RESUMEN
Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition characterized by impaired social interaction, compromised communication, and restrictive or stereotyped behaviours and interests. Due to the complex pathophysiology of ASD, there are currently no available medical therapies for improving the associated social deficits. Consequently, the present study investigated the effects of STX209, a selective γaminobutyric acid type B receptor (GABABR2) agonist, on an environmental rodent model of autism. The mouse model of autism induced by prenatal exposure to valproic acid (VPA) was used to assess the therapeutic potential of STX209 on autismlike behaviour in the present study. This study investigated the effects of STX209 on VPA model mice via behavioral testing and revealed a significant reversal of core/associated autismlike behavior, including sociability and preference for social novelty, novelty recognition, locomotion and exploration activity and marbleburying deficit. This may be associated with STX209 correcting dendritic arborization, spine density and GABABR2 expression in hippocampus of VPA model mice. However, expression of glutamic acid decarboxylase 65/67 in the hippocampus were not altered by STX209. The present results demonstrated that STX209 administration ameliorated autismlike symptoms in mice exposed to VPA prenatally, suggesting that autismlike symptoms in children with a history of prenatal VPA exposure may also benefit from treatment with the GABABR2 agonist STX209.
Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Efectos Tardíos de la Exposición Prenatal , Animales , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/etiología , Trastorno Autístico/inducido químicamente , Trastorno Autístico/tratamiento farmacológico , Conducta Animal , Modelos Animales de Enfermedad , Femenino , Agonistas de Receptores GABA-B/efectos adversos , Ratones , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Conducta Social , Ácido Valproico/efectos adversosRESUMEN
Importance: Unhealthy alcohol use can lead to agitation in the intensive care unit (ICU). Objective: To assess whether high-dose baclofen reduces agitation-related events compared with placebo in patients with unhealthy alcohol use receiving mechanical ventilation. Design, Settings, and Participants: This phase 3, double-blind, placebo-controlled, randomized clinical trial conducted in 18 ICUs in France recruited adults receiving mechanical ventilation who met criteria for unhealthy alcohol use. Patients were enrolled from June 2016 to February 2018; the last follow-up was in May 2019. Interventions: Baclofen (n = 159), adjusted from 50 to 150 mg per day based on estimated glomerular filtration rate, or placebo (n = 155) during mechanical ventilation up to a maximum of 15 days before gradual dose reduction over 3 to 6 days. Main Outcomes and Measures: The primary end point was the percentage of patients with at least 1 agitation-related event over the treatment period. Secondary outcomes included duration of mechanical ventilation, length of ICU stay, and 28-day mortality. Results: Among 314 patients who were randomized (mean age, 57 years; 60 [17.2%] women), 313 (99.7%) completed the trial. There was a statistically significant decrease in the percentage of patients who experienced at least 1 agitation-related event in the baclofen group vs the placebo group (31 [19.7%] vs 46 [29.7%]; difference, -9.93% [95% CI, -19.45% to -0.42%]; adjusted odds ratio, 0.59 [95% CI, 0.35-0.99]). Of 18 prespecified secondary end points, 14 were not significantly different. Compared with the placebo group, the baclofen group had a significantly longer median length of mechanical ventilation (9 vs 8 days; difference, 2.00 [95% CI, 0.00-3.00]; hazard ratio [HR] for extubation, 0.76 [95% CI, 0.60-0.97]) and stay in the ICU (14 vs 11 days; difference, 2.00 [95% CI, 0.00-4.00]; HR for discharge, 0.70 [95% CI, 0.54-0.90]). At 28 days, there was no significant difference in mortality in the baclofen vs placebo group (25.3% vs 21.6%; adjusted odds ratio, 1.24 [95% CI, 0.72-2.13]). Delayed awakening (no eye opening at 72 hours after cessation of sedatives and analgesics) occurred in 14 patients (8.9%) in the baclofen group vs 3 (1.9%) in the placebo group. Conclusions and Relevance: Among patients with unhealthy alcohol use receiving mechanical ventilation, treatment with high-dose baclofen, compared with placebo, resulted in a statistically significant reduction in agitation-related events. However, considering the modest effect and the totality of findings for the secondary end points and adverse events, further research is needed to determine the possible role of baclofen in this setting and to potentially optimize dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT02723383.
