What are the considerations in the pharmacological management of opioid addiction in adolescents?

KEYWORDS:

• Opioid use disorder
• adolescents
• methadone
• buprenorphine
• recovery

1. Introduction

Experimentation with psychoactive drugs commonly begins in adolescence, and younger age of initiating drug use predicts more serious problems [1]. The developing brain is more susceptible to adverse, lasting changes resulting from drug exposure. In the United States, among people less than 18, 0.6% were diagnosable with OUD [2]. In treatment-seeking samples, OUD has been shown to be a chronic, relapsing disorder. The longest follow-up of adolescents with drug problems is a Swedish study, which compared the life trajectories of adolescents diagnosed with a substance use disorder (SUD) with randomly selected age-matched controls [3]. Over 30 years, the SUD group fared significantly worse on mortality, mental health, physical health, criminality, poverty and later substance use disorders. The differences were dramatic and persistent, even in those who subsequently moderated their substance use. The authors proposed that factors other than substance use were contributing to their poor outcomes. Recent US data in adults confirms a strong association between criminality, poor physical and mental health, poverty, other SUDs, and use of opioids [4]. Causality is probably bidirectional. Adverse circumstances are predictors of developing OUD, but OUD disrupts adolescent maturation, entrenching and worsening problems of adjustment.

A critical question is whether there are treatment approaches which can reduce the harm and modify the adverse life trajectory of adolescents with OUD.

2. Efficacy of treatment

In adults, longer retention in treatment is consistently associated with better outcomes, and MAT with methadone or buprenorphine attracts and retains people in treatment better than drug-free approaches [5]. Short-term medication (‘detoxification’) does not contribute to better long-term outcomes. Methadone retains people longer in treatment than buprenorphine. The oral opioid antagonist naltrexone has been markedly less effective in attracting and retaining people in treatment. In short-term studies, extended-release naltrexone (XR-NTX) has obtained somewhat better treatment adherence; in adults it appears of similar efficacy to sublingual buprenorphine-naloxone (BNx) [5]. One limitation is that patients need to be abstinent to commence treatment with naltrexone.

These findings are replicated in the few studies on adolescents. Detoxification, whether short or long, seldom leads to abstinence; three short-term randomized-control trials (RCTs) of brief or very brief buprenorphine treatment reported that relapse rates were high Fonce medication was ceased [6]. A trial comparing XR-NTX with BNx reported similar outcomes in both groups, and rapid relapse on ceasing medication [7]. A study of community treatment in people aged 22 or less with a diagnosis of OUD reported that median retention was 123 days in BNx, 150 days in XR-NTX, 324 days in methadone, and 67 days among youths who received only behavioral health services [8].

Decades earlier, the Drug Abuse Reporting Program (DARP) reported treatment outcomes for a sub-sample of 5,400 adolescents [9]. Retention was higher with methadone maintenance than with therapeutic communities, and time in treatment was the best predictor of reduced opiate use. At four- to six-year follow-up, methadone treatment was associated with a substantial reduction in opioid use, but as with the Swedish cohort [3], young people had poor outcomes in terms of non-opioid substance use, alcohol consumption, employment and productive activities.

3. Adolescents receive no or suboptimal treatment

In the United States, most adolescents with OUD do not receive treatment, and among adolescents who do receive treatment for OUD, a 2017 study reported that less than three percent receive MAT [10]. Concern over whether current models of MAT are adequate to address adolescent problems is one reason for poor uptake. Federal regulations make it difficult for adolescents to access the most effective medication – methadone. Additional obstacles include denial by parents of the presence or severity of SUDs in their offspring, and denial by drug users of the severity of their problems; and on the part of practitioners, limited research to support decisions about medication use and associated psychosocial interventions.

A major concern giving rise to these barriers is that exposing adolescents to regular opioids, administered as treatment, may worsen their problems. Neuroscience is said to show that repeated opioid exposure can produce lasting brain changes, which may contribute not just to the risk of relapse, but to behavioral problems such as the impulsivity commonly seen in addiction [2]. There is concern that in young people with uncertain tolerance and short histories of addiction, regular opioid exposure through treatment may contribute to such lasting brain changes, potentially entrenching addiction and its adverse behavioral and health consequences.

