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. Author manuscript; available in PMC: 2023 Jan 1.
Published in final edited form as: J Subst Abuse Treat. 2021 May 29;132:108494. doi: 10.1016/j.jsat.2021.108494

Effectiveness of medication for opioid use disorders in transition-age youth: A systematic review

Sara J Becker a,b,*, Kelli Scott a,b, Sarah A Helseth a, Kristin J Danko c, Ethan M Balk c, Ian J Saldanha c,d, Gaelen P Adam c, Dale W Steele c,e
PMCID: PMC8628023  NIHMSID: NIHMS1753214  PMID: 34098208

Abstract

Background:

Sequalae of opioid misuse constitute a public health emergency in the United States. A robust evidence base informs the use of medication for opioid use disorders (MOUD) in adults, with far less research in transition-age youth. This systematic review evaluates the effectiveness of MOUD for transition-age youth (age 16 to 25).

Methods:

This synthesis was part of a larger systematic review focused on adolescent substance use interventions. The study team conducted literature searches in MEDLINE, the Cochrane CENTRAL Registry of Controlled Trials, EMBASE, PsycINFO, and CINAHL through October 31, 2019. We screened studies, extracted data, and assessed risk of bias using standard methods. The primary and secondary outcomes were the effect of MOUD on opioid abstinence and treatment retention, respectively.

Results:

The study team screened a total of 33,272 records and examined 1831 full-text articles. Four randomized trials met criteria for inclusion in the current analysis. All four trials assessed a combination of buprenorphine plus cognitive behavioral therapy versus a comparison condition. Some trials included additional behavioral interventions, and the specific duration/dosage of buprenorphine varied. Risk of bias was moderate for all studies. Studies found that buprenorphine was more effective than clonidine, effectively augmented by memantine, and that longer medication taper durations were more effective than shorter tapers in promoting both abstinence and retention. Notably, we did not identify any studies of methadone or naltrexone, adjunctive behavioral interventions were sparingly described, and treatment durations were far shorter than recommended guidelines in adults.

Discussion:

The literature guiding youth MOUD is limited, and more research should evaluate the effectiveness of options other than buprenorphine, optimal treatment duration, and the benefit of adjunctive behavioral interventions. Subgroup analyses of extant randomized clinical trials could help to extend knowledge of MOUD effectiveness in this age cohort.

Keywords: Medication for opioid use disorder, Buprenorphine, Opioid use, Youth

1. Introduction

Overdoses due to opioid misuse and opioid use disorder (OUD) remain a public health emergency. More than 770,000 Americans have died from drug overdoses since 1999, and nearly 7 of 10 overdoses are due to opioids (Centers for Disease Control and Prevention, 2019a). While extensive guidance exists to reduce the risk of overdose in adults (Centers for Disease Control and Prevention, 2019b), far less is known about how to reduce the impact of opioid misuse and opioid use disorder (OUD) in transition-age youth, defined as adolescents (age 16–18) and young adults (age 18–25).

Identifying effective interventions for transition-age youth with OUD is essential because opioid use typically begins during this age range and is associated with an array of sequalae that persist into adulthood, including sexually transmitted infections, unwanted pregnancy, HIV, hepatitis, accidents, and violent crime (Levy, 2019; National Center on Addiction and Substance Abuse, 2011). According to the latest National Household on Drug Use and Health Survey (SAMHSA, 2020a), approximately 2.4 million transition-age youth have misused opioids at least once in their lifetime, and about 380,000 meet full diagnostic criteria for an OUD. Nearly 1800 youth initiate pain reliever or heroin misuse per day (SAMHSA, 2020a). Analysis of national data from the Kaiser Family Foundation (2020) indicates that lethal overdoses attributable to opioids among individuals under the age of 25 increased by 9.7% per year from 1999 to 2018, representing a 6-fold increase in total deaths. Relative to adults over the age of 25, transition-age youth who use opioids experience more rapid progression from experimentation to regular use, more life-time use-related consequences, and greater likelihood of injecting heroin (Woodcock et al., 2015).

