From ion channel biology to clinical practice: suzetrigine as a precision analgesic
Abstract
Acute pain remains one of the most prevalent and burdensome clinical challenges requiring pharmacological intervention, yet opioids — with their well-documented risks of respiratory depression, addiction, and overdose — remain a cornerstone of moderate-to-severe pain management in the absence of efficacious alternatives. Suzetrigine (VX-548) is a novel preferential inhibitor of the voltage-gated sodium channel isoform Nav1.8, recently approved by the US Food and Drug Administration for the treatment of moderate-to-severe acute pain. Through specific inhibition of Nav1.8, which is expressed predominantly in nociceptive sensory neurons of the peripheral nervous system, suzetrigine offers a mechanistically targeted approach to reduce pain at the level of the primary afferent, bypassing the central nervous system circuitry involved in opioid-associated adverse effects. In this review, we examine both the scientific foundation and clinical utility of suzetrigine, integrating evidence from molecular and structural biology, electrophysiology, preclinical animal models, and Phase II and III randomized controlled clinical trials. We discuss the unique allosteric mechanism by which suzetrigine selectively inhibits Nav1.8 to suppress nociceptor excitability, and review six trials, five of which show evidence demonstrating significant analgesic efficacy relative to placebo, and a favorable safety profile. We discuss key limitations of the current clinical evidence base including modest,…
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