REVIEW OF: Trivedi MH et al, N Engl J Med 2021;384(2):140–153

STUDY TYPE: Randomized, double-blind, placebo-controlled trial with sequential parallel comparison design

Methamphetamine use disorder is an increasing cause of overdose deaths in the US. Pharmacologic options are scarce, but pilot studies suggest that bupropion and naltrexone may be effective, either alone or in combination. This study tested them in combination.

The authors designed this double-blind, randomized, placebo-controlled study in two phases. First, patients were randomized to treatment or placebo for six weeks, with three times as many assigned to placebo. In the second stage, patients who responded to placebo were removed, and the remaining placebo non-responders were re-randomized to either more placebo or active treatment for another six weeks, this time with equal numbers in the placebo and treatment arms. The point of this design was to dampen the placebo response in the second phase of the study.

The subjects, recruited through advertisements and direct referrals, were adults with moderate to severe methamphetamine use disorder who wanted to quit or reduce use. On average, they had used methamphetamine on 27 of the previous 30 days. The active combo treatment was extended-release (ER) naltrexone 380 mg IM every three weeks and ER bupropion 450 mg daily.

There were 403 participants in stage 1, and 225 who did not respond to placebo were re-randomized to stage 2. Overall retention was good (77.4%). The primary outcome was response, defined as three out of four urine tests negative for methamphetamine in the last two weeks of stage 1 or stage 2.

In terms of results, naltrexone-bupropion was significantly more effective than placebo. The weighted average response was 13.6% for the active group and 2.5% for placebo (p < 0.001), and the number needed to treat (NNT) was 9. Serious adverse events, such as nausea, vomiting, and constipation, were evenly divided between active and placebo conditions.

TCPR’S TAKE
Naltrexone-bupropion combination is somewhat effective for methamphetamine use disorder. While the NNT of 9 is on the small side, this treatment was backed by a well-designed trial, and in a disorder with such devastating consequences, every tool is important.