Such observational evidence as is available does not support this concern. Adolescents with often short histories of OUD have very high rates of relapse after ceasing the opioid antagonist naltrexone [11], as also occurs after buprenorphine. A study in people <20 years old with OUD reported worst retention and most rapid return to treatment (relapse) in those with initial drug free treatment, better retention and slower return in buprenorphine-treated subjects – and best retention, slowest return in people given methadone [12]. The significantly better results in adolescents given methadone do not support the hypothesis that raising young people’s level of opioid tolerance has entrenched their drug problems. Most importantly, the chronic, relapsing pattern of OUD was not observed among US veterans, many of them young, who became addicted to heroin during service in Vietnam. After detoxification, re-addiction was rare on return to civilian life. The only predictor of re-addiction was pre-exposure criminality [13]. This observation adds to the evidence that people with chronic, relapsing OUD mostly have preexisting vulnerability.

The pressing concern is how to retain young people with OUD in treatment and use the respite from addiction to address their complex social and psychological needs. Here, the limited evidence is not encouraging. MAT retains adolescents in treatment better than drug-free treatment, but compared to outcomes in adults, retention is shorter and relapse after leaving treatment is rapid [11]. The DARP study reported adolescents treated in therapeutic communities showed better results than those on methadone in terms of opiate use, other illicit substance use and employment [9]. Retaining young people in treatment has not usually been sufficient to change their life trajectory.

4. Expert opinion

The United States remains in the grip of an opioid epidemic; the latest, preliminary statistics suggest fatal opioid overdoses continued to increase in 2020. MAT is protective against overdose, and this is a compelling argument to introduce MAT in young people diagnosed with OUD, particularly those with problems in psychological and social functioning. There seems no reason to suppose that vulnerable adolescents caught up in the current opioid epidemic have a different prognosis to people from earlier eras, suggesting early initiation of treatment is preferable.

Recent depot formulations (XR-NTX, depot buprenorphine) are designed to enhance retention and compliance. Studies in adults suggest depot buprenorphine is of similar, modest efficacy as buccal BNx, and XR-NTX and BNx are of similar, limited efficacy [5]. There is much to be learned about optimal use of depot formulations, but evidence to date does not suggest that convenience and maintaining adequate blood levels of medication has translated to increased effectiveness.

Methadone treatment has a strong behavioral structure – daily attendance for supervised administration. This is a barrier to participation, but may have a therapeutic element. One step in expanding access to comprehensive treatment would be for existing adolescent treatment services integrate prescribing methadone or buprenorphine, or link with prescribing services, so that more adolescents receive access to effective care. A second measure to improve access would be to allow primary care prescribing of methadone, with dispensing from community pharmacies [14]. Thirdly, studies are needed into the effectiveness of methadone treatment as a first-line treatment of adolescents with established OUD. Without such research, regulations will be difficult to change.

Not all treatment programs are equally effective. Structured treatment requires a clear rationale for use of medication, individualized objectives of treatment, and regular monitoring and review of progress. Cohesive, goal-directed, and well-organized intervention programmes can help distressed individuals recover and lead essentially normal lives – but they also need a supportive, stable social context [15]. The challenge facing adolescents with OUD is that the context in which they live is often in need of healing. Whether investment in sustained social programs for marginalized youth, provided in conjunction with MAT, can improve outcomes is a further research priority. Until such data is available, however, the immediate priority is to focus on the achievable goals of reducing risk and reducing harm.Funding This manuscript has not been funded.

Declaration of interest

J Bell has received research funding from Indivior, the company which markets buprenorphine between 2013-2014. He has also received speaker’s fees from Indivior (2017), and consulting fees from Martindale Pharma (2016). He is currently chief investigator on a clinical study jointly funded by Uniting Nsw/ACT, and The Australian National Health and Medical Research Council. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.