Journal of Oral & Facial Pain and Headache, 03/2018

Aims: To identify endogenous sources of glial cell line-derived neurotrophic factor (GDNF) at the injury site following inferior alveolar nerve transection (IANX) and to determine whether GDNF signaling promotes the recovery of orofacial pain sensation. Methods: Nociceptive mechanical sensitivity of the facial skin was assessed following IANX (n = 10) or sham operation (n = 7). GDNF-positive cells were identified and the amount of GDNF measured in the injured region of IANX rats (n = 10) and in sham rats (n = 10). The number of trigeminal ganglion neurons with regenerated axons and the nociceptive mechanical sensitivity after continuous GDNF administration at the injury site were also assessed in IANX (n = 28) and sham (n = 12) rats. The effect of GDNF neutralization on nociceptive mechanical sensitivity at the injury site was evaluated using a neutralizing antibody (GFRα1 Nab) in four groups: IANX + phosphate-buffered saline (PBS) (n = 6); sham (n = 12); IANX + GDNF (n = 12); and IANX + GDNF + GFRα1 Nab (n = 12). Statistical analyses included one-way and two-way repeated measures analysis of variance followed by post hoc tests or unpaired t tests. The threshold for statistical significance was set at P .05. Results: Nociceptive mechanical sensitivity was lost over the 5 days following IANX and was recovered by day 13. GDNF was expressed in infiltrating inflammatory cells and had enhanced expression. GDNF administration enhanced axonal regeneration and recovery of nociceptive mechanical sensitivity. GDNF neutralization inhibited the recovery of nociceptive mechanical sensitivity after IANX. Conclusion: GDNF signaling at the injury site facilitates the functional recovery of mechanical nociception following IANX and is an attractive therapeutic target for the functional disturbance of pain sensation. Keywords: GDNF family receptor alpha, glial cell line-derived neurotrophic factor, inferior alveolar nerve injury, mechanical nociception, nerve regeneration

Aims: To assess the analgesic effect of intranasal administration of S-ketamine in different rat models of facial pain. Methods: Nociceptive responses induced by formalin injected into the upper lip and facial hyperalgesia induced by capsaicin or carrageenan injected into the upper lip were used to evaluate the analgesic effect of intranasal ketamine in acute facial pain models in rats (n = 173). The effect of intranasal ketamine on heat and mechanical hyperalgesia induced by constriction of the infraorbital nerve (CION) was also evaluated. In addition, locomotor activity in the open field test was assessed after intranasal ketamine administration. Two-way repeated measures analysis of variance followed by Bonferroni post hoc correction were used to analyze all data. Results: Intranasal ketamine (0.5 mg/kg) failed to modify the first phase of the orofacial formalin test, but reduced the second phase by about 40%. Intranasal ketamine also reduced the facial heat hyperalgesia induced by capsaicin and carrageenan. In the CION model, intranasal ketamine at 0.5 mg/kg reversed the heat hyperalgesia and at 1 mg/kg attenuated the mechanical hyperalgesia 4 and 14 days after the surgery, respectively. The open field test did not reveal locomotor deficits in rats treated with intranasal ketamine. Conclusion: This study has demonstrated that intranasal ketamine produces analgesic effects in inflammatory and neuropathic facial pain models and may represent an adjuvant in the treatment of such conditions, especially when rapid pain relief is needed. Keywords: formalin test, heat hyperalgesia, inflammatory pain, ketamine, mechanical hyperalgesia, NMDA receptors, trigeminal neuropathic pain

