Pharmacological Management of Orofacial Pain.

Orofacial pain is a category of complex disorders, including musculoskeletal, neuropathic and neurovascular disorders, that greatly affect the quality of life of the patient. These disorders are within the fields of dentistry and medicine and management can be challenging, requiring a referral to an orofacial pain specialist, essential for adequate evaluation, diagnosis, and care. Management is specific to the diagnosis and a treatment plan is developed with diverse pharmacological and non-pharmacological modalities. The pharmacological management of orofacial pain encompasses a vast array of medication classes and approaches. This includes anti-inflammatory drugs, muscle relaxants, anticonvulsants, antidepressants, and anesthetics. In addition, as adjunct therapy, different injections can be integrated into the management plan depending on the diagnosis and needs. These include trigger point injections, temporomandibular joint (TMJ) injections, and neurotoxin injections with botulinum toxin and nerve blocks. Multidisciplinary management is key for optimal care. New and safer therapeutic targets exclusively for the management of orofacial pain disorders are needed to offer better care for this patient population.

Oral Glucosamine in the Treatment of Temporomandibular Joint Osteoarthritis: A Systematic Review.

Temporomandibular disorders (TMDs) occur frequently within the general population and are the most common non-dental cause of orofacial pain. Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative joint disease (DJD). There have been several different methods of treatment of TMJ OA listed, including pharmacotherapy among others. Due to its anti-aging, antioxidative, bacteriostatic, anti-inflammatory, immuno-stimulating, pro-anabolic and anti-catabolic properties, oral glucosamine seems to be a potentially very effective agent in the treatment of TMJ OA. The aim of this review was to critically assess the efficacy of oral glucosamine in the treatment of TMJ OA on the basis of the literature. PubMed and Scopus databases were analyzed with the keywords: (temporomandibular joints) AND ((disorders) OR (osteoarthritis)) AND (treatment) AND (glucosamine). After the screening of 50 results, eight studies have been included in this review. Oral glucosamine is one of the symptomatic slow-acting drugs for osteoarthritis. There is not enough scientific evidence to unambiguously confirm the clinical effectiveness of glucosamine supplements in the treatment of TMJ OA on the basis of the literature. The most important aspect affecting the clinical efficacy of oral glucosamine in the treatment of TMJ OA was the total administration time. Administration of oral glucosamine for a longer period of time, i.e., 3 months, led to a significant reduction in TMJ pain and a significant increase in maximum mouth opening. It also resulted in long-term anti-inflammatory effects within the TMJs. Further long-term, randomized, double-blind studies, with a unified methodology, ought to be performed to draw the general recommendations for the use of oral glucosamine in the treatment of TMJ OA.

Cannabinoid therapeutics in orofacial pain management: a systematic review.

The objective of this paper was to investigate the published evidence regarding effects of cannabinoids (natural and synthetic) on post-operative and/or out-of-office pain management in patients suffering from orofacial pain that presents in the dental setting. Three online databases (Ovid (MEDLINE), PubMed (MEDLINE), Scopus) were searched (July 2021). Additional studies were sought through grey literature searching (Cochrane Library Trials and ClinicalTrials.gov) and hand-searching the reference lists of included articles. All studies that analysed cannabinoid products and pain management of conditions that present in the general or specialist dental setting in the English language were included. Of the five articles included, one reported a significant effect on temporomandibular disorder pain relief using a topical cannabidiol formulation compared to a placebo. Four articles reported no significant effects of cannabinoids for pain management across various orofacial pain conditions. Although one study reported a positive effect, insufficient evidence exists to support a tangible clinical benefit of cannabinoids in managing orofacial pain, further research is recommended to investigate the benefits of cannabinoids' use. © 2022 Australian Dental Association.

Limonene, a citrus monoterpene, non-complexed and complexed with hydroxypropyl-ß-cyclodextrin attenuates acute and chronic orofacial nociception in rodents: Evidence for involvement of the PKA and PKC pathway.