Medication for OUD (MOUD) consisting of U.S. Food and Drug Administration (FDA)-approved pharmacotherapy is widely considered the gold standard evidence-based treatment for OUD. For young adults, FDA-approved medications include methadone, buprenorphine (available via sublingual or injection), or naltrexone (available via oral or extended-release injection; U.S. Food and Drug Administration, 2019). For adolescents age 16–18, the only FDA-approved medication is buprenorphine (McCormick, 2002). In a 2016 policy statement, the American Academy of Pediatrics unequivocally stated that buprenorphine should be the first-line treatment for adolescents and young adults with OUD and advocated for increased access to MOUD in this cohort (Levy et al., 2016). However, this policy statement acknowledged the lack of research in this age group and strongly advocated for more rigorous research on developmentally appropriate MOUD treatments, including research on adjunctive behavioral interventions to augment MOUD.

Despite clear consensus around the need to promote MOUD in transition-age youth, research to guide the effective treatment of OUD in this age cohort has been extremely limited. Several narrative reviews have considered the data in support of MOUD for transition-age youth (Borodovsky et al., 2018; Camenga et al., 2019; Hopfer et al., 2002). An early descriptive review by Hopfer et al. (2002) focused on studies of adolescent (defined as individuals under the age of 21 years) heroin use, most of which were uncontrolled before-after studies, and found evidence that retention in treatment was a predictor of treatment outcome and that receipt of methadone was associated with the highest treatment retention. Another narrative review by Borodovsky et al. (2018) focused specifically on studies of buprenorphine in adolescents and young adults with opioid use disorders. It recommended conceptualizing OUD in transition-age youth as a chronic medical condition that requires a long-term management strategy with medication, and called for studies of different delivery MOUD models examining issues, such as medication adherence, duration, and intensity requirements. The most recent narrative review by Camenga et al. (2019) provided a comprehensive overview of studies of buprenorphine, methadone, and naltrexone among transition-age youth. The investigators concluded that the risks of untreated opioid use disorder outweighed the risk of MOUD in this age cohort, but heavily extrapolated from the adult literature due to the limited published research to guide MOUD treatment recommendations in transition-age youth. These prior narrative reviews have advanced knowledge by providing an up-to-date summary of the MOUD literature in transition-age youth. However, such work cannot provide reproducible data due to the lack of replicable review criteria, insufficient consideration of bias, and pooling of results across studies without consideration of study design, methodological quality, or focal outcomes (Rother, 2007).

To date, only one systematic review has rigorously analyzed the evidence base for MOUD in transition-age youth using a replicable search strategy and provided an assessment of risk of bias. In 2014, a Cochrane systematic review by Minozzi and colleagues focused on effective maintenance treatments for adolescents meeting diagnostic criteria for opioid dependence: the investigators identified only two studies, one of which was a conference presentation and was deemed to be of very low quality (Lehmann, 1976). The only published peer-reviewed study (Woody et al., 2008) supported the efficacy of longer-term buprenorphine treatment relative to shorter-term treatment with buprenorphine. As with the narrative reviews, Minozzi et al. (2014) explicitly noted the challenges of drawing conclusions based on so few trials.

The goal of this systematic review was to provide a more current systematic evaluation of MOUD for transition-age youth. We specifically evaluated peer-reviewed, randomized controlled trials (RCTs) evaluating the effectiveness of MOUD to improve opioid abstinence (primary outcome) or treatment retention (secondary outcome). We also examined whether differential effects of MOUD existed as a function of participant characteristics, treatment duration and medication tapering, and adjunctive behavioral interventions to complement MOUD.

2. Methods

The current synthesis of studies focused on MOUD in transition-age youth was part of a larger systematic review of interventions for adolescent substance use. The full comparative effectiveness review and review protocol (PROSPERO identifier CRD42018115388) are available for download from the Agency for Healthcare Research and Quality (AHRQ) website (see https://doi.org/10.23970/AHRQEPCCER225). The review followed established methods outlined in the AHRQ Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Additional methodological details can be found in Steele, Becker, Danko, Balk, Saldanha, et al. (2020b) and Steele, Becker, Danko, Balk, Adam, et al. (2020a).

2.1. Search strategy

The study team conducted literature searches in MEDLINE, the Cochrane CENTRAL Registry of Controlled Trials, EMBASE, PsycINFO, and CINAHL. We used an exhaustive list of search terms capturing the concepts of age (e.g., “adolescent”, “youth”, “teen”, “student”, etc.), substance use (e.g., “opioid”, “drug”, “illicit”, etc.), and interventions (e.g., “treatment”, “therapy”, “counseling”, etc.) from inception to October 31, 2019. The full list of search terms is contained in Appendix A. We scanned reference lists of published clinical practice guidelines and existing systematic reviews for eligible studies. The study team invited a panel of key informants and topic experts to review the draft report to ensure that we did not miss key studies.

