The real-world safety evaluation of the selective NaV1.8 inhibitor suzetrigine: disproportionality analysis and flexible empirical bayes signals from FAERS with external triangulation.

Background: Suzetrigine (Journavx; VX-548), the first selective NaV1.8 voltage-gated sodium channel inhibitor approved by the FDA on 30 January 2025, represents a novel non-opioid option for moderate-to-severe acute pain. Given its recent market entry and unique peripheral mechanism, comprehensive post-marketing safety surveillance is essential. Objective: This study aimed to identify and characterize adverse event signals associated with suzetrigine in the FDA Adverse Event Reporting System (FAERS) using advanced disproportionality and comparator-referenced empirical Bayes (EB) methods, with external triangulation against published literature and WHO VigiBase data. Methods: We analyzed FAERS reports through the first 8 months post-approval. Disproportionality metrics (ROR, PRR, IC) were supplemented by a comparator-referenced EB profiling approach that incorporated suzetrigine, acetaminophen, ibuprofen, and background "other drugs," generating 3,000 posterior draws per preferred term (PT). Signals with EB q05 > 2 and no comparator overlap were classified as suzetrigine-unique. High-priority PTs were triangulated with Phase II/III trial data, systematic reviews, case reports, and VigiBase report counts (February 2026). Results: Of 19 prioritized PTs, 14 were suzetrigine-unique. Dominant clusters included sensory disturbances (paresthesia, burning sensation, skin burning sensation, hypoaesthesia; EB q05 11.43-31.16), musculoskeletal events (muscle spasms EB q05 31.15), and cutaneous reactions (pruritus, rash). These signals were mechanistically consistent with peripheral NaV1.8 blockade of nociceptors and pruriceptors. Literature and VigiBase data corroborated neurological/sensory and musculoskeletal signals; psychiatric signals (euphoric mood, abnormal dreams) lacked external support and were deprioritized. Conclusion: This real-world pharmacovigilance analysis identifies a distinct safety signature for suzetrigine, with neurological and sensory disturbances (e.g., paresthesia, burning sensation, skin burning sensation, hypoaesthesia) emerging as prominent signals not fully characterized in pre-approval trials, whereas musculoskeletal and cutaneous events largely align with labeled reactions. These hypothesis-generating findings highlight the need for focused post-marketing surveillance on neurological/sensory preferred terms through prospective cohort studies and Phase IV trials to quantify incidence, identify risk factors, and optimize risk-minimization strategies for this promising non-opioid analgesic.