Removal of baclofen with hemodialysis is negligible compared to intact kidney excretion in a pediatric overdose: a case report.

INTRODUCTION: Severe baclofen toxicity can result in respiratory failure, hemodynamic instability, bradycardia, hypothermia, seizures, coma, and death. While hemodialysis (HD) is well-described in treating acute baclofen toxicity in patients with end-stage kidney disease or acute kidney injury, the utility of HD for patients with normal kidney function is uncertain. Implementing HD to speed recovery after a large acute baclofen ingestion is appealing, considering: (a) potential for prolonged coma and ventilator-associated morbidity, and (b) baclofen's low protein-binding, low molecular-weight, and moderate volume of distribution. METHODS: We report a 51 kg, 14-year-old girl who presented to the emergency department (ED) with hypotension, obtundation, and status epilepticus after an intentional ingestion of 1200 mg baclofen. Her post-intubation neurologic examination was concerning for coma. A 14-hour post-ingestion baclofen concentration was 882 ng/mL (therapeutic range 80-400 ng/mL). Three urgent-HD sessions were performed to reduce her time on the ventilator. RESULTS: The total baclofen removed in the first three-hour HD session was 3.05 mg. The total urinary elimination of baclofen 42 mg over 24-hours on day one. She was discharged without neurologic deficits to psychiatry on day-14. CONCLUSION: In this case, the amount of baclofen recovered during HD is negligible in comparison to the amount cleared by kidney elimination in this patient with normal kidney function.

Baclofen overdose following recreational use in adolescents and young adults: A case report and review of the literature.

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.

Simultaneous Quantitation of S(+)- and R(-)-Baclofen and Its Metabolite in Human Plasma and Cerebrospinal Fluid using LC-APCI-MS/MS: An Application for Clinical Studies.

Baclofen is a racemic mixture that is commonly used for the treatment for spasticity. However, the optimal dose and dosing interval to achieve effective cerebral spinal fluid (CSF) concentrations of baclofen are not known. Moreover, it is unclear if there are differences in the ability of R- or S-baclofen to cross the blood-brain barrier and achieve effective CSF concentrations. We have validated a liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method with improved selectivity and sensitivity for the simultaneous quantitation of R- and S-baclofen and metabolites in plasma and CSF. Protein precipitation by acetonitrile was utilized to obtain an acceptable recovery of the analytes. The detection and separation of analytes was achieved on a 48 °C-heated Crownpak CR(+) column (150 mm × 4.0 mm, 5µ) with elution using 0.4% formic acid (FA) in water and 0.4% FA in acetonitrile as the mobile phase running at a flow rate of 1.0 mL/min. Accurate quantitation was assured by using this MS/MS method with atmospheric pressure chemical ionization in multiple reaction monitoring (MRM) mode. Therefore, this method is enantioselective, accurate, precise, sensitive, reliable, and linear from 1 to 1500 ng/mL for baclofen and 2 to 4000 ng/mL for the metabolites. An additional method was developed to separate racemic baclofen 3-(4-chlorophenyl)-4 hydroxybutyric acid metabolites for individual concentration determination. Both validated methods were successfully applied to a clinical pharmacokinetic human plasma and CSF study evaluating the disposition of baclofen and metabolites.

Nano-liquid chromatography for enantiomers separation of baclofen by using vancomycin silica stationary phase.

The chiral separation of baclofen (Bac) was obtained by nano-liquid chromatography tandem mass spectrometry (nano-LC-MS/MS) using a 100 µm I.D. fused silica capillary column packed with silica particles chemically modified with vancomycin. Various experimental parameters, such as composition (buffer concentration, water content, organic modifier) and pH of the mobile phase and sample solvent were investigated for method optimization. In order to increase the sensitivity an on-column focusing procedure was applied. Acceptable separation of Bac enantiomers was obtained in less than 11 min eluting in isocratic mode, with 90:10 MeOH/water (v/v) containing 10 mM ammonium acetate at pH 4.5. These optimized experimental conditions were applied to the analysis of human plasma samples spiked with racemic mixture of Bac. The use of a Buckypaper disc as sorbent membrane allows one to recover both enantiomers with yields ≥ 65%. The method was fully validated, following the identification criteria of the European Commission Decision 2002/657/EC.

Pharmacokinetics and toxicity of high-dose baclofen in ICU patients.

