Clinical pharmacokinetics of acamprosate

Acamprosate is a new psychotropic drug used in the treatment of alcohol (ethanol)-dependence. Recent studies suggest that acamprosate inhibits neuronal hyperexcitability by antagonising excitatory amino acids. It is available as a 333 mg enteric-coated tablet, with a recommended dosage of 1.3 g/day for patients with a bodyweight < 60 kg and 2 g/day for patients with a bodyweight > or = 60 kg. Treatment with higher dose strength tablets 2 x 500 mg twice daily is bioequivalent to treatment with the 2 x 333 mg 3 times daily dosage regimen. Acamprosate is absorbed via the paracellular route in the gastrointestinal tract. Absorption is rapid but limited after oral administration. At steady-state, acamprosate has a moderate distribution volume of about 20L. Acamprosate is not protein bound or metabolised. Half of the elimination of acamprosate occurs as unchanged acetyl-homotaurine in urine, the other half might be eliminated by biliary excretion. The administration of the enteric-coated tablets showed a flip-flop mechanism with a terminal elimination half-life 10-fold higher than the 3-hour half-life reported after intravenous infusion. During repeated oral administration of 666 mg 3 times daily, steady-state is reached after 5 to 7 days and leads to plasma concentrations ranging from 370 to 650 micrograms/L. The pharmacokinetics of acamprosate administered as an enteric-coated tablets are time- and dose-independent, and its accumulation ratio is about 2.4 at steady-state. Acamprosate disposition does not differ between males and females. The pharmacokinetics of acamprosate are not modified in patients with hepatic insufficiency or chronic alcoholism. In contrast, renal insufficiency influences the elimination of acamprosate and it is, therefore, contraindicated under such circumstances. Interaction studies have confirmed that when acamprosate is concomitantly administered with food, the amount absorbed is decreased. When combined with diazepam, disulfiram or alcohol, the pharmacokinetic disposition of acamprosate is not modified. Acamprosate does not influence the kinetics of diazepam, alcohol or imipramine and its metabolite desipramine.     

Acamprosate and alcohol: I. Effects on alcohol intake following alcohol deprivation in the rat

Acamprosate (calcium-acetyl homotaurinate) is a new compound in the treatment of alcoholism. Its efficacy has been proven in several clinical trials and registration is now pending in most European countries. The basic mechanisms by which acamprosate elicits its anti-craving action, thereby leading to reduced relapse rates, is not known at the moment. In the present study we describe a rat model of long-term alcohol-drinking which mimics relapse behavior in human alcoholics. The effect of acamprosate was studied in this model. Wistar rats had a free choice between water and alcohol solutions of different concentrations (5, 10, 20% v/v). After two months of continuous alcohol access, rats were deprived of alcohol for three days. Following this deprivation phase, all alcohol solutions were presented again. This procedure was repeated monthly for the following six months. The rats consumed 3.5 +/- 0.3 g/kg alcohol a day. After alcohol deprivation, alcohol intake rose to 5.2 +/- 0.3 g/kg per day resulting in blood alcohol levels of 30 +/- 6 mg/dl. Interestingly, the addition of quinine to the alcohol solutions or the additional presentation of a 5% sucrose solution did not affect the alcohol-deprivation effect after eight months of this intermittent alcohol exposure. However, when acamprosate (50-200 mg/kg i.p.) was administered twice daily, alcohol-drinking following an alcohol-deprivation phase was decreased dose dependently. Given at the highest dose alcohol intake even dropped significantly below baseline drinking. Together, these results show that acamprosate effectively diminishes the alcohol-deprivation effect. Furthermore, the described model seems to be a suitable animal model to screen compounds for their anti-relapse properties and subsequently for their anti-craving action.     

Bridging the gap between alcoholism treatment research and practice: Identifying what works and why.

Despite the proliferation of alcoholism treatment research over the past 2 decades, there is a continued gap between what has been shown to be promising in the extant literature and what is commonly practiced by clinicians in the alcohol treatment field. The present article is an effort to bridge this gap by examining findings from the broad body of alcoholism treatment outcome research to determine how these findings may optimally be used by treatment providers. To this end, the authors provide clinicians with a succinct review of the current alcoholism treatment outcome literature and identify hallmarks of the most empirically supported treatments. Clinical implications of this literature for practitioners working with client with alcohol use disorders are discussed, with a focus on factors underlying effective treatments and on how these factors can be transferred from research to practice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Recent developments in the pharmacotherapy of alcohol dependence.

