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Current Pharmaceutical Design 2010Preclinical studies show that antagonism of the GABA(B) receptor may represent an effective neuropharmacological approach to treat alcohol dependence. Consistent with... (Review)
Review
Preclinical studies show that antagonism of the GABA(B) receptor may represent an effective neuropharmacological approach to treat alcohol dependence. Consistent with preclinical evidence, the majority of the human studies have demonstrated that the prototype GABA(B) receptor antagonist baclofen may represent an effective mediation to treat alcohol-dependent individuals. Specifically, baclofen has shown to reduce alcohol withdrawal symptoms, as well as to reduce alcohol craving and intake, and to promote alcohol abstinence. Notably, baclofen has shown a safe profile when administered to alcoholics, including those with liver cirrhosis. In summary, baclofen represents a safe and effective medication to treat alcohol dependence, thus holding promise as a new pharmacotherapy. However, large studies are needed to confirm the present findings.
Topics: Alcohol Drinking; Alcoholism; Animals; Baclofen; GABA Agonists; GABA-B Receptor Agonists; Humans; Receptors, GABA-B; Substance Withdrawal Syndrome
PubMed: 20482507
DOI: 10.2174/138161210791516440 -
The Cochrane Database of Systematic... Nov 2018Alcohol use disorder (AUD) and alcohol-related impairments belong to the most widespread psychiatric disorders leading to specific psychophysical, affective and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Alcohol use disorder (AUD) and alcohol-related impairments belong to the most widespread psychiatric disorders leading to specific psychophysical, affective and cognitive symptoms and consequences for psychosocial well-being and health. Alcohol consumption is increasingly becoming a problem in many developing regions and AUD prevalence is estimated at 4.1% worldwide, with highest prevalence in European countries (7.5%), and the North America (6.0%). Therapeutic approaches, including pharmacotherapy, play an important role in treating patients with AUD.
OBJECTIVES
To assess the efficacy and safety of baclofen for treating people with AUD, who are currently drinking, with the aim of achieving and maintaining abstinence or reducing alcohol consumption.
SEARCH METHODS
We searched the Cochrane Drugs and Alcohol Specialised Register, CENTRAL, MEDLINE, Embase, two further databases and two clinical trials registries, conference proceedings, and the reference lists of retrieved articles. The date of the most recent search was 30 January 2018.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of at least four weeks' treatment duration and 12 weeks' overall study duration comparing baclofen for relapse prevention of AUD with placebo, no treatment or other treatments.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included 12 RCTs (1128 participants). All studies but three recruited fewer than 100 participants. Participants had a diagnosis of alcohol dependence according the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV or the International Classification of Diseases (ICD)-10 criteria who were currently drinking. The mean age of participants was 48 years, and there were more men (69%), than women. All studies compared baclofen to placebo, except for one study that evaluated baclofen versus acamprosate. The included studies considered baclofen at different doses (range 10 mg a day to 150 mg a day). In all but one of the studies, participants in both the baclofen and placebo groups received psychosocial treatment or counselling of various intensity.We judged most of the studies at low risk of selection, performance, detection (subjective outcome), attrition and reporting bias.We did not find any difference between baclofen and placebo for the primary outcomes: relapse-return to any drinking (RR 0.88, 95% CI 0.74 to 1.04; 5 studies, 781 participants, moderate certainty evidence); frequency of use by percentage of days abstinent (MD 0.39, 95% CI -11.51 to 12.29; 6 studies, 465 participants, low certainty evidence) and frequency of use by percentage of heavy drinking days at the end of treatment (MD 0.25, 