Gabapentin neurotoxicity in a chronic haemodialysis patient

the elderly and in individuals with impaired renal function. We report here the case of a chronic haemodialysis patient who developed signs of neurological toxicity due to gabapentin overdosage. The pharmacokinetics of gabapentin after a 300 mg oral dose were also studied. - Sir, Gabapentin (1-(aminomethyl) cyclohexane acetic acid), a structural analogue of gamma-aminobutyric acid (GABA), has been developed for the treatment of epilepsy. Unlike GABA, gabapentin crosses the blood-brain barrier after systemic administration. Its precise antiepileptic mechanism of action is unknown w1x. Gabapentin is an effective antiepileptic drug in patients with partial and secondarily generalized seizures which remain uncontrolled with existing anticonvulsant drug therapy w2x. In one case, gabapentin was also effective in brachoradial pruritus w3x and in another case in the treatment of post herpetic neuralgia w4x. Following oral administration and intestinal absorption gabapentin is excreted unchanged in urine w5x. Gabapentin clearance is linearly related to creatinine clearance and is decreased in Case. The patient was a 35-year-old female who had epilepsy with generalized tonic seizures for the first time at the age of 12 years. She developed chronic renal failure of unknown origin at the age of 33. One year later, she started intermittent haemodialysis treatment, three times per week. She received valproic acid and was maintained on 1500 mguday in divided doses, with serum levels of 60 pguml (therapeutic levels of 60100 pguml), diazepam 5 mguday, clonazepam 2 mguday, and lamotrigine 25 mg tid. When the patient developed thrombopenia, this was attributed to valproic acid and the drug was stopped progressively. It was replaced by gabapentin 400 mguday. Three weeks later, the patient developed absences, but the electroencephalogram showed no epileptic activity. The plasma gabapentin level was 56.2 mgul (reference level 210 mgul). The dose of gabapentin was decreased to 300 mg following each haemodialysis session. A pharmacokinetic study was performed after the oral administration of 300 mg of gabapentin. Blood samples were collected just before the dialysis session and 2, 4, 12, 24, 48 and 72 h later. The last sample was withdrawn just before the following haemodialysis session. Another blood sample was collected at the end of this dialysis session. Plasma gabapentin concentrations were determined by high-performance liquid chromatography (HPLC). The haemodialysis session lasted 4 h using a polyflux 8 l membrane (synthetic polyamide dialyser, surface area 1.8 m2, thickness 45 mm), with a double needle access to her arteriovenous fistula, with a constant dialysate flow rate at 500 mlumin and a blood flow rate of between 250 to 300 mlumin. Pharmacokinetics. Pharmacokinetic analysis showed that at time 0 before administration of the 300 mg dose, plasma gabapentin concentration was 20.2 mgul. Maximum plasma concentration (Cmax) was 29.4 mgul, area under the concentration-time curve from 0 to infinity (AUC(0-inf )) was 81361 mg hul, and elimination half-life (T1u2) was 2257 h. Discussion. Drug therapy for epilepsy continues to be a challenge for clinicians and patients. Because a significant number of patients exhibit refractory epilepsy, the long-term administration of multiple drug regimens is often required w5x. Gabapentin has a wide therapeutic range. Its major sideeffects include fatigue, somnolence, dizziness, ataxia and visual disturbances w3x. Pharmacokinetic studies in humans have shown that gabapentin is not metabolized, is not bound to serum proteins, and is cleared by renal excretion alone w1x. Gabapentin dosage should thus be adjusted to renal function w1x. For patients with end-stage renal disease maintained on haemodialysis, an initial loading dose of 300400 mg of gabapentin has been recommended w6x. Approximately 35% of gabapentin is removed during a haemodialysis session w6x. Accordingly, administration of 200300 mg of gabapentin after each 4-h dialysis session may replace cleared gabapentin, and may therefore be sufficient to maintain steadystate plasma concentration similar to that in patients with normal renal function w6x. Our patient initially received 400 mguday of gabapentin and developed absences. Gabapentin serum levels at that time were very high. This is in contrast to the suggestion by Verma et al. that gabapentin is extremely well-tolerated even in haemodialysis patients with high serum concentration w7x. Our pharmacokinetic study showed that even the recommended dose of 300 mg gabapentin w6x after each haemodialysis session was excessive and that the patient had very high serum levels. Gabapentin pharmacokinetic values in our patient differed from those previously reported by Wong et al. in haemodialysis patients w6x. However, the pharmacokinetic parameters of gabapentin in our patient should not be compared to those of Wong et al. since our patient was clearly overdosaged. At time 0 before administration, the parameters were already much higher than the Cmax of haemodialysed patients (6 mgul) reported by Wong et al. w6x or in non-uraemic subjects (2.7 mgul) after a dose of 300 mg. Furthermore, gabapentin is not metabolized and is entirely excreted in urine with a clearance that is linearly proportional to creatinine clearance. Consequently, in patients with terminal renal insufficiency accumulation of gabapentin occurs. Gabapentin is a highly hydrophilic compound which diffuses into adipose tissues only weakly. Therefore, excessive accumulation of the drug in plasma easily leads to a concomitant accumulation in cerebrospinal fluid and neurotoxicity. For these reasons, the dose of gabapentin was decreased in our patient to as low as 100 mg after each haemodialysis session. During the subsequent 4 months the patient experienced neither absences nor epileptic seizures. We therefore suggest that in chronic haemodialysis patients gabapentin treatment be initiated with a 300-mg loading dose, as previously advised by Wong et al. w6x. However, post-haemodialysis dosing should be reduced to 100 mg. Furthermore, our case illustrates that in haemodialysis patients plasma gabapentin levels should be monitored if there is a suspicion of drug-induced sideeffects, even in patients receiving the minimal recommended dosage. Acknowledgement. We thank Dr Elisabeth Rey of the Department of Pharmacology, Saint-Vincent de Paul Hospital, Paris, France for her assistance in plasma gabapentin determinations. 2Pitie-Salpetriere Hospital (...truncated)