Asunto(s)
Trastornos Inducidos por Alcohol/tratamiento farmacológico , Alcoholismo/tratamiento farmacológico , Baclofeno/administración & dosificación , Agonistas de Receptores GABA-B/administración & dosificación , Agitación Psicomotora/tratamiento farmacológico , Respiración Artificial , Adulto , Anciano , Alcoholismo/complicaciones , Baclofeno/efectos adversos , Método Doble Ciego , Femenino , Agonistas de Receptores GABA-B/efectos adversos , Humanos , Unidades de Cuidados Intensivos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Agitación Psicomotora/etiologíaRESUMEN
For several decades, studies conducted to evaluate the efficacy of RS(±)-Baclofen in the treatment of alcohol dependence yielded contrasting results. Human and animal studies recently questioned the use of the racemic drug in patients since a potential important role of the different enantiomers has been revealed with an efficacy thought to reside with the active R(+)-enantiomer. Here we conducted experiments in the postdependent rat model of alcohol dependence to compare the efficacy of R(+)-Baclofen or S(-)-Baclofen to that of RS(±)-Baclofen on ethanol intake, seeking, and relapse. R(+)-Baclofen was more effective than RS(±)-Baclofen in reducing ethanol intake and seeking during acute withdrawal and during relapse after abstinence. We also used an original population approach in order to identify drug responders. We found a significant proportion of responders to S(-)-Baclofen and RS(±)-Baclofen, displaying an increase in ethanol intake, and this increasing effect on alcohol intake was not seen in the R(+)-Baclofen group. At an intermediate dose of R(+)-Baclofen, devoid of any motor side effects, we identified a very large proportion of responders (75%) with a large decrease in ethanol intake (90% decrease). Finally, the response to RS(±)-Baclofen on ethanol intake was correlated to plasma level of Baclofen. R(+)-Baclofen and RS(±)-Baclofen were effective in reducing sucrose intake. Our study has important clinical implication since it suggests that the wide variability in the therapeutic responses of patients to RS(±)-Baclofen may come from the sensitivity to the R(+)-Baclofen but also to the one of the S(-)-Baclofen that can promote an increase in ethanol intake.
Asunto(s)
Alcoholismo/tratamiento farmacológico , Baclofeno/química , Baclofeno/uso terapéutico , Agonistas de Receptores GABA-B/química , Agonistas de Receptores GABA-B/uso terapéutico , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Animales , Baclofeno/administración & dosificación , Baclofeno/efectos adversos , Relación Dosis-Respuesta a Droga , Agonistas de Receptores GABA-B/administración & dosificación , Agonistas de Receptores GABA-B/efectos adversos , Masculino , Ratas , Ratas Long-Evans , Recurrencia , Síndrome de Abstinencia a Sustancias/tratamiento farmacológicoRESUMEN
Over the past twenty years, psychotropic drug abuse by young people, especially by teenagers, has received special attention. Here, we present the case of baclofen overdose in a 16-year-old male who recreationally, and probably recurrently, self-administered baclofen. In addition, a review of other cases was conducted. The 16-year-old boy presented to emergency department with digestive signs followed by agitated confusion. Detection and determination of baclofen concentration were achieved using liquid chromatography tandem mass spectrometry. Baclofen was detected in plasma and urine, at 420 ng/mL and 64 900 ng/mL respectively. Further, an English exhaustive literature search was performed using several different scientific databases without any limiting period in order to identify scientific articles dealing with baclofen overdose following a recreational use among adolescent and young adults. Five publications describing baclofen overdoses following a recreational use among adolescents and young adults have been published reporting19 cases, all involving a non-fatal overdose, with baclofen concentrations ranging from less than 20-1322 ng/mL. Baclofen is a psychotropic drug and its recreational use among adolescents and young adults represent a serious problem and should be considered by healthcare professionals. Among young people, baclofen poisoning remains relatively infrequent or most likely underestimated and these observations highlight the importance of constructive communication and joining efforts of clinicians and analytical toxicologists.
