Opioid substitution and antagonist therapy trials exclude the common addiction patient: A systematic review and analysis of eligibility criteria

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, Lehana Thabane

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Background: 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. 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. Methods: We 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. Results: Among 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. Conclusions: Trials 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.

Original languageEnglish (US)
Article number475
Pages (from-to)1
Number of pages1
Issue number1
StatePublished - Oct 21 2015
Externally publishedYes


  • Comorbidity
  • Generalizability
  • Methadone maintenance treatment
  • Methodology
  • Opioid addiction
  • Opioid dependence
  • Opioid use disorder
  • Psychiatric comorbidity

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology (medical)


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