The dose-effect relationship of baclofen in alcohol dependence: A 1-year cohort study

Pignon, Baptiste; Labreuche, Julien; Auffret, Marine; Gautier, Sophie; Deheul, Sylvie; Simioni, Nicolas; Cottencin, Olivier; Bordet, Régis; Duhamel, Alain; Rolland, Benjamin

doi:10.1002/hup.2593

Cited by 12 publications

(8 citation statements)

References 26 publications

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“…However, another trial has found that baclofen, at the maximum dose 270 mg/d, was associated with significantly increased abstinence rates at 12 weeks, compared to placebo ( 21 ). Altogether, these findings suggest that, should baclofen be efficacious for drinking reduction and abstinence maintenance, the efficacious dose ranges could occasionally exceed 180 mg/d, which was also suggested by a recent observational study ( 13 ). However, the spreading use of high dose baclofen has also been associated with some safety concerns, insofar as baclofen exerts a dose-related sedative action that has may potentiate that of alcohol ( 21 , 22 ).…”

Section: Introductionsupporting

confidence: 65%

“…Marketed baclofen consists of a racemic mixture, which could impact the efficacy results of these clinical trials. In addition, a few observational studies have suggested that baclofen could have a dose-effect relationship in AUD ( 13 – 16 ). The use of high doses, namely up to 300 mg/day in some patients, has been reported in clinical practice for a few years ( 13 – 16 ).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, a few observational studies have suggested that baclofen could have a dose-effect relationship in AUD ( 13 – 16 ). The use of high doses, namely up to 300 mg/day in some patients, has been reported in clinical practice for a few years ( 13 – 16 ). In France, an important prescribing practice of high dose baclofen has been observed since 2008 ( 17 ), and has been framed by an official temporary regulatory measure issued by the French drug agency up to the dose of 300 mg/d ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

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Full-Profile Pharmacokinetic Study of High Dose Baclofen in Subjects With Alcohol Use Disorder

et al. 2018

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Baclofen a gamma amino-butyric acid type B (GABA-B) receptor agonist, which has raised some interest for the treatment of alcohol use disorder (AUD), occasionally at dose up to 300 mg/d. We conducted the first full-profile pharmacokinetic study on baclofen in AUD subjects, up to the oral daily dose of 300 mg. Sixty subjects treated for AUD with marketed baclofen were enrolled in a prospective phase-1 study. Participants were divided into four dose groups (1: <60 mg/d; 2: 60–120 mg/d; 3: >120 mg/d-180 mg/d; and 4: >180 mg/d), and they underwent a full-profile pharmacokinetic analysis of baclofen, using a nonlinear mixed effects modeling. The influence of different clinical and biological covariates was assessed in an upward modeling. Fifty-seven participants completed the study (522 observed concentrations collected). Racemic baclofen showed a linear pharmacokinetic profile, corresponding to a one-compartment model, with no influencing clinical or biological factor. The pharmacokinetic parameters of baclofen were (bootstrap 95% confidence intervals): absorption constant (Ka) 1.64 1/h (1.34–2), clearance (Cl/F) 11.6 L/h (10.8–12.3) and volume of distribution (Vd/F) 72.8 L (66.5–80.4) leading to a half-life of 4.4 h. The interindividual variability (IIV) was 44% (19–65), 21% (16–27), and 22% (11–36) for Ka, Cl/F, and Vd/F, respectively. The residual variability was 24% (21–26). No serious adverse event was reported.Registration: EudraCT #2013-003412-46

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Section: Introductionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Full-Profile Pharmacokinetic Study of High Dose Baclofen in Subjects With Alcohol Use Disorder

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“…This latest rationale implies a dose-effect relationship, but also the fact that baclofen dosing should be adjusted on a patient-tailored manner ( 9 , 14 ). This has been one of the arguments for using high doses in some patients.…”

Section: Introductionmentioning

confidence: 99%

Safety Challenges of Using High Dose Baclofen for Alcohol Use Disorder: A Focused Review

