Recent advances in the understanding of the aetiology and therapeutic strategies in burning mouth syndrome: Focus on the actions of cannabinoids.

Burning mouth syndrome (BMS) is a neuropathic pain disorder associated with a burning sensation on oral mucosal surfaces with frequently reported xerostomia, dysgeusia and tingling or paraesthetic sensations. However, patients present no clinically evident causative lesions. The poor classification of the disorder has resulted in a diagnostic challenge, particularly for the clinician/dentist evaluating these individuals. Major research developments have been made in the BMS field in recent years to address this concern, principally in terms of the pathophysiological mechanisms underlying the disorder, in addition to therapeutic advancements. For the purpose of this review, an update on the pathophysiological mechanisms will be discussed from a neuropathic, immunological, hormonal and psychological perspective. This review will also focus on the many therapeutic strategies that have been explored for BMS, including antidepressants/antipsychotics, non-steroidal anti-inflammatories, hormone replacement therapies, phytotherapeutic compounds and non-pharmacological interventions, overall highlighting the lack of controlled clinical studies to support the effectiveness of such therapeutic avenues. Particular focus is given to the cannabinoid system and the potential of cannabis-based therapeutics in managing BMS patients.

Potential Molecular Targets for Treating Neuropathic Orofacial Pain Based on Current Findings in Animal Models.

This review highlights potential molecular targets for treating neuropathic orofacial pain based on current findings in animal models. Preclinical research is currently elucidating the pathophysiology of the disease and identifying the molecular targets for better therapies using animal models that mimic this category of orofacial pain, especially post-traumatic trigeminal neuropathic pain (PTNP) and primary trigeminal neuralgia (PTN). Animal models of PTNP and PTN simulate their etiologies, that is, trauma to the trigeminal nerve branch and compression of the trigeminal root entry zone, respectively. Investigations in these animal models have suggested that biological processes, including inflammation, enhanced neuropeptide-mediated pain signal transmission, axonal ectopic discharges, and enhancement of interactions between neurons and glial cells in the trigeminal pathway, are underlying orofacial pain phenotypes. The molecules associated with biological processes, whose expressions are substantially altered following trigeminal nerve damage or compression of the trigeminal nerve root, are potentially involved in the generation and/or exacerbation of neuropathic orofacial pain and can be potential molecular targets for the discovery of better therapies. Application of therapeutic candidates, which act on the molecular targets and modulate biological processes, attenuates pain-associated behaviors in animal models. Such therapeutic candidates including calcitonin gene-related peptide receptor antagonists that have a reasonable mechanism for ameliorating neuropathic orofacial pain and meet the requirements for safe administration to humans seem worth to be evaluated in clinical trials. Such prospective translation of the efficacy of therapeutic candidates from animal models to human patients would help develop better therapies for neuropathic orofacial pain.

Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain.

Neuropathic pain conditions including neuropathic orofacial pain (NOP) are difficult to treat. Contemporary therapeutic agents for neuropathic pain are often ineffective in relieving pain and are associated with various adverse effects. Finding new options for treating neuropathic pain is a major priority in pain-related research. Cannabinoid-based therapeutic strategies have emerged as promising new options. Cannabinoids mainly act on cannabinoid 1 (CB1) and 2 (CB2) receptors, and the former is widely distributed in the brain. The therapeutic significance of cannabinoids is masked by their adverse effects including sedation, motor impairment, addiction and cognitive impairment, which are thought to be mediated by CB1 receptors in the brain. Alternative approaches have been developed to overcome this problem by selectively targeting CB2 receptors, peripherally restricted CB1 receptors and endocannabinoids that may be locally synthesized on demand at sites where their actions are pertinent. Many preclinical studies have reported that these strategies are effective for treating neuropathic pain and produce no or minimal side effects. Recently, we observed that inhibition of degradation of a major endocannabinoid, 2-arachydonoylglycerol, can attenuate NOP following trigeminal nerve injury in mice. This review will discuss the above-mentioned alternative approaches that show potential for treating neuropathic pain including NOP.

Plasma IL-8 signature correlates with pain and depressive symptomatology in patients with burning mouth syndrome: Results from a pilot study.

