Tolerability Of Baclofen Research Articles

Efficacy and tolerability of baclofen in a U.S. community population with alcohol use disorder: a dose-response, randomized, controlled trial

Identification of new medications for alcohol use disorder (AUD) is important for improving treatment options. Baclofen, a GABAB agonist, has been identified as a potential pharmacotherapy for AUD. In a 16-week double-blind, randomized, placebo-controlled trial, we investigated 30 and 90 mg/day of baclofen compared to placebo and examined effects of dose, sex, and level of pretreatment drinking. One hundred and twenty participants with DSM-IV alcohol dependence (age 46.1 (sd = 10.1) years, 51.7% male) were randomized after exclusion for unstable medical/psychiatric illness and/or dependence on drugs other than nicotine. Seventy-three participants completed the trial. A main effect of baclofen was found [%HDD (F(2,112) = 4.16, p = 0.018, d = 0.51 95%CI (0.06–0.95), 13.6 fewer HDD) and %ABST (F(2,112) = 3.68, p = 0.028, d = 0.49 95%CI (0.04–0.93), 12.9 more abstinent days)] and was driven by the 90 mg/day dose. A sex × dose interaction effect was present for both %HDD (F(2,110) = 5.48, p = 0.005) and %ABST (F(2,110) = 3.19, p = 0.045). Men showed a marginally positive effect for 90 mg/day compared to PBO (%HDD t(110) = 1.88, p = 0.063, d = 0.36 95%CI (−0.09–0.80), 15.8 fewer HDD days; %ABST t(110) = 1.68 (p = 0.096, d = 0.32 95%CI (−0.12–0.76), 15.7 more ABST)) with no effect for 30 mg/day. Women showed a positive effect for 30 mg/day (%HDD, t(110) = 3.19, p = 0.002, d = 0.61 95%CI (0.16–1.05), 26.3 fewer HDD days; %ABST t(110) = 2.73, p = 0.007, d = 0.52 95%CI (0.07–0.96), 25.4 more ABST days) with marginal effects for 90 mg/day on %ABST (p = 0.06) with drop-outs/dose reduction from sedative side-effects of 59% in women at 90 mg/day compared to 5% for men. These findings support the hypothesis that baclofen has efficacy in AUD and suggest that dose and sex be further explored as potential moderators of baclofen response and tolerability.

Efficacy of a second “drug holiday” in the treatment of intrathecal baclofen tolerance – A case study

Spasticity and muscle spasms are common complications following a SCI. Intrathecal baclofen (ITB) infusion is an effective treatment for severe spasticity of spinal cord origin. However, concerns over tolerance remain controversial. It is manifested by an escalation of dose required to produce a previously obtained effect or by a given dose of drug with continued administration. To combat baclofen resistance, a drug holiday is an effective method, interrupting the trend of accelerated dosage by weaning off the baclofen during 4–6 weeks. We report a case of a 45-year-old patient who suffered an accident on 1996 with SCI. He has incomplete tetraplegia AIS B, motor level C5 and sensitive L1. Due to severe uncontrolled spasticity (MAS = 4), he was implanted with a ITB pumb in 2002. Since than, it remained controlled (MAS = 2) with 310 ug/day. In 2009, because the resurgence of severe spasticity (MAS = 5), resistant to a fast increase on daily dose of baclofen until 360 ug/day, drug tolerance was suspected. We conducted a drug holiday over 4weeks and reintroduce baclofen. With 220 ug/day he showed a good control of spasticity (MAS = 1). During 2017, he presented an increase in spasticity (MAS = 4), combined with clonus of lower limbs [Spasm Frequency Scale (SFS) = 2]. We tried to control it, increasing the daily dose of baclofen, without response. He was admitted in CMRA for a second drug holiday. After 4 weeks without any baclofen, we gradually refill the pump. With 60ug/day we noticed an improvement on lower limbs spasticity (MAS = 2) and a decrease on muscle spasms (SFS = 0). He was discharged with this dose, appreciably below from admission. The use of ITB is increasing so we want to highlight the importance of being aware for cases of tolerance to baclofen. In this case, both drug holidays were effective, as measured by MAS and SFS.