2.2. Study eligibility

Eligible studies were RCTs published in peer-reviewed journals that enrolled at least 10 transition-age youth (age 16–25) per treatment arm who met full diagnostic criteria for OUD. RCTs had to specifically assess MOUD, with or without adjunctive behavioral interventions and report the effect of MOUD on opioid abstinence. The larger systematic review assessed problematic substance use excluding nicotine and college student drinking (the latter due to a plethora of published systematic reviews) across a range of substances in adolescents age 12–20. The current systematic review changed the age range due to the sparseness of literature in younger adolescents age 12–15 and to be consistent with prior systematic reviews (Minozzi et al., 2014). Of note, RCTs of adults were eligible if they had a subgroup analysis that specifically reported the effectiveness of MOUD in the target age range.

2.3. Study identification

Two researchers independently screened each of the identified citations for eligibility, using the open-source, online software Abstrackr (http://abstrackr.cebm.brown.edu/), which uses machine learning to expedite the screening process criteria. Two independent researchers reviewed Abstracts meeting eligibility criteria in full to make final decisions about inclusion. The researchers resolved disagreements about eligibility through discussion.

2.4. Data extraction

For each study, we extracted data on the design, population characteristics, interventions, outcomes, and study results. For pharmacological interventions, we extracted data on the type of medication, dosage, frequency, and duration. For behavioral adjunctive interventions, we gathered data on delivery format (group versus individual), duration of each session, total number of sessions, qualifications of the individual delivering the session, and underlying theoretical approach (e.g., cognitive behavioral, motivational interviewing, etc.). The primary outcome was abstinence from opioids, measured as either the proportion of patients submitting negative urine screens or the proportion of negative urine screens submitted per patient. The secondary outcome was retention in treatment, reported as either the proportion of patients remaining in treatment or the average number of days retained in treatment per patient.

A single researcher conducted the majority of data extraction of each article, with review and confirmation by a second senior researcher. Two researchers extracted characteristics of adjunctive behavioral interventions in duplicate: one with expertise in psychology and one with expertise in complex interventions. They discussed discrepant data in detail with a third researcher with expertise in psychology to reach consensus.

2.5. Assessment of study risk of bias

Two investigators assessed the risk of bias in each study using predefined criteria from the Cochrane Risk of Bias tool, including random sequence generation; allocation concealment; blinding of participants, care providers, and outcome assessors; incomplete outcome data; and selective reporting (Higgins et al., 2011). We used these assessments to make overall assessments of risk of bias in each study. We also documented whether studies documented intention-to-treat analyses. In addition, we used relevant questions from the Newcastle Ottawa Scale (Wells et al., n.d), including similarity of groups at baseline, whether any cointerventions differed between groups, absolute and comparative compliance to the interventions, and timing of outcome assessments (i.e., consistency across groups).

2.6. Quantitative synthesis

For the current analysis, we focused on abstracting results on opioid abstinence outcomes measured as either the percent of patients with negative urine screens or the percent of negative urine screens per patient. For abstinence outcomes, we calculated effects as odds ratios (OR) with 95% confidence intervals (CI) to indicate the odds that one treatment arm had superior outcomes. The secondary outcome was retention in treatment, measured as either the proportion of patients retained in treatment or the average duration of time retained per patient. This study reported effects of condition assignment on treatment retention using the statistics included in the original manuscripts.

3. Results

The searches for the full systematic review yielded 33,732 citations, of which 1831 articles underwent full-text review (Fig. 1). The most common reason for exclusion of full-text articles was the age of study participants: we rejected 988 articles because the analyses included adults of any age without any subgroup analyses of the target age range. The full systematic review (Steele, Becker, Danko, Balk, Adam, et al., 2020a; Steele, Becker, Danko, Balk, Saldanha, et al., 2020b) included 118 studies focused on adolescent substance use interventions, of which four comparative studies (described in 13 publications published between 2005 and 2016) met criteria for inclusion in the current analysis.

Fig. 1.

