Treatment of baclofen overdose by haemodialysis: a pharmacokinetic study
Vin-Cent Wu1,2,
Shuei-Liong Lin2,
Shu-Meng Lin3 and
Cheng-Chung Fang3
1 Department of Internal Medicine, Far Eastern Memorial Hospital, 2 Department of Internal Medicine and 3 Department of Emergency Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
Correspondence and offprint requests to: Dr Cheng-Chung Fang, Departments of Emergency Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan. Email: conrad{at}ha.mc.ntu.edu.tw
Keywords: baclofen; haemodialysis; intoxication; pharmacokinetics
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Introduction
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Baclofen is currently used in the treatment of muscle spasticity, especially in patients with multiple sclerosis or in patients with spinal or cerebral disorders. Baclofen is eliminated predominantly by the kidneys [1], putting patients with impaired renal function at particular risk for baclofen accumulation. Several investigators have suggested that haemodialyis is effective in the removal of baclofen [2], however the pharmakokinetics of baclofen elimination during haemodialysis remains unclear. We herein report a baclofen-associated encephalopathy, which was resolved by haemodialysis, and pharmacokinetic data is presented. To our knowledge, this is the first reported case of baclofen-related encephalopathy with pharmacokinetic data during haemodialysis treatment.
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Case
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A 70-year-old woman with end-stage renal disease (ESRD) was treated by haemodialysis regularly for 14 years. She was anuric and received adequate haemodialysis at Kt/V 1.95. She presented with left leg soreness and was given 5 mg of oral baclofen three times daily from the local clinic, receiving a cumulative dose of 45 mg in 3 days. The patient became disoriented, in a state of confusion and was referred to our hospital for evaluation. At admission, she was found drowsy, her blood pressure was 199/60 mmHg and temperature 36.7°C. Laboratory data showed haemoglobin 8.1 g/dl, WBC 4900/mm3, with a normal differential count and platelets 268 000/mm3. Serum sodium was 147.4 mmol/l, potassium 4.42 mmol/l, ammonia <1 µmol/l, sugar 107 mg/dl, urea 51 mmol/l and creatinine 8.26 mg/dl. The transaminases were normal. A brain CT scan showed cortical atrophy and leukoaraiosis. Under the diagnosis of baclofen intoxication, she received emergency haemodialysis. The dialyser had ethylene vinyl alcohol copolymer resin filters with a surface area of 2.0 m2, and the blood flow rate was at a constant 300 ml/h for 4 h without ultrafiltration. There was a complete recovery of consciousness 8 h later. She received another haemodialysis session 30 h after admission. The patient was discharged from the hospital 72 h later in good condition.
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Results
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Serum baclofen concentrations
Blood samples were collected immediately after arrival, and at 4 (start of first haemodialysis), 5, 6, 7, 8 (end of first haemodialysis), 30 (start of second haemodialysis), 32 and 34 h (the end of second haemodialysis) thereafter. Samples of serum were prepared according to the methods published in previous reports with minor modifications [3]. In brief, serum samples (1 ml) were prepared by adding 200 µl of the internal standard [1 µg/ml of 3-amino-3-(4-chlorophenyl)-propionic acid] and 20 µl of 85% ortho-phosphoric acid and then were loaded into Oasis HLB SPE columns (Waters) for extraction. Gas chromatography/mass spectrometry analysis was performed on an Agilent 5890 gas chromatograph coupled with a 5973 mass selective detector and a 7683 injector. Quantitative analysis was carried out on the Agilent ChemStation. Calibrators were baclofen spiked serum samples at concentrations of 25, 50, 200 and 500 ng/ml. The serial serum concentrations of baclofen after admission are shown in Figure 1.

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Fig. 1. Changes of serum baclofen levels with time. (A) The first haemodialysis session. (B) second haemodialysis session.
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Pharmacokinetic calculations
During dialysis, solute elimination occurs via the first-order kinetic process [4]. The distribution of a drug in a dialysed, renal failure patient can be expressed by a one-compartment model [4]. As a result, baclofen plasma concentration (C) vs time profile may be described with the following equation:
where C0 = plasma concentration at admission; Ke = the total elimination rate constant; and t = time after admission.
