Bupropion and Naltrexone in Methamphetamine Use Disorder

Abstract

Background: The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied.

Methods: We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses.

Results: A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone-bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone-bupropion during the trial.

Conclusions: Among adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.).

Figure 1. (facing page). Screening and Randomization.

Participants may have had more than one reason for not undergoing randomization in stage 1. The analysis of the primary outcome was performed in the intention-to-treat population, which included all participants who underwent randomization in stage 1 and all participants who underwent randomization again in stage 2.

Figure 2.. Responses and Methamphetamine-Negative Urine Samples.

The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of a possible four obtained at the end of stage 1 (during weeks 5 through 6) or at the end of stage 2 (during weeks 11 through 12). We calculated the weighted average of the responses in each stage, and the difference between these results was used to determine the overall treatment effect. Panel A shows the percentage of participants with a response and the weighted average of the response in each trial group in the intention-to-treat population, which included all participants who underwent randomization in stage 1 and all participants who underwent randomization again in stage 2. Panel B shows the percentage of methamphetamine-negative urine samples according to stage and trial group in the intention-to-treat population. Placebo/naltrexone–bupropion refers to participants in the placebo group who did not have a response in stage 1 and were assigned to the naltrexone–bupropion group in stage 2. Placebo/placebo refers to participants in the placebo group who did not have a response in stage 1 and were assigned to the placebo group in stage 2. During the 12-week intervention period, participants visited the clinic twice per week, after which they had a visit at week 13 and week 16. The evaluation period was the last 2 weeks of each stage (each evaluation stage is shown in the shaded areas). The number of urine samples obtained indicates the number of urine drug screening results available according to trial group at each visit for all participants in the intention-to-treat population. Results of urine drug screenings obtained at the first visit during week 1 (the day of randomization) are not shown. Results of drug screenings obtained on or before the rerandomization date of each participant in stage 2 are not shown because these samples were obtained when participants were still receiving the regimen assigned in stage 1.