Fig. 1.

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Literature flow diagram identifying studies of medication for opioid use disorders in transition-age youth.

The four included studies assessed pharmacologic interventions in combination with behavioral interventions to reduce opioid use. The study team deemed meta-analysis not to be feasible due to the small number and heterogeneity of studies (Mbuagbaw et al., 2017); in particular, no two studies evaluated the same MOUD condition in terms of dosage, duration, and adjunctive interventions. Effect sizes calculated as odds ratios with 95% confidence intervals were feasible to calculate for each study. Table 1 presents details about the four studies.

Table 1.

Studies of medication for opioid use disorders in transition-age youth: baseline characteristics and interventions.

Lead author, year N initiated/randomized Other substances used Age [eligible] Mean (SD) Male % White % Interventions
Marsch, 2005 36/38 Alcohol
Amphetamine cocaine
Cannabis		 [13, 18]
17.3 (0.7)		 39 97 1. BUP (4-week) + CBT (individual) + CM
2. Clonidine (4-week) + CBT (individual) + CM
Woody, 2008 152/154 Cannabis
Alcohol
Cocaine		 [14, 21]
19.2 (1.5)		 59 74 1. BUP-NAL (2-week) + CBT (group + individual)
2. BUP-NAL (12-week) + CBT (group + individual)
Gonzalez, 2015 80/87 Cannabis [18, 25]
22.6 (1.9)		 66 91 1. BUP-NAL (9-week) + Memantine 30 mg + CBT (group)
2. BUP-NAL (9-week) + Memantine 15 mg + CBT (group)
3. BUP-NAL (9-week) + Placebo + CBT (group)
Marsch, 2016 53/53 Alcohol
Amphetamine cocaine
Cannabis		 [16, 24]
20.5 (2.5)		 58 70 1. BUP-NAL (4-week) + CBT + MI + PE + Fam + CM
2. BUP-NAL (8-week) + CBT + MI + PE + Fam + CM
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Note. N = sample size; SD = standard deviation, BUP = buprenorphine; BUP-NAL = buprenorphine-naloxone; CBT = cognitive behavioral therapy; MI = motivational interviewing; PE = psychoeducation; CM = contingency management; Fam = family-focused intervention.

3.1. Risk of bias

Fig. 2 presents a summary of the risk of bias assessment. Three of the four trials (Gonzalez et al., 2015; Marsch et al., 2005, 2016) were double-blind (e.g., both practitioners and patients were blinded); the fourth (Woody et al., 2008) did not employ blinding. All four trials conducted intention-to-treat analyses and assessed outcomes between 1 and 3 months after induction on MOUD. The most pronounced areas of potential bias across the four trials included incompleteness of outcome data reporting and low compliance with the interventions.

Fig. 2.

Fig. 2.

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Percentage of studies of medication for opioid use disorders in transition-age youth in each risk category.

3.2. Participants

The four trials enrolled a total of 330 transition-age youth, of whom 321 initiated treatment and composed the intention-to-treat samples. All of the studies enrolled youth who met full diagnostic criteria for an OUD with symptoms of dependence. Average age of transition-age youth across studies ranged from 17.4 to 22.6 years. In the studies, 59% of participants were male (range across studies 39–66%) and 80% were White (range 70–97%). In addition, 52% reported heroin as the primary substance of use (range from 21 to 91%) and 44% reported injection or intravenous opioid use (range from 24 to 70%). All studies reported on co-use of at least one other substance: the most commonly reported co-used substances were cannabis, alcohol, cocaine, and amphetamines. Two studies measured co-occurring mental health diagnoses including major depressive disorder, attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder; one study’s participants reported relatively low rates of these co-occurring disorders (10–21%; Marsch et al., 2005), while the second study found higher rates (30–66%; Marsch et al., 2016).

3.3. Interventions

All four studies assessed sublingual buprenorphine (Table 1), formulated as Subutex (buprenorphine only) in one study and as Suboxone (buprenorphine-naloxone) in the other three. One study (Marsch et al., 2005) compared buprenorphine with clonidine. Another study (Gonzalez et al., 2015) compared buprenorphine-naloxone alone to combination buprenorphine-naloxone and memantine. Two studies (Marsch et al., 2016; Woody et al., 2008) compared different buprenorphine-naloxone taper schedules. Woody et al. tested 2-week versus 12-week taper schedules, whereas Marsh et al. tested 4-week versus 8-week taper schedules. Nine treatment arms existed across the four studies: duration of buprenorphine or buprenorphine-naloxone use across study arms ranged from 2 to 12 weeks, with a median duration of 8 weeks.

