Novel combination therapy for methamphetamine- use disorder shows promise.

A study published by M.H. Trivedi and colleagues, in the NEJM, has shown that in moderate to severe methamphetamine use disorder, treatment with the combination of extended-release injectable naltrexone and daily oral extended-release bupropion over a period of 12 weeks shows a better response than placebo.

Methamphetamine is a leading cause of overdose deaths especially in Midwest and west of US. Bupropion is a stimulant-like antidepressant that acts through the norepinephrine and dopamine systems and might ameliorate the dysphoria associated with methamphetamine withdrawal that drives continued use. Naltrexone is an opioid-receptor antagonist that is effective for the treatment of opioid use disorder, perhaps by attenuating the reinforcing effects of substances or cue-induced cravings.

The current study was planned to assess the efficacy of combining these agents for the treatment of methamphetamine use disorder. This randomised double-blind trial was done to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) combined with once-daily oral extended-release bupropion (450 mg per day) as compared with placebo in adult outpatients with moderate or severe methamphetamine use disorder. The 12 week trial was conducted in 2 phases (6 weeks each). Participants received naltrexone-bupropion or placebo during the 1st six week stage. Participants who did not have a response in stage 1 underwent randomisation again in 2nd 6 weeks stage.

Drug screening of urine-sample was done twice a week (total of 24 urine samples per participant [12 in each stage]). Valid samples were considered to be those with a temperature of 32° to 38°C [90° to 100°F]) and a negative test for adulterants. Valid samples were tested for 10 drugs. To encourage adherence, participants were asked to use a smartphone-based application to track tablet ingestion. Trial clinicians, who were unaware of group assignments, met weekly with participants to manage adverse events, assess and encourage adherence to the oral regimen, address participant concerns, and provide counseling for reducing substance use.

The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of a possible four samples obtained at the end of stage 1 (during week 5 through week 6) or the end of stage 2 (during week 11 through week 12).

It was found that 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, defined as the between-group difference in the overall weighted response was 11.1 percentage points.

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. The Secondary Outcomes  (the percentage of participants with methamphetamine-negative urine samples) was 20.4% in the naltrexone–bupropion group and 12.3% in the placebo group in stage 1 and 19.2% in the naltrexone–bupropion group and 13.4% in the placebo group in stage 2. The weighted difference between the two groups in the percentage of participants with methamphetamine negative urine samples was 6.8 percentage points.

It was thus concluded that, 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.

Source: NEJM: N Engl J Med 2021; 384:140-153 DOI: 10.1056/NEJMoa2020214