The patient calling the Rhode Island Buprenorphine Hotline this Saturday morning is a mom. She has been stable on buprenorphine for some time but missed her last appointment because her kids were sick, and her provider will not refill her buprenorphine prescription without a urine drug screen. So, despite having an established provider, she called the hotline — a state-funded, 24/7, on-demand, free, phone-based telehealth service — for help with a bridge prescription until she can be seen in the office. Over the phone, she tells me about her history of fentanyl use and that her provider will only prescribe 16 mg, though she often feels better and has better control of symptoms and cravings with 24 mg.
Fentanyl has been dominant in the U.S. drug supply for years. Yet, buprenorphine and methadone dosing guidelines, which were established based on studies among people who used heroin and prescription opioids (e.g., oxycodone, hydrocodone), have not been re-evaluated in the fentanyl era despite years of data and experience with populations using fentanyl. Further complicating the picture, fentanyl is now routinely found with other compounds, including the veterinary sedative xylazine. In addition to the known high potency of fentanyl, recent preclinical studies indicate that fentanyl is more efficacious as a mu-opioid receptor agonist than morphine and may lead to higher degrees of tolerance and dependence. Based on our experience, some people in the community report using fentanyl 10 or more times per day, often waking up in the middle of the night to use because they are in withdrawal. Others have reported using methamphetamine in an effort to control opioid withdrawal symptoms between fentanyl use and/or extend periods between use because they find they have to use fentanyl so frequently to ward off withdrawal symptoms.
The buprenorphine package insert approved by the FDA states that maintenance daily doses should range from 4 mg to 24 mg, with a recommended target dose of 16 mg for most patients. However, many of our patients with a history of chronic fentanyl use report that 16 mg was not adequately controlling their cravings and withdrawal symptoms, but with a dose increase to 24 mg their symptoms improved. This clinical anecdote, repeated over and over again in our practice by patients, has been echoed by national commentaries from addiction medicine specialists and brought up in many discussions among experts.
In our recent study published in JAMA Network Open, we used statewide data from Rhode Island spanning 2016 to 2020 — a period with widespread fentanyl availability in the drug supply and during which fentanyl was involved in the vast majority of overdose deaths — to directly evaluate the association of buprenorphine maintenance dose and treatment retention. We found that, among patients initiating buprenorphine treatment during this period, those prescribed the recommended target daily dose (16 mg) were 20% more likely to discontinue treatment within 6 months than those prescribed a higher dose (24 mg).
Buprenorphine dosing is only one part of optimizing medications for opioid use disorder (OUD) for populations with a history of fentanyl use. We also need to reevaluate methadone dosing and dispensing guidelines. The Substance Abuse and Mental Health Services Administration (SAMHSA) flexibilities around take-home doses and mobile methadone have marginally improved access, but significant access and operational barriers remain. The daily limits of methadone at the start of treatment do not touch the withdrawal symptoms of many of the people who use fentanyl in our community. Further, in clinical practice, we see patients on high doses of methadone who continue to experience ongoing withdrawal, sometimes continuing to use fentanyl while on methadone to control symptoms. Split dose methadone needs to be a more accessible option for patients. To reduce cardiac risk as more patients require higher methadone doses, we may need to reconsider some old ideas, for example, R-methadone. Adjunctive medications to treat withdrawal and aid with new medication initiation need to be more rigorously studied. While we wait for novel therapeutics, we need to analyze the vast existing clinical data with speed, discipline, and humility to optimize current practice.
Beyond medication optimization, state governments should demand operational efficiencies and evidence-based practices from office-based providers, opioid treatment programs, pharmacies, and hospital systems. This can be as simple as national chain pharmacies not denying to fill buprenorphine prescriptions for patients with certain Medicaid coverages or insurance companies not requiring prior authorization for doses above 16 mg of sublingual formulations or injectable buprenorphine preparations. Operational excellence also extends to coordination among providers. Other simple steps can make a difference in someone’s recovery too, such as creating an accountable answering service system at opioid treatment programs to verify their patient’s methadone dose and last dispense when patients show up in the emergency department reporting they missed a dose.
Operational barriers are often rooted in disorganization, antiquated laws or protocols, or the desire to increase returns on invested capital. Given the state of the overdose crisis, we as a society need to reconcile whether the expanding for-profit substance use treatment industry can make the adjustments both from a medication and operational standpoint to help stem the tide of deaths. Every actor will talk their own book in a silo removed from the realities of the blocking and tackling required to provide the comprehensive care needed for each person with a substance use disorder.
We were able to complete this study, representing potentially a marginal step forward, with data and support from the Rhode Island Department of Health and the National Institute on Drug Abuse. But the question remains: how can we make these data and frankly any marginal improvement actionable? There has been too much time spent gazing at the fire in fentanyl’s wake. Collectively, we need to optimize the existing evidence-based tools that we have access to now.
Rachel S. Wightman, MD, is an associate professor of Emergency Medicine and Epidemiology at Alpert Medical School of Brown University in Providence, Rhode Island. Wightman is a triple board-certified practicing physician in medical toxicology, emergency medicine, and addiction medicine. Francesca L. Beaudoin, MD, PhD, is a professor and chair of Epidemiology and interim academic dean at the Brown University School of Public Health. Beaudoin is a board-certified emergency physician and clinical epidemiologist with expertise in opioid use disorders and pain. Laura C. Chambers, PhD, MPH, is a lead research scientist and assistant professor of the Practice of Epidemiology at the Brown University School of Public Health. She is passionate about working with public health departments and community-based organizations to improve population health and health equity.
Disclosures
This study was funded by the National Institute on Drug Abuse (grant number UG3DA056880). Wightman has grant funding from the NIH, the Foundation for Opioid Response Efforts, and the New York City Department of Health for other research. Beaudoin has grant funding from the NIH, CDC, Arnold Ventures, and the Institute for Clinical and Economic Review for other research. The authors declare they have no conflicts of interest.
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