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Effects of medication assisted treatment (MAT) for opioid use disorder on functional outcomes: A systematic review

Open AccessPublished:March 13, 2018DOI:https://doi.org/10.1016/j.jsat.2018.03.001

      Highlights

      • Little research exists on the functional (cognitive, physical, occupational, behavioral/social) effects MAT
      • Only 30 RCTs and 10 comparison studies reported functional outcomes; these were rarely primary outcomes.
      • Weaknesses in the body of evidence prevent any strong conclusions about the effects of MAT on functional outcomes.

      Abstract

      This systematic review synthesizes evidence on the effects of Medication-Assisted Treatment (MAT) for opioid use disorder (OUD) on functional outcomes, including cognitive (e.g., memory), physical (e.g., fatigue), occupational (e.g., return to work), social/behavioral (e.g., criminal activity), and neurological (e.g., balance) function.
      Five databases were searched from inception to July 2017 to identify English-language controlled trials, case control studies, and cohort comparisons of one or more groups; cross-sectional studies were excluded. Two independent reviewers screened identified literature, abstracted study-level information, and assessed the quality of included studies. Meta-analyses used the Hartung-Knapp method for random-effects models. The quality of evidence was assessed using the GRADE approach.
      A comprehensive search followed by 1411 full text publication screenings yielded 30 randomized controlled trials (RCTs) and 10 observational studies meeting inclusion criteria. The studies reported highly diverse functional outcome measures. Only one RCT was rated as high quality, but several methodologically sound observational studies were identified. The statistical power to detect differences in functional outcomes was unclear in most studies.
      When compared with matched “healthy” controls with no history of substance use disorder (SUD), in two studies MAT patients had significantly poorer working memory and cognitive speed. One study found MAT patients scored worse in aggressive responding than did “healthy” controls. A large observational study found that MAT users had twice the odds of involvement in an injurious traffic accident as non-users.
      When compared with persons with OUD not on MAT, one cohort study found lower fatigue rates among buprenorphine-treated OUD patients. No differences were reported for occupational outcomes and results for criminal activity and other social/behavioral areas were mixed.
      There were few differences among MAT drug types. A pooled analysis of three RCTs found a significantly lower prevalence of fatigue with buprenorphine compared to methadone, while a meta-analysis of the same RCTs found no statistical difference in insomnia prevalence. Three RCTs that focused on cognitive function compared the effects of buprenorphine to methadone; no statistically significant differences in memory, cognitive speed and flexibility, attention, or vision were reported.
      The quality of evidence for most functional outcomes was rated low or very low. In sum, weaknesses in the body of evidence prevent strong conclusions about the effects of MAT for opioid use disorder on functional outcomes. Rigorous studies of functional effects would strengthen the body of literature.

      Keywords

      1. Introduction

      Opioids are a class of drugs that includes the prescription pain relievers oxycodone, hydrocodone, codeine, morphine, and fentanyl, as well as the illicit drug heroin (
      • National Institute on Drug Abuse
      Drugs of abuse: Opioids.
      ). Opioid misuse has increased tremendously since 2000. In 2014, 586,000 Americans had a substance use disorder (SUD) involving heroin and 1.9 million had an SUD involving a prescription pain reliever (
      • Substance Abuse and Mental Health Services Administration, & Center for Behavioral Health Statistics and Quality
      Behavioral health trends in the United States: Results from the 2014 National Survey on Drug Use and Health. Retrieved from Rockville, MD.
      ). The same year, over 28,000 persons died of opioid overdose, an increase of over 400% since 1999 (
      • Centers for Disease Control and Prevention
      Increases in drug and opioid overdose deaths — United States, 2000–2014.
      ). According to a retrospective cohort analysis of data from 2008 through 2010 (
      • Jones C.M.
      Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers - United States, 2002–2004 and 2008–2010.
      ), 80% of new heroin users in the United States started out misusing prescription opioid analgesics.
      Evidence-based treatment for opioid use disorder (OUD) includes medication assisted treatment (MAT): the use of approved medications combined with counseling, other behavioral therapies, and patient monitoring. Medications approved in the US for MAT include methadone, buprenorphine, buprenorphine combined with naloxone, and naltrexone. Methadone was developed in the 1940s and first introduced as a treatment for heroin addicts in the US in the 1960s (
      • Mattick R.P.
      • Breen C.
      • Kimber J.
      • Davoli M.
      Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence.
      ). The FDA began regulating the use of methadone for patients with OUD in 1972 (
      • Ball J.C.
      • Ross A.
      The effectiveness of methadone maintenance treatment: Patients, programs, services, and outcome.
      ). Methadone is administered orally, most often as a liquid, and must be dispensed in a federally licensed opioid treatment program. Buprenorphine for OUD was approved by the Drug Addiction Act of 2000 and by the FDA in 2002 (U.
      • U.S. Department of Health and Human Services
      Quick guide for physicians based on TIP 40. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction.
      ). Buprenorphine is a partial agonist opioid drug receptor modulator that can be prescribed alone or in conjunction with naloxone, an antagonist of the mu-opioid receptor. Buprenorphine can be prescribed only by physicians who have received specialized training or are certified in addiction medicine or psychiatry; it is most often administered either as a pill or sublingually. The FDA approved a buprenorphine implant in 2016 and an injectable extended release buprenorphine formulation in late 2017. Naltrexone, an opioid antagonist, was developed in 1963 and approved in 1984 by the FDA for the treatment of OUD (U.
      • U.S. Department of Health and Human Services
      Quick guide for physicians based on TIP 40. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction.
      ). Extended-release naltrexone (XR-NTX) can be ordered by a physician, physician assistant, or nurse practitioner (
      • Center for Substance Abuse Treatment Division of Pharmacologic Therapies
      Clinical use of extended-release injectable naltrexone in the treatment of opioid use disorder: A brief guide.
      ). In the United States, naltrexone can be administered orally or intramuscularly.
      While evidence of the effectiveness of MAT is quite strong (
      • Fullerton C.A.
      • Kim M.
      • Thomas C.P.
      • Lyman D.R.
      • Montejano L.B.
      • Dougherty R.H.
      • Delphin-Rittmon M.E.
      Medication-assisted treatment with methadone: Assessing the evidence.
      ), MAT drugs have been associated with neurological symptoms such as headache, dizziness, and somnolence (
      • Kitzmiller J.P.
      • Barnett C.J.
      • Steiner N.S.
      • Stoicea N.
      • Kamar N.
      • Luzum J.A.
      • Bergese S.D.
      Buprenorphine: Revisiting the efficacy of transdermal delivery system.
      ). Neurocognitive ability is a key determinant of functional outcomes. Memory, reaction time, cognitive processing speed, and vigilance are measures of neurocognitive ability that affect problem solving, skill acquisition, occupational performance, and social function. A recent meta-analyses of cross-sectional studies that compared performance on cognitive tasks between methadone users and healthy, non-drug using controls found methadone patients scored significantly worse than controls for all outcomes: impulsivity, cognitive flexibility, short-term memory, long-term memory, and attention (
      • Baldacchino A.
      • Armanyous M.
      • Balfour D.J.K.
      • Humphris G.
      • Matthews K.
      Neuropsychological functioning and chronic methadone use: A systematic review and meta-analysis.
      ). Standardized effect sizes were large, ranging from 0.41 to 0.89. Similarly,
      • Wang G.Y.
      • Wouldes T.A.
      • Russell B.R.
      Methadone maintenance treatment and cognitive function: A systematic review.
      synthesized the results from 35 studies, including 22 cross-sectional, five longitudinal, and eight RCTs on the effects of methadone maintenance on cognitive function compared with controls without a history of SUD. Meta-analysis was not conducted. Cognitive impairments among methadone patients included decreased performance on memory (eight studies), attention (two studies), psychomotor speed (four studies), decision-making (two studies), emotional interpretation (two studies), and verbal function (two studies) when compared with controls. However, the authors noted that two studies observed no significant differences, three studies observed small differences, and two studies found improved reaction times among methadone patients.
      In response to the growing epidemic of opioid misuse, the Department of Defense (DoD) commissioned this systematic review on the functional effects of MAT for use in future decision making surrounding MAT and active duty service members. This project goes beyond prior systematic reviews - in addition to including cognitive outcomes (e.g., reaction time), the funder requested we search for studies reporting on physical (e.g., fatigue), occupational (e.g., return to work), social/behavioral (e.g., family function), and neurological (e.g., balance) function. This review also exceeds prior reviews as it rates the quality of evidence for each functional outcome using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach (
      • Balshem H.
      • Helfand M.
      • Schunemann H.J.
      • Oxman A.D.
      • Kunz R.
      • Brozek J.
      • Guyatt G.H.
      GRADE guidelines: 3. Rating the quality of evidence.
      ). While prior reviews included cross-sectional studies, the current review was limited to the strongest study designs: controlled trials and observational studies (cohort or case-control) that compare two or more groups and report baseline and follow-up measures. We believe this is the first systematic review on a wide range of functional outcomes of all MAT medications currently approved for OUD treatment in the United States.

      2. Materials and methods

      The study protocol was posted to PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=58608h on March 5, 2017. The question that guided this study was “What are the effects of MAT (using buprenorphine, buprenorphine plus naloxone, methadone, or naltrexone) for OUD on functional outcomes compared to wait-list, placebo, treatment without medication, any other comparator, or each other (e.g., buprenorphine vs naltrexone)?” PubMed, PsycINFO, EMBASE, CINAHL, Cochrane CENTRAL and CDSR were searched from inception to July 2017 for English-language reports that met the criteria below, summarized using the PICOTSS (participants, interventions, comparators, outcomes, timing, settings, and study design) framework. Appendix A contains the full search terms. Unpublished literature was explicitly excluded from the review due to resource and timeline constraints.

      2.1 Participants

      Studies of adult humans, 18 years of age or older, were eligible. Studies of pregnant women were excluded.

      2.2 Interventions

      Studies evaluating FDA approved MAT for OUD - methadone, buprenorphine, buprenorphine plus naloxone, or naltrexone - were eligible, regardless of route of administration. Studies evaluating MAT interventions not approved in the United States, such as slow-release morphine or heroin, were excluded. Studies of opioid detoxification only, without maintenance, were excluded.

      2.3 Comparators

      Three types of comparison studies were important to the funder for future decision making: 1) Studies of MAT-treated patients with OUD compared to matched untreated “healthy” controls with no history of substance use disorder (SUD), b) studies comparing MAT-treated patients with OUD to persons with OUD who were not treated with MAT (i.e., they received another treatment, placebo, treatment as usual, or no treatment), and c) studies comparing two or more MAT medications.

      2.4 Outcomes

      Studies were required to report functional outcomes, including cognitive processing (e.g., memory, reaction time, attention, vigilance), occupational function (e.g., return to work), physical function, social/behavioral function (criminal activity, arrests, family function), or neurological function. Studies were required to assess outcomes in all participants or screen for the presence or absence of events in all included participants; studies reporting individual adverse events only for selected patients (e.g., reasons for dropping out of the study) were excluded.

      2.5 Timing

      Studies could involve any treatment duration referred to as “maintenance,” and any follow-up period was eligible.

      2.6 Settings

      Studies were limited to outpatient settings (i.e., methadone clinic or doctor's office). Studies conducted in hospitals (inpatient), and residential rehabilitation facilities were excluded. MAT studies that began in other settings (e.g. prison) and followed patients after release, through an outpatient phase, were eligible.

      2.7 Study design

      Studies were limited to controlled trials, with or without random assignment, and observational studies (cohort or case-control) that compare two or more groups and report baseline and follow-up measures. Cross-sectional studies were excluded.
      Because functional outcomes are often reported as secondary outcomes, we did not restrict the literature search to such outcomes, but retrieved and screened all full texts of trials and observational studies of MAT to determine whether relevant outcomes were reported. Prior systematic reviews on MAT were reference-mined for possibly relevant studies.
      Two independent reviewers screened abstracts and full texts using predetermined eligibility criteria. For studies that met inclusion criteria, reviewers abstracted pre-specified study-level information and assessed study quality. For controlled trials, we used the Cochrane Risk of Bias tool (
      • Higgins J.
      • Green S.
      Cochrane handbook for systematic reviews of interventions version 5.1.0.
      ), which assesses random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and providers (performance bias), blinding of outcome assessors (detection bias), completeness of reporting outcome data (attrition bias), and selective outcome reporting (reporting bias). For observational studies, we assessed the representativeness of the MAT patients, the baseline similarity of the compared groups, efforts to match groups or use consecutive patients, how outcomes were obtained (official records, direct observation, or self-report), and whether potential confounders were adjusted for. All abstracted data were checked by the project lead for accuracy.
      Wherever possible, we converted continuous variables to standardized mean differences (SMD) to facilitate the comparison across studies. In general, a standardized effect size of 0.20 or less is considered small, while 0.20 to 0.50 is considered moderate, and 0.80 or more is considered large (
      • Cohen J.
      Statistical power analysis for the behavioral sciences.
      ). Categorical outcomes are expressed as relative risks (RR). The relative risk, or risk ratio, is the ratio of the probability that an event (e.g. insomnia, fatigue, or arrest) will occur in the intervention group to the probability that the event will occur in the comparator group (
      • Schmidt C.O.
      • Kohlmann T.
      When to use the odds ratio or the relative risk?.
      ). We report the 95% confidence intervals (CI) for individual study results and pooled analyses.
      When sufficient data were available, meta-analyses of RCTs were conducted using the Hartung-Knapp method for random-effects models (
      • Hartung J.
      An alternative method for meta-analysis.
      ;
      • Hartung J.
      • Knapp G.
      A refined method for the meta-analysis of controlled clinical trials with binary outcome.
      ;
      • Sidik K.
      • Jonkman J.N.
      Robust variance estimation for random effects meta-analysis.
      ). This approach is preferred when the number of studies to be pooled is small and when there is evidence of heterogeneity (
      • IntHout J.
      • Ioannidis J.P.
      • Borm G.F.
      The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method.
      ). We report the I-squared statistic (
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ) as a measure of between-study heterogeneity; this statistic estimates the proportion of the observed variance that reflects variance in true effect sizes rather than sampling error. I-squared ranges from 0% to 100%, with higher values indicating more heterogeneity. We also reported the tau-squared statistic, which is specific to random effects meta-analysis; a tau-squared of more than one indicates significant heterogeneity (
      • Patsopoulos N.A.
      • Evangelou E.
      • Ioannidis J.P.A.
      Sensitivity of between-study heterogeneity in meta-analysis: Proposed metrics and empirical evaluation.
      ).
      The quality of evidence was assessed for major outcomes using the Grades of Recommendation, Assessment, Development, and Evaluation (or GRADE) approach (
      • Balshem H.
      • Helfand M.
      • Schunemann H.J.
      • Oxman A.D.
      • Kunz R.
      • Brozek J.
      • Guyatt G.H.
      GRADE guidelines: 3. Rating the quality of evidence.
      ). Namely, the body of evidence was assessed based on the following dimensions: study risk of bias/limitations, consistency of results, directness, and precision (
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      ). Per the GRADE system, if RCTs that respond to a particular question are identified, the quality of evidence is initially rated as high and then downgraded if studies have substantial limitations; when results are inconsistent across individual studies or show substantial heterogeneity in pooled analyses; when the result is based on only a single study without independent replication; when conclusions are based on indirect evidence (e.g., effects based on meta-regressions across studies in the absence of head-to-head comparisons); and when pooled results are imprecise estimates of the treatment effect (confidence intervals are wide, spanning effect sizes, with different clinical conclusions).

      3. Results

      3.1 Search results

      Of 6877 citations identified for review (see Fig. 1 below), 5466 citations were excluded at abstract screening. The primary reason for exclusion was that the study did not assess MAT (n = 4425) for opioid use disorder (OUD); these articles may have studied the use of MAT for other purposes (e.g., treatment of alcohol abuse, detoxification). Studies were also excluded if they studied a MAT medication not approved by the FDA (n = 21) or utilized study designs (n = 492) outside the scope of this review. Additionally, 23 duplicate articles were excluded, and five articles could not be retrieved using their citations.
      Based on the full-text review of 1411 articles, 40 studies (30 RCTs and ten observational studies) were included. Publications were excluded if they studied MAT with a medication outside the scope of this review (n = 165), only measured the effects of a co-intervention such as counseling (n = 249), did not report any functional outcomes (n = 324), or utilized out-of-scope study designs (n = 454). Fifty-three articles reported on populations beyond the scope of this review (e.g., adolescents and pregnant women), 43 articles were excluded for setting (inpatient or residential), 13 were not published in English, 58 were conference abstracts, one was a dissertation, and five were excluded for other reasons. There were six articles that reported follow-up on one of the 40 included studies; we abstracted these articles for additional outcome data.
      Most studies were conducted in North America (20) or Europe (16). Publication dates ranged from 1969 to 2017. Appendix B displays characteristics of populations, interventions, and comparators for each included study. Only one RCT was rated as having low risk of bias; common reasons for moderate or high risk of bias ratings included lack of participant blinding, high attrition rate, and lack of reporting of the method of randomization and allocation concealment. Several observational studies were rated as low risk of bias. Appendix C displays the overall Risk of Bias rating for every study along with scores for each assessment item.
      Functional measures were primary outcomes in only six RCTs; it is unclear if the other trials, which were powered statistically to detect differences in illicit drug use or treatment retention, had adequate power to detect differences in functional effects.
      Because many of the trials compare more than one drug, intervention, or control type, we organize the findings by category of functional outcome: cognitive, occupational, physical, social/behavioral and neurological. Within the outcome type, we report results by comparator.

