Opioid use disorder is a chronic, relapsing disease1 of worldwide epidemic proportions.2, 3, 4, 5 Standard of care for opioid use disorder in the USA combines medication with behavioural health services,6 which has been associated with a reduction in deaths from overdose, improved retention of individuals in treatment, less opioid use and relapse, and prevention of infectious diseases.7 Several drugs target the μ-opioid receptor (μOR): the full agonist methadone, the partial agonist buprenorphine, and the antagonist naltrexone. The choice of treatment approach can be guided by various factors, including efficacy, safety, and cost-effectiveness.8 The full agonist methadone is likely to be abused, diverted, and misused, and is therefore more highly regulated than other opioid drugs (ie, it is classified as a schedule CII substance in the USA), and it is usually administered to patients via observed dosing in specialised clinics. To avoid precipitated withdrawal, treatment with naltrexone can start only after the patient is completely withdrawn from opioids, whereas treatment with buprenorphine can be titrated to patients' withdrawal symptoms, yielding a better tolerated transition to treatment. Buprenorphine can alleviate opioid withdrawal signs and symptoms, reduce craving, and can block the subjective effects (eg, so-called drug-liking) of other opioids.
Research in context
Evidence before this study
Despite the burgeoning worldwide opioid epidemic and the proven efficacy of medication-assisted therapy, buprenorphine is an under-used medication for the treatment of opioid use disorder. RBP-6000, referred to as BUP-XR (extended-release buprenorphine), was developed by Indivior with the latest understanding of relationships between buprenorphine plasma concentrations, brain μ-opioid receptor (μOR) occupancy, and the pharmacodynamic effects of buprenorphine. Symptoms of opioid withdrawal are suppressed at buprenorphine plasma concentrations of 1 ng/mL or more (≥50% μOR occupancy), whereas at least 2–3 ng/mL (≥70–80% μOR occupancy) is required to achieve blockade of the subjective effects of a μ-opioid full agonist, such as hydromorphone. We hypothesised that this degree of μOR occupancy would facilitate abstinence from illicit opioid use, attenuate craving and decrease withdrawal symptoms throughout the monthly dosing interval. These observations and hypotheses were supported by literature searches using PubMed, MEDLINE, and Ovid, using the search terms “buprenorphine”, “opioid use disorder”, “medication assisted treatment”, “mu-opioid receptor”, “positron emission tomography [PET]”, “[11C]carfentanil”, “withdrawal symptoms”, “craving”, “relapse”, “reinforcing and subjective effects of opioids”, “hydromorphone”, and “opioid blockade”, with no search restrictions.
Added value of this study
In this study, participants' percentage abstinence was significantly higher in both BUP-XR dose groups than in the placebo group. Treatment outcomes were consistent for control of opioid craving and withdrawal symptoms. Both regimens were safe and well tolerated and had higher mean medication satisfaction scores compared with participants who received individual drug counselling and placebo. There was no compensatory non-opioid illicit drug use with BUP-XR treatment. Notably, these results were obtained under a protocol that did not allow supplemental buprenorphine dosing. To our knowledge, this is the first study to translate hypothesised buprenorphine activity, based on the degree of μOR occupancy, into clinical efficacy.
Implications of all the available evidence
BUP-XR was designed to provide sustained target plasma concentrations of buprenorphine over the monthly dosing period; this approach affords a potential advantage over transmucosal buprenorphine, which might provide opioid blockade for only part of the daily dosing interval and can be associated with return of craving or withdrawal symptoms at the end of the day. Furthermore, monthly dosing by a health-care professional should improve adherence to the regimen and the long-acting nature of the formulation will not allow a patient to discontinue treatment for illicit opioid use. Finally, BUP-XR is distributed to and administered by health-care professionals only, which could reduce risks of diversion, misuse, abuse, and accidental paediatric exposure.
Access to and use of buprenorphine in the USA is limited by a scarcity of qualified prescribers, stemming partly from misunderstandings about buprenorphine.9, 10 For example, prescription of inadequate doses that result in relapse might reinforce negative attitudes and doubt among providers and patients regarding the effectiveness of buprenorphine. Patients who take daily transmucosal formulations of buprenorphine can reach target plasma exposures, but concentrations are often not sustained because of large daily fluctuations, poor treatment adherence, or both.11 Taking medication every day is also a constant reminder of the disease. Furthermore, although buprenorphine can be administered in an office setting, physicians have concerns that take-home transmucosal buprenorphine can be diverted,12 misused, abused, and could result in accidental poisoning in children,13 which are at least partly responsible for the underuse and underdosing of buprenorphine for opioid use disorder.14, 15, 16, 17, 18 Although a 6-month subdermal implant of buprenorphine is available, its indication is limited to patients who have achieved and sustained prolonged clinical stability with relatively low daily doses of buprenorphine.
Buprenorphine formulated in the well established ATRIGEL delivery system (BUP-XR; Albany Molecular Research, Burlington, MA, USA) is the first subcutaneously injected, extended-release, monthly buprenorphine formulation approved by the US Food and Drug Administration (FDA). BUP-XR was designed to provide sustained exposure of buprenorphine over the entire monthly dosing interval and to deliver average buprenorphine plasma concentrations of 2–3 ng/mL or more, which are necessary to block the subjective effects of exogenous opioids (ie, opioid blockade).19, 20 The novel characteristics of BUP-XR mitigate the requirement for daily medication adherence, the risk of subtherapeutic buprenorphine concentrations over the dosing interval, and the need for supplemental buprenorphine. Additionally, both the closed distribution system (BUP-XR is provided to and administered only by health-care professionals) and the inherent properties of the subcutaneous biodegradable depot formulation are expected to reduce the risks presented by take-home medication.
The primary objective of this study was to assess the efficacy of two dosing regimens of BUP-XR in treatment-seeking individuals with opioid use disorder. Other prespecified objectives of this study were to assess the safety and tolerability of BUP-XR, the effects of BUP-XR on patient-reported outcomes, and to assess the relationship between plasma concentrations of BUP-XR and clinical endpoints (exposure-response relationships).