A randomized, open-label, standard controlled, parallel group study of efficacy and safety of baclofen, and chlordiazepoxide in uncomplicated alcohol withdrawal syndrome

BackgroundAlcohol withdrawal syndrome (AWS) is a distressing condition, generally controlled by benzodiazepines (BZD's). Baclofen, a gamma-aminobutyric acid-B (GABAB) agonist, has also shown promising results in controlling AWS. As there are few studies comparing the efficacy and tolerability of chlordiazepoxide with baclofen, the present study was taken up. The objective of this study was to compare efficacy and tolerability of baclofen with chlordiazepoxide in uncomplicated AWS. MethodsSixty subjects with uncomplicated AWS were randomized into two groups of 30 each, to receive baclofen (30 mg) or chlordiazepoxide (75 mg) in decremented fixed dose regime for 9 days. Clinical efficacy was assessed by Clinical Institute Withdrawal Assessment for Alcohol-Revised Scale (CIWA-Ar) and tolerability by the nature and severity of adverse events. Lorazepam was used as rescue medication. Secondary efficacy parameters were Clinical Global Impression scores, symptom-free days, and subject satisfaction as assessed by visual analog scale. This study was registered with Clinical Trial Registry-India (CTRI/2013/04/003588), also subsequently registered with WHO's ICTRP clinical trial portal. ResultsBoth baclofen and chlordiazepoxide showed a consistent reduction in the total CIWA-Ar scores. However, chlordiazepoxide showed a faster and a more effective control of anxiety and agitation requiring lesser lorazepam supplementation, and also showed a better subject satisfaction compared to baclofen. Both the drugs showed good tolerability with mild self-limiting adverse events. ConclusionThe present study demonstrates that baclofen is not as good as chlordiazepoxide in the treatment of uncomplicated AWS. However, baclofen might be considered as an alternative.

The Role of Baclofen in the Treatment of Gastroesophageal Reflux Disease.

Objective. To describe the evidence for baclofen in the treatment of gastroesophageal reflux disease (GERD). Data Sources. A search of PubMed and Google Scholar was performed using the terms baclofen, gastroesophageal reflux disease, and treatment. Study Selection and Data Extraction. Publications were reviewed manually for relevance, and studies that addressed the use of baclofen in the treatment of adult symptomatic GERD patients were included. Data Synthesis. Nine studies were evaluated. Baclofen was shown to significantly reduce transient lower esophageal sphincter relaxations (TLESRs), postprandial acid reflux events, and median number of acid-related symptoms in 6 studies evaluating either a single dose of baclofen or short courses of 2 days or less. Three studies followed patients over a slightly longer period of time. These studies confirmed the results of the shorter trials by finding a decrease in supine duodenal reflux episodes, decreased periods when the pH was less than 4, and improvements in symptom scores in patients refractory to proton pump inhibitors. Side effects most frequently reported included drowsiness and dizziness. Conclusions. Baclofen can be considered for the treatment of refractory GERD following diagnostic evaluation. It has been shown to reduce TLESRs, reflux episodes, and reflux-related symptoms with minimal side effects in short-term trials. Future studies demonstrating the long-term efficacy and tolerability of baclofen in the treatment of GERD would help solidify its place in therapy.

Baclofen : Maintenance of Abstinence in Alcohol Dependent Patients Attending a Joint Liver and Alcohol Treatment Clinic

Introduction Alcohol induced liver disease (ALD) is the predominant cause of alcohol-related mortality in the UK. Therefore helping patients with ALD to quit is a primary treatment goal. Aims/Objectives The primary aim of this study was to measure the effectiveness and tolerability of Baclofen in maintaining abstinence, and to determine if this resulted in a reduction in standard measures of liver damage. Methods An observational prospective clinical audit was performed. Patients with ALD were commenced on Baclofen titrated according to tolerability and response up to 30 mg TDS. Primary outcome measures were severity of physical dependence (SADQ score) and biochemical markers of liver damage GGT, ALT, Bilirubin fibroelastography. These were compared at baseline, and 1 year. Results Of the 243 patients commenced on Baclofen, 151 (85 female 66 male) have completed 1 year follow-up (F/U) of which 130 (86%) have remained engaged. 10 have died. Comparison of baseline (B/L) and 1 year biochemical markers showed a reduction in GGT (c2= 66.8 P Conclusion Baclofen is well tolerated in this very difficult to treat, high risk patient group. It has a positive impact on alcohol consumption, and overall measures of liver function and harm. A RCT is needed to confirm the benefit of Baclofen in this patient group.

