Journal of Oral & Facial Pain and Headache, 01/2016

Aims: To compare the number of comorbidities and the prevalence of five specific comorbidities in people who have temporomandibular disorders (TMD) with or without myofascial pain. Methods: This cross-sectional study included 180 patients seeking TMD treatment in Boston and Montreal hospitals. A selfadministered questionnaire was used to collect information on sociodemographic and behavioral factors, as well as the presence of the following five comorbidities: migraine, chronic fatigue syndrome, irritable bowel syndrome, interstitial cystitis, and restless leg syndrome. TMD was diagnosed using the Research Diagnostic Criteria for TMD. Chi-square and Student t tests were used for categorical and continuous variables, respectively, to test for differences between myofascial (n = 121) and nonmyofascial (n = 59) TMD groups. Multiple logistic regression analysis was used to compare the type and number of self-reported comorbidities in both groups, controlling for confounding variables. Results: The following were found to be significantly higher in the myofascial TMD group than in the nonmyofascial TMD group: self-reported migraine (55% vs 28%, P = .001), chronic fatigue syndrome (19% vs 5%, P = .01), and the mean total number of comorbidities (1.30 vs 0.83, P = .01). Conclusion: Individuals with myofascial TMD had a higher prevalence of self-reported migraine and chronic fatigue syndrome than those with nonmyofascial TMD. Keywords: central sensitivity syndrome, comorbidity, myofascial pain, overlapping conditions, temporomandibular disorders

Aims: To explore whether temporomandibular disorder (TMD) pain patients reporting different levels of pain-related disability differ in terms of illness explanations and treatment expectations. Methods: Consecutive TMD pain patients (n = 399; mean ± SD age, 40.5 ± 12.7 years; 83% women) seeking treatment in primary care completed the Explanatory Model Scale (EMS). Patients were asked to indicate their expectations regarding the treatment. Each patient's pain-related disability level was determined using the Graded Chronic Pain Scale, with scores indicating no (0 disability points), low (1-2 disability points), or high (3-6 disability points) disability. Differences between EMS factor scores were evaluated using the Mann-Whitney U test. Differences between study groups were analyzed using logistic regression. Results: High-disability patients considered physical and stress factors as more important in causing and in aggravating pain and as targets of treatment compared with patients with no disability (P = .0196 and P = .0251, respectively). The great majority of patients indicated they would like to receive information, decrease pain, and increase jaw function, with no significant subtype differences noted. Compared with no-disability patients, low-disability and high-disability patients were more likely to expect increased ability to perform daily functions (P .0001 in both comparisons), increased work ability (P .0001 in both comparisons), and better stress management skills (P = .0014 and P = .0001, respectively). Conclusion: Illness explanations and goals for treatment differ in patients reporting different levels of TMD pain-related disability. Keywords: explanatory models of illness, GCPS, primary health care, RDC/TMD Axis II, TMD pain

Aims: To estimate the effect of social context on dental pain in adults of Colombian ethnic minority groups (CEGs). Methods: Information from 34,843 participants was used. A multilevel model was constructed that had ethnic groups (ie, CEGs and non-CEGs) at level 1 and Colombian states at level 2. Contextual variables included gross domestic product (GDP), Human Development Index (HDI), and Unmet Basic Needs Index (UBNI). Results: Dental pain was observed in 12.3% of 6,440 CEGs. In an unadjusted logistic regression model, dental pain was associated with being a CEG (odds ratio [95% confidence interval], 1.34 [1.22-1.46]; P = .0001). This association remained significant after adjusting for possible confounding variables. An unconditional multilevel analysis showed that the variance in dental pain was statistically significant at the ethnic group level (β = 0.047 ± 0.015; P = .0009) and at the state level (β = 0.038 ± 0.019; P = .02) and that the variation between ethnic groups was higher than the variation between states (55% vs 45%, respectively). In a multivariate model, the variance in dental pain was also statistically significant at the ethnic group level (β = 0.029 ± 0.012; P = .007) and the state level (β = 0.042 ± .019; P = .01), but the variation between states was higher (40% vs 60%). The results of multilevel multivariate analyses showed that dental pain was associated with increasing age (β = 0.009 ± 0.001; P = .0001), lower education level (β = 0.302 ± 0.103; P = .0001), female sex (β = 0.031 ± 0.069; P = .003), GDP (β = 5.136 ± 2.009; P = .002) and HDI (β = 6.862 ± 5.550; P = .004); however, UBNI was not associated with dental pain. Conclusion: The variance in dental pain was higher between states than between ethnic groups in the multivariate multilevel model. Dental pain in CEGs was associated with contextual and individual factors. Considering contextual factors, GDP and HDI may play a major role in dental pain prevalence. Keywords: ethnic groups, multilevel analyses, self-report, socioeconomic factors, toothache