BACKGROUND: Chronic orofacial pain is a serious public health problem with a prevalence of 7-11% in the population. This disorder has different etiologies and characteristics that make pharmacological treatment difficult. Natural products have been shown to be a promising source of treatments for the management of chronic pain, as an example the terpenes. PURPOSE: The aim of this study was to evaluate the anti-nociceptive and anti-inflammatory effects of one of these terpenes, d-limonene (LIM - a common monoterpene found in citrus fruits) alone and complexed with hydroxypropyl-ß-cyclodextrin (LIM/HPßCD) in preclinical animal models. METHODS: Orofacial pain was induced by the administration of hypertonic saline on the corneal surface, the injection of formalin into the temporomandibular joint (TMJ), or chronic constriction injury of the infraorbital nerve (CCI-IoN). The study used male Wistar rats and Swiss mice treated with LIM (50 mg/kg), LIM/HPßCD (50 mg/kg), vehicle (control), gabapentin or morphine, and eyes wiping (induced by hypertonic saline), face rubbing (formalin-induced in TMJ) or mechanical hyperalgesia (provoked by CCI-IoN) were assessed. Additionally, ELISA was used to measure TNF-α, and western blot analysis to assess levels of PKAcα, NFκB, p38MAPK and phosphorylated PKC substrates. Serum levels of aspartate aminotransferase (AST) and alanine transferase (ALT) were also evaluated. RESULTS: LIM and LIM/HPßCD significantly reduced (p < 0.001) corneal nociception and formalin-induced TMJ nociception. In addition, both substances attenuated (p < 0.001) mechanical hyperalgesia in the CCI-IoN model. The antinociceptive effect induced by LIM and HPßCD/LIM was associated with decreased TNF-α levels, downregulation of the NFκB and p38MAPK signalling pathways and reduced PKC substrate phosphorylation and PKA immunocontent. Moreover, the results demonstrated that complexation with HPßCD was able to decrease the therapeutic dose of LIM. CONCLUSION: LIM was found to be a promising molecule for the treatment of orofacial pain due to its capacity to modulate some important mediators essential to the establishment of pain, and HPßCD can be a key tool to improve the profile of LIM.

Anti-nociceptive effects of ECa 233 a standardized extract of Centella asiatica (L.) Urban on chronic neuropathic orofacial pain in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: ECa 233 is a standardized extract of Centella asiatica (L.) Urban, a herb traditionally used to treat a number of diseases including neurological disorders. Accordingly, ECa 233 showed benefits on animal models of cognitive deficits, chronic stress and Parkinson's disease. Analgesic activity of ECa 233 was shown in Tail's flick test in rodent and relieving aphthous ulcer pain in man. Moreover, acute and sub-chronic toxicity testing in rodents and pharmacokinetic study in healthy volunteers, clinical trial phase I demonstrated good safety profiles of ECa 233. AIM OF THE STUDY: This study aims to evaluate the anti-nociceptive effects of ECa 233 and its synergistic effect with gabapentin on chronic neuropathic orofacial pain after 3 weeks infraorbital nerve chronic constriction injury in mice. The peripheral and central nociceptive activities are also examined. MATERIALS AND METHODS: Chronic neuropathic orofacial pain was induced by 3 weeks infraorbital nerve chronic constriction injury. Mice were treated with ECa 233 (30, 100 and 300 mg/kg) and gabapentin (10 mg/kg) by oral gavage starting on day 21 and going on for 14 consecutive days. Mechanical hyperalgesia and allodynia were measured on day 7, 14, 21, 28 and 35 after infraorbital nerve chronic constriction injury. At the end of the experiment, mice were observed for the sedative effect using the locomotor activity, the calcitonin gen-related peptide in trigeminal ganglion and c-fos expression in trigeminal nucleus caudalis were investigated after euthanasia. RESULTS: Infraorbital nerve chronic constriction injury gradually induced marked ipsilateral mechanical hyperalgesia and allodynia. The maximum hyperalgesia and allodynia response presented on day 21 and the response was remained constant until day 35. Treatment with either 300 mg/kg ECa 233 or 10 mg/kg gabapentin were able to attenuate mechanical hyperalgesia and allodynia. The downregulation of calcitonin gen-related peptide on ipsilateral trigeminal ganglion were observed in ECa 233 at 100 and 300 mg/kg and 10 mg/kg gabapentin-treated groups. The c-fos expression on ipsilateral trigeminal nucleus caudalis was also decreased in 300 mg/kg ECa 233 and 10 mg/kg gabapentin-treated groups. CONCLUSION: ECa 233 reduced hyperalgesia and allodynia by modulating the peripheral calcitonin gen-related peptide expression consequently alleviate the nociceptive activity in trigeminal nucleus caudalis. Further clinical trial to proof ECa 233's efficacy in neuropathic pain in man as well as possible attributable mechanism of action should be further investigated.

