Advances in development of medications for alcoholism treatment

Litten, Raye Z.; Allen, John P.

doi:10.1007/s002130050686

Cited by 67 publications

(39 citation statements)

References 55 publications

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“…Perhaps because of this small effect size, some studies have failed to demonstrate naltrexone's efficacy in treating alcohol dependence. For instance, in the UK collaborative trial led by Chick et al, no overall difference was found between the naltrexone 50 mg/day and placebo groups on any of the endpoint measures; however, when individuals with less than 80% pill-taking compliance were excluded from the analysis, naltrexone was associated with a lower percentage of days drinking compared with placebo -12% vs. 20%, respectively [59,60]. With naltrexone treatment, reduced pill-taking compliance is typically the result of adverse events such as nausea that can be reported as significant in up to 15% of trial participants [61].…”

Section: Clinical Studies With Oral Naltrexonementioning

confidence: 98%

Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings

Johnson

2008

Biochemical Pharmacology

237

185

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The past decade has seen an expansion of research and knowledge on pharmacotherapy for the treatment of alcohol dependence. The Food and Drug Administration (FDA)-approved medications naltrexone and acamprosate have shown mixed results in clinical trials. Oral naltrexone and naltrexone depot formulations have generally demonstrated efficacy at treating alcohol dependence, but their treatment effect size is small, and more research is needed to compare the effects of different doses on drinking outcome. Acamprosate has demonstrated efficacy for treating alcohol dependence in European trials, but with a small effect size. In U.S. trials, acamprosate has not proved to be efficacious. Research continues to explore which types of alcohol-dependent individual would benefit the most from treatment with naltrexone or acamprosate. The combination of the two medications demonstrated efficacy for treating alcohol dependence in one European study but not in a multi-site U.S. study. Another FDA-approved medication, disulfiram, is an aversive agent that does not diminish craving for alcohol. Disulfiram is most effective when given to those who are highly compliant or who are receiving their medication under supervision. Of the non-approved medications, topiramate is among the most promising, with a medium effect size in clinical trials. Another promising medication, baclofen, has shown efficacy in small trials. Serotonergic agents such as selective serotonin reuptake inhibitors and the serotonin-3 receptor antagonist, ondansetron, appear to be efficacious only among certain genetic subtypes of alcoholic. As neuroscientific research progresses, other promising medications, as well as medication combinations, for treating alcohol dependence continue to be explored.

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Section: Clinical Studies With Oral Naltrexonementioning

confidence: 98%

Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings

Johnson

2008

Biochemical Pharmacology

237

185

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“…Opiate antagonists (Heinälä et al 2001;Litten and Allen 1998;O'Malley et al 1992;Monti et al 2001;Rubio et al 2001;Volpicelli et al 1992), acamprosate (Ansoms et al 2000;Besson et al 1998;Chick et al 2000;Lesch et al 2001;Rubio et al 2001;Sass et al 1996;Tempesta et al 2000;Litten and Allen 1998; see overview by Mason 2001) or a combination of these drugs (Kranzler and Van Kirk 2001) are currently prescribed to reduce alcohol consumption in alcoholics. In preclinical studies, opiate antagonists are capable of minimizing acute drinking of alcohol (Altshuler et al 1980;Badia-Elder et al 1999;Froehlich et al 1990;Heyser et al 2003;Hölter and Spanagel 1999;Hyytia and Sinclair 1993;Overstreet et al 1999;Samson and Doyle 1985), as well as reducing alcohol seeking by an alcohol conditioned stimulus (Liu and Weiss 2002a;Koob et al 2003).…”

Section: Future Directionsmentioning

confidence: 99%

Conceptual framework for the etiology of alcoholism: a ?kindling?/stress hypothesis

2004

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Rationale-The rationale for proposing the "kindling"/stress hypothesis is to provide a conceptual basis for the insidious development and maintenance of alcohol abuse.Objective and results-An objective of the hypothesis is to emphasize how continued alcohol abuse is linked to progressive neural adaptation. Work has shown that repeated withdrawals from chronic low levels of alcohol sensitize ("kindle") anxiety-like behavior ("anxiety") in rats, a finding consistent with multiple withdrawal kindling of seizure activity. Additionally, stress substitutes for initial cycles of the multiple withdrawal protocol to sensitize withdrawal-induced anxiety, which is indicative that stress is capable of facilitating neuroadaptive processes related to withdrawal. The persistence of adaptation caused by stress and multiple withdrawals is revealed by the appearance of withdrawal-induced anxiety following a future re-exposure to a single 5-day period of alcohol. This persisting adaptation also permits stress to induce anxiety during a period of abstinence-a response not observed in animals without previous exposure to alcohol. Furthermore, stress interacts with repeated withdrawals to enhance voluntary alcohol drinking. Results of other preclinical and clinical studies reported in the literature are integrated with these investigations in support of the proposed hypothesis.Conclusions-The "kindling"/stress hypothesis is based on the premise that repeated withdrawals from cycles of chronic alcohol exposure contribute to a progressive development of persisting adaptive change that sensitizes withdrawal-induced anxiety and allows stress to evoke symptoms associated with negative affect during abstinence. Thus, these consequences of repeated withdrawals account for the evolution of major characteristics of alcoholism, which include worsened acute withdrawal symptoms and increased stress-induced negative affect during abstinence, both of which enhance the likelihood of relapse-and with relapse an inability to limit an abusive pattern of alcohol intake. The "kindling"/stress hypothesis provides a clear strategy for future studies to explore the advancing neural adaptation proposed to contribute to the pathogenesis of alcoholism.