      3.2 Cognitive function

      While several studies compared the cognitive performance of MAT patients to that of “healthy subjects with no history of SUD” or OUD patients on another MAT drug, no studies compared MAT patients to untreated persons with OUD.

      3.2.1 Memory

      Two RCTs randomized persons with OUD to either oral methadone or sublingual buprenorphine and compared performance on the Verbal Learning and Memory Test at eight to ten weeks (
      • Soyka M.
      • Zingg C.
      • Koller G.
      • Kuefner H.
      Retention rate and substance use in methadone and buprenorphine maintenance therapy and predictors of outcome: Results from a randomized study.
      ) or a list learning task from the Memory for Persons Data at six to nine months (
      • Rapeli P.
      • Fabritius C.
      • Kalska H.
      • Alho H.
      Memory function in opioid-dependent patients treated with methadone or buprenorphine along with benzodiazepine: Longitudinal change in comparison to healthy individuals.
      ) to that of a matched, untreated “healthy” control group. Compared with matched controls with no history of SUD or opioid use, the methadone patients in the shorter RCT had higher verbal memory scores (SMD 0.81; 95% CI 0.25, 1.36); in the longer RCT, task performance did not differ significantly between groups (SMD 0.00; CI −0.74, 0.74). Neither study reported significant differences between patients on buprenorphine and healthy controls in the memory tasks (Soyka SMD 0.43; CI −0.11, 0.98; Rapeli SMD −0.57; CI −0.30, 0.16).
      Using the Letter-Number Sequencing task from the Wechsler Memory Scale Version III, Rapeli (
      • Rapeli P.
      • Fabritius C.
      • Kalska H.
      • Alho H.
      Memory function in opioid-dependent patients treated with methadone or buprenorphine along with benzodiazepine: Longitudinal change in comparison to healthy individuals.
      ) reported poorer working memory among MAT patients than among healthy controls at six to nine months for both buprenorphine (SMD −0.89; CI −1.64, −0.14) and methadone (SMD −1.14; CI −1.94, −0.34). There were no significant differences between methadone and buprenorphine (SMD −0.34; CI −2.44, 1.76).

      3.2.2 Attention

      • Soyka M.
      • Lieb M.
      • Kagerer S.
      • Zingg C.
      • Koller G.
      • Lehnert P.
      • Hennig-Fast K.
      Cognitive functioning during methadone and buprenorphine treatment: Results of a randomized clinical trial.
      , reporting on the d2 Test of Attention at eight to 10 weeks, and Rapeli (
      • Rapeli P.
      • Fabritius C.
      • Kalska H.
      • Alho H.
      Memory function in opioid-dependent patients treated with methadone or buprenorphine along with benzodiazepine: Longitudinal change in comparison to healthy individuals.
      ) reporting results for the Test for Attentional Performance (TAP) at six to nine months, found no significant differences between patients on methadone and healthy controls (Rapeli SMD −0.38; CI −1.13, 0.37; Soyka SMD −0.18; CI −0.72, 0.36). Although both studies reported that buprenorphine patients scored worse than healthy controls (Rapeli SMD −0.63; CI −1.42, 0.16; Soyka SMD −0.55; CI −1.10, 0.01), the differences were not statistically significant. One additional trial that randomized 46 patients to either buprenorphine or methadone measured effects on attention (
      • Soyka M.
      • Hock B.
      • Kagerer S.
      • Lehnert R.
      • Limmer C.
      • Kuefner H.
      Less impairment on one portion of a driving-relevant psychomotor battery in buprenorphine-maintained than in methadone-maintained patients: Results of a randomized clinical trial.
      ). Thus, three studies reporting attention outcomes in buprenorphine and methadone patients could be pooled; results found no significant difference between the medications (SMD 0.12; CI −0.76, 0.52; I2 14%). Quality of evidence is low, due to high risk of bias ratings for these studies.

      3.2.3 Cognitive speed

      • Soyka M.
      • Lieb M.
      • Kagerer S.
      • Zingg C.
      • Koller G.
      • Lehnert P.
      • Hennig-Fast K.
      Cognitive functioning during methadone and buprenorphine treatment: Results of a randomized clinical trial.
      measured cognitive and perceptual motor speed using the Trail Making Test, where lower scores indicate faster speed and better performance. At eight to ten weeks, patients on buprenorphine (SMD 0.61; CI 0.02, 1.21) and methadone (SMD 0.74; CI 0.16, 1.33) scored significantly worse than healthy controls. Difference between the two drug groups was statistically insignificant (SMD −0.04; CI −0.62, 0.54).

      3.2.4 Vision

      Patients enrolled in a head to head trial of buprenorphine versus methadone (
      • Soyka M.
      • Hock B.
      • Kagerer S.
      • Lehnert R.
      • Limmer C.
      • Kuefner H.
      Less impairment on one portion of a driving-relevant psychomotor battery in buprenorphine-maintained than in methadone-maintained patients: Results of a randomized clinical trial.
      ) completed a peripheral vision test as part of the Act and React Test System. No difference in mean reaction time (measured in seconds) (SMD 0.0; CI −0.58, 0.58), visual tracking performance (SMD −0.55; CI −1.14, 0.04) or visual perception measured by correct answers on a tachistoscope test (SMD −0.05; CI −0.63, 0.53) was observed at eight to ten weeks.

      3.2.5 Driving

      Linking traffic accident data from police reports and the national police database of injurious crashes to the national health insurance database,
      • Corsenac P.
      • Lagarde E.
      • Gadegbeku B.
      • Delorme B.
      • Tricotel A.
      • Castot A.
      • Orriols L.
      Road traffic crashes and prescribed methadone and buprenorphine: A French registry-based case-control study.
      conducted a case-control study to investigate the association between the use of buprenorphine or methadone and the risk of being responsible for a road traffic crash (N = 72,685). Users of either drug were at higher risk of injurious road traffic crashes than non-users. Analyses of odds ratios (adjusted for age, gender, socioeconomic category, region, location, time of day, month, vehicle type, alcohol level, injury severity, concomitant levels 2 and 3 medicine exposure [for highest levels of risk] and long-term chronic diseases) found use of either agent was associated with a two-fold increase in odds of involvement in an injurious road traffic crash (OR 2.02; CI 1.40, 2.91).

      3.3 Occupational function

      Unlike studies of cognitive performance, several studies that reported occupational outcomes compared MAT patients to persons with OUD not receiving MAT. We identified no studies involving “healthy” controls, and one large cohort study comparing MAT with different drugs.

      3.3.1 Employment

      Three RCTs compared occupational functioning of patients on MAT to that of persons with OUD enrolled in non-MAT interventions. Sees et al. (2000), found no significant difference between patients enrolled in a psychosocially enriched methadone maintenance program and those who underwent a 180-day psychological detoxification program in Addiction Severity Index (ASI) Employment Scores at 12 months (SMD −0.04; CI −0.38, 0.30). At 12 months,
      • Kinlock T.W.
      • Gordon M.S.
      • Schwartz R.P.
      • Fitzgerald T.T.
      • O'Grady K.E.
      A randomized clinical trial of methadone maintenance for prisoners: Results at 12 months postrelease.
      , found that male former prisoners randomized to methadone MAT worked a mean 3.5 days less per month than those assigned to passive referral; however, the difference was not statistically significant (CI −7.01, 0.01 days). Finally
      • Coviello D.M.
      • Cornish J.W.
      • Lynch K.G.
      • Alterman A.I.
      • O'Brien C.P.
      A randomized trial of oral naltrexone for treating opioid-dependent offenders.
      reported that at six months 66% of criminal justice clients randomized to naltrexone were employed, compared to 52% of those randomized to standard psychological treatment without medication. This difference was not statistically significant (RR 1.21; CI 0.80 to 1.84).
      Two observational studies also compared employment outcomes across treatments. Using the US Substance Abuse and Mental Health Services Administration (SAMHSA) Treatment Episode Data Set,
      • Crits-Christoph P.
      • Lundy C.
      • Stringer M.
      • Gallop R.
      • Gastfriend D.R.
      Extended-release naltrexone for alcohol and opioid problems in Missouri parolees and probationers.
      conducted a retrospective analysis of opioid misusers who were under community supervision by a state correctional agency (i.e., on parole or probation) and received outpatient substance abuse treatment (N = 873). The authors compared participants who received extended-release naltrexone (XR-NTX), oral naltrexone, buprenorphine-naloxone, or psychosocial treatment without medication. Controlling for group differences using propensity scores based on several intake variables (e.g., severity), the difference among the four groups in the outcome “increase in the proportion of subjects who were employed (from intake to discharge)” was not significant. A small cohort study of 38 patients in the Netherlands (
      • Reijneveld S.A.
      • Plomp H.N.
      Methadone maintenance clients in Amsterdam after five years.
      ) found that 71% of subjects who left the methadone maintenance system reported “no time spent on paid job in past month” compared to 76% of those who stayed on maintenance five years; this difference was not statistically significant (RR 0.92; CI 0.63, 1.37).

      3.4 Physical function

      While we identified no studies comparing physical function of MAT patients to healthy controls, several studies compared MAT to placebo or treatment of OUD patients without medication. Head to head RCTs of different MAT drugs also reported physical outcomes.

      3.4.1 Fatigue

      One RCT (N = 100) compared naltrexone to a placebo (
      • Tiihonen J.
      • Krupitsky E.
      • Verbitskaya E.
      • Blokhina E.
      • Mamontova O.
      • Fohr J.
      • Zwartau E.
      Naltrexone implant for the treatment of polydrug dependence: A randomized controlled trial.
      ). No significant differences in fatigue were reported (RR 1.00; CI 0.06, 15.55); at ten weeks follow-up, 2% of each group reported this adverse event. Another study compared fatigue in 120 patients randomized to methadone or buprenorphine after six month treatment with that of a group of untreated persons with OUD evaluated upon admission (
      • Giacomuzzi S.M.
      • Ertl M.
      • Kemmler G.
      • Riemer Y.
      • Vigl A.
      • Author A.
      • Department of Psychiatry, A. I. A
      Sublingual buprenorphine and methadone maintenance treatment: A three-year follow-up of quality of life assessment.
      ). Fewer methadone patients (50%) reported fatigue than did the untreated opioid users (RR 0.78; CI 0.56, 1.09); however, the difference was not statistically significant. In the same study, buprenorphine patients were significantly less likely to report fatigue than the untreated group (RR 0.47; CI 0.29 to 0.76); only 30% reported fatigue. The difference in prevalence between the two drug groups was not statistically significant (RR 0.60; CI 0.34, 1.06).
      Fig. 2 (below) displays our pooled analysis of three head-to-head RCTs, (
      • Giacomuzzi S.
      • Kemmler G.
      • Ertl M.
      • Riemer Y.
      Opioid addicts at admission vs. slow-release oral morphine, methadone, and sublingual buprenorphine maintenance treatment participants.
      ;
      • Mattick R.P.
      • Ali R.
      • White J.M.
      • O'Brien S.
      • Wolk S.
      • Danz C.
      Buprenorphine versus methadone maintenance therapy: A randomized double-blind trial with 405 opioid-dependent patients.
      ;
      • Neri S.
      • Bruno C.M.
      • Pulvirenti D.
      • Malaguarnera M.
      • Italiano C.
      • Mauceri B.
      • Noto R.
      Randomized clinical trial to compare the effects of methadone and buprenorphine on the immune system in drug abusers.
      ) which compared fatigue prevalence in buprenorphine patients versus methadone patients. Buprenorphine patients had a significantly lower prevalence of fatigue (15.5% vs 25.1%; RR 0.62; CI 0.41, 0.95; 3 RCTs; I2 5%; tau2 0.126). Quality of evidence for the fatigue meta-analysis is moderate, as the trials had low risk of bias, results were consistent and heterogeneity was insignificant.
      Finally, one trial of sublingual buprenorphine versus buprenorphine implants (
      • Rosenthal R.N.
      • Lofwall M.R.
      • Kim S.
      • Chen M.
      • Beebe K.L.
      • Vocci F.J.
      Effect of buprenorphine implants on illicit opioid use among abstinent adults with opioid dependence treated with sublingual buprenorphine: A randomized clinical trial.
      ) found no statistical difference in reports of somnolence during 24 weeks of treatment (RR 5.11, CI 0.25, 105.01). No patients on sublingual buprenorphine reported somnolence, compared to 2.3% of implant patients.

      3.4.2 Insomnia

      Five RCTs (
      • Fudala P.J.
      • Bridge T.P.
      • Herbert S.
      • Williford W.O.
      • Chiang C.N.
      • Jones K.
      • Tusel D.
      Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone.
      ;
      • Lee J.
      • Friedmann P.
      • Kinlock T.
      • Nunes E.
      • Gordon M.
      • O'Brien C.
      Extended-release naltrexone for opioid relapse prevention among opioid-dependent, criminal justice-involved adults.
      ;
      • Ling W.
      • Casadonte P.
      • Bigelow G.
      • Kampman K.M.
      • Patkar A.
      • Bailey G.L.
      • Beebe K.L.
      Buprenorphine implants for treatment of opioid dependence: A randomized controlled trial.
      ;
      • Rosenthal R.N.
      • Ling W.
      • Casadonte P.
      • Vocci F.
      • Bailey G.L.
      • Kampman K.
      • Beebe K.L.
      Buprenorphine implants for treatment of opioid dependence: Randomized comparison to placebo and sublingual buprenorphine/naloxone.
      ;
      • Tiihonen J.
      • Krupitsky E.
      • Verbitskaya E.
      • Blokhina E.
      • Mamontova O.
      • Fohr J.
      • Zwartau E.
      Naltrexone implant for the treatment of polydrug dependence: A randomized controlled trial.
      ) compared the prevalence of insomnia in participants randomized to MAT vs placebo. Three of the RCTs used buprenorphine, while the others used naltrexone. There was no significant difference at one to six months (RR 1.09; CI 0.77, 1.53; I2 0%; tau2 0.036). Fig. 3 displays the pooled results. Quality of evidence is moderate as no between-study heterogeneity was detected and results were consistent among the studies. Prevalence of insomnia in MAT patients was 15.2%.
      Another study compared MAT patients with untreated persons with OUD evaluated upon admission to substance abuse treatment. This study randomized 120 opioid-dependent patients to either buprenorphine or methadone (
      • Giacomuzzi S.
      • Kemmler G.
      • Ertl M.
      • Riemer Y.
      Opioid addicts at admission vs. slow-release oral morphine, methadone, and sublingual buprenorphine maintenance treatment participants.
      ). At six months follow-up, fewer methadone and buprenorphine patients than persons in the untreated comparison group reported insomnia, but the difference was not statistically significant (methadone: RR 0.72; CI 0.47, 1.08, absolute risk 40%; buprenorphine: RR: 0.75, CI: 0.52, 1.07, absolute risk 30%).
      We also conducted a meta-analysis of three RCTs that compared the prevalence of insomnia between buprenorphine and methadone patients (
      • Giacomuzzi S.
      • Kemmler G.
      • Ertl M.
      • Riemer Y.
      Opioid addicts at admission vs. slow-release oral morphine, methadone, and sublingual buprenorphine maintenance treatment participants.
      ;
      • Mattick R.P.
      • Ali R.
      • White J.M.
      • O'Brien S.
      • Wolk S.
      • Danz C.
      Buprenorphine versus methadone maintenance therapy: A randomized double-blind trial with 405 opioid-dependent patients.
      ;
      • Neri S.
      • Bruno C.M.
      • Pulvirenti D.
      • Malaguarnera M.
      • Italiano C.
      • Mauceri B.
      • Noto R.
      Randomized clinical trial to compare the effects of methadone and buprenorphine on the immune system in drug abusers.
      ). Fig. 4 displays the results. No statistical difference was found (RR 1.12; CI 0.78, 1.62; I2 6%; tau2 0.004). Eighteen percent of methadone patients and 15.9% of buprenorphine patients reported this adverse event. The analysis detected insignificant heterogeneity. Quality of evidence is low because the results were imprecise.

      3.5 Social/behavioral function

      3.5.1 Family functioning

      At one year follow-up,
      • Sees K.L.
      • Delucchi K.L.
      • Masson C.
      • Rosen A.
      • Clark H.W.
      • Robillard H.
      • Hall S.M.
      Methadone maintenance versus 180-day psychosocially enriched detoxification for treatment of opioid dependence: A randomized controlled trial.
      reported no statistically significant decrease (improvement) in ASI family function scores among participants randomized to methadone maintenance compared with those in a “psychologically enriched” detoxification program (SMD −0.01; CI −0.04, 0.02).