Cannabis. Usos y aplicaciones en la práctica odontológica diaria: revisión de la literatura / Cannabis. Uses and applications in daily dental practice: a review of the literature

La evidencia científica presente en la literatura indica que el cannabis puede ser utilizado con fines terapéuticos para tratar distintas afecciones odontológicas. Dado el acceso sencillo a la cavidad bucal, las distintas formulaciones de cannabis pueden aplicarse de forma tópica. La aplicación local de dosis bajas de cannabis ha demostrado alta efectividad para tratar distintas afecciones bucales, constituyendo un tratamiento seguro con baja probabilidad de generar repercusiones sistémicas indeseadas. En la actualidad, está siendo incorporado a materiales convencionales de uso e higiene odontológica con la finalidad de aprovechar sus efectos terapéuticos. El cannabis tiene múltiples usos en odontología: como componen-te de enjuagues bucales y soluciones para la desinfección de conductos radiculares, en tratamientos de trastornos de ansiedad bucal, como complemento en terapias oncológicas, como analgésico para atenuar el dolor inflamatorio y el neuropático, como miorrelajante y condroprotector para tratar trastornos de articulación témporomandibular (ATM) y bruxismo, como osteomodulador para el tratamiento de patologías que comprometen la integridad ósea, como la enfermedad periodontal y la osteoporosis, y para la cicatrización ósea asociada a fracturas, extracciones dentarias e implantes, y como inmunomodulador con potencial terapéutico para tratar patologías autoinmunes como las enfermedades reumáticas. El trata-miento local con cannabis es efectivo, bien tolerado por el paciente y con pocos efectos adversos. Por lo tanto, se puede concluir que el cannabis aporta un enorme abanico de posibilidades terapéuticas para tratar distintas afecciones odontológicas, aunque aún se requiere mayor cantidad de estudios científicos que avalen su utilización en cada situación fisiopatológica particular (AU)

The scientific evidence present in the literature indicates that cannabis can be used for therapeutic purposes to treat different dental conditions. Given the easy access to the oral cavity, the different cannabis formulations can be applied topically. The local application of low doses of cannabis has shown high effectiveness in treating different oral conditions, constituting a safe treatment with a low probability of generating unwanted systemic repercussions. It is currently being incorporated into conventional materials for dental use and hygiene in order to take advantage of its therapeutic effects. Cannabis has multiple uses in dentistry: as a component of mouthwashes and solutions for disinfecting root canals, in the treatment of oral anxiety disorders, as a complement in oncological therapies, as an analgesic to reduce inflammatory and neuropathic pain, as a muscle relaxant and chondroprotective to treat temporomandibular joint disorders and bruxism, as an osteomodulator for the treatment of pathologies that compromise bone integrity, such as periodontal disease and osteoporosis, and or bone healing associated with fractures, dental extractions and implants, and as immunomodulator with therapeutic potential to treat autoimmune pathologies such as rheumatic diseases. Local treatment with cannabis is effective, well tolerated by the patient and with few adverse effects. Local treatment with cannabis is effective, well tolerated by the patient and with few adverse effects. Therefore, it can be concluded that cannabis provides an enormous range of therapeutic possibilities to treat different dental conditions, although more scientific studies are still required to support its use in each particular pathophysiological situation (AU)

Anti-nociceptive efficacy of essential oil-based extracts for the management of orofacial pain: a systematic review of available evidence.