BACKGROUND: High-dose baclofen could prove beneficial in patients with unhealthy alcohol use in intensive care units (ICU). However, the pharmacokinetic properties of baclofen are unknown in this population. Our objectives were to investigate the pharmacokinetics of baclofen and the relationship between baclofen exposure and its toxicity in the ICU. MATERIALS AND METHODS: As part of a healthcare quality improvement project, we conducted a prospective, single-center study in a surgical intensive care unit at Nantes University Hospital in order to assess our local protocol of sedation in patients with consumption of alcohol above the recommended limits by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Baclofen pharmacokinetics were investigated by a non-compartment analysis and a population approach in 20 patients under mechanical ventilation. After a baclofen loading dose on day 1, daily doses were divided into 3 intakes adapted to glomerular filtration rate (GFR) and blood samples were withdrawn on day 3 for pharmacokinetic analysis. Baclofen was administered until extubation or tracheostomy and agitation-related events as well as the potential side effects of baclofen were noted. RESULTS: In this population, pharmacokinetic parameters [absorption latency time = 0.37 h, absorption constant rate = 2.2 h-1, apparent volume of distribution = 105 L, apparent clearance (l/h) = 13.5 × (GFR/103)0.839] were characterized by modified absorption and the influence of renal function: renal failure significantly increased baclofen exposure (p = .007) and significantly decreased baclofen clearance (p = .007) compared with patients without renal failure. When comparing patients with or without possible signs of baclofen toxicity, no difference was found regarding baclofen exposure (p = .34) and plasma peak concentration (p = .26). CONCLUSIONS: The a priori planned algorithm for dose adaptation according to renal clearance appeared to be suitable in our population. Daily administration of 150 mg of baclofen in ICU patients with preserved renal function did not lead to toxic concentrations in the plasma. A dose reduction of approximately 40%, 60% and 70% in patients with mild, moderate and severe renal failure could be suggested.

Baclofen-induced encephalopathy in overdose - Modeling of the electroencephalographic effect/concentration relationships and contribution of tolerance in the rat.

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 116 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€¯14 min, P = 0.008) and duration of encephalopathy (18 versus > 24 h, P = 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 µg/L, ±11.3% versus 12,728 µg/L, ±24.0% [mean, coefficient of variation], P = 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.

LC-MS/MS method for quantification of baclofen in hair: A useful tool to assess compliance in alcohol dependent patients?

To evaluate adherence to treatment, we developed and validated a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for baclofen quantification in hair.Twenty mg was washed twice with dichloromethane, incubated in phosphate buffer (pH 5) for 10 minutes at 95°C, then extracted by liquid-liquid extraction in alkaline condition. Baclofen-d4 was used as the internal standard. This method was applied to assess compliance in4 treated alcohol-dependent patients (3 dead and one living). Blood quantification of baclofen and ethanol were performed in the 4 cases. Hair ethylglucuronide (ethanol metabolite, EtG) measurement (2x3 cm) was associated in 1 patient. Baclofen quantification in hair was validated over the range 10-5000 pg/mg. The accuracy was within 96.0%-110.9% and the precision was less than 9.3%. Baclofen segmental (3x2cm) hair concentrations found in the living patient were 4420, 4260, and 4380 pg/mg, reflecting a regular exposure over the last 6 months and suggesting patient compliance. However, the high EtG level found in this patient in the analyzed segments (225 pg/mg and 215 pg/mg) showed excessive alcohol consumption during the same period, suggesting therapeutic failure. In the 3 deceased patients, the non-segmental analysis of hair showed baclofen concentrations of 15, 545, and 2475 pg/mg. The low concentrations in the 2 first cases are compatible either with a poor compliance or to a beginning of a treatment. This is the first measurement of baclofen in hair of alcohol dependent patients. It could be used as a monitoring biomarker to assess patient's compliance.

Validated Method for the Screening and Quantification of Baclofen, Gabapentin and Pregabalin in Human Post-Mortem Whole Blood Using Protein Precipitation and Liquid Chromatography-Tandem Mass Spectrometry.

