Systemic and intrathecal baclofen produce bladder antinociception in rats.

BACKGROUND: Baclofen, a clinically available GABAB receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder nociception. METHODS: A series of experiments examined the effects of systemic and spinally administered baclofen on bladder nociception in female anesthetized rats. Models of bladder nociception included those which employed neonatal and adult bladder inflammation to produce bladder hypersensitivity. RESULTS: Cumulative intraperitoneal dosing (1-8 mg/kg IP) and cumulative intrathecal dosing (10-160 ng IT) of baclofen led to dose-dependent inhibition of visceromotor responses (VMRs) to urinary bladder distension (UBD) in all tested models. There were no differences in the magnitude of the analgesic effects of baclofen as a function of inflammation versus no inflammation treatments. Hemodynamic (pressor) responses to UBD were similarly inhibited by IT baclofen as well as UBD-evoked excitatory responses of spinal dorsal horn neurons. The GABAB receptor antagonist, CGP 35,348, antagonized the antinociceptive effects of IT baclofen on VMRs in all tested models but did not affect the magnitude of the VMRs by itself suggesting no tonic GABAB activity was present in this preparation. Tolerance to a seven day continuous IT infusion of baclofen was not observed. CONCLUSIONS: These data provide support for a clinical trial of baclofen as a non-opioid treatment of human bladder pain.

GABABR1 in DRN mediated GABA to regulate 5-HT expression in multiple brain regions in male rats with high and low aggressive behavior.

The identity of the mechanism that controls aggressive behavior in rodents is unclear. Serotonin (5-HT) and GABA are associated with aggressive behavior in rodents. However, the regulatory relationship between these chemicals in the different brain regions of rats has not been fully defined. This study aimed to clarify the role of GABABR1 in DRN-mediated GABA to regulate 5-HT expression in multiple brain regions in male rats with high and low aggressive behavior. Rat models of highly and less aggressive behavior were established through social isolation plus resident intruder. On this basis, GABA content in the DRN and 5-HT contents in the PFC, hypothalamus, hippocampus and DRN were detected using ELISA. Co-expression of 5-HT and GB1 in the DRN was detected by immunofluorescence and immunoelectron microscopy at the tissue and subcellular levels, respectively. GB1-specific agonist baclofen and GB1-specific inhibitor CGP35348 were injected into the DRN by stereotaxic injection. Changes in 5-HT levels in the PFC, hypothalamus and hippocampus were detected afterward. After modeling, rats with highly aggressive behavior exhibited higher aggressive behavior scores, shorter latencies of aggression, and higher total distances in the open field test than rats with less aggressive behavior. The contents of 5-HT in the PFC, hypothalamus and hippocampus of rats with high and low aggressive behavior (no difference between the two groups) were significantly decreased, but the change in GABA content in the DRN was the opposite. GB1 granules could be found on synaptic membranes containing 5-HT granules, which indicated that 5-HT neurons in the DRN co-expressed with GB1, which also occurred in double immunofluorescence results. At the same time, we found that the expression of GB1 in the DRN of rats with high and low aggressive behavior was significantly increased, and the expression of GB1 in the DRN of rats with low aggressive behavior was significantly higher than that in rats with high aggressive behavior. Nevertheless, the expression of 5-HT in DRN was opposite in these two groups. After microinjection of baclofen into the DRN, the 5-HT contents in the PFC, hypothalamus and hippocampus of rats in each group decreased significantly. In contrast, the 5-HT contents in the PFC, hypothalamus and hippocampus of rats in each group increased significantly after injection with CGP35348. The significant increase in GABA in the DRN combined with the significant increase in GB1 in the DRN further mediated the synaptic inhibition effect, which reduced the 5-HT level of 5-HT neurons in the DRN, resulting in a significant decrease in 5-HT levels in the PFC, hypothalamus and hippocampus. Therefore, GB1-mediated GABA regulation of 5-HT levels in the PFC, hypothalamus and hippocampus is one of the mechanisms of highly and less aggressive behavior originating in the DRN. The increased GB1 level in the DRN of LA-behavior rats exhibited a greater degree of change than in the HA-group rats, which indicated that differently decreased 5-HT levels in the DRN may be the internal mechanisms of high and low aggression behaviors.

