Opioid Use Disorder Treatment in the Fentanyl Era

To the Editor:

The letter by Hartley et al.¹ describes a novel approach for buprenorphine initiation in an inpatient withdrawal management setting for persons who use fentanyl and were thought to be at risk of buprenorphine-precipitated withdrawal.

Conventional (ie, standard protocol) buprenorphine initiation involves administering 2–4 mg sublingual buprenorphine to patients with objective signs of withdrawal, followed by additional doses of 2–8 mg sublingual buprenorphine after 60–90 minutes if the first dose is well tolerated,² a strategy largely successful for individuals using heroin or prescription opioids. However, the illicit opioid supply in many parts of North America has been adulterated with or replaced by fentanyl and its analogs.³ Recent evidence demonstrates that fentanyl use increases the risks of precipitated withdrawal when using a standard buprenorphine initiation approach,^4–6 but significant gaps still exist in the clinical and mechanistic understanding of this phenomenon. What is the actual incidence of precipitated withdrawal and, among individuals using fentanyl, what are the risk factors for precipitated withdrawal? Is precipitated withdrawal with traditional initiation due to fentanyl’s lipophilicity, which leads to protracted and highly variable renal clearance among individuals with fentanyl use and dependence,⁷ or due to another mechanism, such as mu-opioid receptor desensitization or reduced receptor availability? It is imperative we answer these empirical questions through both clinical research and animal models.

Last, and most importantly, what are the optimal strategies for buprenorphine initiation for individuals with fentanyl use disorder? The past 3 years has seen a flood of case series and reviews of approaches using low-dose initiation.^8–15 Hartley et al add to this literature with an approach that could be used in inpatient withdrawal management settings where full-agonist opioids are unavailable. They protocolized a 48-hour buprenorphine induction during a 3-month proof of concept pilot study that, to date, has successfully initiated more than 50 patients who reported using either primarily or exclusively fentanyl. The method used low doses of buprenorphine (1 mg sublingual) administered immediately upon admission, before the development of significant withdrawal symptoms, and continued for 24 hours, before starting maintenance buprenorphine doses (up to 20 mg sublingual within the first hour) on the second day. Hartley et al describe that this is a “low-to-high dose” approach; however, it should be noted that the traditional initiation process outlined by the American Society of Addiction Medicine guidelines also reaches maintenance doses of 16–24 mg sublingual daily by the second day.²

The United States is amid a historic overdose epidemic, a public health crisis driven by fentanyl and its analogs; during this time, patients deserve equitable, high-quality, and evidence-based care. Innovative research on patient centric interventions to address the fentanyl phenomenon and its effects on opioid use disorder (OUD) treatment is greatly needed. Proof of concept studies such as those of Hartley et al, which are uncontrolled and retrospective, are among the initial steps to develop appropriately informed patient and clinical practice evidence in this space. We additionally need prospective controlled studies that include both traditional outcomes such as overdoses, initiation rates, and retention in care for OUD as well as patient-reported outcomes such as treatment goals and satisfaction.¹⁶ Further research is also needed to examine fentanyl’s unique pharmacokinetics in individuals with OUD and to understand the mechanisms underlying buprenorphine-precipitated withdrawal and fentanyl dependence.