Maintenance treatments for opiate -dependent adolescents

  • Review
  • Intervention

Authors


Abstract

Background

The scientific literature examining effective treatments for opioid-dependent adults clearly indicates that pharmacotherapy is a necessary and acceptable component. Nevertheless, no reviews have been published that systematically assess the effectiveness of pharmacological maintenance treatment in adolescents.

Objectives

To assess the effectiveness of any maintenance treatment alone or in combination with psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions for retaining adolescents in treatment, reducing the use of substances and improving health and social status.

Search methods

We searched the Cochrane Drugs and Alcohol Group's Trials Register (January 2014), the Cochrane Central Register of Controlled Trials (2014, Issue 1), PubMed (January 1966 to January 2014), EMBASE (January 1980 to January 2014), CINAHL (January 1982 to January 2014), Web of Science (1991 to January 2014) and reference lists of articles.

Selection criteria

Randomised and controlled clinical trials of any maintenance pharmacological interventions either alone or associated with psychosocial intervention compared with no intervention, placebo, other pharmacological intervention, pharmacological detoxification or psychosocial intervention in adolescents (13 to 18 years).

Data collection and analysis

We used the standard methodological procedures expected by The Cochrane Collaboration.

Main results

We included two trials involving 189 participants. One study, with 35 participants, compared methadone with levo-alpha-acetylmethadol (LAAM) for maintenance treatment lasting 16 weeks, after which patients were detoxified. The other study, with 154 participants, compared maintenance treatment with buprenorphine-naloxone and detoxification with buprenorphine. We did not perform meta-analysis because the two studies assessed different comparisons.

In the study comparing methadone and LAAM, the authors declared that there was no difference in the use of a substance of abuse or social functioning (data not shown). The quality of the evidence was very low. No side effects, such as nausea, vomiting, constipation, weakness or fatigue, were reported by study participants.

In the comparison between buprenorphine maintenance and buprenorphine detoxification, maintenance treatment appeared to be more efficacious in retaining patients in treatment (drop-out risk ratio (RR) 0.37; 95% confidence interval (CI) 0.26 to 0.54), but not in reducing the number of patients with a positive urine test at the end of the study (RR 0.97; 95% CI 0.78 to 1.22). Self reported opioid use at one-year follow-up was significantly lower in the maintenance group, even though both groups reported a high level of opioid use (RR 0.73; 95% CI 0.57 to 0.95). More patients in the maintenance group were enrolled in other addiction treatment programmes at 12-month follow-up (RR 1.33; 95% CI 0.94 to 1.88). The quality of the evidence was low. No serious side effects attributable to buprenorphine-naloxone were reported by study participants and no patients were removed from the study due to side effects. The most common side effect was headache, which was reported by 16% to 21% of patients in both groups

Authors' conclusions

It is difficult to draft conclusions on the basis of only two trials. One of the possible reasons for the lack of evidence could be the difficulty of conducting trials with young people for practical and ethical reasons.

There is an urgent need for further randomised controlled trials comparing maintenance treatment with detoxification treatment or psychosocial treatment alone before carrying out studies that compare different pharmacological maintenance treatments. These studies should have long follow-up and measure relapse rates after the end of treatment and social functioning (integration at school or at work, family relationships).

Plain language summary

Maintenance treatments for opiate-dependent adolescents

Review question

We reviewed the evidence about the effect of maintenance treatment either alone or associated with psychosocial intervention compared with no intervention, placebo, other pharmacological intervention, pharmacological detoxification or psychosocial intervention in adolescents (13 to 18 years).

Background

Substance abuse among adolescents (13 to 18 years old) is a serious and growing problem. It is important to identify effective treatments for those who are opioid-dependent. The most common drugs used by young people worldwide are cannabis and inhalants. Psychostimulants (ecstasy and amphetamines), cocaine, LSD, heroin and other opioids are also used. Many adolescents who use heroin start by snorting it but some progress to injection. Heroin is used sporadically by the majority who use it, but it can become an addictive disorder. In adults, pharmacotherapy is a necessary and acceptable part of effective treatment for opioid dependence. Among adolescents, medications have been used infrequently and a choice has to be made between detoxification and maintenance treatment. Among maintenance treatment methadone and buprenorphine are the most frequently used drugs. Methadone needs daily doses, while LAAM (levomethadyl acetate hydrochloride) must be taken every two or three days. LAAM has been withdrawn from the market because of concerns about life-threatening effects on the heart .

Psychosocial interventions are interventions that use psychological or social strategy to achieve a therapeutic benefit in inpatient. The most common used approaches are: Cognitive-behavioural therapy,methods based on the assumption that since substance abuse among adolescents is a learned behaviour it can be unlearned as well; contingency management ,which uses reinforcement and punishment contingencies to enhance motivation: family therapy which is based on the conceptualisation that adolescent substance abuse stem from maladaptive family interactions; drug counselling which includes a strong emphasis on abstinence, assistance with social, family and legal problems. It focuses on behaviours and external events rather than intrapsychic processes; therapeutic community and motivational approach which rather than confront the patient's resistance to abstinence in a direct and sometimes aggressive manner, "rolls with resistance". At he same time, he tries to help the patient develop more self-motivation to stop using via specified techniques

Study characteristics

The review authors searched the literature and identified two controlled trials from the USA that involved 187 heroin addicts, aged 14 to 21 years; the participants were treated as outpatients. One study of 37 participants compared methadone with levo-alpha-acetylmethadol (LAAM) for maintenance treatment. After 16 weeks of maintenance treatment the adolescents were detoxified. The second trial of 150 adolescents compared buprenorphine and naloxone as maintenance treatment for nine weeks followed by tapered doses for up to 12 weeks with buprenorphine detoxification over 14 days.

Key results

In the first trial methadone and LAAM led to similar improvements in social functioning. No side effects were reported.

In the second trial the maintenance treatment seemed to be more effective in retaining patients in treatment but not in reducing the use of drugs of abuse. At one-year follow-up, self reported opioid use was clearly less in the maintenance group and more adolescents were enrolled in other addiction programmes. The most common side effect in both groups was headache. No participants left the study because of side effects.

