• Brittany B Dennis, Pavel S Roshanov, Leen Naji, Monica Bawor, James Paul, Carolyn Plater, Guillaume Pare, Andrew Worster, Michael Varenbut, Jeff Daiter, David C Marsh, Dipika Desai, Zainab Samaan, and Lehana Thabane.
• Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada. dennisbb@mcmaster.ca.
• Trials. 2015 Oct 21; 16: 475.

BackgroundEligibility criteria that result in the exclusion of a substantial number of patients from randomized trials jeopardize the generalizability of treatment effect to much of the clinical population. This is important when evaluating opioid substitution and antagonist therapies (OSATs), especially given the challenges associated with treating the opioid-dependent population. We aimed to identify OSAT trials' eligibility criteria, quantify the percentage of the clinical population excluded by these criteria, and determine how OSAT guidelines incorporate evidence from these trials.MethodsWe performed a systematic review to identify the eligibility criteria used across trials. We searched Medline, EMBASE, PsycINFO, Web of Science, Cochrane Library, Cochrane Clinical Trials Registry (CTR), World Health Organization International CTR Platform Search Portal, and the National Institutes of Health CTR databases from inception to January 1, 2014. To quantify the effect of trials' eligibility criteria on generalizability, we applied these criteria to data from an observational study of opioid-dependent patients (n = 394). We then accessed the Canadian, American, British, and World Health Organization (WHO) OSAT guidelines to evaluate how evidence is used in the recommendations.ResultsAmong the 60 trials identified the majority (≥50 % of trials) exclude patients with psychiatric (60 %) and physical comorbidity (51.7 %). Additionally, we found 19 trials exclude patients with current alcohol/substance-use problems (31.7 %), and 29 (48.3 %) exclude patients taking psychotropic medications. These criteria were restrictive and in some cases rendered 70 % of the observational sample ineligible. North American OSAT guidelines made strong recommendations supported by evidence with poor generalizability. National Institute of Health and Care Excellence (NICE) and WHO guidelines for opioid misuse provide a critical assessment of the literature used to inform their recommendations.ConclusionsTrials assessing OSATs often exclude patients with concurrent disorders. If the excluded patients respond differently to treatment, results from these trials are likely to overestimate the true effectiveness of OSATs. North American guidelines should consider these limitations when drafting clinical recommendations.

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