Targeted Therapy for Orofacial Pain: A Novel Perspective for Precision Medicine.

Orofacial pain (OFP) is a dental specialty that includes the diagnosis, management and treatment of disorders of the jaw, mouth, face, head and neck. Evidence-based understanding is critical in effectively treating OFPs as the pathophysiology of these conditions is multifactorial. Since OFP impacts the quality of life of the affected individuals, treating patients successfully is of the utmost significance. Despite the therapeutic choices available, treating OFP is still quite challenging, owing to inter-patient variations. The emerging trends in precision medicine could probably lead us to a paradigm shift in effectively managing the untreatable long-standing pain conditions. Precision medicine is designed based on the patient's genetic profile to meet their needs. Several significant relationships have been discovered based on the genetics and genomics of pain in the past, and some of the notable targets are discussed in this review. The scope of this review is to discuss preclinical and clinical trials that include approaches used in targeted therapy for orofacial pain. Future developments in pain medicine should benefit from current trends in research into novel therapeutic approaches.

Dual orexin receptor antagonist drug suvorexant can help in amelioration of predictable chronic mild stress-induced hyperalgesia.

AIMS: This study aimed to evaluate the involvement of the orexin system in predictable chronic mild stress (PCMS) and the effects of suvorexant, a dual orexin receptor antagonist, on nociceptive behavior in PCMS. MATERIALS AND METHODS: Male C57BL/6 J mice were separated into various PCMS groups: a control group with sawdust on the floor of the rearing cage (C), a group with mesh wire on the floor (M), and a group with water just below the mesh wire (W). Activation of lateral hypothalamic orexin neurons was assessed using immunofluorescence. In another experiment, half of the mice in each group were administered an intraperitoneal injection of suvorexant (10 mg/kg), and the remaining mice were injected with the same amount of vehicle (normal saline). Thermal hyperalgesia was examined using tail immersion and hot plate tests, while mechanical hyperalgesia was investigated using the tail pinch test after 21 days of PCMS. KEY FINDINGS: Animals subjected to PCMS showed an increased percentage of activated orexin neurons in the lateral hypothalamic region after 21 days. Mice raised in the PCMS environment showed increased pain sensitivity in several pain tests; however, the symptoms were significantly reduced by suvorexant administration. SIGNIFICANCE: The findings revealed that PCMS activates hypothalamic orexin neuronal activity, and the use of suvorexant can help attenuate PCMS-induced thermal and mechanical hyperalgesia.

Analgesic Effect of Tranilast in an Animal Model of Neuropathic Pain and Its Role in the Regulation of Tetrahydrobiopterin Synthesis.

Trigeminal neuralgia is unilateral, lancinating, episodic pain that can be provoked by routine activities. Anticonvulsants, such as carbamazepine, are the drugs of choice; however, these possess side-effects. Microvascular decompression is the most effective surgical technique with a higher success rate, although occasionally causes adverse effects. The potential treatment for this type of pain remains unmet. Increased tetrahydrobiopterin (BH4) levels have been reported in association with axonal injury. This study aimed to evaluate the effect of tranilast on relieving neuropathic pain in animal models and analyze the changes in BH4 synthesis. Neuropathic pain was induced via infraorbital nerve constriction. Tranilast, carbamazepine, or saline was injected intraperitoneally to assess the rat's post-intervention pain response. In the von Frey's test, the tranilast and carbamazepine groups showed significant changes in the head withdrawal threshold in the ipsilateral whisker pad area. The motor coordination test showed no changes in the tranilast group, whereas the carbamazepine group showed decreased performance, indicating impaired motor coordination. Trigeminal ganglion tissues were used for the PCR array analysis of genes that regulate the BH4 pathway. Downregulation of the sepiapterin reductase (Spr) and aldoketo reductase (Akr) genes after tranilast injection was observed compared to the pain model. These findings suggest that tranilast effectively treats neuropathic pain.

Managements of sleep bruxism in adult: A systematic review.