Examination of the adjunctive behavioral interventions indicated that all four trials evaluated some form of cognitive behavioral therapy (CBT), a behavioral intervention that provides patients with skills to change maladaptive thoughts and behaviors. One trial (Marsch et al., 2005) used the Adolescent Community Reinforcement Approach (ACRA), delivered via three 1-hour individual sessions per week. Two trials (Gonzalez et al., 2015; Woody et al., 2008) offered CBT using manuals from the National Institute on Drug Abuse Collaborative Cocaine Treatment Study: both offered 90-minute weekly group sessions, and one (Woody et al., 2008) also offered an additional weekly individual session. The fourth trial (Marsch et al., 2016) tested a multi-component CBT model based heavily on ACRA that was “based on a motivational interviewing and community reinforcement approach framework… [that] had three components: psychoeducational, cognitive-behavioral, and family systems.”

Two of the trials, both conducted by Marsch and colleagues (Marsch et al., 2005, 2016), enhanced the provision of ACRA via adjunctive contingency management (CM), a behavioral intervention in which patients receive incentives for meeting treatment goals. In the 2005 trial, ACRA sessions (delivered 3 times per week) were augmented with a CM protocol in which adolescents received escalating vouchers for submitting negative urine screens (maximum earnings up to $152.50) and for attending all of their MOUD dosing visits (maximum earnings up to $20). The 2016 trial supplemented the ACRA sessions (delivered 2 or 3 times per week) with voucher-based CM, with maximum earnings of $798.75 for sustained abstinence and perfect attendance, representing a substantial voucher increase over the earlier study.

The qualifications of the individuals delivering the adjunctive interventions varied. Two studies used master’s level counselors (Marsch et al., 2005; Woody et al., 2008), one used an “experienced psychologist” (Gonzalez et al., 2015), and the fourth did not report this information (Marsch et al., 2016).

3.4. Effects on opioid abstinence

Table 2 summarizes the results of the four studies on opioid abstinence in chronological order. Marsch et al. (2005) randomized 36 adolescents to a 28-day MOUD course of treatment with either buprenorphine or clonidine. In both groups, the study supplemented pharmacologic treatment with a combination of CBT (using an ACRA-based model) and CM. Buprenorphine was more effective to promote abstinence at the 1-month follow-up, measured as percent of patients with negative urine screens, than was clonidine (OR = 4.00, 95% CI 1.00, 16.00). The study reported treatment retention as a secondary outcome. For the duration of the 28-day active intervention period, the study retained 72% of participants receiving buprenorphine, compared with only 39% of those receiving clonidine (p = 0.04).

Table 2.

Studies of medication for opioid use disorders in transition-age youth: outcome data.

Author, year Arm 1 Arm 2 Outcome Follow-up (months) Arm 1
 Arm 2
 Effect (95% CI)
N Outcome N Outcome
Marsch, 2005 BUP + CBT + CM Clonidine + CBT + CM Abstinence (n, %) 1 18 12 (64%) 18 6 (32%) OR 4.0 (1.0, 16.0)
Woody, 2008 BUP-NAL 12-wk + CBT BUP-NAL 2-wk + CBT Negative urine screens (n, %) 1 74 16 (74%) 78 19 (36%) OR 7.1 (2.9, 17.3)
Negative urine screens (n, %) 2 74 22 (77%) 78 25 (46%) OR 5.1 (2.0, 12.8)
Negative urine screens (n, %) 3 74 25 (57%) 78 25 (49%) OR 1.8 (0.8, 4.2)
Gonzalez, 2015 BUP-NAL + MEM 30 mg + CBT BUP-NAL + MEM 15 mg + CBT Abstinence (n, %) 3 28 23 (82%) 27 9 (32%) OR 9.2 (2.6, 32.3)
BUP-NAL + MEM 30 mg + CBT BUP-NAL + placebo + CBT Abstinence (n, %) 3 28 23 (82%) 32 10 (30%) OR 9.2 (2.7, 31.5)
BUP-NAL + MEM 15 mg + CBT BUP-NAL + placebo + CBT Abstinence (n, %) 3 27 9 (32%) 32 10 (30%) OR 0.8 (0.3, 2.3)
Marsch, 2016 BUP-NAL 8-wk + CBT + MI + PE + CM BUP-NAL 4-wk + Placebo + CBT + MI + PE + CM Abstinence (Mean % negative urine screens per patient over 28 days, 95% CI) 2 25 34.6 (23.2, 50.0) 28 17.2 (5.8, 28.6) Cohen’s d 0.57 (0.02, 1.13)
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Note. Bold font indicates statistical significance. Abbreviations: BUP = buprenorphine; BUP-NAL = buprenorphine-naloxone; OR = odds ratio; CI = confidence interval; CBT = cognitive behavioral therapy; CM = contingency management; PE = psychoeducation; MI = motivational interviewing.

