Targeting Nav 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 (Nav) channels, which govern the initiation and propagation of action potentials, have emerged as promising targets for mechanism-based analgesic development. In particular, the Nav1.7–Nav1.9 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 Nav1.7 and Nav1.8. The recent FDA approval of VX-548 (suzetrigine), a first-in-class and highly selective Nav1.8 inhibitor, marks a major milestone that validates peripheral Nav 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.