      3.5.2 Psychological function

      Two studies (including one RCT) reported on effects on the ASI Psychiatric Score. At 12 months,
      • Sees K.L.
      • Delucchi K.L.
      • Masson C.
      • Rosen A.
      • Clark H.W.
      • Robillard H.
      • Hall S.M.
      Methadone maintenance versus 180-day psychosocially enriched detoxification for treatment of opioid dependence: A randomized controlled trial.
      reported no differences in ASI Psychiatric scores between participants with OUD randomized to a methadone maintenance program and those in a detoxification program (SMD −0.20; CI −0.55, 0.14) at 12 months.
      • Aalto M.
      • Visapää J.-P.
      • Halme J.T.
      • Fabritius C.
      • Salaspuro M.
      Effectiveness of buprenorphine maintenance treatment as compared to a syringe exchange program among buprenorphine misusing opioid-dependent patients.
      reported no differences in 12-month ASI Psychiatric scores between participants in a buprenorphine maintenance treatment and a cohort enrolled in a syringe exchange program (SMD 0.04; CI −0.67, 0.75).
      Dunlop (
      • Dunlop A.J.
      • Brown A.L.
      • Oldmeadow C.
      • Harris A.
      • Gill A.
      • Sadler C.
      • Lintzeris N.
      Effectiveness and cost-effectiveness of unsupervised buprenorphine-naloxone for the treatment of heroin dependence in a randomized waitlist controlled trial.
      ) found no significant difference in Short Form 12 mental health scores at four, eight, or twelve weeks between subjects randomized to buprenorphine-naloxone combination or wait list (4 weeks: SMD 0.72; CI 0.14, 1.30; 8 weeks SMD 0.79; CI 0.22, 1.37; 12 weeks SMD 0.89; CI 0.31, 1.47).

      3.5.3 Aggression

      • Gerra G.
      • Zaimovic A.
      • Raggi M.A.
      • Moi G.
      • Branchi B.
      • Moroni M.
      • Brambilla F.
      Experimentally induced aggressiveness in heroin-dependent patients treated with buprenorphine: Comparison of patients receiving methadone and healthy subjects.
      , examined differences in aggression among patients randomized to either oral methadone or sublingual buprenorphine and a healthy control group (total N = 45). Using the Point Subtraction Aggression Paradigm software program, the study measured “aggressive responding,” “escape responding,” and “point-maintained responses” as metrics for aggression at three month follow up. More aggression is indicated by higher scores in the first two measures and a lower score for “point-maintained responses.” Compared to controls, the methadone group scored significantly higher in aggressive responding (SMD 3.83; CI 2.62, 5.03) and lower in point-maintained responses (SMD −6.20; CI −7.92, −4.47). The difference escape responding was not statistically significant (SMD 0.69; CI −0.05, 1.42). The buprenorphine group also scored significantly higher in aggressive responding (SMD 4.01; CI 2.77, 5.25) and lower in point-maintained responses (SMD −1.95; CI −2.82, −1.08) than did healthy controls. The difference in escape responding was not statistically significant (SMD 0.27; CI −0.45, 0.99).
      Comparing the two drug groups, no significant differences were observed in aggressive responding (SMD −0.07; CI −0.79, 0.65) and escape responding (SMD −0.33; CI −1.05, 0.39). However, the buprenorphine group scored significantly better than the methadone group in point-maintained responses (SMD 5.30; CI 3.78, 6.82).
      A recent RCT of naltrexone versus buprenorphine-naloxone combination (
      • Mokri A.
      • Chawarski M.C.
      • Taherinakhost H.
      • Schottenfeld R.S.
      Medical treatments for opioid use disorder in Iran: A randomized, double-blind placebo-controlled comparison of buprenorphine/naloxone and naltrexone maintenance treatment.
      ) reported no difference in the number of participants experiencing “aggression, violence, impulsivity, or self-injury” during 12 weeks of treatment (naltrexone group: 27%; buprenorphine-naloxone group: 33%; RR 0.8; CI 0.48, 1.38).

      3.5.4 Criminal activity

      Two RCTs compared the effects of methadone to those of a passive control condition on engagement in illegal activity.
      • Schwartz R.P.
      • Jaffe J.H.
      • Highfield D.A.
      • Callaman J.M.
      • O'Grady K.E.
      A randomized controlled trial of interim methadone maintenance: 10-month follow-up.
      randomized 319 participants with OUD to either oral methadone or wait list; at ten months, they reported the number of days participants engaged in illegal activity in the past 30.
      • Gordon M.S.
      • Kinlock T.W.
      • Schwartz R.P.
      • O'Grady K.E.
      A randomized clinical trial of methadone maintenance for prisoners: Findings at 6 months post-release.
      randomized 141former prisoners to oral methadone or a passive referral to methadone and at six months reported the number of days participants engaged in crime. Pooled analysis of these two trials showed methadone patients spent significantly less time engaged in crime than did comparison patients (SMD −0.57; 95% CI −1.00, −0.13; I2 74%). Between-study heterogeneity was substantial. While the direction of effects was similar, point estimates varied somewhat, but given the small number of studies, we were unable to investigate sources of systematic differences between the studies.
      Additional studies reported on crime outcomes but could not be pooled. A 5-month double-blind RCT of 95 OUD participants that compared the effects of two methadone doses and a placebo on the mean number of days of illegal activity found no significant difference between 20 mg methadone and placebo (mean difference (MD) 3.00 days; CI −2.34, 8.34). However, 50 mg methadone was significantly more effective than placebo (MD −2.50 days; CI −7.63, −2.63). Comparing the number of crimes committed, both 20 mg (MD 4.0 fewer crimes) and 50 mg (MD 9.23 fewer crimes) methadone were significantly more effective than the placebo (
      • Strain E.C.
      • Stitzer M.L.
      • Liebson I.A.
      • Bigelow G.E.
      Methadone dose and treatment outcome.
      ). Another RCT that randomized 111 offenders with OUD to receive oral naltrexone with standard psychological treatment or standard psychological treatment alone (control) reported no significant difference between groups in the average number of charges (MD-0.30 fewer charges) or convictions per month (MD 0.00 fewer charges; SD not reported;
      • Coviello D.M.
      • Cornish J.W.
      • Lynch K.G.
      • Alterman A.I.
      • O'Brien C.P.
      A randomized trial of oral naltrexone for treating opioid-dependent offenders.
      ). A recent RCT of extended release naltrexone injection versus treatment as usual (
      • Murphy S.M.
      • Polsky D.
      • Lee J.D.
      • Friedmann P.D.
      • Kinlock T.W.
      • Nunes E.V.
      • O'Brien C.P.
      Cost-effectiveness of extended release naltrexone to prevent relapse among criminal justice-involved individuals with a history of opioid use disorder.
      ) reported that the mean number arrests at 78 week follow up was significantly lower in naltrexone patients (SMD −0.23, CI −0.46, −0.01).
      An RCT that compared the effects of methadone and naltrexone (
      • Lobmaier P.P.
      • Kunoe N.
      • Gossop M.
      • Katevoll T.
      • Waal H.
      Naltrexone implants compared to methadone: Outcomes six months after prison release.
      ) found no significant difference in the mean number of days patients engaged in illegal activity (MD 0.50 day; CI −9.98, 10.98).
      One large cohort study (
      • Crits-Christoph P.
      • Lundy C.
      • Stringer M.
      • Gallop R.
      • Gastfriend D.R.
      Extended-release naltrexone for alcohol and opioid problems in Missouri parolees and probationers.
      ) followed participants who received XR-NTX, oral naltrexone, buprenorphine-naloxone, or psychosocial treatment without medication (total N = 2882) and found no significant differences across treatment groups in mean number of arrests 30 days after discharge. The authors suggested that the 30-day follow-up period was too short to assess outcomes such as arrests.

      3.5.5 Arrested or incarcerated – percent of participants

      Six RCTs compared the effects of MAT to various controls on arrests and incarcerations. Comparators included passive referral (
      • Kinlock T.W.
      • Gordon M.S.
      • Schwartz R.P.
      • Fitzgerald T.T.
      • O'Grady K.E.
      A randomized clinical trial of methadone maintenance for prisoners: Results at 12 months postrelease.
      ), wait list (
      • Schwartz R.P.
      • Jaffe J.H.
      • O'Grady K.E.
      • Kinlock T.W.
      • Gordon M.S.
      • Kelly S.M.
      • Ahmed A.
      Interim methadone treatment: Impact on arrests.
      ), behavioral treatment without MAT (
      • Lee J.D.
      • Friedmann P.D.
      • Kinlock T.W.
      • Nunes E.V.
      • Boney T.Y.
      • Hoskinson Jr., R.A.
      • O'Brien C.P.
      Extended-release naltrexone to prevent opioid relapse in criminal justice offenders.
      ;
      • Bale R.N.
      • Van Stone W.W.
      • Kuldau J.M.
      • Engelsing T.M.J.
      • Elashoff R.M.
      • Zarcone V.P.
      Therapeutic communities vs methadone maintenance: A prospective controlled study of narcotic addiction treatment-design and one-year follow-up.
      ), and placebo (
      • Dole V.P.
      • Robinson J.W.
      • Orraca J.
      • Towns E.
      • Searcy P.
      • Caine E.
      • Author A.
      Methadone treatment of randomly selected criminal addicts.
      ;
      • Cornish J.W.
      • Metzger D.
      • Woody G.E.
      • Wilson D.
      • McLellan A.T.
      • Vandergrift B.
      • O'Brien C.P.
      Naltrexone pharmacotherapy for opioid dependent federal probationers.
      ). Three studies reported follow up at six months and three reported at one year. Pooled results are displayed in Fig. 5. No statistically significant difference in arrest rates was observed between MAT patients and those not receiving MAT (MAT: 36.15%; no MAT: 43.19%; RR 0.75; CI 0.46, 1.23; 6 RCTs; I2 85%; tau2 0.065). The I2 statistic indicated substantial heterogeneity, leading to a low quality of evidence rating. Excluding a methadone study from 1969 that reported the largest effect (
      • Dole V.P.
      • Robinson J.W.
      • Orraca J.
      • Towns E.
      • Searcy P.
      • Caine E.
      • Author A.
      Methadone treatment of randomly selected criminal addicts.
      ) did not substantially reduce the heterogeneity (I2 83%). Excluding two studies that reported data from before 1980 reduced the heterogeneity (I2 66%) without substantially altering the effect estimate (RR 0.81; 95% CI 0.50, 1.30).
      Fig. 5
      Fig. 5Percent arrested or incarcerated: MAT vs no MAT.
      Only one head-to-head study reported the prevalence of arrests. An RCT of 116 heroin-dependent inmates compared the effects of buprenorphine-naloxone combination and oral methadone in a correctional setting. Participants transferred to community MAT treatment after release. The percentage of participants who were arrested in the three months following release (MD −0.02; 95% CI −0.33, 0.29) was not significantly different between the buprenorphine-naloxone and methadone groups.
      Three observational studies also reported the percentage of individuals arrested, incarcerated, or engaging in illegal activity. Based on retrospective administrative data on women offenders admitted to the Correctional Service of Canada's opioid maintenance treatment (OMT) program between 2003 and 2008 (N = 137),
      • Farrell-MacDonald S.
      • MacSwain M.A.
      • Cheverie M.
      • Tiesmaki M.
      • Fischer B.
      Impact of methadone maintenance treatment on women offenders' post-release recidivism.
      assessed the impact of OMT on post-release criminal re-offending and correctional readmission. Analysis by Cox proportional hazard modeling showed that patients on continuing Methadone Maintenance Therapy (MMT-C) had a 65% lower risk of returning to custody than a group that terminated treatment post-release and a group of non MMT controls with OUD).
      • Coviello D.M.
      • Zanis D.A.
      • Wesnoski S.A.
      • Lynch K.G.
      • Drapkin M.
      Characteristics and 9-month outcomes of discharged methadone maintenance clients.
      , compared outcomes among 230 opioid dependent patients who received active methadone maintenance or passive referral to a methadone clinic. At six months follow-up, the difference in the percent of each group engaged in illegal activity in the past 30 was not significant (maintenance: 15%; passive referral: 16%; RR 0.89; CI: 0.45, 1.75). Finally, comparing outcomes of patients who left the Netherlands' methadone maintenance system with those who stayed 5 years (N = 38),
      • Reijneveld S.A.
      • Plomp H.N.
      Methadone maintenance clients in Amsterdam after five years.
      found no statistically significant differences in criminal problems (“caught at least one time by police in past half year” - still in treatment: 29%; no longer in treatment: 24%; RR 0.82; CI 0.28, 2.45 and “at least some illegal activity/past week” - still in treatment: 10%; no longer in treatment: 6%; RR 0.62; CI 0.06, 6.25) between the two cohorts.

      3.5.6 Legal status

      Two studies found significant differences between MAT patients and control groups in ASI Legal scores (
      • Aalto M.
      • Visapää J.-P.
      • Halme J.T.
      • Fabritius C.
      • Salaspuro M.
      Effectiveness of buprenorphine maintenance treatment as compared to a syringe exchange program among buprenorphine misusing opioid-dependent patients.
      ;
      • Sees K.L.
      • Delucchi K.L.
      • Masson C.
      • Rosen A.
      • Clark H.W.
      • Robillard H.
      • Hall S.M.
      Methadone maintenance versus 180-day psychosocially enriched detoxification for treatment of opioid dependence: A randomized controlled trial.
      ). Aalto compared a matched cohort of 60 patients enrolled in either buprenorphine maintenance treatment or a syringe exchange program and found the buprenorphine group had significantly better outcomes (i.e. lower ASI Legal Scores) at three, six, and twelve months (12 month SMD −1.25; CI −2.05, −0.48). Sees randomized 179 participants to either methadone maintenance or a “psychologically enriched” detoxification program. At one-year follow-up, the methadone maintenance group had a significantly lower (better) mean ASI Legal Score (SMD 0.50; CI 0.15, 0.85).

      3.6 Neurological function

      Only one study, a head to head trial of buprenorphine versus methadone, reported an outcome in our neurological function category.

      3.6.1 Stress

      • Soyka M.
      • Hock B.
      • Kagerer S.
      • Lehnert R.
      • Limmer C.
      • Kuefner H.
      Less impairment on one portion of a driving-relevant psychomotor battery in buprenorphine-maintained than in methadone-maintained patients: Results of a randomized clinical trial.
      randomized 62 patients to either sublingual buprenorphine or oral methadone. Patients completed the Reactive Stress Tolerance test at eight to ten weeks. The differences in mean score for Phase 1 (SMD 0.12; CI −0.46, 0.69), Phase 2 (SMD −0.11; CI −0.69, 0.46), and Phase 3 (SMD 0.14, CI −0.44, 0.72) were not statistically significant.

      4. Discussion

      4.1 Summary of findings

      We identified at least one study for five functional outcome categories: cognitive, physical, social/behavioral, occupational, and neurological. However, the only specific outcome areas reported in more than one study were verbal memory, attention, insomnia, fatigue, and criminal activity; we conducted meta-analyses on attention, fatigue, insomnia, and arrests. Table 1 summarizes the meta-analysis results by comparator and displays the quality of evidence components and overall ratings.
      Table 1Summary of meta-analysis results.
      OutcomeNumber of studiesRisk of biasConsistencyDirectnessPrecisionPublication biasAbsolute risk, intervention group: n/NRelative effect-direction/magnitude (95% CI)Grade
      MAT patients versus healthy non drug user controls: no meta-analysis possible
      MAT patients versus persons with opioid use disorder (OUD) not on MAT
      Physical function: insomnia—MAT (buprenorphine or naltrexone) versus placebo5 RCTsLowConsistentDirectImpreciseNot calculable57/375No statistically significant difference, RR 1.09 (0.77, 1.53)Moderate
      Behavioral/social function: crime—percentage arrested or convicted, MAT (methadone, naltrexone) versus no MAT6 RCTs

      ModerateInconsistentDirectImpreciseNot calculable190/527No statistically significant difference, RR 0.75 (0.46, 1.23)Low
      MAT drug versus another MAT drug
      Cognitive function: attention, buprenorphine vs methadone3 RCTsHighConsistentDirectImpreciseNot calculableNANo statistically significant difference, SMD −0.12 (−0.76, 0.52)Low
      Physical function: insomnia, buprenorphine vs methadone3 RCTsLowConsistentDirectImpreciseNot calculable46/255No statistically significant difference, RR 1.11 (0.70, 1.75)Low
      Physical function: fatigue, buprenorphine vs methadone3 RCTsLowConsistentDirectPreciseNot calculable25/255Favors buprenorphine RR 0.62 (0.41, 0.95)Moderate
      NOTE: CI = confidence interval; N/A = not applicable; RCT = randomized controlled trial; RR = relative risk; SD = standard deviation; SMD = standardized mean difference. For dichotomous variables, n = number of persons experiencing an event (e.g., arrest), while N = sample size.
      Several of the individual studies that compared OUD patients who received MAT to those who did not reported significant positive effects of MAT on functional outcomes. However, in several studies, MAT patients performed significantly worse than matched healthy controls. Because of the limited number and quality of the studies, the quality of evidence supporting significant differences is low or very low. The only exception is moderate quality evidence supporting a lower prevalence of fatigue with buprenorphine compared to methadone.