The effectiveness of a treatment for alcohol dependence can be appropriately determined only after controlling for the usual clinical course of alcoholism, subgroups of alcohol-dependent individuals, and placebo effects. The results of appropriate treatment trials must also be interpreted in light of the side effects and costs, and there must be assurances that the overall improvement in functioning observed with the drug is significant enough to outweigh the liabilities. In addition, medications are almost always used in combination with education, counseling, and behavioral therapies, and the impact of these additional treatments must be considered. Viewed from this perspective, 3 medications are quite promising regarding their potential future impact in the alcohol field, including naltrexone, the medication with the most available data in the United States. There are additional data regarding buspirone and acamprosate. Intriguing results have also been generated regarding medications that affect serotonin and dopamine brain activity and with alcohol-sensitizing drugs such as disulfiram. However, none of these medications has been proven to be clinically effective in the routine treatment of the average alcoholic… (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acamprosate. A review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification

Acamprosate (calcium acetylhomotaurinate), a synthetic compound with a similar chemical structure to that of gamma-aminobutyric acid, is thought to act via several mechanisms affecting multiple neurotransmitter systems; inhibition of neuronal hyperexcitability by antagonism of excitatory amino acid activity and reduction of calcium ion fluxes has been suggested as its predominant mechanism of action. The drug is the first agent specifically designed to maintain abstinence in alcohol (ethanol)-dependent patients after detoxification. Voluntary oral ethanol consumption in ethanol-preferring or ethanol-dependent rats is dose-dependently reduced by acamprosate: total fluid intake and food consumption are not affected. The drug does not potentiate the acute or chronic toxic effects of ethanol and has no hypnotic, antidepressant, anxiolytic or muscle-relaxant effects in animals. There is no evidence of abuse potential with acamprosate. Oral acamprosate 1.3 or 2 g/day in 3 divided doses administered for 3 to 12 months to alcohol-dependent patients after detoxification was more effective than placebo in preventing alcohol relapse according to abstinence rates, duration of abstinence, gamma-glutamyl transferase levels and/or a variety of other clinical or biological end-points. Concomitant psychosocial/behavioural therapies were used in some trials. Compared with those with placebo, the superior abstinence rates and durations of abstinence with acamprosate were maintained during 6- to 12-month post-treatment follow-up periods, and greater abstinence rates with acamprosate were confirmed in a pooled analysis of data from 11 randomised placebo-controlled trials involving a total of 3338 patients with alcohol dependence. The efficacy of acamprosate appears to be dose dependent and enhanced by the addition of disulfiram. Acamprosate was generally well tolerated in placebo-controlled trials. The most common adverse events were gastrointestinal (especially diarrhoea) or dermatological and were mostly mild and transient. The percentage of patient withdrawals because of adverse events was similar in acamprosate and placebo groups. No trials have compared the efficacy or tolerability of acamprosate with those of other treatment approaches (including opiate antagonists or selective serotonin reuptake inhibitors) aimed at maintaining abstinence in detoxified alcohol-dependent patients. Thus, acamprosate, as an adjunct to psychosocial/behavioural therapies, represents a novel advance for the management of alcohol-dependent patients in the postdetoxification period. Longer term and comparative trials with other active therapies are required to confirm these promising results.     

Review of From denial to recovery: Counseling problem drinkers, alcoholics, and their families.

Reviews the book, From denial to recovery: Counseling problem drinkers, alcoholics, and their families by Lawrence Metzger (see record 1987-98723-000). This book admirably complies with the author's stated reason for writing it: "A compelling reason for writing this book is to aid care givers who may have avoided or been baffled by alcoholic clients in the past. Their lack of training and expertise in dealing with this problem has meant that alcoholics and their family members...have been neglected to the point where the problem simply becomes self-perpetuating and expands generationally." To this end, this book can serve as an excellent introduction to the field of alcoholism treatment for practitioners trained in the behavioral sciences. Unlike many works in the alcoholism literature, this book is properly annotated and, to a large degree, research based. As such, it will appeal to practitioners with a scientific background. The author proceeds to give an excellent overview of the current state of the art in alcoholism treatment. None of the particular criticisms noted should detract from these general observations. Overall, the major strength of this work is its explication of the details of alcoholism treatment in a format which will be palatable to students of the behavioral sciences. It would be an excellent addition to courses on addictions treatment. The most specific strengths of this work are in the diagnostic formulation for differentiating levels of alcohol abuse and the explication of a very thorough alcoholism diagnostic interview. In my view, if the reader can remember that (a) alcoholism is not caused by bad genes, (b) patients who have blackouts must abstain from alcohol, and (c) the self-help movements are the primary treatment modalities for addictions, then this work will be an excellent addition to any library on alcoholism. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Improved autonomic neurocardial balance in short-term abstinent alcoholics treated with acamprosate

