Low‐ and very low‐dose buprenorphine induction: new(ish) uses for an old(ish) medication?

Low-dose buprenorphine initiation is increasingly necessary and is the most accurate and appropriate term to describe the overlapping initiation of buprenorphine with full agonist opioids. Ms C is a 32-year-old female who presented to the hospital with fever and chest pain who was found to have tricuspid valve infective endocarditis. Injection marks were noted on her forearms and she was observed to have opioid withdrawal. Her medical team discussed treatment options for opioid use disorder (OUD) and initiated methadone. She underwent successful cardiac surgery, but on post-operative day 2 she developed torsade de pointes. Her surgeons requested that methadone be transitioned to buprenorphine. The patient has acute post-operative pain and is receiving immediate-release hydromorphone. She is receptive to transitioning to buprenorphine but does not feel that she can abruptly stop full agonist opioids (FAO) and fears precipitated withdrawal. Buprenorphine is a partial opioid agonist with formulations indicated for chronic pain or OUD. Unlike FAO (heroin, fentanyl, methadone, etc.) the partial opioid agonism of buprenorphine necessitates initiation consideration in people taking FAO. International buprenorphine initiation guidelines advise against starting buprenorphine until FAO have been stopped for 8–36 hours to prevent precipitated withdrawal and an initial buprenorphine dose of 2–4 mg [1-4]. This technique is generally well tolerated and successful in patients using heroin and other short-acting opioids; however, clinical realities such as acute and chronic pain requiring FAO, use of pharmaceutical and illicit fentanyl or other high potency synthetic opioids, or methadone present clinical challenges to traditional buprenorphine initiation techniques. Low-dose (< 2 mg) buprenorphine strategies have been developed to address these situations, prevent worsening of acute and/or chronic pain and prevent precipitated opioid withdrawal. The gradual cross-titration with low-dose, and in some cases very low-dose (< 1 mg) buprenorphine allows the partial agonist opioid to slowly displace the FAO from the opioid receptor, thus minimizing symptoms of precipitated opioid withdrawal. Studies with buprenorphine conducted in the 1980s and 1990s demonstrated that doses of up to 2 mg of sublingual liquid (equivalent to 3–4 mg of current buprenorphine tablet/film formulations) did not precipitate opioid withdrawal when provided to patients receiving methadone [5]. This mirrored data obtained from intramuscular and intravenous buprenorphine in patients receiving morphine [6]. The onset of buprenorphine-precipitated withdrawal was dependent upon the dose of the agonist, time since last agonist administration, and the dose of buprenorphine, and induction guidelines recommended optimizing these parameters [6]. The first case-series to further describe therapeutic low-dose buprenorphine initiation in patients receiving FAO was carried out in 2010 in Bern, Switzerland [7]. Since then, there have been 26 case reports or case-series of low-dose and very low-dose techniques. Reports use different low-dose initiation strategies, generally using buccal, intravenous, transdermal or sublingual buprenorphine in doses 25–50% lower than traditional initiation techniques. Most published cases describe successful initiations, raising the specter of publication bias. Several large academic institutions have sought approval from their institutional therapeutics’ committees for the low-dose initiation approach. The process of using low or very low doses of buprenorphine to assist with the transition from FAO to buprenorphine has been described by a variety of terms. Some have referred to this as the ‘Bernese method’, while others have used the term ‘microdose’, ‘microdosing’ or ‘microinduction’. The term ‘microdose’ is scientifically and clinically inaccurate for the procedures that have been described in the literature and on public forums, including social media. ‘Microdosing’ or ‘microdose’ is not a medical term. In the pharmacology literature, ‘microdoses’ are those, often in the range of micrograms, that are designed to have no therapeutic effect or benefit. These very low doses, often less than 1/100 of the pharmacologically active dose, are used in studies of pharmacokinetics and pharmacodynamics [8, 9]. In the ‘microdose’ buprenorphine publications, the authors use larger doses and describe efforts to attain a therapeutic outcome (buprenorphine induction) [10, 11]. Another concern is that the term ‘microdosing’ in the lay literature and media typically refers to hallucinogen microdosing for a range of perceived benefits, many of which have not been explored with great scientific rigor [12]. A recent Google Trends search revealed that the top five health-related searches for the term ‘microdosing’ were related to psilocybin. We argue that the addiction medicine field (and patients and families) would like to avoid confusing this practice with that of initiating treatment for OUD. The term poses a threat to the progress in the field of addiction towards adopting the use of science-based language and practices [13-15]. We contend that a more appropriate terms for buprenorphine induction should be ‘low-dose’ or ‘very low-dose’. The changing international opioid drug supply, including more high-potency synthetic opioids, the growing incidence of opioid overdose deaths, the evolving medical complexity of patients with OUD, poor access to methadone treatment and limited interventions to treat opioid precipitated withdrawal, necessitate thoughtful and well-designed protocols to initiate buprenorphine, a key treatment for OUD in a variety of clinical settings. Low-dose buprenorphine initiation is an increasingly common technique, but rigorous science regarding procedures and outcomes are lacking. At least one hospital-based randomized clinical trial is planned, although it does not include other buprenorphine formulations that are used for this practice [16]. Current low-dose protocols describe a range of doses and a range of formulations over a range of days, and it is not clear which of these provide the optimal outcomes in patients and clinical scenarios. Additionally, it is not clear which patients will benefit from low-dose induction techniques, although it is clear that having access to this technique is important. Clinical challenges have resulted in new ways to use a medication that has been around for decades. As research clarifies the optimal use and protocols for low-dose buprenorphine initiation, we should avoid inaccurate terminology to avoid confusing ourselves, our patients, their families and policymakers. Low-dose buprenorphine induction strategies provide new uses for an established and essential medication. Ms C transitioned to buprenorphine using a low-dose buprenorphine induction to avoid precipitated withdrawal and severe pain. The 7-day transition was based on evidence for the use of buccal buprenorphine starting at 225 μg once daily and increasing to 450 μg twice daily (equivalent to ~2 mg of sublingual buprenorphine) over 3 days and then transitioning to sublingual buprenorphine [10]. None. Melissa Weimer: Conceptualization, writing, editing. David Fiellin: Conceptualization, writing, editing.