It is difficult to draw conclusions about the use of maintenance pharmacological interventions from only two trials. Conducting trials with young people may be difficult for both practical and ethical reasons.

Quality of the evidence

This review was limited by the very low number of trials retrieved. The quality of the evidence was very low for the comparison between methadone and LAAM and low for the comparison between buprenorphine detoxification and buprenorphine maintenance. The evidence is current to January 2014.

Summary of findings(Explanation)

Summary of findings for the main comparison. Buprenorphine maintenance compared to buprenorphine detoxification for opiate-dependent adolescents
  1. 1No allocation concealment.
    2Only one study.
    3Only one study with 154 participants.
    4Participants, providers and outcome assessor not blinded.

Buprenorphine maintenance compared to buprenorphine detoxification for opiate-dependent adolescents
Patient or population:
Settings:
Intervention: buprenorphine-naloxone maintenance
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Buprenorphine-naloxone maintenance
Drop-outs
Number of participants who did not complete the study
Follow-up: 12 weeks
Study population RR 0.37
(0.26 to 0.54)
152
(1 study)
⊕⊕⊝⊝
low 1,2,3
 
795 per 1000 294 per 1000
(207 to 429)
Moderate
795 per 1000 294 per 1000
(207 to 429)
Use of primary substance
Patients with positive urine test at the end of treatment
Follow-up: 12 weeks
Study population RR 0.97
(0.78 to 1.22)
152
(1 study)
⊕⊕⊝⊝
low 1,2,3
 
679 per 1000 659 per 1000
(530 to 829)
Moderate
680 per 1000 660 per 1000
(530 to 830)
Self reported use at 12-month follow-up
Number of participants reporting heroin use
Follow-up: 12 months
Study population RR 0.73
(0.57 to 0.95)
152
(1 study)
⊕⊕⊝⊝
low 1,2,3,4
 
718 per 1000 524 per 1000
(409 to 682)
Moderate
718 per 1000 524 per 1000
(409 to 682)
Enrolment in addiction treatment at 12-month follow-up
Number of participants enrolled in addiction treatment at follow-up
Follow-up: 12 months
Study population RR 1.33
(0.94 to 1.88)
152
(1 study)
⊕⊕⊝⊝
low 1,2,3,4
 
397 per 1000 529 per 1000
(374 to 747)
Moderate
397 per 1000 528 per 1000
(373 to 746)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Several studies have demonstrated that adolescent (under 18 years) substance abuse is a serious and growing problem (Altobelli 2005).

In Europe, the estimated lifetime prevalence of substance abuse for young adults (15 to 34 years) is 32.5% for cannabis, 6.3% for cocaine (ranging from 0.7% to 13.6% in different countries) and 5.5% for amphetamines (ranging from under 0.6% to 12.4 %). Most countries report estimates in the range of 2.1% to 5.8% for ectasy and from 0.1% to 5.4% for LSD. National estimates vary widely between countries for all measures of prevalence. Opioids, mainly heroin, were cited as the primary drug used by more than 200,000 clients entering specialist drug treatment in 29 European countries in 2010, or 48% of all reported treatment entrants (EMCDDA 2012).

In Europe in 2011, the European School Survey Project on Alcohol and Other Drugs (ESPAD) collected data on substance use from more than 100,000 15- to 16-year-old European students from 36 countries. Nearly one in three students (29%) in the ESPAD countries perceived cannabis to be (fairly or very) easily available. On average, 18% of students have tried illicit drugs at least once during their lifetime. Most of them (17%) have used cannabis, while 6% report experience with drugs other than cannabis. After cannabis, amphetamines and ecstasy are in second position, each being mentioned by 3% of students. Lifetime use of cocaine, crack and LSD or other hallucinogens was reported by fewer students (2%) and the rates for heroin and GHB (gamma-hydroxybutyric acid) were even lower (1%). Use of cannabis in the past 12 months was 13%, while use in the past 30 days was claimed to be 7% (ESPAD 2012).

In the USA, recent household survey data indicated that 9.5% of youths aged 12 to 17 were current illicit drug users. This rate was similar to the rates of current illicit drug use in 2005 to 2011, but it was lower than the rates from 2002 to 2004. Among youths aged 12 to 17, 7.2% were current users of marijuana, 2.8% were current non-medical users of psychotherapeutic drugs, 0.8% were current users of inhalants, 0.6% were current users of hallucinogens and 0.1% were current users of cocaine (SAMHSA 2013). In the USA, after 1992 the proportion of young Americans with lifetime use of any drugs had risen considerably to a recent high point of 55% in 1999; it then declined gradually to 47% in 2007 through 2009, and stands at 49% in 2012. The annual prevalence of heroin use among 12th graders fell by half between 1975 and 1979, from 1.0% to 0.5%. The rate then held amazingly steady until 1994. Use rose in the mid- and late-1990s, along with the use of most drugs; it reached peak levels in 1996 among 8th graders (1.6%), in 1997 among 10th graders (1.4%) and in 2000 among 12th graders (1.5%), suggesting a cohort effect. Since these peak levels, use has declined, with annual prevalence in all three grades fluctuating between 0.7% and 0.9% from 2005 through 2011. Use has declined somewhat in the past two years; in the three grades combined, the 2011 to 2012 decline from 0.7% to 0.6% was significant (Monitoring the Future 2013).

In 2010, most Australians aged 14 years and over (60%) had never used an illicit drug. However, around 15% had used one or more illicit drugs in the past 12 months. Cannabis was the most common illicit drug used recently (10.3%), followed by ecstasy (3.0%) and amphetamines and cocaine (each used by 2.1% of people). Many people who used an illicit drug in 2010 also used other drugs, either illicit or licit (AIHW 2011).

Patterns of drug use have changed over time. An analysis of treatment entry data between 2000 and 2009 showed a decrease in drug injection among primary heroin clients in all European countries (from 58% to 36%), particularly in western Europe (EMCDDA 2012). In addition, among opioid users entering treatment in outpatient settings since 2009, those smoking the drug outnumbered those injecting it (EMCDDA 2012).

