Pharmacological Research (Feb 2025)
Efficacy and safety of SHR8554 on postoperative pain in subjects with moderate to severe acute pain following orthopedic surgery: A multicenter, randomized, double-blind, dose-explored, active-controlled, phase II/III clinical trial
- Yanhua Zhao,
- Zhisheng Lu,
- Xuesong Song,
- Haihui Xie,
- Xungang Xiao,
- Guonian Wang,
- Qi Zhou,
- Qingmei Zhang,
- Liang Liu,
- Zhijian Lan,
- Ning Bai,
- Haiyan Wang,
- Zhihao Pan,
- Liang Dong,
- Xianzhong Lin,
- Gang Chen,
- Qinghui Wang,
- Jiangtao Dong,
- Jia Deng,
- Yongshan Nan,
- Jiaqiang Zhang,
- Xiaohua Zhou,
- Yanjuan Huang,
- Yongquan Chen,
- Huanzhong He,
- Ye Yang,
- Dengpan Yao,
- Jintai Jia,
- Shuan Jin,
- Yafeng Zhang,
- Zhonghui Luo,
- Jiangang Li,
- Linzhong Zhang,
- Fang Wang,
- Juehua Jing,
- Jiang Zhu,
- Lin Li,
- Guangda Wang,
- Huajing Guo,
- Qiang Wang,
- Diansan Su,
- Weifeng Yu,
- Xiyao Gu
Affiliations
- Yanhua Zhao
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China
- Zhisheng Lu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China
- Xuesong Song
- Department of Anesthesiology, First Hospital of Jilin University, Changchun, China
- Haihui Xie
- Department of Anesthesiology, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People’s Hospital), Dongguan, China
- Xungang Xiao
- Department of Orthopedics, Chenzhou First People's Hospital, Chenzhou, China
- Guonian Wang
- Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
- Qi Zhou
- Department of Anesthesiology, Chifeng Municipal Hospital, Chifeng, China
- Qingmei Zhang
- Department of Anesthesiology, Chaohu Hospital of Anhui Medical University, Hefei, China
- Liang Liu
- Department of Orthopedics, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, China
- Zhijian Lan
- Department of Anesthesiology, Jinhua Municipal Central Hospital, Jinhua, China
- Ning Bai
- Department of Anesthesiology, Shaanxi Provincial People's Hospital, Xi-an, China
- Haiyan Wang
- Department of Anesthesiology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- Zhihao Pan
- Department of Anesthesiology, Li Hui li Hospital of Ningbo Medical Center, Ningbo, China
- Liang Dong
- Department of Anesthesiology, Liuzhou People's Hospital Affiliated to Guangxi Medical University, Liuzhou, China
- Xianzhong Lin
- Department of Anesthesiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Gang Chen
- Department of Orthopedics, The Second hospital of Jiaxing, Jiaxing, China
- Qinghui Wang
- Department of Anesthesiology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
- Jiangtao Dong
- Department of Orthopedics, Hebei Medical University Third Hospital, Shijiazhuang, China
- Jia Deng
- Department of Anesthesiology, Sichuan Provincial People's Hospital, Chengdu, China
- Yongshan Nan
- Department of Anesthesiology, Yanbian University Hospital, Yanji, China
- Jiaqiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital (Zhengzhou University People’s Hospital), Zhengzhou, China
- Xiaohua Zhou
- Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- Yanjuan Huang
- Department of Anesthesiology, The Third Affiliated Hospital of Guangxi Medical University, Nanning, China
- Yongquan Chen
- Department of Anesthesiology, The First Affiliated Hospital of Wannan Medical College, Wuhu, China
- Huanzhong He
- Department of Anesthesiology, Huzhou Central Hospital, Huzhou, China
- Ye Yang
- Department of Anesthesiology, Beijing Jishuitan Hospital Guizhou Hospital, Guizhou, China
- Dengpan Yao
- Department of Articular Orthopedics, Hefei First People's Hospital, Hefei, China
- Jintai Jia
- Department of Anesthesiology, Heping Hospital Attached to Changzhi Medical College, Changzhi, China
- Shuan Jin
- Department of Anesthesiology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
- Yafeng Zhang
- Department of Articular Orthopaedics, Wuxi Traditional Chinese Medicine Hospital, Wuxi, China
- Zhonghui Luo