Aims: To assess the degree and interrelationship of sleep disturbance and plasma cytokine levels in temporomandibular disorder (TMD) pain patients. Methods: Forty female TMD patients and 20 age-, sex-, and body mass index (BMI)-matched healthy subjects were enrolled. TMD was diagnosed using the Research Diagnostic Criteria for TMD. The TMD patients were classified as having low or high disability according to Graded Chronic Pain Scale findings. The Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were used to measure sleep quality. Plasma concentrations of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) were measured from blood samples collected between 9 am and noon. Statistical analyses included Kruskal-Wallis and one-way analysis of variance tests to compare results between different groups and multivariate general linear models to evaluate the effect of sleep status on cytokine levels. Results: The highdisability group had the highest PSQI and ESS scores (P .001). Plasma levels of IL-1β, IL-6, IL-10, and TNF-α were significantly higher in the patient groups, with the high-disability group exhibiting the highest values (P ≤ .001). The plasma cytokine levels were significantly correlated with PSQI scores (P .05). Plasma levels of IL-10 and TNF-α were significantly associated with the disability level after adjusting for both sleep indices (both P .05). Conclusion: Patients with TMD, especially those with high disability, had elevated plasma cytokine levels and increased ESS and PSQI scores suggestive of sleep disturbance. Keywords: cytokine level, pain, sleep disturbance, temporomandibular disorders

Aims: To test the hypothesis that prolonged jaw opening, as can occur during routine dental procedures, increases nociceptive sensitivity of the masseter muscle and increases cytokine expression. Methods: Sprague-Dawley rats were used to investigate behavioral and cellular changes in response to prolonged jaw opening. A surgical retractor was placed around the maxillary and mandibular incisors, and the jaw was held at near maximal opening for 20 minutes. Head-withdrawal responses to mechanical stimuli applied to the facial skin overlying the left and right masseter muscles were determined following jaw opening. Cytokine levels in the upper cervical spinal cord containing the caudal part of the spinal trigeminal nucleus were evaluated using protein antibody microarrays (n = 3). Statistical analysis was performed using a nonparametric Mann-Whitney U test. Results: Prolonged jaw opening significantly increased nocifensive head withdrawal to mechanical stimuli at 2 hours, and days 3 and 7 postinduction (P .05). The increase in nociceptive response resolved after 14 days. Sustained jaw opening also stimulated differential cytokine expression in the trigeminal ganglion and upper cervical spinal cord that persisted 14 days postprocedure (P .05). Conclusion: These findings provide evidence that near maximal jaw opening can lead to activation and prolonged sensitization of trigeminal neurons that results in nociceptive behavior evoked by stimulation of the masseter muscle, a physiologic event often associated with temporomandibular disorders (TMD). Results from this study may provide a plausible explanation for why some patients develop TMD after routine dental procedures that involve prolonged jaw opening. Keywords: central sensitization, nociception, spinal trigeminal nucleus, temporomandibular disorders, trigeminal ganglion

Aims: To determine whether herpes simplex virus-based vectors can efficiently transduce mouse trigeminal ganglion (TG) neurons and attenuate preexisting nerve injury-induced whisker pad mechanical hypersensitivity in a trigeminal inflammatory compression (TIC) neuropathic pain model. Methods: Tissue transduction efficiencies of replication-conditional and replication-defective vectors to mouse whisker pads after topical administration and subcutaneous injection were assessed using quantitative real-time PCR (qPCR). Tissue tropism and transgene expression were assessed using qPCR and reverse-transcriptase qPCR following topical application of the vectors. Whisker pad mechanical sensitivities of TIC-injured mice were determined using graduated von Frey fibers before and after application of human preproenkephalin expressing replicationconditional vector (KHPE). Data were analyzed using one-way analysis of variance (ANOVA) and post hoc tests. Results: Transduction of target TGs was 8- to 50- fold greater after topical application than subcutaneous injection and ≥ 100-fold greater for replication-conditional than replication-defective vectors. Mean KHPE loads remained constant in TGs (4.5-9.8 × 104 copies/TG) over 3 weeks but were below quantifiable levels (10 copies/tissue) within 2 weeks of application in other nontarget cephalic tissues examined. Transgene expression in TGs was maximal during 2 weeks after topical application (100-200 cDNA copies/mL) and was below quantifiable levels (1 cDNA copy/mL) in all nontarget tissues. Topical KHPE administration reduced TIC-related mechanical hypersensitivity on whisker pads 4-fold (P .05) for at least 1 week. Conclusion: Topically administered KHPE produced a significant antinociceptive effect in the TIC mouse model of chronic facial neuropathic pain. This is the first report in which a gene therapeutic approach reduced trigeminal pain-related behaviors in an established pain state in mice. Keywords: gene therapy, mechanical allodynia, nerve injury, neuropathic pain, trigeminal ganglia

