Fabio Caputo

Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study.

BACKGROUND Intervention to achieve alcohol abstinence represents the most effective treatment for alcohol-dependent patients with liver cirrhosis; however, anticraving drugs might worsen liver disease. We aimed to investigate the effectiveness and safety of baclofen in achieving and maintaining alcohol abstinence in patients with liver cirrhosis. METHODS Between October, 2003, and November, 2006, 148 alcohol-dependent patients with liver cirrhosis were referred to the Institute of Internal Medicine, Rome, Italy. 84 were randomly allocated either oral baclofen or placebo for 12 weeks. Primary outcome was proportion of patients achieving and maintaining alcohol abstinence. Measures of this outcome were total alcohol abstinence and cumulative abstinence duration, which were assessed at outpatient visits. Relapse was defined as alcohol intake of more than four drinks per day or overall consumption of 14 or more drinks per week over a period of at least 4 weeks. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00525252. FINDINGS Of 42 patients allocated baclofen, 30 (71%) achieved and maintained abstinence compared with 12 (29%) of 42 assigned placebo (odds ratio 6.3 [95% CI 2.4-16.1]; p=0.0001). The number of dropouts (termination of treatment) did not differ between the baclofen (6/42 [14%]) and placebo (13/42 [31%]) groups (p=0.12). Cumulative abstinence duration was about twofold higher in patients allocated baclofen than in those assigned placebo (mean 62.8 [SE 5.4] vs 30.8 [5.5] days; p=0.001). No hepatic side-effects were recorded. INTERPRETATION Baclofen is effective at promoting alcohol abstinence in alcohol-dependent patients with liver cirrhosis. The drug is well tolerated and could have an important role in treatment of these individuals.

Dose–Response Effect of Baclofen in Reducing Daily Alcohol Intake in Alcohol Dependence: Secondary Analysis of a Randomized, Double-Blind, Placebo-Controlled Trial

AIMS To explore the effect of baclofen in a dose of 20 mg three times per day, compared with the already studied dose of 10 mg three times per day, in the treatment of alcohol dependence. METHODS We present a secondary analysis of a 12-week double-blind, placebo-controlled, randomized clinical trial with two doses of baclofen, specifically 10 mg t.i.d. and 20 mg t.i.d. Out of 94 subjects consecutively screened, 42 were randomized into the study. Fourteen of the 42 patients were randomly allocated to placebo, 14 to the group treated with baclofen 10 mg t.i.d. (B10 mg) and 14 to the group treated with baclofen 20 mg t.i.d. (B20 mg). RESULTS Compared with patients allocated to placebo, patients allocated to the B10 mg group had a 53% reduction in the number of drinks per day (P < 0.0001) and patients allocated to the B20 mg group had a 68% reduction in the number of drinks per day (P < 0.0001), with respect to the number of drinks per day during the 28 days before randomization. The effect of baclofen 20 mg t.i.d. was greater than that of baclofen 10 mg t.i.d. (P = 0.0214, Wald test) showing a dose-effect relationship. Both doses of baclofen were well tolerated. CONCLUSION This is provisional evidence of a dose-response effect for baclofen in the treatment of alcohol dependence.

Review article: alcoholic liver disease – pathophysiological aspects and risk factors

Alcoholic liver disease has a known aetiology but a complex and incompletely known pathogenesis. It is an extremely common disease with significant morbidity and mortality, but the reason why only a relatively small proportion of heavy drinkers progress to advanced disease remains elusive.

Rapid suppression of alcohol withdrawal syndrome by baclofen

Alcohol withdrawal syndrome is a distressing and at times life-threatening condition in alcohol-dependent patients (1). Usually, symptoms develop within 6 –24 hours after the last drink (2). Early symptoms include raised blood pressure and pulse rate, tremor, hyperreflexia, and anxiety with increased irritability. Clinical management is aimed at symptom relief, prevention of seizures and delirium, and a smooth transition to a treatment program to maintain long-term abstinence from alcohol (3). Benzodiazepines are presently the drug of choice (4). We recently found that baclofen, a -aminobutyric acid (GABA)B receptor agonist used to control spasticity (5), reduced voluntary alcohol intake in alcohol-preferring rats (6), as well as alcohol craving and intake, up to complete alcohol abstinence, in alcohol-dependent patients (7). Furthermore, baclofen suppressed the intensity of alcohol withdrawal syndrome in rats who were physically dependent on alcohol (6). We therefore studied the effects of oral administration of baclofen in patients with severe alcohol withdrawal syndrome.

Gamma-hydroxybutyric acid Efficacy, potential abuse, and dependence in the treatment of alcohol addiction

The main objective in alcoholism therapy is to achieve and maintain abstinence and to prevent relapse. Pharmacotherapy may be necessary in treating persons who are not helped by group or psychosocial support alone. Among the substances experimented with in the past few years, gamma-hydroxybutyric acid has been effective in preventing alcohol withdrawal syndrome and in inducing a reduction in craving and an increase in the abstinence rate in treated alcoholics, in view of the alcohol-mimicking effects of the drug on the central nervous system. However, a possible development of craving for the drug and the risk of abuse and physical dependence have been reported in subjects who used gamma-hydroxybutyric acid for different reasons, including alcoholism therapy. The present review updates the existing differences in drug abuse behavior, side effects, and poisoning in the use of gamma-hydroxybutyric acid in a treatment alcoholism program and in self nonclinical illicit use.

