Oral vs Extended-Release Injectable Naltrexone for Hospitalized Patients With Alcohol Use Disorder: A Randomized Clinical Trial

Abstract

Importance: Alcohol use disorder (AUD) is common in hospital patients. AUD medications are not typically initiated in that setting. The comparative effectiveness between initiation of oral naltrexone and extended-release injectable naltrexone in the hospital is not known.

Objective: To compare the effectiveness of initiating oral naltrexone vs extended-release injectable naltrexone on reduction in alcohol use and health care utilization among medical inpatients with AUD.

Design, setting, and participants: The Alcohol Disorder Hospital Treatment (ADOPT) study is a randomized clinical trial conducted at an urban teaching hospital in the US, with enrollment between June 2016 and March 2020. Inpatients were screened for eligibility, and those with AUD and recent heavy drinking (defined as 5 or more drinks for men and 4 or more drinks for women) were enrolled. Outcomes were assessed at 3-month follow-up; assessors were not blinded to treatment assignment. Data were analyzed from May 2021 to September 2023.

Interventions: Participants received either daily oral naltrexone or monthly extended-release injectable naltrexone. All received medical management with a research nurse who specialized in addiction.

Main measures and outcomes: The primary outcome was change in percentage of heavy drinking days (HDDs) over the past 30 days from baseline to 3-month follow-up, assessed by validated instrument. The secondary outcome was any acute health care utilization (emergency department or hospitalization) at 3-month follow-up over the past 90 days.

Results: Of 248 participants, 199 (80.2%) were male, and the mean (SD) age was 49.4 (10.4) years. The baseline median (IQR) percentage of HDDs in the past 30 days was 80.0% (43.3-100). At 3-month follow-up, the mean percentage of HDDs in the past 30 days was reduced in both groups (oral naltrexone: baseline, 66.7% HDDs; 3-month follow-up, 27.4% HDDs; difference, -38.4 percentage points; 95% CI, -125.0 to 48.2; extended-release injectable naltrexone: baseline, 70.7% HDDs; 3-month follow-up, 23.8% HDDs; difference, -46.4 percentage points; 95% CI, -123.4 to 30.6; P = .14). At follow-up, 59 of 109 in the oral naltrexone arm (54.1%) and 66 of 108 in the extended-release injectable naltrexone arm (61.1%) reported acute health care utilization in the prior 3 months; the odds of this utilization were not significantly different between groups (adjusted odds ratio, 1.34; 95% CI, 0.77-2.33).

Conclusions and relevance: In this randomized clinical trial, when initiated at hospital discharge, oral and extended-release injectable naltrexone did not differ in effectiveness. Participants had substantial reductions in HDDs in both treatment groups; however, there was not a significant difference in the reduction of percentage of HDDs in the past 30 days or acute health care utilization between groups. Hospitalization represents an opportunity to start AUD pharmacotherapy; choice of oral naltrexone vs extended-release injectable naltrexone should be directed by factors such as patient preference and insurance.

Trial registration: ClinicalTrials.gov Identifier: NCT02478489.

Figure 1.. CONSORT Diagram

ITT indicates intention to treat; RWMM, real-world medication management. ^aFour participants were found to be ineligible after the baseline interview (prior to randomization) because they were not fluent in English (n = 1), prescribed anticoagulant medication (n = 1), had a potential future need for opioids (n = 1), and had acute severe psychiatric illness (n = 1). ^bFour randomized participants did not receive medications due to further health concerns (n = 2) or refusal to receive medication (n = 2). ^cThe ITT population includes all participants who were randomized after baseline assessment.

Figure 2.. Outcomes for Oral vs Extended-Release (ER) Injectable Naltrexone Among Patients With Alcohol Use Disorder (N = 248)

Baseline data were not collected for percentage of HDDs in the past 30 days and medication adherence. The reference group for unadjusted and adjusted βs was the oral naltrexone group. Heavy drinking was defined as 5 or more drinks for men and 4 or more drinks for women. ED indicates emergency department; HDD, heavy drinking day; NA, not applicable; OR, odds ratio; SIP-2R, Short Inventory of Problems Revision 2. ^aModels adjusted for sex and race. ^bModels analyzing the primary outcome (change in percentage of HDDs in the prior 30 days) and the secondary outcome (hospitalization or ED visit) use the intention-to-treat population (all participants who completed baseline and were randomized; N = 248) with multiple imputation used to impute outcomes if missing at 3-month follow-up. Baseline characteristics used to carry out the multiple imputation for both the primary and secondary outcomes were the following: treatment group, sex, race (dichotomized as Black or other race [American Indian or Alaskan Native, Asian, Native Hawaiian or Pacific Islander, White, or more than 1 race]), age, Charlson Comorbidity Index score, any acute care utilization in the past 3 months, unhoused, depressive symptoms, anxiety symptoms, any lifetime substance (cannabis, cocaine, amphetamine-type stimulants, opioid, sedatives, hallucinogens, or inhalants) use, abstinence in the 7 days prior to baseline hospitalization (from Timeline Followback calendar method), World Health Organization drinking risk levels, alcohol use motives (specifically, coping motive), and Alcohol, Smoking, and Substance Involving Screening Test substance-specific risk level scores for cannabis and cocaine and highest level of risk for any substance in the Alcohol, Smoking, and Substance Involving Screening Test. ^cModels analyzing other outcomes use the evaluable population (participants randomized with evaluable outcome data [n = 217]). No other outcomes were imputed if missing. ^dThe SIP-2R theoretical range is between 0 and 45, with a higher score indicating more alcohol-related consequences. ^eHigh adherence to ER injectable naltrexone was defined as administration of injectable naltrexone by the study nurse 3 times (this adherence measure did not require research follow-up assessment). Medium or low adherence was defined as 1 or 2 injections. For oral naltrexone, high adherence was defined as participant self-report of taking oral naltrexone for 90 of the past 90 days at the 3-month follow-up assessment, and medium or low adherence was defined as participant self-report of taking oral naltrexone for 0 to 89 of the past 90 days at the 3-month follow-up assessment. A total of 232 patients were evaluable for medication adherence.