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Baclofeno/efectos adversos , Sobredosis de Droga , Agonistas de Receptores GABA-B/efectos adversos , Trastornos Relacionados con Sustancias/complicaciones , Adolescente , Baclofeno/sangre , Baclofeno/orina , Cromatografía Liquida , Agonistas de Receptores GABA-B/sangre , Agonistas de Receptores GABA-B/orina , Humanos , Masculino , Mal Uso de Medicamentos de Venta con Receta , Trastornos Relacionados con Sustancias/diagnóstico , Espectrometría de Masas en TándemRESUMEN
Introduction: For many years, applications for baclofen have widened in the treatment of substance abuse disorder (SUD), mainly alcohol use disorder, with a growing rate of off-label prescriptions in Europe. Clinical effects seem to be both a decrease of craving and anxiety, leading to a decrease of drug or alcohol consumption. We described baclofen poisoning circumstances, therapeutic options and outcomes when used in substance use disorders.Areas covered: This review summarizes the toxicological considerations where baclofen was prescribed in humans for substance use or abuse disorder in randomized clinical trials, case series, case reports and observational studies between 1990 and 2020 according to the Preferred Reporting Items for Systemic reviews and Meta-Analysis.Expert opinion: The most frequent cause of severe intoxication is self-poisoning. A dose above 180 mg are expected to cause severe toxicity and death. The treatment is only symptomatic as no antidote is available. Off-label prescription remains unsafe because the optimal dose is not known and varies greatly between patients. As SUD are frequently associated with psychiatric disorders and such patients may have suicidal thoughts, the risk of self-poisoning is high. Potential co-ingestants should also be considered, especially CNS depressants, and they need to be closely monitored.
Asunto(s)
Alcoholismo/tratamiento farmacológico , Baclofeno/envenenamiento , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Baclofeno/administración & dosificación , Baclofeno/efectos adversos , Relación Dosis-Respuesta a Droga , Agonistas de Receptores GABA-B/administración & dosificación , Agonistas de Receptores GABA-B/efectos adversos , Agonistas de Receptores GABA-B/envenenamiento , Humanos , Uso Fuera de lo Indicado , Ensayos Clínicos Controlados Aleatorios como Asunto , Intento de SuicidioRESUMEN
PURPOSE: Acute enteral baclofen withdrawal can be clinically severe if not identified and managed appropriately. Treatment of baclofen withdrawal includes supportive care and reinitiation of baclofen. There are limited pharmacotherapeutic interventions available to manage symptoms of acute enteral baclofen withdrawal, especially in nonintubated patients. SUMMARY: We describe a 61-year-old Caucasian male with a past medical history of chronic back pain and spinal stenosis who was admitted to the medical intensive care unit with confusion, insomnia, agitation, delirium, and auditory and visual hallucinations. For control of agitation, the patient was administered 10 mg of i.v. haloperidol, 1 mg of i.v. lorazepam, and 14 mg of i.v. midazolam, with minimal improvement noted; therefore, dexmedetomidine was initiated, which led to clinical resolution of his symptoms. Upon further investigation it was determined that the patient was taking approximately 10 baclofen 20-mg tablets a day. According to his pharmacy records, he had filled prescriptions for a total of 738 baclofen tablets in the previous 12 weeks. The patient's presentation and sudden discontinuation of high-dose baclofen led to a diagnosis of baclofen withdrawal. Baclofen was subsequently restarted, and dexmedetomidine was weaned over 36 hours. CONCLUSION: Dexmedetomidine controlled this patient's agitation and delirium without suppressing his respiratory drive and should be considered for management of acute enteral baclofen withdrawal.