      4.2 Limitations

      This review has several strengths: an a priori research design, duplicate study selection and data abstraction of study information, a comprehensive search of electronic databases, risk of bias assessments, and use of comprehensive quality of evidence assessments to formulate review conclusions. To avoid missing relevant studies, we screened 6877 full text articles for functional outcomes. However, our review has several limitations. First, very few studies of MAT reported functional outcomes; 40 MAT studies that met our study design criteria reported cognitive, physical, occupational social/behavioral, or neurological outcomes, while 324 studies were excluded for no functional outcomes. This lack of relevant data was not entirely unexpected, as studies of interventions for substance use disorder (SUD) tend to focus on reduction or cessation of substance use, treatment retention, and harm reduction. Still, as we limited our search to published, peer-reviewed studies, additional data may exist.
      The small number of studies reporting specific functional outcome measures limited the ability to conduct meta-analyses. Only six studies of naltrexone reported functional outcomes; most evidence is based on trials of methadone, buprenorphine, or buprenorphine plus naloxone. Furthermore, the majority of controlled trials had moderate to high risk of bias, primarily due to lack of participant blinding and high attrition rates. Given the difficulties in blinding head-to-head studies of medications that are clearly different in appearance (methadone is usually administered as a syrup, while buprenorphine is sublingual) and the nature of substance use disorder, these challenges were anticipated.
      We did not contact individual study authors: Results and quality ratings reported in the review are based on published data. Finally, although we calculated the I-squared statistic to assess heterogeneity among studies included in the meta-analyses, some undetected heterogeneity may exist. The I-squared statistic depends on statistical power, which is influenced primarily by the number and secondarily by the size of studies; the meta-analyses included a small number of studies, and study sample size was often small compared to typical studies of medications and health care interventions.

      4.3 Prior research

      We identified four recent systematic reviews on MAT and cognitive function (
      • Baldacchino A.
      • Armanyous M.
      • Balfour D.J.K.
      • Humphris G.
      • Matthews K.
      Neuropsychological functioning and chronic methadone use: A systematic review and meta-analysis.
      ;
      • Strand M.C.
      • Fjeld B.
      • Arnestad M.
      • Morland J.
      Can patients receiving opioid maintenance therapy safely drive? A systematic review of epidemiological and experimental studies on driving ability with a focus on concomitant methadone or buprenorphine administration.
      ;
      • Wang G.Y.
      • Wouldes T.A.
      • Russell B.R.
      Methadone maintenance treatment and cognitive function: A systematic review.
      ;
      • Biernacki K.
      • McLennan S.N.
      • Terrett G.
      • Labuschagne I.
      • Rendell P.G.
      • Author A.
      • Victoria A.
      Decision-making ability in current and past users of opiates: A meta-analysis.
      ). All used less restrictive inclusion criteria than our review: The majority included cross-sectional designs with no follow up. The results reported in these publications echo our findings that MAT patients may perform worse than healthy controls. However, it is unclear if the observed differences are due to MAT or to long term use of opioids in general. Although controls are usually matched to patients on demographic and other characteristics, they clearly differ in substance abuse history and may differ in unreported psychological, psychiatric, and family history characteristics that might contribute to poor function.

      5. Conclusions

      Unfortunately, weaknesses in the body of evidence prevent any strong conclusions about the effects of MAT on functional outcomes or differences among medication types. Some studies that compared MAT patients to persons with OUD who did not receive MAT reported significant beneficial effects regarding criminal activity. However, in studies that compared MAT patients to matched healthy controls, they performed worse on measures of aggression, working memory, and cognitive speed. Furthermore, no studies reported performance on specific occupational tasks or discussed the applicability of the outcome measures to military deployment. Still, the results of this systematic review may be of interest to employers and substance abuse treatment providers. Additional well-designed research studies could shine light on how long-term use of MAT effects functional outcomes.

      Conflicts of interest

      None.

      Acknowledgements

      We thank Dr. Fuad Issa at the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury (DCoE), Dr. Melissa Fraine at the Defense Health Agency (DHA), and Dr. Thomas Concannon at RAND for their helpful feedback on the study protocol. We thank Dr. Concannon, Dr. William Sauve at Greenbrook TMS, and Drs. Marija Kelber and Marjorie Campbell of the Deployment Health Clinical Center (DHCC) for their helpful comments on the research. In addition, we thank Dr. Bradley Belsher, project monitor at DCoE, for his ongoing support of the project.

      Financial support

      This research is sponsored by the US Department of Defense, Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury (DCoE), contract number HQ0034-16-D-0001. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the views of the funder.

      Appendix A. Search methodology

      DATABASE SEARCHED AND TIME PERIOD COVERED
      PubMed: January 1, 1970–July 31, 2017.
      LANGUAGE
      English.
      SEARCH STRATEGY
      ((narcotic* OR opiate* OR opioid* OR heroin OR morphine) AND (misuse or abus* or addict* OR habit* OR withdraw*)) OR “Opioid-Related Disorders”[Mesh]
      AND
      “medication assisted treatment” OR “medication-assisted treatment” OR buprenorphine OR methadone OR naltrexone
      AND
      (humans[MESH] OR ((inprocess[sb] OR publisher[sb] OR pubmednotmedline [sb]) NOT (mice[ti] OR mouse[ti] OR rats[ti] OR rat[ti] OR dogs[ti]))).
      DATABASE SEARCHED AND TIME PERIOD COVERED
      PubMed: January 1, 1970–July 31, 2017.
      LANGUAGE
      English.
      SEARCH STRATEGY
      “Opioid-Related Disorders”[Mesh] OR narcotic* OR opiate* OR opioid* OR heroin OR morphine
      AND
      misuse or abus* or addict* OR habit* OR withdraw*
      AND
      random* OR randomized controlled trial[pt] OR randomized controlled trials OR rct* OR blind* OR double-blind* OR single-blind*.
      DATABASE SEARCHED AND TIME PERIOD COVERED
      PsycINFO: January 1, 1970–July 31, 2017.
      LANGUAGE
      English.
      SEARCH STRATEGY
      TI (“medication assisted treatment” OR “medication-assisted treatment” OR buprenorphine OR methadone OR naltrexone) OR SU (“medication assisted treatment” OR “medication-assisted treatment” OR buprenorphine OR methadone OR naltrexone) OR AB (“medication assisted treatment” OR “medication-assisted treatment” OR buprenorphine OR methadone OR naltrexone)
      AND
      TI ((narcotic* OR opiate* OR opioid* OR heroin OR morphine) AND (misuse or abus* or addict* OR habit* OR withdraw*)) OR SU ((narcotic* OR opiate* OR opioid* OR heroin OR morphine) AND (misuse or abus* or addict* OR habit* OR withdraw*)) OR AB ((narcotic* OR opiate* OR opioid* OR heroin OR morphine) AND (misuse or abus* or addict* OR habit* OR withdraw*))
      AND
      TI (randomi* OR “systematic review”) OR SU (randomi* OR “systematic review”) OR AB (randomi* OR “systematic review”).
      DATABASE SEARCHED AND TIME PERIOD COVERED
      PsycINFO: January 1, 1970–July 30, 2017.
      LANGUAGE
      English.
      SEARCH STRATEGY
      [TI (“medication assisted treatment” OR “medication-assisted treatment” OR buprenorphine OR methadone OR naltrexone) OR SU (“medication assisted treatment” OR “medication-assisted treatment” OR buprenorphine OR methadone OR naltrexone) OR AB (“medication assisted treatment” OR “medication-assisted treatment” OR buprenorphine OR methadone OR naltrexone) OR DE “Narcotic Antagonists” OR DE “Nalorphine” OR DE “Naloxone” OR DE “Naltrexone”
      AND
      DE “Opiates” OR DE “Codeine” OR DE “Heroin” OR DE “Morphine”
      AND
      DE “Drug Addiction” OR DE “Addiction” OR DE “Drug Dependency” OR DE “Heroin Addiction” OR DE “Drug Abuse” OR DE “Drug Overdoses” OR DE “Drug Withdrawal” OR DE “Intravenous Drug Usage” OR DE “Substance Use Disorder”.
      OR
      TI (“medication assisted treatment” OR “medication-assisted treatment” OR buprenorphine OR methadone OR naltrexone) OR SU (“medication assisted treatment” OR “medication-assisted treatment” OR buprenorphine OR methadone OR naltrexone) OR AB (“medication assisted treatment” OR “medication-assisted treatment” OR buprenorphine OR methadone OR naltrexone) OR DE “Narcotic Antagonists” OR DE “Nalorphine” OR DE “Naloxone” OR DE “Naltrexone”
      AND
      TI (narcotic* OR opiate* OR opioid* OR heroin OR morphine) AND (misuse or abus* or addict* OR habit* OR withdraw*) OR SU ((narcotic* OR opiate* OR opioid* OR heroin OR morphine) AND (misuse or abus* or addict* OR habit* OR withdraw*) OR AB ((narcotic* OR opiate* OR opioid* OR heroin OR morphine) AND (misuse or abus* or addict* OR habit* OR withdraw*))
      AND
      TI (control* OR case-control*) OR SU (control* OR case-control*) OR AB (control* OR case-control*).
      OR
      TI (random* OR rct*) OR SU (random* OR rct*) OR AB (random* OR rct*)
      AND
      Narrow by Population: - human.
      DATABASE SEARCHED AND TIME PERIOD COVERED
      CINAHL: January 1, 1970–July 31, 2017.
      LANGUAGE
      English.
      SEARCH STRATEGY
      TI (“medication assisted treatment” OR “medication-assisted treatment” OR buprenorphine OR methadone OR naltrexone) OR AB (“medication assisted treatment” OR “medication-assisted treatment” OR buprenorphine OR methadone OR naltrexone) OR SU (“medication assisted treatment” OR “medication-assisted treatment” OR buprenorphine OR methadone OR naltrexone)
      AND
      TI ((narcotic* OR opiate* OR opioid* OR heroin OR morphine) AND (misuse or abus* or addict* OR habit* OR withdraw*)) OR AB ((narcotic* OR opiate* OR opioid* OR heroin OR morphine) AND (misuse or abus* or addict* OR habit* OR withdraw*) OR SU ((narcotic* OR opiate* OR opioid* OR heroin OR morphine) AND (misuse or abus* or addict* OR habit* OR withdraw*))
      AND
      TI (randomi* OR “systematic review”) OR SU (randomi* OR “systematic review”) OR AB (randomi* OR “systematic review”).
      OR
      TI (control* OR case-control) OR AB (control* OR case-control) OR SU (control* OR case-control).
      DATABASE SEARCHED AND TIME PERIOD COVERED
      Cochrane Database of Systematic Reviews, Other Reviews, CENTRAL: January 1, 2000–July 31, 2017.
      SEARCH STRATEGY
      (narcotic* or opiate* or opioid* or heroin or morphine) and (misuse or abus* or addict* or habit* or withdraw*):ti,ab,kw (Word variations have been searched) OR MeSH descriptor: [Opioid-Related Disorders] explode all trees
      AND
      “medication assisted treatment” or “medication-assisted treatment” or buprenorphine or methadone or naltrexone:ti,ab,kw (Word variations have been searched).
      DATABASE SEARCHED AND TIME PERIOD COVERED
      Cochrane CENTRAL: January 1, 1970–July 31, 2017.
      SEARCH STRATEGY
      (narcotic* or opiate* or opioid* or heroin or morphine) and (misuse or abus* or addict* or habit* or withdraw*):ti,ab,kw (Word variations have been searched) OR MeSH descriptor: [Opioid-Related Disorders] explode all trees
      AND
      “medication assisted treatment” or “medication-assisted treatment” or buprenorphine or methadone or naltrexone:ti,ab,kw (Word variations have been searched).
      DATABASE SEARCHED AND TIME PERIOD COVERED
      EMBASE: From inception–July 31, 2017.
      LANGUAGE
      English.
      SEARCH STRATEGY
      ‘narcotic dependence’/exp OR ((narcotic* OR opiate* OR opioid* OR heroin OR morphine) AND (misuse OR abus* OR addict* OR habit* OR withdraw* OR depend*))
      AND
      ‘medication assisted treatment’ OR ‘medication-assisted treatment’ OR buprenorphine OR methadone OR naltrexone
      AND
      random* OR rct* OR blind* OR ‘double blind*’ OR ‘single blind*’ OR systematic OR ‘meta analy*’ OR
      ‘double blind procedure’/de OR ‘randomized controlled trial’/de OR ‘randomized controlled trial (topic)’/de OR ‘systematic review’/de.

      Appendix B. Description of included studies

      Tabled 1
      Study detailsParticipantsIntervention and comparator
      Reference:
      • Aalto M.
      • Visapää J.-P.
      • Halme J.T.
      • Fabritius C.
      • Salaspuro M.
      Effectiveness of buprenorphine maintenance treatment as compared to a syringe exchange program among buprenorphine misusing opioid-dependent patients.


      Location: Europe

      Study design: case-control
      Number enrolled: 60

      Number completed: 54

      Mean age: buprenorphine: 26.7 (4.9), Syringe Exchange Program: 26.5 (4.6)

      Percentage female: 20

      Race/ethnicity: NR

      Years of opioid use: buprenorphine: 3.6 (1.7)

      Syringe Exchange Program: 4.2 (1.8)

      Inclusion criteria: ICD-10 opioid dependence, previous participation in detoxification

      Exclusion criteria: NR
      Intervention: buprenorphine

      Setting: other substance abuse treatment

      Route of administration: oral

      Duration (months): 23

      Non-MAT comparator: Syringe exchange program
      Reference:
      • Bale R.N.
      • Van Stone W.W.
      • Kuldau J.M.
      • Engelsing T.M.J.
      • Elashoff R.M.
      • Zarcone V.P.
      Therapeutic communities vs methadone maintenance: A prospective controlled study of narcotic addiction treatment-design and one-year follow-up.


      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 585

      Number completed: 545

      Mean age: >25 years = 63%

      Percentage female: 0

      Race/ethnicity: White: 39%, Black: 41%, Hispanic: 12%

      Years of opioid use: NR

      Inclusion criteria: Daily narcotics use, no recent hospital treatment

      Exclusion criteria: Major psychiatric problems, pending felony charges
      Intervention: methadone

      Setting: methadone clinic

      Route of administration: oral

      Duration (months): NR

      Non-MAT comparator:

      • 1.
        Residential therapeutic community using group confrontation and support (often called “Synanon style”).
      • 2.
        Residential therapeutic community using limited group confrontation in combination with other therapeutic techniques.
      • 3.
        Residential therapeutic community with emphasis on historical material and reconstruction therapy
      Reference:
      • Compton P.
      • Canamar C.P.
      • Hillhouse M.
      • Ling W.
      Hyperalgesia in heroin dependent patients and the effects of opioid substitution therapy.


      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 103

      Number completed: 51

      Mean age: control: 30.14 (11), buprenorphine: 33.41 (9) methadone: 34.55 (12)

      Percentage female: 35.9

      Race/ethnicity: White: 79.6%, Black: 5.8%, Asian: 1.9%, other: 12.6%

      Years of opioid use: NR

      Inclusion criteria: ≥18 years old; good physical health; no existing conditions that would affect sensitivity to cold or pain responses; no cardiovascular conditions; DSM-IV heroin dependence.

      Exclusion criteria: Sensitivity to methadone or buprenorphine; dependence on other drugs or alcohol; medical conditions that would make participation hazardous; severe psychiatric disorders; levo-alpha-acetylmethadol, methadone or naltrexone within 30 days; discontinued participation in an opiate-substitution program within 30 days; or any pending legal action that could prohibit sustained participation. For the control group: nursing; pregnant; history of substance abuse.
      Intervention 1: methadone

      Setting: other substance abuse treatment

      Route of administration: NR

      Duration (months): 4.5

      Intervention 2: buprenorphine

      Setting: other substance abuse treatment

      Route of administration: NR

      Duration (months): 4.5

      Non-MAT Comparator: drug-free controls
      Reference:
      • Cornish J.W.
      • Metzger D.
      • Woody G.E.
      • Wilson D.
      • McLellan A.T.
      • Vandergrift B.
      • O'Brien C.P.
      Naltrexone pharmacotherapy for opioid dependent federal probationers.


      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 51

      Number completed: 24

      Mean age: 39

      Percentage female: 10

      Race/ethnicity: White: 24%, Black: 62%, Hispanic: 14%

      Years of opioid use: NR

      Inclusion criteria: Federal probationers or parolees; opioid use disorder

      Exclusion criteria: NR
      Intervention: naltrexone

      Setting: an office within the probation department

      Route of administration: oral

      Duration (months): 6

      Non-MAT comparator: Counseling during the first 2 weeks of the study. Twice weekly meetings with parole or probation office with drug use testing (urine and breathalyzer).
      Reference:
      • Corsenac P.
      • Lagarde E.
      • Gadegbeku B.
      • Delorme B.
      • Tricotel A.
      • Castot A.
      • Orriols L.
      Road traffic crashes and prescribed methadone and buprenorphine: A French registry-based case-control study.


      Location: Europe

      Study design: case control
      Number enrolled: 72,685

      Number completed: 72,685

      Mean age: NR

      Percentage female: 31.5

      Race/ethnicity: NR

      Years of opioid use: not applicable

      Inclusion criteria: Police reports identified drivers through their national ID, gender, and date of birth, Data on reimbursed medicines dispensed within six months before the crash were obtained by linking drivers to the national health care insurance database.

      Exclusion criteria: Not applicable
      Intervention: methadone, buprenorphine

      Setting: not applicable, study of traffic accident data

      Route of administration: not applicable

      Duration (months): not applicable

      Non-MAT comparator: General population. Collected from police reports and databases through ID extraction.
      Reference:
      • Coviello D.M.
      • Cornish J.W.
      • Lynch K.G.
      • Alterman A.I.
      • O'Brien C.P.
      A randomized trial of oral naltrexone for treating opioid-dependent offenders.