Woody et al. (2008) evaluated a 2-week dose of buprenorphine-naloxone (“short-term” arm) relative to a 12-week course of buprenorphine-naloxone (“extended” arm). The study augmented both conditions with a 12-week CBT protocol that combined 1 h of group counseling and 1 h of individual counseling. The study collected urine screens during treatment (weeks 4, 8, and 12) and then at follow-up interviews at months 6, 9, and 12. Among 152 adolescents, those randomized to the extended arm were more likely to submit a negative urine screen at weeks 4 and 8, but not at week 12. Follow-up analyses indicated higher rates of opioid-negative urine screens at a 12-month assessment among those receiving the extended taper than those receiving the shorter taper. Secondary analyses of treatment retention indicated that those in the 2-week dose condition were less likely to be retained during the 12-weeks of active intervention (OR = 0.13, 95% CI 0.07, 0.26).

Gonzalez et al. (2015) compared buprenorphine-naloxone plus memantine (either 15 mg or 30 mg) with buprenorphine-naloxone plus placebo in 80 transition-age youth with OUD. All participants also received a 90-minute weekly group CBT session, using the same CBT group protocol as in Woody et al. Participants given buprenorphine-naloxone plus 30 mg of memantine had improved abstinence at 3 months compared with both those in the memantine 15 mg arm (OR = 9.20, 95% CI 2.62, 32.28) and in the placebo arm (OR = 9.20, 95% CI 2.69, 31.46). Memantine 15 mg performed slightly worse than placebo (OR = 0.78, 95% CI 0.27, 2.31), although with an imprecise, nonsignificant estimate.

Marsch et al., 2016 compared a 4-week taper duration versus an 8-week taper duration for buprenorphine-naloxone, in combination with a multi-component behavioral intervention. The study collected multiple urine screens over a 28-day period and calculated an average number of negative screens per patients. Among 53 adolescents, those randomized to the 56-day taper had a significantly higher mean negative urine screens per patients for opioids compared to the 28-day taper group with a moderate effect size (Cohen’s d = 0.57, 95% CI 0.02, 1.13). Secondary analyses indicated that those in the 56-day taper were retained in treatment significantly longer than those in the 28-day taper (37.5 vs. 26.4 days), a difference that was moderate-to-large in size (Cohen’s d = 0.63, 95% CI 0.06, 1.19).

4. Discussion

This review systematically assessed the evidence in support of MOUD to promote opioid abstinence and treatment retention in transition-age youth. A key takeaway from a comprehensive search of peer-reviewed works conducted as part of a larger systematic review (Steele, Becker, Danko, Balk, Adam, et al., 2020a; Steele, Becker, Danko, Balk, Saldanha, et al., 2020b) was the sparseness of evidence: this review identified just four eligible RCTs evaluating buprenorphine in transition-age youth. Only one of the identified trials (Woody et al., 2008) was included in a prior systematic review (Minozzi et al., 2014), demonstrating the need for an updated synthesis of the literature. This work also extended the 2019 narrative review of Camenga and colleagues by identifying an additional study (Gonzalez et al., 2015), including replicable search criteria, assessing risk of bias, and specifying focal outcomes (abstinence and retention).

