Elsevier

Epilepsy Research

Volume 26, Issue 3, February 1997, Pages 423-432
Epilepsy Research

Lamotrigine substitution study: evidence for synergism with sodium valproate?

https://doi.org/10.1016/S0920-1211(96)01007-8Get rights and content

Abstract

Three hundred and forty seven patients with epilepsy from 54 centres across Europe not fully controlled with sodium valproate (VPA, n=117), carbamazepine (CBZ, n=129), phenytoin (PHT, n=92) or phenobarbital (PB, n=9) monotherapy were recruited into a lamotrigine (LTG) substitution study. If 50% or more seizure reduction occurred (responders) on addition of LTG, an attempt was made to withdraw the original antiepileptic drug (AED). If successful, this was followed by a 12 week period of LTG monotherapy. Overall, 73% patients completed the add-on phase (47% responders), 41% attempted AED withdrawal and 23% achieved LTG monotherapy. In the 60 patients (17%) completing the trial by remaining on LTG monotherapy, median monthly seizure frequency was reduced from 6 during baseline to 1.7. Sixteen percent of patients were withdrawn due to adverse effects, mostly during the add-on phase. Dizziness and diplopia occurred most frequently in the CBZ group, nervousness and ataxia in the PHT group, and rash and tremor in the VPA group. Slower LTG dose escalation resulted in fewer withdrawals due to rash in the VPA-treated patients (38% to 8%, P<0.01). The responder rate was higher (P<0.01) in patients with idiopathic tonic-clonic seizures (61%) than in those with partial seizures (43%). The addition of LTG to VPA (64% responders) produced a significantly better response (P<0.001) than adding it to CBZ (41% responders) or PHT (38% responders). This effect was seen for partial (VPA, 57%; CBZ, 39%; PHT, 39%; P<0.02) as well as tonic-clonic seizures (VPA, 70%; CBZ, 53%; PHT, 50%; NS). These data lend credence to the suggestion of therapeutic synergy between LTG and VPA.

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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