Asunto(s)
Baclofeno/efectos adversos , Dexmedetomidina/administración & dosificación , Agonistas de Receptores GABA-B/efectos adversos , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Dolor de Espalda/tratamiento farmacológico , Baclofeno/administración & dosificación , Dolor Crónico/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Agonistas de Receptores GABA-B/administración & dosificación , Humanos , Hipnóticos y Sedantes/administración & dosificación , Masculino , Persona de Mediana Edad , Síndrome de Abstinencia a Sustancias/fisiopatologíaRESUMEN
BACKGROUND: Encephalopathy is reported to have affected 250,000 people in the United States over the last decade, with considerable morbidity and mortality. Baclofen, a gamma-aminobutyric acid-B agonist that acts on the central nervous system, is the drug most widely used to treat spasticity. Baclofen overdose is a potentially deadly condition that can cause encephalopathy and can result from multiple etiologies. Renal disease can contribute to baclofen overdose and encephalopathy, and there are currently no dosing recommendations for patient's on baclofen with renal impairment. CASE DESCRIPTION: We report an unusual case of a man aged 35 years who presented with persistent fevers, seizures, and normal mentation. The patient presented with intrathecal baclofen use and prior exposure to West Nile Virus. He developed acute kidney injury at hospital secondary to vancomycin use, and mental status declined. CONCLUSIONS: This case highlights that patients with baclofen overdose can initially appear to have serious brain injury, however, full patient recovery can occur in <72 hours. This case provides additional insight into the guidelines for the treatment and management for unknown cause encephalopathy. This case also highlights the link between renal disease, baclofen, and encephalopathy through a review of the literature.
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Baclofeno/efectos adversos , Encefalopatías/inducido químicamente , Agonistas de Receptores GABA-B/efectos adversos , Espasmo/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Adulto , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Baclofeno/administración & dosificación , Encefalopatías/complicaciones , Encefalopatías/fisiopatología , Electroencefalografía , Fiebre/etiología , Fiebre/fisiopatología , Agonistas de Receptores GABA-B/administración & dosificación , Humanos , Bombas de Infusión Implantables , Infusión Espinal , Masculino , Meropenem/uso terapéutico , Paraplejía/complicaciones , Convulsiones/etiología , Convulsiones/fisiopatología , Espasmo/etiología , Traumatismos de la Médula Espinal/complicaciones , Vancomicina/efectos adversosRESUMEN
BACKGROUND AND AIMS: Baclofen is a promising drug for treating patients with alcohol-related disorders. Nevertheless, the first randomized clinical trials (mainly with target doses) reported inconsistent efficacy, possibly because of the effective dose widely varying between patients. The Bacloville study aimed to test the efficacy of titrated baclofen for achieving low-risk alcohol consumption. DESIGN: Twelve-month multicenter pragmatic double-blind randomized clinical trial from June 2012 to June 2014. SETTING: Sixty-two French primary care centers. PARTICIPANTS: Out-patients with high-risk alcohol consumption (> 40 g/day for women and > 60 g/day for men). INTERVENTION AND COMPARATOR: Patients were randomly assigned (1 : 1 ratio) to receive titrated baclofen up to 300 mg/day or placebo for 12 months. Switching to open-label baclofen was allowed in cases of perceived inefficacy. MEASUREMENTS: The primary outcome defined success as no or low-risk alcohol consumption (≤ 20 g/day for women and ≤ 40 g/day for men) during the last month of the 1-year follow up, with patients who switched to open-label baclofen classified as failures. FINDINGS: A total of 320 patients were randomized, 162 to baclofen and 158 to placebo (consumption 129 g/day in both arms). Discontinuation rates were 30 and 34% in the baclofen and placebo arms, respectively, and return rates of the last-month diaries were 42 and 34%, respectively. Primary success rates were 57 and 36% in the baclofen and placebo arms, respectively [difference: 21 percentage points, 95% confidence interval (CI) = 8-34, P = 0.003]. When switchers were not classified as failures unless they failed, the success rates were 62 versus 55% (difference: 6 percentage points, 95% CI = -7 to 20). Over 12 months, daily consumption differed between both arms (11 g less in the baclofen arm), as did the number of abstinence days (3.3 days more in the baclofen arm). Adverse events were more frequent with baclofen than placebo and were mostly drowsiness, fatigue and insomnia. Serious adverse events occurred in 85 (seven deaths) and 36 (three deaths) patients with baclofen and placebo, respectively. CONCLUSIONS: Baclofen was more effective than placebo in reducing alcohol consumption to low-risk levels. The number of adverse events and more serious adverse events was greater with baclofen than placebo.
