New developments for the pharmacological treatment of alcohol withdrawal syndrome. A focus on non-benzodiazepine GABAergic medications

Leggio, Lorenzo; Kenna, George A.; Swift, Robert M.

doi:10.1016/j.pnpbp.2007.09.021

Cited by 102 publications

(62 citation statements)

References 124 publications

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“…These observations were also replicated in open-label studies [66,67], and more importantly, another DBPCRCT confirmed the efficacy of baclofen in increasing CAD and reducing alcohol craving, in AD patients with liver cirrhosis, a population usually excluded from alcohol pharmacological trials because the risk to worsen liver disease [68]. The safety of baclofen in patients with alcohol liver disease has been recently confirmed by a small study, where baclofen was administered for 5-8 months in patients with alcoholic hepatitis [69].…”

Section: Baclofensupporting

confidence: 57%

Current and Promising Pharmacotherapies, and Novel Research Target Areas in the Treatment of Alcohol Dependence: A Review

Edwards

Kenna²,

Swift³

et al. 2011

CPD

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Harmful alcohol use is a risk factor in more than 60 diseases and injuries resulting in approximately 2.5 million deaths per year worldwide. In the United States (US) and Europe, there are only a few medications approved for alcohol dependence (AD) however, these medications have only been moderately effective and there is a crucial need for more effective treatments. This review briefly summarizes research on currently approved medications for AD, as well as promising medications like topiramate, baclofen and ondansetron. Topiramate is likely the most promising new treatment for AD, however, further research is needed to determine the optimal dose and appropriate length of treatment. Baclofen, a GABA(B) agonist, is a promising medication as a treatment for AD, especially for patients with AD and severe liver disease. Ondansetron has shown promising results as a potential medication for AD, but only within a certain subtype of individuals. This review also discusses more recent findings on other potential pharmacotherapies for AD, such as serotonin-specific reuptake inhibitors (SSRIs; i.e. sertraline), aripiprazole and prazosin, as well as on some examples of other potentially interesting new neuropharmacological targets (i.e. cannabinoid receptors, CRF, NPY, ghrelin). Finally, the present review also discusses the attempts to personalize medication for AD treatment by alcohol typology and pharmacogenetics.

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Section: Baclofensupporting

confidence: 57%

Current and Promising Pharmacotherapies, and Novel Research Target Areas in the Treatment of Alcohol Dependence: A Review

Edwards

Kenna²,

Swift³

et al. 2011

CPD

Self Cite

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“…Baclofen administration showed a few mild and tolerable side effects also in patients affected by liver cirrhosis [74]. In view of its renal route of excretion, baclofen may be administered to alcohol-dependent patients affected by liver disease that prevents the administration of other drugs metabolized by the liver [170]. However, further studies aimed at evaluating the safety of the drug in patients affected by liver disease should be conducted to avoid any possible risk, such as the onset of acute hepatitis as recently described in a patient affected by AUD after baclofen administration [171].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Tolerability of Baclofen in Substance Use Disorders: A Systematic Review

Agabio¹,

Preti

Gessa

2013

Eur Addict Res

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Background: It has been reported that baclofen, a drug used in the treatment of spasticity, reduces the severity of withdrawal symptoms and substance use disorders (SUDs) for some psychoactive drugs. Aims and Methods: To evaluate the effectiveness and safety of baclofen in the treatment of withdrawal syndrome and/or SUDs, providing (1) an outline of its pharmacological features; (2) a summary of studies that have suggested its possible effectiveness in the treatment of SUDs, and (3) a review of randomized, controlled trials (RCTs) on baclofen and SUDs. Results: Baclofen tolerability is generally considered to be good. Eleven RCTs investigated its effectiveness in the treatment of SUDs. Of these, 5 RCTs found that baclofen is effective, 5 RCTs found that it is ineffective and the results of 1 RCT were not appreciable because it did not achieve the preplanned level of participation. Conclusions: The number of RCTs on baclofen and SUDs is still low, and their results are divergent. Further RCTs should be undertaken, particularly with higher doses of baclofen. Its administration may be suggested in patients who fail to respond to other approved drugs or who are affected by liver disease that prevents their administration, or in patients affected by SUDs for which no approved drugs are available. Treatment should be conducted under strict medical supervision.

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“…However, benzodiazepine treatment of AWS has substantial drawbacks, including its own host of rebound effects upon cessation of treatment and increased risk of relapse into alcohol dependence following its withdrawal (Malcolm, 2003). Other nonbenzodiazepine compounds such as carbamazepine, gabapentin, valproic acid, topiramate, gamma-hydroxybutyric acid, baclofen, and flumazenil have been studied, but have been associated with limited clinical efficacy (Leggio et al, 2008). These studies underscore the urgent need to discover novel treatments of AWS and to develop clinically relevant animal models thereof (Ripley and Stephens, 2011).…”

Section: Introductionmentioning

confidence: 99%

Attenuation of Ethanol Withdrawal by Ceftriaxone-Induced Upregulation of Glutamate Transporter EAAT2

Abulseoud

Camsari

Ruby

et al. 2014

Neuropsychopharmacol

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Alcohol withdrawal syndrome (AWS) is a potentially fatal outcome of severe alcohol dependence that presents a significant challenge to treatment. Although AWS is thought to be driven by a hyperglutamatergic brain state, benzodiazepines, which target the GABAergic system, comprise the first line of treatment for AWS. Using a rat model of ethanol withdrawal, we tested whether ceftriaxone, a b-lactam antibiotic known to increase the expression and activity of glutamate uptake transporter EAAT2, reduces the occurrence or severity of ethanol withdrawal manifestations. After a 2-week period of habituation to ethanol in two-bottle choice, alcohol-preferring (P) and Wistar rats received ethanol (4.0 g/kg) every 6 h for 3-5 consecutive days via gavage. Rats were then deprived of ethanol for 48 h during which time they received ceftriaxone (50 or 100 mg/kg, IP) or saline twice a day starting 12 h after the last ethanol administration. Withdrawal manifestations were captured by continuous video recording and coded. The evolution of ethanol withdrawal was markedly different for P rats vs Wistar rats, with withdrawal manifestations occurring 412 h later in P rats than in Wistar rats. Ceftriaxone 100 mg/ kg per injection twice per day (200 mg/kg/day) reduced or abolished all manifestations of ethanol withdrawal in both rat variants and prevented withdrawal-induced escalation of alcohol intake. Finally, ceftriaxone treatment was associated with lasting upregulation of ethanol withdrawal-induced downregulation of EAAT2 in the striatum. Our data support the role of ceftriaxone in alleviating alcohol withdrawal and open a novel pharmacologic avenue that requires clinical evaluation in patients with AWS.

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New developments for the pharmacological treatment of alcohol withdrawal syndrome. A focus on non-benzodiazepine GABAergic medications

Cited by 102 publications

References 124 publications

Current and Promising Pharmacotherapies, and Novel Research Target Areas in the Treatment of Alcohol Dependence: A Review

Current and Promising Pharmacotherapies, and Novel Research Target Areas in the Treatment of Alcohol Dependence: A Review

Efficacy and Tolerability of Baclofen in Substance Use Disorders: A Systematic Review

Attenuation of Ethanol Withdrawal by Ceftriaxone-Induced Upregulation of Glutamate Transporter EAAT2

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