GABAB receptor signaling in the caudate putamen is involved in binge-like consumption during a high fat diet in mice.

Previous studies suggest that signaling by the gamma-aminobutyric acid (GABA) type B receptor (GABABR) is involved in the regulation of binge eating, a disorder which might contribute to the development of obesity. Here, we show that intermittent access to a high fat diet (HFD) induced binge-like eating behavior with activation of dopamine receptor d1 (drd1)-expressing neurons in the caudate putamen (CPu) and nucleus accumbens (NAc) in wild-type (WT) mice. The activation of drd1-expressing neurons during binge-like eating was substantially increased in the CPu, but not in the NAc, in corticostriatal neuron-specific GABABR-deficient knockout (KO) mice compared to WT mice. Treatment with the GABABR agonist, baclofen, suppressed binge-like eating behavior in WT mice, but not in KO mice, as reported previously. Baclofen also suppressed the activation of drd1-expressing neurons in the CPu, but not in the NAc, during binge-like eating in WT mice. Thus, our data suggest that GABABR signaling in CPu neurons expressing drd1 suppresses binge-like consumption during a HFD in mice.

Application of in vitro data in physiologically-based kinetic models for quantitative in vitro-in vivo extrapolation: A case-study for baclofen.

Physiologically-based kinetic (PBK) models can simulate concentrations of chemicals in tissues over time without animal experiments. Nevertheless, in vivo data are often used to parameterise PBK models. This study aims to illustrate that a combination of kinetic and dynamic readouts from in vitro assays can be used to parameterise PBK models simulating neurologically-active concentrations of xenobiotics. Baclofen, an intrathecally administered drug to treat spasticity, was used as a proof-of-principle xenobiotic. An in vitro blood-brain barrier (BBB) model was used to determine the BBB permeability of baclofen needed to simulate plasma and cerebrospinal concentrations. Simulated baclofen concentrations in individuals and populations of adults and children generally fall within 2-fold of measured clinical study concentrations. Further, in vitro micro-electrode array recordings were used to determine the effect of baclofen on neuronal activity (cell signalling). Using quantitative in vitro-in vivo extrapolations (QIVIVE) corresponding doses of baclofen were estimated. QIVIVE showed that up to 4600 times lower intrathecal doses than oral and intravenous doses induce comparable neurological effects. Most simulated doses were in the range of administered doses. This show that PBK models predict concentrations in the central nervous system for various routes of administration accurately without the need for additional in vivo data.

The effect of GABA-B receptors in the basolateral amygdala on passive avoidance memory impairment induced by MK-801 in rats.

MK-801 (dizocilpine) is a potent non-competitive N-methyl-[D]-aspartate (NMDA) receptor antagonist that affects cognitive function, learning, and memory. As we know, NMDA receptors are significantly involved in memory function, as well as GABA (Gamma-Aminobutyric acid) receptors. In this study, we aimed to discover the effect of GABA-B receptors in the basolateral amygdala (BLA) on MK-801-induced memory impairment. We used 160 male Wistar rats. The shuttle box was used to evaluate passive avoidance memory and locomotion apparatus was used to evaluate locomotor activity. MK-801 (0.125, 0.25, and 0.5 µg/rat), baclofen (GABA-B agonist, 0.0001, 0.001, and 0.01 µg/rat) and phaclofen (GABA-B antagonist, 0.0001, 0.001, and 0.01 µg/rat) were injected intra-BLA, after the training. The results showed that MK-801 at the dose of 0.5 µg/rat, baclofen at the doses of 0.001 and 0.01 µg/rat, and phaclofen at the doses of 0.001 and 0.01 µg/rat, impaired passive avoidance memory. Locomotor activity did not alter in all groups. Furthermore, the subthreshold dose of both baclofen (0.0001 µg/rat) and phaclofen (0.0001 µg/rat) restored the impairment effect of MK-801 (0.5 µg/rat) on memory. Also, both baclofen (0.0001 µg/rat) potentiated the impairment effect of MK-801 (0.125 µg/rat) and phaclofen (0.0001 µg/rat) potentiated the impairment effect of MK-801 (0.125 and 0.25 µg/rat) on passive avoidance memory. In conclusion, our results indicated that BLA GABA-B receptors can alter the effect of NMDA inactivation on passive avoidance memory.

