Context Sustained-release naltrexone implants may improve outcomes of nonagonist treatment of opioid addiction. Objective To compare outcomes of naltrexone implants, oral naltrexone hydrochloride, and nonmedication treatment. Design Six-month double-blind, double-dummy, randomized trial. Setting Addiction treatment programs in St Petersburg, Russia. Participants Three hundred six opioid-addicted patients recently undergoing detoxification. Interventions Biweekly counseling and 1 of the following 3 treatments for 24 weeks: (1) 1000-mg naltrexone implant and oral placebo (NI+OP group; 102 patients); (2) placebo implant and 50-mg oral naltrexone hydrochloride (PI+ON group; 102 patients); or (3) placebo implant and oral placebo (PI+OP group; 102 patients). Main Outcome Measure Percentage of patients retained in treatment without relapse. Results By month 6, 54 of 102 patients in the NI+OP group (52.9%) remained in treatment without relapse compared with 16 of 102 patients in the PI+ON group (15.7%) (survival analysis, log-rank test, P<.001) and 11 of 102 patients in the PI+OP group (10.8%) (P<.001). The PI+ON vs PI+OP comparison showed a nonsignificant trend favoring the PI+ON group (P=.07). Counting missing test results as positive, the proportion of urine screening tests yielding negative results for opiates was 63.6% (95% CI, 60%-66%) for the NI+OP group; 42.7% (40%-45%) for the PI+ON group; and 34.1% (32%-37%) for the PI+OP group (P<.001, Fisher exact test, compared with the NI+OP group). Twelve wound infections occurred among 244 implantations (4.9%) in the NI+OP group, 2 among 181 (1.1%) in the PI+ON group, and 1 among 148 (0.7%) in the PI+OP group (P=.02). All events were in the first 2 weeks after implantation and resolved with antibiotic therapy. Four local-site reactions (redness and swelling) occurred in the second month after implantation in the NI+OP group (P=.12), and all resolved with antiallergy medication treatment. Other nonlocal-site adverse effects were reported in 8 of 886 visits (0.9%) in the NI+OP group, 4 of 522 visits (0.8%) in the PI+ON group, and 3 of 394 visits (0.8%) in the PI+ON group; all resolved and none were serious. No evidence of increased deaths from overdose after naltrexone treatment ended was found. Conclusions The implant is more effective than oral naltrexone or placebo. More patients in the NI+OP than in the other groups develop wound infections or local irritation, but none are serious and all resolve with treatment.

Background Naltrexone is a μ-opioid receptor antagonist that blocks opioid effects. Craving, depression, anxiety, and anhedonia are common among opioid dependent individuals and concerns have been raised that naltrexone increases them due to blocking endogenous opioids. Here we present data that addresses these concerns. Objective Assess the relationship between affective responses and naltrexone treatment. Methods Opioid dependent patients (N=306) were enrolled in a three cell (102ss/cell) randomized, double blind, double dummy, placebo-controlled 6-month trial comparing extended release implantable naltrexone with oral naltrexone and placebo (oral and implant). Monthly assessments of affective responses used a Visual Analog Scale for opioid craving, the Beck Depression Inventory, Spielberger Anxiety Test, and the Ferguson and Chapman Anhedonia Scales. Between group outcomes were analyzed using mixed model analysis of variance (Mixed ANOVA) and repeated measures and the Tukey test for those who remained and treatment and did not relapse, and between the last measure before dropout with the same measure for those remaining in treatment. Results Depression, anxiety, and anhedonia were elevated at baseline but reduced to normal within the first 1-2 months for patients who remained in treatment and did not relapse. Other than a slight increase in two anxiety measures at week two, there were no significant between group differences prior to treatment dropout. Conclusion These data do not support concerns that naltrexone treatment of opioid dependence increases craving, depression, anxiety or anhedonia.

Background Stress is a key precipitant to discontinuing naltrexone and relapsing to opiate abuse. Alpha-2 adrenergic agonists like guanfacine may reduce stress induced craving and have reduced opiate relapse in small clinical trials. Methods This randomized, double blind double dummy placebo-controlled 6-month trial tested oral naltrexone with or without guanfacine for reducing stress and preventing opiate relapse. We randomized 301 patients to: naltrexone 50 mg/day + guanfacine 1 mg/day (n = 75) (N/G), naltrexone + guanfacine placebo (N/P) (n = 76), naltrexone placebo + guanfacine (n = 75) (P/G), and double placebo (n = 75) (P/P). Results Among the 75 patients in each group the percentage still retained on naltrexone treatment at six months was: N/G 26.7%, N/P 19.7% (p = 0.258 to N/G), P/G 6.7% (p < 0.05 to both N groups), and P/P 10.7% (p = 0.013 to N + G). Guanfacine reduced the severity of stress particularly at weeks 10 and 18. Adverse events (AE) were infrequent (4.7%) without group differences, with most common AEs: headache, poor appetite, insomnia, and dizziness. Conclusions Adding guanfacine to naltrexone did not improve treatment retention or opiate free urines, but it reduced both stress and craving at later time points in treatment, which may be related to stress-induced craving and the animal model of incubation of reinstatement. During treatment, HIV risk, anxiety, and depression reduced among all patients in treatment, regardless of group.

Background: Untreated opioid addiction in persons with HIV is associated with poor outcome. Slow release, long-acting, implantable naltrexone may improve outcomes. Methods: We conducted a 48-week outcome study beween July 2011 and April 2015 of opioid addicted males and females starting antiretroviral treatment (ART) for HIV whose viral loadwas ≥1000 copies per mL and were seeking treatment at HIV and Narcology programs in St. Petersburg and the surrounding Leningrad Region, Russian Federation. We stratified participants according to gender, viral load (VL) and CD4 cells per μL, and randomized them to addiction treatment with a naltrexone implant and oral naltrexone placebo (NI), or oral naltrexone and placebo implant (ON). The primary outcome was plasma viral load of ≤400 copies per mL at 24 and 48 weeks. We included all randomized participants in outcome analyses. Treatment staff was blinded to group assignment. The study is complete and registered at ClinicalTrials.gov, NCT01101815 Findings: 238 potential subjects were screened, 35 excluded for not meeting inclusion criteria, 3 declined to participate and 200 were randomized. There was no difference between NI and ON in the number of participants with VL≤400 copies per mL at week 24 (38 [38%] vs 35 [35%] p=0•77) but more NI than ON participants had a VL≤400 copies per mL at week 48 (66 [66%] vs 50 [50%] RR: 1•32 [95% CI: 1•04−1•68] p=0•0451). There were seven serious adverse events: three deaths in NI (one heart disease, one trauma, one AIDS), and four in ON (two overdoses, one pancreatic cancer, one AIDS). The overdose deaths occurred 9-10 months after the last naltrexone dose. Interpretation: The longer the blockade, the more protection from missed doses and the impulsive behaviors that lead to relapse and poor, even fatal outcomes. Commercial development of implants could result in a meaningful addition to current addiction treatment options.