This systematic review aimed to update the management of sleep bruxism (SB) in adults, as diagnosed using polysomnography (PSG) and/or electromyography (EMG). Management methods covered were oral appliance therapy (OAT) with stabilization splints, cognitive-behavioral therapy (CBT), biofeedback therapy (BFT), and pharmacological therapy. A comprehensive search was conducted on MEDLINE, Cochrane Library, and Web of Science up to October 1st, 2021. Reference list searches and hand searches were also performed by an external organization. Two reviewers for each therapy independently performed article selection, data extraction, and risk of bias assessment. The reviewers resolved any disagreements concerning the assortment of the articles by discussion. Finally, 11, 3, 14, and 22 articles were selected for each therapy. The results suggested that OAT tended to reduce the number of SB events, although there was no significant difference compared to other types of splints, that the potential benefits of CBT were not well supported, and that BFT, rabeprazole, clonazepam, clonidine, and botulinum toxin type A injection showed significant reductions in specific SB parameters, although several side effects were reported. It can be concluded that more methodologically rigorous randomized large-sample long-term follow-up clinical trials are needed to clarify the efficacy and safety of management for SB.

Comparative analysis of education, awareness, and knowledge of dentists and physical therapists in the treatment of temporomandibular disorders.

OBJECTIVE: To compare the education, awareness, and knowledge of Filipino dentists and physical therapists (PTs) in terms of temporomandibular disorders (TMDs). METHODS: A 30-item structured online questionnaire was given to recruited PTs and dentists from January 2019 to December 2019. Welch's t-test was used to compare the education, awareness, and knowledge of health professionals. Brown-Forsythe and Welch ANOVA with Games-Howell post hoc were used to compare test scores across the knowledge components. RESULTS: Of the 620 professionals, 46.67% dentists and 6.38% PTs had training in TMD. Professionals with more years of experience and who had previous TMD training were more aware of TMD management. Both dentists and PTs showed the lowest knowledge in TMD pathophysiology. DISCUSSION: This study showed high awareness but low education and knowledge of Filipino dentists and PTs in TMD management. Improving the educational curriculum and refining the training given by accredited professional organizations is suggested.

Peripherally Administered Botulinum Toxin Type A Localizes Bilaterally in Trigeminal Ganglia of Animal Model.

Peripheral nerve injury leads to sensory ganglion hyperexcitation, which increases neurotransmitter release and neuropathic pain. Botulinum toxin type A (BoNT/A) regulates pain transmission by reducing neurotransmitter release, thereby attenuating neuropathic pain. Despite multiple studies on the use of BoNT/A for managing neuropathic pain in the orofacial region, its exact mechanism of transport remains unclear. In this study, we investigated the effects of BoNT/A in managing neuropathic pain in two different animal models and its transport mechanism in the trigeminal nerve. Intraperitoneal administration of cisplatin induced bilateral neuropathic pain in the orofacial region, reducing the head withdrawal threshold to mechanical stimulation. Unilateral infraorbital nerve constriction (IONC) also reduced the ipsilateral head withdrawal threshold to mechanical stimulation. Unilateral peripheral administration of BoNT/A to the rat whisker pad attenuated cisplatin-induced pain behavior bilaterally. Furthermore, contralateral peripheral administration of BoNT/A attenuated neuropathy-induced behavior caused by IONC. We also noted the presence of BoNT/A in the blood using the mouse bioassay. In addition, the Alexa Fluor-488-labeled C-terminal half of the heavy chain of BoNT/A (BoNT/A-Hc) was localized in the neurons of the bilateral trigeminal ganglia following its unilateral administration. These findings suggest that axonal and hematogenous transport are involved in the therapeutic effects of peripherally administered BoNT/A in the orofacial region.

Risk Factors for Tooth Loss in Patients with ≥25 Remaining Teeth Undergoing Mid-Long-Term Maintenance: A Retrospective Study.

Tooth loss represents a diffused pathologic condition affecting the worldwide population. Risk factors have been identified in both general features (smoking, diabetes, economic status) and local tooth-related factors (caries, periodontitis). In this retrospective study, we examined the data of 366 patients with a large number of remaining teeth (≥25) undergoing maintenance therapy in order to identify specific risk factors for tooth loss. The number of remaining teeth, number of non-vital teeth, and number of occlusal units were investigated for their correlation with tooth loss. The mean follow-up of patients was 9.2 years (range 5 to 14). Statistically significant risk factors for tooth loss were identified as number of remaining teeth at baseline (p = 0.05), number of occlusal units (p = 0.03), and number of non-vital teeth in posterior regions (p < 0.001). Multiple logistic regression showed that the number of occlusal units and number of non-vital teeth in the posterior regions were significantly associated with a greater risk of tooth loss (odds ratio 1.88 and 3.17, respectively). These results confirm that not only the number of remaining teeth, but also their vital or non-vital status and the distribution between the anterior and posterior regions influence the long-term survival.

