Blockade of Piezo2 Pathway Attenuates Inflammatory and Neuropathic Pain in the Orofacial Area.

Although previous studies suggest that Piezo2 regulates chronic pain in the orofacial area, few studies have reported the direct evidence of Piezo2's involvement in inflammatory and neuropathic pain in the orofacial region. In this study, we used male Sprague Dawley rats to investigate the role of the Piezo2 pathway in the development of inflammatory and neuropathic pain. The present study used interleukin (IL)-1ß-induced pronociception as an inflammatory pain model. Subcutaneous injection of IL-1ß produced significant mechanical allodynia and thermal hyperalgesia. Subcutaneous injection of a Piezo2 inhibitor significantly blocked mechanical allodynia and thermal hyperalgesia induced by subcutaneously injected IL-1ß. Furthermore, the present study also used a neuropathic pain model caused by the misplacement of a dental implant, leading to notable mechanical allodynia as a consequence of inferior alveolar nerve injury. Western blot analysis revealed increased levels of Piezo2 in the trigeminal ganglion and the trigeminal subnucleus caudalis after inferior alveolar nerve injury. Furthermore, subcutaneous and intracisternal injections of a Piezo2 inhibitor blocked neuropathic mechanical allodynia. These results suggest that the Piezo2 pathway plays a critical role in the development of inflammatory and neuropathic pain in the orofacial area. Therefore, blocking the Piezo2 pathway could be the foundation for developing new therapeutic strategies to treat orofacial pain conditions.

The crucial role of NR2A mediating the activation of satellite glial cells in the trigeminal ganglion contributes to orofacial inflammatory pain during TMJ inflammation.

Temporomandibular joint inflammatory diseases are a significant subtype of temporomandibular disorders (TMD) characterized by inflammatory pain in the orofacial area. The N-methyl-D-aspartate receptor (NMDAR), specifically the NR2A subtype, was crucial in neuropathic pain. However, the exact role of NR2A in inflammatory pain in the TMJ and the molecular and cellular mechanisms mediating peripheral sensitization in the trigeminal ganglion (TG) remain unclear. This study utilized male and female mice to induce the TMJOA model by injecting Complete Freund's adjuvant (CFA) into the TMJ and achieve conditional knockout (CKO) of NR2A in the TG using Cre/Loxp technology. The Von-Frey filament test results showed that CFA-induced orofacial pain with reduced mechanical withdrawal threshold (MWT), which was not developed in NR2A CKO mice. Additionally, the up-regulation of interleukin (IL)-1ß, IL-6, and nerve growth factor (NGF) in the TG induced by CFA did not occur by NR2A deficiency. In vitro, NMDA activated satellite glial cells (SGCs) with high expression of glial fibrillary acidic protein (GFAP), and both NMDA and LPS led to increased IL-1ß, IL-6, and NGF in SGCs. NR2A deficiency reduced these stimulating effects of NMDA and LPS. The regulation of IL-1ß involved the p38, Protein Kinase A (PKA), and Protein Kinase C (PKC) pathways, while IL-6 signaling relied on PKA and PKC pathways. NGF regulation was primarily through the p38 pathway. This study highlighted NR2A's crucial role in the TG peripheral sensitization during TMJ inflammation by mediating ILs and NGF, suggesting potential targets for orofacial inflammatory pain management.

Dosimetry model for photobiomodulation based on anthropometric and hemodynamic variables in patients with orofacial pain post-Covid-19: Study protocol for randomized clinical trial.

