Beneficial effects of the rapid vs. standard procedure for injection naltrexone initiation operate through increased adjunctive medication use.

Abstract

To estimate the extent to which increased use of clonidine and benzodiazepines is associated with the beneficial effect of the rapid versus standard procedure for induction onto extended-release injectable naltrexone (XR-NTX). We conducted two mediation analyses using a doubly robust nonparametric estimation approach. First, we estimated the extent to which the difference in XR-NTX initiation rates comparing the rapid vs. standard induction operated through: (1) differences in categorized daily doses of clonidine and benzodiazepines averaged over the first 3 days of the study, and (2) differences in categorized clonidine and benzodiazepine usage during each of the first 5 days, treated as time-varying mediators, and accounting for time-varying confounders and competing events. Rapid vs. standard induction increased the probability of initiating XR-NTX by day 14 by an estimated 42.4 percentage points (95% CI: 34.6, 50.2), and the natural indirect effect (i.e., mediated effect) through clonidine and benzodiazepine use was associated with a 24.2 percentage point (95% CI: 10.3, 38.0) increased the initiation probability, explaining 57.1% of the total effect. Estimates were similar in the longitudinal mediation analysis. Use of clonidine and benzodiazepines proactively and at higher dosages during the initial days of inpatient medically managed withdrawal, in conjunction with attentive safety monitoring, could improve XR-NTX initiation rates as part of a rapid induction procedure.