Depot Naltrexone Effectively Treats Alcohol Dependence

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Depot Naltrexone Effectively Treats Alcohol Dependence CME

News Author: Laurie Barclay, MD

CME Author: Vega, MD, FAAFP

Release Date: July 15, 2004; Valid for credit through July 15, 2005

July 15, 2004 — Depot naltrexone is effective for treating alcohol

dependence, according to the results of a multicenter study published

in the July issue of Alcoholism: Clinical and Experimental Research.

" Naltrexone has not been prescribed widely, in part because of poor

compliance with the oral formulation, " lead author Henry R. Kranzler,

MD, from the University of Connecticut Health Center in Farmington,

says in a news release. " This is the first multicenter study of depot

naltrexone.... This is also the first multi-center study of naltrexone

in the U.S. to show an advantage of the active medication over placebo. "

Naltrexone blocks brain opiate receptors modulating dopamine and other

neurotransmitters. In addition to being used in heroin addiction,

naltrexone has been shown in previous studies to reduce alcohol

craving and consumption. It is well-tolerated with few adverse

effects, but the oral formulation appears to be effective in improving

alcohol abstinence only in highly compliant individuals.

In addition to improved compliance, advantages of the depot-injection

form of naltrexone compared with oral administration are less

variability in plasma concentrations of both the active drug and the

major metabolite, greater efficacy and fewer adverse effects, and less

first-pass metabolism, which produces a greater ratio of the

metabolite to the parent compound.

In this 12-week study, 315 alcohol-dependent patients were randomized

to receive a monthly intramuscular injection of naltrexone or placebo.

Injections were well-tolerated, and 73.3% of subjects received all

injections. All patients also received five sessions of manual-guided

motivational enhancement therapy. Outcomes included self-reported

alcohol use and levels of & #947;-glutamyl transpeptidase (GGTP).

Compared with the placebo group, patients who received naltrexone

injection had significantly longer times to the first drinking day,

fewer drinking days during treatment, and higher abstinence rate (18%

vs. 10%). GGTP levels were consistent with these self-reported findings.

Adverse effects reported more often in the naltrexone group than in

the placebo group were upper abdominal pain and local reactions to the

injection. A study limitation was the need to repeat a substantial

number of injections.

" Further research with this long-acting formulation of naltrexone is

needed, " Dr. Kranzler says. " Once it is approved for routine use, a

one-month injection can be expected to contribute substantially to

improved alcoholism treatment. "

The National Institutes of Health funded this study.

Alcohol Clin Exp Res. 2004;28:1051-1059

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

* List adverse events associated with naltrexone therapy and their

effect on compliance with medication.

* Describe the efficacy of naltrexone depot in the treatment of

alcoholism.

Clinical Context

Naltrexone has a mixed record in the treatment of alcohol abuse, with

some research indicating a positive effect and others that describe no

difference when naltrexone is compared with placebo. One explanation

for these conflicting results is a difference in rates of compliance

between different studies. Naltrexone is known to produce

gastrointestinal tract adverse effects, such as nausea and abdominal

cramps, as well as neuropsychiatric adverse effects, such as

dizziness, anxiety, and insomnia. On intent-to-treat analyses, higher

withdrawal rates in the naltrexone group can lead to reduced efficacy

compared with placebo.

In an analysis of two studies by Oncken and colleagues that appeared

in the April 2001 issue of Psychopharmacology, gastrointestinal tract,

but not neuropsychiatric, adverse events were associated with higher

noncompliance with naltrexone therapy. The authors of the current

study seek to determine the efficacy, tolerability, and safety of a

depot form of naltrexone. This new preparation promises to provide a

steady-state dose of medication and improve compliance with therapy.

Study Highlights

* Patients with a Diagnostic and Statistical Manual of Mental

Disorders, Fourth Edition, diagnosis of alcohol diagnosis were

recruited from 30 centers to participate in the study. All

participants were between 18 and 65 years old and had experienced 4

heavy drinking days during the 2 weeks prior to study entry.

* Patients were excluded from study participation if they had

participated in an alcohol cessation program 2 or more times in the

past 2 years, if they had received naltrexone or other medicine for

the treatment of addiction in the 30 days, if they had active

substance abuse beyond that of alcohol and tobacco, or if they had

significant liver or cardiac disease.

* Participants were required to demonstrate at least 3 consecutive

days of sobriety prior to receiving naltrexone, 50 mg, orally for 4

days to determine which patients might not tolerate the drug. Those

who tolerated this treatment were randomized to receive either two

initial injections of naltrexone depot, 150 mg, or matching placebo.

Injections with either naltrexone depot, 150 mg, or placebo were then

continued monthly for the 12-week trial.

* All subjects also received motivational enhancement therapy in

five sessions during the study period.

* The main study outcome was the number of nonheavy drinking days.

Other outcomes included the number of abstinent days and the number of

days of heavy drinking. Data for these outcomes were derived from

patient self-reports. Serum GGTP and adverse events were also followed.

* 333 subjects underwent randomization, but 18 were excluded from

one center because of protocol violations. 12.2% of patients could not

tolerate oral naltrexone.

* Baseline data were similar between the two groups, except for

the fact that the participants in the naltrexone group exhibited a

higher level of alcohol dependence. On average, subjects had a history

of more than 20 years of regular intoxication with alcohol, but most

had not undergone prior substance abuse treatments.

* 77.8% of all subjects completed the study, and completion rates

were similar between treatment groups. Withdrawal rates due to adverse

reactions to study medications were also similar between groups (7% in

the naltrexone group and 6% in the placebo group).

* Among adverse events, upper abdominal pain was more common in

the naltrexone group, while irritability and chest pain were more

common with placebo. Subjects in the naltrexone group experienced more

injection site reactions than the placebo group, with pain being the

most common reaction.

* Naltrexone was not statistically superior to placebo in

abstinence from heavy drinking during the study. 23% of subjects in

the naltrexone group reported no heavy drinking compared with 16% of

the placebo group. Participants in the naltrexone group had a median

5-day reduction in the time to first heavy drinking compared with

placebo, a difference which just missed statistical significance.

* Naltrexone was significantly more effective than placebo in

producing abstinence from alcohol (odds ratio [OR], 2.04) and

lengthening the time to the first day of drinking. On average,

participants in the naltrexone group experienced 7.2 more days of

abstinence compared with those in the placebo group.

* GGTP levels decreased by a mean of 15% more in the naltrexone

group compared with the placebo group, but this difference was not

statistically significant.

Pearls for Practice

* Oral naltrexone is associated with numerous adverse events which

can limit its tolerability.

* Naltrexone depot can improve rates of abstinence but does not

affect rates of heavy drinking. It is safe and well-tolerated.

Post Test

1. According to the study by Oncken and colleagues, which of the

following adverse events would most likely reduce compliance with

naltrexone therapy?

a. Anxiety

b. Insomnia

c. Nausea

d. Nervousness

2. Which of the following outcomes were significantly improved with

naltrexone compared with placebo in the current study by Kranzler and

colleagues?

a. Time until first day of heavy drinking

b. Abstinence from heavy drinking

c. GGTP levels

d. Abstinence from any drinking

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