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Original Investigation
December 19, 2018

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

Author Affiliations
  • 1Department of Research and Development in Mental Health, Akershus University Hospital, Lørenskog, Norway
  • 2Norwegian Center for Addiction Research, University of Oslo, Oslo, Norway
  • 3Institute of Clinical Medicine, Campus Ahus, University of Oslo, Oslo, Norway
  • 4Health Services Research Unit, Akershus University Hospital, Lørenskog, Norway
  • 5Department of Addiction Medicine, Haukeland University Hospital, Bergen, Norway
  • 6Faculty of Medicine and Odonthology, The University of Bergen, Bergen, Norway
  • 7Department of Addiction Medicine, Oslo University Hospital, Oslo, Norway
  • 8Vestfold Hospital Trust, Toensberg, Norway
JAMA Psychiatry. Published online December 19, 2018. doi:10.1001/jamapsychiatry.2018.3537
Key Points

Question  Does treatment with injectable extended-release naltrexone unmask or reinforce symptoms of anxiety, depression, or insomnia compared with daily sublingual treatment with combined buprenorphine-naloxone among adults who have opioid dependence but have recently undergone detoxification?

Findings  In this randomized clinical trial of 159 men and women with opioid dependence, both drug treatments were equally effective in reducing symptoms of anxiety and depression, but symptoms of insomnia were significantly further reduced by the extended-release naltrexone treatment. All symptoms were further improved by longer-term extended release naltrexone treatment.

Meaning  Comorbid symptoms of anxiety, depression, or insomnia in abstinence-motivated adults with opioid dependence should not prevent switching from opioid agonist to extended-release naltrexone treatment.


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 [−0.65 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