Aims: To evaluate in mice the antinociceptive effect of copper in spinal and trigeminal nociceptive pathways by using the intraplantar and orofacial formalin tests, respectively, and to examine whether this effect may interact synergistically with ketamine-induced antinociception. Methods: Nociceptive behaviors (licking/ biting of the formalin-injected limb and rubbing/scratching of the formalin-injected orofacial area) in male mice were evaluated during a 45-minute observation period post-formalin injection. Dose-response curves for intraperitoneal (ip) copper sulfate and ketamine allowed their combination in equi-effective doses, and their interaction was determined with isobolographic analysis. The results were examined with one-way analysis of variance followed by the Bonferroni post hoc test. Significance was accepted at an alpha level of .05. Results: Irrespective of the region injected with formalin (upper lip or hindlimb), copper sulfate (0.3, 1.0, and 3.0 mg/kg) and ketamine (1.0, 3.0, and 10 mg/kg) dose-dependently decreased the nociceptive behaviors evoked by formalin injection. Isobolographic analysis showed a superadditive interaction between copper and ketamine at the spinal level, but this interaction was only additive at the trigeminal level. Conclusion: The results suggest that copper salts could be used to synergistically improve the efficacy of some commercial centrally acting analgesic agents, such as ketamine, while reducing the possibility of side effects. However, a synergistic effect probably should not be expected if treatment is for orofacial pain. Keywords: copper, intraplantar formalin, isobologram, ketamine, orofacial formalin

Aims: To evaluate the usefulness of diet board feeding as a model for temporomandibular joint (TMJ) research, characterize dietary loading-related morphometric changes in the mandibular condylar cartilage of aging rats, and investigate changes in type I and type II collagen expression in different age, sex, and diet groups. Methods: Material was collected from a study that examined the effects of 1-year and 2-year diet board feeding on rats. In diet board feeding, rats must gnaw wood to reach their food, leading to a higher masticatory workload. The material analyzed was comprised of 150 TMJ samples from 75 Hsd:Sprague Dawley rats grouped according to feeding method (diet board [experimental group] or ad libitum [control group]), sex, and experiment length (1 or 2 years). The rats were sacrificed at the age of 15 or 26 months (15-M rats or 26-M rats). From the TMJ samples, 5-μm-thick sections were cut parallel to the sagittal plane of the mandibular condyle. Histomorphometric analysis of the thickness of the condylar cartilage and the number of cartilage cells was performed after toluidine blue staining. Immunohistochemical staining included type I and type II collagen antigens. Differences in the thickness of the cellular layer and the number of cells in the condylar cartilage were analyzed by means of a repeatedmeasures analysis of variance (ANOVA) model, and differences in the type of collagen with a one-way random-effects ANOVA model. Results: Condylar cartilage was significantly thicker in the 15-M diet board-fed rats than in the 15-M control rats and in the 26-M rats than in the 15-M rats. The number of cells was larger in the 26-M female rats than in the 26-M male rats. Type I collagen expression was significantly higher in the 15-M diet board-fed female rats than in the 15-M controls. Type II collagen showed increased expression in older rats compared to younger rats. Conclusion: Condylar cartilage is sensitive to the interplay between loading, aging, and sex of middle-aged and older rats. High loading of condylar cartilage increased the thickness of cartilage in younger rats. Keywords: age-related changes, diet board, joint loading, mandibular condylar cartilage, rat, type I collagen, type II collagen

Aims: To evaluate the regional collagen fiber network in the human temporomandibular joint (TMJ) disc by using biochemical magnetic resonance imaging (MRI) and quantitative histology. Methods: MRI of 5 heads (10 TMJ discs) obtained from partially dentate or edentulous cadavers was performed at 3-Tesla MRI by using a flexible, 8-channel transmit-receive coil. After MRI, all 10 discs were processed histologically. Percentages of coronal, sagittal, and transverse collagen fibers were assessed stereologically for the anterior, central, and posterior parts of the disc. An anisotropy index was calculated for collagen fiber arrangement in all three regions of interest. Results: In the central part of the TMJ disc, collagen fibers were arranged anisotropically with a preferentially sagittal direction. In the anterior and posterior parts, evidence for fibers being arranged isotropically (randomly) without preferred direction was found. Mean MRI T2 values appeared to be correlated with the anisotropy index of collagen fibers (r = -0.45; P .05). When tested individually, T2 values of the isotropic anterior and posterior disc regions showed a partial but significant correlation with the anisotropy index of collagen fibers (r = -0.54; P .05), whereas the anisotropic central part did not (P > .05). Conclusion: This study has provided the first systematic comparison of quantitative data on collagen fiber isotropy and anisotropy assessed in histologic sections with biochemical quantitative MRI for human TMJ fibrous cartilage. Keywords: comparison of MRI and histology, fibrocartilage, MRI, temporomandibular joint, 3 Tesla