INTRODUCTION: Orofacial pain and tension headache are symptoms that affect a large portion of the population, compromising productivity, social ability, and functional development. The treatment for reducing painful sensation should be chosen carefully, as pharmacological treatment may bring side effects and overload the organism of patients in pain. Low-level laser therapy has been used with local and systemic [vascular] applications for pain control. However, there is still uncertainty in the literature about the ideal dosimetric parameters for photobiomodulation treatment according to patient characteristics. METHODS: The objective of this project is to validate a dosimetry model based on the relationship between the effects of photobiomodulation with anthropometric and hemodynamic variables, both in local application and systemic application in patients with symptoms of orofacial pain and tension headache. For this purpose, 180 participants with orofacial pain post-covid eligible participants will be randomly assigned to Group 1-Local Photobiomodulation, Group 2-Vascular Photobiomodulation, Group 3-Placebo Local Photobiomodulation, or Group 4-Placebo Vascular Photobiomodulation [Therapy EC-DMC device, São Carlos, Brazil,- 660 nm, 100mW] using stratified block randomization. Before the application, sociodemographic information such as age, skin phototype [classified by the Fitzpatrick scale], weight, height, body mass index [BMI], oxygen saturation [SaO2], blood pressure [BP], heart rate [HR], and thickness of skin, fat, and facial muscles will be collected. During the application, we will collect local temperature, SaO2, BP, and HR. Before and after laser application, blood levels of lactate and hemoglobin, BP, and HR will be measured in the first and last session. In addition to demographic, anthropometric, and hemodynamic variables, the penetrated energy will be quantified using a power meter, and information from orofacial pain and headache symptom questionnaires will be analyzed. The Monte Carlo simulation technique will be used to systematically study the relationship between the light penetration profile into the target tissues and the most relevant variables, namely BMI, tissue layer thicknesses, and skin phototype. Light transmittance, measured in vivo and simulated, will be compared to validate a personalized dosimetry model. DISCUSSION: The results of this study contribute to validating a Monte Carlo Simulation model to calculate the appropriate dosimetry for photobiomodulation therapies in the control of patients with Post-Covid-19 orofacial pain. TRIAL REGISTRATION: Trial registration number: NCT06065969.

The effects of trauma-focused treatment on painful temporomandibular disorders, awake bruxism and sleep bruxism in patients with severe post-traumatic stress disorder.

BACKGROUND: Chronic painful temporomandibular disorders (TMD), awake bruxism and sleep bruxism are often comorbid with post-traumatic stress disorder (PTSD), but the implications for treatment are unknown. OBJECTIVE(S): To explore the effects of PTSD treatment on these conditions. We hypothesized that chronic painful TMD, pain intensity, pain interference, awake bruxism and sleep bruxism would decrease after evidence-based trauma-focused treatment and that this decrease would be maintained at the 6-month follow-up. METHODS: Individuals referred for PTSD treatment were assessed for chronic painful TMD (temporomandibular disorder pain screener), pain intensity, pain interference (Graded Chronic Pain Scale 2.0), awake bruxism and sleep bruxism (oral behaviours checklist) pre-, post-treatment and at the 6-month follow-up. Hypotheses were tested using the Friedman test, followed by a post hoc Wilcoxon signed-rank test. Effect sizes (Cohen's r) are reported. Barely any pain interference was reported, therefore these outcomes were not analysed. RESULTS: In individuals with chronic painful TMD (n = 98), pain intensity, awake bruxism and sleep bruxism decreased across the three time points. Post hoc tests showed that chronic painful TMD (r = 0.59), pain intensity (r = 0.28), awake bruxism (r = 0.51) and sleep bruxism (r = 0.35) decreased between pre- and post-treatment. Between pre-treatment and the 6-month follow-up, chronic painful TMD (r = 0.58), awake bruxism (r = 0.30) and sleep bruxism (r = 0.39) decreased as well. CONCLUSION: The results provide preliminary support for a trauma-sensitive approach for patients with chronic painful TMD and PTSD and suggest that trauma-focused treatment may be beneficial for chronic painful TMD, awake bruxism and sleep bruxism in patients with PTSD and chronic painful TMD.

Prevalence of psychosocial findings and their correlation with TMD symptoms in an adult population sample.

