AUGUST 23, 2023
Results from a new meta-analysis suggest that patient retention is higher for methadone than sublingual buprenorphine after the first month of use, but long-term retention was suboptimal for both drugs, according to investigators. Other outcomes were generally similar between the two drugs, but typically were based on small numbers of studies.
“These findings highlight the imperative for interventions to improve retention [as well as] consideration of client-centered factors such as client
Results from a new meta-analysis suggest that patient retention is higher for methadone than sublingual buprenorphine after the first month of use, but long-term retention was suboptimal for both drugs, according to investigators. Other outcomes were generally similar between the two drugs, but typically were based on small numbers of studies.
“These findings highlight the imperative for interventions to improve retention [as well as] consideration of client-centered factors such as client preference when selecting between methadone and buprenorphine,” lead author Louisa Degenhardt, PhD, wrote in an email. Degenhardt is the deputy director of the National Drug and Alcohol Research Centre at University of New South Wales, in Sydney.
The research, published online May 8 in the Lancet Psychiatry, follows a Cochrane review published in 2014, which came to similar conclusions. The new study updates the previous review in the context of changes to the opioid use environment, such as the appearance of fentanyl and xylazine. It also includes additional physical and mental health, social functioning, and other outcomes. “Many of these outcomes are important for clients and of concern for clinicians, but the question of whether or not there were differences between methadone and buprenorphine had not been systematically assessed,” Degenhardt wrote.
It is unclear why retention should be better with methadone. “There are a range of hypotheses about this, which include the fact that methadone is a full agonist, whereas buprenorphine is a partial agonist. Additionally, there is evidence that doses during induction may not be adequate to retain clients on buprenorphine,” Degenhardt wrote. She noted that induction doses were lower when buprenorphine was introduced to Australia 20 years ago, but doses have risen since then. That in turn has been associated with improved retention, according to a recent study.
Degenhardt called for more research of the factors that predict retention and lead patients to prefer one drug over another. Her own work has identified factors associated with the patient, setting and prescriber that predicted retention. “For example, the more experienced a prescriber was, the better retention; at the client level, younger people, Indigenous people, those in with a history of criminal charges and those with a psychotic disorder had poorer retention,” she wrote.
The study included 32 randomized controlled trials (RCTs) and 69 observational studies that compared buprenorphine and methadone, and 51 RCTs and 124 observational studies of treatment retention with buprenorphine. The combined studies included 1,040,827 participants. Not all studies reported gender, but among those that did, 66.1% were male and 33.9% were female. The mean age was 37.1 years.
After one month, methadone was associated with better retention than buprenorphine. At six months, the pooled effect favored methadone in 16 RCTs (risk ratio [RR], 0.76; 95% CI, 0.67-0.85) and 21 observational studies (RR, 0.77; 95% CI, 0.68-0.86). Adherence to treatment was similar between the two drugs.
The researchers noted differences in secondary outcomes, most of which favored buprenorphine. These included reductions in self-reported cocaine use in RCTs (RR, 0.61; 95% CI, 0.49-0.77; no effect in observational studies) and cardiac dysfunction (in RCTs, RR, 0.04; 95% CI, 0.00-0.62; in observation trials, RR, 0.17; 95% CI, 0.05-0.54). Increased treatment satisfaction was seen with buprenorphine in observational studies (standardized mean difference [SMD], 0.51; 95% CI, 0.16-0.86). Exceptions favoring methadone were reductions in hospitalization in observational studies (SMD, 0.16; 95% CI, 0.09-0.24) and self-reported alcohol use (RR, 1.50; 95% CI, 1.01-2.24). However, the secondary outcomes were also based on small numbers of studies and varied with study types and outcome measures.
The study is useful and shows similar efficacy between the two medications, but an important weakness is that the appearance of fentanyl has altered the landscape of opioid use disorder treatment, according to Eric Strain, MD, who was asked to comment on the study. “They’re looking back at papers that were done 20 years ago, before fentanyl, so interpreting these results in the context of the current drug use climate is a little bit more problematic,” said Strain, the director of the behavioral pharmacology research unit at the Johns Hopkins University School of Medicine, in Baltimore.
Specifically, he pointed out that physicians in the United States are reporting greater difficulty in getting patients to start and then stay on buprenorphine compared with previous years. “The thought is that it is related either to fentanyl or to xylazine, maybe, because that’s another drug that appears to be gaining ground. Then the second aspect is, since buprenorphine is a partial agonist, you don’t get as much of a maximal effect as a full agonist like methadone. So, are you getting these difficulties with treatment retention because [the patient is] using high-potency fentanyl or some fentanyl analog, and you’re not able to get the same agonist effect with buprenorphine that you might see with methadone?” Strain said.
He said buprenorphine is a very good medicine that is particularly useful when combined with psychosocial treatment, adding that in addition to writing a prescription for buprenorphine, it is important to look “at the other factors that are involved in the illness, because it’s a complicated disorder.”
He also endorsed methadone as an effective medication, despite the fact that it is older. “It’s only available through a specialized clinic system, but that clinical system has really expanded dramatically in the last 10 to 15 years in the United States; and especially for somebody who maybe has tried buprenorphine and it hasn’t worked well for them for whatever reason, I would have a low threshold to considering methadone,” Strain said.
Another drug is naltrexone, which was not included in the analysis. It requires patients to be withdrawn from opioids before initiation of treatment, but it can also be effective, according to Strain. “Some patients and families also prefer it because it is an opioid antagonist rather than an agonist or partial agonist,” he said, adding that property eliminates the possibility of abuse, which could occur with buprenorphine and methadone.
—Jim Fring
Degenhardt has received grant support from Indivior and Seqirus. Strain has received research support from Indivior and Masimo. He has advised and received funding from Pear Therapeutics.
