Antoni Gual

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

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence.

This study evaluated the efficacy of as-needed use of the opioid system modulator nalmefene in reducing alcohol consumption in patients with alcohol dependence. Seven hundred and eighteen patients (placebo=360; nalmefene=358), ≥ 18 years of age, with a diagnosis of alcohol dependence, ≥ 6 heavy drinking days and an average alcohol consumption ≥ WHO medium drinking risk level in the 4 weeks preceding screening, were randomised (1:1) to 24 weeks of as-needed placebo or nalmefene 18 mg/day. The co- primary efficacy analyses showed a significantly superior effect of nalmefene compared to placebo in the change from baseline to month 6 in heavy drinking days (group difference: -1.7 days/month [95% CI -3.1; -0.4]; p=0.012) and a better but not significant effect in reducing total alcohol consumption (group difference: -5.0 g/day last month [95% CI -10.6; 0.7]; p=0.088). A subgroup analysis showed that patients who did not reduce their drinking prior to randomisation benefitted more from nalmefene. Improvements in Clinical Global Impression and reductions in liver enzymes were greater in the nalmefene group than in the placebo group. Adverse events were more common with nalmefene; the incidence of adverse events leading to dropout was similar in both groups. This study provides evidence for the efficacy of nalmefene, which constitutes a new pharmacological treatment paradigm in terms of treatment goal (reduced drinking) and dosing regimen (as-needed), in alcohol dependent patients unable to reduce alcohol consumption on their own.

Efficacy of As-Needed Nalmefene in Alcohol-Dependent Patients with at Least a High Drinking Risk Level: Results from a Subgroup Analysis of Two Randomized Controlled 6-Month Studies

Aims: The aim of the study was to investigate the efficacy and safety of as-needed use of nalmefene 18 mg versus placebo in reducing alcohol consumption in patients who did not reduce their alcohol consumption after an initial assessment, i.e. the pooled subgroup of patients with at least a high drinking risk level (men: >60 g/day; women: >40 g/day) at both screening and randomization from the two randomized controlled 6-month studies ESENSE 1 (NCT00811720) and ESENSE 2 (NCT00812461). Methods: Nalmefene 18 mg and placebo were taken on an as-needed basis. All the patients also received a motivational and adherence-enhancing intervention (BRENDA). The co-primary outcomes were number of heavy drinking days (HDDs) and mean total alcohol consumption (g/day) in Month 6 measured using the Timeline Follow-back method. Additionally, data on clinical improvement, liver function and safety were collected throughout the study. Results: The pooled population consisted of 667 patients: placebo n = 332; nalmefene n = 335. There was a superior effect of nalmefene compared with placebo in reducing the number of HDDs [treatment difference: −3.2 days (95% CI: −4.8; −1.6); P < 0.0001] and total alcohol consumption [treatment difference: −14.3 g/day (−20.8; −7.8); P < 0.0001] at Month 6. Improvements in clinical status and liver parameters were greater in the nalmefene group compared with the placebo group. Adverse events and adverse events leading to dropout were more common with nalmefene than placebo. Conclusion: As-needed nalmefene was efficacious in reducing alcohol consumption in patients with at least a high drinking risk level at both screening and randomization, and the effect in this subgroup was larger than in the total population.

Long-term efficacy, tolerability and safety of nalmefene as-needed in patients with alcohol dependence: A 1-year, randomised controlled study

This study evaluated the long-term efficacy and safety of nalmefene treatment in reducing alcohol consumption. We randomised (1:3) 675 alcohol-dependent patients ≥ 18 years of age to 52 weeks of as-needed treatment with placebo or nalmefene 18 mg/day: A total of 112 patients (68%) in the placebo group and 310 (62%) in the nalmefene group completed the study. At month 6, the co-primary outcome variables showed no statistically-significant differences between the treatment groups; but at month 13, nalmefene was more effective than placebo, both in the reduction of the number of heavy drinking days (HDDs) (− 1.6 days/month (95% CI − 2.9; − 0.3); p = 0.017) and the reduction of total alcohol consumption (TAC) (− 6.5 g/day last month (95% CI − 12.5; − 0.4); p = 0.036). In a subgroup analysis of patients with high/very high drinking risk levels at screening and at randomisation (the target population), there was a significant effect in favour of nalmefene on TAC at month 6, and on both HDD and TAC at month 13. Improvements in Clinical Global Impression and liver enzymes were greater with nalmefene, compared to placebo. Most adverse events were mild or moderate, and transient; adverse events, including those leading to dropout, were more common with nalmefene. This study provides evidence for the long-term safety and efficacy of nalmefene as-needed in alcohol-dependent patients whom continue to drink heavily, following a brief intervention.

