Original article
Clinical
Allopurinol as Adjunctive Therapy in Intractable Epilepsy: A Double-blind and Placebo-controlled Trial

https://doi.org/10.1016/j.arcmed.2006.10.010Get rights and content

Background

Adenosine has been proposed to be an endogenous anticonvulsant agent. It inhibits glutamate release from excitatory neurons and neuronal firing. Therefore, adenosine agonists have potential clinical application as antiepileptics. In this double-blind randomized, placebo-controlled trial, we assessed the antiepileptic effect of allopurinol as an adjuvant agent in 38 patients with refractory epilepsy.

Methods

Thirty eight patients were randomly allocated equally to allopurinol + preexisting antiepileptic (Group A) or placebo + preexisting antiepileptic (Group B) for a 6-month, double-blind, placebo-controlled study. The dose of allopurinol was titrated up to 300 mg/day (100 mg TDS). The dose of preexisting medications was maintained without change over the trial. The effect of allopurinol was evaluated by a reduction in the total number of seizures per month and duration of seizure attacks.

Results

Of 38 participants, 32 patients completed the study. There were significant differences between the two groups in terms of reduction in the total number of seizure over the trial. Seizures reduction of >30% in 66%, >50% in 55%, and >60% in 44% of cases in the allopurinol group was achieved after 2 months and persisted during the study. Nevertheless, only during month 4 was there a significant difference between the two groups regarding reduction in seizure duration. In the allopurinol group, two patients had transient rashes, two patients had mild nausea, and two experienced dizziness, but only one patient discontinued the drug due to dizziness. In the placebo group, one patient had rash and one patient had nausea. In addition, no significant hematological or hepatic changes were found during the trial in both groups.

Conclusions

The results suggest allopurinol as a safe and effective adjuvant agent in refractory epilepsy. Based on this study, we suggest that purine metabolism pathways and the specific use of allopurinol should be further investigated with regards to neurobiology and treatment of refractory epilepsy.

Introduction

Adenosine receptors are widely distributed throughout the body. There are increasing therapeutic applications for adenosine receptor agonists and antagonists that act through the four adenosine receptor subtypes AI, A2A, A2B, and A3 1, 2, 3, 4, 5. Adenosine has been proposed to be an endogenous anticonvulsant agent, inhibiting glutamate release from excitatory neurons and neuronal firing. Adenosine agonists therefore have potential clinical applications as antiepileptics (4). Recently, the xanthine oxidase inhibitor allopurinol, which inhibits purine degradation, was suggested for treatment of refractory epilepsy (6). It has been reported that allopurinol exerts its anticonvulsant effect through inhibiting the synthesis of quinolic acid and kynurenine, two endogenous excitatory neurotransmitters 4, 5, 6.

Nevertheless, the efficacy of allopurinol in different clinical trials is not the same 7, 8, 9, 10, 11, 12. In this double-blind randomized, placebo-controlled trial in 38 adult patients with idiopathic refractory epilepsy, we assessed the safety and antiepileptic effect of allopurinol as adjuvant agent.

Section snippets

Trial Organization

The study was a 6-month, parallel group, placebo-controlled trial undertaken in the outpatient neurology clinic of Sina General Hospital, Tehran University of Medical Sciences, Tehran, Iran from January 2003 to January 2006.

Participants

Participants were epileptic patients between the ages of 18 and 55 years. Patients who met the following criteria were admitted to the trial: clearly recognizable and reliably documented idiopathic epileptic seizure, seizure frequency not less than 3 per month, no response

Results

Thirty eight patients were randomized to trial medication. No significant differences were identified between patients randomly assigned to Group A or B with regard to basic demographic data including age and gender (Table 1). Six patients dropped out of the trial leaving 32 patients who completed the trial (two from allopurinol [one due to dizziness and one due to no response] and four patients from the placebo group [three patients due to no response and one due to nausea]). Seizure types in

Discussion

The rationale to use allopurinol for its antiepileptic effect in different types of seizures was derived from previous evidence of its efficacy in refractory seizures 7, 8, 9, 10, 11, 12. Concerning the putative mechanism of action, allopurinol is an inhibitor of the enzyme xanthine oxidase, the final step in purine metabolism, converting hypoxanthine and xanthine into uric acid 1, 2, 3, 4, 5.

Accumulation of hypoxanthine and xanthine may favor the action of the enzyme

Acknowledgments

The authors would like to thank Dr. T. Tolyat who was involved in preparing the placebo and to the staff of Iran Epilepsy Society (especially Ms. F. Javadi) for their kind help to the study team. We would also like to thank Dr. A.R. Noorian for assistance in editing the draft of the paper.

References (13)

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