Search Results (46)

Background: Burning Mouth Syndrome (BMS) is a chronic orofacial pain condition characterized by a burning sensation in the oral cavity without identifiable lesions. It predominantly affects women (especially postmenopausal) but can occur in men. BMS is considered a multifactorial neuropathic pain disorder involving both peripheral small-fiber neuropathy and central dysregulation, often accompanied by taste alterations (dysgusia) and xerostomia despite normal oral exams. Treatment is challenging, with modest responses to agents like clonazepam, tricyclic antidepressants, or gabapentinoids. Observations: We present a 67-year-old male with recalcitrant primary BMS who showed complete remission temporally associated with occipital nerve blockade, likely affecting central trigeminocervical pathways. Initial therapy with amitriptyline (25 mg) and gabapentin (900 mg/day) yielded ~30% pain relief. Given suspected central sensitization, greater and lesser occipital nerve (GON) blocks were administered in series. After the first, second, and third ON blocks, pain was reduced by ~50%, 80%, and 100%, respectively. Remission persisted at one-year follow-up under continued medications. A mild recurrence (~20% of baseline pain) responded fully to a fourth GON block, maintaining another year of pain-free status. Lessons: This case underscores the complex central mechanisms in BMS and illustrates that modulating central pain circuits via occipital nerve blockade, through trigeminocervical convergence mechanisms, without direct trigeminal intervention. We discuss the diagnostic challenges of BMS, the rationale of occipital neuromodulation, and how this novel therapeutic strategy compares with current literature, supporting the hypothesis of central sensitization in BMS. Full article

Chronic pain is increasingly regarded as a condition of glia–neuronal dysregulation driven by persistent neuroinflammatory signaling. Following injury to nerves or tissues, glial cells, including astrocytes or satellite glial cells, undergo changes in their phenotype, thereby amplifying painful stimuli mediated by cytokines, chemokines, or ATP signaling. In response to injuries, activated microglia release several mediators such as BDNF, IL-1β, or TNF-α, thereby disrupting chloride homeostasis and inducing disinhibition in the dorsal horn, and sustaining maladaptive neuroimmune activity. Dysfunction of astrocytes, characterized by impaired glutamate clearance via excitatory amino acid transporter 2 and elevated C-X-C motif chemokine ligand 1 (CXCL1) and ATP release, drives neuronal sensitization, loss of neuroprotective metabolic support, and persistence of pain. In peripheral ganglia, connexin–43–mediated satellite glial cell coupling leads to hyperexcitability, resulting in neuropathic and orofacial pain and contributing to peripheral neuroinflammation. Presently, there is no unified framework for glial cell types, and the molecular mechanisms underlying microglial, astrocyte, and satellite glial cell contributions to the transition to chronic pain from acute pain are not completely elucidated. This review synthesizes current evidence on cellular and molecular mechanisms linking glial reactivity to pain chronification through sustained neuroinflammatory remodeling and impaired neuroprotection. It evaluates therapeutic strategies, including purinergic receptor P2X4 and toll-like receptor 4 antagonists, to metabolic reprogramming, exosome therapy, and neuromodulation, aimed at restoring homeostatic glial function and re-establishing neuroprotective glia–neuron interactions. A deeper understanding of the temporal and spatial dynamics of glial activation may enable personalized, non-opioid interventions that not only achieve durable analgesia but also prevent progressive neuroinflammatory damage and support long-term functional recovery. Full article

Nerve Growth Factor (NGF) is a neurotrophin essential for the maintenance and growth of sensory and sympathetic nerve fibers. In pathological conditions, NGF is widely implicated in peripheral and central sensitization mechanisms, significantly contributing to the genesis and maintenance of chronic pain. Anti-NGF monoclonal antibodies, developed for the management of osteoarthritis pain, have demonstrated clinical efficacy and good tolerability in several animal species, particularly dogs and cats. Although their use is currently limited to the management of osteoarthritis pain, preclinical and clinical evidence indicates their potential therapeutic role in other pathological conditions characterized by chronic pain, such as oncological conditions like osteosarcoma, idiopathic cystitis, inflammatory bowel disease, and neuropathies. This review aims to provide an updated overview of the potential clinical applications of anti-NGF monoclonal antibodies beyond osteoarthritis, analyzing their pathophysiological rationale, available scientific evidence, possible therapeutic advantages, and limitations that remain to be addressed. Full article