OBJECTIVE: Experimental studies have shown that essential oil (EO)-based extracts derived from medicinal plants exhibit antinociceptive activity. The aim of the present systematic review was to assess the anti-nociceptive efficacy of EO-based extracts for the management of orofacial pain (OFP). MATERIALS AND METHODS: To address the focused question "Are EO-based formulations effective for the management of OFP disorders?", indexed databases were searched without time and language restrictions using the preferred reporting items for systematic reviews and meta-analysis guidelines. Risk of bias (ROB) was assessed. RESULTS: Eight studies were included and processed for data extraction. Two studies were clinical (one in adults and one in children) and 6 were performed in rodents. Results from one clinical study showed that inhalation of EO-extracts does not affect subjective toothache scores; and results from the study on children reported that inhalation of lavender oil reduces anxiety and pain during and after tooth extraction. Results from all experimental studies showed that administration of EO-extracts reduces orofacial nociceptive behavior. The ROB was high in 50% and 83.3% of the clinical and experimental studies, respectively. CONCLUSIONS: The anti-nociceptive efficacy of EO-extracts for the management of OFP remains debatable. Further well-designed and power-adjusted randomized clinical trials are needed in this regard.

Dextrose Prolotherapy Versus Lidocaine Injection for Temporomandibular Dysfunction: A Pragmatic Randomized Controlled Trial.

Objective: Several intraarticular injections, including dextrose and lidocaine, are reported to reduce pain and dysfunction in temporomandibular dysfunction (TMD) and increase maximal jaw opening; our goal was to determine whether dextrose/lidocaine outperforms sterile water/lidocaine for TMD. Design: Pragmatic randomized controlled trial. Setting: Outpatient clinic. Subjects: Chronic (≥3 months) of moderate-to-severe (≥6/10) jaw or facial pain meeting research-specific TMD criteria. Intervention: Blinded intraarticular dextrose prolotherapy (DPT) (20% dextrose/0.2% lidocaine) versus intraarticular lidocaine (0.2% lidocaine in sterile water) at 0, 1, and 2 months. Participants were then unblinded and offered DPT by request for 9 additional months. Main outcome measures: Primary: Numerical Rating Scale (0-10 points) score for facial pain and jaw dysfunction; percentage achieving ≥50% improvement in pain and dysfunction (0, 3, and 12 months). Secondary: Maximal interincisal opening (MIO; 0 and 3 months). Intention-to-treat analysis was by joint using mixed-model regression. Results: Randomization of 29 participants (25 female, 47 ± 17 years, 43 joints) produced similar groups. Three-month pain and dysfunction improvements were similar, but more DPT-treated joints improved by ≥50% in pain (17/22 vs. 6/21; p = 0.028). The MIO improved in both groups (5.6 ± 5.8 mm vs. 5.1 ± 7.0 mm; p = 0.70). From 3 to 12 months, minimal DPT was received by original DPT and lidocaine recipients, 0.5 ± 0.9 and 0.6 ± 1.5 injections, respectively, with only 2 out of 21 joints in the original lidocaine group receiving more than 1 dextrose injection after 3 months. Twelve-month analysis revealed that joints in the original DPT group improved more in jaw pain (4.8 ± 2.4 points vs. 2.6 ± 2.9 points; p = 0.026) and jaw dysfunction (5.3 ± 2.6 points vs. 2.7 ± 2.3 points; p = 0.013). More DPT than lidocaine-treated joints improved by ≥50% in both pain (19/22 vs. 5/21; p = 0.003) and dysfunction (17/22 vs. 7/21; p = 0.040). There were no adverse events; satisfaction was high. Conclusions: Intraarticular DPT resulted in clinically important and statistically significant improvement in pain and dysfunction at 12 months compared to lidocaine injection (ClinicalTrials.gov identifier NCT01617356).

Natural products for orofacial nociception in pre-clinical studies: A systematic review.

OBJECTIVE: The aim of this systematic review was to summarize the use of natural products (NP) in the treatment of orofacial nociception in animal models. METHODS: Pre-clinical studies that have evaluated the efficacy of NPs in experimental orofacial nociception were sought in the Medline, Web of Science, Scopus, Embase, SciELO, LILACS and Scholar databases in January 2020, covering the period since the inception of each one. Two reviewers independently selected the studies, extracted the data and evaluated the risk of bias of the included studies. RESULTS: We included 41 records in qualitative synthesis. Fifty different NPs were investigated. All studies presented positive results for at least one orofacial nociception test. Regarding the risk of bias, most studies presented poor experimental design, mainly lack of randomization and blinding. The main class of isolated compounds tested was terpenes, of which monoterpenes were investigated in the majority of the studies. CONCLUSION: These results indicate that NPs are effective in treating experimental orofacial nociception and highlight some of these NPs, mainly terpenes, suggesting their potential for translational research.

