BACKGROUND: Mental health status may be improved in patients receiving treatment with the opioid antagonist extended-release naltrexone (XR-NTX), but longer-term outcomes remain unexamined. OBJECTIVES: This study aims to assess changes in symptoms of anxiety, depression, and insomnia among opioid-dependent individuals in long-term treatment with XR-NTX and to explore possible associations between such symptoms and the use of illicit opioids. METHODS: After completing an initial 3-month randomized clinical trial and an extended 9-month follow-up study, 50 opioid-dependent individuals (9 women) chose to continue treatment with XR-NTX at their own discretion for a prolonged period of up to 2 years. Symptoms of anxiety, depression, and insomnia were assessed every 4th week. In addition, the participants reported use of illicit opioids. RESULTS: The participants reported improved mental health status during up to 3 years treatment with XR-NTX. Symptoms of anxiety and depression were reduced from mean 18.0 (SD:6.1) to 12.3 (SD:4.4) (p <
0.001), and from 30.5 (SD:9.1) to 17.8 (SD:5.4) (p <
0.01), respectively, whereas symptoms of insomnia were reduced from 14.2 (SD:7.9) to 3.6 (SD:3.6), (p <
0.001). The reduction in these symptoms was more pronounced in participants who did not relapse to opioid use (n = 35) during the study. CONCLUSION: Long-term treatment with XR-NTX may promote a reduction in symptoms of anxiety, depression, and insomnia in opioid-dependent individuals. Those who managed to stay abstinent from opioids were likelier to experience a greater reduction in symptoms compared to those who relapsed to opioid use during the 3-year treatment period. CLINICALTRIALS: gov no. NCT01717963.