Targeting Na_v Channels for Pain Relief: Structural Insights and Therapeutic Opportunities

Pain is an unpleasant but essential sensory experience that serves as a protective mechanism, yet it can also manifest maladaptively in a wide range of pathological conditions. Current analgesic strategies rely heavily on opioid medications and non-steroidal anti-inflammatory drugs (NSAIDs); however, concerns regarding addiction, tolerance, and dose-limiting adverse effects highlight the urgent need for safer and more effective therapeutics. Voltage-gated sodium (Na_v) channels, which govern the initiation and propagation of action potentials, have emerged as promising targets for mechanism-based analgesic development. In particular, the Na_v1.7-Na_v1.9 subtypes have attracted substantial interest owing to their enrichment in the peripheral nervous system-despite broader expression elsewhere-and their central roles in nociception, offering the potential for non-addictive, subtype-selective pain modulation. This review summarizes the physiological roles of these channels in nociception, examines how disease-associated mutations shape pain phenotypes, and highlights recent advances in drug discovery targeting Na_v1.7 and Na_v1.8. The recent FDA approval of VX-548 (suzetrigine), a first-in-class and highly selective Na_v1.8 inhibitor, marks a major milestone that validates peripheral Na_v channels as clinically actionable targets for analgesia. We also discuss the remaining challenges and emerging opportunities in the pursuit of next-generation, mechanism-informed analgesics.