Description of the intervention

Numerous medications have been used successfully in the treatment of adolescents with a broad array of psychiatric disorders (Hunt 1990; Kaminer 1995). In contrast, medications have been infrequently used in treating substance abuse disorders among adolescents. Nevertheless, they have generally been shown to be a promising component of such interventions (Kaminer 1995). Methadone may still be the medication that is most widely used but buprenorphine is seen as having some advantages for adolescents because of its excellent safety profile and the absence of long-term complications (Levy 2007; Smith 2012). Younger patients who present for treatment for drug dependence often have a shorter history of drug use than treatment-seeking adults. Treatment early in the course of the disorder presents the opportunity to prevent co-morbidities associated with drug use, including acute and chronic medical conditions, and psychiatric and social complications (Levy 2007).

How the intervention might work

The scientific literature evaluating effective treatments for opioid-dependent adults clearly indicates that pharmacotherapy is an acceptable, often necessary, component of treatments. There is debate as to whether adolescents with opioid dependence should be treated with pharmacotherapies or whether they should be considered 'too young'. There is also a debate regarding the choice between detoxification or maintenance treatments for these people. The use of pharmacotherapy for the treatment of substance abuse among adolescents in ambulatory settings lags behind that for adults and largely consists of efforts to adapt adult treatment modalities (Galanter 2007). Moreover, if clinicians decide to treat opioid-dependent young people with pharmacotherapies, they need updated information on their efficacy in this group of patients. Methadone maintenance strikingly demonstrates the disjuncture between adolescent and adult treatment. State and local laws often restrict adolescents' access to methadone programmes; even if allowed adolescents must often receive written parental consent. However, methadone maintenance has been a key component of a recent, successful outpatient programme in the USA (Kellogg 2006).

Why it is important to do this review

Despite this need, no research has been conducted to characterise or evaluate systematically pharmacotherapy maintenance treatment interventions for opioid-abusing adolescents (Hopfer 2002).

Many Cochrane reviews have been published on the effectiveness of various maintenance treatments: methadone (Faggiano 2003; Mattick 2009), buprenorphine (Mattick 2014), levo-alpha-acetylmethadol (LAAM) (Clark 2002), heroin (Ferri 2011), naltrexone (Lobmaier 2008; Minozzi 2011), psychosocial intervention alone (Mayet 2005) and psychosocial combined with maintenance pharmacological interventions (Amato 2011). In the published literature only one systematic review published in 2002, including studies reporting treatment of opiate-using adolescents, that identified nine observational studies published from 1972 to 1998, was identified (Hopfer 2002). .

Objectives

To assess the effectiveness of any maintenance treatment alone or in combination with psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions for retaining adolescents in treatment, reducing the use of substances and improving health and social status.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and controlled clinical trials (CCTs).

Types of participants

Opiate-dependent adolescents (up to 18 years old). We did not apply any restriction on participants with physical or psychological illness.

Types of interventions

Experimental intervention
  • Any opioid agonist treatment (methadone, buprenorphine, LAAM, heroin) alone or associated with psychosocial intervention for maintenance treatment

Control intervention
  • No intervention

  • Different opioid agonist treatments

  • Other pharmacological interventions

  • Any detoxification intervention

  • Psychosocial interventions alone

Types of comparisons foreseen
  • Any pharmacological maintenance treatment versus no treatment

  • Any pharmacological maintenance treatment versus other pharmacological treatment

  • Any pharmacological maintenance treatment plus psychosocial treatment versus any psychosocial treatment alone

  • Any pharmacological maintenance treatment versus any psychosocial treatment

  • Maintenance treatments versus detoxification treatments

Types of outcome measures

Primary outcomes
  1. Drop-outs, measured as the number of participants that did not complete the maintenance treatment

  2. Use of primary substance, measured as number of participants with opiate-positive urinalysis during and at the end of treatment or using self reported data, or both

  3. Results at follow-up, measured as the number of participants relapsed at the end of follow-up

Secondary outcomes
  1. Use of other substances of abuse

  2. Side effects

  3. Mortality (any cause)

  4. Non-fatal overdose

  5. Criminal activity

  6. Social functioning (integration at school or at work, family relationships)

Search methods for identification of studies

Electronic searches

For this update, we revised the search strategy and re-ran searches in the following databases:

  1. Cochrane Drugs and Alcohol Group's Trials Register (January 2014);

  2. Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 1);

  3. MEDLINE (PubMed) (from 1966 to January 2014);

  4. EMBASE (embase.com) (from 1980 to January 2014);

  5. CINAHL (EBSCO) (1982 to January 2014);

  6. Web of Science (1991 to January 2014).

We searched the databases using a strategy developed by incorporating the filter for identification of RCTs (Lefebvre 2011), combined with selected MeSH and free-text terms related to alcohol dependence. For details on the searches see Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5 and Appendix 6.

We also searched some of the main electronic sources of ongoing trials:

  1. Current Controlled Trials (www.controlled-trials.com/);

  2. Clinical Trials.gov (www.clinicaltrials.gov/);

  3. International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/en).

Searching other resources

We also searched the references of the articles obtained and conference proceedings likely to contain trials relevant to the review (Annual Scientific Meeting of the College on Problems of Drug Dependence, European College of Neuropsychopharmacology, American Psychiatric Association).

We contacted investigators and relevant trial authors to seek information about unpublished or incomplete trials.

We contacted the authors of included studies and experts in the field in various countries to find out if they knew of any other published or unpublished controlled trials. All searches included non-English language literature and we assessed studies with English abstracts for inclusion. When considered likely to meet the inclusion criteria, we translated studies.

Data collection and analysis

Selection of studies

Two authors (SM, CB) independently inspected the search hits by reading the titles and abstracts. We obtained each potentially relevant study located in the search in full text and three authors (SM, CB, LM) assessed them for inclusion independently. We resolved doubts by discussion between the authors.

Data extraction and management

Three review authors (SM, CB, SV) extracted data independently. We discussed any disagreement and resolved it by consensus. We planned to summarise key findings narratively in the first instance and assess the potential for meta-analysis where possible.

