Abstract

Acute postoperative pain remains undertreated for many patients, sustaining exposure to opioids and associated harms. Voltage-gated sodium channel NaV1.8 is a key driver of nociceptor excitability under inflammatory conditions, making it an attractive peripheral target for analgesia. This narrative review synthesizes mechanistic, translational, and clinical evidence on selective NaV1.8 inhibition, focusing on suzetrigine (VX-548). We summarize channel physiology and binding mechanisms, appraise emerging pharmacodynamic biomarkers that index small-fiber activity, and examine early clinical data that suggest analgesic benefit with the potential to reduce opioid requirements. We also outline boundaries of effect where centrally maintained pain or small-fiber loss may limit response, and we discuss safety considerations relevant to perioperative use. Taken together, the evidence supports a precision-guided approach in which selective NaV1.8 blockade is paired with standardized sensory biomarkers and clinically meaningful outcomes such as pain trajectories, functional recovery, and opioid stewardship metrics. Suzetrigine’s profile positions it as a promising candidate within a broader shift toward targeted, non-opioid analgesics that act at the source of nociceptive drive while preserving cognition and motor function.