      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 111

      Number completed: 34

      Mean age: 33.5

      Percentage female: 18

      Race/ethnicity: White: 47%, Black: 26%, Hispanic: 27%

      Years of opioid use: Heroin: 7.7

      Inclusion criteria: Age 18 to 55; DSM-IV opioid dependence; good general health as determined by a physical exam and lab tests; assigned to probation/parole for a minimum of 6 months; and being at least 3 days opioid-free prior to study (per drug testing).

      Exclusion criteria: Severe alcohol dependence requiring medical supervision for withdrawal; clinically significant abnormalities in hematology, chemistry, or urinalysis; dementia, mental retardation, schizophrenia, or psychosis; clinically significant cardiovascular, neurological, hepatic, renal, pulmonary, metabolic, endocrine, or gastrointestinal disorders; chronic pain disorder; or taken an opioid antagonist within the prior six months. Pregnant women also excluded.
      Intervention: naltrexone

      Setting: university research offices

      Route of administration: oral

      Duration (months): 6

      Non-MAT comparator: TAU (treatment as usual): psychological treatment at one of several community-based treatment programs or at the university.
      Reference:
      • Coviello D.M.
      • Zanis D.A.
      • Wesnoski S.A.
      • Lynch K.G.
      • Drapkin M.
      Characteristics and 9-month outcomes of discharged methadone maintenance clients.


      Location: United States or Canada

      Study design: cohort comparison
      Number enrolled: 490

      Number completed: 230

      Mean age: 44.2

      Percentage female: 18

      Race/ethnicity: White: 45%; Black: 51%; Hispanic: 4%; Asian: NR; other: NR

      Years of opioid use: heroin: 17.7; other opioids: 3.0

      Inclusion criteria: Discharged from methadone treatment program in a 3-year period, regardless of whether they completed “successfully.”

      Exclusion criteria: NR
      Intervention: methadone

      Setting: methadone clinic

      Route of administration: oral

      Duration (months): 3

      Non-MAT comparator: No methadone maintenance in past 3 months.
      Reference:
      • Crits-Christoph P.
      • Lundy C.
      • Stringer M.
      • Gallop R.
      • Gastfriend D.R.
      Extended-release naltrexone for alcohol and opioid problems in Missouri parolees and probationers.


      Location: United States or Canada

      Study design: cohort comparison
      Number enrolled: 2;882

      Number completed: 2;882

      Mean age: 34.7 (10.5)

      Percentage female: 25.2

      Race/ethnicity: White: 57.1%; Black: 39.7%; Other: 3.2%

      Years of opioid use: NR

      Inclusion criteria: ≥18 years old; opioid use as their primary, secondary, or tertiary substance use problem at admission; individuals who were on parole or probation

      Exclusion criteria: NR
      Intervention 1: naltrexone

      Setting: NR

      Route of administration: implant

      Duration (months): 3

      Intervention 2: naltrexone

      Setting: NR

      Route of administration: oral

      Duration (months): 2

      Intervention 3: buprenorphine-naloxone combination

      Setting: NR

      Route of administration: NR

      Duration (months): 2.5

      Non-MAT comparator: Psychosocial treatment, mean length = 85 days
      Reference:
      • Dole V.P.
      • Robinson J.W.
      • Orraca J.
      • Towns E.
      • Searcy P.
      • Caine E.
      • Author A.
      Methadone treatment of randomly selected criminal addicts.


      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 32

      Number completed: NR

      Mean age: 30.0 (5.1)

      Percentage female: NR

      Race/ethnicity: White: 46.8%; Black: 31.2%; Asian: 21.9%

      Years of opioid use: 12.7

      Inclusion criteria: Opioid dependence for at least 5 years; at least 5 convictions; not already committed to the custody of addiction services agency

      Exclusion criteria: NR
      Intervention: methadone

      Setting: prison; then methadone clinic

      Route of administration: oral

      Duration (months): NR

      Non-MAT comparator: Untreated controls
      Reference:
      • Dunlop A.J.
      • Brown A.L.
      • Oldmeadow C.
      • Harris A.
      • Gill A.
      • Sadler C.
      • Lintzeris N.
      Effectiveness and cost-effectiveness of unsupervised buprenorphine-naloxone for the treatment of heroin dependence in a randomized waitlist controlled trial.




      Location: Australia/NZ

      Study design: randomized controlled trial
      Number enrolled: 50

      Number completed: 40

      Mean age: 36.9 (8.1)

      Percentage female: 44.0

      Race/ethnicity: NR

      Years of opioid use: 13.5 (9.6)

      Inclusion criteria: ≥18 years old; dependent on heroin and no other substance (according to DSM-IV-IR); used heroin at least 20 of 28 days prior; stable housing

      Exclusion criteria: Pregnant; breastfeeding; children aged 16-years or younger at home and current child protection services involved; pending court case with a reasonable risk of a custodial sentence; dependent on other substances than heroin; opioid agonist treatment in the past month or >two weeks of consecutive treatment in the past three months; major medical or psychiatric conditions
      Intervention: buprenorphine-naloxone combination

      Setting: Outpatient/take home

      Route of administration: Oral

      Duration (months): 3

      Non-MAT comparator: Wait list
      Reference:
      • Farrell-MacDonald S.
      • MacSwain M.A.
      • Cheverie M.
      • Tiesmaki M.
      • Fischer B.
      Impact of methadone maintenance treatment on women offenders' post-release recidivism.


      Location: United States or Canada

      Study design: cohort comparison
      Number enrolled: 137

      Number completed: 137

      Mean age: continued MMT: 33.0 (7.2); MMT-T: 34.5 (8.0); no MMT 31.3 (7.4)

      Percentage female: 100

      Race/ethnicity: NR

      Years of opioid use: NR

      Inclusion criteria: Study used administrative data on a sample of women federal offenders initiated on MMT while incarcerated between 2003 and 2008 who were released into the community

      Exclusion criteria: NR
      Intervention: methadone

      Setting: prison; then community

      Route of administration: oral

      Duration (months): NR

      Non-MAT comparator: Offenders incarcerated and then community-released who were assessed at correctional intake as having a moderate to severe opioid abuse problem, but who did not participate in MMT while incarcerated
      Reference:
      • Fudala P.J.
      • Bridge T.P.
      • Herbert S.
      • Williford W.O.
      • Chiang C.N.
      • Jones K.
      • Tusel D.
      Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone.


      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 326

      Number completed: 243

      Mean age: buprenorphine-naloxone combination: 38.1 (8.3); buprenorphine: 36.6 (8.9); placebo: 38.0 (9.3)

      Percentage female: 35.3

      Race/ethnicity: White: 61%; Black: 28.5%; Hispanic: 7.1%; Asian: 2.2%; other: 1.2% (Native American)

      Mean years of opioid use: 7

      Inclusion criteria: Age 18 to 59; opiate dependence per DSM-IV; seeking opiate-substitution therapy

      Exclusion criteria: Pregnant or nursing women; conditions that made study participation medically hazardous; dependence on other drugs; other psychiatric diagnosis; and use of use of opiate-substitution drug within prior14 days
      Intervention 1: buprenorphine-naloxone combination

      Setting: doctor's office

      Route of administration: oral

      Duration (months): 1

      Intervention 2: buprenorphine

      Setting: doctor's office

      Route of administration: oral

      Duration (months): 1

      Non-MAT comparator:

      Placebo plus counseling
      Reference:
      • Gerra G.
      • Zaimovic A.
      • Raggi M.A.
      • Moi G.
      • Branchi B.
      • Moroni M.
      • Brambilla F.
      Experimentally induced aggressiveness in heroin-dependent patients treated with buprenorphine: Comparison of patients receiving methadone and healthy subjects.


      Location: Europe

      Study design: randomized controlled trial
      Number enrolled: 45

      Number completed: NR

      Mean age: heroin users: 25 (5.3); healthy controls: 24.4 (3.6)

      Percentage female: 0

      Race/ethnicity: NR

      Years of opioid use: 9.2 (3.9)

      Inclusion criteria: Male; opioid dependent. Fifteen healthy male volunteers who were recruited from hospital staff, university students, and workers, were matched to the patients for age.

      Exclusion criteria: Severe chronic liver or renal disease; chronic physical disorders; recent weight loss or obesity; endocrinopathies; immunopathies; HIV disease.
      Intervention 1: buprenorphine

      Setting: other (outpatient center)

      Route of administration: oral

      Duration (months): 3

      Intervention 2: methadone

      Setting: other (outpatient center)

      Route of administration: oral

      Duration (months): 3

      Non-MAT comparator:

      Healthy (per medical exam and lab tests) male volunteers; recruited from hospital staff; university students; and workers; and who were matched to the patients for age (20–33 years: mean ± S.D. = 24.4 ± 3.6 years); served as controls.
      Reference:
      • Giacomuzzi S.M.
      • Riemer Y.
      • Ertl M.
      • Kemmler G.
      • Rössler H.
      • Hinterhuber H.
      • Kurz M.
      Buprenorphine versus methadone maintenance treatment in an ambulant setting: A health-related quality of life assessment.


      Location: Europe

      Study design: cohort comparison
      Number enrolled: 67

      Number completed: 53

      Mean age: methadone: 26.2; buprenorphine: 30.2

      Percentage female: 34

      Race/ethnicity: NR

      Years of opioid use: methadone: 7.9; buprenorphine: 9.2

      Inclusion criteria: Opioid dependence per DSM-IV

      Exclusion criteria: NR. Subjects could be discharged for drug trafficking or aggressive behavior.
      Intervention 1: methadone

      Setting: university hospital

      Route of administration: oral

      Duration (months): 6

      Intervention 2: buprenorphine

      Setting: university hospital

      Route of administration: oral

      Duration (months): 6

      Non-MAT comparator: none
      Reference:
      • Giacomuzzi S.M.
      • Ertl M.
      • Kemmler G.
      • Riemer Y.
      • Vigl A.
      • Author A.
      • Department of Psychiatry, A. I. A
      Sublingual buprenorphine and methadone maintenance treatment: A three-year follow-up of quality of life assessment.


      Location: Europe

      Study design: randomized controlled trial
      Number enrolled: 53

      Number completed: 35

      Mean Age: methadone: 29.9 (5.5); buprenorphine 33.4 (7.6)

      Percentage female: 40

      Race/ethnicity: NR

      Years of opioid use: 11.3

      Inclusion criteria: Opioid dependence per DSM-IV

      Exclusion criteria: NR
      Intervention 1: buprenorphine

      Setting: NR

      Route of administration: oral

      Duration (months): 36

      Intervention 2: methadone

      Setting: NR

      Route of administration: NR

      Duration (months): 36

      Non-MAT comparator: none
      Reference:
      • Giacomuzzi S.
      • Kemmler G.
      • Ertl M.
      • Riemer Y.
      Opioid addicts at admission vs. slow-release oral morphine, methadone, and sublingual buprenorphine maintenance treatment participants.


      Location: Europe

      Study design: randomized controlled trial
      Number enrolled: 240

      Number completed: NR

      Mean age: methadone: 27.3 (6.4); buprenorphine: 26.3 (7.5); morphine: 27.8 (4.8); control at admission: 25.3 (7.1)

      Percentage female: 40.4

      Race/ethnicity: NR

      Years of opioid use: 8.1 years (SD 5.6)

      Inclusion criteria: ≥17 years old; opioid dependence per DSM-IV or participation in a methadone, sublingual buprenorphine, or slow-release oral morphine maintenance program for 6 months; live within commuting distance.

      Exclusion criteria: Acute medical conditions; current use of antipsychotic medication; participation in another clinical trial. Forced discharge criteria were limited to drug trafficking or aggressive behavior.
      Intervention 1: methadone

      Setting: university psychiatry department

      Route of administration: oral

      Duration (months): 6

      Intervention 2: buprenorphine

      Setting: university psychiatry department

      Route of administration: oral

      Duration (months): 6

      Non-MAT comparator: Opioid users seeking a maintenance treatment program
      Reference:
      • Gossop M.
      • Marsden J.
      • Stewart D.
      • Lehmann P.
      • Strang J.
      Methadone treatment practices and outcome for opiate addicts treated in drug clinics and in general practice: Results from the National Treatment Outcome Research Study.


      Location: Europe



      Study design: cohort comparison
      Number enrolled: 452

      Number completed: 452

      Mean age: 29

      Percentage female: 26.5

      Race/ethnicity: NR

      Years of opioid use: 8.8

      Inclusion criteria: All consecutive patients treated at a participating agency during the time period

      Exclusion criteria: NR
      Intervention 1: methadone

      Setting: methadone clinic

      Route of administration: oral

      Duration (months): NR

      Intervention 2: methadone

      Setting: doctor's office

      Route of administration: oral

      Duration (months): NR

      Non-MAT comparator: none
      Reference:
      • Kinlock T.W.
      • Gordon M.S.
      • Schwartz R.P.
      • Fitzgerald T.T.
      • O'Grady K.E.
      A randomized clinical trial of methadone maintenance for prisoners: Results at 12 months postrelease.
      (also
      • Gordon M.S.
      • Kinlock T.W.
      • Schwartz R.P.
      • O'Grady K.E.
      A randomized clinical trial of methadone maintenance for prisoners: Findings at 6 months post-release.
      )

      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 211

      Number completed: 204

      Mean age: 40.3 (7.1)

      Percentage female: 0

      Race/ethnicity: White: 24.0%; Black: 69.6%; Hispanic: NR; Asian: NR; other: 6.4%

      Years of opioid use: NR

      Inclusion criteria: Anticipated release from prison in 3 to 6 months; opioid dependence per DSM-IV; medical clearance; residing in Baltimore following release. Those who did not meet the heroin-dependence criterion were eligible if they were enrolled in an opioid treatment program in the year before incarceration.

      Exclusion criteria: Renal or liver failure; pending/unadjudicated charges which could have resulted in transfer to another correctional facility and/or additional prison time; and a pending parole hearing.
      Intervention: methadone

      Setting: prison; then community

      Route of administration: oral

      Duration (months): 12

      Non-MAT comparator:

      • 1.
        Counseling only—counseling in prison; with passive referral to treatment upon release.
      • 2.
        Counseling and transfer—counseling in prison; with immediate access to methadone maintenance treatment upon release from prison; but no maintenance treatment in prison.
      Reference:
      • Lee J.D.
      • Friedmann P.D.
      • Kinlock T.W.
      • Nunes E.V.
      • Boney T.Y.
      • Hoskinson Jr., R.A.
      • O'Brien C.P.
      Extended-release naltrexone to prevent opioid relapse in criminal justice offenders.


      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 308

      Number completed: 245

      Mean age: Sample mean 44 years; intervention 44.4 (9.2); control 43.2 (9.4)

      Percentage female: 15

      Race/ethnicity: White: intervention 20.4%; control 19.4%; Black: intervention 53.3%; control 47.7%; Hispanic: intervention 24.3%; control 29.0%

      Years of opioid use: NR

      Inclusion criteria: Age 18 to 60 years; opioid dependence per DSM-IV; goal of opiate-free treatment rather than opioid agonist or partial-agonist maintenance; an opioid-free status as confirmed by negative urine; residence in the community and receipt of an adjudicated sentence that included supervision in the previous year, release from jail or prison, a plea-bargain arrangement, or any community supervision; good health per history and physical exam.

      Exclusion criteria: Dependence on alcohol or other drugs; pregnancy or a plan to conceive; untreated psychiatric disorder or medical condition that might make participation hazardous; allergy to naltrexone; diagnosis of chronic pain; drug overdose in the past 3 years
      Intervention: naltrexone

      Setting: doctor's office

      Route of administration: injection

      Duration (months): 6

      Non-MAT comparator: Counseling focused on adverse events, the prevention of relapse and overdose, and support for community treatment involvement from the same trial personnel.
      Reference:
      • Ling W.
      • Casadonte P.
      • Bigelow G.
      • Kampman K.M.
      • Patkar A.
      • Bailey G.L.
      • Beebe K.L.
      Buprenorphine implants for treatment of opioid dependence: A randomized controlled trial.


      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 163

      Number completed: 88

      Mean age: buprenorphine: 35.8 (11.0); placebo: 39.3 (11.7)

      Percentage female: 31.3

      Race/ethnicity: White: 74.8%; Black: 12.3%; Hispanic: 14.7%; other: 12.9%

      Years of opioid use: NR

      Inclusion criteria: Aged 18 to 65 years; opioid dependence per DSM-IV

      Exclusion criteria: AIDS; dependence on other drugs or alcohol; received medication treatment for opioid dependence within the previous 90 days; diagnosis of chronic pain.
      Intervention: buprenorphine

      Setting: VA

      Route of administration: implant

      Duration(months): 6

      Non-MAT comparator: Placebo implant
      Reference:
      • Lobmaier P.P.
      • Kunoe N.
      • Gossop M.
      • Katevoll T.
      • Waal H.
      Naltrexone implants compared to methadone: Outcomes six months after prison release.


      Location: Europe

      Study design: randomized controlled trial
      Number enrolled: 46

      Number completed: unclear

      Mean age: 35.1 (7.0)

      Percentage female: 6.5

      Race/ethnicity: NR

      Years of opioid use: NR

      Inclusion criteria: Heroin dependence for at least 2 months prior to incarceration; sentence time remaining.

