New Antiepileptic Medications

Epitomes-Neurology

WJM, November 1995-Vol 163, No. 5 receptors. Several subgroups of the receptor sites have

been identified. The 5-HTID and 5-HTlB receptors appear to be the most important sites in the pathogenesis of migraine. Another study measuring cerebral blood flow using positron emission tomographic scanning has revealed a progressive reduction in the blood flow originating from the occipital region and spreading anteriorly during the headache, which resembles Leao's spreading depression. These two observations challenge the timehonored concept of the vascular theory of migraine; at the same time, investigators have also demonstrated that antimigraine drugs that act at serotonin-receptor sites also prevent the neurogenic inflammation of blood vessels mediated by substance P-containing nerve fibers in the trigeminal vascular system. The recent introduction of sumatriptan succinate represents the most important advance in the treatment of migraine headache in several decades. This drug was designed specifically to be active at serotonin-receptor sites and acts as a selective agonist at 5-HT1D receptors, causing vasoconstriction of cephalic vessels. The drug also acts at the presynaptic 5-HT1-like receptors of the sensory nerve endings to block "neurogenic inflammation." This observation has led to a reevaluation of the other commonly used drugs like ergotamine tartrate and dihydroergotamine mesylate. These drugs have now been shown to be active at the same receptor sites. Sumatriptan is effective in controlling an acute migraine headache-and cluster headache, even though it has not been approved by the Food and Drug Administration for this indication-in more than 75% of patients. The response is so specific that some headache specialists think that the diagnosis should be reevaluated if the drug is not effective. A definite advantage over the conventional medications is that it is effective at any stage of the headache, but there is a high recurrence rate (almost 40%), probably related to the short half-life. Most patients experience cephalic symptoms of burning and tingling, and at least a third of patients complain of tightness of the throat. This last symptom is thought to be caused by spasm of the pharyngeal and esophageal muscles. These effects are short-lived. Uncontrolled hypertension, coronary artery disease, and basilar and hemiplegic migraine are contraindications for the use of this drug. A few deaths have been reported. These were from cardiac causes and mostly were in patients in whom the underlying cardiac disorders were unrecognized. N. VIJAYAN, MD

Sacramento, California REFERENCE Woods RP, lacoboni M, Mazziotta JC: Bilateral cerebral spreading depression during spontaneous migraine headache. N Engl J Med 1994; 331:1689-1692

New Antiepileptic Medications SINCE AUGUST 1993, three new antiepileptic medications have become available: felbamate, gabapentin, and lamotrigine. Together they represent a new generation of medications, characterized by less neurotoxicity and

475

poorly understood mechanisms of action compared with older antiepileptic drugs. Although their indications are similar, their unique pharmacokinetic and toxicity profiles are likely to dictate preferences. Gabapentin is indicated for the adjunctive treatment of partial seizures with or without secondary generalization. Pharmacologically, it embodies many properties of an ideal anticonvulsant. It is not bound to protein, not metabolized, is without drug-drug interactions, and has a high therapeutic index. For these reasons, gabapentin is ideal for use in elders and in polytherapy. Three-times-per-day dosing is necessary, however, because of a half-life of five to seven hours. Somnolence, dizziness, and ataxia are common side effects, but gabapentin can be rapidly titrated with good tolerance. Postmarketing clinical experience suggests that the maximum recommended dosage of 1,800 mg per day may be subtherapeutic and that dosages upwards of 3,600 mg per day to 4,800 mg per day may result in better seizure control. Lamotrigine has been approved by the Food and Drug Administration for the adjunctive treatment of partial seizures in patients aged 16 years and older. Experience from its extensive use in Europe suggests, however, that it may have a broad spectrum of antiepileptic activity, similar to valproic acid, in the treatment of generalized seizure disorders and the Lennox-Gastaut syndrome. Lamotrigine can be involved in drug-drug interactions because of its hepatic metabolism. Enzyme-inducing antiepileptic medications, such as phenytoin, carbamazepine, and barbiturates, will halve its natural half-life of 25 hours, and valproic acid will almost triple it. Because of the nausea associated with higher doses, twice-a-day dosing is recommended. Its side effects include diplopia, drowsiness, and ataxia. Rash, rarely leading to the Stevens-Johnson syndrome, is a possible risk but may be minimized by avoiding the concomitant use of valproic acid and "starting low and going slow" in escalating the dose. Felbamate is indicated for use as monotherapy or adjunctive therapy in patients with partial seizures with or without secondary generalization and as adjunctive therapy in patients with the Lennox-Gastaut syndrome. Its use has been complicated by drug-drug interactions and idiosyncratic reactions, namely aplastic anemia and hepatotoxicity, sometimes with fatal consequences. The risk of aplastic anemia, presently estimated at 1 in 3,500, is alarming when compared with the 1 in 40,000 to 1 in 100,000 risk of aplastic anemia associated with the use of chloramphenicol. The manufacturer's recommendations that blood cell counts and liver enzyme levels be measured weekly or biweekly and that consent forms printed on package inserts be signed by patients taking felbamate further restrict its use to patients whose seizures are refractory to other medications. The lesson set forth by felbamate is that any antiepileptic medication has the potential for idiosyncratic reactions. The role of new antiepileptic medications in the face of more established drugs will surely evolve as more experience is gained in their use. At present, however, they are most likely to be beneficial as adjunctive therapy

476

Epitomes-Neurology

WJM, November 1995-Vol 163, No. 5 WJM,

November

1995-Vol

163,

No.

Epitomes-Neurology

5

for partial seizure disorders and the Lennox-Gastaut syndrome, when indicated. EUN-KYU LEE, MD Sacramento, Califomnia

REFERENCES Dichter MA: Integrated use of old and new antiepileptic drugs. Curr Opin Neurol 1995; 8:95-102

Matsuo F, Bergen D, Faught E, et al: Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. Neurology 1993; 43:2284-2291 Pennell PB, Ogaily MS, Macdonald RL: Aplastic anemia in a patient receiving felbamate for complex partial seizures. Neurology 1995; 45:456-460 Ramsay RE: Clinical efficacy and safety of gabapentin. Neurology 1994; 44:S23-S30

ADVISORY PANEL TO THE SECTION ON NEUROLOGY ROBERT G. MILLER,

MD

Advisory Paniel Chair CMA Couticil on Scientific Affairs Representative San Francisco

RICHARD M. LOWENTHAL, MD CMA Sectiont Chair Santa Barbara

DAVID P. RICHMAN, MD

NANCY A. NIPARKO, MD

Section Editor University of California, Davis

Los Angeles Society ofNeurological

Scientces Woodland Hills

CARTER G. MOSHER, MD CMA Section Secretary Sacramtiento MARJORIE E. SEYBOLD, MD CMA Section Assistanit Secretarv San Diego

A. DOUGLAS WILL, MD Loma Linda University

LESLIE J. DORFMAN, MD Stanford Univ'ersity

STANLEY VAN DEN NoORT, MD University of Californiia, Irvine ROBERT C. COLLINS, MD University of California, Los Anigeles LEON J. THAL, MD University of California, Satz Diego

MICHAEL AMINOFF, MD University of California, San Francisco

J. P. VAN DER MEULEN, MD University of Southern California

LAURENCE L. JACOBS, MD Orange Cou,ity Neurological Society Newport Beach

GEORGE A. PALMA, MD Sacramento Neurological Society L4oomis CHARLES K. JABLECKI, MD Satz Diego Neurological Society Satz Diego