Analgesic effects of the CTK 01512-2 toxin in different models of orofacial pain in rats.

BACKGROUND: Orofacial pain is clinically challenging, having therapeutic failures and side effects. This study evaluated the antinociceptive activities of the CTK 01512-2 toxin, the TRPA1 channel antagonist, and the selective inhibitor of the N-type voltage-gated calcium channels (N-type VGCC), in different pain models. MATERIALS AND METHODS: The trigeminal ganglia were stimulated in vitro with capsaicin. The in vivo models received subcutaneous (sc) injections of formalin into the upper lip of the rats, Freund's Complete Adjuvant (FCA) into the temporomandibular joint (TMJ), and infraorbital nerve constrictions (IONC). CTK 01512-2 at concentrations of 30, 100, and 300 pmol/site, intrathecally (ith), and MVIIA at 10, 30, and 100 pmol/site in the formalin test, guided the doses for the models. The glutamate levels in the CSF of the rats that were submitted to IONC were analyzed. RESULTS: CTK 01512-2 decreased the nociceptive behavior in the inflammatory phase of the formalin test (65.94 ± 7.35%) and MVIIA in the neurogenic phase (81.23 ± 3.36%). CTK 01512-2 reduced facial grooming with FCA in the TMJ (96.7 ± 1.6%), and in the IONC neuropathy model, it decreased heat hyperalgesia (100%) and cold hyperalgesia (81.61 ± 9.02%). The levels of glutamate in the trigeminal ganglia in vitro (81.40 ± 8.59%) and in the CSF in vivo (70.0 ± 9.2%) were reduced. CONCLUSIONS: The roles of TRPA1 in pain transduction and the performance of CTK 01512-2 in the inhibition of the N-type VGCCs were reinforced. This dual activity may represent an advantage in clinical treatments.

Euphorbia bicolor (Euphorbiaceae) Latex Extract Reduces Inflammatory Cytokines and Oxidative Stress in a Rat Model of Orofacial Pain.

Recent studies have reported that the transient receptor potential V1 ion channel (TRPV1), a pain generator on sensory neurons, is activated and potentiated by NADPH oxidase-generated reactive oxygen species (ROS). ROS are increased by advanced oxidation protein products (AOPPs), which activate NADPH oxidase by upregulating Nox4 expression. Our previous studies reported that Euphorbia bicolor (Euphorbiaceae) latex extract induced peripheral analgesia, partly via TRPV1, in hindpaw-inflamed male and female rats. The present study reports that E. bicolor latex extract also can evoke analgesia via reduction of oxidative stress biomarkers and proinflammatory cytokines/chemokines in a rat model of orofacial pain. Male and female rats were injected with complete Freund's adjuvant (CFA) into the left vibrissal pad to induce orofacial inflammation, and mechanical allodynia was measured by the von Frey method. Twenty-four hours later, rats received one injection of E. bicolor latex extract or vehicle into the inflamed vibrissal pad. Mechanical sensitivity was reassessed at 1, 6, 24, and/or 72 hours. Trigeminal ganglia and trunk blood were collected at each time point. In the trigeminal ganglia, ROS were quantified using 2',7'-dichlorodihydrofluorescein diacetate dye, Nox4 protein was quantified by Western blots, and cytokines/chemokines were quantified using a cytokine array. AOPPs were quantified in trunk blood using a spectrophotometric assay. E. bicolor latex extract significantly reduced orofacial mechanical allodynia in male and female rats at 24 and 72 hours, respectively. ROS, Nox4, and proinflammatory cytokines/chemokines were significantly reduced in the trigeminal ganglia, and plasma AOPP was significantly reduced in the trunk blood of extract-treated compared to vehicle-treated rats. In vitro assays indicate that E. bicolor latex extract possessed antioxidant activities by scavenging free radicals. Together our data indicate that the phytochemicals in E. bicolor latex may serve as novel therapeutics for treating oxidative stress-induced pain conditions.

Polarized Polychromatic Noncoherent Light (Bioptron Light) as Adjunctive Treatment in Chronic Oral Mucosal Pain: A Pilot Study.

