Efficacy and Safety of Anrikefon (HSK21542) for Postoperative Pain. A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Postoperative pain remains one of the most prevalent and inadequately managed complications after surgery. Conventional μ-opioid agonists, while effective, carry risks of dependence, and gastrointestinal intolerance. Anrikefon (HSK21542), a novel peripherally restricted κ-opioid receptor agonist, offers potent analgesia without central opioid-related adverse effects. However, evidence across clinical trials remains fragmented. To address this gap, we conducted this systematic review and meta-analysis. Comprehensive searches of PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov through November 2025, identified three Randomized Controlled Trials (n = 718) evaluating intravenous Anrikefon (1.0 µg/kg) versus placebo for postoperative pain. Pooled analysis using random-effects models demonstrated a significant improvement in SPID₀-₂₄h with Anrikefon (MD = -14.73; 95% CI -21.7 to -7.75; p < 0.0001), and reduced rescue analgesic use within 12 h (RR = 0.59; 95% CI 0.49-0.71; p < 0.00001). The proportion of patients achieving Numerical Rating Scale (NRS) ≤ 3 at 12 h was higher with Anrikefon (RR = 1.37; 95% CI 1.07-1.75; p = 0.01). The overall incidence of Treatment-Emergent Adverse Events (TEAEs) and postoperative nausea and vomiting (PONV) was low, with one trial reporting non-inferior efficacy and notably fewer gastrointestinal adverse events compared with intravenous tramadol (50 mg). These findings support Anrikefon as a promising adjunct with potentially lower risk for dependence, warranting further large-scale and comparative investigations.