Double blind placebo controlled randomized pilot clinical trial of baclofen (Baclosan®) for alcohol dependence

To study efficacy and safety of baclofen for treatment of alcohol dependence. 32 patients with alcohol dependence had been randomized into one of two treatment groups (16 patients in each): patients of the 1st group were treated with baclofen (50 mg/day) for 3 months while patients of the 2nd one received identically looking placebo. All the study subjects were scheduled to come to the clinic on the weekly basis to control alcohol use and compliance with the study medications (by riboflavin marker in urine) and also - for psychiatric evaluations (severity of craving for alcohol, anxiety and depression). Alcohol use evaluated with the Time Line Follow Back technique and gamma-glutamiltranspeptidase activity in blood. To assess anxiety Spielberger state-trait inventory and Hamilton scale were used. Depression was assessed with Montgomery-Ashberg scale. To evaluate carving for alcohol used Obsessive-Compulsive Drinking scale, Penn Alcohol Craving scale, and Visual Analog Scale of Craving. Overall treatment effect assessed with the Clinical Global Impression scale. The study design was double blind. Baclofen did no differ significantly from placebo on either of primary or secondary outcome variables. However, primary outcome variables of retention in treatment and drinking were slightly better in the baclofen group compared to placebo, and those differences were close to the level of statistical significance. There were no differences between the groups in either rate of adverse events or liver enzymes activity which is an evidence of safety and good tolerability of baclofen in alcohol dependent patients. Further studies of baclofen for alcohol dependence in the larger sample size are needed.

Baclofen as Add-On to Standard Psychosocial Treatment for Alcohol Dependence: a Randomized, Double-Blind, Placebo-Controlled Trial With 1 Year Follow-Up

BackgroundLimited clinical trials and case-reports yielded conflicting results regarding the efficacy of baclofen (a GABAB agonist) in the treatment of alcohol dependence. The aim of this study was to test the efficacy and tolerability of baclofen in alcohol dependent patients in Israel. MethodsThe study was a double-blind, placebo-controlled, randomized trial comparing 50mg/day of baclofen to placebo over 12weeks, in addition to a standard psychosocial intervention program, with 26-week and 52-week follow-up observations. The percentages of heavy drinking days and abstinent days were the primary outcome measures, and craving, distress and depression levels; self-efficacy; social support from different sources; and health-related quality of life (HRQL) were secondary outcomes. Tolerability was also examined. ResultsSixty-four patients were randomized; 62% completed the 12-week trial and 37% completed the 52-week follow-up. No between group differences were found in the percentages of heavy drinking and abstinent days. A significant reduction in levels of distress, depression and craving and improved HRQL occurred for both arms, whereas self-efficacy and social support remained unchanged in both groups. No adverse events were observed. ConclusionsUnlike previous positive trials in Italy, and similarly to a negative trial in the USA, we found no evidence of superiority of baclofen over placebo in the treatment of alcohol dependence. However, the high placebo response undermines the validity of this conclusion. Therefore, more placebo-controlled trials are needed to either verify or discard a possible clinical efficacy of baclofen for alcohol dependence.

Individualised Treatment of Alcohol Dependent Patients with Baclofen: A Clinical Observation

Abstract Objective: The objective of this observational study was to investigate the effectiveness, safety and tolerability of baclofen in individualised doses for the treatment of alcohol dependence in a sample of patients suffering from additional co-occurring mental disorders. Methods: Fifteen subjects requesting baclofen treatment to achieve abstinence from, or reduction of, alcohol consumption, were included in the study. Baclofen was titrated individually responding to the participants' reports of drug side effects and reductions in drinking and craving. At the start and the end of the observation period (24 weeks) patients self-reported their number of standard drinks per day and rated their alcohol craving by means of the Obsessive Compulsive Drinking Scale (OCD-S). Liver enzymes, Carbohydrate Deficient Transferrin (CDT) and Ethyl Glucuronide in Hair (HEtG) were measured twice. Results: At the end of the observation period eleven patients were abstinent or low-risk drinking. Mean baclofen dose was 116 mg/d (range 30-225 mg/d). Baclofen was well tolerated and did not interfere with pre-existing pharmacotherapy. Three patients did not benefit from the treatment. The clinical presentation of one patient improved although his alcohol consumption remained higher than the NIAAA recommendations. We observed indications of baclofen misuse in one patient. Conclusion: Baclofen treatment with individually titrated doses between 30 mg/d to 200 mg/d was associated with suppression of, or reduction in, alcohol consumption and craving in the majority of patients. In view of the small sample size, high motivation of the participants, and absence of a control group we caution against an over estimation of our findings.