There has been a rapid increase in the number of prescriptions for baclofen (BLF), gabapentin (GBP) and pregabalin (PGL) in the UK since their introduction to therapy. Recent studies across the European Union and USA have shown the illicit abuse potential of these drugs and deaths have been observed. A simple, reliable and fully validated method was developed for the screening and quantification of BLF, GBP and PGL in human post-mortem (PM) blood. The analytes and their deuterated analogs as internal standard were extracted from blood using a single addition acetonitrile protein precipitation reaction followed by analysis using liquid chromatography-tandem mass spectrometry (LC-MS-MS) with triggered dynamic multiple reaction monitoring mode for simultaneous confirmation and quantification. The assay was linear from 0.05 to 1.00 µg/mL for BLF and 0.5 to 50.0 µg/mL for GBP and PGL, respectively with r2 > 0.999 (n = 9) for all analytes. Intra-day and inter-day imprecisions (n = 80) were calculated using one-way ANOVA; no significant difference (P > 0.99) was observed for all analytes over 8 non-consecutive days. The average recovery for all analytes was >98.9%. The limits of detection and quantification were both 0.05 µg/mL for BLF, and 0.5 µg/mL for GBP and PGL. The method was highly selective with no interference from endogenous compounds or from 54 drugs commonly encountered in PM toxicology. To prove method applicability, 17 PM blood samples submitted for analysis were successfully analyzed. The concentration range observed in PM blood for BLF was 0.08-102.00 µg/mL (median = 0.25 µg/mL), for GBP 1.0-134.0 µg/mL (median = 49.0 µg/mL) and 2.0-540.0 µg/mL (median = 42.0 µg/mL) for PGL.

Self-poisoning with baclofen in alcohol-dependent patients: national reports to French Poison Control Centers, 2008-2013.

BACKGROUND: Alcohol use disorders are frequently associated with self-intoxication in attempted suicide. In France since 2008, the off-label use of baclofen for treatment of alcohol dependence has greatly increased, leading to temporary regulation of use of the drug. At the request of the national authorities, the French Poison Control Centers carried out a retrospective survey to give an overview of baclofen exposure in this population. METHODS: A retrospective study was carried out from January 2008 to December 2013, focusing on baclofen exposures in alcohol-dependent patients managed by the nine national French Poison Control Centers. RESULTS: 294 observations of baclofen exposures in alcohol-dependent patients were identified in our database. Of these, 220 were suicide attempts by self-poisoning and 74 were unintentional. The mean age of patients was 41.7 years, with a sex-ratio of 1.6. Patients attempting suicide with baclofen were younger than those with unintentional exposures, and 43.6% of them were women (vs 22.9%, p < 0.01). The mean supposed ingested dose was higher (480.7 mg) in patients who attempted suicide (vs 192.5 mg, p < 0.0001). 21.8% of intentional exposures involved baclofen alone. Psychiatric comorbidity (50.4%) was more frequent in the group of self-poisoning (p < 0.001). 132 patients were coded as severely exposed (60.0%). Nine victims died, but the causal link between self-poisoning with baclofen and fatal outcome should be interpreted with particular caution. CONCLUSIONS: Baclofen self-poisoning by alcohol-dependent patients is a serious concern for the French health authorities. Our results are similar to those previously published, suggesting that most patients with baclofen overdose should be admitted to an intermediate or intensive care unit as the clinical course requires close monitoring. Because suicidal ideation and suicide attempts are more prevalent in people with substance use disorders than in the general population, and because of the lack of recommendations governing baclofen prescription in such a situation, its use needs to be better controlled.

Liquid chromatography high resolution mass spectrometry for the determination of baclofen and its metabolites in plasma: Application to therapeutic drug monitoring.

Baclofen is used to manage alcohol dependence. This study describes a simple method using liquid chromatography coupled to high-resolution mass spectrometry (LC-HR-MS) developed in plasma samples. This method was optimized to allow quantification of baclofen and determination of metabolic ratio of its metabolites, an oxidative deaminated metabolite of baclofen (M1) and its glucuronide form (M2). The LC-HR-MS method on Exactive® apparatus is a newly developed method with all the advantages of high resolution in full-scan mode for the quantification of baclofen and detection of its metabolites in plasma. The present assay provides a protein precipitation method starting with 100 µL plasma giving a wide polynomial dynamic range (R2 > 0.999) between 10 and 2000 ng/mL and a lower limit of quantitation of 3 ng/mL for baclofen. Intra- and inter-day precisions were <8.1% and accuracies were between 91.2 and 103.3% for baclofen. No matrix effect was observed. The assay was successfully applied to 36 patients following baclofen administration. Plasma concentrations of baclofen were determined between 12.2 and 1399.9 ng/mL and metabolic ratios were estimated between 0.4 and 81.8% for M1 metabolite and on the order of 0.3% for M2 in two samples.