Effect of High-Dose Baclofen on Agitation-Related Events Among Patients With Unhealthy Alcohol Use Receiving Mechanical Ventilation: A Randomized Clinical Trial.

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.

Is R(+)-Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side.

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.

Combined the GABA-A and GABA-B receptor agonists attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism.

Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized primarily by two core behavioral symptoms of social communication deficits and restricted/repetitive behaviors. Investigating the etiological process and identifying an appropriate therapeutic target remain as formidable challenges to overcome ASD due to numerous risk factors and complex symptoms associated with the disorder. Among the various mechanisms that contribute to ASD, the maintenance of excitation and inhibition balance emerged as a key factor to regulate proper functioning of neuronal circuitry. In this study, we employed prenatally exposed to valproic acid (VPA) to establish a validated ASD mouse model and found impaired inhibitory gamma-aminobutyric acid (GABAergic) neurotransmission through a presynaptic mechanism in these model mice, which was accompanied with decreased GABA release and GABA-A and GABA-B receptor subunits expression. And acute administration of individual GABA-A or GABA-B receptor agonists partially reversed autistic-like behaviors in the model mice. Furthermore, acute administration of the combined GABA-A and GABA-B receptor agonists palliated sociability deficits, anxiety and repetitive behaviors in the animal model of autistic-like behaviors, demonstrating the therapeutic potential of above cocktail in the treatment of ASD.

Role of the GABAa and GABAb receptors of the central nucleus of the amygdala in compulsive cocaine-seeking behavior in male rats.

RATIONALE: Compulsive cocaine use, defined as the continued use despite the dire consequences, is a hallmark of cocaine addiction. Thus, understanding the brain mechanism regulating the compulsive cocaine-seeking and cocaine-taking behaviors is essential to understand cocaine addiction and the key to identification of the molecular targets for the development of medications against this condition. OBJECTIVE: This study aimed to determine how the GABAa and GABAb receptors of the central nucleus of the amygdala (CeA) regulate the compulsive cocaine-seeking behavior. METHODS: Male Wistar outbred rats were trained to self-administer intravenous cocaine (0.4 mg/kg/infusion) under a chained schedule. The compulsive cocaine-seeking behavior was measured as the cocaine-seeking behavior in the face of footshock punishment. The role of the GABA receptors of CeA in the regulation of such behavior was determined by measuring the dose-dependent effects of the GABAa agonist muscimol or the GABAb agonist baclofen bilaterally microinjected into the CeA on the punished cocaine-seeking behavior. RESULTS: The cocaine-seeking behavior was inhibited by footshock punishment in an intensity-dependent manner. Both muscimol and baclofen dose-dependently increased the punished cocaine-seeking behavior. However, the potency of muscimol but not baclofen was negatively correlated with the effects of punishment. CONCLUSION: These data indicate that the CeA GABAa receptors play a key role in the regulation of the compulsive cocaine-seeking behavior and suggest that an increase in the function of the GABAa receptors possibly induced by cocaine or genetic factors may be an important mechanism involved in the development of or vulnerability to the compulsive cocaine use and addiction.

Combination of acamprosate and baclofen (PXT864) as a potential new therapy for amyotrophic lateral sclerosis.