2018

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Since the early 2000s, the gamma-aminobutyric acid type B (GABA-B) receptor agonist baclofen has been extensively used for treating alcohol use disorder (AUD). In some countries, like France, Australia, or Germany, baclofen has been used at patient-tailored dose regimens, which can reach 300 mgpd or even more in some patients. The GABA-B-related pharmacology of baclofen expose patients to a specific profile of neuropsychiatric adverse drug reactions (ADRs), primarily some frequent sedative symptoms whose risk of occurrence and severity are both related to the absolute baclofen dosing and the kinetics of dose variations. Other frequent neuropsychiatric ADRs can occur, i.e., tinnitus, insomnia, or dizziness. More rarely, other serious ADRs have been reported, like seizures, manic symptoms, or sleep apnea. However, real-life AUD patients are also exposed to other sedative drugs, like alcohol of course, but also benzodiazepines, other drugs of abuse, or other sedative medications. Consequently, the occurrence of neuropsychiatric safety issues in these patients is essentially the result of a complex multifactorial exposure, in which baclofen causality is rarely obvious by itself. As a result, the decision of initiating baclofen, as well as the daily dose management should be patient-tailored, according the medical history but also the immediate clinical situation of the patient. The overall safety profile of baclofen, as well as the clinical context in which baclofen is used, have many similarities with the use of opiate substitution medications for opiate use disorder. This empirical statement has many implications on how baclofen should be managed and dosing should be adjusted. Moreover, this constant patient-tailored adjustment can be difficult to adapt in the design of clinical trials, which may explain inconsistent findings in baclofen-related literature on AUD.

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“…CNS depression is a well-recognized symptom associated with baclofen intoxication and is increased by concomitant ethanol consumption. It should be kept in mind that baclofen may be taken at the same time as alcohol by patients for whom total abstinence is not the goal ( 8 , 37 ). Sedation, dizziness and confusion are by far the most frequent symptoms related to self-poisoning with baclofen.…”

Section: Discussionmentioning

confidence: 99%

How to Manage Self-Poisoning With Baclofen in Alcohol Use Disorder? Current Updates

et al. 2018

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Specialists in addiction medicine continue to debate whether baclofen is still indicated to treat alcohol use disorders in view of conflicting results as to its efficacy. This review summarizes current knowledge on self-poisoning with baclofen focusing of alcohol-use disorder in order to provide an overview of the reliable scientific knowledge on management of such an intoxication. Moreover, as alcohol-dependent patients experience many psychiatric co-morbidities, the risk in suicide attempt using baclofen seems real. Numerous studies have suggested that patients given daily-doses of baclofen higher than 80 mg/day are more likely to attempt suicides than others. Following an ingestion of a large amount of baclofen, central nervous system depression is usually observed. Seizures require the patient to be admitted in intensive care unit and should be treated like other toxicological seizures. Cardiac complications include prolonged QTc interval, degree heart block, premature atrial contractions, and supraventricular tachycardia, hypotension and bradycardia. In cases of intoxication, the elimination half-life of baclofen may last between 12 and 36 h post-overdose and renal failure is known to delay its clearance. Rarely measured in clinical practice, the toxic level of baclofen blood level ranges from 1.1 to 3.5 mg/l, and coma or fatal intoxication are observed from 6 to 9.6 mg/l. Baclofen withdrawal has been observed but making the diagnosis of withdrawal in case of suspected self-poisoning is difficult as baclofen intoxication and baclofen withdrawal share many clinical signs. Admission to hospital to manage of suicide attempt with baclofen is mandatory and should not be limited to baclofen alone. It needs to include other aspects of the overall care of patients with alcohol disorders (psychological and psychosocial interventions, management of comorbid mental conditions and physical complications).

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The dose-effect relationship of baclofen in alcohol dependence: A 1-year cohort study

Abstract: The relationship between dose of baclofen and favorable drinking outcome was U-shaped, that is, was increased at low and high doses compared to medium doses.

Cited by 12 publications

References 26 publications

Full-Profile Pharmacokinetic Study of High Dose Baclofen in Subjects With Alcohol Use Disorder

Full-Profile Pharmacokinetic Study of High Dose Baclofen in Subjects With Alcohol Use Disorder

Safety Challenges of Using High Dose Baclofen for Alcohol Use Disorder: A Focused Review

How to Manage Self-Poisoning With Baclofen in Alcohol Use Disorder? Current Updates

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