95% CI -1.25 to 1.76; 3 studies, 186 participants, moderate certainty evidence); number of participants with at least one adverse event (RR 1.04, 95% CI 0.99 to 1.10; 4 studies, 430 participants, high certainty evidence); the dropout rate at the end of treatment (RR 0.98, 95% CI 0.77 to 1.26, 8 studies, 977 participants, high certainty evidence) and dropout due to adverse events (RR 1.11, 95% CI 0.59 to 2.07; 7 studies, 913 participants, high certainty evidence).We found evidence that baclofen increases amount of use (drink per drinking days), (MD 1.55, 95% CI 1.32 to 1.77; 2 studies, 72 participants, low certainty evidence).Among secondary outcomes, there was no difference on craving (MD 1.38, 95% CI -1.28 to 4.03, 5 studies, 469 participants), and anxiety (SMD 0.07, 95% CI -0.14 to 0.28; 5 trials, 509 participants). We found that baclofen increased depression (SMD 0.27, 95% CI 0.05 to 0.48; 3 studies, 387 participants).Concerning the specific adverse events we found that baclofen increased: vertigo (RR 2.16, 95% CI 1.24 to 3.74; 7 studies, 858 participants), somnolence/sedation (RR 1.48, 95%CI 1.11 to 1.96; 8 studies, 946 participants), paraesthesia (RR 4.28, 95% CI 2.11 to 8.67; 4 studies, 593 participants), and muscle spasms/rigidity (RR 1.94, 95%CI 1.08 to 3.48; 3 studies, 551 participants). For all the other adverse events we did not find significant differences between baclofen and placebo.For the comparison baclofen versus acamprosate, we were only able to extract data for one outcome, craving. For this outcome, we found that baclofen increased craving compared with acamprosate (MD 14.62, 95% CI 12.72 to 16.52; 1 study, 49 participants).
AUTHORS' CONCLUSIONS
None of the primary or secondary outcomes of the review showed evidence of a difference between baclofen and placebo. The high heterogeneity among primary studies results limits the interpretation of the summary estimate, the identification of moderators and mediators of baclofen's effects on alcohol use remains a challenge for further research. Even though some results from RCTs are promising, current evidence remains uncertain regarding the use of baclofen as a first-line treatment for people with AUDs.
Topics: Acamprosate; Alcohol Deterrents; Alcohol Drinking; Alcoholism; Baclofen; Craving; Depression; Female; GABA-B Receptor Agonists; Humans; Male; Middle Aged; Patient Dropouts; Randomized Controlled Trials as Topic; Recurrence
PubMed: 30484285
DOI: 10.1002/14651858.CD012557.pub2 -
Molecules (Basel, Switzerland) Jul 2020The γ-aminobutyric acid (GABA) type B receptor (GABA-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABA receptor, the receptor... (Review)
Review
The γ-aminobutyric acid (GABA) type B receptor (GABA-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABA receptor, the receptor mediates the neurotransmission of GABA, the main inhibitory neurotransmitter in the central nervous system (CNS). In recent decades, the receptor has been extensively studied with the intention being to understand pathophysiological roles, structural mechanisms and develop drugs. The dysfunction of the receptor is linked to a broad variety of disorders, including anxiety, depression, alcohol addiction, memory and cancer. Despite extensive efforts, few compounds are known to target the receptor, and only the agonist baclofen is approved for clinical use. The receptor is a mandatory heterodimer of the GABA and GABA subunits, and each subunit is composed of an extracellular Venus Flytrap domain (VFT) and a transmembrane domain of seven α-helices (7TM domain). In this review, we briefly present the existing knowledge about the receptor structure, activation and compounds targeting the receptor, emphasizing the role of the receptor in previous and future drug design and discovery efforts.
Topics: Baclofen; Binding Sites; Drug Development; GABA-B Receptor Antagonists; Humans; Ligands; Models, Molecular; Protein Conformation, alpha-Helical; Receptors, GABA-B
PubMed: 32646032
DOI: 10.3390/molecules25133093 -
Journal of Ayub Medical College,... 2019Spasticity after spinal cord injury is a major problem that can limit the effectiveness of rehabilitation programs. Oral baclofen is more frequently used in treating...
