Lamotrigine substitution study: evidence for synergism with sodium valproate?
Introduction
Lamotrigine (LTG, Lamictal®, 6-[2,3-dichlorophenyl]-1,2,3-triazine-3,5-diamine) is a new antiepileptic drug (AED) that has been shown to be effective in controlled trials as add-on and monotherapy for partial seizures with and without secondary generalisation and for idiopathic tonic-clonic seizures 3, 10, 12, 18. Anticonvulsant polytherapy frequently results in marginal or no improvement in seizure control, whereas side-effects and pharmacokinetic interactions are substantially more common 1, 17. Indeed, enzyme inducers such as carbamazepine (CBZ), phenytoin (PHT) and phenobarbital (PB) accelerate lamotrigine (LTG) metabolism, whereas sodium valproate (VPA) inhibits it [2]. This has led to the practice of treating patients with a single AED whenever possible 4, 16. The early clinical experience with LTG, as with all new AEDs, has been as adjuvant therapy, and a frequently asked question is whether the original AED could be withdrawn in responders. This multicentre study was performed in patients with poorly controlled epilepsy receiving treatment with a single AED, to assess whether it was possible to withdraw the original agent in patients responding to additional LTG.
Section snippets
Patient characteristics
Patients entering the study had to be at least 16 years of age, receiving treatment with a single AED (VPA, CBZ or PHT in all centres and PB in some centres), and had to have experienced at least two seizures per month during the pre-trial baseline on unchanged medication. Each had to have a confident diagnosis of epilepsy uncomplicated by pseudoseizures, but could be suffering from any seizure type according to the International Classification [7].
Study design
Patients who had kept a 12 week baseline
Accountability
A total of 347 patients from 54 centres were recruited, 345 (99%) of whom entered the add-on phase. Table 2 summarises the demographic data and seizure histories at the start of the trial. The groups appear balanced for all characteristics, apart from seizure type. Seventy-two percent of patients taking VPA had idiopathic epilepsy compared with 49% for CBZ and 61% for PHT. As there were only nine patients taking PB, these data will not be further discussed although they are included in the
Discussion
This open study provided a number of intriguing results. When LTG was added to the patients' existing AED therapy, nearly half had a seizure reduction of at least 50%. The response in patients with idiopathic tonic-clonic seizures was significantly better than that for partial seizures with or without secondary generalisation. This provides further evidence that LTG is particularly effective against idiopathic seizures [20]. In addition, 17% of patients with treatment-resistant seizures were
Acknowledgements
We gratefully acknowledge the contribution of the following investigators who recruited patients for the study.
Austria: Professor E. Ott, Graz; Belgium: Dr P. Louis, Antwerp; Dr P. Tugendhaft, Brussels; Dr M. Van Zandijcke, Brugge; Denmark: Dr J. Ankerlius, Vejle; Dr J. Boas, Glostrup; Dr M. Dalby, Aarbus; Professor M. Dam, Hvidovre; Dr M. Friis, Odense; Dr J. Hansen, Sonderborg; Professor P. Hubbe, Frederiksberg; Dr B. Pederson, Aalborg; Dr P. Sorensen, Copenhagen; France: Dr A. Arzimanoaglou,
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