Randomised clinical trial: the effect of baclofen in patients with gastro‐oesophageal reflux ‐ a randomised prospective study

Baclofen, a GABA(B) agonist, has been shown to reduce transient lower oesophageal sphincter relaxations (TLESRs), a major cause of gastro-oesophageal reflux disease (GERD). To examine the effect and tolerability of baclofen in GERD patients over a 2-week period. Forty-three GERD patients with abnormal 24-h pH tests were prospectively randomised to receive baclofen or placebo in a double-blind fashion for 2 weeks. Oesophageal manometry, 24-h pH monitoring, and a standard questionnaire was administered, before and after treatment. Thirty-four patients completed the study. In the baclofen group there were significant decreases in 24-h pH score (P = 0.020), percent of upright reflux episodes (P = 0.016), percent total time pH <4 (P = 0.003), number of reflux episodes (P = 0.018), number of reflux episodes longer than 5 min (P = 0.016), number of postprandial reflux episodes (P = 0.045), and percentage of time pH <4 (P = 0.003). No significant changes in reflux parameters were noted in the placebo group. Patients receiving baclofen had significantly less belching (P = 0.038), regurgitation (P = 0.036) and overall symptom score (P = 0.004) whereas placebo patients had less heartburn (P = 0.001), chest pain (P = 0.002), regurgitation (P = 0.017) and overall symptom score (P = 0.000). However, there were no significant differences in changes of reflux parameters or symptoms when comparing the two groups. Drowsiness did not limit baclofen use. Baclofen was associated with a significant decrease in percent upright reflux by 24-h pH monitoring and a significant improvement in belching, regurgitation and overall symptom score. Baclofen may be more effective in patients with predominantly upright reflux and belching.

Efficacy and Safety of Baclofen for Alcohol Dependence: A Randomized, Double‐Blind, Placebo‐Controlled Trial

Recent clinical trials and case-reports indicate that baclofen, a GABA(B) agonist, may have efficacy for alcohol dependence. Baclofen has been shown to enhance abstinence, to reduce drinking quantity, to reduce craving, and to reduce anxiety in alcohol-dependent individuals in 2 placebo-controlled trials in Italy. However, the clinical trial data with baclofen is limited. The purpose of the present study was to test the efficacy and tolerability of baclofen in alcohol dependence in the United States. The study was a double-blind, placebo-controlled, randomized study comparing 30 mg/d of baclofen to placebo over 12 weeks of treatment and utilizing 8 sessions of BRENDA, a low-intensity psychosocial intervention. One hundred and twenty-one subjects were screened to yield 80 randomized subjects (44 men) with randomization balanced for gender. Percent heavy drinking days was the primary outcome measure with other drinking outcomes, anxiety levels, and craving as secondary outcomes. Tolerability was examined. Seventy-six percent of subjects completed the study. No difference by drug condition was seen in percentage of heavy drinking days where on-average rates were 25.5% (±23.6%) for placebo and 25.9% (±23.2%) for baclofen during treatment (t(73)=0.59, p=0.56). Similarly, no differences were seen by drug condition in percentage of days abstinent, time to first drink, or time to relapse to heavy drinking. Baclofen was associated with a significant reduction in state anxiety (F(1,73)= 5.39, p=0.02). Baclofen was well tolerated with only 2 individuals stopping baclofen because of adverse events. There were no serious adverse events. Baclofen, a GABA(B) agonist, represents a possible new pharmacotherapeutic approach to alcohol dependence. Despite encouraging preclinical data and prior positive clinical trials with baclofen in Italy, the current trial did not find evidence that baclofen is superior to placebo in the treatment of alcohol dependence. Additional clinical trial work is necessary to establish whether baclofen does or does not have therapeutic efficacy in alcohol dependence and, if it does, what factors are predictive of response.

Suppression of stretch reflex activity after spinal or systemic treatment with AMPA receptor antagonist NGX424 in rats with developed baclofen tolerance

Baclofen (a GABA(B) receptor agonist) is the most commonly used anti-spasticity agent in clinical practice. While effective when administered spinally or systemically, the development of progressive tolerance represents a serious limitation for its long-term use. The goal of the present study was to characterize the treatment potency after intrathecal or systemic treatment with the selective AMPA receptor antagonist NGX424 on stretch reflex activity (SRA) and background muscle activity (BMA) in rats with developed baclofen tolerance. Animals were exposed to 10 min of spinal ischaemia to induce an increase in BMA and SRA. Selected animals were implanted with an intrathecal PE-5 catheter and infused intrathecally with baclofen (1 µg·h⁻¹ ) for 14 days. Before and after baclofen infusion, changes in BMA and SRA were measured at 2 day intervals. After development of baclofen tolerance, the animals were injected intrathecally (1 µg) or subcutaneously (3, 6 or 12 mg·kg⁻¹) with NGX424, and changes in BMA and SRA were measured. Intrathecal or systemic delivery of NGX424 significantly suppressed the BMA and SRA in baclofen-tolerant animals. This effect was dose dependent. The magnitude of BMA and SRA suppression seen after 1 µg (intrathecal) or 12 mg·kg ⁻¹ (s.c.) of NGX424 injection was similar to that seen during the first 5 days of baclofen infusion. CONCLUSIONS AND IMPLICATIONS These data demonstrate that the use of NGX424 can represent an effective therapy to modulate chronic spasticity in patients who are refractory or tolerant to baclofen treatment.