      Exclusion criteria: Untreated major depression or psychosis; pregnant; severe hepatic impairment.
      Intervention 1: naltrexone

      Setting: prison; then community

      Route of administration: implant

      Duration (months): 6

      Intervention 2: methadone

      Setting: prison; then community

      Route of administration: oral

      Duration (months): 6

      Non-MAT comparator: none
      Reference:
      • Magura S.
      • Lee J.D.
      • Hershberger J.
      • Joseph H.
      • Marsch L.
      • Shropshire C.
      • Rosenblum A.
      Buprenorphine and methadone maintenance in jail and post-release: A randomized clinical trial.


      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 116

      Number completed: 91

      Mean age: buprenorphine: 38.4 (7.9) methadone: 40.7 (9.1)

      Percentage female: 0

      Race/ethnicity: White: NR; Black: 25%; Hispanic: 63.8%; Asian: NR; other: NR

      Years of opioid use: NR

      Inclusion criteria: 18–65 years of age; inmates who were eligible for the Key Extended Entry Program (KEEP); sentenced to between 10 and 90 days of jail time; expected to reside in New York City after release

      Exclusion criteria: Already on methadone treatment upon remand to Rikers; psychotic symptoms requiring intervention; AIDS or serious opportunistic infection requiring treatment; unable to complete an English-language interview
      Intervention 1: buprenorphine-naloxone combination

      Setting: prison; then community

      Route of administration: oral

      Duration (months): 3

      Intervention 2: methadone

      Setting: prison; then community

      Route of administration: oral

      Duration (months): 3

      Non-MAT comparator: none
      Reference:
      • Mattick R.P.
      • Ali R.
      • White J.M.
      • O'Brien S.
      • Wolk S.
      • Danz C.
      Buprenorphine versus methadone maintenance therapy: A randomized double-blind trial with 405 opioid-dependent patients.


      Location: Australia; New Zealand

      Study design: randomized controlled trial
      Number enrolled: 405

      Number completed: 216

      Mean age: 30 (8)

      Percentage female: 31

      Race/ethnicity: other: English-speaking background: methadone 79%; buprenorphine: 79%; non-English-speaking background: methadone: 16% buprenorphine: 16%; indigenous: methadone: 5%; buprenorphine: 6%

      Years of opioid use: methadone: 7.6 (6.7); buprenorphine: 7.7 (7.0)

      Inclusion criteria: ≥18 years old; opioid dependence per DSM-IV; lived within commuting distance of the clinic.

      Exclusion criteria: Pregnant or nursing women; medical condition that may make participation hazardous; using anticonvulsant medication, disulfiram, or antipsychotic medication; in opioid replacement treatment in the preceding 30 days; unable to attend the clinic daily; in a study of buprenorphine previously; or currently in another clinical trial.
      Intervention 1: buprenorphine

      Setting: clinic

      Route of administration: oral

      Duration (months): 3.25

      Intervention 2: methadone

      Setting: methadone clinic

      Route of administration: oral

      Duration (months): 3.25

      Non-MAT comparator: None
      Reference:
      • Metrebian N.
      • Groshkova T.
      • Hellier J.
      • Charles V.
      • Martin A.
      • Forzisi L
      • Strang J.
      Drug use, health and social outcomes of hard-to-treat heroin addicts receiving supervised injectable opiate treatment: Secondary outcomes from the randomized injectable opioid treatment trial (RIOTT).
      (also
      • Gordon M.S.
      • Kinlock T.W.
      • Schwartz R.P.
      • O'Grady K.E.
      A randomized clinical trial of methadone maintenance for prisoners: Findings at 6 months post-release.
      )

      Location: Europe

      Study design: randomized controlled trial
      Number enrolled: 127

      Number completed: NR

      Mean age: 37.2 (6.5)

      Percentage female: 27

      Race/ethnicity: White: 96

      Years of opioid use: 16.6

      Inclusion criteria: Locally residing, treatment-resistant, chronic, opiate-dependent patients receiving oral substitution treatment (methadone or buprenorphine treatment) for at least 6 months - who, despite this, were still injecting street heroin on most days.

      Exclusion criteria: NR
      Intervention 1: methadone

      Setting: methadone clinic

      Route of administration: injection

      Duration (months): 6

      Intervention 2: methadone

      Setting: methadone clinic

      Route of administration: oral

      Duration (months): 6

      Non-MAT comparator: Supervised injectable heroin (not used as MAT in the United States.)
      Reference:
      • Mokri A.
      • Chawarski M.C.
      • Taherinakhost H.
      • Schottenfeld R.S.
      Medical treatments for opioid use disorder in Iran: A randomized, double-blind placebo-controlled comparison of buprenorphine/naloxone and naltrexone maintenance treatment.


      Location: Middle East

      Study design: randomized controlled trial
      Number enrolled: 129

      Number completed: 102

      Mean age: 28.6 (5.9)

      Percentage female: NR

      Race/ethnicity: NR

      Years of opioid use: 7.5

      Inclusion criteria: Opioid dependence per DSM-IV-TR

      Exclusion criteria: Dependence on other drugs or alcohol; psychosis; major mood disorder; suicide or violence risk; severe medical problems; elevated liver enzymes
      Intervention 1: naltrexone

      Setting: Outpatient

      Route of administration: Oral

      Duration (months): 3

      Intervention 2: buprenorphine-naloxone combination

      Setting: Outpatient

      Route of administration: Oral

      Duration (months): 3

      Non-MAT comparator: None
      Reference:
      • Murphy S.M.
      • Polsky D.
      • Lee J.D.
      • Friedmann P.D.
      • Kinlock T.W.
      • Nunes E.V.
      • O'Brien C.P.
      Cost-effectiveness of extended release naltrexone to prevent relapse among criminal justice-involved individuals with a history of opioid use disorder.


      Location: US/Canada

      Study design: randomized controlled trial
      Number enrolled: 208

      Number completed: 145

      Mean age: 43.8 (9.3)

      Percentage female: 15.25

      Race/ethnicity: 19.9% White; 50.5% Black; 26.7% Latino/a

      Years of opioid use: NR

      Inclusion criteria: Age 18 to 60 years; opioid dependence per DSM-IV; goal of opiate-free treatment rather than opioid agonist or partial-agonist maintenance; an opioid-free status as confirmed by negative urine; residence in the community and receipt of an adjudicated sentence that included supervision or, in the previous year, release from jail or prison, a plea-bargain arrangement, or any community supervision; good health per history and physical exam.

      Exclusion criteria: Dependence on alcohol or other drugs; pregnancy or a plan to conceive; untreated psychiatric disorder or medical condition that might make participation hazardous; allergy to naltrexone; diagnosis of chronic pain; drug overdose in the past 3 years
      Intervention: Naltrexone

      Setting: Outpatient Substance Abuse Tx

      Route of administration: Injection

      Duration (months): 6

      Non-MAT comparator: Counseling focused on adverse events, preventing relapse and overdose, and supporting any community treatment involvement
      Reference:
      • Neri S.
      • Bruno C.M.
      • Pulvirenti D.
      • Malaguarnera M.
      • Italiano C.
      • Mauceri B.
      • Noto R.
      Randomized clinical trial to compare the effects of methadone and buprenorphine on the immune system in drug abusers.




      Location: Europe



      Study design: randomized controlled trial
      Number enrolled: 62



      Number completed: 57



      Mean age: methadone: 27 (6); buprenorphine: 24 (5)



      Percentage female: 11.3



      Race/ethnicity: NR



      Years of opioid use: methadone: 2; buprenorphine: 2



      Inclusion criteria: Opioid dependence per DSM-IV



      Exclusion criteria: Severe psychiatric illness; dependence on other drugs or alcohol.
      Intervention: methadone



      Setting: other substance abuse treatment



      Route of administration: oral



      Duration (months): 12



      Intervention 2: buprenorphine



      Setting: other substance abuse treatment



      Route of administration: oral



      Duration (months): 12



      Non-MAT comparator: none
      Reference:
      • Neumann A.M.
      • Blondell R.D.
      • Jaanimagi U.
      • Giambrone A.K.
      • Homish G.G.
      • Lozano J.R.
      • Azadfard M.
      A preliminary study comparing methadone and buprenorphine in patients with chronic pain and coexistent opioid addiction.


      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 54

      Number completed: 26

      Mean age: 38.3 (9.7)

      Percentage female: 46.3

      Race/ethnicity: White: 85.2%

      Years of opioid use: NR

      Inclusion criteria: 18 years or older; chronic nonmalignant pain; addicted to prescription opioids.

      Exclusion criteria: Homeless; on parole; unable to give consent due to neuro or psychiatric disorder; co-occurring psychiatric disorder; cardiac issues; prior history of methadone or buprenorphine treatment; pregnant women.
      Intervention: buprenorphine-naloxone combination

      Setting: doctor's office

      Route of administration: oral

      Duration (months): 6

      Intervention 2: methadone

      Setting: doctor's office

      Route of administration: oral

      Duration (months): 6

      Non-MAT comparator: none
      Reference:
      • Newman R.G.
      • Whitehill W.B.
      Double-blind comparison of methadone and placebo maintenance treatments of narcotic addicts in Hong Kong.


      Location: Asia

      Study design: randomized controlled trial
      Number enrolled: 100

      Number completed: 100

      Mean age: 38

      Percentage female: NR

      Race/ethnicity: NR

      Years of opioid use: methadone: 15; control: 12

      Inclusion criteria: Male; age 22–58 years; history of heroin dependence for ≥4 year; at least one prior course of treatment; 3 consecutive positive urine tests for opioids; voluntary application for admission; proven local residence.

      Exclusion criteria: Criminal justice referrals; major psychiatric or medical illness
      Intervention: methadone

      Setting: methadone clinic

      Route of administration: oral

      Duration (months): NR

      Non-MAT comparator: Weaned from methadone by dose reduction; detoxification completed after 60 days. Thereafter, controls were maintained on a placebo solution.
      Reference:
      • Rapeli P.
      • Fabritius C.
      • Kalska H.
      • Alho H.
      Memory function in opioid-dependent patients treated with methadone or buprenorphine along with benzodiazepine: Longitudinal change in comparison to healthy individuals.
      (also
      • Rapeli P.
      • Fabritius C.
      • Kalska H.
      • Alho H.
      Cognitive functioning in opioid-dependent patients treated with buprenorphine, methadone, and other psychoactive medications: Stability and correlates.
      )

      Location: Europe

      Study design: case control
      Number enrolled: 43

      Number completed: unclear

      Mean age: methadone: 29.2 (6.8); buprenorphine: 27.7 (6.8); control: 28.7 (9.6)

      Percentage female: 44.2

      Race/ethnicity: NR

      Years of opioid use: methadone: 15.0 (5.1); buprenorphine: 13.4 (5.2)

      Inclusion criteria: 18 to 50 years old; native Finnish speaker; opioid dependence diagnosis per DSM-IV; start of opioid substitute therapy during the last 2 months; treatment using methadone; buprenorphine; or buprenorphine/naloxone.

      Exclusion criteria: Current intoxication; ongoing binge on any substance of abuse; or any extra psychoactive drug dose within 24 h; uncontrolled polysubstance abuse; acute alcohol abuse; acute axis I psychiatric morbidity other than substance abuse; severe brain injury; chronic neurological disease; history of other than substance induced psychoses; epileptic seizures; HIV; pregnancy; or primary cognitive deficit.
      Intervention: methadone

      Setting: other substance abuse treatment

      Route of administration: oral

      Duration (months): 6–9

      Intervention 2: buprenorphine

      Setting: other substance abuse treatment

      Route of administration: oral

      Duration (months): 6–9

      Non-MAT comparator: Healthy non drug-using adults
      • Reijneveld S.A.
      • Plomp H.N.
      Methadone maintenance clients in Amsterdam after five years.


      Location: Europe

      Study design: cohort comparison
      Number enrolled: 38

      Number completed: 38

      Mean age: current clients: 31.0 (1.5) and former clients 30.1 (1.2)

      Percentage female: 36.8

      Race/ethnicity: NR

      Years of opioid use: current clients 14.6 and former clients 11.9

      Inclusion criteria: Born in the Netherlands or a (former) Dutch colony (Surinam or the Dutch Antilles); registered inhabitant of the city of Amsterdam; and registered in the central methadone registry for the first time 5 years ago.

      Exclusion criteria: Clients who had left care were only included if they had received methadone in at least two instances 50 days apart to exclude clients only passing through the methadone maintenance system.
      Intervention: methadone

      Setting: doctor's office

      Route of administration: oral

      Duration (months): varies

      Non-MAT comparator: Individuals who enrolled in methadone maintenance but dropped out
      • Rosenthal R.N.
      • Ling W.
      • Casadonte P.
      • Vocci F.
      • Bailey G.L.
      • Kampman K.
      • Beebe K.L.
      Buprenorphine implants for treatment of opioid dependence: Randomized comparison to placebo and sublingual buprenorphine/naloxone.


      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 287

      Number completed: 163

      Mean age: 35.7

      Percentage female: 39

      Race/ethnicity: White: 83.3%; Black: 13.0%

      Years of opioid use: NR

      Inclusion criteria: Aged18–65 years; opioid dependence per DSM-IV

      Exclusion criteria: Pregnancy; AIDS; a clinically low platelet count; dependence on other drugs; received methadone or buprenorphine within 90 days; diagnosis of chronic pain.
      Intervention: buprenorphine

      Setting: home

      Route of administration: implant

      Duration (months): 6

      Intervention 2: buprenorphine-naloxone combination

      Setting: other substance abuse treatment

      Route of administration: oral

      Duration (months): 6

      Non-MAT comparator: Placebo implants plus counseling
      Reference:
      • Rosenthal R.N.
      • Ling W.
      • Casadonte P.
      • Vocci F.
      • Bailey G.L.
      • Kampman K.
      • Beebe K.L.
      Buprenorphine implants for treatment of opioid dependence: Randomized comparison to placebo and sublingual buprenorphine/naloxone.


      Location: US or Canada

      Study design: randomized controlled trial
      Number enrolled: 176

      Number completed: 165

      Mean age: 39 (11)

      Percentage female: 40.9

      Race/ethnicity: 94.9% White; 2.8% Black; 0.6% Asian/Pacific Islander; 1.7% Other

      Years of opioid use: NR

      Inclusion criteria: 18–65 years-old; opioid dependence; received sublingual buprenorphine for ≥6 months as an outpatient; and no evidence of opioid withdrawal or illicit opioid-positive urine samples at least 90 days prior

      Exclusion criteria: Pregnancy; lactation; planning pregnancy; lack of available implant sites; coagulopathy within 90 days; contraindication to MAT; chronic pain requiring opioids; AIDS; significant medical problems; dependence on drugs other than opioids or nicotine; pending legal action.
      Intervention 1: buprenorphine

      Setting: Outpatient substance abuse tx

      Route of administration: Implant

      Duration (months): 6

      Intervention 2: Buprenorphine

      Setting: Outpatient substance abuse tx

      Route of administration: Oral

      Duration (months): 6

      Non-MAT comparator: None
      Reference:
      • Schwartz R.P.
      • Jaffe J.H.
      • O'Grady K.E.
      • Kinlock T.W.
      • Gordon M.S.
      • Kelly S.M.
      • Ahmed A.
      Interim methadone treatment: Impact on arrests.
      (also
      • Schwartz R.P.
      • Jaffe J.H.
      • O'Grady K.E.
      • Kinlock T.W.
      • Gordon M.S.
      • Kelly S.M.
      • Ahmed A.
      Interim methadone treatment: Impact on arrests.
      )

      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 319

      Number completed: 134

      Mean age: 41.4 (6.0)

      Percentage female: 41

      Race/ethnicity: White: 6.6%; Black: 93.4%; Hispanic: NR; Asian: NR; other: NR

      Years of opioid use: NR

      Inclusion criteria: NR

      Exclusion criteria: NR
      Intervention: methadone

      Setting: clinic

      Route of administration: NR

      Duration (months): 10

      Non-MAT comparator: Wait list
      • Sees K.L.
      • Delucchi K.L.
      • Masson C.
      • Rosen A.
      • Clark H.W.
      • Robillard H.
      • Hall S.M.
      Methadone maintenance versus 180-day psychosocially enriched detoxification for treatment of opioid dependence: A randomized controlled trial.


      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 179

      Number completed: 134

      Mean age: methadone detoxification 39.4 (7.91); methadone maintenance 39.4 (8.57)

      Percentage female: 41.3

      Race/ethnicity: White: 51.4%; Black: 30.2%; Hispanic: 12.8%; other: 5.6%

      Years of opioid use: methadone detoxification 15.7 (9.26); MMT 16.6 (9.42)

      Inclusion criteria: Age ≥ 18 years; opioid dependence per DSM-III-R; urine screening positive for opioid other than methadone and negative for methadone.

      Exclusion criteria: Psychiatric or medical conditions that contraindicated methadone treatment; enrolled in other substance abuse treatment; methadone treatment within previous week or involved in a follow-up phase of a methadone detoxification research; not expected to remain in study for 1 year; no signs of opioid withdrawal on three occasions; pregnant or breastfeeding.
      Intervention: methadone detoxification only

      Setting: VA

      Route of administration: oral

      Duration (months): 14

      Intervention 2: methadone

      Setting: VA

      Route of administration: oral

      Duration (months): 14

      Non-MAT comparator: none
      Reference:
      • Senay E.C.
      • Barthwell A.G.
      • Marks R.
      • Bokos P.
      • Gillman D.
      • White R.
      Medical maintenance: a pilot study.