Background: Orofacial pain (OFP) and headache are common and disabling conditions in people with head and neck cancer (HNC), although their clinical characteristics and underlying pain mechanisms remain poorly studied, leading to worse diagnosis and, thus, management. Therefore, this review aims to synthesize the literature regarding clinical features, pain descriptors, mechanisms, and assessment tools of OFP and/or headache in adults with HNC. Methods: A scoping review was conducted following the Arksey and O’Malley framework and reported using PRISMA-ScR guidelines. We searched PubMed, Embase, Scopus, and Web of Science. Quantitative and qualitative original studies were included. Data were charted and summarized using narrative synthesis. Results: Of 3647 records initially retrieved, 32 studies met the inclusion criteria. Most studies were observational and heterogeneous in design, population, and pain assessment methods. OFP was highly prevalent, with neuropathic descriptors (e.g., burning, electric shocks, tingling) reported in 13.1% to 64.5% of patients, although heterogeneity in study design and tools used to assess this potential pain mechanism was high. Pain was frequently localized at the tumor site, although pain in other regions beyond the head and neck was also reported. Pain intensity was generally moderate, although varied across studies. OFP and headache in HNC patients were often neuropathic in nature and contributed significantly to disability and reduced quality of life. Most articles lacked mechanistic classifications of pain, although some suggested that central sensitization may be involved in some patients. Conclusions: Orofacial pain and headache are prevalent, under-characterized symptoms in HNC patients. There is an urgent need for standardized assessments using validated tools to improve phenotyping and inform targeted treatment strategies. Full article

Orofacial pain encompasses a spectrum of disorders ranging from musculoskeletal disorders, such as myofascial pain, and temporomandibular disorders to neuropathic situations, such as trigeminal neuralgia and painful post-traumatic trigeminal neuropathy, and neurovascular pain such as orofacial migraine and cluster orofacial pain. Each require tailored prophylactic pharmacotherapy, such as carbamazepine, gabapentin, pregabalin, amitriptyline, metoprolol, and topiramate. Yet a substantial subset of patients remains refractory. Botulinum toxin type A (BoNT-A) has demonstrated growing efficacy in the treatment of multiple forms of orofacial pain, which covers the whole range of these disorders. We describe the analgesic properties of BoNT-A for each of the three following orofacial pain disorders: neuropathic, myofascial, and neurovascular. Then, we conclude with a section on the neuromodulatory mechanisms of BoNT-A. This lays the basis for the generation of a hypothesis for the segmental therapeutic action of BoNT-A on the whole range of orofacial pain disorders. In addition, the advantage of BoNT-A for providing a safe sustained effect after a single application for chronic pain prophylaxis is discussed, as opposed to the daily use of current conventional prophylactic medications. Finally, we summarize the clinical applications of BoNT-A for chronic orofacial pain therapy. Full article