There is currently no therapy impacting the course of amyotrophic lateral sclerosis (ALS). The only approved treatments are riluzole and edaravone, but their efficacy is modest and short-lasting, highlighting the need for innovative therapies. We previously demonstrated the ability of PXT864, a combination of low doses of acamprosate and baclofen, to synergistically restore cellular and behavioral activity in Alzheimer's and Parkinson's disease models. The overlapping genetic, molecular, and cellular characteristics of these neurodegenerative diseases supported investigating the effectiveness of PXT864 in ALS. As neuromuscular junction (NMJ) alterations is a key feature of ALS, the effects of PXT864 in primary neuron-muscle cocultures injured by glutamate were studied. PXT864 significantly and synergistically preserved NMJ and motoneuron integrity following glutamate excitotoxicity. PXT864 added to riluzole significantly improved such protection. PXT864 activity was then assessed in primary cultures of motoneurons derived from SOD1G93A rat embryos. These motoneurons presented severe maturation defects that were significantly improved by PXT864. In this model, glutamate application induced an accumulation of TDP-43 protein in the cytoplasm, a hallmark that was completely prevented by PXT864. The anti-TDP-43 aggregation effect was also confirmed in a cell line expressing TDP-43 fused to GFP. These results demonstrate the value of PXT864 as a promising therapeutic strategy for the treatment of ALS.

Individualized, High-Dose Baclofen for Reduction in Alcohol Intake in Persons With High Levels of Consumption.

Alcohol use disorders (AUD) are common and impairing. Many pharmacologic interventions have been approved for AUD; baclofen is one among these. More than a dozen randomized controlled trials (RCTs) have examined the safety and efficacy of baclofen in AUD; these RCTs have been pooled in 4 recent meta-analyses, each with different study selection criteria, different objectives, different methods, and different results. The general impression from these meta-analyses is that the benefits with baclofen are unimpressive in patients with AUD. With the background that individualized, rather than fixed, high dosing with baclofen could be critical for success, a large (n = 320), industry-independent, 62-center French RCT (the Bacloville trial) examined whether individually uptitrated, high-dose baclofen could reduce alcohol consumption in heavy drinkers across a year of treatment. The study design, the high dropout rate, and the statistical methods of this trial threw up several complexities; in consequence, the main primary and secondary outcomes could not be satisfactorily interpreted. However, there were many other secondary outcomes that seemed to favor baclofen over placebo, though certain concerns remained. This RCT is explained and its findings are carefully dissected and interpreted. It is concluded that individualized treatment with high-dose baclofen (30-300 mg/d) may be a useful second-line approach in heavy drinkers who wish to reduce levels of alcohol intake; baclofen may be particularly useful in patients with liver disease, for whom certain other pharmacologic interventions are relatively contraindicated. However, the risk of serious adverse events with high-dose baclofen, and its pharmacodynamic interaction with alcohol, must both be kept in mind. Practical issues are discussed.

[Intrathecal baclofen therapy in brain injury and recovery of persistent vegetative state. Apropos of a case]. / Baclofeno intratecal en daño cerebral y recuperación de estado vegetativo persistente. A propósito de un caso.

Patients with brain injury and spasticity are candidates for intrathecal baclofen therapy (ITB) when maximal doses of oral antispastic drugs fail. Some authors have described an improvement in the level of consciousness in patients with brain injury and disorder of consciousness treated with ITB for spasticity. We present the case of a 43-year-old patient with brain injury, spasticity, and permanent vegetative state (PVS) who showed an improvement in the level of consciousness after ITB for spasticity. We performed an ITB infusion test, assessing the spasticity with the Modified Ashworth Scale (MAS) and level of consciousness with the Coma Recovery Scale-Revised (CRS-R) and observed an improvement in the spasticity and the level of consciousness. Consequently, the ITB pump was implanted and the patient recovered from PVS to minimal conscious state (MCS). We conclude that ITB is indicated in patients with brain injury and spasticity. We suggest the improvement in the level of consciousness as a possible additional benefit. There is a lack of evidence to recommend ITB in patients with altered level of consciousness.