Aims: To assess the prevalence of posterior disc displacement (PDD) in patients with temporomandibular disorders (TMD) through a systematic review of the literature and meta-analysis, as well as to assess features associated with PDD such as chief complaint, signs and symptoms, morphologic condyle and disc alterations, and PDD management. Methods: A systematic literature search was performed in the US National Library of Medicine's PubMed/ MEDLINE and Cochrane Library databases to identify all peer-reviewed, English-language manuscripts related to PDD. A critical appraisal checklist provided by the Joanna Briggs Institute for studies reporting prevalence data was used to assess the quality of the included manuscripts. A meta-analysis was conducted using software MetaXL 5.3 (EpiGear International Pty Ltd) add-in for Microsoft Excel. Pooled prevalence and 95% confidence intervals (CIs) were calculated using the software. Heterogeneity of the included studies was assessed using the Higgins I2 test and Cochran's Q (with P value; .05 was considered significant). Results: A total of 21 articles were selected for qualitative data synthesis: 2 case reports, 14 observational studies, and 5 studies that reported PDD in various conditions. Quantitative data analysis was performed for the 14 observational studies, of which 13 reported prevalence with respect to the number of joints affected and 9 reported prevalence with respect to the number of patients affected. The overall pooled prevalence of PDD for the number of joints affected was 0.7% (95% CI: 0.005 to 0.008). The pooled prevalence of PDD for the number of patients was 0.9% (95% CI: 0.007 to 0.011). PDD was found to be associated with osseous changes, including changes in the morphology of the condyle, disc, and articular eminence; osseous abnormalities (erosion, osteophytes); and joint effusion. Conclusion: This meta-analysis showed a very low prevalence rate of PDD in TMD patients. The limited literature did not allow conclusions to be drawn about the PDD-related features. Keywords: arthrography, magnetic resonance imaging, musculoskeletal disease, posterior disc displacement, prevalence, temporomandibular joint disc, temporomandibular joint disorders

Aims: To conduct a systematic review and meta-analysis to determine the efficacy of low-level laser therapy (LLLT) in treating temporomandibular myofascial pain in adults compared to laser placebo. Methods: Randomized, placebo-controlled studies were identified by a search on March 2, 2016 and updated on February 9, 2017 in the PubMed, Web of Science, and Cochrane Library databases. Three of the authors assessed the studies for risk of bias. Outcomes included pain reduction on a visual analog scale (VAS) and interincisal opening. Results: The initial search strategy yielded 142 unduplicated references assessed independently by three review authors. After evaluation, this number was reduced to eight relevant studies for inclusion in this review. Of these eight studies, four were at unclear risk of bias and four were at high risk. In a meta-analysis, pain intensity was significantly reduced after treatment in the group that received LLLT as compared to laser placebo (an average of 2.2 units on a scale of 0 to 10) (P = .005) and an average of 2.4 units 3 to 4 weeks later (P = .022). Pooled results showed a significant increase in interincisal opening at 1 month after treatment (P = .012), but not when the treatment was completed (P = .079). Conclusion: The findings from this systematic review showed that LLLT seems to be effective in reducing pain in patients with temporomandibular myofascial pain with moderate-quality evidence. However, due to the high heterogeneity, small number, and high risk of bias of the included studies, the results are not definitive, and further well-designed studies are needed. Keywords: low-level laser therapy, meta-analysis, myofascial pain, randomized controlled trials, visual analog scale