Background: Post-traumatic trigeminal neuropathic pain (PTTNP) is a chronic condition often caused by dental procedures such as implant placement or tooth extraction. It involves persistent pain and sensory disturbances, negatively affecting the quality of life of patients. Methods: This retrospective observational study was conducted at Chosun University Dental Hospital and included 120 patients diagnosed with PTTNP involving the orofacial region. Patient data were collected between January 2014 and December 2023. Among them, 79 patients (65.8%) developed PTTNP following dental implant placement, with a total of 121 implants analyzed. The inferior alveolar nerve was most frequently involved. Clinical factors, including the time to treatment, removal of the causative factor, the Sunderland injury grade, and the type of treatment, were evaluated. Pain intensity and sensory changes were assessed using the visual analog scale (VAS). Results: Treatment initiated within the early post-injury period, commonly regarded as within three months, and implant removal tended to improve outcomes. Pharmacological therapy was the most commonly employed modality, particularly gabapentinoids (e.g., gabapentin, pregabalin) and tricyclic antidepressants such as amitriptyline. However, combined therapy, which included pharmacologic, physical, and surgical approaches, was associated with the greatest sensory improvement. Conclusions: Prompt, multidisciplinary intervention may enhance recovery in patients with PTTNP. Implant-related injuries require careful management, and multimodal strategies appear more effective than monotherapies. Full article

The existing literature offers limited experimental evidence on the role of botulinum neurotoxin type E (BoNT-E) in pain transmission. The present study investigated the antinociceptive effects of subcutaneously administered BoNT-E in chronic orofacial pain conditions. This study used orofacial formalin-induced pronociceptive behavior and complete Freund’s adjuvant (CFA)-induced thermal hyperalgesia as inflammatory pain models in male Sprague Dawley rats. A neuropathic pain model was also developed by causing an injury to the inferior alveolar nerve. Subcutaneously administered BoNT-E (6, 10 units/kg) significantly reduced nociceptive behavior during the second phase of the formalin test compared to that of the vehicle treatment. These doses similarly alleviated thermal hypersensitivity in the CFA-treated rats. Moreover, BoNT-E (6, 10 units/kg) markedly attenuated mechanical allodynia in rats with an inferior alveolar nerve injury. At a dose of 10 units/kg, BoNT-E produced antinociceptive effects that became evident 8 h post-injection and persisted for 48 h. Notably, BoNT-E (10 units/kg) significantly reduced the number of c-fos-immunostained neurons in the trigeminal subnucleus caudalis of rats with an inferior alveolar nerve injury. In comparison, intraperitoneally administered gabapentin (30, 100 mg/kg) demonstrated significant mechanical anti-allodynic effects but exhibited lower analgesic efficacy than that of BoNT-E. These findings highlight the potential of BoNT-E as a therapeutic agent for chronic pain management. Full article

Orofacial pain (OFP) includes chronic pain conditions categorized into musculoskeletal (MS), neurovascular (NV), and neuropathic (NP) pain types, encompassing temporomandibular disorders (TMD), migraines, trigeminal neuralgia (TN), post-traumatic neuropathies, and burning mouth syndrome (BMS). These conditions significantly affect quality of life; yet, their underlying metabolic disruptions remain inadequately explored. Salivary metabolomics provides a non-invasive method to investigate biochemical alterations associated with OFP subtypes. This study aimed to identify pain-specific salivary metabolites across chronic OFP types and examine their correlations with clinical characteristics. Saliva samples from 63 OFP patients (TMD, migraines, TN, post-traumatic neuropathies, BMS) and 37 pain-free controls were analyzed using liquid chromatography–mass spectrometry (LC-MS) targeting 28 metabolites linked to pain. Statistical analyses determined significant metabolite changes and associations with pain subtypes and patient characteristics. Among the 28 analyzed metabolites, 18 showed significant differences between OFP patients and controls. Key amino acids, including DL-glutamic acid, DL-aspartic acid, DL-citrulline, spermidine, and DL-ornithine, were significantly elevated in MS, NV, and NP pain types compared to controls. Additionally, DL-glutamine, DL-valine, and DL-phenylalanine were distinctively elevated in TMD and migraine patients. BMS displayed fewer alterations, with significantly lower levels of DL-proline, DL-tryptophan, DL-glutamic acid, DL-asparagine, and DL-aspartic acid compared to other pain types but elevated spermidine levels relative to controls. Salivary metabolomics revealed distinct metabolic alterations in OFP subtypes, providing insights into potential biomarkers for diagnosis and monitoring. These findings offer a foundation for personalized approaches in OFP management, although further research is required to validate and expand these results. Full article

