Article

Efficacy and Tolerability of Long-Acting Injectable Naltrexone for Alcohol DependenceA Randomized Controlled Trial

Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill 27599-7160, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 30.39). 05/2005; 293(13):1617-1625. DOI: 10.1001/jama.293.13.1617

ABSTRACT Context
Alcohol dependence is a common disorder associated with significant
morbidity and mortality. Naltrexone, an opioid antagonist, has been shown
to be effective for treatment of alcohol dependence. However, adherence to
daily oral pharmacotherapy can be problematic, and clinical acceptance and
utility of oral naltrexone have been limited.Objective
To determine efficacy and tolerability of a long-acting intramuscular
formulation of naltrexone for treatment of alcohol-dependent patients.Design, Setting, and Participants
A 6-month, randomized, double-blind, placebo-controlled trial conducted
between February 2002 and September 2003 at 24 US public hospitals, private
and Veterans Administration clinics, and tertiary care medical centers. Of
the 899 individuals screened, 627 who were diagnosed as being actively drinking
alcohol-dependent adults were randomized to receive treatment and 624 received
at least 1 injection.Intervention
An intramuscular injection of 380 mg of long-acting naltrexone (n = 205)
or 190 mg of long-acting naltrexone (n = 210) or a matching volume
of placebo (n = 209) each administered monthly and combined with
12 sessions of low-intensity psychosocial intervention.Main Outcome Measure
The event rate of heavy drinking days in the intent-to-treat population.Results
Compared with placebo, 380 mg of long-acting naltrexone resulted in
a 25% decrease in the event rate of heavy drinking days (P = .03) and 190 mg of naltrexone resulted in a 17% decrease
(P = .07). Sex and pretreatment abstinence
each showed significant interaction with the medication group on treatment
outcome, with men and those with lead-in abstinence both exhibiting greater
treatment effects. Discontinuation due to adverse events occurred in 14.1%
in the 380-mg and 6.7% in the 190-mg group and 6.7% in the placebo group.
Overall, rate and time to treatment discontinuation were similar among treatment
groups.Conclusions
Long-acting naltrexone was well tolerated and resulted in reductions
in heavy drinking among treatment-seeking alcohol-dependent patients during
6 months of therapy. These data indicate that long-acting naltrexone can be
of benefit in the treatment of alcohol dependence.

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Alcohol dependence is a major public health problem, which worldwide
is the fourth leading cause of disability.1 Alcohol
dependence is present in approximately 4% of the US adult population,2 is common among primary care patients,3- 4 and
may contribute to more than 100 000 preventable deaths per year.5 Addiction counseling, behavioral treatments, and self-help
groups (eg, Alcoholics Anonymous) are the primary interventions used to treat
alcohol dependence in the United States. Although these treatments are often
effective, a substantial number of patients fail to complete them or relapse.6

Similar to diabetes, hypertension, and asthma, alcohol dependence is
increasingly recognized as a chronic disease in which genetic vulnerability
and social and environmental factors are involved in the etiology and course
of the disease.7 As with other chronic diseases,
long-term comprehensive management strategies are necessary to achieve and
sustain the benefits of alcohol dependence treatment. Pharmacotherapy represents
an emerging treatment option that could be used by primary care practitioners
and addiction specialists.8

In 1994, naltrexone was approved by the US Food and Drug Administration
to treat alcohol dependence after the medication was shown to reduce drinking
frequency and the likelihood of relapse to heavy drinking.9- 10 Naltrexone,
an opioid antagonist, is thought to reduce the reinforcing subjective or behavioral
response to alcohol.11- 12 In about
3200 alcohol-dependent patients in at least 19 published controlled studies,
oral naltrexone, compared with placebo, has shown efficacy in the treatment
of alcohol dependence although some studies have reported no or minimal effectiveness.13- 18 Despite
substantial evidence of efficacy, clinical use of naltrexone has been limited,
in part because of the heterogeneity in treatment response.19

One documented reason for the heterogeneity of response across naltrexone
trials has been poor adherence to the daily medication regimen.20- 23 Adherence
to a daily oral medication regimen is a general problem in medicine.7 Additional challenges to adherence in the context
of substance abuse include variable patient motivation toward treatment; impaired
cognitive function, particularly executive function; and denial.24 As
a prototypical addictive disorder, alcohol dependence is thought to involve
dysfunction of the brain’s reward system with attendant impaired control
over drives and motivation.25 Moreover, treatment
may directly conflict with the behaviors and rewards associated with the abused
substance.26

Since the 1970s, several efforts have been made to develop a parenteral
extended-release naltrexone,27- 29 and
1 formulation has reported an effect on abstinence.29 Recently,
a new polylactide-co-glycolide (PLG)–based, long-acting naltrexone formulation
that releases naltrexone for 1 month following a single injection was developed.30 We conducted a 6-month, multicenter, randomized,
double-blind, placebo-controlled study of the efficacy and safety of 2 dosing
levels of this long-acting injectable formulation of naltrexone in combination
with a low-intensity psychosocial intervention for treatment of alcohol dependence.

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