In 1994, the U.S. Food and Drug Administration approved naltrexone, an orally administered opiate receptor antagonist, for the treatment of alcohol dependence. Since then, studies of its effectiveness have produced conflicting results. This may be due, at least in part, to variation in medication compliance. The July issue of Alcoholism: Clinical & Experimental Research contains findings from the first multi-site examination of the effectiveness of an inject-able, long-acting formulation of naltrexone: significantly fewer drinking days and a greater likelihood of total abstinence during the three-month study period.
"Naltrexone has not been prescribed widely," explained Henry R. Kranzler, professor of psychiatry at the University of Connecticut Health Center and first author of the study, "in part because of poor compliance with the oral formulation." The typical oral dose of naltrexone is 50 milligrams per day. Studies have shown that only individuals who are highly compliant have greater reductions in alcohol consumption and risk of relapse than those individuals treated with a placebo.
Naltrexone works by blocking brain opiate receptors, which in turn, modulate other brain chemicals like dopamine. Originally marketed for the treatment of heroin addiction, researchers discovered the medication could also block alcohol craving and reduce alcohol consumption, leading to less relapse drinking and more abstinent days. Although it is well tolerated and does not produce many adverse effects, naltrexone does not work for everyone.
"This is the first multi-center study of ‘depot naltrexone,’" added Kranzler. "Multi-center studies are valuable because they provide a better reflection than single-site studies of the likely utility of a medication in clinical settings. This is also the first multi-center study of naltrexone in the U.S. to show an advantage of the active medication over placebo. The only previous multi-center study of the drug in the U.S. was in the Veterans’ Affairs system and it showed no advantages of naltrexone over placebo treatment. Our findings provide evidence for a beneficial effect of naltrexone in a group of treatment clinics distributed throughout the U.S."
Kranzler and his colleagues conducted a multi-site trial with 315 alcohol-dependent patients who were randomly assigned to receive either an intramuscular injection of naltrexone (n=158) or a placebo (n=157) once a month, for three months. All patients also received five sessions of manual-guided motivational enhancement therapy during the 12 weeks of the study. Results were based on self-reported alcohol use as well as levels of gamma-glutamyl transpeptidase (GGTP), a liver enzyme that is increased in response to heavy alcohol consumption.
Patients who received the naltrexone injection had significantly longer times to the first drinking day, significantly fewer drinking days during treatment, and a significantly greater abstinence rate than those individuals who received a placebo injection. In addition, an objective measure of drinking – that is, the GGTP levels – showed results that were consistent with the self-reported findings.
Kranzler said there are three major advantages to the depot/injection form of naltrexone. "One," he said, "is greater medication compliance; by giving a depot injection, the problem with non-compliance, which occurs relatively commonly among alcoholics, is reduced. Two, [there is] less variability in plasma concentrations of both the active drug and the major metabolite compared to the oral formulation. This can produce greater efficacy and fewer adverse effects. Three, less first-pass metabolism of the depot formulation produces a greater ratio of the metabolite to the parent compound, which can produce fewer adverse effects."
Several side effects, however, were reported. "The side effect that was greater in the naltrexone group than in the placebo group was upper abdominal pain, which is commonly associated with naltrexone," said Kranzler. "In addition, there were some local reactions to the injection, including pain, swelling and bruising."
In summary, said Kranzler, the study’s results provide clear evidence for the beneficial effects of the injection form of naltrexone over a placebo injection, including a doubling of the rate of abstinence. "Further research with this long-acting formulation of naltrexone is needed," he said, "but once it is approved for routine use, a one-month injection can be expected to contribute substantially to improved alcoholism treatment."
Funding for this Addiction Science Made Easy project is provided by the Addiction Technology Transfer Center National Office, under the cooperative agreement from the Center for Substance Abuse Treatment of SAMHSA.
Articles were written based on the following published research:
Kranzler, H.R., Wesson, D.R., & Billot, L. Naltrexone depot for treatment of alcohol dependence: A multicenter, randomized, placebo-controlled clinical trial. (July 2004). Alcoholism: Clinical & Experimental Research, 28(7) 1051-1059.