Extending the Treatment Options in Alcohol Dependence: A Randomized Controlled Study of As-Needed Nalmefene

Central Institute of Mental Health (KM), University of Heidelberg, Mannheim, Germany
Biological psychiatry (Impact Factor: 10.26). 12/2012; 73(8). DOI: 10.1016/j.biopsych.2012.10.020
Source: PubMed


There is a large treatment gap in alcohol dependence, and current treatments are only moderately effective in preventing relapse. New treatment modalities, allowing for reduction of alcohol consumption as a treatment goal are needed. This study evaluated the efficacy of as-needed use of the opioid system modulator nalmefene in reducing alcohol consumption in patients with alcohol dependence.

Six hundred and four patients (placebo = 298; nalmefene = 306),≥18 years of age, with a diagnosis of alcohol dependence,≥6 heavy drinking days, and average alcohol consumption≥World Health Organization medium drinking risk level in the 4 weeks preceding screening, were randomized (1:1) to 24 weeks of as-needed placebo or nalmefene 18 mg.

Patients taking placebo (n = 289) and patients taking nalmefene (n = 290) were included in the efficacy analyses. At Month 6, there was a significant effect of nalmefene compared with placebo in reducing the number of heavy drinking days (-2.3 days [95% confidence interval:-3.8 to-.8]; p = .0021) and total alcohol consumption (-11.0 g/day [95% confidence interval:-16.8 to-5.1]; p = .0003). Improvements in Clinical Global Impression and liver enzymes were larger in the nalmefene group compared with placebo at Week 24. Adverse events (most mild or moderate) and dropouts due to adverse events were more common with nalmefene than placebo. The number of patients with serious adverse events was similar in the two groups.

Nalmefene provides clinical benefit, constitutes a potential new pharmacological treatment paradigm in terms of the treatment goal and dosing regimen, and provides a method to address the unmet medical need in patients with alcohol dependence that need to reduce their alcohol consumption.