Development of baclofen tolerance in a rat model of chronic spasticity and rigidity

Systemic or spinal treatment with baclofen has been associated with the development of tolerance in patients with chronic spasticity. In the present study, we used a rat model of spinal ischemia-induced spasticity to characterize the development of baclofen tolerance after chronic intrathecal (i.t.) baclofen infusion. Following the induction of spinal ischemia and the development of behavioral spasticity, animals were implanted with i.t. catheters connected to osmotic pumps to continuously infuse baclofen (1.0 μg/0.5 μl/h). Hindleg peripheral muscle resistance (PMR) was measured periodically after initiation of chronic infusion and after bolus i.t. baclofen injection (1.0 μg). Peripheral muscle resistance was significantly decreased at the onset of baclofen infusion, however, after 5–7 days of infusion a progressive return of spasticity was noted, where baseline PMR values returned to preinfusion levels. At the same time, the efficacy of bolus i.t. baclofen treatment also decreased, where after 5 days of baclofen infusion 1.0 μg (i.t.) baclofen only reduced PMR by 10% (compared to 40–50% preinfusion). Baclofen efficacy progressively returned once continuous infusion was stopped. These data demonstrate that transient spinal ischemia leads to the development of spasticity which is sensitive to spinal baclofen. Chronic i.t. infusion leads to a progressive development of tolerance. This model offers potential to study tolerance mechanisms after spinal injury, and aid in drug discovery for use in baclofen-tolerant patients.

Recurrent intrathecal baclofen pump catheter leakage: A surgical observation with recommendations

Intrathecal baclofen pump catheter complications are the most common cause for failure in drug delivery. A 4-year-old boy presented with repeated signs of baclofen tolerance despite progressive increases in dosing. External computerized interrogation of the pump and radiograph evaluation of the pump-catheter-intrathecal sac system were normal. Subsequently, he was taken to the emergency room for baclofen overdosage and brought to the operating room for exploration of the implant. Intraoperative assessment of the pump catheter found a cut on the catheter neck that was visible only when the catheter neck was flexed. The catheter was replaced without complications. Two months later, the patient returned with similar symptoms. Repeat computerized and radiographic assessment of the pump were normal. Intraoperative assessment showed a cut within the same portion of the catheter as previously discovered. The catheter cut was in the least flexible portion, the pump-catheter neck, which was found to be overlying the iliac crest in both surgeries. The authors hypothesize that the repetitive compressive forces of the catheter overlying the iliac crest led to catheter breakdown. Surgical placement of the pump-catheter neck should be superio-medial to reduce the likelihood of either internal or external compressive forces. J Pediatr Surg 37:E17. Copyright 2002, Elsevier Science (USA). All rights reserved.

Naltrexone and/or sertraline in outpatients with alcoholism and depression

Limited clinical trials and case-reports yielded conflicting results regarding the efficacy of baclofen (a GABAB agonist) in the treatment of alcohol dependence. The aim of this study was to test the efficacy and tolerability of baclofen in alcohol dependent patients in Israel.The study was a double-blind, placebo-controlled, randomized trial comparing 50 mg/day of baclofen to placebo over 12 weeks, in addition to a standard psychosocial intervention program, with 26-week and 52-week follow-up observations. The percentages of heavy drinking days and abstinent days were the primary outcome measures, and craving, distress and depression levels; self-efficacy; social support from different sources; and health-related quality of life (HRQL) were secondary outcomes. Tolerability was also examined.Sixty-four patients were randomized; 62% completed the 12-week trial and 37% completed the 52-week follow-up. No between group differences were found in the percentages of heavy drinking and abstinent days. A significant reduction in levels of distress, depression and craving and improved HRQL occurred for both arms, whereas self-efficacy and social support remained unchanged in both groups. No adverse events were observed.Unlike previous positive trials in Italy, and similarly to a negative trial in the USA, we found no evidence of superiority of baclofen over placebo in the treatment of alcohol dependence. However, the high placebo response undermines the validity of this conclusion. Therefore, more placebo-controlled trials are needed to either verify or discard a possible clinical efficacy of baclofen for alcohol dependence.