Pain sensitivity increases with sleep disturbance under predictable chronic mild stress in mice.

Even though it has been well documented that stress can lead to the development of sleep disorders and the intensification of pain, their relationships have not been fully understood. The present study was aimed at investigating the effects of predictable chronic mild stress (PCMS) on sleep-wake states and pain threshold, using the PCMS rearing conditions of mesh wire (MW) and water (W) for 21 days. Exposure to PCMS decreased the amount of non-rapid eye movement (NREM) sleep during the dark phase. Moreover, the chronicity of PCMS decreased slow-wave activity (SWA) during NREM sleep in the MW and W groups in both the light and dark phases. Mechanical and aversively hot thermal hyperalgesia were more intensified in the PCMS groups than the control. Higher plasma corticosterone levels were seen in mice subjected to PCMS, whereas TNF-α expression was found higher in the hypothalamus in the W and the trigeminal ganglion in the MW group. The W group had higher expression levels of IL-6 in the thalamus as well. The PCMS paradigm decreased SWA and may have intensified mechanical and thermal hyperalgesia. The current study also suggests that rearing under PCMS may cause impaired sleep quality and heightened pain sensation to painful mechanical and aversively hot thermal stimuli.

Effects of sitting posture and jaw clenching on neck and trunk muscle activities during typing.

Neck pain is one of the most common musculoskeletal complaints. Evidence suggests that increased activities of neck and trunk muscles are one of the mechanisms related to neck pain. Jaw clenching and sitting posture may modulate the muscle activity in neck and trunk muscles during typing. The present study aimed to assess the effects of different postural positions and clenching conditions on neck and trunk muscle activities. Thirteen healthy adults (39.8 ± 5.0 years) performed computer typing tasks in four conditions (two postural positions [upright vs slouched] and two jaw clenching conditions [clenching vs non-clenching]). Integrated surface electromyography (iEMG) was measured in sternocleidomastoid (SCM), upper trapezius (uTP) and middle trapezius (mTP) muscles and compared between conditions. The Friedman and Wilcoxon signed-rank tests with Bonferroni's corrections were used to estimate the condition-specific differences in the iEMG data. The statistical significance level was set at 5%. In both postural positions, iEMGSCM was significantly greater under the jaw clenching than under the non-clenching condition (χ2  = 21.700, P < .01). Under both jaw clenching conditions, iEMGuTP was significantly greater in the slouched than in the upright postural position (χ2  = 23.182, P < .01). No significant differences in iEMGmTP were seen across conditions (χ2  = 5.018, P = .10). Sitting posture and jaw clenching appear to influence activities of different muscles.

Immediate Effect of Masticatory Muscle Activity with Transcutaneous Electrical Nerve Stimulation in Muscle Pain of Temporomandibular Disorders Patients.

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive treatment modality for acute and chronic pain. However, little information for muscle activity is available on the immediate effects of TENS in masticatory muscle pain related to temporomandibular disorders (TMDs). The present study aimed to evaluate the immediate effects of TENS treatment on TMD-related muscle pain. Thirty-six patients with TMD-related muscle pain and 39 healthy subjects served as TMD and control groups, respectively. For objective evaluations, maximum mouth opening, and maximum bite force were measured before and after TENS. The pain intensity was assessed according to a 100-mm visual analog scale (VAS). TENS was applied to painful muscles for 20 min with frequencies of 100-200 Hz. The treatment outcome was evaluated using Global Rating of Change (GRC) scales. In the TMD group, VAS values significantly decreased after TENS. Although there was significant increase in the maximum mouth opening after TENS for only TMD group, the maximum bite force of both groups was significantly greater after TENS. According to GRC scales, one patient with TMD-related muscle pain expressed negative feelings after TENS. Conclusively, TENS treatment might quickly relieve pain in masticatory muscles and improve masticatory functions in patients with TMD-related muscle pain.