Spasticity after spinal cord injury is a major problem that can limit the effectiveness of rehabilitation programs. Oral baclofen is more frequently used in treating spasticity than other antispasmodic agents due to its proven overall efficacy. Herein, we are reporting two SCI patients who reported unusual response to baclofen. Case 1 (28-year-old male) his injury was classified as T3 AIS-A. Case 2 (36-year-old male) his injury was classified as T4 AIS-A. Both cases reported worsening of spasms with the initiation of baclofen and the rapid improvement upon discontinuing the medication. The effect was dose-dependent as reported by both of our patients. Our impression is a rebound spasm secondary to baclofen as evident by the severity of spasm and spasticity that were directly proportional to the baclofen dose. Awareness of this reversible side effect is essential for its management. Moreover, it might provide a clue to understanding the mechanism of action of baclofen.
Topics: Administration, Oral; Adult; Baclofen; GABA-B Receptor Agonists; Humans; Male; Spinal Cord Injuries
PubMed: 31094129
DOI: No ID Found -
Pain Medicine (Malden, Mass.) 2008
Meta-Analysis Review
Intrathecal baclofen and catheter tip inflammatory mass lesions (granulomas): a reevaluation of case reports and imaging findings in light of experimental, clinicopathological, and radiological evidence.
Topics: Baclofen; Catheters, Indwelling; Granuloma, Foreign-Body; Humans; Injections, Spinal; Myelitis
PubMed: 18489628
DOI: 10.1111/j.1526-4637.2008.00468.x -
Human Psychopharmacology Mar 2020To assess whether baclofen-treated alcohol dependent participants show different subjective and psychophysiological responses to appetitive cues during an alcohol cue...
OBJECTIVE
To assess whether baclofen-treated alcohol dependent participants show different subjective and psychophysiological responses to appetitive cues during an alcohol cue reactivity task compared to placebo, and whether these responses are associated with prospective drinking outcomes.
METHODS
Forty-two alcohol dependent participants (placebo: n = 12, low-dose baclofen [30 mg/day] n = 18, high-dose baclofen [75 mg/day]: n = 12) completed an alcohol cue reactivity task, whereby water and alcohol beverage cues were presented, with subsequent recovery periods, and subjective alcohol craving and psychophysiological indices (skin conductance; cardiovascular measures: heart rate, high-frequency heart rate variability) were recorded.
RESULTS
High-dose baclofen-treated participants showed both overall cue reactivity to water and alcohol cues and greater recovery effects during recovery periods, revealed by high-frequency heart rate variability, when compared to low-dose- and placebo-treated participants. There were no medication effects on subjective craving. In high-dose baclofen participants only, there was a predictive effect of lower baseline heart rate variability and fewer post-test percentage of heavy drinking days.
CONCLUSION
There was a dose-specific rescuing effect of high-dose baclofen on the dynamic modulation of cardiovascular responses to eliciting cues. Investigation of treatment responses using psychophysiological techniques may elucidate baclofen's mechanisms of action, and identify subgroups amenable to treatment.
Topics: Alcoholism; Baclofen; Craving; Cues; Dose-Response Relationship, Drug; Female; GABA-B Receptor Agonists; Galvanic Skin Response; Heart Rate; Humans; Male; Middle Aged
PubMed: 32045501
DOI: 10.1002/hup.2722 -
La Revue de Medecine Interne Jan 2015
Topics: Alcoholism; Baclofen; Behavior; Dissent and Disputes; Drug Repositioning; France; History, 21st Century; Humans; Practice Patterns, Physicians'; Randomized Controlled Trials as Topic; Spasm; Therapies, Investigational
PubMed: 25175490
DOI: 10.1016/j.revmed.2014.08.002 -
International Journal of Clinical... Jul 1991This study is intended to alert the clinician to the insidious symptoms of baclofen overdose, its prevention and treatment. In a group of 43 patients suffering from... (Review)
Review
This study is intended to alert the clinician to the insidious symptoms of baclofen overdose, its prevention and treatment. In a group of 43 patients suffering from previously intractable spasticity and a total treatment time of 2,422 weeks, 7 events of intrathecal baclofen overdose happened in 5 patients. On two occasions, a bolus injection caused an overdose (dose 50 and 280 micrograms). The 5 events during continuous infusion intoxication only happened in high dosed patients. The overdose symptoms occurred in one patient when she was lying in supine position (800 micrograms/24 h), in another patient after repair of CSF leakage by an autologous epidural bloodpatch (1,920 micrograms/24 h) and in tolerant patients, once during maximal dose adjustments (2,400 micrograms/24 h) and twice ca. 6 hours following reinitiation of the intrathecal baclofen infusion after a "drug holiday" treatment (27 and 55 micrograms/h). We could not confirm the reported similarity of baclofen overdose with the anticholinergic syndrome. Especially, the bradycardia and hypotension are more in accord with the reported clinical picture of oral baclofen overdose. In the absence of a pure baclofen antagonist and the varying symptoms of intrathecal baclofen, intoxication make rational treatment difficult. We observed that the advised physostigmine therapy is not always effective and safe. The occasionally doubtful antidotal benefits of physostigmine must be weighted against major side-effects. The classical approach of decreasing the absorption of a drug by lowering baclofen levels in the CSF by lumbar puncture drainage was successful. This approach together with conservative symptomatic treatment in an intensive care environment is probably a better and safer alternative than physostigmine alone as an antidote.