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    • " placebo had clinical relevance with respect to mortality , when combined with results from meta - analyses of all relevant clinical studies . In other words : the relative drinking level reductions observed in patients with a high or very high DRL at screening and randomization between compared arms from the nalmefene RCTs ( Gual et al . , 2013 ; Mann et al . , 2013 ; Van den Brink et al . , 2013 , 2014 ) are large enough to expect reduced mortality in the future . The ques - tion is , how the effect size of the present study compares to other effect sizes . First , the effect sizes of pharmacological treatment for alcohol use disorders in general compare favorable to the effects of other treatment"
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    ABSTRACT: Reduction of long-term mortality risk, an important clinical outcome for people in alcohol dependence treatment, can rarely be established in randomized controlled trials (RCTs). We calculated the reduction in all-cause mortality risk using data from short-term (6 and 12 months) double-blind RCTs comparing as-needed nalmefene treatment to placebo, and mortality risks from meta-analyses on all-cause-mortality risk by reduction of drinking in people with alcohol dependence. A reduction in drinking in the RCTs was defined by shifts in drinking risk levels established by the European Medicines Agency. Results showed that the reduction of drinking in the nalmefene group was associated with a reduction in mortality risk by 8% (95% CI: 2%, 13%) when compared to the placebo group. Sensitivity analyses confirmed a significant effect. Thus comparing the difference between nalmefene and placebo in reduction in drinking levels with results on all-cause mortality risk from meta-analyses indicated a clinically relevant reduction in mortality risk. Given the high mortality risk of people with alcohol dependence, abstinence or a reduction in drinking have been shown to reduce mortality risk and should be considered treatment goals.
    Journal of Psychopharmacology 09/2015; DOI:10.1177/0269881115602487 · 3.59 Impact Factor
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    • "In the context of contingency management, financial motivation would be expected to make self-report especially vulnerable to inaccurate under-reporting of drinking. Clinical interventions often rely on self-report measures, but there is a definite move toward and increased reliance upon other alcohol use biomarkers (e.g., Anton et al., 2002; Kranzler et al., 2004; Mann et al., 2013; Pettinati et al., 2010) to objectively detect alcohol use. However, biomarkers can be unreliable indicators of alcohol use. "
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    ABSTRACT: Recently, we demonstrated that transdermal alcohol monitors could be used in a contingency management procedure to reduce problematic drinking; the frequency of self-reported heavy/moderate drinking days decreased and days of no to low drinking increased. These effects persisted for three months after intervention. In the current report, we used the transdermal alcohol concentration (TAC) data collected prior to and during the contingency management procedure to provide a detailed characterization of objectively measured alcohol use. Drinkers (n=80) who frequently engaged in risky drinking behaviors were recruited and participated in three study phases: a 4-week Observation phase where participants drank as usual; a 12-week Contingency Management phase where participants received $50 each week when TAC did not exceed 0.03g/dl; and a 3-month Follow-up phase where self-reported alcohol consumption was monitored. Transdermal monitors were worn during the first two phases, where each week they recived $105 for visiting the clinic and wearing the monitor. Outcomes focused on using TAC data to objectively characterize drinking and were used to classify drinking levels as either no, low, moderate, or heavy drinking as a function of weeks and day of week. Compared to the Observation phase, TAC data indicated that episodes of heavy drinking days during the Contingency Management phase were reduced and episodes of no drinking and low to moderate drinking increased. These results lend further support for linking transdermal alcohol monitoring with contingency management interventions. Collectively, studies to date indicate that interventions like these may be useful for both abstinence and moderation-based programs. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Drug and Alcohol Dependence 04/2015; 149. DOI:10.1016/j.drugalcdep.2014.12.021 · 3.42 Impact Factor
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    • "Several studies have reported a high degree of individual variability in treatment response to naltrexone, which has been theorized to contribute to naltrexone's modest efficacy in treating alcohol use disorders (Kranzler and Van Kirk, 2001; Ray et al., 2010; Rosner et al., 2010; Streeton and Whelan, 2001). As other opioid receptor antagonists are also effective in the treatment of alcohol use disorders (e.g., nalmefene; Mann et al., 2013) and are commonly used as probes of hormonal function (e.g., naloxone), understanding factors that contribute to individual differences in response to opioid receptor antagonists is a priority. While most studies of individual differences have focused on examining how genetic variability may contribute to opioid receptor antagonist responsivity (Chamorro et al., 2012; Ray et al., 2010), sex differences in response to opioid receptor antagonists have also been reported, with women demonstrating greater cortisol and prolactin responses, more adverse subjective effects, and better treatment outcomes than men (al'Absi et al., 2004; Epperson et al., 2010; Epstein and King, 2004; King et al., 2013; Lovallo et al., 2012b; Roche et al., 2010). "
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    ABSTRACT: Women often exhibit larger hormonal and subjective responses to opioid receptor antagonists than men, but the biological mechanisms mediating this effect remain unclear. Among women, fluctuations in estradiol (E2) and progesterone (P4) across the menstrual cycle (MC) affect the endogenous opioid system. Therefore, the goal of the current study was to compare acute naltrexone response between women in the early follicular phase of the MC (low E2 and P4), women in the luteal phase of the MC (high E2 and P4), and men. Seventy healthy controls (n=46 women) participated in two morning sessions in which they received 50mg naltrexone or placebo in a randomized, counterbalanced order. Women were randomized to complete both sessions in either the early follicular (n=23) or luteal phase of the MC. Serum cortisol, salivary cortisol, prolactin, luteinizing hormone (LH), and subjective response were assessed upon arrival to the laboratory and at regular intervals after pill administration. In luteal and early follicular women but not men, naltrexone (vs. placebo) increased serum cortisol and prolactin levels from baseline; however, the naltrexone-induced increases in these hormones were significantly greater in luteal women than early follicular women. Additionally, only luteal women demonstrated an increase from baseline in salivary cortisol levels and the severity of adverse drug effects in response to naltrexone. In sum, the results indicate that luteal phase women are more sensitive to acute hormonal and subjective effects of naltrexone than early follicular women and men. These findings may have important implications for the use of naltrexone in women. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Psychoneuroendocrinology 10/2014; 52. DOI:10.1016/j.psyneuen.2014.10.013 · 4.94 Impact Factor
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