Risk Factors for Tooth Loss in Patients Undergoing Mid-Long-Term Maintenance: A Retrospective Study.

In this retrospective study, we identified risk factors for tooth loss in patients undergoing mid-long-term maintenance therapy. We surveyed 674 maintenance patients for ≥5 years after active treatment who visited a dental clinic between January 2015 and December 2016. Of these, 265 were men (mean age 54.6 ± 8.0 years old) and 409 were women (mean age 54.0 ± 7.9 years old). Study variables included patient compliance, sex, number of teeth lost, cause of tooth loss (dental caries, periodontal disease, root fracture, others, vital or non-vital teeth), age at start of maintenance, number of remaining teeth at start of maintenance, smoking, use of salivary secretion inhibitors, presence of diabetes mellitus, condition of periodontal bone loss, and use of a removable denture. Most lost teeth were non-vital teeth (91.7% of all cases) and the most common cause of tooth loss was tooth fracture (62.1% of all cases). A statistically significant risk factors for tooth loss was number of remaining teeth at the start of maintenance (p = 0.003).

Changes in oxygen and carbon dioxide in the genesis of sleep bruxism: a mechanism study.

PURPOSE: Rhythmic masticatory muscle activity (RMMA), a biomarker of sleep bruxism (SB), has been associated with mild hypoxia and/or big breaths in some adults with non-sleep-disordered breathing. The purpose of this study was to investigate that concurrent oxygen and carbon dioxide fluctuations are among the physiological variables that contribute to RMMA onset. METHODS: Twelve subjects (5 female, 7 male, mean age: 43 ± 11) underwent polysomnography recording in a sleep laboratory. RMMA index and apnea-hypopnea index were calculated. Oxygen saturation (SpO2) was estimated by finger pulse oximeter and end-tidal CO2 (ETCO2) by nasal airflow cannula before and after RMMA onset. Given the expected response time delay between actual arterial hypoxemia and fingertip pulse detection, we adjusted the SpO2 desaturation onset to the onset of masseter muscle activity using a 17 s criterion based on ETCO2 shifts. RESULTS: SpO2 was slightly but significantly lower than at baseline (max: -0.6%) in the 6-4 s before RMMA onset and significantly higher in the 6-18 s after onset (0.9%; p < 0.05). Although ETCO2 before RMMA onset did not differ from baseline, it decreased at 8-10 s after onset (-1.7 mmHg: p < 0.05). No changes in SpO2 or ETCO2 in relation to RMMA onset reached a critical clinical threshold. CONCLUSIONS: The mild transient hypoxia observed before RMMA onset was not associated with a change in ETCO2. The mild and brief oxygen fluctuations before RMMA onset may reflect a physiological response that seems to have little influence on SB genesis.

Effects of exercise therapy on painful temporomandibular disorders.

Temporomandibular disorders (TMD) are common chronic musculoskeletal pain conditions among orofacial pain. Painful TMD condition such as myalgia and arthralgia can be managed by exercise therapy. However, as it is hard to access actual effect of each modality that is included in an exercise therapy programme due to multiple choice of the management modality, their efficacy remains controversial. Therefore, this review focused on the effects of exercise therapy for the management of painful TMD. The aims of this review were to summarise the effects of exercise therapy for major symptoms of painful TMD and to establish a guideline for the management of painful TMD, resulting in higher quality and reliability of dental treatment. In this review, exercise modalities are clearly defined as follows: mobilisation exercise, muscle strengthening exercise (resistance training), coordination exercise and postural exercise. Furthermore, pain intensity and range of movements were focused as outcome parameters in this review. Mobilisation exercise including manual therapy, passive jaw mobilisation with oral appliances and voluntary jaw exercise appeared to be a promising option for painful TMD conditions such as myalgia and arthralgia. This review addressed not only the effects of exercise therapy on various clinical conditions of painful TMD shown in the past, but also an urgent need for consensus among dentists and clinicians in terms of the management of each condition, as well as terminology.

Validity of Peer Evaluation for Team-Based Learning in a Dental School in Japan.