BACKGROUND: Burning mouth syndrome (BMS) is a neuropathic orofacial pain condition of unknown aetiology that encompasses intra-oral burning pain without abnormal clinical findings. Psychological, neural and inflammatory processes are associated with BMS pathogenesis. Currently, studies characterising plasma cytokine/chemokine profiles with pain and depression in patients with BMS are lacking. Considering that inflammation is associated with the pathophysiology of BMS, and that inflammation is closely associated with pain and depression, we aimed to correlate depressive symptomatology and oral cavity pain with plasma cytokine/chemokine signatures in a cohort of patients with BMS. METHODS: In this study, plasma protein levels of Th1 cytokines (IFN-γ, IL-2, IL-12p70, TNF-α), Th2 cytokines (IL-4, IL-10, IL-6, IL-13) and the chemokine IL-8 were assessed in patients with BMS (n = 10) and healthy volunteers (n = 10), using pro-inflammatory-10-plex assays. Clinical histories, alongside self-rated oral cavity pain intensities and depressive symptomatology were assessed using a visual analogue scale and the 16-item Quick Inventory of Depressive Symptomatology questionnaires, respectively. RESULTS: We present evidence that BMS is associated with increased depressive symptomatology and enhanced oral cavity pain. Plasma isolated from BMS patients display enhanced expression of the pro-inflammatory chemokine IL-8, when compared to plasma from healthy individuals. Plasma IL-8 signature correlates with pain and depressive symptomatology in the study cohort. CONCLUSIONS: Overall, these findings indicate that plasma IL-8 profiles are dysregulated in BMS and that modulation of IL-8 production in the disorder may be a tool in the management of BMS symptomatology.

Plasma N-acylethanolamine and endocannabinoid levels in burning mouth syndrome: Potential role in disease pathogenesis.

OBJECTIVE: The objective was to measure endocannabinoid (eCB) ligands and non-cannabinoid N-acylethanolamine (NAE) molecules in plasma from individuals with burning mouth syndrome (BMS) and to determine whether plasma eCB/NAE levels correlated with pain, inflammation and depressive symptomatology in this cohort. STUDY DESIGN: Plasma content of the eCBs, anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), and the NAE molecules, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were assessed in healthy subjects (n = 8) and in a cohort of newly diagnosed BMS patients (n = 9) using liquid chromatography-tandem mass spectrometry. Plasma eCBs and NAE profiles were correlated with self-rated oral cavity pain intensities, depressive symptomatology and plasma IL-8 levels. RESULTS: Plasma levels of PEA, but not OEA, AEA or 2-AG, were significantly elevated in patients with BMS, when compared to plasma from healthy individuals. Plasma PEA, OEA and AEA levels correlated with depressive symptomatology. CONCLUSIONS: This is the first evidence to indicate that circulating eCB/NAE levels are altered in BMS.

Neuron-Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region.

Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate-glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron-glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP.

Non-neuronal cells act as crucial players in neuropathic orofacial pain.

BACKGROUND: Following peripheral nerve damage, various non-neuronal cells are activated, triggering accumulation in the peripheral and central nervous systems, and communicate with neurons. Evidence suggest that neuronal and non-neuronal cell communication is a critical mechanism of neuropathic pain; however, its detailed mechanisms in contributing to neuropathic orofacial pain development remain unclear. HIGHLIGHT: Neuronal and non-neuronal cell communication in the trigeminal ganglion (TG) is believed to cause neuronal hyperactivation following trigeminal nerve damage, resulting in neuropathic orofacial pain. Trigeminal nerve damage activates and accumulates non-neuronal cells, such as satellite cells and macrophages in the TG and microglia, astrocytes, and oligodendrocytes in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2). These non-neuronal cells release various molecules, contributing to the hyperactivation of TG, Vc, and C1-C2 nociceptive neurons. These hyperactive nociceptive neurons release molecules that enhance non-neuronal cell activation. This neuron and non-neuronal cell crosstalk causes hyperactivation of nociceptive neurons in the TG, Vc, and C1-C2. Here, we addressed previous and recent data on the contribution of neuronal and non-neuronal cell communication and its involvement in neuropathic orofacial pain development. CONCLUSION: Previous and recent data suggest that neuronal and non-neuronal cell communication in the TG, Vc, and C1-C2 is a key mechanism that causes neuropathic orofacial pain associated with trigeminal nerve damage.

