Targeting Sensory Neuropathies Through Neurotrophin-Based Approaches.

Chronic temporomandibular disorders (TMD) represent a heterogeneous group of musculoskeletal conditions involving the temporomandibular joint (TMJ), masticatory muscles, and associated structures (). Pain trajectories among TMD patients vary; approximately 15% develop chronic pain lasting for at least three months (), 20% of which progress to refractory chronic pain (R-TMD) (, ). R-TMD is characterized by persistent or worsening symptoms which are unresponsive to standard multimodal therapies (). Chronic TMD is typically managed with a multimodal approach, including pharmacologic and behavioral interventions, therapies, and occasionally surgery (). Self-care and oral analgesics are first-line strategies and play critical roles in chronic pain management, in addition to the pharmacologic approach. However, these therapies often provide inadequate relief, contributing to significant individual and societal burdens for patients with R-TMD (). Moreover, prolonged use raises concerns about adverse effects (). The advanced management strategies of R-TMD are further complicated by comorbidities (). Evidence suggests impaired endogenous pain modulation contributes to persistence and treatment resistance. Psychosocial factors, including cognitive difficulties, pain-related rumination, depressive symptoms, and reduced quality of life, also contribute to pain maintenance and functional impairment (). Neuromodulation encompasses implantable and non-implantable technologies, electrical or chemical, for the purpose of improving quality of life and functioning of humans (, ). It is applied across conditions such as chronic pain, psychiatric disorders, and neurological diseases, offering a targeted alternative to -or potentially enhancing—the pharmacologic treatments with different side effect profiles (). Vagal nerve stimulation (VNS), first introduced in the late 1990s for refractory epilepsy (), was FDA-approved in 1997 for refractory epilepsy and in 2005 for treatment-resistant depression (). Traditional VNS requires surgical implantation, but non-invasive VNS (nVNS) has since been developed to stimulate the vagus nerve at the cervical level (in the neck) (, ) or via auricular branches (around the ear) (, ). The FDA cleared non-invasive VNS in the late 2010's for cluster headache and migraine (). Unlike transcutaneous electrical stimulation (TENS) which provide short-term localized pain relief, VNS targets afferent pathways to induce long-term modulation of central nervous system activity, offering broader and longer-lasting effects on neurological, psychiatric, and autonomic functions.