Opioid agonist treatment for pharmaceutical opioid dependence

PHARMACEUTICAL opioids are commonly used for pain in Australia, with an estimated 3.1 million people dispensed at least one opioid per year between 2016 and 2017. Recent increases in pharmaceutical opioid use in high income countries have contributed to fatal overdoses. Although illicit opioids are the leading cause of opioid-related deaths in North America, prescription opioids still cause most deaths in Australia.

Opioid agonist treatment (OAT, often called opioid substitution treatment) has increasingly been used to treat pharmaceutical opioid dependence in Australia. These treatments, including methadone and buprenorphine, are commonly prescribed by GPs in primary care. Numerous randomised controlled trials have demonstrated the health benefits of OAT, such as reductions in substance use, overdose mortality and infectious disease transmission, and increased social benefits such as reduction in crime, and health benefits such as an increase in quality-adjusted life years.

Why did we do the review?

Most of the research that positions OAT as the most effective treatment for opioid dependence has come from studies that included people who were dependent on heroin. For this reason, we did a systematic review to see what research was available on OAT specifically for the treatment of people experiencing pharmaceutical opioid dependence. We identified studies comparing full and partial opioid agonist maintenance treatments (defined as at least 30 days), as well as those comparing opioid agonist maintenance treatment with placebo, detoxification, opioid antagonists (such as naltrexone) or other psychological interventions. This year we updated the review, finding two additional randomised trials to include.

What did we examine?

We focused on outcomes of opioid use and treatment retention (ie, how many people stayed in treatment till the end of the trial). We considered outcomes such as pain, quality of life and employment; however, few studies examined most of these secondary outcomes. The review outcomes were patient-focused, and trials generally did not report on prescriber factors.

What did we find?

• Eight randomised trials, with 709 participants.
• Overall very low to moderate quality evidence.
• Four studies comparing methadone and buprenorphine.
• Four studies comparing maintenance buprenorphine with a comparison group that was not opioid maintenance treatment (eg, detoxification or naltrexone).
• Many of these trials recruited people who used heroin and people who used pharmaceutical opioids, so we re-analysed trial data looking only at people who used pharmaceutical opioids.

When comparing methadone with buprenorphine maintenance, it seemed that methadone may keep more people in treatment for longer than buprenorphine, although we found most of the variability in the results was due to one study from Iran with people who injected buprenorphine. When that study was removed in a sensitivity analysis, there was no difference in treatment retention between buprenorphine and methadone.

We also found that people on methadone self-reported less opioid use than people taking buprenorphine, although when an objective measure of drug use (urine testing) was examined, there was no difference between methadone and buprenorphine.

When comparing buprenorphine maintenance with other non-opioid treatments (eg, detoxification, naltrexone, or psychological treatments), buprenorphine kept more people in treatment, and led to lower rates of opioid use.

Due to the relatively small size of the studies and the use of open label designs, in which the participants and the researchers knew which medication the person in the study was receiving, some caution is needed in interpreting results. Also, seven of the eight studies were from the US, with one from Iran, and it’s possible that not all findings are transferable to the Australian context.

No randomised trials examining OAT for pharmaceutical opioid dependence have been done in Australia. Recently, in Australia, there have been new formulations of OAT, including newer extended-release injectable formulations of buprenorphine. To date, data on their use for treatment of pharmaceutical opioid dependence are limited, which may be of interest for future review updates. The current review only identified trials with oral methadone and sublingual buprenorphine.

What are the implications for practice?

There was low certainty evidence favouring methadone over buprenorphine for pharmaceutical opioid dependence on some outcomes, but the difference between the treatments was small, and was no longer evident when heterogeneity was considered.

Given the similar outcomes between methadone and buprenorphine in this population, factors such as methadone’s effect on respiration, the greater restrictions on unsupervised dosing with methadone, and patient and clinician preference should also inform which medication may suit patients best. When comparing buprenorphine maintenance with non-OAT options the difference is clearer: buprenorphine maintenance treatment is better at keeping people in treatment and reducing opioid use.

Our review demonstrated better outcomes with longer term treatment, highlighting that treatment retention is important. This requires long term accessibility to OAT prescribers, yet threats to telehealth services, challenges with Medicare-subsidised “bulk-billing” care, GP workforce shortages, and low rates of OAT prescribing in Australia (, and ) can all compromise this.

This review did not specifically address prescriber barriers or enablers to OAT prescribing but hesitancy among GP prescribers is well known. In improving patient outcomes with pharmaceutical opioid dependence, evidence-based care and system level factors must be considered.

Professor Suzanne Nielsen, from Monash University, is the Deputy Director of Monash Addiction Research Centre and an NHMRC Career Development Fellow

Wai Chung Tse, from Monash University, is an MD Candidate at Monash University School of Medicine and a researcher at Monash Addiction Research Centre with a special interest in Emergency Medicine and Public Health

Dr Pallavi Prathivadi is a GP and researcher. She completed her PhD at the Monash University Department of General Practice in 2021, where she studied GP opioid prescribing practices. She was a 2020–2021 Fulbright Scholar at the Stanford University School of Medicine.

Dr Briony Larance, from University of Wollongong, is a Senior Research Fellow in the School of Psychology and has an adjunct appointment with the National Drug and Alcohol Research Centre at the University of New South Wales.

The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.

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