The aim of this study was to determine the validity of peer evaluation for team-based learning (TBL) classes in dental education in comparison with the term-end examination records and TBL class scores. Examination and TBL class records of 256 third- and fourth-year dental students in six fixed prosthodontics courses from 2013 to 2015 in one dental school in Japan were investigated. Results of the term-end examination during those courses, individual readiness assurance test (IRAT), group readiness assurance test (GRAT), group assignment projects (GAP), and peer evaluation of group members in TBL classes were collected. Significant positive correlations were found between all combinations of peer evaluation, IRAT, and term-end examination. Individual scores also showed a positive correlation with group score (total of GRAT and GAP). From the investigation of the correlations in the six courses, significant positive correlations between peer evaluation and individual score were found in four of the six courses. In this study, peer evaluation seemed to be a valid index for learning performance in TBL classes. To verify the effectiveness of peer evaluation, all students have to realize the significance of scoring the team member's performance. Clear criteria and detailed instruction for appropriate evaluation are also required.

Mandibular movement during sleep bruxism associated with current tooth attrition.

PATIENT: Observation of attrition patterns suggests that mandibular movement in sleep bruxism (SB) may be associated with current tooth attrition. The aim of this study was to confirm this phenomenon by investigating mandibular movement and masseter muscle activity. The subject was a healthy 21-year-old Japanese male. We recorded biological signals including mandibular movement and masseter electromyograms (EMGs) with a polysomnograph. Based on the EMG using Okura's criteria, SB events were classified into clenching, grinding and mixed types according to mandibular movement criteria. The close-open mandibular movement cycles (CO-cycles) during grinding and mixed type events were selected based on mandibular movement trajectories. DISCUSSION: Fifty-eight CO-cycles were selected in seven grinding and three mixed types. We found that SB mandibular movements associated with current tooth attrition. Excessive lateral movements (ELM) beyond the canine edge-to-edge position were observed in the closing (10.3%) and opening (13.8%) phases of the CO-cycle. Total masseter muscle activity was significantly higher during voluntary grinding (VGR) than during CO-cycle including ELM (working side: P=0.036, balancing side: P=0.025). However, in the middle and late parts of the opening phase, working side masseter muscle activity was significantly higher during CO-cycle including ELM than during VGR (P=0.012). In the early part of the closing phase, balancing side masseter muscle activity was significantly higher during CO-cycle including ELM than during VGR (P=0.017). CONCLUSION: These findings suggest that excessive forceful grinding during ongoing SB events may have caused canine attrition in this patient.

Comparison between flipped classroom and team-based learning in fixed prosthodontic education.

PURPOSE: We previously investigated the effects of team-based learning (TBL) on fixed prosthodontic education and reported that TBL could have higher efficiency with high student satisfaction than traditional lecture. In the current report, we introduced flipped classroom to the fixed prosthodontic education and compared their effectiveness based on the final examination score in addition to TBL. METHODS: Participants were 41 students from Tokushima University School of Dentistry who attended a fixed prosthodontics course. The first six classes adopted the flipped classroom style while the latter eight classes adopted TBL. To evaluate the relationship between learning styles and their effectiveness, we compared results from the term-end examination between the curriculum covered by flipped classroom and TBL-style classes. To draw comparisons, a referential examination with the same questions was conducted to eight faculty members who had not attended any of these classes. RESULTS: Term-end examination results showed that TBL classes had slightly higher scores than flipped classroom classes. Referential examination results also showed higher scores for the same curriculum and no significant interaction was found between class formats and the term-end and referential examination scores. Analysis revealed no noticeable difference in the effectiveness of the class formats. CONCLUSION: Our previous study reported that TBL had higher efficiency than traditional style lecture. In the current study, there was no statistical difference in the examination score between flipped classroom and TBL. Therefore, we conclude that both styles are highly effective than traditional style lecture and constitute valid formats for clinical dental education.

A longitudinal retrospective study of the analysis of the risk factors of implant failure by the application of generalized estimating equations.

