Safinamide dual molecular mechanisms: sodium channel and glutamate modulation as a translational rationale for neuropathic pain – A narrative review

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Abstract Introduction Neuropathic pain is a chronic and debilitating condition characterized by maladaptive changes in peripheral and central nervous system pathways. It is driven by abnormal neuronal excitability and excitatory neurotransmission. Among the key contributors are voltage-gated sodium channels (VGSCs) and glutamatergic mechanisms, both of which play pivotal roles in peripheral and central sensitization. Content This narrative review was conducted through a structured literature search of PubMed/MEDLINE, Embase, Web of Science, Scopus, ClinicalTrials.gov , Google Scholar, and relevant gray literature sources. Search terms included safinamide, Xadago, sodium channels, Nav1.7, Nav1.8, glutamate, NMDA, AMPA, mGluR, EAAT, neuropathic pain, and neuropathy. English-language in vitro , animal, and human studies were considered, and evidence was synthesized according to mechanistic relevance, preclinical findings, clinical pain outcomes, and translational limitations. Summary Through selective interaction with inactivated sodium channel states that are common in hyperexcitable neurons and presynaptic regulation of glutamate without interfering with normal transmission. Safinamide is able to suppress ectopic discharges, decrease central sensitization, and alleviate neuroinflammation. Preclinical models reveal the strong dose-dependent antinociceptive activity, the restoration of sodium current densities, and the decreased evoked glutamate overflow. There are clinical studies of the populations with the PD that demonstrate that pain-related outcomes improve significantly and depend on the improvement of motor symptoms to a lesser extent. Safinamide’s balanced profile has the potential benefits of improved tolerability and multimodal activity compared to conventional sodium channel blockers or direct NMDA antagonists. Outlook Although the existing clinical evidence outside the context of Parkinson’s disease is still scarce, its pharmacodynamic characteristics make it possible to develop further studies in a variety of neuropathic pain syndromes using biomarker-based, randomized controlled trials.