Use of Buprenorphine to Treat Fentanyl Distress Produces Few Adverse Reactions

Last year, the Biden administration loosened regulations for buprenorphine, making the life-saving medication used to treat opioid addiction more accessible. However, some clinicians, as well as persons who use fentanyl, have been reluctant to use buprenorphine. They fear triggering a severe withdrawal reaction known as “precipitated withdrawal” (PW), which can discourage patients from ever seeking treatment again and clinicians from using the medication for future patients.

A new study across 28 emergency departments (EDs) with a high prevalence of fentanyl use provides reassurance. It found that the incidence of precipitated withdrawal is rare—less than one percent, a result that pleasantly surprised the researchers. The study was published in JAMA Network on March 30.

“Precipitated withdrawal is very stressful for both the patient and the clinician. It’s horrible when it happens—you’re creating harm where you’re supposed to heal,” says Gail D’Onofrio, MD, Albert E. Kent Professor of Emergency Medicine, and professor of epidemiology (chronic diseases) and of medicine (core addiction). “We are very excited to share these results so that clinicians will be motivated to offer—and patients to accept—buprenorphine.”

Buprenorphine works by binding to the same brain receptors to which fentanyl and other opioids bind, which helps relieve withdrawal symptoms and opioid cravings. However, if administered too soon, the medication pushes the opioid off the receptor and triggers precipitated withdrawal. To avoid this, clinicians are urged to wait until a patient is in mild or moderate withdrawal before the patient takes buprenorphine. “Precipitated withdrawal can lead to the patient never wanting to receive buprenorphine again, and the clinician to never want to prescribe it again, so it has serious ramifications for both the patient and prescriber,” says David Fiellin, MD, professor of medicine (general medicine), of emergency medicine, and of public health.

The latest study arose as part of an ongoing trial, ED INNOVATION, which is evaluating outpatient treatment engagement among ED patients initiated on either sublingual or a 7-day extended-release injectable buprenorphine formulation in the ED. The study examined a cohort of 1,200 patients across 28 geographically diverse EDs from June 2020 to October 2022. This is the first study that reports the incidence of precipitated withdrawal in a prospective trial using uniform surveillance, operational definitions, and adjudicated outcomes to document buprenorphine induced PW in persons using fentanyl.

“We’re excited to say that we found that buprenorphine is safe to treat opioid withdrawal in an ED setting, despite escalating use of fentanyl,” says D’Onofrio of the precipitated withdrawal rate of less than one percent.

Eager to share their findings, the team wanted to publish these results right away, separate from their ongoing trial. “This is one of the great things about conducting systematic prospective research,” says Kathryn Hawk, MD, associate professor of emergency medicine and of epidemiology (chronic diseases.) “Aside from evaluating our primary outcome comparing the effectiveness of two buprenorphine formulations, we’re able to systematically evaluate other outcomes—in this case, incidences of precipitated withdrawal—as well.”

Beyond buprenorphine, methadone is the only other effective agonist treatment. However, because access to methadone is highly regulated and restricted to opioid treatment programs only, the team feels a major sense of relief to have found that buprenorphine is a safe option to use in the ED. “Only approximately 13% of individuals with opioid use disorder receive medications for treatment of their addiction,” says D’Onofrio. “If we found buprenorphine to be unsafe, it would limit the treatment options for these patients severely.”

The researchers hope their findings will help clinicians be less worried about initiating buprenorphine and more emergency physicians will utilize the medication in their practice. Furthermore, providers can be reassured that in the rare instances in which precipitated withdrawal did occur in the cohort, the patients were treated successfully, and did not require hospitalization. “In the context of an overwhelming overdose crisis, and this being a medication that decreases mortality by as much as 50 percent, we need to eliminate as many barriers as possible to the use of this medication,” says Fiellin. “This study demonstrates that it can be safely provided in the emergency department setting and likely more frequently in other settings as well.”