PURPOSE: Many studies have identified risk factors for dental implant failure, although few have investigated the correlation among implant fixtures within single patients. A better analytical method may include repeated measures analysis including generalized estimating equations (GEE). This retrospective cohort study aimed to (1) identify the risk factors for failure of dental implantation and (2) evaluate an analytical method using GEE analysis. METHODS: We analyzed data on early and late implant failures in 296 patients providing 721 rough surface dental implants (2.44 implants per patient). Potential predictors of implant failure included age, gender, smoking, location of implant, use of bone augmentation, number of remaining teeth, opposing tooth condition, fixture length, fixture diameter and type of suprastructure (fixed or removable partial denture). The likelihood of early and late implant failure was estimated by GEE. RESULTS: The early failure rate was 1.5% (11/721 implants, 7/296 patients) and the 10-year cumulative survival rate was 94.0% (7/710 implants, 5/293 patients). The GEE analysis revealed that a significant risk factor for early implant failure was smoking (p<0.01), whereas significant risk factors for late failure were maxillary implant (p=0.02), posterior implant (p<0.01), number of remaining teeth (≥20) (p<0.01), opposing unit being a removable partial denture or nothing (p=0.04) and having a removable type suprastructure (p<0.01). CONCLUSIONS: GEE analysis showed that smoking was a risk factor for early implant failure, and several risk factors were identified for late implant failure.

A preliminary investigation of reproducibility of EMG signals during daytime masticatory muscle activity using a portable EMG logging device.

Continuous parafunctional masseter muscle activities (MMA) that are associated with daytime bruxism have been suspected to be one of the main pathoetiology for orofacial pain. The purpose of this study was to examine the long-term stability and reliability of daytime EMG measurement of MMA using a portable device (Actiwave; CamNtech Ltd). Daytime masseter muscle EMG of five subjects were recorded for four days in their normal living environment. There was no significant time dependent effect on EMG amplitude during recording period. A total of 4923 MMA events were detected in all analysis periods (129.4h) and classified into phasic type (1209 events, 24.6%), tonic type (1759 events, 37.0%), and mixed type (1377 events, 28.0%). There was no significant difference in the number of occurrence among three MMA types. With respect to the duration and peak MMA, there were significant differences among three MMA types. The result of this study indicated that Actiwave can be used to measure MMA events during daytime with high stability and reliability under the normal living environment and it was suspected that parafunctional habits may be associated with the occurrence patterns of MMA during daytime.

Effects of team-based learning on fixed prosthodontic education in a Japanese School of Dentistry.

The aims of this study were to evaluate the quality of team-based learning (TBL) in prosthodontics education for fourth-year dental students at Tokushima University School of Dentistry and to compare this teaching method with traditional lecture-based delivery. Participants in the study were 36 students (22 males and 14 females) who attended the TBL-style fixed prosthodontics course. Ten 60-minute classes were held. The first three were traditional lecture-style classes and were followed by one class introducing the TBL style. The remaining six classes constituted the TBL-format fixed prosthodontics course. The effectiveness of TBL was evaluated through student questionnaires at the end of each class and the results of the term-end examination. The questionnaire revealed high student approval for TBL-style learning, and active group discussion among students during TBL was a key factor in these ratings. In the results of the term-end examination, there were significantly higher scores on the questions that covered TBL-taught material than those covering traditional lecture-taught topics. The results of this study suggest that TBL-style lecture was more effective than traditional-style lecture for teaching fixed prosthodontics and that TBL was a more efficient mode of delivering dental education than traditional lecture-based teaching.

Effect of an exclusion range of jaw movement data from the intercuspal positionon the estimation of the kinematic axis point.

In patients who have lost natural occlusal contacts, the centric relation is usually estimated based on several anatomical factors such as the temporomandibular joint and masticatory muscles except dental arch. The clinical procedure to record the centric relation often depends on the clinician's expertise and technique; an objective method to determine proper occlusal position is desirable. The kinematic axis point (KAP) is kinematically estimated from sagittal movements and is an ideal posterior reference point that is used in dental articulators for reproducing jaw movement. Occlusal registration using the KAP may serve as a definite objective technique. The aim of this study is to investigate the effect of the exclusion range of sagittal jaw movement data from the intercuspal position (ICP) on the estimation of the KAP. The complete and incomplete sagittal border movement data of dentate subjects were used to estimate the KAPs. The locations of the estimated KAPs were compared. The results indicate that the incomplete sagittal border jaw movement data set does not include data points inside a 7 mm distance from the ICP can be used for estimation of the KAP. In conclusion, the sagittal border jaw movement data around the ICP is not indispensable in the valid identification of the KAP.