Asunto(s)
Trastornos Relacionados con Alcohol/tratamiento farmacológico , Baclofeno/administración & dosificación , Agonistas de Receptores GABA-B/administración & dosificación , Adulto , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Baclofeno/efectos adversos , Método Doble Ciego , Femenino , Estudios de Seguimiento , Agonistas de Receptores GABA-B/efectos adversos , Reducción del Daño , Humanos , Masculino , Persona de Mediana Edad , Pacientes AmbulatoriosAsunto(s)
Baclofeno/efectos adversos , Trastorno por Atracón/tratamiento farmacológico , Agonistas de Receptores GABA-B/efectos adversos , Uso Fuera de lo Indicado/legislación & jurisprudencia , Psicosis Inducidas por Sustancias/etiología , Prescripciones de Medicamentos/normas , Francia , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The objective of our study was to determine whether treatment with baclofen is neurologically safe with respect to exposure during recovery from spinal cord injury. We performed a secondary longitudinal analysis of a cohort of adult patients with traumatic acute spinal cord injury. Cumulative baclofen dose was computed over the first 4 weeks following injury from concomitant medication information from a completed clinical trial. The main outcome measure was neurologic status, which was assessed over 52 weeks with "marked recovery" defined as the conversion to higher sensory and motor function. To complete the drug safety profile, drug toxicity was assessed with assays from standard blood work. Multivariable Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). Of the cohort (n = 651), 18% (n = 115) received baclofen within 4 weeks post injury. Baclofen use was associated with higher rates of marked neurologic recovery, even after adjustment for injury severity (HR = 2.1, 95% CI 1.5-3.0 for high dose vs none). Baclofen exposure was not associated with liver or renal side effects. The use of other medications indicated for spasticity was not associated with neurological outcomes. Overall, this longitudinal analysis provides level 3 evidence on the neurologic safety of baclofen and potential beneficial effects on recovery in the early days after acute traumatic spinal cord injury. The usefulness of concomitant medication files from completed clinical trials is highlighted. We also highlight the importance of incorporating logical patient questions and neurological outcomes into research addressing drug safety.
Asunto(s)
Baclofeno/uso terapéutico , Agonistas de Receptores GABA-B/uso terapéutico , Traumatismos de la Médula Espinal/tratamiento farmacológico , Adulto , Baclofeno/efectos adversos , Femenino , Agonistas de Receptores GABA-B/efectos adversos , Humanos , Estudios Longitudinales , Masculino , Modelos de Riesgos Proporcionales , Recuperación de la Función , Tacto/efectos de los fármacosRESUMEN
BACKGROUND: Narcolepsy is a disabling sleep-wake disorder characterized by the pentad symptoms of excessive daytime sleepiness, sleep paralysis, sleep fragmentation, sleep-related hallucinations, and cataplexy. There is no curative therapy for narcolepsy. Treatment is therefore symptom directed. Symptom management is generally directed at improving excessive daytime sleepiness, sleep fragmentation, and cataplexy. First-line treatment for excessive daytime sleepiness is typically daily use of wake-promoting agents, such as modafinil or armodafinil, or stimulant therapy, such as methylphenidate or amphetamines. Alternatively, sodium oxybate can be used nightly for improved cataplexy, sleep consolidation, and following day wakefulness. These therapies can be limited in some patients because of inadequate efficacy, poor tolerability, or side effects. METHODS: We describe five narcolepsy patients with severe excessive daytime sleepiness who had an inadequate response or experienced side effects with the initial therapies but had a positive response to treatment with baclofen. RESULTS: These patients reported subjective improvement in sleep maintenance without fragmentation and daytime sleepiness. Average Epworth Sleepiness Scale assessment before treatment was 15.8 with post-treatment assessment being 10.4 (P < 0.05). CONCLUSIONS: Baclofen may be an effective treatment for excessive daytime sleepiness and sleep fragmentation in narcolepsy and warrants further study.
