Anxiety, Depression, and Insomnia Among Adults With Opioid Dependence Treated With Extended-Release Naltrexone vs Buprenorphine-Naloxone: A Randomized Clinical Trial and Follow-up Study

Abstract

Importance: Extended-release naltrexone (XR-NTX) is a promising alternative treatment of opioid addiction but has never been compared with opioid agonist treatment for effects on symptoms of anxiety, depression, and insomnia.

Objective: To investigate whether XR-NTX unmasks or reinforces current comorbid symptoms of anxiety, depression, or insomnia compared with opioid agonist treatment.

Design, setting, and participants: In this prospective randomized clinical trial, 159 men and women aged 18 to 60 years with opioid dependence were randomized to 12 weeks of treatment with either XR-NTX or combined buprenorphine-naloxone (BP-NLX) followed by a 9-month, open-label treatment study with participant choice of 1 of these 2 drugs. The study was conducted at outpatient addiction clinics in 5 urban hospitals in Norway, with the clinical trial performed from November 1, 2012, to October 23, 2015, and the follow-up study completed on July 23, 2016. All analyses were conducted using an intention-to-treat sample.

Interventions: Extended-release naltrexone hydrochloride, 380 mg, administered as an injection every 4 weeks or flexible doses (4-24 mg; target dosage 16 mg/d) of daily oral combined BP-NLX.

Main outcomes and measures: Every 4 weeks, symptoms of anxiety and depression were assessed using the 25-item Hopkins Symptom Checklist, and symptoms of insomnia were assessed using the Insomnia Severity Index.

Results: In total, 159 participants were randomized to treatment with either XR-NTX (n = 80) or BP-NLX (n = 79), and 105 participants (66.0%) completed the trial. The treatment groups showed similar distributions of age (mean [SD], 36.4 [8.8] vs 35.7 [8.5] years), sex (61 [76.3%] women and 54 [68.4%] men), and duration of heroin use (mean [SD], 6.9 [5.8] vs 6.7 [5.2] years). For the clinical trial period, no overall differences were detected between treatment groups for anxiety (effect size [95% CI], -0.14 [-0.47 to 0.19]) or depression (effect size [95% CI], -0.12 [-0.45 to 0.21]) scores, but the insomnia score was significantly lower in the XR-NTX group (effect size [95% CI], -0.32 [-0.61 to -0.02]; P = .008). In the follow-up period, no overall differences could be detected in the effect size [95% CI] of scores for anxiety (0.04 [-0.34 to 0.42]), depression (-0.04 [-0.42 to 0.33]), or insomnia (0.04 [-0.33 to 0.42]) between participants continuing with and participants switching to XR-NTX. No significant sex differences between the 2 treatment groups were detected.

Conclusions and relevance: Comorbid symptoms of anxiety, depression, or insomnia in abstinence-motivated persons with opioid dependence should not prevent switching from treatment with an opioid agonist to treatment with XR-NTX.

Trial registration: ClinicalTrials.gov Identifier: NCT01717963.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.. CONSORT Flowchart

aAn additional 5 patients continued combined buprenorphine-naloxone (BP-NLX) treatment in the follow-up period but were not included in the analysis. XR-NTX indicates extended-release naltrexone hydrochloride.

Figure 2.. Changes in Anxiety, Depression, and Sleep Scores During the Randomized Clinical Trial Portion of the Study and in the Follow-up Period

The 25-item Hopkins Symptom Checklist mean anxiety subscale (A) and mean depression subscale (B) scores and the Insomnia Severity Index scores (C) among participants randomized to extended-release naltrexone (XR-NTX) or combined buprenorphine-naloxone (BP-NLX) treatment from baseline (week 0) to week 12 and receiving XR-NTX during the follow-up period (from week 16 to week 48) analyzed using a linear mixed model. Values in parentheses on the y-axes indicate minimum and maximum values of each scale; error bars represent 95% CI.