Henri-Jean Aubin

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.

The Economic Burden of Alcohol Dependence in Europe

AIMSnTo determine the economic burden pertaining to alcohol dependence in Europe.nnnMETHODSnDatabase searching was combined with grey literature searching to identify costs and resource use in Europe relating to alcohol dependence as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) or the World Health Organisations International Classification of Diseases (ICD-10). Searches combined MeSH headings for both economic terms and terms pertaining to alcohol dependence. Relevant outcomes included direct healthcare costs and indirect societal costs. Main resource use outcomes included hospitalization and drug costs.nnnRESULTSnCompared with the number of studies of the burden of alcohol use disorders in general, relatively few focussed specifically on alcohol dependence. Twenty-two studies of variable quality were eligible for inclusion. The direct costs of alcohol dependence in Europe were substantial, the treatment costs for a single alcohol-dependent patient lying within the range €1591-€7702 per hospitalization and the annual total direct costs accounting for 0.04-0.31% of an individual countrys gross domestic product (GDP). These costs were driven primarily by hospitalization; in contrast, the annual drug costs for alcohol dependence were low. The indirect costs were more substantial than the direct costs, accounting for up to 0.64% of GDP per country annually. Alcohol dependence may be more costly in terms of health costs per patient than alcohol abuse.nnnCONCLUSIONSnThis review confirms that alcohol dependence represents a significant burden for European healthcare systems and society. Difficulties in comparing across cost-of-illness studies in this disease area, however, prevent specific estimation of the economic burden.

Emerging pharmacotherapies for alcohol dependence: A systematic review focusing on reduction in consumption

BACKGROUNDnEuropean Medicines Agency guidelines recognize two different treatment goals for alcohol dependence: abstinence and reduction in alcohol consumption. All currently approved agents are indicated for abstinence. This systematic review aimed to identify drugs in development for alcohol dependence treatment and to establish, based upon trial design, if any are seeking market authorization for reduction in consumption.nnnMETHODSnWe searched PubMed and Embase (December 2001-November 2011) to identify agents in development for alcohol dependence treatment. Additional studies were identified by searching ClinicalTrials.gov and the R&D Insight and Clinical Trials Insight databases. Studies in which the primary focus was treatment of comorbidity, or n≤20, were excluded. Studies were then classified as abstinence if they: described a detoxification/alcohol withdrawal period; enrolled patients who had undergone detoxification previously; or presented relapse/abstinence rates as the primary outcome. Studies in patients actively drinking at baseline were classified as reduction in consumption.nnnRESULTSnOf 602 abstracts identified, 45 full-text articles were eligible. Five monotherapies were in development for alcohol dependence treatment: topiramate, fluvoxamine, aripiprazole, flupenthixol and nalmefene. Nalmefene was the only agent whose sponsor was clearly seeking definitive approval for reduction in consumption. Development status was unclear for topiramate, fluvoxamine, aripiprazole and flupenthixol. Fifteen agents were examined in published exploratory investigator-initiated trials; the majority focused on abstinence. Ongoing (unpublished) trials tended to focus on reduction in consumption.nnnCONCLUSIONSnWhile published studies generally focused on abstinence, ongoing trials focused on reduction in consumption, suggesting a change in emphasis in the approach to treating alcohol dependence.

Is Baclofen a Revolutionary Medication in Alcohol Addiction Management? Review and Recent Updates

Baclofen, a γ-aminobutyric acid (GABA)-B receptor agonist, represents a promising drug in alcohol addiction management. Animal models have shown its action at various stages of the process of alcohol addiction. Moreover, initial open and randomized controlled trials have shown the efficacy of 30 mg/day baclofen on alcohol craving, intake, and relapse prevention. It may also decrease alcohol withdrawal symptoms. However, these initial studies were conducted by the same Italian team; 2 American studies, using a different methodology, did not confirm these effects. Following recent reports by an alcohol-dependent French physician who treated himself with high doses (120-270 mg/day), claiming prolonged suppression of alcohol craving and absence of dependence symptoms, baclofen has since received wide media exposure in France where it has been called the treatment for alcoholism. An open-label French study supports these findings. In addition, baclofen seems to be particularly interesting because of its safety and tolerance, even in patients with cirrhosis. Thus, baclofen should benefit from further studies of its biobehavioral mechanisms, dose-response effect, and indications in various alcoholic patient profiles.