Topics: Adult; Aged; Baclofen; Drug Overdose; Female; Humans; Injections, Spinal; Male; Muscle Spasticity; Physostigmine; Spinal Puncture
PubMed: 1889914
DOI: No ID Found -
Toxicological Sciences : An Official... Jul 2018Baclofen, a γ-amino-butyric acid type-B receptor agonist with exponentially increased use at high-dose to facilitate abstinence in chronic alcoholics, is responsible...
Baclofen, a γ-amino-butyric acid type-B receptor agonist with exponentially increased use at high-dose to facilitate abstinence in chronic alcoholics, is responsible for increasing poisonings. Tolerance and withdrawal syndromes have been reported during prolonged treatment but their contribution to the variability of baclofen-induced neurotoxicity in overdose is unknown. We studied baclofen-induced effects on rat sedation, temperature, and ventilation and modeled baclofen pharmacokinetics and effect/concentration relationships aiming to investigate the consequences of repeated baclofen pretreatment and to characterize withdrawal syndrome. Baclofen-induced dose-dependent sedation (p <0.01), hypothermia (p <.001) and respiratory depression (p <.01) were altered in repeatedly baclofen-pretreated rats (p <.05). Repeatedly baclofen-pretreated rats did not exhibit respiratory depression following baclofen overdose due to limitations on baclofen-induced increase in inspiratory (p <.01) and expiratory times (p <.01). Only slight hypoxemia without respiratory acidosis was observed. Baclofen discontinuation resulted in hyperlocomotion and non-anxiogenic withdrawal symptoms. Regarding pharmacokinetics, repeated baclofen pretreatment increased the peak concentration (p <.05) and absorption constant rate (p <.05) and reduced the distribution volume (p <.0001) and elimination half-life (p <.05). Analysis of the effect/concentration relationships indicated that plasma baclofen concentration decreases more rapidly than all studied neuro-respiratory effects, in tolerant and non-tolerant rats. Taken together, our findings supported the role of brain distribution in baclofen-induced neurotoxicity expression and its probable involvement in tolerance-related attenuation in addition to physiological adaptations of ventilation. In conclusion, repeated pretreatment attenuates baclofen-attributed neurotoxicity in overdose and results in post-discontinuation withdrawal syndrome. Our findings suggest both pharmacodynamic and pharmacokinetic mechanisms whose relative contributions to the variability of baclofen-induced neurotoxicity in overdose remain to be established.
Topics: Animals; Baclofen; Brain; Dose-Response Relationship, Drug; Drug Tolerance; Male; Neurotoxicity Syndromes; Rats, Sprague-Dawley; Respiratory Insufficiency; Substance Withdrawal Syndrome; Tissue Distribution
PubMed: 29945230
DOI: 10.1093/toxsci/kfy073 -
Journal of Neurosurgery May 1997
Topics: Baclofen; Humans; Infusion Pumps; Injections, Spinal
PubMed: 9126919
DOI: 10.3171/jns.1997.86.5.0917a