Standard Buprenorphine Treatment Still Viable in the Age of Fentanyl

The rapid rise of fentanyl and other potent synthetic opioids have created a crisis of confidence among treatment providers, noted John Mariani, M.D., an associate professor of clinical psychiatry at Columbia University Irving Medical Center, at APA’s Annual Meeting today.

There is a belief that buprenorphine just isn’t that effective anymore, Mariani said, referencing the rumors that buprenorphine is less likely to prevent relapse and more likely to precipitate withdrawal symptoms among people who use fentanyl.

But Mariani hoped that at the conclusion of the session, attendees would appreciate that while the current “age of fentanyl” requires a shift in thinking, the basic approach to buprenorphine-assisted opioid management remains the same.

Mariani acknowledged that initiating buprenorphine in people exposed to fentanyl can pose challenges. Fentanyl is lipophilic (readily absorbs into fats), so molecules can linger in cell membranes and other fatty tissues for days once the drug is stopped; this extends the length of withdrawal compared with natural opioids. Further, though fentanyl is extremely potent, it has less affinity for opioid receptors than buprenorphine, so buprenorphine can kick fentanyl out of receptors easily. This leads to a large reduction in receptor activity, leading to more severe withdrawal than with natural opioids.

This heightened sensitivity to withdrawal has led many clinicians to advocate for alternative buprenorphine initiation strategies, Mariani noted. One school of thought is to start high — initiate with as much as 20 mg buprenorphine daily versus the typical standard of 8 mg — to maximize buprenorphine potency and block out any lingering fentanyl immediately. Other clinicians believe it’s better to start low (2 mg or less) over several days to let the fentanyl clear our naturally to avoid medication-precipitated withdrawal.

Sandra Comer, Ph.D., a professor of neurobiology (in psychiatry) at Columbia University, said that the risk of precipitated withdrawal is still hotly debated. While many case reports and case series have documented buprenorphine-precipitated withdrawal among patients using fentanyl, some recent clinical trials have disputed this. She cited a 2023 study from researchers at Yale University and colleagues that tracked 1,200 patients with opioid use disorder (with about 70% fentanyl positive) for seven days after being initiated on buprenorphine (8 mg to 12 mg) in the emergency department. This study identified just nine cases of precipitated withdrawal among this large patient sample.

One can rightly argue that clinical trials and routine clinical practice are different, Mariani said. “Maybe this just means that we need to make clinical practice a little more rigorous,” he said. Patients using fentanyl may require more attention early on and during follow-up, and doses can be adjusted depending on individual circumstances, but the overall standard approach can still work, he said.

Mariani believes a straightforward way to provide some extra care in the age of fentanyl is to make injectable buprenorphine — available in weekly and monthly formulations — the first-line approach. The monthly formulation of buprenorphine provides strong and steady concentrations of buprenorphine (higher than with oral formulations) for at least five weeks, making patient management easier.

Comer reinforced this idea, offering a preview of some research that will soon appear in JAMA Network Open. Her study is a re-analysis of a seminal 2018 clinical trial that demonstrated injectable buprenorphine was not inferior to sublingual buprenorphine. When examining patients based on fentanyl exposure, she found that after 24 weeks of treatment, about 50% receiving buprenorphine injections were still opioid-free, versus just 20% of those taking oral buprenorphine.

Injections still require individuals to initiate with oral buprenorphine for a period before switching, but Mariani noted he and other researchers are exploring ways to make this initiation protocol as quick as possible.

Mariani and other speakers at this session were part of an expert panel that put together a set of practice-based guidelines for buprenorphine treatment in the fentanyl age last year. The guidelines — which are geared toward outpatient providers — are part of the Providers Clinical Support System-Medications for Opioid Use Disorders program, funded by the Substance Abuse and Mental Health Services Administration. ■

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