Standardized investigations on resting heart rate variability (HRV) should provide more information on acamprosate's human pharmacodynamic properties because acamprosate interacts with several neurotransmitter systems which are also involved in maintaining autonomic neurocardiac balance. We performed HRV measurements prospectively in 69 healthy controls and 19 chronic alcoholics to prove the hypotheses that: (1) compared to healthy controls, chronic alcoholics show disturbances in neurocardiac vagal function; and (2) in alcoholics, acamprosate treatment (6-8 days) should further decrease parasympathetic activity if acamprosate interacts with central gamma-aminobutyric acidA receptors in vivo. Cardiovagal dysfunction was initially present in 21% of the alcoholics. After treatment. however, their neurocardiac sympathetic-parasympathetic balance improved significantly.     

Co-morbidity and familial aggregation of alcoholism and anxiety disorders

BACKGROUND: This study examined the patterns of familial aggregation and co-morbidity of alcoholism and anxiety disorders in the relatives of 165 probands selected for alcoholism and/or anxiety disorders compared to those of 61 unaffected controls. METHODS: Probands were either selected from treatment settings or at random from the community. DSM-III-R diagnoses were obtained for all probands and their 1053 first-degree relatives, based on direct interview or family history information. RESULTS: The findings indicate that: (1) alcoholism was associated with anxiety disorders in the relatives, particularly among females; (2) both alcoholism and anxiety disorders were highly familial; (3) the familial aggregation of alcoholism was attributable to alcohol dependence rather than to alcohol abuse, particularly among male relatives; and (4) the the pattern of co-aggregation of alcohol dependence and anxiety disorders in families differed according to the subtype of anxiety disorder; there was evidence of a partly shared diathesis underlying panic and alcoholism, whereas social phobia and alcoholism tended to aggregate independently. CONCLUSIONS: The finding that the onset of social phobia tended to precede that of alcoholism, when taken together with the independence of familial aggregation of social phobia and alcoholism support a self-medication hypothesis as the explanation for the co-occurrence of social phobia and alcoholism. In contrast, the lack of a systematic pattern in the order of onset of panic and alcoholism among subjects with both disorders as well as evidence for shared underlying familial risk factors suggests that co-morbidity between panic disorder and alcoholism is not a consequence of self-medication of panic symptoms. The results of this study emphasize the importance of examining co-morbid disorders and subtypes thereof in identifying sources of heterogeneity in the pathogenesis of alcoholism.     

The cultural context of psychological approaches to alcoholism: Can we control the effects of alcohol?

Argues that the unique history of alcohol use in the US has led to the ascendance of disease theory as the dominant conception of alcoholism. Social-scientific research has consistently conflicted with disease theory, but psychological and other nondisease conceptions of alcoholism are not well-represented in the public consciousness, in treatment programs, or in policies for affecting nationwide drinking practices. Conflict in the field has intensified in the last decade, most notably surrounding the issue of controlled drinking in alcoholism treatment. It is suggested that the current cultural attitude toward alcoholism in the US, one strongly influenced by disease notions, has not led to an improvement in society's drinking problems and that there continues to be a need for psychologists to present alternative views of alcoholism. The concepts of dependence and addiction as related to alcohol and to drugs are discussed. (3 p ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Alcohol abuse in individuals exposed to trauma: A critical review.

In this article, the author critically reviews studies on the relationship between exposure to trauma, posttraumatic stress disorder (PTSD), and alcohol abuse. After establishing that strong relationships exist between exposure to traumatic events and alcohol problems, and particularly between the diagnoses of PTSD and alcoholism, the author discusses various factors, theories, and possible mechanisms to account for these associations. Moreover, she discusses applications of these findings to the assessment and treatment of people exposed to trauma who abuse alcohol. Finally, the author outlines novel methods for testing theoretical hypotheses and makes suggestions for methodological improvements in future research. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Alcohol and tension reduction: cognitive and physiological effects

Previous research indicates that the tension reduction hypothesis of alcoholism has received little empirical support. There is also evidence that cognitive and social variables mediate the effects of alcohol. The present investigation with 40 male undergraduates examined separately the cognitive and pharmacological effects of alcohol by manipulating Ss' expectancies. It was found that although alcohol is a pharmacologic sedative and reduces anxiety, the cognition that one is drinking alcohol increases anxiety. (15 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Self-efficacy change as a mediator of associations between therapeutic bond and one-year outcomes in treatments for alcohol dependence.