Aims: To determine whether subjects with temporomandibular disorders (TMD) manifesting as chronic myofascial pain (MFP) involving the masseter muscle present with significantly greater masseter muscle width, as evidenced by ultrasound, compared to individuals without MFP. Methods: A case-control study was carried out. A total of 31 subjects presenting with MFP of the masticatory muscles involving the masseter muscle and 35 controls with TMD but no diagnosis of MFP, matched by age and sex, were included. Ultrasound was used to measure the maximum width of both masseter muscles at the intermediate point between the origin and insertion of the muscle in the light occlusal contact (LOC) position and under maximum contraction. Each side was analyzed separately. Means were compared by using single-factor analysis of variance and Mann-Whitney U test; P .05 was considered to reflect statistical significance. Results: In the study group, the right masseter muscle had a mean ± standard deviation width of 8.6 ± 1.8 mm under LOC (controls: 8.6 ± 1.6 mm; P = .85) and 11.5 ± 2.1 mm under maximum contraction (controls: 11.7 ± 1.9 mm; P = .86). The analagous measures in the left masseter muscle were 8.6 ± 1.6 mm under LOC (controls: 8.2 ± 1.5 mm; P = .42) and 11.3 ± 1.8 mm under maximum contraction (controls: 11.5 ± 1.8 mm) (P = .79), respectively. The increase in width of the right masseter muscle was 2.9 ± 2.1 mm (controls: 3.1 ± 1.2 mm; P = .67) in absolute terms and 1.4 ± 0.3 mm (controls: 1.4 ± 0.2 mm; P = .91) in relative values (width at maximum contraction/LOC width). In the case of the left masseter muscle, the respective values were 2.8 ± 1.7 mm (controls: 3.2 ± 0.9 mm; P = .25) and 1.3 ± 0.2 mm (controls: 1.4 ± 0.1 mm; P = .32). Conclusion: There were no statistically significant differences in masseter muscle width between MFP subjects and control subjects under LOC conditions or maximum contraction. The increase in width under maximum contraction was likewise not significantly different between the groups. Keywords: chronic pain, masseter, myofascial pain, ultrasound

Aims: To investigate the local and segmental effects of therapeutic ultrasound at a dose of 0.4 w/cm2 with 100% duty cycle for 5 minutes compared to the effect of sham ultrasound on painful masticatory muscles. Methods: A total of 20 adult female subjects with bilateral masseter myalgia diagnosed according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) were included. Each subject was randomized to either an active ultrasound group or a sham ultrasound group. The intervention was applied to each masseter muscle for 5 minutes. Measures included pre- and post-self-reported pain intensity recorded on a verbal rating scale (VRS), pressure pain thresholds for the masseter (PPT-M) and temporalis (PPT-T) muscles, and intraoral temperature for the masseter muscle. Preintervention score was subtracted from the postintervention score for all measures to calculate mean change in pain, and nonparametric Mann-Whitney test was used to compare the groups. Statistical significance was set at P .05. Results: Changes in VRS did not show a significant difference between groups (P > .05). There were significant increases in PPT-M and intraoral temperature in the ultrasound group compared to the sham group (P .05). There was no significant difference in PPT-T (P > .05), suggesting no segmental effect. Conclusion: Therapeutic ultrasound produced an immediate increase in PPT-M and intraoral temperature compared to sham ultrasound in female subjects with bilateral masseter myalgia. Keywords: myalgia, TMD, ultrasound