Burning mouth syndrome (BMS) is a chronic idiopathic orofacial pain disorder, characterized by persistent burning sensations and pain without clear pathological causes. Recent research suggests that small fiber neuropathy (SFN) may play a significant role in the neuropathic pain and sensory disturbances associated with BMS. Following PRISMA guidelines, this systematic review aims to evaluate and synthesize current evidence supporting SFN’s involvement in BMS. The protocol is registered in PROSPERO (CRD42024555839). The results show eight studies reported reductions in nerve fiber density in tongue biopsies (ranging from 30% to 60%), along with morphological changes indicative of small fiber damage. Additionally, an increase in TRPV1-positive, NGF-positive, and P2X3-positive fibers, overexpression of Nav1.7, and slight underexpression of Nav1.9 mRNA were observed in BMS patients. Quantitative Sensory Testing in seven studies revealed sensory abnormalities such as reduced cool detection and cold pain thresholds. Blink reflex and corneal confocal microscopy also indicated peripheral and central small fiber damage, along with increased artemin mRNA expression. The evidence strongly supports SFN as a key factor in the pathophysiology of BMS, particularly due to reductions in nerve fiber density and altered sensory thresholds. However, variability across studies highlights the need for larger, standardized research to establish causal relationships and guide therapeutic strategies. Full article

The trigeminal sensory system consists of the trigeminal nerve, the trigeminal ganglion, and the trigeminal sensory nuclei (the mesencephalic nucleus, the principal nucleus, the spinal trigeminal nucleus, and several smaller nuclei). Various sensory signals carried by the trigeminal nerve from the orofacial area travel into the trigeminal sensory system, where they are processed into integrated sensory information that is relayed to higher sensory brain areas. Thus, knowledge of the trigeminal sensory system is essential for comprehending orofacial pain. This review elucidates the individual nuclei that comprise the trigeminal sensory system and their synaptic transmission. Additionally, it discusses four types of orofacial pain and their relationship to the system. Consequently, this review aims to enhance the understanding of the mechanisms underlying orofacial pain. Full article

Despite the unique and complex nature of cancer pain, the activation of different ion channels can be related to the initiation and maintenance of pain. The transient receptor potential vanilloid 4 (TRPV4) is a cation channel broadly expressed in sensory afferent neurons. This channel is activated by multiple stimuli to mediate pain perception associated with inflammatory and neuropathic pain. Here, we focused on summarizing the role of TRPV4 in cancer etiology and cancer-induced pain mechanisms. Many studies revealed that the administration of a TRPV4 antagonist and TRPV4 knockdown diminishes nociception in chemotherapy-induced peripheral neuropathy (CIPN). Although the evidence on TRPV4 channels’ involvement in cancer pain is scarce, the expression of these receptors was reportedly enhanced in cancer-induced bone pain (CIBP), perineural, and orofacial cancer models following the inoculation of tumor cells to the bone marrow cavity, sciatic nerve, and tongue, respectively. Effective pain management is a continuous problem for patients diagnosed with cancer, and current guidelines fail to address a mechanism-based treatment. Therefore, examining new molecules with potential antinociceptive properties targeting TRPV4 modulation would be interesting. Identifying such agents could lead to the development of treatment strategies with improved pain-relieving effects and fewer adverse effects than the currently available analgesics. Full article

Painful traumatic trigeminal neuropathy (PTTN) is a chronic neuropathic pain that may develop following injury to the trigeminal nerve. Etiologies include cranio-orofacial trauma that may result from dental, surgical, or anesthetic procedures or physical trauma, such as a motor vehicle accident. Following nerve injury, there are various mechanisms, including peripheral and central, as well as phenotypic changes and genetic predispositions that may contribute to the development of neuropathic pain. In this article, we review current literature pertaining to the cellular processes that occur following traumatic damage to the trigeminal nerve, also called cranial nerve V, that results in chronic neuropathic pain. We examine the neurobiology and pathophysiology based mostly on pre-clinical animal models of neuropathic/trigeminal pain. Full article

