Opioid substitution and antagonist therapy trials exclude the common addiction patient: a systematic review and analysis of eligibility criteria.
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.
Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada. dennisbb@mcmaster.ca.
Brittany B
BB
Dennis
Schulich School of Medicine and Dentistry, University of Western Ontario, 4, 1465 Richmond Street, London, ON, N6G 2M1, Canada. proshano@uwo.ca.
Pavel S
PS
Roshanov
Michael G. Degroote School of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada. leennaji2@gmail.com.
Leen
L
Naji
McMaster Integrative Neuroscience Discovery and Study Program, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada. baworm@mcmaster.ca.
Monica
M
Bawor
Department of Anesthesia, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada. james_paul@sympatico.ca.
James
J
Paul
Canadian Addiction Treatment Centres, 13291 Yonge Street, Richmond Hill, ON, L4E 4L6, Canada. cplater@toxpro.ca.
Carolyn
C
Plater
Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada. pareg@mcmaster.ca.
Guillaume
G
Pare
Canadian Addiction Treatment Centres, 13291 Yonge Street, Richmond Hill, ON, L4E 4L6, Canada. worster@mcmaster.ca.|Department of Medicine, Hamilton General Hospital, 237 Barton St East, Hamilton, ON, L8L 2X2, Canada. worster@mcmaster.ca.
Andrew
A
Worster
Canadian Addiction Treatment Centres, 13291 Yonge Street, Richmond Hill, ON, L4E 4L6, Canada. MVarenbut@canatc.ca.
Michael
M
Varenbut
Canadian Addiction Treatment Centres, 13291 Yonge Street, Richmond Hill, ON, L4E 4L6, Canada. jdaiter@toxpro.ca.
Jeff
J
Daiter
Canadian Addiction Treatment Centres, 13291 Yonge Street, Richmond Hill, ON, L4E 4L6, Canada. dmarsh@nosm.ca.|Northern Ontario School of Medicine, Ramsey Lake Road, Sudbury, ON, P0M, Canada. dmarsh@nosm.ca.
David C
DC
Marsh
Population Genomics Program, Chanchlani Research Centre, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada. dipika.desai@phri.ca.
Dipika
D
Desai
Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada. samaanz@mcmaster.ca.|Population Genomics Program, Chanchlani Research Centre, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada. samaanz@mcmaster.ca.|Peter Boris Centre for Addictions Research, St. Joseph's Healthcare Hamilton, 100 West 5th Street, Hamilton, ON, L9C 0E3, Canada. samaanz@mcmaster.ca.|Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada. samaanz@mcmaster.ca.
Zainab
Z
Samaan
Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada. thabanl@mcmaster.ca.|Centre for Evaluation of Medicine, 25 Main Street West, Hamilton, ON, L8P 1H1, Canada. thabanl@mcmaster.ca.|System Linked Research Unit, 175 Longwood Road, South Hamilton, L8P 0A1, Canada. thabanl@mcmaster.ca.
Lehana
L
Thabane
D015897:Comorbidity; D055030:Drug Users / Q000523:psychology; D004608:Eligibility Determination; D019317:Evidence-Based Medicine; D006801:Humans; D009292:Narcotic Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D058850:Opiate Substitution Treatment / Q000009:adverse effects; D009293:Opioid-Related Disorders / Q000175:diagnosis / Q000453:epidemiology / Q000523:psychology / Q000628:therapy*; D018579:Patient Selection; D017410:Practice Guidelines as Topic; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000592:standards; D016896:Treatment Outcome
D009292:Narcotic Antagonists