[Identification and quantitative determination of baclofen in human blood by HPLC with mass spectrometry detection]. / Identifikatsiia i kolichestvennoe opredelenie baklofena v krovi metodom VÉZhKh s mass-spektrometricheskim detektirovaniem.

A method of identification and quantitative determination of baclofen in blood by HPLC with mass spectrometry detection has been developed. It is characterized by high sensitivity, specificity, linearity, accuracy, reproducibility, and a low detection for quantitative determination. The method has been used for diagnostics of acute baclofen poisoning in patients.

Baclofen Toxicity Causing Acute, Reversible Dyskinesia.

The following unique case demonstrates an episode of acute dyskinesia secondary to oral baclofen toxicity. We discuss an 80-year-old man with a history of Stage III chronic kidney disease, coronary artery disease, diabetes and stroke who presented to the Emergency Department with new onset of behavioral changes and irregular jerking movements. The patient had been recently prescribed baclofen 10mg twice daily for a back strain he suffered; he subsequently was admitted to the hospital, and his symptoms resolved within 48 hours of admission and discontinuance of baclofen.

Validated Method for the Quantification of Baclofen in Human Plasma Using Solid-Phase Extraction and Liquid Chromatography-Tandem Mass Spectrometry.

A highly sensitive and fully validated method was developed for the quantification of baclofen in human plasma. After adjusting the pH of the plasma samples using a phosphate buffer solution (pH 4), baclofen was purified using mixed mode (C8/cation exchange) solid-phase extraction (SPE) cartridges. Endogenous water-soluble compounds and lipids were removed from the cartridges before the samples were eluted and concentrated. The samples were analyzed using triple-quadrupole liquid chromatography-tandem mass spectrometry (LC-MS-MS) with triggered dynamic multiple reaction monitoring mode for simultaneous quantification and confirmation. The assay was linear from 25 to 1,000 ng/mL (r(2) > 0.999; n = 6). Intraday (n = 6) and interday (n = 15) imprecisions (% relative standard deviation) were <5%, and the average recovery was 30%. The limit of detection of the method was 5 ng/mL, and the limit of quantification was 25 ng/mL. Plasma samples from healthy male volunteers (n = 9, median age: 22) given two single oral doses of baclofen (10 and 60 mg) on nonconsecutive days were analyzed to demonstrate method applicability.

[Lethal intoxication with baclofen].

The objective of the present study was to select and develop simpler methods for the quantitative determination of baclofen in blood with the use of HPLC and tandem MS (MS-MS) techniques and its qualitative determination in cadaveric organs by the GC/MS technique. These mathods were shown to be suitable for the purpose of forensic medical analysis, clinical, toxicological, and therapeutic monitoring. The special emphasis is laid on the methods used to investigate the biological materials obtained from the subjects who died from baclofen intoxication.

Baclofen overdose treated with continuous venovenous hemofiltration.

PURPOSE: Overdose with baclofen, a derivative of the inhibitory neurotransmitter γ-aminobutyric acid, may lead to severe respiratory and central nervous system depression and can be life-threatening. Prolonged half-lives of baclofen, of up to 34 h, have been reported in patients after overdose. Hemodialysis has proven to be a successful approach to improve clearance of baclofen, but the value of continuous venovenous hemofiltration (CVVH) is unclear. We applied CVVH in a patient with acute baclofen overdose. METHODS: Pharmacokinetic measurements of baclofen in serum and hemofiltrate were made at six time points after hospital admission. Baclofen concentration-time data were analyzed using non-compartmental methods, and the relative contribution of clearance by hemofiltration to total baclofen clearance was calculated. RESULTS: Baclofen concentrations in serum varied between 1.81 and 0.05 mg/L. Concentrations of baclofen in hemofiltrate were within the same range (between 0.74 and 0.05 mg/L), and the elimination half-life during hemofiltration was estimated at 4.8 h. Total clearance and clearance via hemofiltration were estimated at 6.6 and 2.4 L/h, indicating that clearance could be increased by approximately 57 % by applying hemofiltration. CONCLUSIONS: The presented case demonstrates the usefulness of CVVH in the treatment of baclofen overdose and indicates that CVVH can be used as an alternative to hemodialysis in patients with overdose of baclofen.