Alcohol use disorders in the elderly: A brief overview from epidemiology to treatment options

Alcohol-use-disorders (AUDs) afflict 1-3% of elderly subjects. The CAGE, SMAST-G, and AUDIT are the most common and validated questionnaires used to identify AUDs in the elderly, and some laboratory markers of alcohol abuse (AST, GGT, MCV, and CDT) may also be helpful. In particular, the sensitivity of MCV or GGT in detecting alcohol misuse is higher in older than in younger populations. The incidence of medical and neurological complications during alcohol withdrawal syndrome in elderly alcoholics is higher than in younger alcoholics. Chronic alcohol abuse is associated with tissue damage to several organs. Namely, an increased level of blood pressure is more frequent in the elderly than in younger adults, and a greater vulnerability to the onset of alcoholic liver disease, and an increasing risk of breast cancer in menopausal women have been described. In addition, the prevalence of dementia in elderly alcoholics is almost 5 times higher than in non-alcoholic elderly individuals, approximately 25% of elderly patients with dementia also present AUDs, and almost 20% of individuals aged 65 and over with a diagnosis of depression have a co-occurring AUD. Moreover, prevention of drinking relapse in older alcoholics is, in some cases, better than in younger patients; indeed, more than 20% of treated elderly alcohol-dependent patients remain abstinent after 4 years. Considering that the incidence of AUDs in the elderly is fairly high, and AUDs in the elderly are still underestimated, more studies in the fields of epidemiology, prevention and pharmacological and psychotherapeutic treatment of AUDs in the elderly are warranted.

The therapeutic potential of gamma-hydroxybutyric acid for alcohol dependence: balancing the risks and benefits. A focus on clinical data

There is an increasing interest in studying the role of GABAergic medications in the treatment of alcohol dependence. The GABAergic drug gamma-hydroxybutyric acid (GHB) has been investigated in Europe as a possible treatment for alcohol dependence. In some European Countries, GHB has been approved as a treatment for alcohol dependence. However, this drug has also shown addictive properties, therefore raising questions about its safety in treating alcohol-dependent subjects. More recent research is focusing on the possibility of identifying alcohol-dependent subtypes without risk of developing GHB abuse. Finally, GHB and naltrexone combined together represent a possible approach deserving future investigations.

Gamma hydroxybutyric acid (GHB) for the treatment of alcohol dependence: a review.

Gamma-hydroxybutyric acid (GHB) is a short-chain fatty acid structurally similar to the inhibitory neurotransmitter γ-aminobutyric acid. Clinical trials have demonstrated that 50–100 mg/kg of GHB fractioned into three or six daily doses is able to suppress alcohol withdrawal symptoms and facilitates the maintenance of abstinence from alcohol. These studies have also shown that GHB craving episodes are a very limited phenomenon (about 10–15%). Thus, physicians with access should consider the clinical efficacy of GHB as a valid pharmacological tool for the treatment of alcohol addiction.

Suppression of alcohol Delirium tremens by baclofen administration: A case report

Delirium tremens (DT) is a clinical condition that appears in some patients affected by severe alcohol withdrawal syndrome (AWS). DT represents a serious complication, being characterized by elevated morbidity and mortality. Benzodiazepines are presently the drug of choice; however their use is related to several side effects. Baclofen is a stereoselective &ggr;-aminobutyric acid (GABAB) receptor agonist. Recent studies show that baclofen is able to suppress alcohol withdrawal symptoms. At present there are no data on the effects of baclofen administration in AWS complicated by DT. Here, we report a case of DT successfully treated with baclofen. This result indicates that the efficacy of baclofen in the treatment of DT should be examined in future clinical trials.

γ-Hydroxybutyric acid in the treatment of alcoholism: dosage fractioning utility in non-responder alcoholic patients

Gamma-hydroxybutyric acid (GHB) has recently been introduced in clinical practice for alcoholism management, due to its utility in inducing abstinence from alcohol. In the present study we investigated the usefulness of greater dosage fractioning of GHB in non-responder alcoholics to the usual three administrations per day. A total of 154 alcoholics were admitted to the study and were treated with GHB (50 mg/Kg orally administered three times per day) for 8 weeks (phase 1); the patients who continued to drink alcohol in phase 1 were administered the same dose of GHB divided into six times per day for another 8 weeks (phase 2). Of the 154 patients, 115 completed phase 1; 78 (67.8%) of these began and maintained abstinence (group A) while 37 subjects (32.2%) continued to drink alcohol (group B) showing a craving significantly higher than group A at the end of phase 1 (P < 0.001); in these patients the major fractioning of the drug in phase 2 caused a significant reduction in craving (P < 0.005) and 26 (70.2%) began and maintained abstinence. Moreover no significant differences in final craving score between group A and B was observed. Within the limits of an open study, our data show that non-responder subjects to the conventional fractioning of GHB seem to benefit from the greater fractioning of the drug and seem to indicate the need for a slow-release form of GHB with a prolonged action.