Intravenous Patient-Controlled Analgesia Versus Oral Opioids to Maintain Analgesia for Severe Cancer Pain: A Randomized Phase III Trial

BACKGROUND: Effective management of severe cancer pain remains challenging. Our phase II study suggested that intravenous patient-controlled analgesia with hydromorphone (IPCA-HM), delivered either as bolus-only or continuous infusion, is superior to oral morphine for patients with severe cancer pain, with bolus-only potentially providing comparable efficacy to infusion while resulting in a lower rate of morphine equivalent dose (MED) escalation. This phase III study aimed to validate these findings. PATIENTS AND METHODS: Patients with solid tumors and severe cancer pain (≥7 at rest on an 11-point Numeric Rating Scale [NRS]) who achieved successful 24-hour IPCA-HM dose-finding were randomized (2:2:1) to bolus-only IPCA-HM (bolus), continuous infusion IPCA-HM (infusion), or oral morphine (oral) for 6 days. The primary outcome was average NRS score over days 1-3 (3DNRS). RESULTS: Of 1,349 patients from 48 oncology centers, 542 received bolus, 540 infusion, and 267 oral. Mean [SD] 3DNRS scores were 2.36 [0.89], 2.26 [0.87], and 2.94 [1.16], respectively. Both IPCA-HM arms were statistically significantly better than the oral arm in 3DNRS scores (bolus vs oral: mean difference, 0.58 [95% CI, 0.42 to 0.74]; infusion vs oral: 0.68 [95% CI, 0.52 to 0.84]; both P<.001). Bolus was noninferior to infusion (mean difference, 0.10 [95% CI, -0.01 to 0.20]; predefined noninferiority margin, 0.3; P<.001), achieving noninferiority in opioid-naïve, but not opioid-tolerant, patients. Median (IQR) total MEDs over days 1-6 were 400 (260-692) mg, 643 (380-1,117) mg, and 867 (540-1,313) mg for the bolus, infusion, and oral arms, respectively. Opioid-related adverse events (all grade 1 or 2) were comparable between the bolus (20.1%) and infusion (23.0%) arms, and both were lower than in the oral arm (33.7%). CONCLUSIONS: For severe cancer pain, both IPCA-HM regimens provided statistically significantly better pain relief compared with oral morphine. The bolus regimen achieved noninferior efficacy compared with infusion while requiring lower opioid doses, providing a safe and effective analgesic option.

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Journal
Journal of the National Comprehensive Cancer Network
Published
2026-05-12
DOI
https://doi.org/10.6004/jnccn.2025.7476
Primary Topic
Pain Management and Opioid Use
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article
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article

Intravenous Patient-Controlled Analgesia Versus Oral Opioids to Maintain Analgesia for Severe Cancer Pain: A Randomized Phase III Trial

Rongbo Lin, Wei Lu, Jun Liu, Bisheng Zhu et al.
Journal of the National Comprehensive Cancer Network
Pain Management and Opioid Use
article

Intravenous Patient-Controlled Analgesia Versus Oral Opioids to Maintain Analgesia for Severe Cancer Pain: A Randomized Phase III Trial

Rongbo Lin, Wei Lu, Jun Liu, Bisheng Zhu, 陈绍军, Hanxiang An, 骆玉霜, Xiaodong Wu, Zhongchao Huo, Feng Fu, Xia Lv, Shanlan Yang, Shen Zhao, Xi Zhang, Jincai Zhong, Yiming Bi, Zhichun Zhang, Yuehua Chen, Lei Cao, Yongsheng Zhao, Deng Hong, Chen Yunfang, Shaowei Lin, Liyu Su, H Y Zou, L N Cui, Jun Liang, Tao Sun, Tao Ren, Chunxiang Shang, Mingqian Lu, Li Zhuang, Shuqiang Wu, Lang He, Pengtao Chen, Cheng Huang, Liyan Gong, Hong Gao
article en

