Gabapentin

Of the antiepileptic drugs (AEDs) approved in the United States since 1993, gabapentin is one of the most widely used to treat seizures and other conditions, especially chronic pain. It has not been approved as monotherapy, and there is no evidence that it is any more effective or even as effective as older AEDs when used alone, but it has several advantages:

  • It is usually well tolerated, even when rapidly titrated upward.
  • It bypasses hepatic metabolism, being almost completely renally excreted unchanged.
  • It lacks pharmacokinetic interactions with other drugs.

Although there is no parenteral form, the contents of the capsules or the oral solution may be administered through feeding tubes. Its spectrum of action, encompassing partial seizures, including those with secondary generalization, is appropriate for most stroke patients with new-onset seizures.

In patients with refractory epilepsy and no renal impairment, there is a dose-related improvement in seizure control between 900 mg per day and at least 1,800 mg per day. Higher doses (up to 3,600 mg per day or more) have led to improved control in some patients.

For the hospitalized patient with a first seizure, initiation with 300 mg 3 times a day is reasonable. If tolerated and necessary, this can be increased over 1 to 3 days to 600 mg three times a day. In patients with impaired renal function, these doses should be scaled back in proportion to creatinine clearance. A slower titration in less acute settings is 300 mg at bedtime, adding an additional 300-mg dose every 1 to 3 days.

Side effects are usually transient and mild. They include fatigue, dizziness, and sedation. Hypotension may occur rarely.

Lamotrigine

Lamotrigine has been approved as an adjunct and a monotherapy agent for treating partial or tonic-clonic seizures. However, the slow titration regimen required to minimize the chance of an allergic reaction, particularly rash, limits its use in hospitalized patients. It is a good alternative for patients who have not responded well to one of the enzyme-inducing drugs; if the response to the combination is favorable, then the initial drug may be cautiously withdrawn over several weeks.

When added to a regimen including valproate, which markedly inhibits the metabolism of lamotrigine, the titration rate must be still slower, starting in adults at 25 mg every other day, rather than 50 mg per day. The approved guidelines for using this drug do not encompass initiating it in patients not taking AEDs or in patients taking valproate without an enzyme-inducing drug. Experience suggests, however, that a reasonable approach is to start patients not taking AEDs at 25 mg every other day, and to start those taking valproate without an enzyme-inducing drug at 12.5 mg every other day.

Topiramate

Topiramate is another relatively new AED that needs to be slowly titrated to avoid primarily cognitive side effects. A starting dose of 25 mg per day, increasing weekly by 25 mg to a target of 200–400 mg per day, is recommended. Especially in the elderly, even lower doses may be efficacious.

Of note is a 1–2% risk of renal stones, suggesting avoidance in patients prone to this condition, or at least careful attention to hydration. Cognitive side effects, particularly word-finding difficulties, are seen particularly at high doses and rapid titration rates. There are also rare reports of acute glaucoma occurring within the first few weeks of treatment. Weight loss is also moderately frequent, and metabolic acidosis has been reported.

Oxcarbazepine

Oxcarbazepine is closely related to carbamazepine but has a different metabolic profile and less impact on hepatic enzymes. For example, no effect on warfarin metabolism has been found. It is approved as monotherapy, and the starting dose, 300 mg twice daily, is considered therapeutic. It can be increased at a rate of 300 mg twice daily every week to a maximum of 1,200 mg twice daily, although slower rates probably minimize side effects.

Adverse effects are similar to those of carbamazepine, consisting mainly of dizziness and diplopia at high doses, hyponatremia, and an allergic rash. Cross-reactivity with carbamazepine is estimated at 25–30%.

Oxcarbazepine metabolism is accelerated by enzyme-inducing AEDs, and oxcarbazepine itself may decrease phenytoin levels by approximately 30%.

Levetiracetam

Levetiracetam is unrelated to the other AEDs, with respect to both chemical structure and activity in various animal models. It is approved for adjunctive treatment of partial seizures, but probably has a broader spectrum, with particular efficacy against myoclonus. The recommended starting dose of 500 bid is considered therapeutic; however, because doses should be adjusted in accordance with renal clearance, lower starting doses should be used in the elderly, such as 250 mg bid. Similarly, the standard titration rate of an additional 500 mg bid every two weeks to a maximum of 1500 mg bid should be scaled back in elderly patients or those with renal impairment. Adverse effects include sedation and, perhaps more than some other AEDs, psychobehavioral effects including irritability, depression, and rarely more severe reactions such as psychosis. Levetiracetam is processed primarily via renal excretion, and does not involve the hepatic P450 system; therefore, there are no pharmacokinetic reactions with other drugs

Tiagabine

Tiagabine is approved as adjunctive therapy for partial seizures. In elderly patients, a starting dose of 2-4 mg hs, increased by a similar amount at weekly intervals, can be used, to a target of 24-48 mg/d, taken on a bid up to qid schedule. Slow titration is needed to minimize the primary adverse effect of sedation. Other cognitive and behavioral side effects may also be seen, and there are rare reports of nonconvulsive status epilepticus at doses of 48 mg/d and higher.

Zonisamide

Zonisamide is also approved as adjunctive therapy for partial seizures (though it can also treat myoclonus as well), and requires slow titration. The recommended starting dose of 100 mg/d, increasing every two weeks by an additional 100 mg/d to a target of 200 mg bid, can be used in elderly patients, although lower doses and slower titrations rates may be better tolerated. It can produce an allergic rash, though cross-reactivity with sulfa drugs is not as frequent as initially suspected. Other concerns include sedation, cognitive-behavioral side effects, renal stones, and, more frequently, weight loss.

Benzodiazepines

Benzodiazepines have a limited but important role in the treatment of seizures in patients with stroke or other serious illnesses. Parenteral administration allows onset of activity within minutes, which is useful especially in the treatment of status epilepticus. Duration of action is limited, however, particularly for diazepam, which is redistributed out of the brain into other fatty tissues within 15–20 minutes. Lorazepam, by contrast, may remain active for 4–12 hours. Clonazepam has an even longer half-life but is not usually used intravenously in the United States.

Other routes of administration are worthy of consideration for conditions milder than generalized convulsive status epilepticus. For example, if a patient has clusters of seizures with recovery between them, rectal diazepam gel is approved, safe, and effective. Dosing depends on patient weight but ranges between 10 and 20 mg for adults. Alternatives include sublingual lorazepam, 0.5–2.0 mg, or buccal midazolam, 2–4 mg. Both result in more rapid absorption than oral administration, but both require patient cooperation. Similar methods can be used to treat simple or complex partial status epilepticus without secondary generalization.

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Reviewed By: 
Steven C. Schachter, MD
on: 
Thursday, April 1, 2004