BACKGROUND AND AIM: Some studies suggested an association between Temporomandibular Disorders (TMD) and psychosocial status, but most of them are focused on samples of patients looking for treatment or present limits of sample representativeness. The aim of the present study was to evaluate the psychosocial status in a large sample of adult population, further than to assess its association to TMD symptoms, oral behaviours, and self-reported facial trauma. RESULTS: the study sample included 4299 subjects older than 18 years randomly recruited from general population in public spaces during their daily life (1700 Males, 2599 Females mean ± SD age = 40.4 ± 18.1). Psychosocial status and pain-related disability were assessed by means of Patient Health Questionnaire 4 (PHQ-4) and Graded Chronic Pain Scale (GCPS). TMD symptoms were assessed by RDC/TMD and validated screening tools for TMD pain. Oral Behaviours Checklist was used to investigate on oral behaviours. Logistic regression model was used to evaluate the association of the psychosocial status, TMD symptoms, trauma, and oral behaviours. The association was tested using both univariate and multivariate models. The PHQ4 evaluation showed a severe impairment in 4.6% of our sample, moderate in 18.8% and mild in 32.5%. We found a Characteristic Pain Intensity (CPI) level and Interference Score greater that 30 respectively in 36.2% and 22.2% of the study sample. The GCPS status revealed a high disability with severe limitation in 2.5% of the sample, high disability with moderate limitation in 7.0%, low disability high pain intensity in 7.4% and low disability low pain intensity in 37.8%. Anxiety and depression's levels were significantly associated with gender, TMD pain, coexistence of TMD Pain and sound, and oral behaviours. GCPS status was significantly associated with age, TMD Pain, coexistence of TMD pain and sound, trauma, and oral behaviours. CONCLUSIONS: In the general population, psychosocial impairment is associated to TMD pain, female gender, and report of oral behaviours. Hence, in adults with TMD accompanied by pain, psychosocial status should also be evaluated.

Temporomandibular Joint Pain Measurement by Bite Force and Von Frey Filament Assays in Mice.

Temporomandibular joint (TMJ) pain and osteoarthritis (OA) are common and debilitating disorders that impair patients' quality of life. The mechanisms driving diseases-related pain are poorly understood, and current treatments fail to provide effective and long-term therapeutic effects. Additionally, pain assessment in research, particularly orofacial pain, poses several challenges that complicate studies in both clinical and basic science settings. Therefore, we have established an inflammatory TMJ pain mouse model via intra-articular injection of CFA (Complete Freund's Adjuvant) and evaluated pain behaviors by bite force measurement and the von Frey filament test. Mice with CFA injection exhibited orofacial pain behaviors compared to PBS injection, including reduced bite force and head withdrawal threshold in the von Frey filament test. These methods are relatively easy to execute to have reproducible results and can be potentially extended to pain studies for other disease models related to TMJ disorders. Together, bite force, and the von Frey filament tests are reliable in measuring orofacial pain, as demonstrated in CFA injection-induced painful TMJOA mouse models.

The preliminary study of the effects of individual musculoskeletally stable position in the treatment of temporomandibular disorders.

BACKGROUND: Temporomandibular Disorders (TMD) is the dysfunction of group of muscles and bones in the joint area, the main symptoms of TMD are the pain of the chewing muscles and (or) the temporomandibular joints, mandibular movement disorders and joint noise. This study was designed to explore the therapeutic effects following Individual Musculoskeletally Stable (IMS) position stabilization splint therapy for TMD patients using Fricton index, cone beam computed tomography (CBCT) and surface-Electromyogram (sEMG). METHODS: In this study, we enrolled 31 TMD patients (ranging from 18 to 26 years old, including 7 males and 24 females), first Fricton index was used to evaluate the clinical curative effect of TMD with the treatment of IMS stabilization splint; then CBCT was used to observe the TMJ condylar position changes of TMD before and after the treatment of IMS stabilization splint; finally sEMG was used to observe the changes of electromyography of anterior temporalis (AT) and masseter muscles (MM) of TMD before and after the treatment of IMS stabilization splint. RESULTS: The course of treatment was 6-8 months, with an average of 7.6 months. After the IMS stabilization splint treatment, TMD symptoms relieved, especially in pain, mandibular movement disorder, but still slightly inferior in the treatment of joint noise. And there was a statistically significant difference in the anterior and inner joint space, the condyle had the tendency of moving forward and outward. AT presented reduction significantly of EMG value at rest position after treatment. CONCLUSIONS: IMS stabilization splint is a therapeutic reversible treatment for TMD, especially for pain and mandibular movement disorder; it produces effects of forward and outward condylar movement and elimination of the masticatory muscles antagonism.

Nutritional Strategies for Chronic Craniofacial Pain and Temporomandibular Disorders: Current Clinical and Preclinical Insights.

