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
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 bia...
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2025-02-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Yanhua Zhao |
| collection | DOAJ |
| description | 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. |
| format | Article |
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| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-d87bcc7d38874d9eac3c48492a92fc992025-02-08T04:59:38ZengElsevierPharmacological Research1096-11862025-02-01212107576Efficacy 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 trialYanhua Zhao0Zhisheng Lu1Xuesong Song2Haihui Xie3Xungang Xiao4Guonian Wang5Qi Zhou6Qingmei Zhang7Liang Liu8Zhijian Lan9Ning Bai10Haiyan Wang11Zhihao Pan12Liang Dong13Xianzhong Lin14Gang Chen15Qinghui Wang16Jiangtao Dong17Jia Deng18Yongshan Nan19Jiaqiang Zhang20Xiaohua Zhou21Yanjuan Huang22Yongquan Chen23Huanzhong He24Ye Yang25Dengpan Yao26Jintai Jia27Shuan Jin28Yafeng Zhang29Zhonghui Luo30Jiangang Li31Linzhong Zhang32Fang Wang33Juehua Jing34Jiang Zhu35Lin Li36Guangda Wang37Huajing Guo38Qiang Wang39Diansan Su40Weifeng Yu41Xiyao Gu42Department 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, ChinaDepartment 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, ChinaDepartment of Anesthesiology, First Hospital of Jilin University, Changchun, ChinaDepartment of Anesthesiology, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People’s Hospital), Dongguan, ChinaDepartment of Orthopedics, Chenzhou First People's Hospital, Chenzhou, ChinaDepartment of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, ChinaDepartment of Anesthesiology, Chifeng Municipal Hospital, Chifeng, ChinaDepartment of Anesthesiology, Chaohu Hospital of Anhui Medical University, Hefei, ChinaDepartment of Orthopedics, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, ChinaDepartment of Anesthesiology, Jinhua Municipal Central Hospital, Jinhua, ChinaDepartment of Anesthesiology, Shaanxi Provincial People's Hospital, Xi-an, ChinaDepartment of Anesthesiology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, ChinaDepartment of Anesthesiology, Li Hui li Hospital of Ningbo Medical Center, Ningbo, ChinaDepartment of Anesthesiology, Liuzhou People's Hospital Affiliated to Guangxi Medical University, Liuzhou, ChinaDepartment of Anesthesiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, ChinaDepartment of Orthopedics, The Second hospital of Jiaxing, Jiaxing, ChinaDepartment of Anesthesiology, Affiliated Zhongshan Hospital of Dalian University, Dalian, ChinaDepartment of Orthopedics, Hebei Medical University Third Hospital, Shijiazhuang, ChinaDepartment of Anesthesiology, Sichuan Provincial People's Hospital, Chengdu, ChinaDepartment of Anesthesiology, Yanbian University Hospital, Yanji, ChinaDepartment of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital (Zhengzhou University People’s Hospital), Zhengzhou, ChinaDepartment of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, ChinaDepartment of Anesthesiology, The Third Affiliated Hospital of Guangxi Medical University, Nanning, ChinaDepartment of Anesthesiology, The First Affiliated Hospital of Wannan Medical College, Wuhu, ChinaDepartment of Anesthesiology, Huzhou Central Hospital, Huzhou, ChinaDepartment of Anesthesiology, Beijing Jishuitan Hospital Guizhou Hospital, Guizhou, ChinaDepartment of Articular Orthopedics, Hefei First People's Hospital, Hefei, ChinaDepartment of Anesthesiology, Heping Hospital Attached to Changzhi Medical College, Changzhi, ChinaDepartment of Anesthesiology, Central Hospital Affiliated to Shandong First Medical University, Jinan, ChinaDepartment of Articular Orthopaedics, Wuxi Traditional Chinese Medicine Hospital, Wuxi, ChinaDepartment of Anesthesiology, The First Affiliated Hospital of University of South China, Hengyang, ChinaDepartment of Anesthesiology, Qujing No.1 Hospital, Qujing, ChinaDepartment of Anesthesiology, Second hospital of Shanxi Medical University, Taiyuan, ChinaDepartment of Anesthesiology, Honghui Hospital, Xi-an, ChinaDepartment of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, ChinaDepartment of Anesthesiology, The Second Hospital Affiliated to Suzhou University, Suzhou, ChinaDepartment of Anesthesiology, General Hospital of the Northern Theater of the Chinese People's Liberation Army, Shenyang, ChinaDepartment of Orthopedics, Yantai Yuhuangding Hospital, Yantai, ChinaDepartment of Anesthesiology, The First People's Hospital of Changde City, Changde, ChinaDepartment of Orthopedics, Yixing People's Hospital, Jiangsu, ChinaDepartment 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.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.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.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.http://www.sciencedirect.com/science/article/pii/S1043661825000015PostoperativeAnalgesiaPatient controlledPhase II/III clinical trialOrthopedic surgerySHR8554 |
| spellingShingle | 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 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 Pharmacological Research Postoperative Analgesia Patient controlled Phase II/III clinical trial Orthopedic surgery SHR8554 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Postoperative Analgesia Patient controlled Phase II/III clinical trial Orthopedic surgery SHR8554 |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825000015 |
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