Electrophysiological evidence of abnormal activation of the cerebral network of involuntary attention in alcoholism

OBJECTIVE Increased distractibility is a common impairment in alcoholism, but objective evidence has remained elusive. Here, a task designed to investigate with event-related brain potentials (ERPs) the neural mechanism underlying distraction was used to show abnormal involuntary orienting of attention in chronic alcoholism. METHODS Fifteen alcoholics and 17 matched healthy controls were instructed to ignore auditory stimuli while concentrating in the discrimination of immediately following visual stimuli. The auditory sequences contained repetitive standard tones occasionally replaced by deviant tones of slightly higher frequency, or by complex novel sounds. RESULTS Deviant tones and novel sounds distracted visual performance, i.e. increased reaction time to visual stimuli, similarly in patients and controls. Compared to controls, however, alcoholics showed ERP abnormalities, i.e. enhanced P3a amplitudes over the left frontal region, and a positive posterior deflection instead of the frontally distributed reorienting negativity (RON). CONCLUSIONS The enhanced P3a to novelty and subsequent positive wave instead of RON in alcoholics suggests encoding into working memory of task-irrelevant auditory events and provides neurophysiological markers of impaired involuntary attention mechanisms in chronic alcoholism.

Prevalence of and Potential Influencing Factors for Alcohol Dependence in Europe

Alcohol use disorders (AUDs), and alcohol dependence (AD) in particular, are prevalent and associated with a large burden of disability and mortality. The aim of this study was to estimate prevalence of AD in the European Union (EU), Iceland, Norway, and Switzerland for the year 2010, and to investigate potential influencing factors. The 1-year prevalence of AD in the EU was estimated at 3.4% among people 18-64 years of age in Europe (women 1.7%, men 5.2%), resulting in close to 11 million affected people. Taking into account all people of all ages, AD, abuse and harmful use resulted in an estimate of 23 million affected people. Prevalence of AD varied widely between European countries, and was significantly impacted by drinking cultures and social norms. Correlations with level of drinking and other drinking variables and with major known outcomes of heavy drinking, such as liver cirrhosis or injury, were moderate. These results suggest a need to rethink the definition of AUDs.

General Practitioners Recognizing Alcohol Dependence: A Large Cross-Sectional Study in 6 European Countries

PURPOSE Although alcohol dependence causes marked mortality and disease burden in Europe, the treatment rate is low. Primary care could play a key role in reducing alcohol-attributable harm by screening, brief interventions, and initiating or referral to treatment. This study investigates identification of alcohol dependence in European primary care settings. METHODS Assessments from 13,003 general practitioners, and 9,098 interviews (8,476 joint number of interviewed patients with a physician’s assessment) were collected in 6 European countries. Alcohol dependence, comorbidities, and health service utilization were assessed by the general practitioner and independently using the Composite International Diagnostic Interview (CIDI) and other structured interviews. Weighted regression analyses were used to compare the impact of influencing variables on both types of diagnoses. RESULTS The rate of patients being identified as alcohol dependent by the CIDI or a general practitioner was about equally high, but there was not a lot of overlap between cases identified. Alcohol-dependent patients identified by a physician were older, had higher rates of physicial comorbidity (liver disease, hypertension), and were socially more marginalized, whereas average consumption of alcohol and mental comorbidity were equally high in both groups. CONCLUSION General practitioners were able to identify alcohol dependence, but the cases they identified differed from cases identified using the CIDI. The role of the CIDI as the reference standard should be reexamined, as older alcohol-dependent patients with severe comorbidities seemed to be missed in this assessment.