Assessment of risk of bias in included studies

We changed the criteria for assessing the methodological quality of included studies from that described in our protocol to conform with the recommended methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

The recommended approach for assessing risk of bias in studies included in Cochrane reviews is a two-part tool, addressing six specific domains (namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other issues). The first part of the tool involves describing what was reported to have happened in the study. The second part of the tool involves assigning a judgement relating to the risk of bias for that entry as 'high', 'low' or 'unclear' risk of bias. To make these judgements we used the criteria indicated in the Cochrane Handbook for Systematic Reviews of Interventions and their applicability to the addiction field. For a detailed description of the criteria used see Higgins 2011.

We have addressed the domains of sequence generation, allocation concealment (avoidance of selection bias) and selective outcome reporting (avoidance of reporting bias) in the 'Risk of bias' tool with a single entry for each study.

We considered separately the blinding of participants, personnel and outcome assessors (avoidance of performance bias and detection bias) for objective outcomes (drop-outs, use of substance of abuse measured by urine analysis, participants relapsed at the end of follow-up, participants engaged in further treatments) and for subjective outcomes (duration and severity of signs and symptoms of withdrawal, including patient self rating, side effects and social functioning (integration at school or at work, family relationships)).

We considered incomplete outcome data (avoidance of attrition bias) for all outcomes except for drop-out from treatment, which is very often the primary outcome measure in trials on addiction. We have assessed separately the results at the end of the study period and the results at follow-up.

For drop-out from treatment we judged that only sequence generation and allocation concealment could be relevant because lack of blinding is unlikely to influence data collection and incomplete outcome data could not be used for this outcome. For use of substance assessed by urine analysis we judged that sequence generation, allocation concealment and incomplete outcome data could influence the results. For subjective outcomes we also judged that lack of blinding of outcome assessors could influence the data.

Measures of treatment effect

We analysed dichotomous outcomes by calculating the risk ratio (RR) for each trial, with the uncertainty in each result expressed with the confidence interval (CI). We analysed continuous outcomes by calculating the mean difference (MD) with 95% CI.

Drop-out from treatment was reported as the number of participants who did not complete the detoxification treatment. The use of primary substance was reported as number of participants with opiate-positive urine analysis during and at the end of treatment or with self reported data. The results at follow-up were measured as number of participants relapsed at the end of follow-up. We did not use data presented as numbers of positive urine tests over total number of tests in the experimental and control group as a measure of substance abuse. This is because using tests instead of the participants as the unit of analysis violates the hypothesis of independence among observations. In fact, the results of tests done in each participant are not independent. For outcomes assessed by scales we compared and pooled the differences in mean score from the end of treatment to baseline (post- minus pre-) in the experimental and control group. In case of missing data for the standard deviation of the change, we imputed this measure using the standard deviation at the end of treatment for each group.

Assessment of heterogeneity

We analysed heterogeneity by means of the I2 statistic and the Chi2 test. The cut-off points were an I2 value of more than 50% and a P value for the Chi2 test of less than 0.1.

Assessment of reporting biases

We planned to use funnel plots (plots of the effect estimate from each study against the sample size or effect standard error) to assess the potential for bias related to the size of the trials, which could indicate possible publication bias. However, we included only two trials so this was not feasible.

Data synthesis

We planned to combine the RR or the MD from the individual trials through meta-analysis where possible (comparability of intervention and outcomes between trials) using a random-effect models as some variability was expected in the studies included. However, we included only two trials with different comparisons, which prevented the possibility of performing meta-analysis.

Sensitivity analysis

To incorporate our assessment of risk of bias in the review process we planned first to plot the intervention effects estimates stratified for risk of bias for each relevant domain. If differences in the results were present among studies at different risks of bias, we planned to perform sensitivity analysis by excluding studies with high risk of bias from the analysis. This was not done because only two studies were included in the review.

Results

Description of studies

Results of the search

This is an update of a Cochrane review first published in 2009. In the first version of our review we identified 2917 references. After excluding duplicates we identified 2595 potentially relevant references. Of these, we excluded 2586 on the basis of title and abstract, leaving 10 studies that we acquired in full text for more evaluation. Out of these, we excluded seven studies. We included one study, one was an ongoing trial and we classified one study as awaiting assessment because was finished but not yet published and the authors could not give us the data. Immediately before the publication of the review (November 2008) the ongoing study was published, so we decided to include it. See Figure 1.

Figure 1.

Flow chart of studies in the review published in 2009.

At the 2014 update, we retrieved 1004 further references after excluding duplicates. We excluded 989 articles on the basis of title and abstract and we acquired 15 in full text for more detailed evaluation. Out of these, two (Woody 2009 and Woody 2013) were errata corrige of Woody 2008. We excluded the other 13 retrieved studies. The ongoing trial by Marsch found in the first version of the review has been completed but not yet published. We found two conference proceedings about that withut useful data. This study compared two different buprenorphine detoxification schedules, so it has been excluded (Marsch 2009). See Figure 2.

Figure 2.

Study flow diagram for 2014 update.

For substantive descriptions of the studies see the Characteristics of included studies and Characteristics of excluded studies tables

Included studies

Two studies met the inclusion criteria (Lehmann 1973; Woody 2008). No further studies were retrieved at the 2014 update.

  • Types of comparisons: LAAM maintenance versus methadone maintenance (Lehmann 1973); buprenorphine-naloxone maintenance versus buprenorphine detoxification (Woody 2008)

  • Participants: 187 heroin-addicted adolescents (14 to 21 years old)

  • Duration of the trials: 16 weeks after which patients were detoxified (Lehmann 1973); 12 weeks (Woody 2008)

  • Settings: outpatients

  • Country: USA

Excluded studies

Overall, 19 studies did not meet the criteria for inclusion in this review. The grounds for exclusion were:

Risk of bias in included studies

See Figure 3; Figure 4.

Figure 3.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Figure 4.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Allocation

Sequence generation and allocation concealment

We judged one study to be at high risk of bias because no information was reported either about sequence generation and allocation concealment, or whether the study was in fact randomised or not (Lehmann 1973). We judged the other study to be at low risk of bias for sequence generation and at high risk of bias for allocation concealment (Woody 2008).

