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: 35.29). 05/2005; 293(13):1617-1625. DOI: 10.1001/jama.293.13.1617


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
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

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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Available from: James C Garbutt, Oct 06, 2015
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    • "NTX decreases days of heavy drinking (Anton et al., 2006) and alcohol relapse (Streeton & Whelan, 2001) and is superior to acamprosate and/or behavioral counseling (Anton et al., 2006). Once-monthly injectable extended-release naltrexone (XR-NTX) confers an adherence advantage (Garbutt et al., 2005; Swift, 2007) over daily oral formulations and is feasible for use in primary care settings (Lee et al., 2010). XR-NTX administration combined with brief medical management counseling reduces alcohol consumption even during holiday periods where heavy drinking is common (Lapham, Forman, Alexander, Illeperuma, & Bohn, 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In Peru, the HIV epidemic is concentrated in men who have sex with men (MSM) and transgender women (TGW). Multiple studies correlate alcohol use disorders (AUDs) with risky sexual behaviors among Peruvian MSM. Qualitative research was used to inform a clinical trial on the acceptability of medication-assisted therapies to assist management of AUDs and improve antiretroviral therapy (ART) adherence among MSM/TGW in Peru. Three focus groups involving HIV-infected or HIV-uninfected MSM/TGW (n = 26) with AUDs (AUDIT ≥ 8) were transcribed, translated from Spanish into English, and analyzed using thematic content analysis. Despite having an AUD, participants considered themselves "social" drinkers, minimized their drinking behaviors, and differed about whether or not alcohol problems could be treated. Participants expressed skepticism about medication for treating AUDs. Three concepts emerged as necessary components of a treatment program for alcohol problems: cost, family support, and the potential to drink less alcohol without attaining total abstinence. This study reveals important areas of education to increase potential acceptability of a medication for treating AUDs among MSM/TGW. Given the social conditions and knowledge base of the participants, medication-assisted therapies using naltrexone may be a beneficial strategy for MSM with AUDs. © The Author(s) 2015.
    American journal of men's health 03/2015; DOI:10.1177/1557988315576775 · 1.15 Impact Factor
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    • "CBT and MI approaches targeting ART adherence and retention in care produce short-term, but not sustained benefits among MSM with AUDs (Parsons, Golub, Rosof, & Holder, 2007). Among the three approved pharmacological medications that treat AUDs (Naltrexone, Acamprosate , and Disulfiram), only naltrexone, in its oral or extended-release formulation, is superior to either acamprosate alone (Anton et al., 2006; Zarkin et al., 2008) or to behavioral therapies in HIV-uninfected persons (Anton et al., 2006; Garbutt et al., 2005). Few studies, however, have investigated the influence of naltrexone on HIV treatment outcomes among patients prescribed ART (Traore, Thiero, Dao, Kounde, & Faye, 2011), but data are beginning to emerge (Springer, Altice, Herme, & Di Paola, 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: As international guidelines increase access to antiretroviral therapy (ART) globally, ART adherence becomes increasingly important to achieve HIV treatment as prevention (TasP) goals. In the concentrated HIV epidemic among men who have sex with men (MSM) and transgendered women (TGW) in Lima, Peru, the independent correlates of ART nonadherence were examined to inform treatment intervention priorities. Cross sectional survey of HIV-infected MSM and TGW who are engaged in clinical care in Lima, Peru. From June to August 2012, 302 HIV-infected Peruvian MSM/TGW from three clinical care sites were recruited using convenience sampling to participate in a cross-sectional computer-assisted adherence survey. Several standardized screening measures associated with ART nonadherence were examined in order to determine the independent correlates of optimal (≥90%) and perfect (100%) adherence, which were assessed using logistic regression. Of the 302 participants recruited, 263 (87.1%) were prescribed ART. Among those prescribed ART, 229 (87.1%) reported optimal and 146 (55.5%) reported perfect adherence. The prevalence of alcohol use disorders (AUD; 43.2%), alcohol dependence (5.3%), recent drug use (6.0%), and depression (44.5%) was high, and most participants had some evidence of neurocognitive impairment. Meeting criteria for having an AUD and depression were collinear (p < 0.001). On multivariate analysis, having an AUD was inversely related and the only independent correlate of optimal (AOR = 0.427; 95% CI = 0.187-0.976) and perfect (AOR = 0.552; 95% CI = 0.327-0.930) ART adherence. AUDs are highly prevalent among Peruvian HIV-infected MSM and contribute significantly to ART nonadherence. These findings support the need for screening and treating underlying AUDs. In order to meet HIV TasP goals, evidence-based strategies targeting AUDs are likely to directly improve ART adherence and indirectly improve overall individual health, HIV treatment engagement, and reduce transmission to sexual partners among this vulnerable and disproportionally affected population.
    AIDS Care 10/2014; 27(1):1-12. DOI:10.1080/09540121.2014.963013 · 1.60 Impact Factor
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    • "In randomized controlled trials for treating AUDs in HIV uninfected patients, MAT using naltrexone (NTX) has been the most effective treatment (Anton, O'Malley, et al., 2006). A newer, injectable extended release formulation (XR-NTX) has been more recently approved for alcohol dependence (Garbutt, Kranzler, et al., 2005) as well as opioid dependence (Krupitsky, Nunes, et al., 2011) and may have adherence advantages over daily medication self-administration (Garbutt et al., 2005). Though longitudinal cohort data in HIV-infected patients preliminarily suggest it to be safe (Lucey, Silverman, et al., 2008; Sax, Kornetsky, et al., 1994; Yen, Ko, et al., 2006), NTX using either formulation has not been empirically tested solely in HIVinfected patients, many of whom are also co-infected with HCV, and who are simultaneously prescribed antiretroviral therapy (ART). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Extended-release naltrexone (XR-NTX), an approved treatment for opioid or alcohol dependence, is an once-monthly injectable formulation of naltrexone. Hepatotoxicity concerns have limited its use, necessitating further investigation. This study aims to examine hepatic enzyme levels in participants of 2 randomized placebo-controlled trials (RCTs) of XR-NTX. Hepatic transaminases were measured in 85 patients enrolled in RCTs of XR-NTX among HIV-infected prisoners, transitioning to the community and receiving treatment for either dependence on alcohol (52.9%), opioids (44.7%) or both (16.5%). Baseline characteristics included HCV co-infection (55.7%), antiretroviral therapy (81%), mental illness (39%) and receiving psychiatric medications (34.1%). Levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) were not statistically different between persons randomized to placebo (N = 24) and XR-NTX (N = 61) arms. These results confirm XR-NTX is safe to use among opioid and alcohol dependent HIV-infected released prisoners receiving ART with high rates of co-morbid HCV infection and mental illness.
    Journal of substance abuse treatment 07/2014; 47(1). DOI:10.1016/j.jsat.2014.02.008 · 2.90 Impact Factor
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