      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 130

      Number completed: 130

      Mean age: 41.4

      Percentage female: 33

      Race/ethnicity: White: 70.8%; Black: 17.7%; Hispanic: 11.5%

      Years of opioid use: NR

      Inclusion criteria: Age 21–60 years; in methadone treatment for past year; no plans to attend detoxification in coming year; not on parole or probation; clean urines for most recent 6-month period; employed or engaged in appropriate activity; no arrests.

      Exclusion criteria: NR
      Intervention: methadone

      Setting: home

      Route of administration: oral

      Duration (months): 6

      Intervention 2: methadone

      Setting: methadone clinic

      Route of administration: oral

      Duration (months): 6

      Non-MAT comparator: none
      Reference:
      • Soyka M.
      • Hock B.
      • Kagerer S.
      • Lehnert R.
      • Limmer C.
      • Kuefner H.
      Less impairment on one portion of a driving-relevant psychomotor battery in buprenorphine-maintained than in methadone-maintained patients: Results of a randomized clinical trial.


      Location: Europe

      Study design: randomized controlled trial
      Number enrolled: 62

      Number completed: 46

      Mean age: buprenorphine: 34.2; methadone: 32

      Percentage female: 41.3

      Race/ethnicity: NR

      Years of opioid use: buprenorphine: 11.5; methadone: 11

      Inclusion criteria: Opioid dependence per DSM-IV; free of withdrawal symptoms when tested; had a driver's license (valid or withdrawn) or were experienced drivers.

      Exclusion criteria: Disabling physical disorder; organic brain disorder.
      Intervention 1: buprenorphine

      Setting: unclear

      Route of administration: NR

      Duration (months): 2–2.5 (entire study)

      Intervention 2: methadone

      Setting: unclear

      Route of administration: NR

      Duration (months): follow up at 2–2.5 months (entire study 6 months)

      Non-MAT comparator: none
      Reference:
      • Soyka M.
      • Lieb M.
      • Kagerer S.
      • Zingg C.
      • Koller G.
      • Lehnert P.
      • Hennig-Fast K.
      Cognitive functioning during methadone and buprenorphine treatment: Results of a randomized clinical trial.


      Location: Europe

      Study design: randomized controlled trial
      Number enrolled: 59

      Number completed: 46

      Mean age: NR

      Percentage female: NR

      Race/ethnicity: NR

      Years of opioid use: NR

      Inclusion criteria: No history of organic brain syndrome, seizures, or memory loss; no cognitive or memory impairment; IQ ≥ 85; no neurological or psychiatric diagnosis or history other than opioid dependence. Healthy normal controls were matched for age, sex, and education level.

      Exclusion criteria: NR
      Intervention: methadone

      Setting: outpatient clinic

      Route of administration: oral

      Duration (months): 6

      Intervention 2: buprenorphine

      Setting: other; outpatient clinic

      Route of administration: oral

      Duration(months): 6

      Non-MAT comparator: Healthy normal controls matched for age, sex, and education level.
      • Strain E.C.
      • Stitzer M.L.
      • Liebson I.A.
      • Bigelow G.E.
      Methadone dose and treatment outcome.


      Location: United States or Canada

      Study design: randomized controlled trial
      Number enrolled: 95

      Number completed: 95

      Mean age: 34.7 (5.2)

      Percentage female: 32

      Race/ethnicity: Black: 52%

      Years of opioid use: 7.4

      Inclusion criteria: Aged 18 to 50 years; history of intravenous opioid dependence (e.g. documentation of previous treatment for opioid dependence, legal involvement secondary to opioid use, urine sample positive for opioids, physical exam consistent with needle use), no chronic medical illnesses; absence of major mental illness.

      Exclusion criteria: Pregnancy
      Intervention: methadone

      Setting: methadone clinic

      Route of administration: oral

      Duration (months): 9

      Intervention 2: methadone

      Setting: methadone clinic

      Route of administration: oral

      Duration (months): 9

      Non-MAT comparator: Placebo in addition to a 35-day methadone detoxification starting at 25 mg in the first week; and decreasing by 5 mg each week.
      • Strang J.
      • Marsden J.
      • Cummins M.
      • Farrell M.
      • Finch E.
      • Gossop M.
      • Welch S.
      Randomized trial of supervised injectable versus oral methadone maintenance: Report of feasibility and 6-month outcome.


      Location: Europe

      Study design: randomized controlled trial
      Number enrolled: 37

      Number completed: 33

      Mean age: IV MMT; 31.9; oral MMT; 32.1

      Percentage female: IV MMT; 9.5; oral MMT; 6.3

      Race/ethnicity: other; nonwhite; IV MMT; 9.5%; oral MMT: 12.5%

      Years of opioid use: NR

      Inclusion criteria: Age ≥ 23 years; illicit injecting for ≥3 years; at least one previous episode of opiate substitution treatment.

      Exclusion criteria: Pregnant; serious medical or psychiatric condition.
      Intervention: methadone

      Setting: methadone clinic

      Route of administration: injection

      Duration (months): 6

      Intervention 2: methadone

      Setting: methadone clinic

      Route of administration: oral

      Duration (months): 6

      Non-MAT comparator: none
      • Tiihonen J.
      • Krupitsky E.
      • Verbitskaya E.
      • Blokhina E.
      • Mamontova O.
      • Fohr J.
      • Zwartau E.
      Naltrexone implant for the treatment of polydrug dependence: A randomized controlled trial.


      Location: Europe

      Study design: randomized controlled trial
      Number enrolled: 100

      Number completed: 40

      Mean age: placebo: 29.3 (4.38); naltrexone: 28.0 (4.10)

      Percentage female: NR

      Race/ethnicity: NR

      Years of opioid use: placebo: 8.7 (2.83); naltrexone: 8.2 (3.75)

      Inclusion criteria: Age 18 to 50 years; concurrent amphetamine and opioid dependence per DSM-IV; high school graduate; negative urine toxicology and alcohol breath tests; no psychotropic medications; at least one relative willing to participate in the treatment (e.g.; to monitor the administration of medications; assist in follow-up; and provide outcome data); nearby residence.

      Exclusion criteria: Significant cognitive impairment, psychiatric disorder, or medical condition; a significant laboratory abnormality such as severe anemia, unstable diabetes, or liver function test; pregnancy; pending legal charges with potential incarceration; participation in another drug treatment study or program.
      Intervention: naltrexone

      Setting: other substance abuse treatment

      Route of administration: implant

      Duration (months): 2.5

      Non-MAT comparator: Placebo implant

      Appendix C. Risk of bias tables

      Tabled 1
      Risk of bias items for controlled trials
      ReferenceWas allocation sequence (randomization method) adequately generated?Was allocation adequately concealed (prior to assignment)?Were participants adequately blinded?Were outcome assessors adequately blinded?Incomplete outcome data (attrition bias) because of amount, nature, or handling of incomplete outcome dataIs there evidence of selective outcome reporting bias (yes/no)?Intention-to-treat analysis? (yes/no)Group similarity at baselineWas there incomplete compliance with interventions across groups?Additional bias: bias because of problems not covered elsewhere in the tableOverall ROB
      • Bale R.N.
      • Van Stone W.W.
      • Kuldau J.M.
      • Engelsing T.M.J.
      • Elashoff R.M.
      • Zarcone V.P.
      Therapeutic communities vs methadone maintenance: A prospective controlled study of narcotic addiction treatment-design and one-year follow-up.
      NoNoNoYesNoNoNoUnclearUnclearNoHigh
      • Compton P.
      • Canamar C.P.
      • Hillhouse M.
      • Ling W.
      Hyperalgesia in heroin dependent patients and the effects of opioid substitution therapy.
      UnclearNoNoNoYesNoNoYesNoNoHigh
      • Cornish J.W.
      • Metzger D.
      • Woody G.E.
      • Wilson D.
      • McLellan A.T.
      • Vandergrift B.
      • O'Brien C.P.
      Naltrexone pharmacotherapy for opioid dependent federal probationers.
      UnclearUnclearNoUnclearYesNoYesYesYesNoModerate
      • Coviello D.M.
      • Cornish J.W.
      • Lynch K.G.
      • Alterman A.I.
      • O'Brien C.P.
      A randomized trial of oral naltrexone for treating opioid-dependent offenders.
      YesUnclearNoYesNoNoYesNoUnclearNoModerate
      • Dole V.P.
      • Robinson J.W.
      • Orraca J.
      • Towns E.
      • Searcy P.
      • Caine E.
      • Author A.
      Methadone treatment of randomly selected criminal addicts.
      YesUnclearNoNoNoNoNoYesUnclearYesHigh
      • Dunlop A.J.
      • Brown A.L.
      • Oldmeadow C.
      • Harris A.
      • Gill A.
      • Sadler C.
      • Lintzeris N.
      Effectiveness and cost-effectiveness of unsupervised buprenorphine-naloxone for the treatment of heroin dependence in a randomized waitlist controlled trial.
      YesYesYesNoNoNoYesYesNoNoModerate
      • Fudala P.J.
      • Bridge T.P.
      • Herbert S.
      • Williford W.O.
      • Chiang C.N.
      • Jones K.
      • Tusel D.
      Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone.
      YesYesYesYesNoNoNoYesNoNoModerate
      • Gerra G.
      • Zaimovic A.
      • Raggi M.A.
      • Moi G.
      • Branchi B.
      • Moroni M.
      • Brambilla F.
      Experimentally induced aggressiveness in heroin-dependent patients treated with buprenorphine: Comparison of patients receiving methadone and healthy subjects.
      UnclearUnclearNoNoUnclearNoNoYesUnclearNoHigh
      • Giacomuzzi S.
      • Kemmler G.
      • Ertl M.
      • Riemer Y.
      Opioid addicts at admission vs. slow-release oral morphine, methadone, and sublingual buprenorphine maintenance treatment participants.
      UnclearUnclearNoNoNoNoUnclearYesNoNoHigh
      • Kinlock T.W.
      • Gordon M.S.
      • Schwartz R.P.
      • Fitzgerald T.T.
      • O'Grady K.E.
      A randomized clinical trial of methadone maintenance for prisoners: Results at 12 months postrelease.
      (also reported in
      • Gordon M.S.
      • Kinlock T.W.
      • Schwartz R.P.
      • O'Grady K.E.
      A randomized clinical trial of methadone maintenance for prisoners: Findings at 6 months post-release.
      )
      UnclearUnclearNoNoNoNoYesYesNoNoModerate
      • Lee J.D.
      • Friedmann P.D.
      • Kinlock T.W.
      • Nunes E.V.
      • Boney T.Y.
      • Hoskinson Jr., R.A.
      • O'Brien C.P.
      Extended-release naltrexone to prevent opioid relapse in criminal justice offenders.
      YesUnclearNoNoNoNoYesYesUnclearNoModerate
      • Ling W.
      • Casadonte P.
      • Bigelow G.
      • Kampman K.M.
      • Patkar A.
      • Bailey G.L.
      • Beebe K.L.
      Buprenorphine implants for treatment of opioid dependence: A randomized controlled trial.
      UnclearYesYesYesYesNoYesYesNoNoModerate
      • Lobmaier P.P.
      • Kunoe N.
      • Gossop M.
      • Katevoll T.
      • Waal H.
      Naltrexone implants compared to methadone: Outcomes six months after prison release.
      YesYesNoNoYesNoYesYesYesYesHigh
      • Magura S.
      • Lee J.D.
      • Hershberger J.
      • Joseph H.
      • Marsch L.
      • Shropshire C.
      • Rosenblum A.
      Buprenorphine and methadone maintenance in jail and post-release: A randomized clinical trial.
      YesYesYesYesYesNoNoYesYesNoModerate
      • Mattick R.P.
      • Ali R.
      • White J.M.
      • O'Brien S.
      • Wolk S.
      • Danz C.
      Buprenorphine versus methadone maintenance therapy: A randomized double-blind trial with 405 opioid-dependent patients.
      YesYesYesYesYesNoYesYesYesNoModerate
      • Metrebian N.
      • Groshkova T.
      • Hellier J.
      • Charles V.
      • Martin A.
      • Forzisi L
      • Strang J.
      Drug use, health and social outcomes of hard-to-treat heroin addicts receiving supervised injectable opiate treatment: Secondary outcomes from the randomized injectable opioid treatment trial (RIOTT).
      (also reported in
      • Byford S.
      • Barrett B.
      • Metrebian N.
      • Groshkova T.
      • Cary M.
      • Charles V.
      • Strang J.
      Cost-effectiveness of injectable opioid treatment v. oral methadone for chronic heroin addiction.
      )
      YesYesNoYesNoNoYesYesUnclearNoModerate
      • Mokri A.
      • Chawarski M.C.
      • Taherinakhost H.
      • Schottenfeld R.S.
      Medical treatments for opioid use disorder in Iran: A randomized, double-blind placebo-controlled comparison of buprenorphine/naloxone and naltrexone maintenance treatment.
      YesYesYesYesNoNoUnclearUnclearYesNoModerate
      • Murphy S.M.
      • Polsky D.
      • Lee J.D.
      • Friedmann P.D.
      • Kinlock T.W.
      • Nunes E.V.
      • O'Brien C.P.
      Cost-effectiveness of extended release naltrexone to prevent relapse among criminal justice-involved individuals with a history of opioid use disorder.
      YesYesYesUnclearNoNoYesYesUnclearNoModerate
      • Neri S.
      • Bruno C.M.
      • Pulvirenti D.
      • Malaguarnera M.
      • Italiano C.
      • Mauceri B.
      • Noto R.
      Randomized clinical trial to compare the effects of methadone and buprenorphine on the immune system in drug abusers.
      YesUnclearNoNoNoNoNoYesNoNoHigh
      • Neumann A.M.
      • Blondell R.D.
      • Jaanimagi U.
      • Giambrone A.K.
      • Homish G.G.
      • Lozano J.R.
      • Azadfard M.
      A preliminary study comparing methadone and buprenorphine in patients with chronic pain and coexistent opioid addiction.
      YesUnclearNoYesYesNoNoYesYesNoHigh
      • Newman R.G.
      • Whitehill W.B.
      Double-blind comparison of methadone and placebo maintenance treatments of narcotic addicts in Hong Kong.
      UnclearUnclearYesYesYesNoYesYesUnclearNoModerate
      • Rosenthal R.N.
      • Ling W.
      • Casadonte P.
      • Vocci F.
      • Bailey G.L.
      • Kampman K.
      • Beebe K.L.
      Buprenorphine implants for treatment of opioid dependence: Randomized comparison to placebo and sublingual buprenorphine/naloxone.
      YesYesYesYesYesNoYesYesNoNoModerate
      • Rosenthal R.N.
      • Lofwall M.R.
      • Kim S.
      • Chen M.
      • Beebe K.L.
      • Vocci F.J.
      Effect of buprenorphine implants on illicit opioid use among abstinent adults with opioid dependence treated with sublingual buprenorphine: A randomized clinical trial.
      YesYesYesYesNoNoYesYesNoNoLow
      • Schwartz R.P.
      • Jaffe J.H.
      • O'Grady K.E.
      • Kinlock T.W.
      • Gordon M.S.
      • Kelly S.M.
      • Ahmed A.
      Interim methadone treatment: Impact on arrests.
      (also reported in
      • Schwartz R.P.
      • Jaffe J.H.
      • Highfield D.A.
      • Callaman J.M.
      • O'Grady K.E.
      A randomized controlled trial of interim methadone maintenance: 10-month follow-up.
      )
      YesUnclearNoNoNoNoNoYesUnclearNoModerate
      • Sees K.L.
      • Delucchi K.L.
      • Masson C.
      • Rosen A.
      • Clark H.W.
      • Robillard H.
      • Hall S.M.
      Methadone maintenance versus 180-day psychosocially enriched detoxification for treatment of opioid dependence: A randomized controlled trial.
      YesYesNoYesNoNoYesYesYesNoModerate
      • Senay E.C.
      • Barthwell A.G.
      • Marks R.
      • Bokos P.
      • Gillman D.
      • White R.
      Medical maintenance: a pilot study.
      UnclearUnclearNoUnclearUnclearNoNoYesUnclearNoModerate
      • Soyka M.
      • Hock B.
      • Kagerer S.
      • Lehnert R.
      • Limmer C.
      • Kuefner H.
      Less impairment on one portion of a driving-relevant psychomotor battery in buprenorphine-maintained than in methadone-maintained patients: Results of a randomized clinical trial.
      UnclearUnclearNoNoYesNoNoYesUnclearNoHigh
      • Soyka M.
      • Lieb M.
      • Kagerer S.
      • Zingg C.
      • Koller G.
      • Lehnert P.
      • Hennig-Fast K.
      Cognitive functioning during methadone and buprenorphine treatment: Results of a randomized clinical trial.
      UnclearUnclearNoYesYesNoUnclearYesUnclearYesHigh
      • Strain E.C.
      • Stitzer M.L.
      • Liebson I.A.
      • Bigelow G.E.
      Methadone dose and treatment outcome.
      UnclearYesYesUnclearYesNoNoYesYesNoModerate
      • Strang J.
      • Marsden J.
      • Cummins M.
      • Farrell M.
      • Finch E.
      • Gossop M.
      • Welch S.
      Randomized trial of supervised injectable versus oral methadone maintenance: Report of feasibility and 6-month outcome.
      YesYesNoYesNoNoNoYesNoNoModerate
      • Tiihonen J.
      • Krupitsky E.
      • Verbitskaya E.
      • Blokhina E.
      • Mamontova O.
      • Fohr J.
      • Zwartau E.
      Naltrexone implant for the treatment of polydrug dependence: A randomized controlled trial.
      YesYesYesYesYesNoYesYesNoNoModerate
      Risk of bias for observational studies
      ReferenceRepresentativeness of the exposed cohortSelection of the nonexposed cohort (e.g., healthy controls or opioid-dependent participants receiving a different medication or not receiving MAT)Ascertainment of exposureDemonstration that outcome of interest was not present at start of studyComparability of cohorts on the basis of the design or analysisAssessment of outcomeWas follow-up long enough for outcome to occur?Adequacy of follow-up cohortsOverall ROB
      • Aalto M.
      • Visapää J.-P.
      • Halme J.T.
      • Fabritius C.
      • Salaspuro M.
      Effectiveness of buprenorphine maintenance treatment as compared to a syringe exchange program among buprenorphine misusing opioid-dependent patients.
      Truly representative of the average MAT patient in the communityDrawn from a different sourceSecure recordYesControls for demographics, controls for additional factorsSelf-reportYesDropout rate not acceptableHigh
      • Corsenac P.
      • Lagarde E.
      • Gadegbeku B.
      • Delorme B.
      • Tricotel A.
      • Castot A.
      • Orriols L.
      Road traffic crashes and prescribed methadone and buprenorphine: A French registry-based case-control study.
      Somewhat representative of the average MAT patient in the communityDrawn from the same community as the exposed cohortSecure recordYesControls for demographics, controls for additional factorsRecord linkYesComplete follow-up—all subjects accounted forLow
      • Coviello D.M.
      • Zanis D.A.
      • Wesnoski S.A.
      • Lynch K.G.
      • Drapkin M.
      Characteristics and 9-month outcomes of discharged methadone maintenance clients.
      Truly representative of the average MAT patient in the communityDrawn from the same community as the exposed cohortSecure record, structured interviewYesControls for demographics, controls for additional factorsSelf-reportYesSubjects lost to follow-up unlikely to introduce biasLow
      • Crits-Christoph P.
      • Lundy C.
      • Stringer M.
      • Gallop R.
      • Gastfriend D.R.
      Extended-release naltrexone for alcohol and opioid problems in Missouri parolees and probationers.
      Selected group of users (e.g., volunteers)Drawn from the same community as the exposed cohortSecure recordYesControls for demographicsRecord linkYesFollow-up rate not acceptableModerate
      • Farrell-MacDonald S.
      • MacSwain M.A.
      • Cheverie M.
      • Tiesmaki M.
      • Fischer B.
      Impact of methadone maintenance treatment on women offenders' post-release recidivism.
      Selected group of users (e.g., volunteers)Drawn from the same community as the exposed cohortSecure recordYesControls for demographicsRecord linkYesComplete follow-up—all subjects accounted forLow
      • Giacomuzzi S.M.
      • Ertl M.
      • Kemmler G.
      • Riemer Y.
      • Vigl A.
      • Author A.
      • Department of Psychiatry, A. I. A
      Sublingual buprenorphine and methadone maintenance treatment: A three-year follow-up of quality of life assessment.
      No description of the derivation of the cohortNo description of the derivation of the nonexposed cohortSecure record, structured interviewYesNo differences in population characteristicsIndependent blind assessmentYesFollow-up rate not acceptable those lostHigh
      • Giacomuzzi S.M.
      • Riemer Y.
      • Ertl M.
      • Kemmler G.
      • Rössler H.
      • Hinterhuber H.
      • Kurz M.
      Buprenorphine versus methadone maintenance treatment in an ambulant setting: A health-related quality of life assessment.
      Somewhat representative of the average MAT patient in the communityDrawn from the same community as the exposed cohortSecure recordYesControls for additional factorsSelf-reportYesFollow-up rate not acceptableModerate
      • Gossop M.
      • Marsden J.
      • Stewart D.
      • Lehmann P.
      • Strang J.
      Methadone treatment practices and outcome for opiate addicts treated in drug clinics and in general practice: Results from the National Treatment Outcome Research Study.
      Truly representative of the average MAT patient in the communityNot applicableSecure recordYesControls for demographicsSelf-reportYesFollow-up rate not acceptableModerate
      • Rapeli P.
      • Fabritius C.
      • Kalska H.
      • Alho H.
      Memory function in opioid-dependent patients treated with methadone or buprenorphine along with benzodiazepine: Longitudinal change in comparison to healthy individuals.
      Truly representative of the average MAT patient in the communityDrawn from a different sourceSecure recordYesControls for additional factorsIndependent blind assessmentYesFollow-up rate not acceptableModerate
      • Reijneveld S.A.
      • Plomp H.N.
      Methadone maintenance clients in Amsterdam after five years.
      Truly representative of the average MAT patient in the communityDrawn from the same community as the exposed cohortSecure recordYesNo differences in population characteristicsSelf-reportYesSubjects lost to follow-up unlikely to introduce biasLow

