Efficacy of extended-release naltrexone in patients with relatively higher severity of alcohol dependence.
ABSTRACT Because some literature reviews have suggested that naltrexone's benefit may be limited to less-severe alcohol dependence, and exclusively to reduction in heavy drinking rather than abstinence, we examined the efficacy of once per month, injectable extended-release naltrexone (XR-NTX 380 mg) in patients with relatively higher severity alcohol dependence.
Post hoc analyses examined data from a multicenter, placebo-controlled, 24-week randomized trial of XR-NTX for alcohol dependence (N = 624). We analyzed treatment effects in alcohol-dependent patients who had higher baseline severity, as measured by: (i) the Alcohol Dependence Scale (ADS) or (ii) having been medically detoxified in the week before randomization. Efficacy was also examined via the relationship between pretreatment severity indices and reporting at least 4 days of lead-in abstinence prior to treatment-a major predictor of good outcome in the original study.
Higher severity alcohol-dependent patients, defined by the ADS, when receiving XR-NTX 380 mg (n = 50) compared with placebo (n = 47), had significantly fewer heavy-drinking days in-trial (hazard ratio=0.583; p = 0.0049) and showed an average reduction of 37.3% in heavy-drinking days compared with 27.4% for placebo-treated patients (p = 0.039). Among those who had a detoxification just prior to randomization, these reductions were 48.9% (XR-NTX 380 mg; n = 11) and 30.9% (placebo; n = 15) (p = 0.004). Subjects with at least 4 days of pretreatment abstinence (n = 82) versus those without (n = 542) had significantly higher pretreatment ADS scores (p = 0.002) and were more likely to require detoxification prior to randomization (p < 0.001). Patients with lead-in abstinence experienced significantly better maintenance of initial and 6-month abstinence.
These secondary analyses support the efficacy of XR-NTX 380 mg in relatively higher severity alcohol dependence for both reduction in heavy drinking and maintenance of abstinence, with implications for the role of adherence pharmacotherapy.
[Show abstract] [Hide abstract]
ABSTRACT: The results of placebo-controlled trials (RCTs) with acamprosate or naltrexone vary substantially. Those differences have been attributed to differing patient characteristics, recruitment strategies, treatment settings and remuneration systems. We tested these assumptions by comparing a new double-blind, placebo-controlled randomized trial conducted in Germany (called PREDICT Study) with data from the US COMBINE Study. PREDICT was designed according to the protocol of the COMBINE Study. A total of 426 alcohol-dependent patients were compared to 459 COMBINE Study patients corresponding to the treatment cells in PREDICT. All patients received acamprosate, naltrexone or placebo for 3 months (PREDICT) or 4 months (COMBINE). Biweekly manualized 'medical management' to enhance compliance was delivered in both studies. Time until the first occurrence of heavy drinking was the main outcome measure. PREDICT found neither acamprosate nor naltrexone to supply any additional benefit compared with placebo, which is at variance with a positive naltrexone effect being reported in the COMBINE Study. A secondary comparison between both studies showed better overall treatment outcomes in PREDICT, although these patients had been more severely affected than their COMBINE counterparts. The divergence in results may be attributable to basic differences in the treatment environments (such as in-patient pre-treatment versus primary outpatient care). We suggest that identically designed RCTs conducted in different parts of the world may help improve the external validity of RCTs. This approach could be called 'comparative efficacy research'.Addiction Biology 12/2013; 18(6):937-46. DOI:10.1111/adb.12012 · 5.93 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: The goal of this systematic review was to identify moderators of naltrexone efficacy in the treatment of alcohol dependence. We searched Pubmed, CINHAL, Embase, Psycinfo and the Cochrane Library from 1990 to April 2012 and reference lists of pertinent review articles, which yielded 622 trial, pooled analysis, and review articles. Using pre-established eligibility criteria, two reviewers independently determined whether abstracts contained evidence of demographic or biological characteristics, i.e. moderators, influencing naltrexone response in alcohol dependence. We assessed each publication for risk of bias and evaluated the strength of the body of evidence for each moderator. Twenty-eight publications (on 20 studies) met criteria for data synthesis. These included 26 publications from 12 randomized, placebo-controlled trials, 3 non-randomized, non-placebo studies, and 1 randomized, non-placebo study. In addition, there were 2 publications from pooled analyses of 4 randomized, placebo-controlled trials. Family history of alcohol problems and the Asn40Asp polymorphism of the μ-opioid receptor gene showed a positive association with efficacy in four out of five and three out of five studies respectively. Other moderators reported to be associated with efficacy included male sex (2/5 studies), pretreatment drinking (2/2 studies), and high craving (2/5 studies). However, the overall risk of bias in the published literature is high. The identification of naltrexone-responsive alcohol dependent patients is still in development. Studies to date point to two potential moderators-family history and presence of the OPRM1 Asn40Asp polymorphism-as having the strongest evidence. However, the data to date are still insufficient to recommend that any moderator be used in determining clinical treatment.Addiction 03/2014; 109(8). DOI:10.1111/add.12557 · 4.60 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Alcoholic hepatitis is an acute manifestation of alcoholic liver disease with mortality as high as 40-50 % in severe cases. Patients usually have a history of prolonged alcohol abuse with or without a known history of liver disease. Although there is significant range in severity at presentation, patients with severe alcoholic hepatitis typically present with anorexia, fatigue, fever, jaundice, and ascites. The use of either pentoxifylline or corticosteroids in those with severe disease (Maddrey's discriminate function >32) has significant mortality benefit. The addition of N-acetylcysteine to corticosteroids decreases the incidences of hepatorenal syndrome, infection, and short-term mortality, but does not appear to significantly affect 6-month mortality. Nutritional support with high-calorie, high-protein diet is recommended in all patients screening positive for malnutrition. Liver transplantation for a highly selected group of patients with severe alcoholic hepatitis may be an option in the future, but is not currently recommended or available at most transplant institutions.Digestive Diseases and Sciences 05/2014; 59(10). DOI:10.1007/s10620-014-3173-8 · 2.26 Impact Factor