Blinding

We judged both studies to be at low risk of bias for the objective outcomes. For the subjective outcomes, we judged one study to be at unclear risk of bias (Lehmann 1973), whereas we judged the other to be at high risk of bias (Woody 2008).

Incomplete outcome data

We judged one study to be at unclear risk of bias because it was stated that "the participants were followed until they remained in treatment", but the number of participants who dropped out from treatment before the end of the study was not reported (Lehmann 1973). We judged the other study to be at low risk of bias because the number of participants who dropped out and the reasons are reported for each arm (Woody 2008).

Selective reporting

We judged one study to be at high risk of bias because the drop-out rate from treatment, a measure usually utilised in drug addiction trials, was not reported (Lehmann 1973). We judged the other study to be at low risk of bias (Woody 2008).

Effects of interventions

See: Summary of findings for the main comparison Buprenorphine maintenance compared to buprenorphine detoxification for opiate-dependent adolescents

We did not perform any meta-analysis because the two studies assessed different comparisons.

Comparison 1: Any pharmacological maintenance treatment versus other pharmacological treatment (levo-alpha-acetylmethadol (LAAM) versus methadone)

Primary outcomes
Drop-outs, measured as the number of participants that did not complete the maintenance treatment

The results were not reported.

Use of primary substance, measured as number of participants with opiate-positive urinalysis during and at the end of treatment or using self reported data, or both

The authors reported that there were no positive urine tests for non-prescribed drugs in either group (data not reported).

Results at follow-up, measured as the number of participants relapsed at the end of follow-up

The results were not reported.

Secondary outcomes
Use of other substances of abuse

The authors reported that there were no positive urine tests for non-prescribed drugs in either group (data not reported).

Side effects

The authors stated that no side effects, such as nausea, vomiting, constipation, weakness or fatigue, were reported.

Social functioning (integration at school or at work, family relationships)

The authors reported that there were no differences between groups in the performance of job functions (which improved during the fourth week of treatment), athletic involvement, high school and education involvement (which started only after the eighth week of treatment), or community and home improvement (which improved after the fourth week of treatment) (data not reported).

Mortality (any cause), Non fatal overdose, criminal activity:

the study did not assess these outcomes

Comparison 2: Maintenance treatment versus detoxification treatment(buprenorphine-naloxone maintenance for nine weeks then tapered to week 12 versus buprenorphine detoxification for 14 days

Primary outcomes
Drop-outs, measured as the number of participants that did not complete the maintenance treatment

The risk ratio (RR) was 0.37 (95% confidence interval (CI) 0.26 to 0.54) in favour of maintenance treatment (Analysis 1.1).

Use of primary substance, measured as number of participants with opiate-positive urinalysis during and at the end of treatment or using self reported data, or both

The RR was 0.97 (95% CI 0.78 to 1.22): there was no significant difference between the groups (Analysis 1.2).

Results at follow-up, measured as the number of participants relapsed at the end of follow-up

For self reported heroin use at 12 months the RR was 0.73 (95% CI 0.57 to 0.95) in favour of maintenance treatment(Analysis 1.3). For enrolment in addiction treatment programmes at 12 months the RR was 1.33 (95% CI 0.94 to 1.88) (Analysis 1.4). There is therefore a trend in favour of maintenance treatment.

Secondary outcomes
Use of other substances of abuse

There was no significant difference between groups in alcohol and marijuana use. For cocaine use, the RR was 0.12 (95% CI 0.02 to 0.90) in favour of maintenance treatment(Analysis 1.5; Analysis 1.6; Analysis 1.7).

Side effects

The authors stated that no serious side effects attributable to buprenorphine-naloxone were reported and no patients were removed from the study due to side effects. The most common side effect was headache, which was reported by 16% to 21% of patients in both groups.

Mortality (any cause)

One death due to methadone overdose (as reported by the medical examiner's report) occurred in the maintenance group in a patient who dropped out after three doses and was not located until her obituary appeared in a newspaper three months later. No further information was reported in the study.

Non fatal overdose, criminal activity, social functionning:

the study did not assess these outcomes

Discussion

Summary of main results

Despite a comprehensive search of the published and unpublished literature, we found only two studies. One compared levo-alpha-acetylmethadol (LAAM) and methadone in a maintenance treatment of 16 weeks followed by detoxification (Lehmann 1973). This study found no difference in the use of a substance of abuse or social functioning. The other study compared maintenance treatment with buprenorphine-naloxone for nine weeks then tapered until 12th week with 14 days of detoxification with buprenorphine (Woody 2008). Maintenance treatment appeared to be more efficacious in retaining patients in treatment but not in reducing patients with a positive urine test at the end of the study. Self reported opioid use at one-year follow-up was significantly lower in the maintenance group, even though both groups reported a high level of opioid use and more patients in the maintenance group were enrolled in other addiction treatment programmes at 12-month follow-up.

A systematic review published in 2002, including studies reporting treatment of opiate-using adolescents, identified nine observational studies published from 1972 to 1998 (Hopfer 2002). The following treatment modalities were considered in the primary studies: methadone maintenance in six studies, therapeutic communities in two studies, psychotherapy in two studies and long- and short-term detoxification treatment in three studies. The numbers of participants included in the studies ranged from 5400 to 37. The majority of the studies were uncontrolled and observational. The largest comparative study, which reported the treatment outcomes for a sub-sample of 5400 adolescents enrolled in the Drug Abuse Reporting Program in the US, showed that retention was highest with methadone maintenance than with the therapeutic community, whereas all treatment modalities (methadone maintenance, therapeutic community, detoxification and outpatient drug-free) were associated with a large reduction in opiate use. Time in treatment is the best predictor of reduced opiate use. At four- to six-year follow-up, methadone treatment was associated with a substantial reduction in opiate use, but young people did poorly when non-opioid substance use, alcohol consumption, employment and productive activities were considered. Young people in the therapeutic community showed better results than those on methadone maintenance treatment in terms of opiate use, other illicit substance use and employment.

