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The new antiepileptics

MagazineOctober 2005 (Vol. 16 Issue 7)The new antiepileptics

The traditional, or first-line, antiepileptic drugs (AEDs) - such as carbamazepine, phenobarbitol, phenytoin, primidone and valproate sodium - may have a high success rate in newly diagnosed cases (capable of rendering nearly 80 per cent of patients seizure-free), but they bring with them a host of unwanted side-effects

The traditional, or first-line, antiepileptic drugs (AEDs) - such as carbamazepine, phenobarbitol, phenytoin, primidone and valproate sodium - may have a high success rate in newly diagnosed cases (capable of rendering nearly 80 per cent of patients seizure-free), but they bring with them a host of unwanted side-effects. These can include rickets, weight gain, enlargement of the gums, reproductive dysfunction, and a long list of mental and behavioural side-effects - not to mention the possible dangerous interactions with commonly prescribed medications such as the blood-thinner warfarin and the Pill.

These drugs are the dinosaurs of the pharmaceutical industry - for example, phenobarbitol has been around for nearly a century. As a result, they are familiar, inexpensive and readily available, so physicians are comfortable using them.

However, taking into account the number of epileptics who discontinue these AEDs because of adverse reactions, the percentage of patients treated is probably lower than claimed. Add to that the 20 per cent of patients with treatment-refractory epilepsy (which doesn't respond to the traditional drugs), and it's no surprise that a slew of new AEDs has recently arrived to address the gap in the market.

The new-generation AEDs include felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate and zonisamide, to name but a few. With the exception of oxcarbazepine, these drugs are only approved by the US Food and Drug Administration for use in patients for whom older medications have failed, or in combination with an older drug in cases of treatment-resistant partial epilepsy (Ann Clin Biochem, 1999; 36: 10-9), even though studies have shown that topiramate, lamotrigine and gabapentin are effective as stand-alone treatment and that treatment-responsive patients will respond to any AED, whether old or new.

With treatment-responsive epileptics, doctors believe that it's just a matter of matching the patient to the drug that is the best tolerated and carries the lowest risk of side-effects (Neurology, 2004; 62: 1252-60).

Side-effects: that's where the new AEDs differentiate themselves. These newer agents are supposedly involved in fewer drug interactions and, because each has a unique mode of action, their side-effect profiles vary widely and offer doctors more choices. As a group, they are considered to have a better side-effect profile than the older class of drugs, and to be safer for women of childbearing age.

Nevertheless, little is known of the possible cognitive and behavioural problems that may accompany treatment. In a comparison of all AEDs, three of the newer ones - levetiracetam, topiramate and zonisamide - were all linked to a higher risk of psychiatric side-effects (Neurol Rev, 2004; 12: e-pub). So, you may not have seizures, but you could go crazy while taking them.

As for the other new AEDs, felbamate has proved effective, but is not often prescribed because of a possible increased risk of liver failure and aplastic anaemia. Gabapentin, touted as the 'safest', with minimal side-effects and drug interactions, nevertheless has limited effectiveness against seizures. Topiramate has few drug interactions, but is associated with drowsiness, lethargy, anorexia and weight loss (J Postgrad Med, 2003; 49: 202-6). As with some of the old AEDs, oxcarbazepine and lamotrigine carry a risk of skin rash.

There is not enough good-quality clinical-trial evidence to support the use of newer AEDs rather than older drugs (whether alone or in combination with older ones), or to support the use of one newer AED over another. However, the newer AEDs, though expensive, may be cost-effective in patients who experience side-effects with older AEDs, or for whom the older drugs just don't work. Also, in some cases, drug interactions with older AEDs may mean patients have to use a newer AED (Health Technol Assess, 2005; 9: 1-157, iii-iv).

At best, the new AEDs provide more options for patients who respond to drugs. However, this class of drugs doesn't offer a wider range of choice for those with treatment-refractory epilepsy, which was presumably their original intention.

The ketogenic diet (see box below) may be a useful alternative for such patients and, in fact, may well be a smart place to start after a first seizure.

Research shows that delaying medication in early epilepsy reduces short-term seizures without increasing the chances of chronic epilepsy (Lancet, 2005; 365: 2007-13).

The benefits of improved seizure control need to be weighed against drug side-effects. It may be best to take your time and evaluate your possible treatment choices, including dietary changes and alternative therapies - and now, a wider variety of AEDs.

Kim Wallace

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