Extended-Release Buprenorphine and Its Evaluation With Patient-Reported Outcomes

Medications used for the treatment of opioid use disorder are highly effective not only in preventing relapse to drug taking and facilitating recovery but also in preventing overdoses. As such, expanding treatment with medications for opioid use disorders has become a key strategy for addressing the current US overdose crisis, which in 2019 caused 70 630 deaths.¹ However, preventing overdoses requires that patients be retained on medications for opioid use disorder, which has been challenging. Retention rates are quite low; overall, 40% to 50% of patients treated with methadone or buprenorphine relapse within a 6-month period of treatment initiation.¹ In this respect, strategies to enhance retention on medications for opioid use disorder would benefit patients and be of value in mitigating the overdose mortality epidemic.¹

In other areas of medicine, an effective strategy for improving adherence has been the use of extended-release (ER) formulations. It is established that multiple doses of a medication required each day can reduce adherence,² and there may be particular advantages for ER injectable formulations in the treatment of chronic health conditions, such as addictions.³ In the treatment of opioid use disorder, ER formulations have been developed for naltrexone (1 month) and buprenorphine (1 week, 1 month, and 6 months). Randomized clinical trials have shown these ER formulations to be at least as efficacious as the immediate-release formulations and have been the basis for their submission for approval or actual approval by the US Food and Drug Administration (FDA).

The National Institute on Drug Abuse (NIDA), as part of the National Institutes of Health Helping End Addiction Long-term initiative, is supporting studies to accelerate the development of new ER formulations of medications for opioid use disorder (eg, an ER formulation of methadone) and to evaluate effectiveness and implementation of FDA-approved ER formulations.⁴ The goal of this work is to provide clinicians and patients with options that can address key clinical barriers to care for persons with opioid use disorder, which are typically chronic conditions. For example, ER formulations may offer particular benefits for treatment in justice settings, for homeless populations, and in rural communities because of the difficulty in accessing consistent care by patients in these settings.

However, missing from most of the work in medication development, including for opioid use disorder, has been the voice of the patient. What do patients want? How do they respond to the various approaches to treatment? While there may be modest variations in adverse effects and tolerability in general for the different formulations, the underlying pharmacology is generally identical. Thus, differences are expected to be in their use in practice. Does a new formulation address a clinical need? Is it acceptable to patients and clinicians? These questions fall under the broad category of patient-reported outcomes (PROs) and, as such, have emerged as an important area of research in recent years. For example, determining meaningful PROs for use in the development of medications for opioid use disorder and other addictive disorders has been a shared goal of both the FDA and NIDA.^5,6 The goal of this work is to align medication development with outcomes of relevance and meaning to the persons most affected by the conditions. However, studying such outcomes in clinical trials remains rare.

Addressing this very issue, Lintzeris and colleagues⁷ conducted a randomized effectiveness trial of daily sublingual buprenorphine compared with injectable depot ER buprenorphine (weekly or monthly) for opioid use disorder, with the primary outcome of global treatment satisfaction—a PRO.⁷ While secondary outcomes included opioid abstinence and retention in care, the main goal was to focus on both the primary outcome and a range of PROs.

Results of this study consistently demonstrated the superiority of the ER injectable buprenorphine vs the daily oral formulation across many outcomes.⁷ Effect sizes were substantial. For example, the number needed to treat to achieve the Treatment Satisfaction Questionnaire for Medications global satisfaction score of at least 80 was only 5.1 for the ER formulation vs the oral.⁷ Of note, the study also found no difficulty in transitioning patients who were receiving oral buprenorphine to the ER formulation, a finding that has not been emphasized previously in the literature.⁷

The study by Lintzeris and colleagues⁷ is well designed and executed, with some important implications for treatment development. Using PROs instead of drug abstinence as the primary outcome is innovative, and using a comparative effectiveness design is another strength. Importantly, the practice-based nature of the study, in which real-world settings with few exclusion criteria were used to recruit participants, suggests the likely generalizability of findings. However, because this type of patient-centered research may be influenced by the overall clinical context, applicability of results from a treatment system in Australia to other countries (including the United States) is not certain. Specifically, treatment included observed dosing of oral buprenorphine, although participants were allowed to take as many as 6 doses per week without supervision, and included at least weekly clinical visits, whereas in the United States, monthly appointments are typical. Would this affect the study outcomes? Does more frequent follow-up for oral medication in Australia relate to its lesser acceptability? Thus, PROs for ER formulations of medications for opioid use disorder need to be studied in other systems of care to determine whether the advantages are consistent across care systems. Nevertheless, the findings that the ER buprenorphine formulation was well tolerated, acceptable to patients, and produced generally more positive PROs than daily oral buprenorphine are an encouraging signal for others developing ER formulations for addictive disorders.

The study by Lintzeris et al⁷ highlights the importance of considering PRO measures in clinical trials. Even if efficacy is no different for various formulations, PROs may provide an important reason to select a new formulation. Patient preferences and apparently improved function may prove to be useful secondary outcomes in medication trials, and the measures used in this new study deserve consideration.⁶

In the current opioid epidemic, when overdose deaths are increasingly being associated with fentanyl, the ER buprenorphine formulations may offer unique benefits. Fentanyl’s high intrinsic potency as an opioid agonist drug makes it a very addictive and lethal drug, and its high profit in the illicit drug market has led to a rapid expansion across the United States. By providing more stable plasma buprenorphine levels than oral formulations, ER buprenorphine formulations obviate the troughs in plasma levels at the end of the daily dosing period that can trigger relapse. Thus, they may have particular value for reducing fentanyl-related overdoses, which can occur with relapse to opioids. Finally, the greater treatment satisfaction by patients receiving ER buprenorphine suggests that ER formulations might help to improve long-term retention and, as such, be a valuable tool to help combat the current opioid epidemic and reduce its associated mortality.

Published: May 10, 2021. doi:10.1001/jamanetworkopen.2021.9708

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Compton WM et al. JAMA Network Open.

Corresponding Author: Wilson M. Compton, MD, MPE, Office of the Director, National Institute on Drug Abuse, 301 N Stonestreet Ave, 3WFN Room 09D18, MSC 6025, Bethesda, MD 20892-6025 (wcompton@nida.nih.gov).

Conflict of Interest Disclosures: Dr Compton reported having stock holdings in General Electric, 3M, and Pfizer outside the submitted work. No other disclosures were reported.

Disclaimer: The opinions expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Institute on Drug Abuse, the National Institutes of Health, or the US Department of Health and Human Services.