- Department of Anesthesiology, The First Affiliated Hospital of University of South China, Hengyang, China
- Jiangang Li
- Department of Anesthesiology, Qujing No.1 Hospital, Qujing, China
- Linzhong Zhang
- Department of Anesthesiology, Second hospital of Shanxi Medical University, Taiyuan, China
- Fang Wang
- Department of Anesthesiology, Honghui Hospital, Xi-an, China
- Juehua Jing
- Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Jiang Zhu
- Department of Anesthesiology, The Second Hospital Affiliated to Suzhou University, Suzhou, China
- Lin Li
- Department of Anesthesiology, General Hospital of the Northern Theater of the Chinese People's Liberation Army, Shenyang, China
- Guangda Wang
- Department of Orthopedics, Yantai Yuhuangding Hospital, Yantai, China
- Huajing Guo
- Department of Anesthesiology, The First People's Hospital of Changde City, Changde, China
- Qiang Wang
- Department of Orthopedics, Yixing People's Hospital, Jiangsu, China
- Diansan Su
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Corresponding author at: Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Weifeng Yu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Corresponding authors at: Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Xiyao Gu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Corresponding authors at: Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Journal volume & issue
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Vol. 212
p. 107576
Abstract
Biased µ-opioid receptor (MOR) agonists enhance pain relief by selectively activating G protein-coupled receptor signaling and minimizing β-arrestin-2 activation, resulting in fewer side effects. This multicenter Phase II/III trial evaluated the optimal dosage, efficacy, and safety of SHR8554, a biased MOR agonist, for postoperative pain management following orthopedic surgery. In Phase II, 121 patients were divided into four groups to receive varying patient-controlled analgesia (PCA) doses of SHR8554 or morphine. Phase III involved 320 patients with similar groupings, including a placebo group. The primary outcome was the resting summed pain intensity difference over 24 hours (rSPID24). Secondary outcomes included rSPID and active-SPID (aSPID) at other time points, rescue analgesia received, cumulative dose of analgesics, and satisfaction scores. Safety endpoints included treatment-emergent adverse events (TEAEs) and AE of special interest (AESIs). In both phases, SHR8554 demonstrated significant analgesic efficacy. In Phase II, the least squares (LS) mean differences in rSPID24 compared to morphine for the 0.05 mg,0.1 mg, and 0.2 mg SHR8554 groups were 16.8 (p = 0.01), 7.4 (p = 0.27), and 0.2 (p = 0.98), respectively. Phase III confirmed the efficacy of the 0.05 mg and 0.1 mg SHR8554 doses compared to placebo, with LS mean differences of 15.4 (p = 0.0001) and −19.8 (p < 0.0001), respectively. Trends in other secondary outcomes mirrored these findings. Safety analysis revealed that the 0.2 mg SHR8554 group had higher incidences of TEAEs (83.3 %) and AESIs (33.3 %) compared to other groups in Phase II. Similarly, in Phase III, the incidences of TEAEs were 81.0 %, 73.4 %, and 74.1 % in the 0.05 and 0.1 mg SHR8554 and morphine groups, respectively, compared with 61.3 % in the placebo group, while the AESIs were 29.1 %, 20.3 %, and 24.7 % compared with 12.5 % in the placebo group. In conclusion, SHR8554 exhibited efficacy compared to placebo and safety comparable to morphine for patients experiencing moderate-to-severe acute pain following unilateral total knee replacement or knee ligament reconstruction surgery. Trial Registration: Trial Name: Study on the Efficacy and Safety of SHR8554 Injection for Postoperative Analgesia in Orthopedics: Multicenter, Randomized, Double Blind, Dose Exploration, Placebo/Positive Control, Phase II/III Clinical Trial Registered on: chinadrugtrials.org.cn Identifier: CTR20220639.
