Doctors test a new way to help people quit fentanyl
Buprenorphine works for opioid use disorder. But a new way of starting it using small doses seems less effective, UCSF study finds.
University of California - San Francisco
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,” said Suen, an assistant professor at the UCSF Division of General Internal Medicine and an addiction medicine specialist. “But when people expect it to work, and it doesn’t work for them, they feel like there’s something wrong with them.”
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.
Authors: Additional UCSF authors include Amy Y. Chiang, PhD, Hannah R. Snyder, MD, John Neuhaus, PhD, Janet M. Myers, PhD, Kelly R. Knight, PhD, and Alexander R. Bazazi, MD, PhD.
Funding: The study was funded by the Agency for Healthcare Research and Quality (grant K12HS026383) and the National Institute on Drug Abuse (grants 1K23DA060329 and 2K24DA042720). See the study for disclosures.
About UCSF: The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health, which serves as UCSF's primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area. UCSF School of Medicine also has a regional campus in Fresno. Learn more at ucsf.edu, or see our Fact Sheet.
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Journal
JAMA Network Open
Smoking opioids is associated with lower mortality than injecting but is still high-risk
Society for the Study of Addiction
A new study published today in the scientific journal Addiction has found that opioid smoking appears to be associated with lower mortality risk compared with opioid injecting. The authors, however, caution that opioid smoking still carries a substantial overdose risk and that these results should not be interpreted as suggesting that opioid smoking is safe.
The study analysed substance use treatment data from 2006 to 2021, comparing 287,481 individuals who reported smoking opioids as their primary form of substance use and an equal weighted number of individuals who reported injecting opioids as their primary form of substance use. The outcome of interest was death during treatment, within one year of treatment admission.
The analysis found a mortality rate of 6.5 per 1000 person-years in the smoking cohort and 9.7 in the injection cohort. The mortality rate ratio was 0.67, meaning people who primarily smoked opioids died at two-thirds of the rate of people who primarily injected opioids.
Although smoking rather than injecting opioids may mitigate some risks, smoking opioids still carries a significant risk of death. Smoking recently surpassed injection as the most common route of administration identified among opioid-related fatal overdoses in the United States1, likely driven in part by the rising popularity of opioid smoking and the decrease in opioid injecting.2
Lead author Dr. George Karandinos, a clinical and research fellow at Massachusetts General Hospital and Harvard Medical School, comments: “Smoking opioids instead of injecting likely reduces injection-associated complications like the transmission of HIV and hepatitis C and other serious infections. Our study suggests that smoking also appears to be associated with a lower risk of death. Overestimating the safety of smoking, however, could encourage people to lower their vigilance against overdose, eliminating or reversing any potential risk reduction. People who use opioids and those caring for them must understand that while smoking may reduce harm relative to injection, opioid smoking is not safe. People who smoke opioids should still seek treatment, carry naloxone, avoid using opioids while alone, and avoid sharing smoking equipment, which can lead to inadvertent fentanyl resin exposure and overdose.”
Senior author Dr. Daniel Ciccarone adds: “Smoking opioids can be done to deliver a large and rapid dose, as would occur with injection use, and those specific ways of smoking have significant risk for overdose.”3
1Tanz LJ. Routes of drug use among drug overdose deaths — United States, 2020–2022. In: Morbidity and Mortality Weekly Report [internet]; 2024 [cited 2024 Feb 15];73. Available from: https://www.cdc.gov/mmwr/volumes/73/wr/mm7306a2.htm
2Karandinos G, Unick J, Ondocsin J, Holm N, Mars S, Montero F, et al. Decrease in injection and rise in smoking and snorting of heroin and synthetic opioids, 2000–2021. Drug and Alcohol Dependence. 2024 Oct 1;263:111419.
3Ciccarone D, Holm N, Ondocsin J, Schlosser A, Fessel J, Cowan A, Mars SG. Innovation and adaptation: The rise of a fentanyl smoking culture in San Francisco. PLoS One. 2024 May 22;19(5):e0303403. doi: 10.1371/journal.pone.0303403.
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For editors:
This paper is available to read online on the Wiley Online Library after the embargo has lifted (https://onlinelibrary.wiley.com/doi/10.1111/add.16740) or you may request an early copy from Jean O’Reilly, Editorial Manager, Addiction, jean@addictionjournal.org.
To speak with lead author Dr. George Karandinos, please contact him at Massachusetts General Hospital by email (gkarandinos@mgh.harvard.edu), copying in McKenzie Ridings in the Massachusetts General Hospital External Communications team (mridings@mgb.org).
Full citation for article: Karandinos G, Unick J, and Ciccarone D. Mortality risk among individuals who smoke opioids compared with those who inject: A propensity score-matched cohort analysis of US national treatment data. Addiction. 2025. DOI: 10.1111/add.16740
Primary funding: National Institutes of Health/National Institute on Drug Abuse, Research Grant, award number: R01 DA054190.
Declaration of interests: Dr. Ciccarone reports financial support as a scientific advisor to Celero Systems and as an expert witness for Motley-Rice LLC.
Addiction (www.addictionjournal.org) is a monthly international scientific journal publishing peer-reviewed research reports on alcohol, substances, tobacco, gambling, editorials, and other debate pieces. Owned by the Society for the Study of Addiction, it has been in continuous publication since 1884.
Journal
Addiction
Method of Research
Observational study
Subject of Research
People
Article Title
Mortality risk among individuals who smoke opioids compared with those who inject: A propensity score-matched cohort analysis of US national treatment data
Article Publication Date
23-Jan-2025
COI Statement
Dr. Ciccarone reports financial support as a scientific advisor to Celero Systems and as an expert witness for Motley-Rice LLC.
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