Furthermore, during dialysis, the total elimination constant rate (Ke) equals the non-renal removal rate constant (Knr), plus the renal removal rate constant (Kr), plus the dialysis removal rate constant (Kd). Kr equals zero in this anuria patient, and Knr can be calculated from the two samples collected before haemodialysis. Therefore, the Kd can be calculated by the given Ke and Knr. The pharmacokinetic data of baclofen in this patient are Ke = 0.336/h, Knr = 0.045/h and Kd = 0.291/h; while the data of total elimination half-life (t1/2) during haemodialysis is 2.06 h, 15.5 h for non-renal t1/2.
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Discussion
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Baclofen is a ß-(p-chlorophenyl) derivative of the neurotransmitter
-aminobutyric acid (GABA). This centrally acting GABA agonist is prescribed as therapy for spasticity in the spinal cord region. Ingested baclofen is absorbed rapidly and completely, thereafter 6985% are excreted without changes in urine and 15% are metabolized by the liver to its inactive deaminated product, ß-(p-chlorophenyl)-
-hydroxybutyric acid [1,5]. The half-life is between 4.5 and 6.8 h in healthy subjects, but increases in ESRD, and an accumulation phenomenon can occur [1]. Baclofen is moderately lipophilic, 30% of the drug is protein bound, and can penetrate the bloodbrain barrier, entering the central nervous system after systemic application [6]. Concentrations of baclofen in cerebral spinal fluid (CSF) have been described to be 8.4 times lower than those simultaneously present in plasma [5]. It has a volume of distribution of 0.83 l/kg in adult [7] and 2.58 l/kg in children [8].
The therapeutic range of baclofen is
80400 ng/ml in normal subjects [9], but the appropriate serum level of baclofen in patients with severely impaired renal function remains unclear. Several authors have suggested that patients with renal failure are more susceptible to baclofen toxicity [2]. This may explain why our patient was comatose, although her plasma baclofen concentrations were all within the therapeutic range of normal subjects.
Several observations of baclofen-associated encephalopathy have been reported in patients with ESRD [10]. Patients with severely impaired renal function generally develop baclofen intoxication soon after the initiation of therapy [2]. Altered consciousness has been the major manifestation in patients with severely impaired renal function. Other symptoms, such as respiratory depression muscular hypotonia and generalized hyporeflexia have been observed in patients of baclofen intoxication with normal renal function [2]. Most ESRD patients experienced marked improvement in clinical toxicity following haemodialysis, compared with patients who did not receive haemodialysis [2]. We measured the changes of baclofen serum concentration during haemodialysis and found that the serum baclofen eliminated up to 79% during the 4 h of the haemodialysis session. Haemodialysis shortened the baclofen half-life from 15.5 to 2.06 h in this patient. Therefore, it is reasonable to suggest that haemodialysis should be used as a treatment modality in cases of baclofen intoxication with renal failure.
According to a previous report, patient consciousness improved with several hours time lag after haemodialysis [2]. This delay may be due to the redistribution of baclofen in crossing the bloodbrain barrier [2]. This may explain longer central nervous system depression despite reductions in serum drug concentrations to negligible amounts. The consciousness improved after just one session of haemodialysis in this patient, which was different from previous reports where two or more sessions were necessary [2]. Because there were no serum levels and other pharmacokinetic data in previous reports [2], it is difficult to compare the effectiveness of haemodialysis in this report. In our patient, early diagnosis, early start of haemodialysis and lower serum concentrations of baclofen may have resulted in the difference. The larger surface area of our artificial kidney may be another possible cause.
In conclusion, it is necessary to reduce baclofen dosage in patients with renal disease and especially in ESRD patients. Haemodialysis is an appropriate treatment of baclofen intoxication in ESRD patients.
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Acknowledgments
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The authors thank Dr Chun-Chen Yang for comments and criticism of this article. This study was supported by The Ta-Tung Kidney Foundation.
Conflict of interest statement. None declared.
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Received for publication: 27.12.03
Accepted in revised form: 5. 4.04