This narrative review provides an overview of current knowledge on the impact of nutritional strategies on chronic craniofacial pain associated with temporomandibular disorders (TMDs). Individuals experiencing painful TMDs alter their dietary habits, avoiding certain foods, possibly due to chewing difficulties, which might lead to nutrient deficiencies. Our literature investigation revealed that the causal links between nutritional changes and craniofacial pain remain unclear. However, clinical and preclinical studies suggest that nutraceuticals, including vitamins, minerals, polyphenols, omega-3 fatty acids, isoprenoids, carotenoids, lectins, polysaccharides, glucosamines, and palmitoylethanolamides, could have beneficial effects on managing TMDs. This is described in 12 clinical and 38 preclinical articles since 2000. Clinical articles discussed the roles of vitamins, minerals, glucosamine, and palmitoylethanolamides. The other nutraceuticals were assessed solely in preclinical studies, using TMD models, mostly craniofacial inflammatory rodents, with 36 of the 38 articles published since 2013. Our investigation indicates that current evidence is insufficient to assess the efficacy of these nutraceuticals. However, the existing data suggest potential for therapeutic intervention in TMDs. Further support from longitudinal and randomized controlled studies and well-designed preclinical investigations is necessary to evaluate the efficacy of each nutraceutical intervention and understand their underlying mechanisms in TMDs.

Differential activation of lateral parabrachial nuclei and their limbic projections during head compared with body pain: A 7-Tesla functional magnetic resonance imaging study.

Pain is a complex experience that involves sensory, emotional, and motivational components. It has been suggested that pain arising from the head and orofacial regions evokes stronger emotional responses than pain from the body. Indeed, recent work in rodents reports different patterns of activation in ascending pain pathways during noxious stimulation of the skin of the face when compared to noxious stimulation of the body. Such differences may dictate different activation patterns in higher brain regions, specifically in those areas processing the affective component of pain. We aimed to use ultra-high field functional magnetic resonance imaging (fMRI at 7-Tesla) to determine whether noxious thermal stimuli applied to the surface of the face and body evoke differential activation patterns within the ascending pain pathway in awake humans (n=16). Compared to the body, noxious heat stimulation to the face evoked more widespread signal changes in prefrontal cortical regions and numerous brainstem and subcortical limbic areas. Moreover, facial pain evoked significantly different signal changes in the lateral parabrachial nucleus, substantia nigra, paraventricular hypothalamus, and paraventricular thalamus, to those evoked by body pain. These results are consistent with recent preclinical findings of differential activation in the brainstem and subcortical limbic nuclei and associated cortices during cutaneous pain of the face when compared with the body. The findings suggest one potential mechanism by which facial pain could evoke a greater emotional impact than that evoked by body pain.

Systemic Factors Affecting Pain Management in Dentistry.

There are several factors that affect a patient's experience of pain. These include both local and systemic factors. The systemic factors that affect patients' dental and orofacial pain experience include, but not limited to, hormonal, nutritional, systemic infections, neurodegenerative, and autoimmune, among others. Comprehensive medical history is essential to delineate any possible systemic factors affecting pain experience. A thorough review of systems should form the foundation, since multiple factors can affect the prognosis of pain management. This would facilitate early recognition and trigger prompt referrals to the appropriate medical professionals. This helps to reduce the health care burden.

The link between cutaneous allodynia and pain/sensitivity in teeth and gums during migraine episodes.

BACKGROUND: Migraine is one of the most common primary headaches worldwide, while toothache is the most common pain in the orofacial region. The association of migraine pain, and oral pain is unknown. This study aims to investigate the association between migraine and dental and gingival pain with the presence of allodynia. METHODS: A questionnaire comprising demographic data with the ID-Migraine (IDM) tool, an Allodynia Symptom Checklist (ASC), and inquiries about pain and sensitivity in the teeth and gums during migraine attacks was administered to the participants and 762 responded the survey. The study classified participants based on the ASC, and the relationship between allodynia and pain/sensitivity in the teeth and/or gums during migraine attacks was analyzed. The statistical analyses utilized Chi-square tests and the Fisher-Exact test. RESULTS: Among 762 migraine patients, 430 (56.44%) were classified as allodynia (+), while 332 (43.56%) were classified as allodynia (-) (p < 0.001). Additionally, 285 participants (37.5%) reported experiencing pain and sensitivity in the teeth and gums during migraine attacks, with a significant relationship observed between allodynia and pain/sensitivity in the teeth and/or gums during migraine attacks (p < 0.001). CONCLUSION: The findings of this study have important clinical implications. For migraine patients who are non-allodynic, the presence of pain and sensitivity in their teeth and gums during migraine attacks may indicate underlying dental diseases or the need for dental treatment especially root canal treatment. However, for allodynic patients, such symptoms may not necessarily indicate the presence of dental diseases or the need for dental treatment especially root canal treatment. These results underscore the significance of considering the presence of allodynia in the assessment and management of oral symptoms during migraine attacks.

