New antiepileptic drugs

In recent years, several new antiepileptic drugs have been introduced. These drugs are used as add-on therapy in patients whose epilepsy is not controlled by established treatments. Vigabatrin is used in partial or focal epilepsy and infantile spasms. Lamotrigine is particularly useful in treating generalised epilepsies. Gabapentin, topiramate and tiagabine are effective in the treatment of partial epilepsies, but their efficacy in generalised epilepsies is not established. All the new drugs have potential adverse effects, some of which may be serious, and their safety in pregnancy is unknown.

Over the past 5 years, new drugs have been marketed in Australia for the treatment of epilepsy. These drugs can be used as add-on therapy in the treatment of patients with partial and, in some cases, generalised epilepsy, not controlled by antiepileptic drugs. The established antiepileptic drugs remain as first-line treatment. Sodium valproate is the drug of choice in most patients with generalised epilepsy and particularly for the management of absence and myoclonic seizures. Carbamazepine is best for patients with partial or focal epilepsy, in particular complex and simple partial seizures. However, the established antiepileptic drugs have potential adverse effects and are known to be teratogenic, and not all patients respond to treatment. There is, therefore, a need for other treatments for some patients and the new drugs are a welcome addition.

Vigabatrin is an analogue of GABA (gamma-aminobutyric acid), an inhibitory neurotransmitter. The drug increases GABA levels by irreversibly inhibiting GABA transaminase, the enzyme responsible for the catabolism of GABA.

This mechanism of action means that plasma concentrations do not correlate with therapeutic or toxic effects and are not measured routinely in clinical practice. The dose is 1500-3000 mg/day, usually given in two divided doses. The drug is not a liver enzyme inducer and is not bound to plasma proteins. Vigabatrin can cause a small reduction in plasma concentrations of phenytoin when the drugs are used together.

Vigabatrin is particularly effective in the treatment of partial or focal epilepsies. It is also effective for treating infantile spasms and, in some centres, vigabatrin is first-line treatment for this condition. The drug is less effective in generalised epilepsies. It may exacerbate absence and myoclonic seizures and should be avoided in these conditions. The effectiveness of vigabatrin as monotherapy has not been established, although preliminary studies suggest the drug is comparable to carbamazepine.

Adverse effects include drowsiness, mood changes with depression and aggression, and rarely psychosis. The drug should be avoided in patients with a past history of significant psychiatric illness. Safety in pregnancy has not been established. More recently, there have been concerns regarding the development of visual loss in patients treated with vigabatrin. This may be due to retinal toxicity, but the significance and frequency of this adverse effect are unclear.

Lamotrigine acts by blocking voltage-dependent sodium channels and inhibiting the release of excitatory amino acids. This may stabilise neurons in epileptic foci.

The half-life of lamotrigine, when given as monotherapy, is approximately 30 hours. Patients should begin with a low dose, which is then increased at two-week intervals until an optimum response is achieved. Sodium valproate inhibits the metabolism of lamotrigine, increasing the half-life from 30 hours to 60 hours. Enzyme-inducing drugs such as carbamazepine and phenytoin reduce the half-life to approximately 15 hours. Lamotrigine may also interact with carbamazepine resulting in ataxia and diplopia. These resolve on reduction of either the carbamazepine or lamotrigine dose. The basis of the interaction is unclear. Lamotrigine is not highly protein-bound (55% bound), nor a liver enzyme inducer.

Patients begin lamotrigine with 25 mg/day if treated with a liver enzyme inducer, and 25 mg every second day if taking sodium valproate. The maximum daily dose for patients not on sodium valproate is approximately 200-400 mg and if on sodium valproate, a maintenance dose of 100-200 mg is recommended. Usually two divided doses are given to minimise adverse effects. The clinical value of monitoring plasma levels is unclear.

Lamotrigine has a broad spectrum of action. It is effective in both partial and generalised epilepsy. Studies in patients with intractable partial epilepsy reported 22% of patients achieved at least a 50% reduction in seizure frequency. Postmarketing experience has shown lamotrigine to also be useful in generalised epilepsy and it has become a useful alternative to sodium valproate in the treatment of primary generalised epilepsy. The drug is also effective in treating secondary generalised epilepsy, in particular Lennox Gastaut syndrome, a condition usually refractory to other therapy.

Although lamotrigine is currently marketed as add-on therapy, several international trials have assessed its effectiveness as monotherapy in the treatment of patients with newly diagnosed epilepsy. The results suggest lamotrigine is as effective as carbamazepine and phenytoin, but is associated with fewer adverse effects.