Overall completeness and applicability of evidence

The methodological quality of the study Lehmann 1973 is too low and it has insufficient participants to allow us to draw any conclusions about the comparison of LAAM versus methadone for short-term maintenance treatment. The study Woody 2008 compares a short-term maintenance treatment with a 14-day detoxification. More than a maintenance treatment, the 12weeks of buprenorphine-naloxone could be considered a long-term detoxification following a two-month stabilisation period. One study with 150 participants is too little evidence on which to base any firm conclusions.

Quality of the evidence

One included study is very old (published in 1973) and of very low quality. It is not specified whether it is a randomised study, nor does it declare whether it was double-blind. The study does not report any information about sequence generation or allocation concealment, it does not report drop-out data and it does not report figures for the outcomes (these are assessed only with narrative description) (Lehmann 1973). We judged the quality of evidence to be low for the comparison between buprenorphine detoxification and buprenorphine maintenance (Woody 2008). The reasons for the low quality grading were that there was no allocation concealment or blinding of participants, personnel and outcome assessor, and because only one trial with 154 participants was found for this comparison.

Potential biases in the review process

A particularly important component of a review is the identification of relevant studies. Publication bias has long been recognised as a problem in this regard since it means that the likelihood of finding studies is related to the results of those studies. One way to investigate whether a review is subject to publication bias is to prepare a 'funnel plot' and examine this for signs of asymmetry. We could not explore the possibility of publication bias using a funnel plot because only one study was retrieved for each comparison. However, we looked for all potentially includible studies using a comprehensive search, which also considered conference proceedings and registers of ongoing trials. We wrote to the authors of the published trials on detoxification and maintenance asking for other trials and we looked at the references of published narrative reviews. Therefore we can be reasonably sure that relevant randomised and quasi-randomised trials have not been missed.

Authors' conclusions

Implications for practice

It is difficult to draw conclusions on the basis of only two trials with few participants. One of the possible reasons for the lack of evidence could be the difficulty of conducting trials with young people for practical and ethical reasons.

Implications for research

From observational studies it appears that of all the treatment modalities commonly used for adolescents (i.e. methadone maintenance, long- and short-term detoxification, therapeutic community and psychosocial treatment), methadone maintenance is associated with the highest retention while all treatment modalities are associated with promising results for opiate use ( Hopfer 2002).

There is an urgent need for further randomised controlled trials comparing maintenance treatment with detoxification treatment or psychosocial treatment alone before carrying out studies that compare different pharmacological maintenance treatments. These studies should have long follow-up and measure relapse rates after the end of treatment and social functioning (integration at school or at work, family relationships).

Acknowledgements

We want to thank Zuzana Mitrova for help throughout the process.

Data and analyses

Download statistical data

Comparison 1. Buprenorphine-naloxone maintenance versus buprenorphine detoxification
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Drop-outs1152Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.26, 0.54]
2 Patients with positive urine test at the end of treatment1152Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.78, 1.22]
3 Self reported heroin use at 12-month follow-up1152Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.57, 0.95]
4 Enrolment in addiction treatment at 12-month follow-up1152Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.94, 1.88]
5 Self reported alcohol use1152Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.49, 1.59]
6 Self reported marijuana use1152Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.33, 1.20]
7 Self reported cocaine use1152Risk Ratio (M-H, Fixed, 95% CI)0.12 [0.02, 0.90]
Analysis 1.1.

Comparison 1 Buprenorphine-naloxone maintenance versus buprenorphine detoxification, Outcome 1 Drop-outs.

Analysis 1.2.

Comparison 1 Buprenorphine-naloxone maintenance versus buprenorphine detoxification, Outcome 2 Patients with positive urine test at the end of treatment.

Analysis 1.3.

Comparison 1 Buprenorphine-naloxone maintenance versus buprenorphine detoxification, Outcome 3 Self reported heroin use at 12-month follow-up.

Analysis 1.4.

Comparison 1 Buprenorphine-naloxone maintenance versus buprenorphine detoxification, Outcome 4 Enrolment in addiction treatment at 12-month follow-up.

Analysis 1.5.

Comparison 1 Buprenorphine-naloxone maintenance versus buprenorphine detoxification, Outcome 5 Self reported alcohol use.

Analysis 1.6.

Comparison 1 Buprenorphine-naloxone maintenance versus buprenorphine detoxification, Outcome 6 Self reported marijuana use.

Analysis 1.7.

Comparison 1 Buprenorphine-naloxone maintenance versus buprenorphine detoxification, Outcome 7 Self reported cocaine use.

Appendices

Appendix 1. Cochrane Drugs and Alcohol Group Trials Register search strategy

Diagnosis =opioid* or opiate* AND free text=maintenance

Appendix 2. CENTRAL search strategy

  1. MeSH descriptor: [Opioid-Related Disorders] explode all trees

  2. ((drug or substance) near (abuse* or addict* or dependen* or disorder*)):ti,ab,kw (Word variations have been searched)

  3. ((opioid* or opiate*) near (abuse* or addict* or dependen*)):ti,ab,kw (Word variations have been searched)

  4. (detox* or desintoxi* or disintoxi*):ti,ab,kw

  5. #1 or #2 or #3 or #4

  6. MeSH descriptor: [Heroin] explode all trees

  7. (opioid* or opiate* or opium or heroin):ti,ab,kw (Word variations have been searched)

  8. MeSH descriptor: [Methadone] explode all trees

  9. "methadone":ti,ab,kw (Word variations have been searched)

  10. #6 or #7 or #8 or #9

  11. #5 AND #10

Appendix 3. PubMed search strategy

  1. "Opioid-Related Disorders"[MeSH]

  2. (detox*[tiab] OR withdraw*[tiab] OR abstinen*[tiab] OR abstain*[tiab])

  3. (opioid*[tiab] AND (abuse*[tiab] OR addict*[tiab] OR dependen*[tiab]))

  4. ((drug[tiab] OR substance[tiab]) AND (use*[tiab] OR abuse*[tiab] OR misuse*[tiab] OR addict*[tiab] OR dependen*[tiab] OR disorder*[tiab]))

  5. #1 OR #2 OR #3 OR #4

  6. heroin [MeSH]