Objective: Aim of this study was to assess the efficacy of polarized polychromatic noncoherent light (Bioptron light) in the treatment of chronic oral mucosal pain (COMP). Patients and methods: Twenty-two patients affected by COMP were treated with standardized pharmacological protocols in association with Bioptron light (90 W; light wavelength = 480-3400 nm; degree of polarization = 95%; specific power density = 40 mW/cm2; energy density = 2.4 J/cm). The outcome measures were intensity of pain [measured by visual analog scale (VAS) score] and signs reduction (measured by Eisen score) recorded at baseline (t0), after 4 weeks (t1), and after 8 weeks (t2). Signs and symptoms scores were compared with those of a cohort of comparable patients selected from institutional medical record files. Results: Patients in pharmacological treatment associated with Bioptron showed a significant VAS score decrease at t1 and t2 (t0 = 6.9, t1 = 3.9, t2 = 1.8, p < 0.05), whereas the patients in exclusive pharmacological treatment showed a significant VAS score improvement only at t2. Comparing the VAS score at t1 and t2 in the two groups, a significant improvement was recorded in patients undergoing Bioptron adjunctive treatment (t1 = 3.9 vs. 5.9; p < 0.05 and t2 = 1.8 vs. 3.6; p < 0.05). In both groups Eisen score improved at t1 and t2, but in the Bioptron-treated patients the improvement was statistically better at t1 (1.9 vs. 0.8; p < 0.05) and at t2 (2.7 vs. 1.4; p < 0.05). Conclusions: In COMP patients, Bioptron use associated with pharmacological treatment allows a better and faster signs and symptoms reduction when compared with the exclusive pharmacological treatment. Further controlled studies are needed to establish the relative and absolute effectiveness of Bioptron in COMP management.

Molecular mechanism underlying orofacial antinociceptive activity of Vanillosmopsis arborea Baker (Asteraceae) essential oil complexed with ß-cyclodextrin.

BACKGROUND: Vanillosmopsis arborea Baker has recognized economic value owing to the high content of (-)-α-bisabolol (BISA) in the essential oil of its stem (EOVA). The antinociceptive effect of EVOA has already been demonstrated, and ß-cyclodextrin (ßCD) is known to improve the analgesic effect of various substances. PURPOSE: Thus, we aimed to evaluate the orofacial antinociceptive effect of a complex containing EOVA-ßCD in rodents. METHODS: EOVA was obtained by simple hydrodistillation, and the essential oil was complexed with ßCD. The animals (n = 6/group) were treated orally with EOVA-ßCD (10 or 50 mg/kg), or vehicle (control), and subjected to cutaneous orofacial nociception (formalin, capsaicin, acidic saline or glutamate), corneal (hypertonic saline) or temporomandibular (formalin) tests. The expression of FOS protein was analyzed in the spinal cord. Molecular docking was performed using the 5-HT3 and M2 receptors and BISA. RESULTS: The oral administration of EOVA-ßCD reduced nociceptive behaviour. Moreover, EOVA-ßCD decreased FOS expression. The molecular docking study indicates that BISA interacts with 5-HT3 and M2 receptors, indicating the potential mechanism of action of the tested compound. CONCLUSIONS: Our results indicate that EOVA-ßCD possesses orofacial antinociceptive effect, indicating that this complex can be used in analgesic drug development.

Non-invasive therapies for management of temporomandibular disorders: a systematic review

Introduction: As a multifactorial disease, temporomandibular disorders (TMD) require a complex therapeutic approach, being noninvasive therapies the first option for most patients. The aim of this study was to perform a systematic review to analyze the most common non-invasive therapies used for TMD management. Methods: The review was done by searching electronic databases to identify controlled clinical trials related to pharmacologic and non-invasive treatments. Of all potential articles found, 35 were included in this review. Results: Low-level laser therapy (LLLT), occlusal splints (OS) and oral exercises/ behavior education (OE/BE) were the most common therapies used. LLLT showed significant results in pain and movement improvement in most studies. OS was usually combined to other therapies and resulted in improvement of pain. OE/BE showed significant results when combined with ultrasound, LLLT, and manual therapy. Conclusions: Non-invasive treatments can provide pain relief and should be prescribed before surgical procedures. LLLT was the therapy with the higher number of studies showing positive results. Based in heterogeneity of treatment protocols, diagnostic and outcomes criteria used, new well-designed randomized controlled trials (RCT) are necessary. (AU)

The efficacy of dextrose prolotherapy over placebo for temporomandibular joint hypermobility: A systematic review and meta-analysis.