Efficacy of different low-level laser therapy sessions in the management of masseter muscle trigger points.

BACKGROUND: Low-level laser therapy (LLLT) is one of the recent treatment modalities for myofascial pain dysfunction syndrome with trigger points. The objective of the present study was to examine the impact of varying LLLT sessions on the treatment of masseter muscle trigger points. METHODS: 90 patients diagnosed with orofacial pain and trigger points in the masseter muscle for at least 6 months were selected and divided into 3 groups (n = 30) based on the number of LLLT sessions provided to patients. Patients in Group I received one session/per week, group II received two sessions/per week, and Group III received three sessions/per week. The sessions continued for 4 weeks, evaluations of pain levels, maximum mouth opening (MMO), and quality of life were conducted before and after the procedure at 1, 2, 3, 4, and 8 weeks. RESULTS: The pain scores exhibited a highly statistically significant difference among the three groups (p < 0.001) over the 8-week study period. MMO was statistically significantly different between groups at week 4 and week 8. The Oral Health Impact Profile-14 (OHIP-14) score was statistically significant difference between groups at week 8. The time showed a highly significant effect on the study outcomes within each group. CONCLUSION: Increased the number of LLLT sessions reduced the pain improved the MMO, and subsequently improved the quality of life. GOV ID: NCT06327204 - retrospectively registered.

Evaluation of the single and combined therapeutic effects of individually manufactured earplug therapy in patients with myogenous temporomandibular disorders: A randomized controlled clinical trial.

OBJECTIVE: To evaluate the effect of individually manufactured earplug therapy on pain intensity (PI), symptom severity (SS), and maximum mouth opening (MMO), in patients with myogenous temporomandibular disorders (TMD). METHODS: One-hundred-twenty patients were randomly allocated to six groups: Groups EP (earplug), OS (occlusal splint), EX (exercise), EPO (earplug with occlusal splint), EPE (earplug with exercise), and C (control). Outcomes were PI (assessed with a visual analog scale (VAS)), SS (assessed with the modified Symptom Severity Index Questionnaire (mSSI)), and MMO (evaluated with a digital caliper). Measurements were performed at T0 (before the therapy), T1 (1-month follow-up), and T2 (3-month follow-up). Data were analyzed using one-way analysis of variance (ANOVA), Tukey's HSD, and chi-square tests (alpha = 0.05). RESULTS: At T1 and T2, the greatest VAS and mSSI reduction was detected for the groups EPE (VAS = 5.3 ± 1.05, 3.3 ± 0.7; mSSI = 38.2 ± 2.27, 43.6 ± 3.94) and EPO (VAS = 5.2 ± 0.91, 3.2 ± 0.78; mSSI = 36.3 ± 3.97, 42.2 ± 3.19), respectively (p < 0.05). At T1, occlusal splint groups (groups OS (34.8 ± 2.97 mm) and EPO (33.8 ± 3.49 mm)) gave the highest MMO values, while T2 values did not constitute a significant difference with T1 (p > 0.05). CONCLUSIONS: The short-term use of combined earplug therapy resulted in a decrease in both PI and SS. Improvement in MMO in participants using occlusal splints was observed in the 1st month and was maintained through the 3rd month. CLINICAL RELEVANCE: Earplug therapy can be applied as a complementary therapy to occlusal splint and exercise treatments to decrease PI and SS in patients with myogenous TMD. To achieve functional recovery such as MMO, its combined use with splints should be taken into consideration by clinicians.

Efficacy of botulinum neurotoxin A in persistent idiopathic dentoalveolar pain: a case series.