Empirically-supported treatments for alcohol dependence exist, yet understanding of influences contributing to the intended behavior change is limited. The current study, a secondary analysis of the recent multisite COMBINE trial (The COMBINE Study Research Group, 2003), tested a mediational model wherein change in client self-efficacy for abstinence was examined as a potential mediator of associations between client report of the therapeutic bond and one-year outcomes of drinking frequency, drinking consequences, and psychiatric functioning. For analyses, the 1383 COMBINE trial participants were grouped as follows: 1) those receiving study medications (naltrexone, acamprosate, naltrexone + acamprosate, placebo) and enrolled in medication management (MM) only (n = 607), 2) those receiving study medications/MM and also enrolled in a combination behavioral intervention (CBI) as well (n = 619), and 3) those enrolled in CBI only (n = 157). Mediation analyses using the product-of-coefficients approach indicated self-efficacy change during treatment significantly mediated associations between the therapeutic bond with the CBI therapist and each of the three one-year outcomes among those exclusively receiving CBI, but failed to do so among those receiving pills/MM (with or without CBI). Effect sizes were small, but indicated that variance in bond-outcome associations was partially mediated by self-efficacy change for trial participants. Findings advance understanding of proximal client change processes during delivery of treatments for alcohol dependence. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Matching treatment to alcoholism subtypes.

In the field of alcoholism treatment, as in mental health treatment more generally, no one treatment model is equally effective for all patients and problem types. Literature in both alcohol treatment and in psychotherapy research suggests some relationships in common between treatment efficacy and patient coping style, drinking patterns, and family dynamics. This literature suggests that "internalizing" alcoholics, whose drinking tends to be steady and to be functionally interwoven with family dynamics, will benefit more from family systems oriented treatments than from symptom- or individually focused treatments. Conversely, "externalizing" alcoholics may derive more benefit from symptom-focused cognitive and behavioral treatments than from family systems treatment. An ongoing research project designed to test these hypotheses and the development of treatment manuals that may increase differential treatment efficacy is described. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fluoxetine in depressed alcoholics. A double-blind, placebo-controlled trial

BACKGROUND: The selective serotonergic medication fluoxetine has demonstrated efficacy in the treatment of major depression and has suggested efficacy in the treatment of alcoholism. However, no completed trials with any selective serotonergic medication have been reported in patients who display both major depression and alcoholism, despite previous observations that both depression and alcoholism are associated with low serotonergic functioning. METHODS: Fifty-one patients diagnosed as having comorbid major depressive disorder and alcohol dependence were randomized to receive fluoxetine (n = 25) or placebo (n = 26) in a 12-week, double-blind, parallel-group trial. Weekly ratings of depression and alcohol consumption were obtained throughout the 12-week course of the study. RESULTS: The improvement in depressive symptoms during the medication trial was significantly greater in the fluoxetine group than in the placebo group. Total alcohol consumption during the trial was significantly lower in the fluoxetine group than in the placebo group. CONCLUSIONS: Fluoxetine is effective in reducing the depressive symptoms and the alcohol consumption of patients with comorbid major depressive disorder and alcohol dependence. It is unknown whether these results generalize to the treatment of less depressed and less suicidal alcoholics.     

Contributions of behavioral science to alcohol research: Understanding who is at risk and why.

Behavioral science has been an active participant in alcohol research progress over the past 30 years, particularly in the areas of prevention and treatment methodology. However, alcoholism results from the interaction between complex biological and behavioral systems, and in recent years, combined behavioral and biological studies, primarily of alcohol effects on the brain and of the genetics of alcoholism, have begun the much more complex process of elucidating the links between biology and specific alcohol use behaviors. It is this combined research that ultimately will produce the pharmacological and behavioral interventions that will improve the efficiency and effectiveness of alcohol prevention and treatment methods. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prospective relations between growth in drinking and familial stressors across adolescence.