Aims: To describe pain catastrophizing in temporomandibular disorder (TMD) patients in relation to disability and pain persistence. Methods: A total of 163 TMD patients underwent a complete TMD evaluation according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), including the Pain Catastrophizing Scale (PCS). Patients were divided into subgroups according to their PCS, Graded Chronic Pain Scale (GCPS), and pain persistence scores. The GCPS and pain persistence subgroups were assigned as dependent variables in a stepwise multiple logistic regression model. The ability of the DC/TMD Axis II parameters and of the PCS to discriminate between patients of low and high disability (according to the GCPS) and low and high pain persistence were examined using area under the receiver operating characteristic (ROC) curve. α .05 was considered to reflect statistical significance. Results: Significant differences were found between high and low pain catastrophizing patients as to socioeconomic parameter, Axis I diagnoses, pain persistence, and Axis II evaluation. The parameters with significant discriminant ability for pain persistence were pain catastrophizing, depression, and nonspecific physical symptoms, with no significant differences between them. Depression increased the odds of high disability by 1.2, while pain catastrophizing increased the odds for high pain persistence more than 6-fold. Pain catastrophizing was not significantly associated with pain disability, and depression was not significantly associated with pain persistence. Conclusion: High-pain catastrophizing TMD patients were similar to patients with other chronic pain conditions, but differed from TMD patients as a group. The findings of this study support the addition of an assessment for pain catastrophizing to the DC/TMD for early identification of TMD patients who might be at higher risk for developing chronic pain. Keywords: DC/TMD, pain catastrophizing, pain persistence, temporomandibular disorders

Aims: To determine whether a difference in standing balance exists among individuals with cervicogenic headache, those with migraine, and asymptomatic controls. Methods: A total of 24 participants with cervicogenic headache, 24 with migraine, and 24 asymptomatic controls of similar age, gender, and body mass index were included. Standing balance was assessed with a swaymeter under the conditions of eyes open and closed; on firm and soft surfaces; and in comfortable and narrow stances (for a total of eight testing conditions). Each condition was tested for 30 seconds. The outcome measures were sway area and displacement. Multivariate analysis of variance with Bonferroni post hoc test were used to analyze between-group differences in the postural sway variables. Results: Both headache groups had significantly larger sway areas than the control group during comfortable stance with eyes open and with eyes closed on a soft surface (P .05) and during narrow stance with eyes closed on firm and soft surfaces (P .05). The overall results demonstrated significantly greater sway in the anterior-posterior direction and less sway in the medial-lateral direction in selected tests in the cervicogenic headache group compared to the migraine group. Conclusion: Individuals with cervicogenic headache and those with migraine have impaired balance during standing, but possibly to a different extent and pattern. Assessment of balance in patients with cervicogenic headache and migraine should be considered in clinical practice. Keywords: balance, cervicogenic headache, headache, migraine, sensorimotor dysfunction

Aims: To investigate whether a shortened dental arch (SDA), as identified by reduced posterior occlusal contacts, is a risk factor for the progression of temporomandibular joint (TMJ) intra-articular disorders (ID), as identified using imaging techniques. Methods: This multisite, prospective observational study with a mean follow-up period of 7.9 years had a sample of 345 participants with at least 1 temporomandibular disorder (TMD) diagnosis at baseline. SDA was defined as reduced occlusal posterior support due to lack of occlusal intercuspal contacts in the molar region on the left and/or right side. SDA was assessed at baseline and at follow-up with metalized Mylar Tape. The presence or absence of a TMJ ID and the specific TMJ ID diagnoses for baseline and follow-up images were established by a calibrated, blinded radiologist at each of three sites by using bilateral magnetic resonance imaging for soft tissue imaging for disc displacement and by bilateral multidetector computed tomography or cone beam computed tomography for hard tissue imaging for degenerative joint diseases. Wilcoxon rank sum test and linear regression analyses were used to test for an impact of SDA on TMJ ID status. Results: At baseline, TMJ ID status of either side was not significantly affected by the presence of SDA on the ipsilateral or contralateral side of the jaw (all P > .05). Furthermore, the presence or absence of SDA at baseline was also not a significant predictor for progression of the TMJ ID status between baseline and follow-up (all P > .05). Conclusion: The findings of this study suggest that there is no significant effect of SDA on progression of TMJ ID. Keywords: intra-articular disorders, observational study, risk factor, shortened dental arch, temporomandibular joint