Mark Chung

A study led by Yale School of Public Health and Yale School of Medicine researchers found that precipitate withdrawal in patients using buprenorphine, one of three FDA-approved medications to treat opioid dependence, was less than one percent. 

According to David Fiellin, an author on the study and professor of general medicine, emergency medicine and public health at YSM, this result came as a surprise. Many clinicians and patients are hesitant to prescribe or use the drug, he said, due to the concern that precipitate withdrawal may be common in patients taking this drug who also have used fentanyl, a common and potent synthetic opioid.

Kathryn Hawk — co-author, emergency physician at YSM and addiction researcher — explained that precipitate withdrawal is a “function of the pharmacology of buprenorphine.” Both buprenorphine and fentanyl bind and activate the mu receptors, which are located in different areas of the brain and work to modulate various physiological functions. Buprenorphine helps treat patients with a substance use disorder by preventing other opioids from occupying these mu receptors. 

However, if buprenorphine is administered too soon after the consumption of fentanyl, this can lead to precipitate withdrawal. 

“Buprenoprhine is very effective at treating opioid withdrawal, but if given to an individual with opioid use disorder while opioids are still on the mu receptors, the buprenorphine can displace the opioids and cause a significant increase in opioid withdrawal symptoms,” Hawk wrote. “Precipitated withdrawal is an unpleasant experience for the patient and the provider and has the potential to reduce both patient and clinician willingness to initiate treatment with the medication.”

According to Fiellin, some symptoms of precipitate withdrawal include acute nausea, vomiting, diarrhea, pain, agitation, anxiety and insomnia.

For this reason, many clinicians were concerned when the Biden administration loosened regulations on buprenorphine, eliminating the requirement for medical providers to obtain waivers before prescribing buprenorphine. These clinicians feared that the removal of those restrictions could lead to more incidences of precipitate withdrawal in patients.  

The YSPH study — led by Hawk, Fiellin and Gail D’Onofrio, an Albert E. Kent Professor of Emergency Medicine at YSM, in collaboration with researchers from the University of Pennsylvania, University of Kentucky College of Medicine and Highland Hospital Oakland — looked at the rate of precipitate withdrawal in approximately 1,200 patients across eight emergency departments with a high prevalence of patients using fentanyl. 

When patients were initiated buprenorphine with the standard initiation process, the researchers found that only 0.76 percent of patients experienced precipitate withdrawal. 

According to Fiellin, this study was unique because the researchers objectively defined metrics for precipitate withdrawal, and external experts adjudicated the research findings. 

“The findings are novel and have important implications for clinicians and patients who may shy away from buprenorphine initiation in patients using fentanyl,” Fiellin wrote. “Given the ongoing overdose death crisis and since we know that buprenorphine … treat[s] opioid use disorder and can substantially decrease mortality, we believed it was important to get these findings out quickly.”

This data for this paper came out of a larger and ongoing study led by D’Onofrio and Fiellin called ED INNOVATION, which looks at the extended-release of buprenorphine in patients receiving the medication via injection for seven days. 

The researchers hypothesized in this larger study that more patients will successfully reach formal addiction treatment if they receive the extended-release of buprenorphine. 

While the ED INNOVATION study is currently still ongoing, D’Onofrio explained that it was important for the researchers to publish these results on buprenorphine separately and as soon as possible, since buprenorphine is one of the few safe, unrestricted options available to treat patients with opioid use disorder. 

Edel Aron GRD ’24 applauds the YSPH researchers for exploring the side effects of medications like buprenorphine.

“It is important to do large, well-designed and well-conducted peer-reviewed studies to ensure that patients are getting the best possible treatment,” Aron wrote. “Hopefully work like this will be helpful in fighting the opioid epidemic.”

Currently, it is estimated that 2.1 million Americans suffer an opioid use disorder. The free and confidential treatment referral hotline for addiction is 1-800-662-HELP.