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Baclofeno/farmacología , Agonistas de Receptores GABA-B/farmacología , Narcolepsia/tratamiento farmacológico , Adolescente , Baclofeno/administración & dosificación , Baclofeno/efectos adversos , Depresores del Sistema Nervioso Central/efectos adversos , Femenino , Agonistas de Receptores GABA-B/administración & dosificación , Agonistas de Receptores GABA-B/efectos adversos , Humanos , Masculino , Oxibato de Sodio/efectos adversos , Resultado del TratamientoAsunto(s)
Baclofeno/efectos adversos , Lorazepam/uso terapéutico , Psicosis Inducidas por Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Ansiolíticos/uso terapéutico , Agonistas de Receptores GABA-B/efectos adversos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIM: to describe trends in baclofen reports to Australia's largest Poisons Information Centre (PIC) and present a case series detailing severity of overdoses. SHORT SUMMARY: PBS data demonstrates baclofen use is increasing in Australia, while calls to NSWPIC illustrate an increase in number of exposures associated with toxicity. Baclofen toxicity may require prolonged intensive care admission. To minimize harms associated, especially with off-label baclofen prescribing for AUD, prescribers should pay careful attention to psychiatric comorbidities, and closely monitor treatment and dispensing. METHODS: this is a retrospective observational study of baclofen overdoses reported to New South Wales PIC (NSWPIC) from January 1 2004 to 31 December 2016. In addition, referrals to a metropolitan toxicology service relating to baclofen toxicity from 2014 to 2017 were analysed. The number of Pharmaceutical Benefit Scheme (PBS) claims for baclofen were also reviewed. RESULTS: during the 13-year study period, 403 cases of baclofen toxicity were reported to NSWPIC. There was a 230% increase in annual exposures over this period, 71% of patients were symptomatic, with 77% requiring hospitalization. Coingestants were reported in 53%, with 57% being psychoactive medications (including alcohol). An increase in number of baclofen dispensing episodes was also noted. From the five cases of deliberate self-harm reported to the metropolitan toxicology service, three obtained baclofen for management of alcohol use disorder (AUD) and required prolonged treatment in the intensive care unit (ICU). CONCLUSIONS: NSWPIC data shows an increase in number of calls regarding intentional baclofen exposures in parallel with increase the number of baclofen PBS claims. These closely parallel the increase in dispensing of baclofen since 2008. Case studies presented reinforce the severity of baclofen toxicity. Together, they demonstrate the potential risk of harm of baclofen prescribing, and the greater need for caution. Baclofen should be considered carefully in patients high risk of overdose or be used only in specialist services with close monitoring.
