Enriched enrollment randomized withdrawal trial designs of analgesics: focus on methodology.

OBJECTIVES: To systematically identify and critically assess clinical trials that use enriched enrollment randomized withdrawal (EERW) trial design as a methodology for assessing the effect of analgesics pain.
METHODS: A comprehensive literature search was conducted through April 2007 in Medline and Embase to identify all randomized controlled trials that use EERW trial designs. Data were collected from relevant trials and tabulated. Results were categorized on the basis of study designs, preenrichment and postenrichment disposition, discontinuation rates, primary and secondary efficacy results, and respective P values.
RESULTS: The literature search identified 2875 unique citations, most of which were deemed inappropriate for this analysis. The primary reasons for exclusion included inappropriate study design, no available abstract, not a clinical study, and therapeutic area not related to chronic pain. Eight EERW clinical trials of analgesics were identified. Half of the trials were in chronic low back pain, and 5 of 8 trials used an opioid as the active drug. Of the 8 trials, 5 used a parallel design and 3 used crossover designs. The primary efficacy parameter used was pain scores or time to discontinuation, and statistically and clinically significant effects in active treatments relative to placebo were observed after randomization in all trials. The median magnitude of effect was 1.7 on a 10-point scale. Time to exit was a more statistically powerful endpoint than mean pain intensity. DISCUSSIONS: EERW trials are an emerging type of study design that in certain settings may offer advantages over traditional trial designs in characterizing the effects of analgesic medications.