A Comparison between Enriched and Nonenriched Enrollment Randomized Withdrawal Trials of Opioids for Chronic Noncancer Pain

Abstract

An enriched enrollment randomized withdrawal (EERW) trial design has been advocated to be useful for the study of drugs that are beneficial to only a fraction of the individuals who take them. Some investigators defend the use of enrichment designs for opioids in chronic noncancer pain (CNCP), reasoning that opioids may appear to underperform in clinically heterogeneous contexts, ie, that substantial efficacy in a particular patient subgroup may be diluted or masked by poor efficacy in another subgroup. The authors previously published a systematic review of opioids for CNCP in 2006; however, at that time, there were only a few EERW trials available for comparison. This more exhaustive, updated review compares the results between EERW and non-EERW trials of opioids for a variety of CNCP conditions.BACKGROUND: An enriched enrollment randomized withdrawal (EERW) design excludes potential participants who are nonresponders or who cannot tolerate the experimental drug before random assignment. It is unclear whether EERW design has an influence on the efficacy and safety of opioids for chronic noncancer pain (CNCP).OBJECTIVES: The primary objective was to compare the results from EERW and non-EERW trials of opioids for CNCP. Secondary objectives were to compare weak versus strong opioids, subgroups of patients with different types of pain, and the efficacy of opiods compared with placebo versus other drugs.METHODS: MEDLINE, EMBASE and CENTRAL were searched up to July 2009, for randomized controlled trials of any opioid for CNCP. Meta-analyses and meta-regressions were conducted to compare the results. Treatment efficacy was assessed by effect sizes (small, medium and large) and the incidence of adverse effects was assessed by a clinically relevant mean difference of 10% or greater.RESULTS: Sixty-two randomized trials were included. In 61 trials, the duration was less than 16 weeks. There was no difference in efficacy between EERW and non-EERW trials for both pain (P=0.6) and function (P=0.3). However, EERW trials failed to detect a clinically relevant difference for nausea, vomiting, somnolence, dizziness and dry skin/itching compared with non-EERW. Opioids were more effective than placebo in patients with nociceptive pain (effect size=0.60, 95% CI 0.49 to 0.72) and neuropathic pain (effect size=0.56, 95% CI 0.38 to 0.73).CONCLUSION: EERW trial designs appear not to bias the results of efficacy, but they underestimate the adverse effects. The present updated meta-analysis shows that weak and strong opioids are effective for CNCP of both nociceptive and neuropathic origin.