by G.D.C., A.S.A., and M.E. The results were critically examined by all authors. G.D.C. had a primary role in preparing the manuscript, which was edited by M.E., and P.C.R.C. 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J Cranio Mand Func 3:197-208.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"the-journal-of-headache-and-pain","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tjhp","sideBox":"Learn more about [The Journal of Headache and Pain](https://thejournalofheadacheandpain.biomedcentral.com/)","snPcode":"10194","submissionUrl":"https://submission.nature.com/new-submission/10194/3","title":"The Journal of Headache and Pain","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Temporomandibular disorders, Myofascial pain, Refractory pain, Chronic pain, Phenotype","lastPublishedDoi":"10.21203/rs.3.rs-6261328/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6261328/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eResistance to treatments have been assessed in chronic conditions such as migraine, but not in temporomandibular disorders (TMD). This study aimed to identify factors that influence treatment outcome in patients with myofascial TMD pain.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSeventy-two females were divided into three groups: TMD successful to treatment (TMD-S, n=24), TMD resistant to treatment (TMD-R, n=24) and Controls without TMD (n=24). Criteria for resistance included: less than 30% pain reduction after three months of conservative treatment and an average pain intensity \u0026gt;50 mm (VAS) during the last month. Quantitative sensory testing (QST), psychosocial status and genetic polymorphisms were examined. ANOVA on ranks (psychosocial variables) with Dunn’s test as post-hoc or ANOVA (age and somatosensory variables) with Tukey test as post-hoc test, and Dwass-Steel-Critchlow-Fligner test (genetic variables) were used for univariate groups comparisons. Multivariate statistics were used to identify outcomes that separated the groups.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eQST assessment revealed lower baseline pressure pain threshold and higher wind-up ratio in the trigeminal and spinal areas in the TMD-R group compared with the other groups (p=0.01). Also, the TMD-R group presented higher values in all assessed psychosocial variables (p\u0026lt;0.01) and higher prevalence of the HTR1A polymorphism rs6295 (p=0.02) compared with the other groups at baseline. Multivariate analysis showed that the three strongest separators between TMD-R and TMD-S were sleeping quality, central sensitization, and depressive symptoms.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePsychosocial, somatosensory, and genetic alterations are related to unsuccessful treatment response in myofascial TMD patients.\u003c/p\u003e","manuscriptTitle":"Who is the patient with resistant myofascial temporomandibular disorders pain? A somatosensory, psychosocial, and genetic characterization","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-31 11:17:09","doi":"10.21203/rs.3.rs-6261328/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-15T06:46:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-14T16:34:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"240242536352302389257499167246376097961","date":"2025-04-10T12:12:59+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-10T10:35:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3948996682233624714188068637368571891","date":"2025-04-10T09:11:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-08T11:54:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"274195093158799978200972656535902984433","date":"2025-04-08T11:32:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"144973913809372351928492025058280436606","date":"2025-04-08T08:53:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"216355518716491736626178684291315872445","date":"2025-03-30T20:19:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"25139812843261890938395576157465166829","date":"2025-03-20T14:06:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-20T09:14:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-20T03:23:11+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-20T03:22:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Journal of Headache and Pain","date":"2025-03-19T11:50:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-journal-of-headache-and-pain","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tjhp","sideBox":"Learn more about [The Journal of Headache and Pain](https://thejournalofheadacheandpain.biomedcentral.com/)","snPcode":"10194","submissionUrl":"https://submission.nature.com/new-submission/10194/3","title":"The Journal of Headache and Pain","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6c66a157-78c0-433e-8425-785a2cdab0d6","owner":[],"postedDate":"March 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-12T16:07:10+00:00","versionOfRecord":{"articleIdentity":"rs-6261328","link":"https://doi.org/10.1186/s10194-025-02055-7","journal":{"identity":"the-journal-of-headache-and-pain","isVorOnly":false,"title":"The Journal of Headache and Pain"},"publishedOn":"2025-05-06 15:57:28","publishedOnDateReadable":"May 6th, 2025"},"versionCreatedAt":"2025-03-31 11:17:09","video":"","vorDoi":"10.1186/s10194-025-02055-7","vorDoiUrl":"https://doi.org/10.1186/s10194-025-02055-7","workflowStages":[]},"version":"v1","identity":"rs-6261328","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6261328","identity":"rs-6261328","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}