Pain is common and associated with substance use among persons with HIV (PWH), yet limited management strategies exist. We assessed the feasibility, tolerability, and safety of low-dose naltrexone and standard dose nalmefene to treat chronic pain among PWH with past-year heavy alcohol use in a randomized, double-blinded, 2-arm study (planned enrollment 8 per arm). Participants were recruited in St. Petersburg, Russia between May and October 2018 and randomized to receive either nalmefene (16 mg) or low-dose naltrexone (4.5 mg) for 8 weeks. The primary outcome was tolerability of medication at eight weeks. Study visits included assessments of pain interference and severity, as well as cold-pressor testing. All participants in the nalmefene arm (N = 3) discontinued the study medication early due to side effects; nalmefene was subsequently deemed intolerable and this arm was terminated. The mean tolerability score at 8-weeks in the low-dose naltrexone arm was 90.7 (SD 22.44), median was 100 (IQR 95- 100), and median cold pain tolerance was approximately 10 s higher at the end of the 8 weeks. Low-dose naltrexone was well-tolerated, but nalmefene was not, in this sample. Further research is warranted to explore low-dose naltrexone's potential efficacy as a non-addictive treatment for pain in this population. ClinicalTrials.gov identifier: NCT03278886. [ABSTRACT FROM AUTHOR]