In a 12-week, two-stage, double-blind, placebo-controlled trial published in NEJM, individuals with moderate-to-severe methamphetamine use disorder (MUD) were randomized to receive either a combination of extended-release injectable naltrexone (every 3 weeks) plus daily oral extended-release bupropion or placebo for 6 weeks. In the second stage, nonresponders in the placebo group were randomized again for another 6 weeks. The response rates during the last 2 weeks of each stage for the primary outcome of at least three (of four) negative urine tests were higher in the combined-treatment group than in the placebo group (weighted average response across the two stages, 13.6% vs. 2.5%; overall treatment effect, 11 percentage points; P<0.001).
Randomized trials in this population are usually difficult to perform due to high attrition and low adherence rates. However, in this trial, attrition was low (23%) and adherence was high (≥75%) in all groups. Reasons for the low attrition and high adherence have implications for real-world application of this and other pharmacological treatments in MUD.
Early abstinence has been shown to be associated with improved retention in clinical trials of pharmacological therapies in MUD, and this association is thought to be mediated by delay discounting (a decline in the perceived value of a reward that is delayed). Patients who receive effective treatment and achieve abstinence may see a benefit in continuing to participate in the trial. In this trial, the percentage of negative urine samples in the naltrexone/bupropion group increased markedly during the first 2 weeks and tapered thereafter.
However, delay discounting does not explain the high adherence rate in placebo recipients. The pre-screened participants in this trial might have been highly motivated and willing to adhere to the trial protocol. Further, patients were followed closely throughout the trial with an injection given by another person every 3 weeks, the use of smartphone-based medication adherence tracking, and once-weekly meetings with a clinician and twice weekly urine testing. The rigorous oversight also could have encouraged ongoing participation and adherence.
Substance use disorders are also known to be associated with lower income. In this study, only 39% of participants were employed. The financial compensation provided by the investigators could have motivated participants to remain in the trial and adhere with the protocol.
Although the clinical benefit of combination treatment was not large in this trail, the results suggest that real-world application of effective treatments for MUD require selected motivated patients, contingency management, and clinical teams that provide close treatment-adherence monitoring, particularly at the beginning of treatment.
The following NEJM Journal Watch summary provides more details of the study.
Bupropion plus Naltrexone for Methamphetamine Use Disorder
Christopher W. Goodman, MD and Allan S. Brett, MD reviewing Trivedi MH et al. N Engl J Med 2021 Jan 14
This combination was superior to placebo, but the number needed to treat was relatively high.
Methamphetamine use and its associated harms have been increasing, and effective treatment is lacking. Because small studies have suggested that bupropion and naltrexone, used individually, might have some efficacy, researchers combined them in this randomized trial: Bupropion (450 mg daily) plus extended-release injectable naltrexone (380 mg every 3 weeks) were compared with placebo in 403 adults with moderate-to-severe methamphetamine use disorder. In stage 1, participants received naltrexone-bupropion or placebo. Then, after 6 weeks, nonresponders in the placebo group were randomized again to naltrexone plus bupropion or placebo for another 6 weeks in stage 2.
The primary outcome was defined as at least three negative urine tests for methamphetamine (out of 4 tests) during the last 2 weeks of each stage. Across the two stages, response rates were significantly higher with active treatment than with placebo (13.6% vs. 2.5%). The number needed to treat to achieve 1 successful outcome was 9.
Comment: Although the effects were modest and the trial duration was short, naltrexone plus bupropion was better than placebo in patients with moderate-to-severe methamphetamine use disorder. Given the limited treatment options and the recalcitrance of methamphetamine addiction, these are promising results. The so-called “fourth wave” of the opioid epidemic is characterized by the rise of stimulant use alongside of opioids, and we are in dire need of more treatment options.
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James is a 2020-2021 NEJM Editorial Fellow and a graduate of the National University of Ireland, Galway. He has a Masters of Science in Evidence-Based Healthcare from University College London and completed Basic Specialist Training in general internal medicine with the Royal College of Physicians in Ireland.