Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-0942-4) contains supplementary material, which is available to authorized users.
Highlights
Eligibility 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
During full-text review 77 articles were excluded, whereby 10 articles identified during the hand-search of Cochrane reviews were duplicates, seven studies did not review an outcome of interest, 36 studies were not randomized trials, one study showed contamination of intervention, six studies used data-linkage/retrospective data design, one study stratified all analyses by sex, and six studies were performed in a specialized population
One of the higher quality studies published in the Lancet by Schottenfeld et al (2008) provides a list of conditions they deemed problematic for inclusion into the trial without once discussing how such conditions were measured, “Patients were ineligible if they were dependent on alcohol, benzodiazepines, or sedatives; had concentrations of liver enzymes greater than three times the upper limit of normal; were dangerous to themselves or others; were psychotic or had major depression; or had life-threatening medical problems,” [19]
Summary
Eligibility 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. A recent investigation from the RAND provides assessments of the costs of opioid addiction and estimate a range from €2,627 to €60,665 per person, per year. These estimates are comprised of data from American, Australian and Canadian populations and quote the most generalizable estimates encompassing the highest scope of costs (health care, lost worker productivity) at €21,904 per person per year [7]
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