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“…Acamprosate and naltrexone have each demonstrated efficacy and safety in randomized, double-blind, placebo-controlled trials in alcohol-dependent outpatient volunteers (Garbutt et al 1999;Litten and Allen 1998;Mason 2001;Mason and Ownby 2000;Swift 1999). Neither medication interacts with alcohol or has abuse potential or rebound effects when discontinued.…”

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confidence: 99%

A Pharmacokinetic and Pharmacodynamic Drug Interaction Study of Acamprosate and Naltrexone

Mason

2002

Neuropsychopharmacology

105

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Recent efforts to develop pharmacological interventions for relapse-prevention in newly abstinent alcoholics initially focused on acamprosate (Campral ®, Aotal ®) in Europe and naltrexone (ReVia ®) in the United States of America. Acamprosate and naltrexone have each demonstrated efficacy and safety in randomized, double-blind, placebo-controlled trials in alcohol-dependent outpatient volunteers (Garbutt et al. 1999;Litten and Allen 1998;Mason 2001;Mason and Ownby 2000;Swift 1999). Neither medication interacts with alcohol or has abuse potential or rebound effects when discontinued. Despite these similarities, acamprosate and naltrexone induce their action via very different mecha- Address correspondence to: Barbara Mason, Alcohol Disorders Research Unit, 1400 N.W. 10th Avenue, Suite 307A, Miami, FL 33136. Tel.: (305) 243-4059; E-mail: bjmason246@aol.com Received February 12, 2002; revised April 18, 2002; accepted April 22, 2002. Online publication: 5/7/02 at www.acnp.org/citations/Npp 050702298. N EUROPSYCHOPHARMACOLOGY 2002 -VOL . 27 , NO . 4 Interaction Study of Acamprosate and Naltrexone 597 nisms and may affect different behavioral aspects of alcohol dependence. Acamprosate is a centrally acting synthetic analog of the naturally occurring amino acid neuromediator taurine (Dahchour and de Witte 2000). Chronic alcohol exposure is associated with decreased GABAergic transmission and increased glutamate activity (Grant et al. 1990;Hoffman and Tabakoff 1994). Although the precise mechanism of action or cellular target of acamprosate is not fully elucidated, acamprosate appears to modulate N-methyl-D -aspartate (NMDA) receptor activity in the glutamate system, and to inhibit the upregulation of voltage-gated Ca 2 ϩ channels that is induced by chronic alcohol ingestion and states of withdrawal (Allgaier et al. 2000;Popp and Lovinger 2000). Thus, acamprosate may act on neurobiological mechanisms that may persist for many months following alcohol withdrawal, and that may contribute to the vulnerability for drinking relapse (Borg 1988).The clinical safety and efficacy of acamprosate was evaluated in 16 placebo-controlled, double-blind trials of 3, 6, or 12 months duration conducted across 11 European countries and involving more than 4,500 male and female outpatients with alcohol dependence (Barrias et al. 1997;Besson et al. 1998;Chick et al. 2000a;Geerlings et al. 1997;Gual and Lehert 2001;Ladewig et al. 1993;Lhuintre et al. 1985Lhuintre et al. , 1990Paille et al. 1995;Pelc et al. 1992Pelc et al. , 1997Poldrugo 1997;Rousseaux et al. 1996;Sass et al. 1996;Tempesta et al. 2000;Whitworth et al. 1996). Fourteen of 16 trials showed a significant advantage for acamprosate over placebo on abstinence measures. There are no serious or rate-limiting adverse effects associated with acamprosate. Mild and transient diarrhea is the only drug-related adverse event that differed consistently from placebo across studies. Acamprosate is not metabolized. It is eliminated by the kidneys and is contra-indicated in cases of re...

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Advances in development of medications for alcoholism treatment

Cited by 67 publications

References 55 publications

Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings

Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings

Conceptual framework for the etiology of alcoholism: a ?kindling?/stress hypothesis

A Pharmacokinetic and Pharmacodynamic Drug Interaction Study of Acamprosate and Naltrexone

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