OBJECTIVES: Persistent idiopathic dentoalveolar pain (PIDP) is a challenging clinical entity associated with both physical and emotional consequences. Currently, the management is symptom-based and includes both topical and/or systemic treatments. More recently, botulinum neurotoxin-A (BONT-A) has been suggested as a treatment option. MATERIALS AND METHODS: We present a case series of 9 patients (5 female) with mean age 56 ± 15 diagnosed with PIDP. All patients reported prior experience with systemic drugs without a sufficient pain-relieving effect. BONT-A (BOTOX, Allergan) 100 U diluted with saline solution was used and the dose ranged from 20U to 50U distributed in 3 sites (intraoral and/or extraoral) per session. Patients underwent further injections (50U) monthly if pain severity measured using a Numerical Rating Scale (NRS 0-10) was still > 3 for 3 months. Pain severity and characteristics were recorded at baseline (T0), after 1 month (T1), 2 months (T2) and 3 months (T3). RESULTS: Mean pain intensity at baseline was NRS 6 (4-10). Latency before analgesic effect was at least 5-10 days after injection. Minor adverse effects were sickness and muscular hypotonia. Pain significantly reduced to NRS 4 (0-8) at T1, to NRS 2 (0-8) at T2 and to NRS 2 (NRS 0-8) at T3. Patients' functional variables (discomfort while chewing, talking, swallowing) were also recorded. CONCLUSIONS: BONT-A is widely used and although the exact mechanism of action remains unclear, it can be used effectively in reducing pain for a variety of conditions including PIDP. CLINICAL RELEVANCE: Our results suggest that BONT-A seems to be an alternative therapeutic approach for patients with PIDP.

Occlusal interventions for managing temporomandibular disorders.

BACKGROUND: Temporomandibular disorders (TMD) are conditions related to the musculoskeletal structure of the temporomandibular joint, which may lead to muscle or joint pain and other health issues. TMD may present in muscles only (myogenous), joints only (arthrogenous), or both (mixed), and may affect one side or both sides of the face. Myogenous TMD may present with or without limited mouth opening. Arthrogenous TMD may present as disc displacement with or without reduction ('reduction' meaning the articular disc resumes its normal position when the jaw is moving). Occlusal interventions change the occlusal relationship of maxillary and mandibular teeth to improve the alignment of the tooth contact, with the aim of relieving pain, and improving psychosocial functioning and quality of life. Occlusal interventions include splints and adjustments. Occlusal splints are specially designed mouth guards; they are generally classified as stabilisation, reflex or repositioning splints. Occlusal adjustment is the grinding down of teeth to improve occlusion. OBJECTIVES: To assess the effects of occlusal interventions in people diagnosed with temporomandibular disorders (TMD), compared to other interventions or no treatment, on joint pain, muscle pain at rest and when chewing, quality of life, discomfort, and recurrence. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched following sources up to 9 August 2022: Cochrane Oral Health's Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, Embase via Ovid, and two trials registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of occlusal interventions (splints or adjustment) for managing TMD compared with no treatment, placebo, occlusal splint with a different mechanism of action, or other active treatments. DATA COLLECTION AND ANALYSIS: We adopted standard Cochrane methods to select studies, extract and analyse data, assess the risk of bias in the studies, and judge the certainty of the evidence. We reported outcomes as short term (three months or less) or long term (more than three months). MAIN RESULTS: We included 57 studies (2846 participants) that compared occlusal splints with no treatment, placebo, or another treatment. Most of the studies evaluated full hard stabilisation splint (FHSS) as the occlusal splint. We judged only one study to be at low risk of bias. Our key outcomes of interest were self-reported joint pain when chewing, muscle pain at rest and when chewing, discomfort, severity and frequency of joint noise, and recurrence rate. The duration of the studies ranged from 5 weeks to 84 months. The key results presented below were measured between 4.4 weeks and 4 months. It is important to note that we have very low certainty in the evidence for all comparisons and outcomes assessed. There may be little to no difference in self-reported joint pain when chewing between occlusal splint (FHSS) and placebo (non-occlusal splint) (RR 1.88, 95% CI 0.94 to 3.75; 1 study, 60 participants with mixed TMD), or pharmacological therapy (diclofenac) (RR 2.10, 95% CI 0.83 to 5.30; 1 study, 29 participants with osteoarthritis), but the evidence is very uncertain. Occlusal splint (FHSS) may reduce muscle pain when chewing compared to no treatment (MD -1.97, 95% CI -2.37 to -1.57; 1 study, 84 participants with disc displacement without reduction), but may have little to no effect when compared to physical therapy (low-level laser) (RR 0.17, 95% CI 0.02 to 1.26; 1 study, 40 participants) or acupuncture (with needles) (MD 0.10, 95% CI -0.80 to 1.00, 1 study, 40 participants) in people with myofascial pain TMD, but the evidence is very uncertain. There may be little to no difference in muscle pain at rest when occlusal splint (FHSS) is compared to no treatment (MD -11.63, 95% CI -29.37 to 6.11; 1 study, 37 participants) or physical therapy (physiotherapy) (MD -0.19, 95% CI -1.25 to 0.87; 1 study, 72 participants) in myofascial pain TMD, but the evidence is very uncertain. There may be little to no difference in severity of joint noise when occlusal splint (FHSS) is compared to no treatment, but the evidence is very uncertain (MD -0.58, 95% CI -7.09 to 5.93; 1 study, 20 participants). When FHSS is compared to physical therapy (specifically, orofacial myofunctional therapy), physical therapy may reduce severity of joint noise, but the evidence is very uncertain (MD 5.92, 95% CI 0.18 to 11.66; 1 study, 20 participants with mixed TMD). There may be little to no difference in frequency of joint noise when occlusal splint (FHSS) is compared to placebo (non-occlusal splint) (RR 1.18, 95% CI 0.63 to 2.20; 1 study, 60 myofascial pain TMD participants), occlusal splint with a different mechanism of action (RR 0.80, 95% CI 0.07 to 9.18; 1 study, 9 participants with disc displacement with reduction), or physical therapy (jaw exercise) (RR 1.50, 95% CI 0.32 to 6.94; 1 study, 18 participants with myofascial pain TMD), but the evidence is very uncertain. Discomfort and recurrence rate were not reported in any study. We judged the certainty of the evidence to be very low for all outcomes in all comparisons due to limitations in study design and imprecision. AUTHORS' CONCLUSIONS: This review included 57 RCTs with 2846 participants, but the final results are inconclusive, so the research questions remain unanswered. Occlusal splints of the FHSS type may reduce muscle pain when chewing compared to no treatment, but the evidence is very uncertain. Orofacial myofunctional therapy may reduce severity of joint noise compared to occlusal splint (FHSS), but the evidence is very uncertain. For all other comparisons and outcomes, there may be little or no difference between groups, although the evidence is also very uncertain for these findings. Overall, we found insufficient evidence to reach conclusions regarding the effectiveness of occlusal interventions for managing symptoms of TMD, despite the available studies including almost 3000 participants. To make a useful contribution to the debate about the best way to treat TMD, any further research must be well-designed, with enough participants to reach the optimal information size for meaningful results; it requires recruitment from primary care, consensus around key outcomes and measures, and, ideally, long-term follow-up of three to five years, plus inclusion of a cost-effectiveness component.

