Nature Communications (May 2025)

HSK21542 in patients with postoperative pain: two phase 3, multicentre, double-blind, randomized, controlled trials

  • Yinbo Zhong,
  • Younian Xu,
  • Qian Lei,
  • Mengchang Yang,
  • Saiying Wang,
  • Xiaoling Hu,
  • Haihui Xie,
  • Yalan Li,
  • Zhong Qin,
  • Zhengfeng Gu,
  • Jiaqiang Zhang,
  • Yuexin Wang,
  • Jinglei Wu,
  • Haiying Wang,
  • Yue Ming,
  • Zhongyuan Xia,
  • Haoyu Zhai,
  • Ke Jiang,
  • Peng Zhang,
  • Zhiping Wang,
  • Liangrong Wang,
  • Lin Li,
  • Zhigang Cheng,
  • Huayong Jiang,
  • Guonian Wang,
  • Jingli Chen,
  • Zhibin Zhao,
  • Xiangdong Chen,
  • Min Yan

DOI
https://doi.org/10.1038/s41467-025-60013-y
Journal volume & issue
Vol. 16, no. 1
pp. 1 – 13

Abstract

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Abstract HSK21542, a peripherally restricted kappa opioid receptor agonist, was evaluated for efficacy and safety in patients with postoperative pain following abdominal surgery. This was assessed in two phase 3, multicentre, randomized, double-blind, controlled trials (HSK21542-301 [ClinicalTrials.gov identifier, NCT04738357] and HSK21542-303 [ClinicalTrials.gov identifier, NCT05390905]) in China. HSK21542-301 was a dual-arm study comparing HSK21542 1.0 μg/kg with placebo, while HSK21542-303 involved three arms comparing HSK21542 1.0 μg/kg with tramadol 50 mg/dose and placebo. All treatments were administered intravenously. The primary endpoint was the time-weighted summed pain intensity differences over 24 h (SPID0-24 h). Both HSK21542-301 (least squares [LS] mean [± standard error], −39.1 [1.88] vs −27.4 [1.89]; P < 0.001) and HSK21542-303 (−64.0 [2.25] vs −45.9 [2.25]; P < 0.001) demonstrated superiority of HSK21542 over placebo in terms of SPID0-24 h, while HSK21542-303 showed non-inferiority to tramadol (LS mean difference, −1.1; 95% confidence interval, −7.4 to 5.1; P < 0.001). Furthermore, HSK21542 had a comparable safety profile to placebo, inducing fewer gastrointestinal adverse events compared with tramadol. Grade ≥3 treatment-emergent adverse events occurred in eight (5.9%) and three (2.3%) patients in the HSK21542 arm of HSK21542-301 and HSK21542-303, respectively. In conclusion, HSK21542 showed potent analgesic effect and was well tolerated in patients who underwent abdominal surgery and experienced postoperative pain.