Risk of experiencing an overdose event for patients undergoing treatment with medication for opioid use disorder.
Overdose risk during a course of treatment with medication for opioid use disorder (MOUD) has not been clearly delineated. In this study, the authors sought to address this gap by leveraging a new data set from three large pragmatic clinical trials of MOUD: CTN-0027 (START), CTN-0030 (POATS), and CTN-0051 (X:BOT).
Adverse event logs, including overdose events, from the three trials (N=2,199) were harmonized, and the overall risk of having an overdose event in the 24 weeks after randomization was compared for each study arm (one methadone, one naltrexone, and three buprenorphine groups), using survival analysis with time-dependent Cox proportional hazard models.
Results found that by week 24, 39 participants had =1 overdose event. The observed frequency of having an overdose event was 15 (5.30%) among 283 patients assigned to naltrexone, eight (1.51%) among 529 patients assigned to methadone, and 16 (1.15%) among 1,387 patients assigned to buprenorphine. Notably, 27.9% of patients assigned to extended-release naltrexone never initiated the medication, and their overdose rate was 8.9% (7/79), compared with 3.9% (8/204) among those who initiated naltrexone.
Controlling for sociodemographic and time-varying medication adherence variables and baseline substance use, a proportional hazard model did not show a significant effect of naltrexone assignment. Significantly higher probabilities of experiencing an overdose event were observed among patients with baseline benzodiazepine use (hazard ratio=3.36, 95% CI=1.76, 6.42) and those who either were never inducted on their assigned study medication (hazard ratio=6.64, 95% CI=2.12, 19.54) or stopped their medication after initial induction (hazard ratio=4.04, 95% CI=1.54, 10.65).
Conclusions: Patients undergoing MOUD treatment remain at risk of overdose events in the first 24 weeks after seeking treatment. The strongest message from these data is that patients who fail to initiate medication, or stop their medication, are at greater risk of experiencing an overdose event. The pharmacology of methadone, buprenorphine, and naltrexone is such that they all substantially lower overdose risk if taken as prescribed. Patients should be educated about overdose risk, the protective effect of MOUD, and the danger of discontinuing medication. Benzodiazepine use is also a signal of risk, and patients taking benzodiazepines should be evaluated and treated for mental health problems as part of an effort to wean them off benzodiazepines. The risk of overdose after discontinuing naltrexone may be greater than for other medications, although the present data are not definitive on this point, and the overall effect of naltrexone assignment on overdose was not statistically significant. Future large trials should implement more systematic assessments of overdose events based on a clear operationalization of overdose, querying actively rather than relying on spontaneous report, with detailed characterization of the event, including the substances involved and whether there was suicidal intent.
Related editorial: An editorial about this paper was published in the American Journal of Psychiatry in May 2023: Connery HS & Weiss RD. Drug overdose prevention: An exercise in optimism. American Journal of Psychiatry 2023;180:5. [doi: 10.1176/appi.ajp.20230170]
Related protocols: CTN-0027, CTN-0030, CTN-0051