An international phase III randomized, double-blind, double-dummy trial comparing duloxetine and pregabalin for opioid-refractory neuropathic cancer pain.

12013 Background: Management of neuropathic cancer pain (NCP) refractory to standard-dose opioids remains a major clinical challenge, and direct comparative evidence between adjuvant analgesics is limited. This study aimed to compare the efficacy and safety of duloxetine and pregabalin in patients with opioid-refractory NCP. Methods: We conducted an international, multicenter, double-blind, randomized controlled trial. Adult cancer patients who continued to experience pain despite opioid analgesia were eligible to participate if they met the International Association for the Study of Pain criteria for neuropathic pain and had a Brief Pain Inventory (BPI) Item 3 (worst pain in the past 24 hours) score of ≥4. Inpatients and outpatients from Japan and Australia were randomized at a ratio of 1:1 to the duloxetine group (D group) or the pregabalin group (P group). The study drugs were titrated up to duloxetine 60mg daily or pregabalin 150mg twice daily until day 14 (D14). The primary endpoint was BPI item 3 at D14. Secondary endpoints included the change in BPI item 3 from baseline at D14, and the proportion of patients achieving ≥1 points, ≥2 points, ≥30% and ≥50% pain reduction. The primary endpoint was analyzed using a two-sided Student’s T-test (α=0.05) under the intention-to-treat principle. A sample size of 64 patients per group was estimated to detect a mean difference of 1.0 (SD 2.0) with 80% power. Results: Between February 2020 and June 2025, 147 patients were enrolled across 18 institutions. Baseline BPI item 3 scores were similar between the D and P groups (7.23 vs 7.04). At D14, mean scores were 5.62 and 5.45, with no significant difference (P=0.70), corresponding to mean reductions of 1.57 and 1.55, respectively. Rates of pain reduction (≥1 point, ≥2 points, ≥30%, ≥50%) were similar between groups (D: 53/45/36/25% vs P: 50/36/26/19%). Grade ≥2 adverse events included decreased appetite (29％), nausea (21％), fatigue (20％), in the D group, and constipation (23%), decreased appetite (16％), dizziness/fatigue (12％), in the P group. Conclusions: No significant difference in analgesic efficacy was observed between duloxetine and pregabalin in patients with opioid-refractory NCP. The magnitude of pain reduction exceeded the mean NRS change typically associated with placebo (approximately 0.5–1.0 points), and the response rates for ≥50% pain reduction were substantially higher than the ≈3% reported for placebo in a prior NCP study. The estimated numbers needed to treat were low (4.6 for duloxetine and 6.3 for pregabalin) and were smaller than those reported in non-cancer neuropathic pain, suggesting comparable or potentially greater efficacy. However, given the relatively high incidence of adverse events and the distinct adverse event profiles of each drug, careful and individualized treatment selection balancing efficacy and tolerability is warranted. Clinical trial information: jRCTs051190097.