More than 15 years ago, Yale's Gail D'Onofrio started studying the effectiveness of sublingual (under-the-tongue) buprenorphine for treatment of opioid use disorder (OUD) in the emergency department. At the time, buprenorphine was already being used in primary care populations at Yale by David Fiellin, so D'Onofrio and Fiellin decided to test if and how it could work for patients in the ED.
In the years since, their work has advanced multiple trials testing the effectiveness of different formulations and doses of buprenorphine. In the latest study, D'Onofrio and Fiellin examined the effectiveness of a seven-day, extended-release type of buprenorphine in 29 emergency departments across the United States.
They found that the injectable version was just as safe and effective as the traditional daily sublingual version in follow up treatment engagement, a finding that could help make treatment accessible to more patients. A total of 40.5% (extended-release) and 38.5% (sublingual) of patients were in treatment at seven days and 44% and 45% at 30 days. The results were published in JAMA.
"The emergency department is an ideal setting to initiate treatment, as that is where patients receive care who are either in withdrawal, after an overdose, with complications of addiction such as infections, or for any other health reason," said D'Onofrio, the Albert E. Kent Professor of Emergency Medicine and professor of medicine at Yale School of Medicine (YSM) and lead author of the study.
Due to its gradual uptake in the bloodstream, the extended-release formulation can offer a "direct to inject" approach for immediate care with patients who present with "minimal" opioid withdrawal. In the Clinical Opiate Withdrawal Scale (COWS), which measures withdrawal on a scale of zero to 48, this would include those with a score of four to seven. Patients receiving sublingual dosing must have a COWS of eight or greater, thus patients in lower states of withdrawal have only a discharge option with self-start instructions.
According to the new findings, patients in the extended-release group also reported less craving, less illicit opioid use, and greater satisfaction at seven-day follow-up. Both types of buprenorphine worked well for patients with OUD in the ED, with less than 1% of patients experiencing what is known as "precipitated withdrawal," a sudden, intense onset of opioid withdrawal symptoms when a partial agonist such as buprenorphine is given while a full opioid agonist such as fentanyl is still on board.
"My team is continually trying to improve access to treatment as we know that even though opioid agonist treatments such as buprenorphine and methadone are proven to reduce use and craving, prevent infections, and save lives, only 20% of patients with OUD receive this evidence-based treatment," said D'Onofrio, also a professor of epidemiology (chronic diseases) at the Yale School of Public Health and lead author of the new study published in JAMA. "Studying an extended-release preparation is one step along this journey."
Reducing barriers
OUD affects 5.7 million people in the United States and leads to high rates of early death. Treatment gaps remain despite available effective medication. Traditionally, clinicians prescribe sublingual buprenorphine medication in the form of a tablet or strip. That requires patients to pick it up at a pharmacy after discharge and self-administer it daily for one week.
Extended-release buprenorphine is administered by injection and remains in a person's system - and protects them from overdose - for seven days. This type of buprenorphine has the potential to eliminate many barriers for the patient, from transportation and pharmacy availability to insurance issues with prior authorization, the researchers say.
But to better understand how the two types of buprenorphine compare, the Yale researchers decided to conduct a randomized clinical trial featuring 2,000 patients at 29 EDs across the country. The trial included adult patients in the ED with untreated OUD and a COWS score of four or higher from July 12, 2020, to August 21, 2024.
Patients were randomized to receive either a 24-milligram subcutaneous injection of a seven-day extended-release or administration of sublingual buprenorphine with a seven-day prescription of buprenorphine.
The injection was given to patients in the ED if their COWS score was four or greater; the sublingual initial dose was administered to patients in the ED with COWS scores of eight or greater, or they were provided with instructions to self-administer if COWS scores were between four and seven. Both groups were provided with a referral for ongoing medication with a scheduled appointment within seven days. The researchers then measured the patients' treatment engagement after seven days, and again after 30 days.
Following the evidence
Through this study, the researchers found either type of buprenorphine, whether an extended-release or traditional sublingual, were equally effective in engaging patients at seven- and 30-days post-ED visits. They also learned that, for both, precipitated withdrawal was rare (less than 1%), and overdose rates were also substantially reduced
"Many clinicians are reluctant to administer buprenorphine as they are frightened of precipitated withdrawal," D'Onofrio said. "The evidence just does not support that thinking."
Other Yale authors include Kathryn Hawk, James Dziura, Patricia Owens, Shara Martel, Edouard Coupet Jr., E. Jennifer Edelman, and David Fiellin.
The study was funded by the National Institutes of Health through the Helping to End Addiction Long-Term (HEAL) Initiative, the National Institute on Drug Abuse, and Braeburn Pharmaceuticals, which provided the medication supply free of charge.