The identified MOUD research on transition-age youth focused predominantly on the efficacy of short-term, sublingual buprenorphine and buprenorphine-naloxone, with focal outcomes including abstinence (measured as percent of patients submitting negative urine screens or percent of negative urine screens per patient) and treatment retention (measured as percent of patients still engaged in treatment or weeks engaged in treatment per patient). Buprenorphine or buprenorphine-naloxone was more effective than clonidine (in one study), when augmented by memantine (in one study), and when tapered over longer rather than shorter durations (in two studies). Risk of bias across studies was moderate. Of note, two of the areas contributing to risk of bias, namely low compliance and incomplete outcome data, do not necessarily reflect weaknesses of the research methods, but rather reflect well-documented challenges retaining patients with OUD in treatment and research (Chang et al., 2018; Hadland et al., 2018).

Though all identified studies evaluated sublingual, short-term buprenorphine, the sparseness of studies provided little evidence to guide its administration. Specifically, no RCTs to date have examined buprenorphine (sublingual or implant) delivered over an extended period of time, akin to MOUD maintenance. All treatment arms described in the current synthesis administered buprenorphine for a median of 8 weeks. This duration falls well below current evidence-based treatment guidelines for buprenorphine administration in adults (Kumar et al., 2017), which recommend a minimum of 8 weeks of buprenorphine in the induction phase alone; clinical MOUD administration typically lasts for several months or may even continue indefinitely, depending on the needs of the patient. Indeed, a recent retrospective examination of Medicaid claims for MOUD reported a median buprenorphine retention of more than 4 months among transition-age youth (Hadland et al., 2018). With clinical MOUD prescribing practices already extending well beyond available research evidence, a pressing need exists for RCTs of MOUD maintenance in transition-age youth.

Studies of methadone and naltrexone were also lacking. Limited research focus on methadone is to be expected in transition-age youth, given FDA special requirements for prescribing methadone to youth between the ages of 16 and 18 (Institute of Medicine, 1995). Even so, the current review specifically aimed to identify studies of MOUD in young adults (age 18–25) and did not identify any trials of methadone or naltrexone meeting inclusion criteria. The lack of methadone studies was particularly surprising, as there is ample evidence supporting methadone’s effectiveness to treat OUD (Mattick et al., 2009) as well as indications that it produces higher rates of treatment retention among adolescents with heroin use (Hopfer et al., 2002). Furthermore, methadone is frequently administered to young adults in clinical contexts (e.g., Bagley et al., 2020). The lack of randomized trials assessing medication options other than buprenorphine in this age group is a major limitation to current knowledge and warrants urgent study.

The current synthesis also highlights the need for RCTs to determine what, if any, incremental benefits this population may receive from MOUD when combined with behavioral interventions. National guidelines for MOUD recommend adjunctive behavioral interventions to promote adherence to pharmacotherapy and support relapse prevention skills (Substance Abuse and Mental Health Services Administration, 2020b): such interventions may be particularly relevant for transition-age youth, especially those in late adolescence, who often initiate treatment due to external pressures and may struggle with intrinsic motivation (Battjes et al., 2003). In the current systematic review, individual or group-based CBT-type therapy was delivered in conjunction with buprenorphine in every arm of every identified study, making it impossible to parse the effectiveness of CBT as an adjunctive treatment.

Other investigators have noted the scarcity of data on adjunctive behavioral interventions. A recent systematic review by Welsh et al. (2020) identified just three studies (reflecting two distinct datasets) testing the efficacy of behavioral therapies for transition-age youth with OUD; all were nonrandomized and none included comparison conditions that enabled researchers to test the benefits of adding a behavioral intervention to MOUD. Systematic reviews of the adult-focused MOUD literature have not reached consensus regarding the benefit of a combined MOUD and behavioral approach: some reviews have concluded that behavioral interventions do not add incremental benefit (Amato et al., 2011), while others have suggested that the data generally support adjunctive interventions, with the incremental utility varying across study, treatment modality, medication, and/or outcomes assessed (Dennis et al., 2020; Dugosh et al., 2016; Gregory & Ellis, 2020).

Several important directions exist for future research into the augmentation of MOUD with behavioral interventions for transition-age youth. Given the financial costs and workforce demands associated with some behavioral interventions (e.g., CM rewards in the Marsch et al., 2016 study cost $800 per patient), future studies must determine the minimum level of therapy needed to exceed the benefits of MOUD-only approaches. Likewise, researchers should focus their inquiry on treatment modalities with the strongest empirical support in the broader youth substance use literature, such as family-based therapies (Hogue et al., 2018; Steele, Becker, Danko, Balk, Adam, et al., 2020a).

