Suzetrigine (a NaV1.8 inhibitor) versus placebo for acute postoperative pain: A systematic review and meta-analysis of randomized controlled trials

BACKGROUND: NaV1.8 channels, expressed in peripheral nociceptors, mediate sustained pain signaling. Their inhibition offers a potential opioid-sparing strategy for postoperative pain, although efficacy and safety remain incompletely defined. We synthesized randomized evidence for suzetrigine versus placebo in postoperative pain. METHODS: We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant meta-analysis of randomized controlled trials comparing suzetrigine (a NaV1.8 inhibitor) versus placebo in surgical patients. The primary outcome was 24-hour pain with the Numeric Pain Rating Scale; secondary outcomes included 48-hour pain, change-from-baseline, and adverse events. Risk of bias was assessed with the Cochrane Risk of Bias 2 tool, and for analyses, we used Hartung-Knapp models with heterogeneity and prediction intervals reported. Random-effects models used Hartung-Knapp adjustments (2-sided α = 0.05). RESULTS: We included 4 randomized datasets across 2 phase 3 publications (n = 1584; 1009 intervention, 575 placebo). The mean participant age was 44.9 years; 92.3% were women. Procedures included abdominoplasty (n = 823) and bunionectomy (n = 761). Suzetrigine significantly reduced pain at 24 hours (mean difference = -0.93; 95% confidence interval [CI], -1.38 to -0.48; I2 = 66.0%) and 48 hours (mean difference = -1.02; 95% CI, -1.32 to -0.72; I2 = 11.8%). Analyses of change-from-baseline confirmed consistent benefit. Subgroup analyses revealed similar effects across surgery types. A lower incidence of nausea (risk ratio = 0.63; 95% CI, 0.42-0.95) and dizziness (risk ratio = 0.57; 95% CI, 0.34-0.96) was observed in the suzetrigine group, with no significant differences in headache, vomiting, or constipation. Meta-regressions showed no moderation by sample size or publication year. Risk of bias was low in 2 studies and raised "some concerns" in 2. CONCLUSION: Suzetrigine produced modest reductions in pain at 24 to 48 hours versus placebo. Because opioid consumption was not consistently reported, no conclusions can be drawn regarding opioid-sparing.