Thresholds for adjunctive medication usage and probability of initiating injectable naltrexone.

Abstract

Aims: To estimate the effectiveness of different thresholds for administering opioid withdrawal medications (clonidine and clonazepam) on the probability of successfully initiating extended-release naltrexone (XR-NTX) among participants with opioid use disorder (OUD) during medically managed withdrawal.

Design: Secondary analysis of a multisite clinical trial comparing a rapid vs. standard approach for XR-NTX initiation, 2021-2022.

Setting: Six community inpatient addiction treatment units in the United States.

Participants: English-speaking adults seeking treatment for DSM-5 OUD and expressing interest in XR-NTX treatment (n = 415).

Measurements: We estimated the extent to which the following thresholds for adjunctive medication administration would affect the probability of initiating XR-NTX over time: 1) where adjunctive medications were given in response to at mild-to-moderate withdrawal symptoms or greater [Clinical Opiate Withdrawal Scale (COWS) score ≥ 5), 2) where adjunctive medications were given in response to minimal withdrawal symptoms or greater (COWS score ≥ 3) and 3) where adjunctive medications were given regardless of withdrawal symptoms. Using a longitudinal sequentially doubly robust estimator, we estimated the cumulative probability of XR-NTX initiation under each of these three treatment regimes while accounting for dropout and initiation of other medications as competing events.

Findings: The estimated probability of initiating XR-NTX by day 14 was 50.4% [95% confidence interval (CI) = 41.8-58.9) under the no-threshold regime, 43.9% (95% CI = 39.1-48.7) under the regime of waiting for minimal withdrawal symptoms and 38.5% (95% CI = 34.3-42.6) under the regime of waiting for mild-to-moderate withdrawal symptoms. Probability of XR-NTX initiation was a statistically significant 11.9 percentage points higher (95% CI = 3.6-20.2) under the no-threshold regime versus the mild-to-moderate threshold regime, and a non-statistically significant 6.4 percentage points (95% CI = -0.8 to 13.7) higher under the no-threshold regime versus the minimal threshold regime.

Conclusions: Providing clonidine and clonazepam daily during the first five days of medically managed opioid withdrawal appears to statistically significantly increase the likelihood of initiating extended-release naltrexone treatment compared with waiting for mild-to-moderate withdrawal symptoms to administer adjunctive medications. To improve initiation rates, providers may consider lowering the threshold at which they provide adjunctive medications, giving these medications preemptively or to manage even minimal withdrawal symptoms.