Aims: To evaluate whether the purinergic receptor subtype P2X3 (P2X3R) in trigeminal ganglion (TG) neurons is involved in hyperalgesia of the temporomandibular joints (TMJs) and masseter muscles associated with placement of an occlusal interference. Methods: Forty-five rats were randomized into five groups (ie, for days 1, 3, 7, 14, or 28; nine rats per group). Six rats from each group were chosen to receive the occlusal interference, and the remaining three rats were sham-treated controls. On days 1, 3, 7, 14, and 28 after placement of the occlusal interference, the mechanical pain threshold (MPT) to stimulation of the TMJs or masseter muscles was examined using von Frey filaments. Seven days after the occlusal interference placement, changes in MPT were tested after administration of the P2X3R antagonist A-317491 into the TMJs and masseter muscles (60 μg/site) in six rats. The expression of P2X3R in the TGs was investigated by immunohistochemistry and quantitative polymerase chain reaction (qPCR). Retrograde tracing was combined with immunofluorescence to identify TMJ and masseter muscle afferent neurons in the TGs of six premature rats. Results: The TMJ and masseter muscle MPTs were decreased after placement of the occlusal interference, and the P2X3R antagonist reversed the mechanical hyperalgesia that was caused by the occlusal interference placement. The frequency of P2X3R-immunoreactive cells increased in small-sized neurons in the TG after occlusal interference. By contrast, there was no increase in medium-sized TG neurons. P2X3R mRNA increased on day 3. Retrograde tracing indicated that the TMJ and masseter muscle afferent neurons in the TG expressed P2X3R. Conclusion: Upregulated P2X3R expression in the TG may contribute to orofacial pain development induced by an occlusal interference. P2X3R may be a therapeutic target for chronic TMJ or masseter muscle pain. Keywords: masseter muscle, occlusal interference, orofacial hyperalgesia, P2X3 receptor, temporomandibular joint

Aims: To investigate whether the protective effect of testosterone on the development of temporomandibular joint (TMJ) nociception in male rats is mediated by the activation of central opioid mechanisms. Methods: Experiments were performed on 156 male Wistar rats. A pharmacologic approach was used to assess the ability of opioid receptor antagonists infused into the dorsal portion of the brainstem and adjacent to the caudal component (subnucleus caudalis) of the spinal trigeminal nucleus to block the protective effect of testosterone in male rats. The TMJ injection of 0.5% formalin was used as a nociceptive stimulus. One-way or two-way ANOVA was used for data analyses. Results: The injection of 0.5% formalin into the TMJ induced a significant nociceptive behavior in gonadectomized male rats (P .05), but not in naïve, sham, and testosteronereplaced gonadectomized rats, confirming that testosterone prevents the development of TMJ nociception. The injection of either the nonselective opioid receptor antagonist naloxone (15 μg) or the simultaneous injection of the μ-opioid receptor antagonist Cys2, Tyr3, Orn5, Pen7amide (CTOP, 30 μg) and the κ-opioid receptor antagonist Nor-Binaltorphimine (Nor-BNI, 90 μg) significantly increased the 0.5% formalin-induced behavioral response in sham and testosteronereplaced gonadectomized rats (P .05) but had no effect in gonadectomized rats. However, the injection of each selective opioid receptor antagonist alone or the simultaneous injection of μ- or κ- and δ-opioid receptor antagonists had no effect. Conclusion: These findings indicate that the protective effect of endogenous testosterone on the development of TMJ nociception in male rats is mediated by the activation of central opioid mechanisms. Furthermore, the coactivation of central μ- and κ-opioid receptors is necessary for testosterone to protect male rats from developing TMJ nociception. Keywords: nociception, opioid receptors, pain, temporomandibular joint, testosterone

This article reports a case of secondary short-lasting unilateral neuralgiform headache with conjunctival injection and tearing following head and neck trauma due to a violent assault. Following the incident, the patient began experiencing 4 to 30 shooting/sharp pain attacks per day in the left anterior temporal and supraorbital areas, with an intensity of 10/10 on a numeric rating scale. Each attack lasted between 10 and 60 seconds. These attacks were accompanied by ipsilateral conjunctival injection, tearing, ptosis of the left eye, blurry vision, and occasional rhinorrhea. Significant improvements in sleep, autonomic symptoms, and pain were observed with a combination of melatonin 10 mg per day, gabapentin 300 mg twice daily, physical therapy, and psychotherapy. This case highlights the relevance of a multidisciplinary approach in the treatment of challenging cases when there is evidence of more than one contributing factor, with the aim of reducing pain and improving the patient's quality of life. Keywords: cervical trauma, gabapentin, melatonin, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing, trigeminal-autonomic cephalalgias