Orofacial antinociceptive activity of codeine-associated geraniol in mice: a controlled triple-blind study.

This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.

Impact of streptozotocin-induced diabetes on experimental masseter pain in rats.

This study aimed to assess the influence of streptozotocin (STZ)-induced diabetes on the nociceptive behavior evoked by the injection of hypertonic saline (HS) into the masseter muscle of rats. Forty male rats were equally divided into four groups: a) isotonic saline control, which received 0.9% isotonic saline (IS), (Ctrl-IS); b) hypertonic saline control, which received 5% HS (Ctrl-HS); c) STZ-induced diabetic, which received IS, (STZ-IS); d) STZ-induced diabetic, which received HS (STZ-HS). Experimental diabetes was induced by a single intraperitoneal injection of STZ at dose of 60 mg/kg dissolved in 0.1 M citrate buffer, and 100 µL of HS or IS were injected into the left masseter to measure the nociceptive behavior. Later on, muscle RNA was extracted to measure the relative expression of the following cytokines: cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF-α), and interleukins (IL)-1ß, -2, -6, and -10. One-way analysis of variance (ANOVA) was applied to the data (p < 0.050). We observed a main effect of group on the nociceptive response (ANOVA: F = 11.60, p < 0.001), where the Ctrl-HS group presented the highest response (p < 0.001). However, nociceptive response was similar among the Ctrl-IS, STZ-IS, and STZ-HS group (p > 0.050). In addition, the highest relative gene expression of TNF-α and IL-6 was found in the masseter of control rats following experimental muscle pain (p < 0.050). In conclusion, the loss of somatosensory function can be observed in deep orofacial tissues of STZ-induced diabetic rats.