Results from a multi-site clinical trial supported by the National Institutes of Health showed that less than 1% of people with opioid use disorder whose drug use includes fentanyl experienced withdrawal when starting buprenorphine in the emergency department. The findings, which appeared today in JAMA Network Open, are strong evidence that buprenorphine, a medication approved by the U.S. Food and Drug Administration to treat opioid use disorder, can be safely started in the emergency department without triggering withdrawal, even for people who use stronger opioids. Clinician concern over this type of withdrawal can be a barrier to using this treatment.
Withdrawal induced by medications to treat opioid use disorder – called precipitated withdrawal – is a debilitating experience marked by rapid onset of symptoms such as aches, nausea and vomiting, diarrhea, and abdominal cramps that can occur within two hours after the first dose of buprenorphine. Although instances of buprenorphine-precipitated withdrawal have only been reported in relatively small case studies and anecdotal evidence, some clinicians and patients worry that the risk of experiencing precipitated withdrawal from buprenorphine might be increased among people who use fentanyl. This has led some clinicians to prescribe buprenorphine at lower doses, especially for people using extremely potent illicit opioids such as fentanyl. Because initiating low-dose buprenorphine following initial cessation of illicit opioids can be less effective in relieving these symptoms, individuals may be more likely to resume use of illicit opioids.
The study, supported by the National Institute on Drug Abuse (NIDA) through NIH’s Helping to End Addiction Long-term Initiative, or NIH HEAL Initiative, should help assuage concerns over precipitated withdrawal following buprenorphine treatment in the emergency department.
“We are in an overdose crisis, and we need to deploy every tool we have to help address it,” said Nora D. Volkow, M.D., director of NIDA. “The emergency department is a crucial care setting for people with substance use disorders. This study provides further evidence that all emergency department physicians can and should be using buprenorphine to help individuals take the first steps into treatment and toward recovery.”
There has been an urgent need to better understand how the prevalence of fentanyl in the drug supply affects the process of addiction treatment for people with opioid use disorder. The study addressed this question prospectively by analyzing data from 1,200 individuals at 28 U.S. emergency departments participating in an ongoing clinical trial. The trial is comparing the relative impact of a weekly extended-release buprenorphine injection at a dose of 24 milligrams versus daily administration of 8 to 16 mg buprenorphine as a tablet or film.
The trial recruited adult patients with untreated moderate to severe opioid use disorder, opioid-positive and methadone-negative urine tests, and a Clinical Opiate Withdrawal Scale score greater than or equal to 4. In this study, precipitated withdrawal was defined as when a patient demonstrated marked escalation by five points or more on the Clinical Opiate Withdrawal Scale within two hours of starting buprenorphine. Researchers found that despite high fentanyl use prevalence – about 70% – among 1,200 people with opioid use disorder, precipitated withdrawal occurred in nine out of the total 1,200 people, or 0.76%, and only 1% of those who had used fentanyl. The rate of precipitated withdrawal was similar to that reported in people using heroin or prescription opioids without fentanyl.
“Clinicians should encourage patients with opioid use disorder to take buprenorphine if they need it,” said lead author Gail D’Onofrio, M.D., professor of emergency medicine at Yale University, New Haven, Connecticut. “We know that less than 23% of people with opioid use disorder are getting treated for it, and we only have a few medications for opioid use disorder that have been found to be very effective for opioid withdrawal to date. If we take away one of these, we’re going to have an even bigger gap between need and treatment. We hope that both clinicians and patients understand that buprenorphine is a safe and effective option.”
These findings build upon existing evidence that administering buprenorphine in emergency departments helps people begin addiction treatment and that higher-dose buprenorphine (more than the standard upper limit of 16 mg) is safe and well tolerated in people with opioid use disorder experiencing withdrawal symptoms. They also bolster support for expanding access to buprenorphine. Recent legislation removed barriers to access, including the elimination of the X-Waiver in December 2022, and policy efforts have been initiated that maintain COVID-19 era-initiated flexibilities related to prescribing buprenorphine via telehealth evaluations.
“The emergency department is an important touchpoint for providing life-saving medication and resources for people at risk for overdose,” said Rebecca G. Baker, Ph.D., director of the NIH HEAL Initiative. “We need to meet people where they are amid an increasingly deadly overdose crisis.”
This work was supported by NIDA’s Clinical Trials Network (UG1DA015831-18S7), a nationwide consortium aimed at testing drug use interventions and delivering evidence-based therapies to diverse patient populations. Additional support was provided by the NIH HEAL Initiative.
About substance use disorders: Substance use disorders are chronic, treatable conditions from which people can recover. In 2021, over 46 million people in the United States had at least one substance use disorder. Substance use disorders are defined in part by continued use of substances despite negative consequences. They are also relapsing conditions, in which periods of abstinence (not using substances) can be followed by a return to use. Stigma can make individuals with substance use disorders less likely to seek treatment. Using preferred language can help accurately report on substance use and addiction. View NIDA’s online guide.
About the National Institute on Drug Abuse (NIDA): NIDA is a component of the National Institutes of Health, U.S. Department of Health and Human Services. NIDA supports most of the world’s research on the health aspects of drug use and addiction. The Institute carries out a large variety of programs to inform policy, improve practice, and advance addiction science. For more information about NIDA and its programs, visit www.nida.nih.gov.
About the NIH HEAL Initiative: The Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, is an aggressive, trans-NIH effort to speed scientific solutions to stem the national opioid public health crisis. Launched in April 2018, the initiative is focused on improving prevention and treatment strategies for opioid misuse and addiction, and enhancing pain management. For more information, visit: https://heal.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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G. D’Onofrio, et al. Incidence of Precipitated Withdrawal during a Multi-site Emergency Department-Initiated Buprenorphine Clinical Trial in the Era of Fentanyl. JAMA Network Open. DOI: 10.1001/jamanetworkopen.2023.6108 (2023).