Importantly, the current findings are limited by the sparseness of the evidence. This review excluded 988 adult studies of substance use interventions that included transition-age youth, because none of them contained subgroup analyses that would have supported inferences about effectiveness in this age cohort. The paucity of studies in this age cohort has left many basic empirical questions unanswered, such as under which conditions MOUD is most effective. In the same vein, every treatment condition delivered adjunctive behavioral interventions, but the interventions were often not described in sufficient detail to inform replication in clinical practice. Implications of the synthesized research are further constrained by moderate risk of bias across the four randomized trials. Review also did not assess potential adverse events of MOUD. Finally, the transition-age youth who participated in the reviewed studies were overwhelmingly White (ranging from 70% to 97% across the four studies) and the degree to which these findings are applicable to racial and ethnic-minority youth is unclear.

4.1. Future directions

This synthesis of the MOUD literature supports the effectiveness of buprenorphine relative to clonidine, when augmented with memantine, and when delivered with longer-tapers relative to shorter tapers. This systematic review highlights several concrete directions for future research. First, studies that evaluate the effectiveness of buprenorphine over longer durations are needed to more accurately reflect current clinical practice. Second, a need exists for RCTs of the effectiveness of methadone and naltrexone to treat OUD in transition-age youth, as these interventions are used routinely in clinical practice but lack empirical support in this age cohort. Third, investigators should conduct subgroup analyses of the effectiveness of MOUD in transition-age youth. Extant clinical trials should be re-analyzed to examine intervention effectiveness in this developmentally vulnerable age group. Fourth, future research should seek to establish what, if any, incremental benefit adjunctive behavioral interventions may offer transition-age youth receiving MOUD, including evaluation of potentially effective behavioral treatments (e.g., family therapy) that have not been evaluated in this population to date. Finally, investigators must ensure that clinical trials proactively recruit, engage, and retain underrepresented patients to ensure that clinical trial outcomes are generalizable to the population of individuals in need of MOUD. By conducting new randomized trials or re-analyzing prior trials, researchers have the potential to provide critical insights and address these questions in order to guide clinical practice and ultimately to reduce the impact of OUD on transition-age youth.

Supplementary Material

Appendix A

Acknowledgements

The authors would like to thank Drs. Anthony Spirito, Sarah Badgley, and Cathy Friedman for serving as subject matter expert consultants on the systematic review.

Role of funding sources

This review was funded under contract HHSA 290-2015-00002-I, Task Order HHSA29032011T, Agency for Healthcare Research and Quality, US Department of Health and Human Services. The authors of this article are responsible for its content. Statements in the article do not necessarily represent the official views of or imply endorsement by Agency for Healthcare Research and Quality or the Department of Health and Human Services. The effort of Dr. Helseth was supported by K23DA048062. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funder.

Footnotes

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jsat.2021.108494.

Registration

This trial has been registered with PROSPERO (https://www.crd.york.ac.uk/prospero) (identifier CRD42018115388).

CRediT author contribution statement

Dr. Becker served as the Scientific Lead, contributed to systematic review conceptualization and design, categorized intervention components, reviewed data collection, and led the drafting and revision of this manuscript; Dr. Scott extracted and categorized intervention components and contributed to the drafting of the manuscript; Dr. Helseth contributed to the drafting and revision of the manuscript; Dr. Danko assisted in review conceptualization and design, categorized intervention components, and critically reviewed the manuscript; Dr. Balk assisted in review conceptualization and design, reviewed data collection, extracted data, conducted risk of bias assessments, and critically reviewed the manuscript; Ms. Adam performed the literature search, led data extraction from the opioid trials, contributed to interpretation of data, and critically reviewed the manuscript; Dr. Saldanha participated in data collection, risk of bias assessments, and interpretation of data and reviewed the manuscript; Dr. Steele served as the Systematic Review Lead, conceptualized and designed the systematic review, designed data collection instruments and supervised data collection, performed data analysis and interpretation of data, and contributed to critical review of this manuscript. All authors reviewed multiple drafts and approved the final version.

Declaration of competing interest

None.

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Supplementary Materials

Appendix A
NIHMS1753214-supplement-Appendix_A.docx (42.9KB, docx)

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