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Baclofeno/efectos adversos , Sobredosis de Droga/epidemiología , Sobredosis de Droga/terapia , Agonistas de Receptores GABA-B/efectos adversos , Centros de Información/tendencias , Centros de Control de Intoxicaciones/tendencias , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Bases de Datos Factuales/tendencias , Sobredosis de Droga/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nueva Gales del Sur/epidemiología , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Baclofen is a centrally acting GABAB receptor agonist and it is used widely for the treatment of spasticity, persistent hiccups and multiple sclerosis. The renal system is the main route of excretion, thus people with suboptimal renal function are prone to baclofen intoxication. Multiple doses of baclofen have been associated with toxicity, but it is very unusual that single dose can do so. CASE PRESENTATION: A 47 year old female patient with end stage renal disease (ESRD) presented with a sudden onset of altered mental status and state of unconsciousness after the ingestion of one tablet of baclofen 25 mg. All other possible causes were ruled out and a diagnosis of baclofen toxicity was considered. The patient showed dramatic improvement after an extra two sessions of hemodialysis. CONCLUSIONS: We highly recommend that more educational efforts are made for health care professionals about the possible risk of baclofen toxicity among kidney-impaired patients. We also recommend avoiding baclofen use if evidence of chronic renal disease is present and to seek other alternatives for pain management.
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Baclofeno/toxicidad , Agonistas de Receptores GABA-B/toxicidad , Fallo Renal Crónico/diagnóstico por imagen , Síndromes de Neurotoxicidad/diagnóstico por imagen , Baclofeno/efectos adversos , Femenino , Agonistas de Receptores GABA-B/efectos adversos , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/tratamiento farmacológico , Persona de Mediana Edad , Síndromes de Neurotoxicidad/sangreRESUMEN
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.
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Disuasivos de Alcohol/uso terapéutico , Consumo de Bebidas Alcohólicas/prevención & control , Alcoholismo/tratamiento farmacológico , Baclofeno/uso terapéutico , Agonistas de Receptores GABA-B/uso terapéutico , Acamprosato/uso terapéutico , Disuasivos de Alcohol/efectos adversos , Baclofeno/efectos adversos , Ansia/efectos de los fármacos , Depresión/inducido químicamente , Femenino , Agonistas de Receptores GABA-B/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Pacientes Desistentes del Tratamiento/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como Asunto , RecurrenciaRESUMEN
BACKGROUND: There are no available medications for the management of alcohol dependence for patients with alcoholic liver disease (ALD).AimsTo conduct a multisite, double blind, placebo-controlled, randomised clinical trial of baclofen in the treatment of alcohol dependence, with or without liver disease (trial registration: ClinicalTrials.gov, NCT01711125). METHOD: Patients (n = 104) were randomised to placebo, baclofen 30 mg/day or 75 mg/day for 12 weeks. Primary outcomes included survival time to lapse (any drinking), relapse (≥5 drinks per day in men and ≥4 in women), and the composite outcome of drinks per drinking day, number of heavy drinking days, and percentage days abstinent. RESULTS: There was a significant effect of baclofen (composite groups) on time to lapse (χ2 = 6.44, P<0.05, Cohen's d = 0.56) and relapse (χ2 = 4.62, P<0.05, d = 0.52). A significant treatment effect of baclofen was observed for percentage days abstinent (placebo 43%, baclofen 30 mg 69%, baclofen 75 mg 65%; P<0.05). There was one serious adverse event (overdose) directly related to medication (75 mg). CONCLUSIONS: Baclofen may be an effective treatment option for patients with ALD. However, given the profile of adverse events, the role for this medication might be best limited to specialist services.Declaration of interestNone.
