Transdermal buprenorphine in the treatment of chronic pain: Results of a Phase III, multicenter, randomized, double-blind, placebo-controlled study

Background: Buprenorphine, a potent opioid analgesic, has been available in parenteral and oral or sublingual (SL) formulations for >25 years. In 2001, the buprenorphine transdermal delivery system (TDS) was introduced at 3 release rates (35, 52.5, and 70 mug/h) for the treatment of chronic cancer and noncancer pain. Objective: This study compared the analgesic efficacy and tolerability of buprenorphine TDS at a release rate of 35 mug/h with those of buprenorphine SL and placebo in patients with severe or very severe chronic cancer or noncancer pain. Methods: This multicenter, double-blind, placebo-controlled, parallel-group trial was 1 of 3 Phase III studies involved in the clinical development of buprenorphine TDS. It comprised a 6-day open-label run-in phase in which patients received buprenorphine SL 0.8 to 1.6 mg/d as needed and a double-blind phase in which patients were randomized to receive 3 sequential patches containing buprenorphine TDS 35 mug/h or placebo, each lasting 72 hours. Rescue analgesia consisting of buprenorphine SL 0.2-mg tablets was available as needed throughout the double-blind phase. The main outcome measures were (1) the number of buprenorphine SL tablets required in addition to buprenorphine TDS during the double-blind phase compared with the placebo group and compared with the buprenorphine SL requirement during the run-in phase, and (2) patients' assessments of pain intensity, pain relief, and duration of sleep uninterrupted by pain in the double-blind phase compared with the run-in phase. Adverse events were documented throughout the study. Results: One hundred thirty-seven patients were included in the double-blind phase (90 buprenorphine TDS, 47 placebo). The buprenorphine TDS group included 47 men and 43 women (mean [SD] age, 56.0 [12.1] years), and the placebo group included 23 men and 24 women (mean age, 55.7 [12.9] years). Forty-five patients had cancer-related pain and 92 had noncancer-related pain. The 2 treatment groups were comparable with respect to sex distribution, age, height, and body weight. Patients receiving buprenorphine TDS significantly reduced their consumption of buprenorphine SL tablets in the double-blind phase compared with patients receiving placebo (reduction of 0.6 [0.4] mg vs 0.4 [0.4] mg; P = 0.03). The relationship between the buprenorphine SL dose in the run-in phase and the number of buprenorphine SL tablets required in the double-blind phase was dose dependent in the active-treatment group only Patients' assessments of pain intensity and pain relief suggested better analgesia with buprenorphine TDS than with placebo, although the differences did not reach statistical significance. The proportion of patients who reported sleeping for >6 hours uninterrupted by pain in the double-blind phase compared with the run-in phase increased by 6.4% in the buprenorphine TDS group (35.6% vs 29.2%, respectively), compared with a decrease of 5.9% in the placebo group (40.4% vs 46.3%); no statistical analysis of sleep duration data was performed. Buprenorphine TDS was well tolerated, with adverse events generally similar to those associated with other opioids. The incidence of systemic adverse events in the double-blind phase was similar in the 2 treatment groups (28.9% buprenorphine TDS, 27.6% placebo), with the most common adverse events being nausea, dizziness, and vomiting. After patch removal, skin reactions (mainly mild or moderate pruritus and erythema) were seen in 35.6% of the buprenorphine TDS group and 25.5% of the placebo group. Conclusions: In the population studied, buprenorphine TDS provided adequate pain relief, as well as improvements in pain intensity and duration of pain-free sleep. It may be considered a therapeutic option for the treatment of moderate to severe chronic pain. Copyright (C) 2004 Excerpta Medica, Inc.