Tolerability of High-dose Baclofen in the Treatment of Patients with Alcohol Disorders: A Retrospective Study

Rigal, Laurent; Hoang, Léa Legay; Alexandre-Dubroeucq, Constance; Pinot, Juliette; Jeunne, Claire Le; Jaury, Philippe

doi:10.1093/alcalc/agv052

Cited by 32 publications

(25 citation statements)

References 21 publications

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“…The mean baclofen daily dose was 79.7 mg, very close to that reported in the study of Marsot et al (77.9 mg) even if higher daily doses were seen in the literature for observational follow‐up of alcoholic patients treated with baclofen . Baclofen was mainly prescribed three times a day with equally divided dosages and some patients take their highest doses in the morning despite side effects reported such as somnolence, asthenia and vertigo and craving symptoms that usually occur in the evening. Of interest, half of our patients were followed up in a Hepato‐Gastroenterology department and at least 36 patients (25%) had associated alcoholic liver disease (with a slight elevation of AST).…”

Section: Discussionsupporting

confidence: 76%

Population pharmacokinetics of oral baclofen at steady‐state in alcoholic‐dependent adult patients

Chevillard

Sabo

Tod

et al. 2017

Fundamemntal Clinical Pharma

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Baclofen has been proposed for few years to help treating alcohol dependence at higher doses than those used in neurology. Baclofen pharmacokinetics has been previously well described at low oral or intravenous doses but remains poorly investigated with such high oral doses. We here describe dose regimens of baclofen in 143 alcohol-dependent patients treated with steady-state oral doses of baclofen. Plasma baclofen levels were measured in blood samples using liquid chromatography coupled with tandem mass spectrometry. One hundred and forty-nine baclofen concentrations were sampled 30 min to 15 h after the last dose, and baclofen pharmacokinetics was determined using population pharmacokinetics approach. Our population, whose average age and BMI were 51.5 years and 25.5 kg/m , respectively, was composed of two-thirds of men. Daily baclofen doses ranged from 15 to 250 mg and 26% were higher than 120 mg. A one-compartment model with first-order absorption and elimination allowed to determine mean values for clearance (CL/F), volume of distribution (V/F) and absorption rate constant at 8.0 L/h, 44.5 L and 2.23 h , respectively. Inter-individual variability on CL/F and V/F was 27.4 and 86% for the parameters. None of the demographic and biological covariates significantly decreased inter-individual variability. A proportional relationship between oral dose and plasma baclofen exposure indicated a linear pharmacokinetics of baclofen even at doses over 120 mg/day. Our large population study evidenced a linear pharmacokinetics of oral baclofen even at high daily doses with an inter-individual variability of baclofen exposure that could not be explained by demographic and biological data.

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Section: Discussionsupporting

confidence: 76%

Population pharmacokinetics of oral baclofen at steady‐state in alcoholic‐dependent adult patients

Chevillard

Sabo

Tod

et al. 2017

Fundamemntal Clinical Pharma

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“…Although a recent clinical trial found that HDB had a significant effect on abstinence maintenance , the sample size of that trial was small, and the results of two clinical trials with larger samples are still being awaited . Moreover, HDB is known to induce frequent neuropsychiatric adverse drug reactions, such as sedation, dizziness, insomnia, and tinnitus . More rarely, seizures, manic symptoms, and baclofen withdrawal syndromes have been associated with HDB .…”

Section: Resultsmentioning

confidence: 99%

Pharmacotherapy for Alcohol Dependence: The 2015 Recommendations of the French Alcohol Society, Issued in Partnership with the European Federation of Addiction Societies