Prevalence and Mechanisms of Hyperhomocysteinemia in Chronic Alcoholics

BACKGROUND Homocysteine (Hcy) is formed as an intermediary in methionine metabolism. Impairment of Hcy remethylation or transulfuration leads to hyperhomocysteinemia, which is considered as a risk factor for atherosclerotic vascular disease and stroke in chronic alcoholics. The aim of the study was to investigate the prevalence of hyperhomocysteinemia in chronic alcoholics and the influence of alcohol consumption, vitamin deficiencies and liver damage on the plasma levels of Hcy. METHODS 228 chronic alcoholic patients consecutively admitted for detoxication, classified according to clinical and biochemical data in normal liver (n = 117), and in mild to moderate liver disease (n = 111), and 49 healthy controls were studied. Blood levels of Hcy, vitamin B6, vitamin B12 and folate were measured. RESULTS Plasma Hcy was significantly higher in chronic alcoholics than in controls (9.66 +/- 8.1 vs. 6.93 +/- 2.33 mumol/liter, p < 0.025). Furthermore, plasma Hcy levels were significantly higher in chronic alcoholics with liver injury (12.17 +/- 10.14 mumol/liter) than in those with normal liver and in controls (p < 0.001). The prevalence of hyperhomocysteinemia was also significantly higher in alcoholics with liver damage than in those with normal liver and in controls (29.7%, 5.1%, and 2%, respectively, p < 0.001). Serum folate values were lower in chronic alcoholics than in controls (4.7 +/- 2.6 vs. 7.6 +/- 2.4 nmol/liter, p < 0.001). The lowest values of folate were found in alcoholics with liver disease, especially in those with hyperhomocysteinemia, with a negative correlation between the two parameters. CONCLUSIONS Moderate hyperhomocysteinemia is common in chronic alcoholics, mainly in those with liver damage, suggesting that, although folate deficiencies may have a contributory role, liver impairment, through changes in methionine metabolism, is the most important mechanism for the elevated plasma Hcy found in these patients.

Reduction of alcohol consumption and subsequent mortality in alcohol use disorders: systematic review and meta-analyses.

OBJECTIVE To determine whether a reduction in drinking in individuals with alcohol use disorders resulted in reduced mortality risk. DATA SOURCES Electronic searches were performed of MEDLINE, EMBASE, and ISI Web of Science and references of identified articles were searched up to May 2012 using these keywords: (alcohol dependence OR alcohol abuse) AND (mortality) AND (cohort OR follow-up). Only English-language articles were included. STUDY SELECTION Sixteen cohort studies were identified that reported all-cause mortality risk by drinking groups measuring change in alcohol intake among people with alcohol use disorders. DATA EXTRACTION Numbers of participants and deaths in each group; odds ratios (ORs); and demographic, clinical, and methodological variables were extracted. RESULTS In comparison to continued heavy drinking, a reduction below heavy levels of alcohol use (including abstention) was associated with a substantially reduced risk of mortality (random-effects pooled OR = 0.41; 95% CI, 0.34-0.50; P < .001). The OR was 0.35 (95% CI, 0.20-0.60; P < .001) for those who reached abstention and 0.61 (95% CI, 0.39-0.94; P = .026) for those who did not reach abstention but substantially reduced their consumption. The pooled OR for abstention compared to reduced consumption was 0.42 (95% CI, 0.19-0.92; P = .031). Meta-regression models did not reveal significant influences of study characteristics examined. CONCLUSIONS Reduction of drinking in alcohol use disorders was associated with a marked reduction in mortality risk for those who reached abstinence or reduced drinking compared to continued heavy drinkers. Those who reached abstention showed the smallest mortality risk, lower than the risk for reduced consumption without abstinence.

Contextual Determinants of Alcohol Consumption Changes and Preventive Alcohol Policies: A 12-Country European Study in Progress

Beginning with France in the 1950s, alcohol consumption has decreased in Southern European countries with few or no preventive alcohol policy measures being implemented, while alcohol consumption has been increasing in Northern European countries where historically more restrictive alcohol control policies were in place, even though more recently they were loosened. At the same time, Central and Eastern Europe have shown an intermediate behavior. We propose that country-specific changes in alcohol consumption between 1960 and are explained by a combination of a number of factors: (1) preventive alcohol policies and (2) social, cultural, economic, and demographic determinants. This article describes the methodology of a research study designed to understand the complex interactions that have occurred throughout Europe over the past five decades. These include changes in alcohol consumption, drinking patterns and alcohol-related harm, and the actual determinants of such changes.