A pilot study assessing pharmacokinetics and tolerability of oral and intravenous baclofen in healthy adult volunteers.

Our objective was to characterize baclofen pharmacokinetics and safety given orally and intravenously. Twelve healthy subjects were enrolled in a randomized, open-label, crossover study and received single doses of baclofen: 3 or 5 mg given intravenously and 5 or 10 mg taken orally with a 48-hour washout. Blood samples for baclofen analysis were collected pre-dose and at regular intervals up to 24 hours post-dose. Clinical response was assessed by sedation scores, ataxia, and nystagmus. Mean absolute bioavailability of oral baclofen was 74%. Dose-adjusted areas under the curve between the oral and intravenous arms were statistically different (P = .0024), whereas area under the curve variability was similar (coefficient of variation: 18%-24%). Adverse effects were mild in severity and not related to either dose or route of administration. Three- and 5-mg intravenous doses of baclofen were well tolerated. Seventy-four percent oral bioavailability indicates that smaller doses of intravenous baclofen are needed to attain comparable total drug exposures.

Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy.

OBJECTIVE: To characterize the population pharmacokinetics (PK) of oral baclofen and assess impact of patient-specific covariates in children with cerebral palsy (CP) in order to support its clinical use. SUBJECTS DESIGN: Children (2-17 years of age) with CP received a dose of titrated oral baclofen from 2.5 mg 3 times a day to a maximum tolerated dose of up to 20 mg 4 times a day. PK sampling followed titration of 10-12 weeks. Serial R- and S-baclofen plasma concentrations were measured for up to 16 hours in 49 subjects. Population PK modeling was performed using NONMEM 7.1 (ICON PLC; Ellicott City, Maryland). RESULTS: R- and S-baclofen showed identical concentration-time profiles. Both baclofen enantiomers exhibited linear and dose/kg-proportional PK, and no sex differences were observed. Average baclofen terminal half-life was 4.5 hours. A 2-compartment PK model with linear elimination and transit absorption steps adequately described concentration-time profiles of both baclofen enantiomers. The mean population estimate of apparent clearance/F was 0.273 L/h/kg with 33.4% inter-individual variability (IIV), and the apparent volume of distribution (Vss/F) was 1.16 L/kg with 43.9% IIV. Delayed absorption was expressed by a mean transit time of 0.389 hours with 83.7% IIV. Body weight, a possible genetic factor, and age were determinants of apparent clearance in these children. CONCLUSION: The PK of oral baclofen exhibited dose-proportionality and were adequately described by a 2-compartment model. Our population PK findings suggest that baclofen dosage can be based on body weight (2 mg/kg per day) and the current baclofen dose escalation strategy is appropriate in the treatment of children with CP older than 2 years of age.

Pharmacokinetic characterization of baclofen in patients with chronic kidney disease: dose adjustment recommendations.

The pharmacokinetics of baclofen is well delineated in subjects with normal kidney function (KF); however, pharmacokinetics data in patients with chronic kidney disease (CKD) are not and dosage recommendations remain empirical. The effects of CKD on baclofen pharmacokinetics were assessed through a multi-center, open-label, single 5-mg dose, pharmacokinetics study. The KF was measured as the creatinine clearance (CrCL) calculated with the Cockroft-Gault (C-G) equation or as the estimated glomerular filtration rate (eGFR) using subjects' CKD-EPI equation. Subjects were assigned to 1 of 4 groups based on their CrCL (>80 mL/min, 50-80 mL/min; 30-50 mL/min and <30 mL/min). Cmax was not statistically different between the groups, while AUC and T1/2el increased, and CL/F decreased, with increasing severity of CKD. Baclofen's oral clearance and CrCL were statistically significantly correlated, and the trend was the same when classifying subjects either with the CKD-EPI or C-G equations. Linear equations using KF as variable were set to recommend individual dose reduction in CKD patients. Results suggest a mean dose reduction of 1/3, 1/2, and 2/3 in patients with mild, moderate, and severe CKD respectively, in order to achieve baclofen exposure comparable to that observed in healthy subjects.