Background: The efficacy of topical treatments in alleviating neuropathic pain is well-established. However, there is a paucity of research on topical interventions designed specifically for intra-oral application, where the tissue composition differs from that of exposed skin. Methods: This comprehensive review endeavors to assess the extant evidence regarding the efficacy of topical treatments in addressing neuropathic pain within the oral cavity. Utilizing combinations of search terms, we conducted a thorough search across standard electronic bibliographic databases—MEDLINE (via PubMed), Embase, Google Scholar, and Up to Date. The variables under scrutiny encompassed topical treatment, local intervention, chronic oral and orofacial pain, and neuropathic pain. All pertinent studies published in the English language between 1992 and 2022 were included in our analysis. Results: Fourteen relevant manuscripts were identified, primarily consisting of expert opinions and case reports. The comprehensive review suggests that topical treatments, especially when applied under a stent, could be effective in mitigating neuropathic pain in the oral area. However, it is crucial to conduct further studies to confirm these preliminary results. The limitations of the reviewed studies, mainly the reliance on expert opinions, small sample sizes, inconsistent study designs, and a lack of long-term follow-up data, highlight the need for more rigorous research. Conclusions: Although initial findings indicate topical treatments may be effective for oral neuropathic pain, the limitations of current studies call for more thorough research. Further comprehensive studies are essential to validate the efficacy of these treatments, standardize procedures, and determine long-term results. This will provide clearer guidance for treating chronic neuropathic pain in the oral cavity. Full article

Background: The aim of this paper is to provide a systematic review of the literature regarding the clinical use of botulinum toxin (BTX) to treat various orofacial neuropathic pain disorders (NP). Methods: A comprehensive literature search was conducted using Medline, Web of Science, and the Cochrane Library databases. Only randomized clinical trials (RCT) published between 2003 and the end of June 2023, investigating the use of BTX to treat NP, were selected. PICO guidelines were used to select and tabulate the articles. Results: A total of 6 RCTs were selected. Five articles used BTX injections to treat classical trigeminal neuralgia, and one to treat post-herpetic neuralgia. A total of 795 patients received BTX injections. The selected studies utilised different doses and methods of injections and doses. All the selected studies concluded superiority of BTX injections over placebo for reducing pain levels, and 5 out 6 of them highlighted an improvement in the patient’s quality of life. Most of the studies reported transient and mild side effects. Conclusion: There is evidence of the efficacy of BTX injections in orofacial pain management. However, improved study protocols are required to provide direction for the clinical use of BTX to treat various orofacial neuropathic pain disorders. Full article

Orofacial pain represents a multidisciplinary biomedical challenge involving basic and clinical research for which no satisfactory solution has been found. In this regard, trigeminal pain is described as one of the worst pains perceived, leaving the patient with no hope for the future. The aim of this review is to evaluate the latest discoveries on the involvement of neurotrophins in orofacial nociception, describing their role and expression in peripheral tissues, trigeminal ganglion, and trigeminal nucleus considering their double nature as “supporters” of the nervous system and as “promoters” of nociceptive transmission. In order to scan recent literature (last ten years), three independent researchers referred to databases PubMed, Embase, Google Scholar, Scopus, and Web of Science to find original research articles and clinical trials. The researchers selected 33 papers: 29 original research articles and 4 clinical trials. The results obtained by the screening of the selected articles show an interesting trend, in which the precise modulation of neurotrophin signaling could switch neurotrophins from being a “promoter” of pain to their beneficial neurotrophic role of supporting the nerves in their recovery, especially when a structural alteration is present, as in neuropathic pain. In conclusion, neurotrophins could be interesting targets for orofacial pain modulation but more studies are necessary to clarify their role for future application in clinical practice. Full article