      Appendix D. Bibliography of included studies

      40 studies reported in 46 publications

      Aalto, Mauri, Jukka-Pekka Visapää, Jukka T. Halme, Carola Fabritius, and Mikko Salaspuro, “Effectiveness of Buprenorphine Maintenance Treatment as Compared to a Syringe Exchange Program Among Buprenorphine Misusing Opioid-Dependent Patients,” Nordic Journal of Psychiatry, Vol. 65, No. 4, September 2011, pp. 238–243.
      Bale, Richard N., William W. Van Stone, John M. Kuldau, Thomas M. J. Engelsing, Robert M. Elashoff, and Vincent P. Zarcone, “Therapeutic Communities vs Methadone Maintenance: A Prospective Controlled Study of Narcotic Addiction Treatment—Design and One-Year Follow-Up,” Archives of General Psychiatry, Vol. 37, No. 2, February 1980, pp. 179–193.
      Byford, Sarah, Barbara Barrett, Nicola Metrebian, Teodora Groshkova, Maria Cary, Vikki Charles, Nicholas Lintzeris, and John Strang, “Cost-Effectiveness of Injectable Opioid Treatment V. Oral Methadone for Chronic Heroin Addiction,” The British Journal of Psychiatry, Vol. 203, No. 5, November 2013, pp. 341–349.
      Compton, Peggy, Catherine P. Canamar, Maureen Hillhouse, and Walter Ling, “Hyperalgesia in Heroin Dependent Patients and the Effects of Opioid Substitution Therapy,” The Journal of Pain, Vol. 13, No. 4, April 2012, pp. 401–409.
      Cornish, James W., David Metzger, Geroge E. Woody, David Wilson, A. Thomas McLellan, Barry Vandergrift, and Charles P. O'Brien, “Naltrexone Pharmacotherapy for Opioid Dependent Federal Probationers,” Journal of Substance Abuse Treatment, Vol. 14, No. 6, November–December 1997, pp. 529–534.
      Corsenac, Philippe, Emmanuel Lagarde, Blandine Gadegbeku, Bernard Delorme, Aurore Tricotel, Anne Castot, Nicholas Moore, Pierre Philip, Bernard Laumon, and Ludivine Orriols, “Road Traffic Crashes and Prescribed Methadone and Buprenorphine: A French Registry-Based Case-Control Study,” Drug and Alcohol Dependence, Vol. 123, No. 1–3, June 1, 2012, pp. 91–97.
      Coviello, Donna M., James W. Cornish, Kevin G. Lynch, Arthur I. Alterman, and Charles P. O'Brien, “A Randomized Trial of Oral Naltrexone for Treating Opioid-Dependent Offenders,” The American Journal on Addictions, Vol. 19, No. 5, September–October 2010, pp. 422–432.
      Coviello, Donna M., Dave A. Zanis, Susan A. Wesnoski, Kevin G. Lynch, and Michelle Drapkin, “Characteristics and 9-Month Outcomes of Discharged Methadone Maintenance Clients,” Journal of Substance Abuse Treatment, Vol. 40, No. 2, March 2011, pp. 165–174.
      Crits-Christoph, Paul, Christie Lundy, Mark Stringer, Robert Gallop, and David R. Gastfriend, “Extended-Release Naltrexone for Alcohol and Opioid Problems in Missouri Parolees and Probationers,” Journal of Substance Abuse Treatment, Vol. 56, September 2015, pp. 54–60.
      Dole, Vincent P., J. Waymond Robinson, John Orraca, Edward Towns, Paul Searcy, and Eric Caine, “Methadone Treatment of Randomly Selected Criminal Addicts,” The New England Journal of Medicine, Vol. 280, No. 25, June 19, 1969, pp. 1372–1375.
      Dunlop, A.J., A. L. Brown, C. Oldmeadow, A. Harris, A. Gill, C. Sadler, K. Ribbons, J. Attia, D. Barker, P. Ghijben, J. Hinman, M. Jackson, J. Bell, N. Lintzeris, “Effectiveness and cost-effectiveness of unsupervised buprenorphine-naloxone for the treatment of heroin dependence in a randomized waitlist controlled trial” Drug Alcohol Depend. Vol.174, 2017, pp.181–191.
      Farrell-MacDonald, S, M. A. MacSwain, M. Cheverie, M. Tiesmaki, and B. Fischer, “Impact of Methadone Maintenance Treatment on Women Offenders' Post-Release Recidivism,” European Addiction Research, Vol. 20, No. 4, 2014, pp. 192–199.
      Fudala, Paul J., T. Peter Bridge, Susan Herbert, William O. Williford, C. Nora Chiang, Karen Jones, Joseph Collins, Dennis Raisch, Paul Casadonte, R. Jeffrey Goldsmith, Walter Ling, Usha Malkerneker, Laura McNicholas, John Renner, Susan Stine, and Donald Tusel, “Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone,” New England Journal of Medicine, Vol. 349, No. 10, September 4, 2003, pp. 949–958.
      Gerra, Gilberto, Amir Zaimovic, Maria Augusta Raggi, Gabriele Moi, Barbara Branchi, Mirko Moroni, and Francesca Brambilla, “Experimentally Induced Aggressiveness in Heroin-Dependent Patients Treated with Buprenorphine: Comparison of Patients Receiving Methadone and Healthy Subjects,” Psychiatry Research, Vol. 149, No. 1–3, January 15, 2007, pp. 201–213.
      Giacomuzzi, Salvatore, Georg Kemmler, Markus Ertl, and Yvonne Riemer, “Opioid Addicts at Admission Versus Slow-Release Oral Morphine, Methadone, and Sublingual Buprenorphine Maintenance Treatment Participants,” Substance Use and Misuse, Vol. 41, No. 2, 2006, pp. 223–244.
      Giacomuzzi, Salvatore M., Markus Ertl, Georg Kemmler, Yyvonne Riemer, and Alexander Vigl, “Sublingual Buprenorphine and Methadone Maintenance Treatment: A Three-Year Follow-Up of Quality of Life Assessment,” The Scientific World Journal, Vol. 5, No. 24, 2005, pp. 452–468.
      Giacomuzzi, Salvatore M., Yyvonne Riemer, Markus Ertl, Georg Kemmler, H Rössler, Hans H. Hinterhuber, and M. Kurz, “Buprenorphine Versus Methadone Maintenance Treatment in an Ambulant Setting: A Health-Related Quality of Life Assessment,” Addiction, Vol. 98, No. 5, May 2003, pp. 693–702.
      Gordon, Michael S., Timothy W. Kinlock, Robert P. Schwartz, and Kevin E. O'Grady, “A Randomized Clinical Trial of Methadone Maintenance for Prisoners: Findings at 6 Months Post-Release,” Addiction, Vol. 103, No. 8, August 2008, pp. 1333–1342.
      Gossop, Michael, John Marsden, Duncan Stewart, Petra Lehmann, and John Strang, “Methadone Treatment Practices and Outcome for Opiate Addicts Treated in Drug Clinics and in General Practice: Results from the National Treatment Outcome Research Study,” British Journal of General Practice, Vol. 49, No. 438, January 1999, pp. 31–34.
      Kinlock, Timothy W., Michael S. Gordon, Robert P. Schwartz, Terrence T. Fitzgerald, and Kevin E. O'Grady, “A Randomized Clinical Trial of Methadone Maintenance for Prisoners: Results at 12 Months Postrelease,” Journal of Substance Abuse Treatment, Vol. 37, No. 3, October 2009, pp. 277–285.
      Lee, Joshua D., Peter D. Friedmann, Timothy W. Kinlock, Edward V. Nunes, Tamara Y. Boney, Randall A. Hoskinson, Jr., Donna Wilson, Ryan McDonald, John Rotrosen, Marc N. Gourevitch, Michael Gordon, Marc Fishman, Donna T. Chen, Richard J. Bonnie, James W. Cornish, Sean M. Murphy, and Charles P. O'Brien, “Extended-Release Naltrexone to Prevent Opioid Relapse in Criminal Justice Offenders,” New England Journal of Medicine, Vol. 374, No. 13, March 31, 2016, pp. 1232–1242.
      Ling, Walter, Paul Casadonte, George Bigelow, Kyle M. Kampman, Ashwin Patkar, Genie L. Bailey, Richard N. Rosenthal, and Katheirne L. Beebe, “Buprenorphine Implants for Treatment of Opioid Dependence: A Randomized Controlled Trial,” JAMA, Vol. 304, No. 14, October 13, 2010, pp. 1576–1583.
      Lobmaier, Philipp P., Nikolaj Kunøe, Michael Gossop, Tormod Katevoll, and Helge Waal, “Naltrexone Implants Compared to Methadone: Outcomes Six Months After Prison Release,” European Addiction Research, Vol. 16, No. 3, 2010, pp. 139–145.
      Magura, Stephen, Joshua D. Lee, Jason Hershberger, Herman Joseph, Lisa Marsch, Carol Shropshire, and Andrew Rosenblum, “Buprenorphine and Methadone Maintenance in Jail and Post-Release: A Randomized Clinical Trial,” Drug Alcohol Dependence, Vol. 99, No. 1–3, January 1, 2009, pp. 222–230.
      Mattick, Richard P., Robert Ali, Jason M. White, Susannah O'Brien, Seija Wolk, and Cath Danz, “Buprenorphine Versus Methadone Maintenance Therapy: A Randomized Double-Blind Trial with 405 Opioid-Dependent Patients,” Addiction, Vol. 98, No. 4, April 2003, pp. 441–452.
      Metrebian, Nicola, Teodora Groshkova, Jennifer Hellier, Vikki Charles, Anthea Martin, Luciana Forzisi, Nicholas Lintzeris, Deborah Zador, Hugh Williams, Tom Carnwath, Soraya Mayet, and John Strang, “Drug Use, Health and Social Outcomes of Hard-to-Treat Heroin Addicts Receiving Supervised Injectable Opiate Treatment: Secondary Outcomes from the Randomized Injectable Opioid Treatment Trial (RIOTT),” Addiction, Vol. 110, No. 3, March 2015, pp. 479–490.
      Mokri, A., M. C. Chawarski, H. Taherinakhost, R. S. Schottenfeld, “Medical treatments for opioid use disorder in Iran: a randomized, double-blind placebo-controlled comparison of buprenorphine/naloxone and naltrexone maintenance treatment,” Addiction, Vol. 111, 2016, pp. 874–882.
      Murphy, S.M., D. Polsky, J. D. Lee, P. D. Friedmann, T. W. Kinlock, E. V. Nunes, R. J. Bonnie, M. Gordon, D. T. Chen, T. Y. Boney, C. P. O'Brien, “Cost-effectiveness of extended release naltrexone to prevent relapse among criminal justice-involved individuals with a history of opioid use disorder,” Addiction. Volume 111, 2017, pp. 1440–1450.
      Neri, S., C. M. Bruno, D. Pulvirenti, M. Malaguarnera, C. Italiano, B. Mauceri, G. Abate, D. Cilio, S. Calvagno, A. Tsami, L. Ignaccolo, D. Interlandi, L. Prestianni, M. Ricchena, and R. Noto, “Randomized Clinical Trial to Compare the Effects of Methadone and Buprenorphine on the Immune System in Drug Abusers,” Psychopharmacology, Vol. 179, No. 3, May 2005, pp. 700–704.
      Neumann, Anne M., Richard D. Blondell, Urmo Jaanimägi, Amanda K. Giambrone, Gregory G. Homish, Jacqueline R. Lozano, Urszula Kowalik, and Mohammadreza Azadfard, “A Preliminary Study Comparing Methadone and Buprenorphine in Patients with Chronic Pain and Coexistent Opioid Addiction,” Journal of Addictive Diseases, Vol. 32, No. 1, January 2013, pp. 68–78.
      Newman, Robert G., and Walden B. Whitehill, “Double-Blind Comparison of Methadone and Placebo Maintenance Treatments of Narcotic Addicts in Hong Kong,” Lancet, Vol. 2, No. 8141, September 8, 1979, pp. 485–488.
      Rapeli, Pekka, Carola Fabritius, Hely Kalska, and Hannu Alho, “Memory Function in Opioid-Dependent Patients Treated with Methadone or Buprenorphine Along with Benzodiazepine: Longitudinal Change in Comparison to Healthy Individuals,” Substance Abuse Treatment, Prevention, and Policy, Vol. 4, No. 6, 2009.
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