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
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    • "Studies document the efficacy and tolerability of the extended-release formulation in clinical trials (Garbutt et al., 2005; Lapham, Forman, Alexander, Illeperuma, & Bohn, 2009), effectiveness in primary care for treatment of alcohol dependence (Lee, Grossman, DiRocco, et al., 2010) and use with drunken driving offenders (Finigan, Perkins, Zold-Kilbourn, Parks & Stringer, 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Medication Research Partnership (a national health plan and nine addiction treatment centers contracted with the health plan) sought to facilitate the adoption of pharmacotherapy for alcohol and opioid use disorders. Qualitative analysis of interviews with treatment center change leaders, individuals working for the manufacturer and its technical assistance contractor, and health plan managers extracted details on the processes used to order, store, bill for, and administer extended-release naltrexone. Qualitative themes were categorized using domains from the Consolidated Framework for Implementation Research (intervention characteristics, outer setting, inner setting, and provider characteristics). Characteristics of XR-NTX that inhibited use included the complexity of ordering and using the medication; cost was also a barrier. Outer setting barriers reflected patient needs and external health plan policies on formulary coverage, benefit management, and reimbursement. Program structures, the lack of physician linkages, a culture resistant to the use of medication, and unease with change were inner setting elements that limited use of XR-NTX. Patient stereotypes and a lack of knowledge about XR-NTX affected practitioner willingness to treat patients and prescribe XR-NTX. The Consolidated Framework for Implementation Research provided a useful lens to understand and interpret the processes affecting access to XR-NTX.
    Full-text · Article · Nov 2015 · Journal of substance abuse treatment
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    • "Some studies have found high baseline depression to predict better response to NAL (Kiefer et al., 2005), while others have reported the inverse (Morley et al., 2006; Morley, Teesson, Sannibale, Baillie, & Haber, 2010). Finally, among demographic predictors, NAL has been found to be more effective than placebo for men but not women in some studies (Garbutt et al., 2005; Hernandez-avila et al., 2006), but not others (Baros, Latham, & Anton, 2008; Morley et al., 2010). The very mixed picture that emerges regarding predictors of AD and PTSD outcome may be due to variable methodologies and trauma samples across studies, as well as limitations in the statistic approaches employed—which have typically been hierarchical regressions covarying for a small number of putative confounding variables (e.g., baseline severity). "
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    ABSTRACT: Objective: The present study examined predictors and moderators of treatment response among 165 adults meeting Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for comorbid posttraumatic stress disorder (PTSD) and alcohol dependence (AD), who were randomized to 24 weeks of Naltrexone (NAL), NAL and prolonged exposure (PE), pill placebo, or pill placebo and PE. All participants received supportive counseling for alcohol use. Method: Six domains of predictors or moderators (23 variables) were evaluated using measures of PTSD (Posttraumatic Stress Symptom Scale Interview) and AD (days drinking from the timeline follow-back interview) collected every 4 weeks throughout treatment. Multilevel modeling with the Fournier approach was used to evaluate predictors and moderators of rates of symptom improvement and posttreatment outcomes. Results: Combat trauma, sexual assault trauma, and higher baseline anxiety sensitivity predicted slower improvement and poorer PTSD outcome. Combat trauma, White race, and higher baseline drinking severity predicted poorer drinking outcome. PTSD severity moderated the efficacy of PE on PTSD outcomes, such that the benefit of PE over no-PE was greater for participants with higher baseline PTSD severity. Baseline depressive severity moderated the efficacy of PE on drinking outcomes, whereby the benefit of PE over no-PE was greater for participants with higher depressive symptoms. NAL effects were most beneficial for those with the longest duration of AD. Conclusion: These results suggest that concurrent, trauma-focused treatment should be recommended for PTSD-AD patients who present with moderate or severe baseline PTSD and depressive symptoms. Future research should examine the mechanisms underlying poorer outcome among identified subgroups of PTSD-AD patients. (PsycINFO Database Record
    Full-text · Article · Oct 2015 · Journal of Consulting and Clinical Psychology
    • "Interestingly, a gender analysis showed that in the high-dose naltrexone group, only men experienced a decrease in drinking; women in the high-dose group actually reported an increase in drinking. A follow-up analysis of theGarbutt et al. (2005)study revealed additional findings pertaining to the efficacy of the injectable naltrexone (O'Malley et al., 2007). For individuals who reported four days or greater of abstinence prior to treatment, the highdose naltrexone was significantly associated with more patients who sustained complete abstinence for the entirety of the trial compared to placebo. "
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    ABSTRACT: Alcohol use disorders (AUDs) represent a significant health burden worldwide. Currently, there are three medications approved by the U.S. Food and Drug Administration for the treatment of AUDs, and other drugs are being prescribed off-label for this purpose. However, response rates for pharmacologic treatment are low, and extant research suggests that treatment effects may partially depend on genetic factors. Personalized medicine, or using a patient's genetics and/or personal history to determine efficacy of treatment prior to prescription, is an emerging tool that will help clinicians treat their patients more effectively and safely. This review systematically discusses current findings from AUD pharmacotherapy trials examining disulfiram, acamprosate, naltrexone, the injectable naltrexone, and topiramate. Furthermore, it presents pharmacogenetics findings associated with these medications in an attempt to further the field of personalized medicine. Research from trials examining AUDs and comorbid major depressive disorder and anxiety disorders is also presented, and pharmacogenetic findings for these treatments are discussed. Lastly, the authors comment on the present and future states of the field of personalized medicine for AUD.
    No preview · Article · Oct 2015
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