Although there is much empirical support for the relation between stress and alcohol consumption in adolescence, it is unclear whether exposure to stressors is associated with overall trajectories or temporary elevations in drinking. Moreover, little research has explored whether the stress–alcohol use association in adolescence may be explained by shared risk factors that produce both individual differences in stress exposure and elevated risk for alcohol use. The present study tested these hypotheses within the context of a state-trait model of family stressors in a prospectively studied sample of children at high risk for alcoholism: children of alcoholic parents and matched controls (n = 451). Levels and growth in alcohol use were modeled longitudinally from ages 13 to 17. Results indicated that shared risk factors accounted for 53% of the impact of trait family stressors on growth in adolescent drinking, but time-specific exposure to familial stressors still predicted short-term boosts in alcohol use in adolescence. These findings imply that trait familial stressors mark adolescents at risk for alcohol use and also impact adolescent alcohol use within a short time frame (i.e., over 1 year vs. over many years) when they occur above and beyond the adolescent’s “usual load” of stressors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Review of Neuropsychology of alcoholism: Implications for diagnosis and treatment.

Reviews the book, Neuropsychology of alcoholism: Implications for diagnosis and treatment edited by Oscar A. Parsons, Nelson Butters, and Peter E. Nathan (see record 1987-98184-000). This book is an important work because it organizes empirical findings and presents theoretical and research issues in the rapidly expanding area of neuropsychological evaluation and recovery in alcoholic populations. This up-to-date, comprehensive overview includes chapters written by internationally recognized experts in the areas of structural changes in the brain accompanying alcohol abuse, neuropsychological deficits associated with alcoholism, recovery of functions with continued abstinence, and remediation efforts with alcoholics. The book is divided into four sections: Changes in Brain Structure and Function in Alcoholics, Neuropsychological Consequences of Alcohol Abuse, Recovery and Remediation of Neuropsychological Functions, and Implications for Treatment and Future Research Directions. Overall, this is an excellent reference book and is thought-provoking in its presentation of research ideas. This is an important work every researcher in this area should examine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Outcomes of treatment for alcohol problems: Current methods, problems, and results.

This overview of current methods, problems, and results of psychological treatment for alcohol abuse, including alcoholism, begins by considering three common and troublesome assumptions about such treatment. A discussion of external and internal validity problems that are specific to alcoholism treatment research follows, and promising solutions are reviewed. Current data are discussed on who is treated for alcohol problems in this country. Next, detailed consideration is given to factors that predict response to alcoholism treatment, including variables associated with treatment type, setting, and intensity; such factors specific to patients as age, gender, ethnicity, socioeconomic status and education, psychopathology, marital and occupational status, and motivation for change; and environmental and other extratreatment factors. The article concludes with a review of current data on nonproblem-drinking treatment goals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Computed tomography in the diagnosis of buccal space masses

BACKGROUND: Despite ongoing intensive research using sophisticated new molecular tools and methods, the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA) is still not completely understood. HYPOTHESES: In this paper the two favorite hypotheses of the pathogenesis of rheumatoid arthritis currently discussed are introduced and compared. Hypothesis 1 is focussing on the central role of the T cells and T cell dependent phenomena in the pathogenetic scenario of RA. In contrast, hypothesis 2 stresses the role of altered synovial fibroblasts and their specific features critical for the destruction of inflamed joints. Both hypotheses are thoroughly discussed and suggestions for further research activities are made. CONCLUSION: Insights in the pathogenesis of RA provide options to develop new therapeutic strategies aimed at the inhibition of pathogenetic relevant processes.     

Alcoholism and alcohol abuse among women: report of the Council on Scientific Affairs. American Medical Association

We describe characteristics of women alcohol abusers, risk factors for alcoholism in women, barriers to treatment, and implications and strategies for physicians dealing with alcohol abuse in women patients, including risk assessments and intervention strategies. Alcohol abuse and alcoholism have a different physiologic effect on women than on men. Societal attitudes about women and alcohol and internal (self-perception) and external (environmental) factors can create barriers to the detection and treatment of female alcohol abusers. Physicians are in an excellent position to address the medical, psychologic, and social concomitants of alcoholism and alcohol abuse. The Council on Scientific Affairs recommends that physicians become more active in the prevention, diagnosis, and treatment of alcohol-related problems in women, including the diseases that may be associated with chronic alcohol abuse and the effect of alcohol on the developing fetus. Specific American Medical Association policy and recommendations for physician practice are included.