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.

Post-traumatic Trigeminal Neuropathy Associated With Endodontic Therapy: A Systematic Review.

A painful or non-painful trigeminal nerve lesion brought on by trauma that exhibits symptoms and/or clinical evidence of trigeminal nerve dysfunction is known as painful post-traumatic trigeminal neuropathy (PTTN). In relation to this, the term post-traumatic persistent dentoalveolar pain (PDAP) is an idiopathic condition of chronic neuropathic origin that manifests as a diagnostic challenge for dental practitioners. Neuropathic pain is defined by the International Association for the Study of Pain (IASP) as "pain initiated or caused by a primary lesion or dysfunction in the nervous system." PDAP is located primarily in the teeth and jaws. This study systematically reviews how likely it is to get painful PTTN if the patient received endodontic therapy and the duration between doing root canal therapy (RCT) and getting PTTN. A systematic review was carried out using key search terms from PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) with English as the only permitted language. There were strict inclusion requirements. The 10 articles that were included showed a prevalence of an endodontic procedure anywhere from three to 48 months following post-endodontic treatment, and it mainly affects females in their mid-40s with no variation regarding the areas, whether it is in the maxilla or mandible. The lack of information about the association between RCT and PTTN led practitioners to make wrong diagnoses, which made the patient unwilling to seek further help. So, in this review, we identified some visible characteristics that can help in that process.

Trigeminal Neuralgia: Basic and Clinical Aspects.

The trigeminal nerve is the largest of all cranial nerves. It has three branches that provide the main sensory innervation of the anterior two-thirds of the head and face. Trigeminal neuralgia (TN) is characterized by sudden, severe, brief, and stabbing recurrent episodes of facial pain in one or more branches of the trigeminal nerve. Pain attacks can occur spontaneously or can be triggered by non-noxious stimuli, such as talking, eating, washing the face, brushing teeth, shaving, a light touch or even a cool breeze. In addition to pain attacks, a proportion of the patients also experience persistent background pain, which along with autonomic signs and prolonged disease duration, represent predictors of worse treatment outcomes. It is now widely accepted that the presence of a neurovascular compression at the trigeminal root entry zone is an anatomic abnormality with a high correlation with classical TN. However, TN may be related to other etiologies, thus presenting different and/or additional features. Since the 1960s, the anticonvulsant carbamazepine is the drug of choice for TN treatment. Although anti-epileptic drugs are commonly used to treat neuropathic pain in general, the efficacy of carbamazepine has been largely limited to TN. Carbamazepine, however, is associated with dose-limiting side-effects, particularly with prolonged usage. Thus, a better understanding and new treatment options are urgently warranted for this rare, but excruciating disease.

Psychotherapy in the treatment of chronic refractory orofacial pain. Case reports / Psicoterapia no tratamento da dor orofacial crônica refratária. Relato de casos

ABSTRACT BACKGROUND AND OBJECTIVES: Psychological intervention can contribute to repairing the quality of life and altering behavior while dealing with chronic orofacial pain, especially those that can become refractory to treatments. Thus, the objective of this study was to present the narratives of three patients with refractory chronic neuropathic pain during the process of psychotherapeutic intervention and the follow-up results. CASE REPORTS: Pain behavior, pain perception and depressive and anxious symptoms were assessed. Patients were under treatment at the Orofacial Pain Clinic and the instruments used in the beginning and end of psychotherapy were the visual analog scale, Beck Inventories (anxiety and depression), Wisconsin Pain Inventory, McGill Pain Questionnaire and Pain Catastrophizing Scale. They attended weekly 50-minute sessions. Each narrative was qualitatively analyzed and the comparison between the evaluations made before and after psychotherapy was included in the context of a phenomenological approach. CONCLUSION: Emotional familiar conflicts and fear of pain crises were the most important aspects described by these patients. Case 1 presented the less cooperative profile and secondary gains. Despite of that, all cases presented improvement and psychotherapy helped to cope with their problems and pain. There was a remarkable impact on the life of patients as well as on their cooperation with pain treatments while helping the patients to build a proactive attitude and to understand their role in their condition.

