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.