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Efficacy and Tolerability of Long-Acting Injectable Naltrexone for Alcohol Dependence

Background: A new polyactide-co-glycolide (PLG)-based long-acting naltrexone formulation (Vivitrex®), which releases naltrexone for one-month following a single injection, was recently developed and may minimize the current problems concerning compliance with the oral naltrexone formulation. Non-compliance has been proposed as one of the problems that has limited the clinical use of oral naltrexone.

Objective: The purpose of this study was to determine the efficacy and tolerability of a long-acting intramuscular formulation of naltrexone for the treatment of alcohol-dependent patients.

Methods: This was a 6-month, multicenter, randomized, double-blind, placebo-controlled study enrolling 627 patients. Male or non-pregnant, non-lactating female outpatients aged 18 years or older were eligible to participate if they were diagnosed with alcohol dependence according to DSM-IV criteria, had a minimum of 2 episodes of heavy drinking per week during the 30 days prior to screening, and had a negative urine test result for opiates and methadone on the day of randomization. Exclusion criteria included: evidence of liver failure; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than three times the upper limit of normal; any clinically significant medical condition that would adversely affect safety or study participation; major depression with suicidal ideation, psychosis, or bipolar disorder; dependence within the past year on benzodiazepines, opiates or cocaine; more than seven days of inpatient treatment for substance abuse in the month before screening; and use of opiates, oral naltrexone, or disulfiram in the two weeks before screening. Patients were assigned to receive either long-acting injectable naltrexone 380 mg (4mL), 190 mg (2mL) or placebo. Intramuscular gluteal injections were given at four-week intervals, and all patients also received 12 sessions of standardized supportive therapy using the Biopsychosocial, Report, Empathy, Needs, Direct advice, and Assessment (BRENDA) model. The primary outcome measure was the event rate of heavy drinking days over 24 weeks using an event rate ratio. Secondary end points included the event rate of “risky” drinking days adapted from the National Institute on Alcohol Abuse and Alcoholism and the event rate of any drinking days. The study also assessed changes in serum gamma-glutamyl transferase concentrations over time, time to study discontinuation and adverse events. Sub-analyses were conducted for the predefined randomization factors of sex, lead-in abstinence, and treatment goal of abstinence. An intent-to-treat analysis was used for the primary and secondary endpoints, and the study did not report power.

Results: Four-hundred and one patients (64%) received all six injections (naltrexone 360 mg: n=130, naltrexone 190 mg: n=137, placebo: n=134), and 463 (74%) received at least four injections. The median rate of therapy sessions completed was 92% (11 of 12 possible), and 267 (43%) patients attended all therapy sessions. Results for the primary and secondary endpoints were reported as the hazard ratio (HR) with 95% confidence interval. Patients treated with naltrexone 380 mg experienced a 25% greater reduction in the rate of heavy drinking relative to placebo-treated patients [0.75 (0.60-0.94), p=0.03], and patients treated with naltrexone 190 mg reported a 17% greater reduction in heavy drinking than placebo-treated patients [0.83 (0.68-1.02), p=0.07]. Statistically significant differences between treatment groups were not observed with either secondary outcome measure: risky drinking [naltrexone 380 mg 0.90 (0.76-1.07) p=0.23; naltrexone 190 mg 0.95 (0.81-1.13), p=0.58]; or non-abstinent days [380 mg 0.96 (0.83-1.11) p=0.58; 190 mg 0.98 (0.85-1.14), p=0.80]. There was a 15% reduction in gamma-glutamyl transferase observed during the study for the overall sample. Study discontinuations secondary to adverse events occurred in 29 (14.1%) patients in the 380 mg group, 14 (6.7%) in the 190 mg group, and 14 (6.7%) in the placebo groups (p=0.04 for 380 mg vs. 190 mg and placebo). Eleven (5.4%) patients in the 380 mg group experienced serious adverse events compared to 10 (4.8%) in the 190 mg group and 15 (7.2%) in the placebo groups. Sub-analyses of the primary outcome measure revealed that the treatment effect among men in the 380 mg group was significant [HR 0.56 (0.41-0.77), p<0.001], but not among women [HR 1.23 (0.85-1.78), p=0.28], when compared to placebo. Treatment effects were greater for patients with lead-in abstinence [HR 0.20 (0.07-0.62), p=0.005] compared with patients who were not abstinent during the lead-in period [HR 0.79 (0.62-1.00), p=0.05] in the naltrexone 380 mg group vs. placebo. Lead-in abstinence also resulted in a treatment effect in the 190 mg group vs. placebo [HR 0.05 (0.02-0.15), p<0.001]. The authors concluded that long-acting injectable naltrexone is well tolerated and is associated with a significant reduction in heavy drinking among treatment-seeking alcohol-dependent patients during a six-month period.

Strengths: This was a randomized, double-blind, placebo-controlled, multicenter study. Randomization was designed to balance the allocation of patients to treatment groups based on defined characteristics that had the potential to affect the study’s results. Appropriate statistical tests were used and confidence intervals were reported.

Weaknesses: The study was funded, conducted and designed by Alkermes, the developer and future manufacturer of Vivitrex®, which could have introduced bias into the study results. The success of blinding was not determined, and the study did not report a power. The hazard ratios used to express treatment results only provide relative information; therefore, the clinical significance of the results is questionable. The exclusion criteria were very extensive, and may have excluded patients with conditions associated with adherence problems. A large percentage of patients did not receive all 6 injections.

Conclusion: Based on the preliminary results of this study, injectable naltrexone may be an effective and well-tolerated treatment for alcohol-dependent patients. Further studies need to be conducted with the actual results reported, not just hazard ratios, in order to determine the clinical significance of the effects. The issue brought up in the introduction, and the rationale for the use of a long-acting injectable formulation of naltrexone was to promote compliance. This study did not address this issue; therefore, additional studies will need to be performed comparing adherence differences between injectable and oral formulations. The long-term efficacy and safety results of injectable naltrexone, as well as the appropriate duration of treatment, need to be determined. At the most effective study dose of 380 mg, the discontinuations due to adverse events were significantly higher when compared to the 190 mg dose and placebo, which could influence the clinical usefulness of this agent.

Barbutt JC, Kranzler HR, O’Malley SS, Gastfriend DR, Pettinati HM, Silverman BL, Loewy JW,

Ehrich EW. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA 2005;293(13):1617-25.

Julie LeRose, Pharm.D. Candidate