  7. heroin [tiab]

  8. opioid*[tiab] OR opiate* [tiab]

  9. methadone [MeSH]

  10. methadone [MeSH]

  11. #6 OR #7 OR #8 OR #9 OR #10

  12. adolescent [MeSH]

  13. adolescen* OR teen* OR young people OR young person* OR young adult* OR youth* OR girl* OR boy* OR juvenile*

  14. #12 OR #13

  15. randomized controlled trial [pt]

  16. controlled clinical trial [pt]

  17. random*[tiab]

  18. placebo [tiab]

  19. drug therapy [sh]

  20. randomly [tiab]

  21. trials [tiab]

  22. groups [tiab]

  23. #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22

  24. animals [mh] NOT humans [mh]

  25. #23 NOT #24

  26. #5 AND #11 AND #14 AND #25

Appendix 4. EMBASE search strategy

  1. drug abuse/exp

  2. addiction/exp

  3. ((drug OR substance) NEAR/5 (abuse* OR depend* OR addict*)):ab,ti

  4. detox*:ab,ti OR withdraw*:ab,ti OR abstinen*:ab,ti OR abstain*:ab,ti

  5. #1 or #2 or #3 or #4

  6. 'diamorphine'/exp

  7. 'methadone'/exp

  8. heroin:ab,ti OR methadone:ab,ti OR opioid*:ab,ti OR opiate*:ab,ti

  9. #6 or #7 or #8

  10. 'adolescent'/exp OR adolescen*:ab,ti OR teen*:ab,ti OR youth*:ab,ti OR girl$*:ab,ti OR boy*:ab,ti OR juvenile*:ab,ti OR (young NEAR/3 people):ab,ti OR (young NEAR/3 person*):ab,ti OR (young NEAR/3 adult*):ab,ti

  11. 'crossover procedure'/exp OR 'double blind procedure'/exp OR 'single blind procedure'/exp OR 'controlled clinical trial'/exp OR 'clinical trial'/exp OR 'randomized controlled trial'/exp OR placebo:ab,ti OR 'double blind':ab,ti OR 'single blind':ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti OR random*:ab,ti OR factorial*:ab,ti OR crossover:ab,ti OR (cross:ab,ti AND over:ab,ti)

  12. #5 AND #9 AND #10 AND #11AND [embase]/lim

Appendix 5. CINAHL search strategy

  1. (MH "Substance Use Disorders+")

  2. TX(detox* or withdraw* or abstinen* or abstain*)

  3. TX((opioid* or opiate*) and (abuse* or addict* or dependen*))

  4. S1 or S2 or S3

  5. MH heroin or TX heroin

  6. TX (opioid* or opiate*)

  7. TX opium

  8. MH methadone or¬ TX methadone

  9. S5 or S6 or S7 or S8

  10. MH adolescence

  11. TI adolescen* or TI teen* or TI young people or TI young person* or TI young adult* or TI youth* or TI girl* OR TIboy* or TI juvenile*

  12. AB adolescen* or AB teen* or AB young people or AB young person* or AB young adult* or AB youth* or AB girl* OR AB boy* or AB juvenile*

  13. S10 or S11 or S12

  14. MH "Clinical Trials+"

  15. PT Clinical trial

  16. TI clinic* N1 trial* or AB clinic* N1 trial*

  17. TI ( singl* or doubl* or trebl* or tripl* ) and TI ( blind* or mask* )

  18. AB ( singl* or doubl* or trebl* or tripl* ) and AB ( blind* or mask* )

  19. TI randomi?ed control* trial* or AB randomi?ed control* trial*

  20. MH "Random Assignment"

  21. TI random* allocat* or AB random* allocat*

  22. MH "Placebos"

  23. TI placebo* or AB placebo*

  24. MH "Quantitative Studies"

  25. S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21 or S22 or S23 or S24

  26. S4 and S9 and S13 and S25

Appendix 6. Web of Science search strategy

  1. TS=((( heroin OR opiate* OR opioid* OR methadone) same (abuse* OR depend* OR addict* OR disorder* OR detox* OR withdraw* OR abstinen* OR abstain*))) AND TS=(adolescen* OR teen* OR young people OR young person* OR young adult* OR early adult* OR youth* OR girl* OR boy* OR juvenile*)

  2. TS= clinical trial* OR TS=research design OR TS=comparative stud* OR TS=evaluation stud* OR TS=controlled trial* OR TS=follow-up stud* OR TS=prospective stud* OR TS=random* OR TS=placebo* OR TS=(single blind*) OR TS=(double blind*)

  3. #2 AND #1

Databases=SCI-EXPANDED, SSCI, A&HCI Timespan=2008-2013

What's new

DateEventDescription
23 April 2014New citation required but conclusions have not changedNo new studies included.
23 April 2014New search has been performedNew search. Background updated. 'Summary of findings' table created.

History

Protocol first published: Issue 3, 2008
Review first published: Issue 2, 2009

DateEventDescription
28 December 2008New search has been performedChange in review status.
19 October 2008New search has been performedChange in review status.
18 October 2008AmendedConverted to new format.

Contributions of authors

Silvia Minozzi and Cristina Bellisario inspected the search hits by reading the titles and abstracts. Silvia Minozzi and Laura Amato wrote the review. Silvia Minozzi, Cristina Bellisario and Simona Vecchi extracted data from the articles. Simona Vecchi performed the bibliographic searches. Marina D avoli supervised.

Declarations of interest

None known.

Sources of support

Internal sources

  • Department of Epidemiology ASL RM E, Italy.