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Alcoholismo/tratamiento farmacológico , Baclofeno/farmacología , Agonistas de Receptores GABA-B/farmacología , Hepatopatías Alcohólicas/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud , Adulto , Alcoholismo/complicaciones , Baclofeno/administración & dosificación , Baclofeno/efectos adversos , Método Doble Ciego , Femenino , Agonistas de Receptores GABA-B/administración & dosificación , Agonistas de Receptores GABA-B/efectos adversos , Humanos , Hepatopatías Alcohólicas/etiología , Masculino , Persona de Mediana EdadRESUMEN
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. Baclofen overdose may induce severe encephalopathy and electroencephalographic (EEG) abnormalities. Whether prior prolonged baclofen treatment may influence the severity of baclofen-induced encephalopathy in overdose has not been established. We designed a rat study to characterize baclofen-induced encephalopathy, correlate its severity with plasma concentrations and investigate the contribution of tolerance. Baclofen-induced encephalopathy was assessed using continuous EEG and scored based on a ten-grade scale. Following the administration by gavage of 116â¯mg/kg baclofen, EEG rapidly and steadily impaired resulting in the successive onset of deepening sleep followed by generalized periodic epileptiform discharges and burst-suppressions. Thereafter, encephalopathy progressively recovered following similar phases in reverse. Periodic triphasic sharp waves, non-convulsive status epilepticus and even isoelectric signals were observed at the most critical stages. Prior repeated baclofen administration resulted in reduced severity (peak: grade 7 versus 9; peak effect length: 382⯱â¯40 versus 123⯱â¯14â¯min, Pâ¯=â¯0.008) and duration of encephalopathy (18 versusâ¯>â¯24â¯h, Pâ¯=â¯0.0007), supporting the acquisition of tolerance. The relationship between encephalopathy severity and plasma baclofen concentrations fitted a sigmoidal Emax model with an anticlockwise hysteresis loop suggesting a hypothetical biophase site of action. The baclofen concentration producing a response equivalent to 50% of Emax was significantly reduced (8947⯵g/L, ±11.3% versus 12,728⯵g/L, ±24.0% [mean, coefficient of variation], Pâ¯=â¯0.03) with prior prolonged baclofen administration. In conclusion, baclofen overdose induces early-onset and prolonged marked encephalopathy that is significantly attenuated by prior repeated baclofen treatment. Our findings suggest a possible role for the blood-brain barrier in the development of tolerance; however, its definitive involvement remains to be demonstrated.
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Baclofeno/efectos adversos , Encefalopatías/inducido químicamente , Encefalopatías/fisiopatología , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Sobredosis de Droga/fisiopatología , Animales , Baclofeno/sangre , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos/fisiología , Electroencefalografía , Agonistas de Receptores GABA-B/efectos adversos , Agonistas de Receptores GABA-B/sangre , Masculino , Modelos Biológicos , Distribución Aleatoria , Ratas Sprague-Dawley , Sueño/efectos de los fármacos , Sueño/fisiologíaRESUMEN
RATIONALE: Preclinical studies suggest that the GABAB receptor is a potential target for treatment of substance use disorders. However, recent clinical trials report adverse effects in patients treated with the GABAB receptor agonist baclofen and even question efficacy. How can the discrepancy between preclinical and clinical findings be explained? OBJECTIVE: To test efficacy and adverse effects of baclofen and the novel GABAB positive allosteric modulator (PAM) CMPPE in rat addiction models, which were developed in accordance with DSM. METHODS: We used a well-characterized rat model of long-term alcohol consumption with repeated deprivation phases that result in compulsive alcohol drinking in a relapse situation, and a rat model of long-term intravenous cocaine self-administration resulting in key symptoms of addictive behavior. We tested repeated baclofen (0, 1, and 3 mg/kg; i.p.) and CMPPE doses (0, 10, and 30 mg/kg; i.p.) in relapse-like situations, in either alcohol or cocaine addicted-like rats. RESULTS: Baclofen produced a weak anti-relapse effect at the highest dose in alcohol addicted-like rats, and this effect was mainly due to the treatment-induced sedation. CMPPE had a better profile, with a dose-dependent reduction of relapse-like alcohol drinking and without any signs of sedation. The cue-induced cocaine-seeking response was completely abolished by both compounds. CONCLUSION: Positive allosteric modulation of the GABAB receptor provides efficacy, and no observable side effects in relapse behavior whereas baclofen may cause, not only sedation, but also considerable impairment of food intake or metabolism. However, targeting GABAB receptors may be effective in reducing certain aspects of addictive-like behavior, such as cue-reactivity.