Sex differences in outcomes of methadone maintenance treatment for opioid addiction: a systematic review protocol

Background Use of methadone for the treatment of opioid addiction is an effective harm-reduction approach, although variability in treatment outcomes among individuals has been reported. Men and women with opioid addiction have been known to differ in factors such as opioid use patterns and characteristics at treatment entry; however, little has been reported about differences in methadone treatment outcomes between men and women. Therefore, we present a protocol for a systematic review which aims to provide a summary of existing literature on sex differences in outcomes of methadone treatment for opioid addiction. Methods/Design Electronic search of PubMed/MEDLINE, EMBASE, PsycINFO, and CINAHL databases will be conducted using a priori defined search strategy. Two authors (MB and BBD) will independently screen potential articles for eligibility using pre-determined inclusion and exclusion criteria and extract key information using a data extraction form designed for this study. Discrepancies will be resolved using a third party (ZS). The primary outcome will be sex differences in response to treatment defined as abstinence from illicit opioid use. We will also assess sex differences in treatment outcomes including treatment retention, remission status post-treatment, polysubstance abuse, methadone dose, drug-related adverse events, health status, psychological status, mortality, criminal activity, high risk sexual behavior, social support/relations, and employment. A meta-analysis will be conducted if possible; risk of bias and overall quality of evidence will be assessed to determine confidence in the estimates. Discussion We anticipate that this review will highlight how men and women differ in methadone treatment outcomes and allow us to generate conclusions that can be applied to treatment in a clinical setting. Systematic review registration PROSPERO CRD42013006549


Is the source population (cases, controls, cohorts) appropriate and representative of the population of interest?
0 (high risk of bias) 1 2 3 (low risk of bias) Example of low risk of bias: A consecutive sample or random selection from a population that is representative of the condition under study.
Example of moderate risk of bias: A consecutive sample or random selection from a population that is not highly representative of the condition under study.
Example of high risk of bias: The source population cannot be defined or enumerated (i.e. volunteering or self-recruitment).

Domain of evaluation: Methods to control confounding (i.e. Performance bias)
Is the sample size adequate and is there sufficient power to detect a meaningful difference in the outcome of interest? 0 (high risk of bias) 1 2 3 (low risk of bias) Example of low risk of bias: Sample size was adequate and there was sufficient power to detect a difference in the outcome.
Example of high risk of bias: Sample size was small and there was not enough power to test outcome of interest.
Did the study identify and adjust for any variables or confounders that may influence the outcome? 0 1 2 3 0 = Definitely no (high risk of bias) 1 = Mostly no 2 = Mostly yes 3 = Definitely yes (low risk of bias) (high risk of bias) (low risk of bias) Example of low risk of bias: The study identified and adjusted for all possible confounders that may influence estimates of association between exposure and outcome (i.e. Was the patient being treated for a medical condition such as chronic pain and was being prescribed opioids while on methadone treatment?) Example of moderate risk of bias: The study identified and reported possible variables that may influence the outcome but did not explore the interaction.
Example of high risk of bias: The study either did not report any variables of influence or acknowledge variables of influence when it was clear they were present.

Domain of evaluation: Statistical methods (i.e. Detection bias)
Did the study use appropriate statistical analysis methods relative to the outcome of interest? 0 (high risk of bias) 1 2 3 (low risk of bias) Example of low risk of bias: The study reported use of appropriate statistical analysis as required (i.e. adjusting for an unbalanced distribution of a specific covariate among sexes, or correcting for multiple testing error) Example of moderate risk of bias: The study either used correct statistical methods but did not report them well, or used the incorrect methods but reported them in detail.
Example of high risk of bias: The study did not use appropriate statistical analysis as required (i.e. did not adjust for an unbalanced distribution of a specific covariate among sexes, or correct for multiple testing error when necessary) or did not report them adequately.
Is there little missing data and did the study handle it accordingly? 0 (high risk of bias) 1 2 3 (low risk of bias) Example of low risk of bias: The study acknowledged missing data to be less than 10% and specified the method of handling it.
Example of moderate risk of bias: The study either had greater than 15% but they specified the method they used to handle it.
Example of high risk of bias: The study had greater than 15% missing data and did not handle it at all.

Domain of evaluation: Methods for measuring outcome variables (i.e. Information bias)
Is the methodology of the outcome measurement explicitly stated and is it appropriate? 0 (high risk of bias) 1 2 3 (low risk of bias) Example of low risk of bias: The study provides a detailed description of the outcome measure(s) which are appropriate for the outcome of interest.
Example of moderate risk of bias: The study provides a somewhat complete description of outcome measurements and they are justified.
Example of high risk of bias: The study provides limited information on the methods of measuring the outcome and the measure is not appropriate considering the outcome.
Is there an objective assessment of the outcome of interest? 0 (high risk of bias) 1 2 3 (low risk of bias) Example of low risk of bias: The study used objective methods to discern the outcome status of participants (i.e. laboratory measurements, medical records).
Example of moderate risk of bias: The study relied on subjective data as the primary method to discern outcome status of participants (i.e. self-report).
Example of high risk of bias: The study had limited reporting about assessment of outcomes.