Abstract

BACKGROUND: Effective management of severe cancer pain remains challenging. Our phase II study suggested that intravenous patient-controlled analgesia with hydromorphone (IPCA-HM), delivered either as bolus-only or continuous infusion, is superior to oral morphine for patients with severe cancer pain, with bolus-only potentially providing comparable efficacy to infusion while resulting in a lower rate of morphine equivalent dose (MED) escalation. This phase III study aimed to validate these findings. PATIENTS AND METHODS: Patients with solid tumors and severe cancer pain (≥7 at rest on an 11-point Numeric Rating Scale [NRS]) who achieved successful 24-hour IPCA-HM dose-finding were randomized (2:2:1) to bolus-only IPCA-HM (bolus), continuous infusion IPCA-HM (infusion), or oral morphine (oral) for 6 days. The primary outcome was average NRS score over days 1-3 (3DNRS). RESULTS: Of 1,349 patients from 48 oncology centers, 542 received bolus, 540 infusion, and 267 oral. Mean [SD] 3DNRS scores were 2.36 [0.89], 2.26 [0.87], and 2.94 [1.16], respectively. Both IPCA-HM arms were statistically significantly better than the oral arm in 3DNRS scores (bolus vs oral: mean difference, 0.58 [95% CI, 0.42 to 0.74]; infusion vs oral: 0.68 [95% CI, 0.52 to 0.84]; both P<.001). Bolus was noninferior to infusion (mean difference, 0.10 [95% CI, -0.01 to 0.20]; predefined noninferiority margin, 0.3; P<.001), achieving noninferiority in opioid-naïve, but not opioid-tolerant, patients. Median (IQR) total MEDs over days 1-6 were 400 (260-692) mg, 643 (380-1,117) mg, and 867 (540-1,313) mg for the bolus, infusion, and oral arms, respectively. Opioid-related adverse events (all grade 1 or 2) were comparable between the bolus (20.1%) and infusion (23.0%) arms, and both were lower than in the oral arm (33.7%). CONCLUSIONS: For severe cancer pain, both IPCA-HM regimens provided statistically significantly better pain relief compared with oral morphine. The bolus regimen achieved noninferior efficacy compared with infusion while requiring lower opioid doses, providing a safe and effective analgesic option.

Journal of the National Comprehensive Cancer Network
Hebei University of Engineering (CN), Shenyang Medical College (CN), Hebei Medical University (CN), Fujian Medical University (CN), Guiyang Medical University (CN), Harbin Medical University (CN), Guangxi Medical University (CN), Xiamen University (CN), Peking University (CN), Kunming Medical University (CN), Liaoning University of Traditional Chinese Medicine (CN), Qinghai University Affiliated Hospital (CN), Yinchuan First People's Hospital (CN), First Affiliated Hospital of Xiamen University (CN), Chinese People's Armed Police Force Medical College Affiliated Hospital (CN), Xian Central Hospital (CN), Liuzhou Maternal and Child Health Hospital (CN), Liuzhou General Hospital (CN), Zhumadian Central Hospital (CN), Binzhou Medical College Hospital (CN), Qinghai No.3 People's Hospital (CN), Zhejiang Cancer Hospital (CN), Xianning Central Hospital (CN), Guizhou Cancer Hospital (CN), Third Affiliated Hospital of Harbin Medical University (CN), Ningxia Hui Autonomous Region Peoples Hospital (CN), Xi'an Medical University (CN), Affiliated Hospital of Guizhou Medical University (CN), Xingtai People's Hospital (CN), Fuzhou Dermatosis Prevention Hospital (CN), First People’s Hospital of Zunyi (CN), Binzhou People's Hospital (CN), People's Hospital of Xinjiang Uygur Autonomous Region (CN), Zhongshan Hospital of Xiamen University (CN), First Affiliated Hospital of GuangXi Medical University (CN), First Affiliated Hospital of Chengdu Medical College (CN), Hainan General Hospital (CN), Chengdu Second People's Hospital (CN), Chengdu Fifth People's Hospital (CN), Peking University International Hospital (CN), Fourth Affiliated Hospital of Guangxi Medical University (CN), Affiliated Hospital of Liaoning University of Traditional Chinese Medicine (CN), The Central Hospital of Shaoyang (CN), Fujian Provincial Cancer Hospital (CN), Yichang Central People's Hospital (CN), Xiamen Chang Gung Hospital (CN), Hainan Medical College Hospital (CN), The Fourth People's Hospital of Ningxia Hui Autonomous Region (CN)
Good health and well-being
Openalex Percentile: Top 5%
Pain Management and Opioid Use
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