Delivering a medication reliably and demonstrating that it works are separate achievements. A placebo-controlled trial of extended-release naltrexone in 100 actively using, methamphetamine-dependent men who have sex with men achieved high injection adherence but did not demonstrate a reduction in methamphetamine-positive urine results relative to placebo.
Coffin and colleagues’ paper appeared online in 2017 and in the 2018 volume of Addiction. Its result concerns naltrexone alone, under a particular schedule and in a selected population. It should retain that identity when compared with studies combining naltrexone with another medication.
What did the randomized comparison involve?
Fifty participants received 380 mg of extended-release naltrexone and fifty received matching placebo. Investigators administered three intramuscular gluteal injections at four-week intervals over twelve weeks. Both groups received weekly visits, urine testing and approximately thirty minutes of substance-use counseling using cognitive behavioral and motivational approaches.
Participants wanted to reduce or stop methamphetamine use and met the study’s dependence criteria. Enrollment also required reported sexual activity with men while under methamphetamine’s influence during the preceding six months. The study excluded several conditions that could compromise safe participation. This was not a population sample of everyone using methamphetamine.
What happened to the urine results?
The reported urine-positivity trajectory comparison gave a ratio of 0.95, with a 95% confidence interval of 0.76–1.20. The interval included no difference. Observed positivity declined in both groups, from 78% to 70% with naltrexone and from 74% to 64% with placebo.
Improvement within the active group therefore cannot establish a medication effect. The relevant comparison is whether the active group improved more than its randomized control. Counseling, repeated contact, changes in motivation and other shared influences could contribute to changes in both groups.
Craving and several self-reported risk measures also declined without a significant advantage for naltrexone. Urine positivity was a repeated categorical testing outcome, not a measurement of dose consumed, circulating methamphetamine concentration or functioning at a particular event.
Why does adherence matter here?
Injection adherence was 96.7% in the naltrexone group and 91.3% with placebo. Ninety percent of active participants received all three injections. High delivery rates make it harder to explain the null result solely by saying that participants generally failed to receive medication.
The investigators also examined cumulative injections and several sensitivity analyses, including treating missing urines as positive. These did not reveal a significant benefit. Adherence strengthens the interpretation of the tested regimen’s result; it does not establish that every biological response was identical or that every conceivable treatment effect was excluded.
How far does the null finding extend?
The trial was designed to detect a substantial reduction in urine positivity. A nonsignificant result is not proof of an exactly zero effect. Its confidence interval, power assumptions and selected population remain relevant. Most participants had HIV-positive serostatus, and all were recruited in a particular San Francisco setting.
The authors specifically identified naltrexone in isolation as a limitation. A later successful combination trial would not retroactively make this monotherapy trial positive, nor would this null trial invalidate a different combination, dosing interval or population.
No serious adverse event was judged related to study medication, and adverse-event frequencies did not differ significantly between groups. A hundred-person, twelve-week observation cannot establish absence of uncommon harms. The useful historical conclusion is precise: reliable delivery of this monthly monotherapy did not translate into a demonstrated advantage on the measured methamphetamine-use outcomes.
Source
Coffin PO, Santos GM, Hern J, et al. Extended-Release Naltrexone for Methamphetamine Dependence among Men Who Have Sex with Men: A Randomized Placebo-Controlled Trial. Addiction. 2018;113(2):268–278; online 2017. doi:10.1111/add.13950.
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