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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). 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. 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). 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.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic symptom that has no proven pharmacologic treatment. The purpose of this double-blind randomized placebo-controlled trial was to evaluate a novel compounded topical gel for this problem. Methods Patients with CIPN were randomized to baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to determine its effect on numbness, tingling, pain, and function. The primary endpoint was the baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks. Results Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO arm over placebo in both the sensory ( p  = 0.053) and motor subscales ( p  = 0.021). The greatest improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity. Conclusion Topical treatment with BAK-PLO appears to somewhat improve symptoms of CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research is needed with increased doses to better clarify the clinical role of this treatment in CIPN.

•An increase in psychotropic drug abuse has been documented worldwide.•Baclofen poisoning remains relatively underestimated among young people.•The case of a baclofen overdose in an adolescent who misused baclofen is reported.•Other similar cases were also reviewed.•The recreational use of baclofen represents an important public health concern. 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.

STX209 (arbaclofen), a selective GABA-B agonist, is hypothesized to modulate the balance of excitatory to inhibitory neurotransmission, and has shown preliminary evidence of benefit in fragile X syndrome. We evaluated its safety, tolerability, and efficacy in non-syndromic autism spectrum disorders, in an 8-week open-label trial enrolling 32 children and adolescents with either Autistic Disorder or Pervasive Developmental Disorder—Not Otherwise Specified, and a score ≥17 on the Aberrant Behavior Checklist (ABC)—Irritability subscale. STX209 was generally well-tolerated. The most common adverse events were agitation and irritability, which typically resolved without dose changes, and were often felt to represent spontaneous variation in underlying symptoms. Improvements were observed on several outcome measures in this exploratory trial, including the ABC-Irritability (the primary endpoint) and the Lethargy/Social Withdrawal subscales, the Social Responsiveness Scale, the CY-BOCS-PDD, and clinical global impression scales. Placebo-controlled study of STX209 is warranted.

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.

Introduction Off-label prescribing (OLP) may raise serious safety concerns that traditional spontaneous reporting of adverse drug reactions (ADRs) may not identify in a timely manner. In France, the ‘Multidisciplinary Consultation Service for Off-Label Prescribing in Addiction Medicine’ (CAMTEA) is a proactive regional system established to identify ADRs associated with the OLP of baclofen for alcohol dependence. Objective The aim was to demonstrate, using the French pharmacovigilance database (FPVD), that CAMTEA allowed for the reporting of a substantial amount of ADRs, comparable in nature to those provided via spontaneous reporting. Method The 2012–2013 FPVD notifications associated with baclofen OLP were extracted. The ten most frequent types of ADRs among ‘serious’ and ‘non-serious’ reports were listed. The frequency of each type of ADR was compared between CAMTEA and spontaneous reporting, and the magnitudes of the differences were assessed using standardized differences. Results A total of 428 baclofen reports (1043 ADRs) were identified, among which 221 (51.64%) originated from CAMTEA. The ten most frequent ADRs in ‘serious’ reports were (1) confusion (17.3%), (2) seizures (11.5%), (3) drowsiness/sedation (11.5%), (4) agitation (10.9%), (5) coma (9.6%), (6) hallucinations (7.7%), (7) falls (7.1%), (8) behavioral disorders (5.8%), (9) withdrawal syndrome (5.1%), and (10) space–time disorientation (5.1%). A standardized difference of <0.2 was identified for six out of the ten most frequent ‘serious’ ADRs, and eight of the ten ‘non-serious’ ADRs. Conclusion A proactive regional pharmacovigilance system could collect a substantial amount of safety data on a specific OLP practice. The profile of the ADRs collected was similar to that seen in the nationwide spontaneous reporting system.

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 γ-aminobutyric 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 autism-like 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 autism-like behavior, including sociability and preference for social novelty, novelty recognition, locomotion and exploration activity and marble-burying 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 autism-like symptoms in mice exposed to VPA prenatally, suggesting that autism-like symptoms in children with a history of prenatal VPA exposure may also benefit from treatment with the GABABR2 agonist STX209.

A 61-year-old patient with alcohol use disorder (AUD) was referred for suspicion of sleep apnea syndrome (SAS). He had incurred three road accidents attributed to sleepiness over the previous year, shortly after initiation of high-dose (100 mg b.i.d.) treatment with baclofen, a molecule increasingly used in the management of AUD. Polysomnography revealed a severe central SAS (CSAS) with an apnea-hypopnea index (AHI) of 81.6/h. Baclofen was suggested as a possible cause of the CSAS, and after its withdrawal, a second polysomnography was done, showing the disappearance of the central apneas and a shift to severe obstructive SAS (AHI 43.9/h), for which a positive airway pressure (CPAP) treatment was initiated. A third polysomnography was performed under CPAP after reintroduction of baclofen (50 mg b.i.d.) by the patient, showing reappearance of the CSAS (AHI 42.1/h). This case report illustrates the deleterious effect of baclofen on breathing physiology during sleep. Since it is typically prescribed off label at high doses to a population of patients potentially using other substances that inhibit the ventilatory drive, this possible adverse effect is a major concern. When considering the use of baclofen in patients with AUD, the potential for sleep-disordered breathing should be weighed and carefully monitored.

The amino acid gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the nervous system. The mesolimbic dopamine system is a major component of the brain’s reward pathways, and GABA neurons are part of this system, decreasing the activity of dopamine neurons through the inhibitory effects of GABA-B receptors. Because the mesolimbic dopamine system has been linked to the reinforcing effects of alcohol and other drugs of abuse, baclofen (LioresalThe amino acid gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the nervous system. The mesolimbic dopamine system is a major component of the brain’s reward pathways, and GABA neurons are part of this system, decreasing the activity of dopamine neurons through the inhibitory effects of GABA-B receptors. Because the mesolimbic dopamine system has been linked to the reinforcing effects of alcohol and other drugs of abuse, baclofen (Lioresal ® , Gablofen ® ), a GABA-B receptor agonist drug, has been investigated in preclinical studies as a potential treatment for addictions. Baclofen reduces the reinforcing effects of alcohol and other drugs in animals, providing justification for clinical studies in human beings. Two open-label and two placebo-controlled studies in humans found that baclofen was effective for reducing alcohol craving and intake, but one placebo-controlled study found no benefit for baclofen. Baclofen is a safe and well-tolerated novel drug treatment for alcohol dependence.

The use of high-dose baclofen emerged in 2008 in the treatment of alcohol-use disorders. Its prescription is still off-label in France, but recent trials have suggested the interest of using high doses for alcohol dependence, so we have to deal with an increase in its use. However, we still have few data about the adverse effects of a high-dose baclofen prescription, especially in complex addictive disorders. We present a case of a 32-year-old man who sought treatment for gambling disorders (GDs). He had complex addictive disorders, including alcohol-use disorders and GDs. He developed a severe GD, after treatment with a high dose of baclofen. The maximum dose was 160 mg/day, prescribed for his alcohol-use disorders. According to the Naranjo algorithm, the score was +7, it enabled to conclude that problem of gambling was probably imputable to baclofen. We discuss this case with reference to literature.