Adverse effects of lamotrigine include a cutaneous reaction which appears to be more common in patients also being treated with sodium valproate, in children, and if the dose of lamotrigine is increased rapidly. The rash is usually a maculopapular rash, but more serious reactions including Stevens-Johnson syndrome have been reported. Other adverse effects include headache and dizziness that appear to be dose related. The safety in pregnancy is not established. An unusual but useful feature of lamotrigine is that patients often report or are noted by their family to be more alert.

Gabapentin is a structural analogue of GABA, but its mode of action is unclear. It has a short half-life (6 hours), is not bound to plasma proteins, is not a liver enzyme inducer and its pharmacokinetic profile is characterised by a lack of drug interactions. The value of monitoring gabapentin plasma concentrations is unclear and is currently not routine.

The drug is effective in the treatment of partial seizures. Most of the early studies used a daily dose of 900-1800 mg, but postmarketing experience and subsequent trials have shown greater efficacy at much higher doses. Daily doses of up to 2400 mg, if tolerated, are now recommended. The efficacy of gabapentin in the management of generalised epilepsies, in particular the treatment of absence and myoclonic seizures, is not established.

Adverse effects are relatively uncommon with drowsiness, somnolence and fatigue often being dose related. These symptoms may occur when starting the drug and often resolve with time. The safety of gabapentin in pregnancy is not known.

Topiramate has several mechanisms of action. These include blocking voltage-dependent sodium channels, enhancing the activity of GABA, blocking excitatory transmission and weak inhibition of carbonic anhydrase isoenzymes. Topiramate is not highly protein-bound (15% bound), is rapidly absorbed and has a relatively long half-life (18-23 hours). It is usually given twice a day because its plasma concentration is decreased when it is taken in combination with phenytoin or carbamazepine. The drug has weak enzyme-inducing properties that may reduce the efficacy of the oral contraceptive pill.

Clinical trials have shown the efficacy of topiramate in partial onset epilepsy, particularly in reducing the frequency of secondarily generalised seizures. There are clinical reports of its value in treating generalised epilepsy including the Lennox Gastaut syndrome. The recommended daily dose is 200-400 mg in divided doses. The value of monitoring plasma topiramate levels is uncertain.

Tiagabine is the latest of the new antiepileptic drugs. It inhibits GABA reuptake, thereby increasing GABA levels. The drug is highly protein-bound (96% bound) and has a short half-life (5-8 hours). While tiagabine has been shown to be useful in the treatment of partial epilepsies, its efficacy as monotherapy and in generalised epilepsies has not been established. The recommended initial dose is 7.5 mg/day given as 3 divided doses and gradually increased, as tolerated, up to 30 mg/day. The clinical value of monitoring plasma tiagabine levels is unclear. The most common adverse effect is somnolence, particularly following introduction of the drug, which is usually dose related. The safety of tiagabine in pregnancy is unknown.

The new antiepileptic drugs are currently used as add-on therapy for the management of patients with seizure disorders. The new antiepileptic drugs reduce seizure frequency by more than 50% in 25-50% of the patients treated with conventional antiepileptic drugs. Their role as monotherapy is as yet unclear and the spectrum of activity and the role of these drugs in treating seizure disorders will become better defined. Vigabatrin and gabapentin are useful in the treatment of partial seizures and lamotrigine in the treatment of both partial and generalised seizures. The role of topiramate and tiagabine is less well established, but studies suggest efficacy in the treatment of partial seizures. Topiramate will probably also have a role in the management of generalised epilepsies.

Given the overlap in clinical indications, choice of one of the newer antiepileptic drugs is often based on known adverse effects, interactions (see box) and familiarity with using a particular drug. It is likely that some of these drugs will become alternative first-line treatments.

Beydoun A. Monotherapy trials of new antiepileptic drugs. Epilepsia 1997;38 (9 Suppl):21S-31S.

Fisher RS. Emerging antiepileptic drugs. Neurology 1993;43(5 Suppl): 12S-20S.

Kilpatrick C. The role of newer anticonvulsants in the management of epilepsy. Aust N Z J Med 1995;25:114-6.

Smith D, Baker G, Davies G, Dewey M, Chadwick DW. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia 1993;34:312-22.

The following statements are either true or false.

1. All the new antiepileptic drugs can be used as add-on therapy for partial seizures.

2. The effect of the oral contraceptive pill may be reduced by topiramate.