OBJECTIVE: The aim of the systematic review was to analyse the available evidence in order to assess the efficacy of dextrose prolotherapy in improving outcomes in temporomandibular joint (TMJ) hypermobility patients as compared to placebo. METHODS: An electronic search of PubMed, Scopus, CENTRAL and Google scholar databases was performed for English language papers published up to February 2018. Randomised clinical trials (RCTs) and controlled clinical trials (CCTs) comparing dextrose prolotherapy with placebo for TMJ hypermobility were included. RESULTS: Three RCTs were included in the review. Frequency of subluxation/dislocation was reported by two trials which found no difference between dextrose and placebo. A statistical significant difference in reduction of MMO with the use of dextrose prolotherapy was seen on pooling of data (random: MD = -3.32, 95% CI -5.26 to -1.28; P = 0.0008; I2  = 0%). A statistical significant difference in pain reduction was also seen with dextrose as compared to placebo (random: MD = -1, 95% CI -1.58 to -0.42; P = 0.0007; I2  = 0%). CONCLUSION: Within the limitations of the study, dextrose prolotherapy may cause significant reduction in mouth opening and pain associated with TMJ hypermobility. Conclusions with regard to reduction of episodes of subluxation/dislocation cannot be drawn. There is a need of more high-quality RCTs with larger sample size and homogenous prolotherapy protocol to draw stronger conclusions on the effect of dextrose prolotherapy in patients with TMJ hypermobility.

Orofacial antinociceptive effect of Mimosa tenuiflora (Willd.) Poiret.

Mimosa tenuiflora (Willd.) Poiret, popularly known in Brazil as "jurema-preta" is widely used against bronchitis, fever, headache and inflammation. Its antioxidant, anti-inflammatory and antinociceptive potential has already been reported. To assess the orofacial antinociceptive effect of M. tenuiflora, ethanolic extracts of M. tenuiflora (leaves, twigs, barks and roots) were submitted to in vitro tests of antioxidant activity. The extract with the highest antioxidant potential was partitioned and subjected to preliminary chemical prospecting, GC-MS, measurement of phenolic content and cytotoxicity tests of the fraction with the highest antioxidant activity. The nontoxic fraction with the highest antioxidant activity (FATEM) was subjected to tests of acute and chronic orofacial nociception and locomotor activity. The possible mechanisms of neuromodulation were also assessed. The EtOAc fraction, obtained from the ethanolic extract of M. tenuiflora barks, was the one with the highest antioxidant potential and nontoxic (FATEM), and Benzyloxyamine was the major constituent (34.27%). FATEM did not alter the locomotor system of mice and reduced significantly the orofacial nociceptive behavior induced by formalin, glutamate, capsaicin, cinnamaldehyde or acidic saline compared to the control group. FATEM also inhibited formalin- or mustard oil-induced temporomandibular nociception. In addition, it also reduced mustard oil-induced orofacial muscle nociception. However, FATEM did not alter hypertonic saline-induced corneal nociception. Neuropathic nociception was reversed by treatment with FATEM. The antinociceptive effect of FATEM was inhibited by naloxone, L-NAME and glibenclamide. FATEM has pharmacological potential for the treatment of acute and neuropathic orofacial pain and this effect is modulated by the opioid system, nitric oxide and ATP-sensitive potassium channels. These results lead us to studies of isolation and characterization of bioactive principles.

The therapeutic potential of cystathionine gamma-lyase in temporomandibular inflammation-induced orofacial hypernociception.