Rolland

Paille

Gillet³

et al. 2015

CNS Neurosci Ther

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The treatment of alcohol dependence consists of either alcohol detoxification or abstinence maintenance programs or drinking reduction programs. The therapeutic objective is the result of a decision made jointly by the physician and the patient. For alcohol detoxification, benzodiazepines (BZDs) are recommended in first-line (grade A). BZD dosing should be guided by regular clinical monitoring (grade B). Residential detoxification is more appropriate for patients with a history of seizures, delirium tremens, unstable psychiatric comorbidity, or another associated substance use disorder (grade B). BZDs are only justified beyond a 1-week period in the case of persistent withdrawal symptoms, withdrawal events or associated BZD dependence (grade B). BZDs should not be continued for more than 4 weeks (grade C). The dosing and duration of thiamine (vitamin B1) during detoxification should be adapted to nutritional status (EC). For relapse prevention, acamprosate and naltrexone are recommended as first-line medications (grade A). Disulfiram can be proposed as second-line option in patients with sufficient information and supervision (EC). For reducing alcohol consumption, nalmefene is indicated in first line (grade A). The second-line prescription of baclofen, up to 300 mg/day, to prevent relapse or reduce drinking should be carried out according to the "temporary recommendation for use" measure issued by the French Health Agency (EC). During pregnancy, abstinence is recommended (EC). If alcohol detoxification is conducted during pregnancy, BZD use is recommended (grade B). No medication other than those for alcohol detoxification should be initiated in pregnant or breastfeeding women (EC). In a stabilized pregnant patient taking medication to support abstinence, the continuation of the drug should be considered on a case-by-case basis, weighing the benefit/risk ratio. Only disulfiram should be always stopped, given the unknown risks of the antabuse effect on the fetus (EC). First-line treatments to help maintain abstinence or reduce drinking are off-label for people under 18 years of age and should thus be considered on a case-by-case basis after the repeated failure of psychosocial measures alone (EC). Short half-life BZDs should be preferred for the detoxification of elderly patients (grade B). The initial doses of BZDs should be reduced by 30 to 50% in elderly patients (EC). In patients with chronic alcohol-related physical disorders, abstinence is recommended (EC). Any antidepressant or anxiolytic medication should be introduced after a psychiatric reassessment after 2-4 weeks of alcohol abstinence or low-risk use (grade B). A smoking cessation program should be offered to any smokers involved in an alcohol treatment program (grade B).

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“…5,6 In a recent retrospective survey including 116 patients receiving high-dose baclofen, the most frequently noted adverse effects involved disruption of the wake-sleep cycle, with 52% of patients reporting somnolence. 18 In the Baclofen for the Treatment of Alcohol Dependence (BACLAD) study, 6 sleep disturbances and fatigue were reported in 32% and 46% of patients, respectively, taking baclofen. However, none of these studies included sleep recordings.…”

Section: Cheyne-stokes Respiration None Nonementioning

confidence: 99%

Severe Central Sleep Apnea Associated With Chronic Baclofen Therapy

Olivier

Joyeux‐Faure

Gentina³

et al. 2016

Chest

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Baclofen, a gamma-aminobutyric acid-B agonist with muscle-relaxant properties, is widely used in patients with severe spasticity. In animals, baclofen has been shown to decrease respiratory drive. In humans, however, use of baclofen at the standard dose did not significantly impair sleep-disordered breathing in a susceptible population of snorers. Recently, there has been increasing interest in the role of baclofen for the treatment of alcohol dependence. We describe severe central sleep apnea (CSA) in four patients with none of the conditions commonly associated with CSA who were receiving chronic baclofen therapy for alcohol withdrawal. In one patient, baclofen withdrawal was associated with a complete resolution of CSA. Three patients were treated by adaptive servo-ventilation while continuing their treatment with baclofen. Given the increasing number of patients receiving baclofen for alcohol withdrawal treatment, physicians should be aware that these patients might be affected by severe CSA. Future studies are required to determine the mechanisms, prevalence, and treatment modalities of sleep-disordered breathing associated with baclofen usage.

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Tolerability of High-dose Baclofen in the Treatment of Patients with Alcohol Disorders: A Retrospective Study

Abstract: High-dose baclofen exposes patients with alcohol disorders to many adverse effects. Generally persistent, some adverse effects appear at low doses and may be dangerous.

Cited by 32 publications

References 21 publications

Population pharmacokinetics of oral baclofen at steady‐state in alcoholic‐dependent adult patients

Population pharmacokinetics of oral baclofen at steady‐state in alcoholic‐dependent adult patients

Pharmacotherapy for Alcohol Dependence: The 2015 Recommendations of the French Alcohol Society, Issued in Partnership with the European Federation of Addiction Societies

Severe Central Sleep Apnea Associated With Chronic Baclofen Therapy

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