Low-dose initiation of buprenorphine for people using fentanyl fails to deliver expected results

During the COVID-19 pandemic, when fentanyl overdoses surged, doctors were desperate to find ways of helping their patients. 

They knew that buprenorphine could help people stop using opioids, but it was much harder to start the treatment for those who used fentanyl, which lasts longer in the body. Taking buprenorphine while fentanyl is still active can push someone abruptly into withdrawal. 

So, they started giving patients small doses of the drug over a series of days to slowly build up the drug in their systems until their bodies could handle a higher dose of buprenorphine.  

Now, doctors at UC San Francisco have tested this microdosing approach, known as low-dose initiation, and found that most of the time it does not work. Of 126 participants, just 34% were able to work up to a full dose of buprenorphine using this new approach.

Leslie W. Suen, MD, MAS, the study's first author, said she was disappointed by the results but the findings need to be shared. 

This doesn't seem like it's working the way we had hoped. But when people expect it to work, and it doesn't work for them, they feel like there's something wrong with them."   

Leslie W. Suen, MD, MAS, assistant professor at the UCSF Division of General Internal Medicine and an addiction medicine specialist

The study, the largest evaluation of low-dose buprenorphine initiation, appears in JAMA Network Open on Jan. 24.  

Buprenorphine is the most widely used of the three drugs that are approved to treat opioid use disorder. Other treatments include methadone, which is dispensed through certified treatment clinics, and injectable naltrexone, a longer-acting treatment that is prescribed when a person is no longer physically dependent on opioids. 

Although buprenorphine is proven effective, the drug is largely underutilized due to a range of issues, including a dearth of physicians trained to prescribe the medication, insurance issues and stigma.  

Buprenorphine is what's known as a partial opioid agonist, meaning that it works by only partly binding to the receptor that creates the "high" without offering the level of euphoria of stronger opioids. 

The promise of low-dose initiation  

Before the introduction of fentanyl, buprenorphine had higher success rates, but starting it often meant that people had to stop their opioid use and experience some withdrawal before taking it. If people had opioids in their bodies and took buprenorphine, they could experience extreme worsening of their withdrawal from the buprenorphine. Because heroin and other opioids leave the body predictably, starting buprenorphine was easy. People could stop their opioids, wait several hours, and then start buprenorphine.  

But fentanyl is stored longer in the fat cells, and it's harder to predict how long it takes to leave the body. People would stop their opioid use and wait the appropriate amount before starting buprenorphine, but they would still experience precipitated withdrawal from fentanyl. Doctors hoped that slowly introducing the buprenorphine would help reduce the discomfort, and people could stop using fentanyl when they felt ready or once the buprenorphine got to a good dose.   

The participants were treated at two outpatient substance-use disorder clinics in San Francisco between May 2021 and November 2022. They opted either for seven days of taking low doses of buprenorphine before getting up to an optimal dose (dosing two or three times a day), or four days of treatment (dosing four times a day). Taking different doses can be confusing, so the researchers gave them the medication in a bubble pack to help them manage their treatment.  

At follow-up visits, 38% of those with the four-day regimen achieved successful buprenorphine initiation and 28% were successful on the seven-day protocol, for an overall success rate of 34%. Overall, 22% stayed on the drug for at least 28 days. Repeated attempts yielded lower rates of success than the first attempt. 

Suen said the findings indicate that more options are needed to support people initiating buprenorphine. She and her fellow researchers are already involved in a follow-up study to determine why this promising approach is proving to be less effective than hoped.