RESUMO JUSTIFICATIVA E OBJETIVOS: A intervenção psicoterapêutica é uma ferramenta importante para melhorar a qualidade de vida de pacientes com dor orofacial crônica, especialmente aqueles que se tornam refratários aos tratamentos. Assim, o objetivo deste estudo foi apresentar, na forma de narrativa, três casos de pacientes com dor facial refratária ao longo do processo de intervenção psicoterapêutica e os resultados obtidos. RELATO DOS CASOS: Observou-se o comportamento, a percepção da dor e sintomas ansiosos e depressivos. Os pacientes estavam sob tratamento na Equipe de Dor Orofacial e os instrumentos utilizados no início e no final da intervenção foram a escala visual analógica, os Inventários de Beck para Ansiedade e Depressão, o Inventário de Dor de Wisconsin, o Questionário de Dor McGill e a Escala de Catastrofização de Dor. Os pacientes foram atendidos semanalmente em sessões de 50 minutos. Cada narrativa foi analisada qualitativamente e a comparação entre as avaliações (antes e depois do tratamento) foi incluída em um contexto de abordagem fenomenológica. CONCLUSÃO: Conflitos familiares emocionais e medo das crises de dor foram os aspectos mais importantes descritos pelos pacientes. O caso 1 apresentou um perfil menos cooperador, embora todos tenham apresentado melhora em algum âmbito avaliado. A proposta psicoterapêutica os auxiliou no enfrentamento do sofrimento por conta de seus problemas e da dor. Houve um impacto notável na vida dos pacientes como em sua cooperação com os tratamentos, uma vez que aprender a lidar com seu sofrimento os conduziu a uma postura mais proativa através do entendimento de seus papéis no tratamento da condição dolorosa.

Spatial and Temporal Brain Responses to Noxious Heat Thermal Stimuli in Burning Mouth Syndrome.

Burning mouth syndrome (BMS) is an idiopathic orofacial pain condition. Although the pathophysiology of BMS is not clearly understood, central and peripheral neuropathic mechanisms are thought to be involved. The authors compared brain response to noxious heat stimuli in 16 right-handed women with primary BMS and 15 sex- and age-matched right-handed healthy female controls. A thermal stimulus sequence of 32 °C to 40 °C to 32 °C to 49 °C was repeated 4 times in a cycle. Warm and noxious heat stimuli were delivered with a Peltier thermode placed on the right palm or right lower lip for 32 s each in a session. Functional magnetic resonance imaging data were obtained by recording echoplanar images with a block design. Statistical Parametric Mapping 8 software was used to analyze the data. Patients and controls both reported feeling more pain during palm stimulation than during lip stimulation. Repetition of noxious heat stimulus on the lower lip but not on the palm induced habituation in brain activity in the cingulate cortex without reduction in pain perception. Multiple regression analysis revealed a correlation between perceived pain intensity and suppression of brain activity in the anterior cingulate cortex when the repeated thermal sequence was applied at the lower lip. Furthermore, the response of the parahippocampal area differed in BMS patients and controls when the same repeated thermal sequence was applied at the palm. The authors' findings indicate that BMS patients show specific brain responses due to impaired function of the central and peripheral nervous systems (clinical trial registration: UMIN000015002).

Neuropathic orofacial pain: cannabinoids as a therapeutic avenue.

Neuropathic orofacial pain (NOP) exists in several forms including pathologies such as burning mouth syndrome (BMS), persistent idiopathic facial pain (PIFP), trigeminal neuralgia (TN) and postherpetic neuralgia (PHN). BMS and PIFP are classically diagnosed by excluding other facial pain syndromes. TN and PHN are most often diagnosed based on a typical history and presenting pain characteristics. The pathophysiology of some of these conditions is still unclear and hence treatment options tend to vary and include a wide variety of treatments including cognitive behaviour therapy, anti-depressants, anti-convulsants and opioids; however such treatments often have limited efficacy with a great amount of inter-patient variability and poorly tolerated side effects. Analgesia is one the principal therapeutic targets of the cannabinoid system and many studies have demonstrated the efficacy of cannabinoid compounds in the treatment of neuropathic pain. This review will investigate the potential use of cannabinoids in the treatment of symptoms associated with NOP.