[Intra-nucleus accumbens shell injection of baclofen blocks the reconsolidation of conditioned place preference in morphine-addicted mice].

Preclinical studies suggest that the GABAB receptor is a potential target for treatment of substance use disorders. Baclofen (BLF), a prototypical GABAB receptor agonist, is the only specific GABAB receptor agonist available for application in clinical addiction treatment. The nucleus accumbens shell (AcbSh) is a key node in the circuit that controls reward-directed behavior. However, the relationship between GABAB receptors in the AcbSh and memory reconsolidation was unclear. The aim of this study was to investigate the effect of intra-AcbSh injection of BLF on the reconsolidation of morphine reward memory. Male C57BL/6J mice were used to establish morphine conditioned place preference (CPP) model and carry out morphine reward memory retrieval and activation experiment. The effects of intra-AcbSh injection of BLF on morphine-induced CPP, reinstatement of CPP and locomotor activity were observed after environmental cues activating morphine reward memory. The results showed that intra-AcbSh injection of BLF (0.06 nmol/0.2 µL/side or 0.12 nmol/0.2 µL/side), rather than vehicle or BLF (0.01 nmol/0.2 µL/side), following morphine reward memory retrieval abolished morphine-induced CPP by disrupting its reconsolidation in mice. Moreover, this effect persisted for more than 14 days, which was not reversed by a morphine priming injection. Furthermore, intra-AcbSh injection of BLF without morphine reward memory retrieval had no effect on morphine-associated reward memory. Interestingly, administration of BLF into the AcbSh had no effect on the locomotor activity of mice during testing phase. Based on these results, we concluded that intra-AcbSh injection of BLF following morphine reward memory could erase morphine-induced CPP by disrupting its reconsolidation. Activating GABAB receptor in AcbSh during drug memory reconsolidation may be a potential approach to prevent drug relapse.

Toxicological considerations in the prescription of baclofen for the treatment of substance use disorders.

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.

Encephalopathy of Unknown Origin in a Baclofen Patient: Case Report and Review of the Literature.

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.

Enteral baclofen withdrawal managed with intravenous dexmedetomidine: A case report.

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.

Effect of Topical Baclofen 5% on Post-Hemorrhoidectomy Pain: Randomized Double Blind Placebo-Controlled Clinical Trial.

BACKGROUND: Baclofen is an agonist for a subtype of gamma-amino butyric acid (GABA-B) receptors and traditionally been used for the systemic treatment of spasticity. Topical application of baclofen has been shown to reduce pain in patients with localized neuropathic pain. OBJECTIVES: In this study, we investigate the efficacy of baclofen cream (5%) in reducing postoperative pain and analgesic requirement after open hemorrhoidectomy. DESIGN: The patients were randomly assigned to either baclofen (5%) cream or placebo immediately after surgery and then every 12 h for 14 days. PATIENTS: A total of 66 patients with third- and fourth-degree hemorrhoids undergoing open hemorrhoidectomy were randomly assigned to this trial. SETTING: This study was conducted at a single educational hospital. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes were intensity of pain, measured with a visual analog scale, and the analgesic requirement, measured by the amount of the acetaminophen consumption. RESULTS: No significant difference was found in baseline characteristics between the two groups. Postoperative pain score of the baclofen group was significantly lower on week 1 (P = 0.01) and week 2 (P = 0.02) than the placebo group. Similarly, patients in the baclofen group consumed significantly less analgesic medication on week 1 (P = 0.025) and week 2 (P = 0.024) than the control group. CONCLUSION: Topical application of baclofen effectively relieves pain after hemorrhoidectomy with minimal side effects.

Titrated baclofen for high-risk alcohol consumption: a randomized placebo-controlled trial in out-patients with 1-year follow-up.

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.

Baclofen Unusual Response In Spinal Cord Injury Patients.

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.