Hydrogen sulfide (H2S) is an endogenous neuromodulator produced mainly by the enzyme cystathionine gamma-lyase (CSE) in peripheral tissues. A pronociceptive role of endogenously produced H2S has been previously reported by our group in a model of orofacial inflammatory pain. Using the established persistent orofacial pain rat model induced by complete Freund's adjuvant (CFA) injection into temporomandibular joint (TMJ), we have now investigated the putative role of endogenous H2S modulating hypernociceptive responses. Additionally, plasmatic extravasation on TMJ was measured following different treatments by Evans blue dye quantification. Thus, rats were submitted to Von Frey and Formalin tests in orofacial region before and after pharmacological inhibition of the CSE-H2S system combined or not with CFA-induced TMJ inflammation. Pretreatment with CSE inhibitor, propargylglycine (PAG; 88.4 µmol/kg) reduced temporomandibular inflammatory pain when injected locally as well as systemically. In particular, local PAG injection seems to be more effective for hypernociceptive responses in orofacial persistent inflammation since its action is evidenced in the majority analyzed periods of the inflammatory process compared to its systemic use. Moreover, local injection seems to act on temporomandibular vascular permeability, evidenced by decreased plasmatic extravasation induced by local PAG administration. Our data are consistent with the notion that the endogenous synthetized gas H2S modulates persistent orofacial pain responses revealing the pharmacological importance of the CSE inhibitor as a possible therapeutic target for their control.

Effects of cocoa-enriched diet on orofacial pain in a murine model.

OBJECTIVES: To investigate and discuss the effects of cocoa on orofacial pain. SETTING AND SAMPLE POPULATION: The Department of Orthodontics at the University of Florida (UF). Male and female hairless rats (N=20/group) were tested. MATERIALS AND METHODS: Rats were tested using the Orofacial Pain Assessment Device (OPAD) before and after changing their food from the standard chow to a cocoa-enriched or control-equivalent diet. RESULTS: Male rats fed the cocoa diet had a significantly higher operant pain index when tested at 37°C as compared to control diet-fed animals. Female rats on the cocoa diet had a significantly higher pain index when tested at 18°C and 44°C, as compared to animals fed the control diet. Capsaicin-induced pain was inhibited, with cocoa-diet male rats having a significantly higher pain index than control-diet male rats and cocoa-diet female rats at both 37°C and 44°C. Cocoa-diet female rats had a significantly higher pain index at 44°C than control-diet females. Mechanical sensitivity was affected following capsaicin cream, with a significantly decreased tolerated bottle distance in both cocoa- and control-diet animals, but there was no difference between cocoa- and control-diet groups. CONCLUSION: Using the OPAD operant system, we demonstrated that a diet rich in cocoa was effective in inhibiting neurogenic inflammatory pain in rats. This has implications for the use of novel alternative therapies such as diet modification for pain control.

Enhancement of orofacial antinociceptive effect of carvacrol, a monoterpene present in oregano and thyme oils, by ß-cyclodextrin inclusion complex in mice.

Orofacial pain is associated with diagnosis of chronic pain of head, face, mouth, neck and all the intraoral structures. Carvacrol, a naturally occurring isoprenoid with diverse class of biological activities including anti-inflammatory, analgesic, antitumor and antioxidant properties. Now, the antinociceptive effect was studied in mice pretreatment with carvacrol (CARV) and ß-cyclodextrin complex containing carvacrol (CARV-ßCD) in formalin-, capsaicin-, and glutamate- induced orofacial nociception. Mice were pretreated with vehicle (0.9% Nacl, p.o.), CARV (10 and 20mg/kg, p.o.), CARV-ßCD (10 and 20mg/kg, p.o.) or MOR (10mg/kg, i.p.) before the nociceptive behavior induced by subcutaneous injections (s.c.) of formalin (20µl, 2%), capsaicin (20µl, 2.5µg) or glutamate (20µl, 25µM) into the upper lip respectively. The interference on motor coordination was determined using rotarod and grip strength meter apparatus. CARV-ßCD reduced the nociceptive during the two phases of the formalin test, whereas CARV did not produced the reduction in face-rubbing behavior in the initial phase. CARV-ßCD (20mg/kg, p.o.) produced 49.3% behavior pain while CARV alone at 20mg/kg, p.o, produced 28.7% of analgesic inhibition in the second phase of formalin test. CARV, CARV-ßCD and Morphine (MOR) showed a significant reduction against nociception caused by capsaicin or glutamate injection. Thus the encapsulation of carvacrol in ß-cyclodextrin can acts as a considerable therapeutic agent with pharmacological interest for the orofacial pain management.