Altérations cognitives liées au tabac

INTRODUCTIONnTobacco is an important source of somatic diseases and causes high mortality. It is associated with cognitive disorders which tend to maintain addictive mechanisms. In the short term, the nicotine contained in tobacco enhances attention and memory.nnnMETHODnTo realize this review, we made a research, we made a research on Medline, Embase, PsycInfo, Google Scholar using the single or combined key-words tobacco, nicotine, addiction, dependence, cognitive disorders, executive function, memory, attention, neuropsychological. We selected English or French articles from 1987 to 2008 by privileging controlled studies.nnnRESULTSnThis effect can be observed in smokers (with or without withdrawal symptoms), non-smokers and in patients suffering from cognitive disorders. In the long term, tobacco accelerates dementia processes. It is associated with an increased risk of cognitive deterioration. This deterioration concerns mainly memory and processing speed. These results were reported in prospective studies. They contradict early reports, that suggested smoking could actually be protective against certain central neural system disorders. These early results relayed on case-control studies, which were certainly biased by a healthy survival effect. Further studies are required to evaluate nicotines long term effect and its potential efficacy in treating and preventing cognitive disorders or dementia.

Wim van den Brink and colleagues reply to Des Spence and Alain Braillon

Two opinions about nalmefene, a new drug for treating alcohol dependence, were recently published in the BMJ : Des Spence refers to nalmefene as bad medicine and Alain Braillon accuses the European Medicines Agency (EMA) of having performed a junk evaluation of it.1 2 We challenge their arguments.nnSpence incorrectly mentions that nalmefene was added to “extensive counselling,” whereas patients in the study in fact received only short sessions (10-15 minutes) of support to enhance compliance and motivation from their doctors, which is very close to standard clinical management. He then talks about the “dark art of subgroup analysis” but fails to mention that the results from the total group analyses were all very similar to those of the subgroup analyses.3 4 5 Indeed, the subgroup analysis was clearly marked as secondary analyses performed to …

1107 – Esense 1 - randomised controlled 6-month study of as-needed nalmefene: subgroup analysis of alcohol dependent patients with high drinking risk level

Introduction We describe the efficacy and safety of as-needed use of nalmefene in the subgroup of patients with a high drinking risk level (DRL; men:>60g/day; women:>40g/day); i.e. a group of patients with a great unmet medical need for. Objectives To evaluate the 6 month efficacy and safety of as-needed use of nalmefene 18mg versus placebo in a subgroup of alcohol-dependent patients with high DRL from a randomised controlled trial [NCT00812461]. Methods All patients received a motivational and adherence-enhancing intervention (BRENDA) in combination with either nalmefene or placebo. Number of heavy drinking days (HDDs) and total alcohol consumption (TAC) were measured using the Timeline Follow-back method. Additionally, data on clinical improvement, liver function and safety were collected throughout the study. Results The study population consisted of 317 patients: placebo N=162; nalmefene N=155 (mean age 44.8±10.3 years; 69% men; mean HDDs: 22±6.2/month; mean TAC 111±47.9g/day). Mean number of HDDs decreased to 10 days/month and mean TAC decreased to 43g/day at month 6 in the nalmefene group. There was a superior effect of nalmefene compared to placebo in reducing the number of HDDs (-2.7 [95% CI: -5.0;-0.3];p=0.0253) and TAC -10.3 [-20.2;-0.5];p=0.0404). Improvements in clinical status and alanine amino transferase were greater in the nalmefene group compared to the placebo group (p Conclusions As-needed nalmefene was efficacious in reducing alcohol consumption in patients with high risk for alcoholrelated harm.

EPA-0255 – Clinical relevance of as-needed treatment with nalmefene in alcohol dependent patients

Introduction The opioid system modulator nalmefeneis the first pharmacological therapy approved in the European Union for reduction of alcohol consumption. Objectives To evaluate the clinical relevance of the reduction of alcohol consumption in patients with at least high drinking risk level at screening and randomisation from the two, identically designed, randomised controlled 6-month studies ESENSE1 (NCT00811720) and ESENSE2 (NCT00812461) of nalmefene versus placebo. Methods Study medication was taken as-needed. All patients received a motivational and adherence-enhancing intervention (BRENDA). Response criteria were based on alcohol consumption at month 6 and Clinical Global Impression – Severity of Illness/Improvement (CGI-S/I), Short Form Health Survey version 2 (SF-36) mental component summary(MCS) scores at week 24. Clinical relevance was also studied using the Drinker Inventory of Consequences (DrInC), Alcohol Dependence Scale (ADS), and liver function variables. Results Pooled study population: 667 patients (placebo N=332; nalmefene N=335). The proportion of responders was higher in the nalmefene group than in the placebo group with odds ratios for response consistently significantly (p Conclusions In view of the immense alcohol-related burden to society, the harm to the individual and the large treatment gap partly due to a reluctance to engage in abstinence, the effect of nalmefene is clearly clinically relevant.