External sources

  • No sources of support supplied

Differences between protocol and review

We changed the criteria for assessing the methodological quality of included studies to conform with the recommended methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Lehmann 1973

MethodsControlled clinical trial
Recruitment modality not described
Participants35 male and female heroin addicts aged 16 to 21 years
Other characteristics of patients not reported
Interventions

(1) LAAM 10 mg every 72 hours and placebo in the intervening days (14 patients)

(2) Daily methadone in doses sufficient to maintain a comfortable state (21 patients)

Duration of trial: 16 weeks, after which patients were detoxified

Outcomes

Use of substance of abuse

Side effects

Social functioning (integration at school or at work, family relationships)

Notes

Country: USA

Setting: outpatients

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High risk

No information reported; does not specify if the study was randomised

Comment: we judged the study to be at high risk of bias because no information is given about randomisation, i.e. it is not clear if the study is randomised or not

Allocation concealment (selection bias)High risk

No information reported; does not specify if the study was randomised

Comment: we judged the study to be at high risk of bias because no information is given about randomisation, i.e. it is not clear if the study is randomised or not

Blinding (performance bias and detection bias)
Objective outcomes (drop-out, use of substances measured by urine analysis)
Low riskQuote: "double blind comparison of LAAM and methadone"
Blinding (performance bias and detection bias)
Subjective outcomes (use of substances measured by self report, side effects)
Unclear riskThe study stated that there was a "double blind comparison of LAAM and methadone" but no further information is given
Incomplete outcome data (attrition bias)
All outcomes except drop out
Unclear risk

Quote: "the participants were followed until they remained in treatment"

Comment: does not report the percentage of patients who remained in treatment until the end of the study

Selective reporting (reporting bias)High riskDrop-out from treatment, a measure usually utilised in drug addiction trials, is not reported

Woody 2008

  1. a

    DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, fourth edition
    LAAM: levo-alpha-acetylmethadol

MethodsMulticentre randomised controlled trial
Recruitment modality described
Participants154 participants who met the DSM-IV diagnostic criteria for opioid dependence and who sought outpatient treatment; 152 randomised
Mean age: 19 years
Only 1 participant was 15 years old and no participants were 14 years old
Male: 59%
White: 56%
Interventions

(1) Maintenance group: 12 weeks buprenorphine-naloxone; up to 24 mg/day buprenorphine and 0.5 mg naloxone for 9 weeks and then tapered to week 12; 74 patients

(2) Detoxification group: up to 14 mg/day and then tapered to day 14; 78 patients

Both groups were offered 1 weekly individual and 1 group counselling

Outcomes

Primary outcome: opioid-positive urine test results at weeks 4, 8 and 12

Secondary outcomes: drop-out, self reported use, enrolment in addiction treatment outside the assigned condition, other drug use, adverse events
Results at 6, 9, 12 months follow-up: self reported opioid use, self reported other drug use, other addiction treatment received

Notes

Country: USA

Setting: outpatients

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation occurred through an automated 24-hour service at the Veterans Affairs Cooperative Studies Program in Perry Point, Maryland, which was programmed to randomise patients separately by site. At each site, a biased coin randomisation protected against severe imbalance of sex, ethnicity, route of administration and age across the treatment groups. Age was dichotomised as 14 to 18 years or 18 to 21 years, ethnicity as the majority ethnic group versus all others within the site and route of administration as injecting or non-injecting
Allocation concealment (selection bias)High riskBalance was assessed by comparing the group sum of the binary indicators as each new patient was randomised. If both groups were balanced when a new patient was being randomised, then each group had an allocation probability of 1/2; if there was an imbalance, then the group with the higher score on the sum of indicators received an allocation probability of 1/3 and the other group a probability of 2/3
Blinding (performance bias and detection bias)
Objective outcomes (drop-out, use of substances measured by urine analysis)
Low risk

Patients and providers impossible to blind to the nature of the intervention (14 days detoxification versus 12 weeks maintenance)

Comment: objective outcomes unlikely to be biased by lack of blinding

Blinding (performance bias and detection bias)
Subjective outcomes (use of substances measured by self report, side effects)
High risk

Patients and providers impossible to blind to the nature of the intervention (14 days detoxification versus 12 weeks maintenance)

Outcome assessor not blinded: "Research assistant likely knew groups assignment because the study was not blinded"

Incomplete outcome data (attrition bias)
All outcomes except drop out
Low riskNumber of participants withdrawn from the study reported for each group. Reasons for withdrawal given. Analysis on the basis of the intention-to-treat principle: "patients were contacted at all assessment points regardless of whether they remained in treatment"
Selective reporting (reporting bias)Low risk 

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    CCT: controlled clinical trial
    RCT: randomised controlled trial

Baer 2007Intervention did not meet the inclusion criteria: only psychosocial intervention without pharmacological detoxification
Chakrabarti 2010Outcome did not meet the inclusion criteria: baseline patient characteristics of Woody 2008 trial
Ebner 2007Study design did not meet the inclusion criteria: not a RCT or CCT
Fiellin 2008Study design did not meet the inclusion criteria: not a RCT or CCT
Forcehimes 2008Intervention did not meet the inclusion criteria: psychosocial intervention - the same pharmacological intervention was given to both groups
Godley 2004Study design did not meet the inclusion criteria: not a RCT or CCT
Hill 2013Outcome did not meet the inclusion criteria: association between cannabis use during opioid dependence treatment and positive urine drug screens for opioids; no raw data for cannabis use in the 2 groups provided
Hulse 2010Participants did not meet the inclusion criteria: adults
Kemp 2007Intervention did not meet the inclusion criteria: only psychosocial intervention without pharmacological detoxification
Lloyd 1974Study design did not meet the inclusion criteria: not a RCT or CCT
Marsch 2005Intervention did not meet the inclusion criteria: detoxification treatment
Marsch 2009Intervention did not meet the inclusion criteria: detoxification treatment
Moore 2014Study design did not meet the inclusion criteria: qualitative study
Polsky 2010Outcome did not meet the inclusion criteria: cost-effectiveness analysis of the Woody 2008 trial
Reimer 2011Participants did not meet the inclusion criteria: adults
Subramaniam 2011Outcome did not meet the inclusion criteria: predictors of abstinence (secondary analysis of the Woody 2008 trial)
Warden 2012Outcome did not meet the inclusion criteria: predictors of attrition (secondary analysis of the Woody 2008 trial)
Weiss 2013Comparison did not meet the inclusion criteria: both groups received maintenance treatment
Wilcox 2013Outcome did not meet the inclusion criteria: concordance between self report and urine drug screen data(secondary analysis of the Woody 2008 trial)

Ancillary