STOWE, VERMONT—Antiepileptic drugs have been found useful for the treatment of a variety of disorders besides seizures and neuropathic pain. At the recent Headache Update 2000 symposium, cosponsored by the Headache Cooperative of New England and the University of Massachusetts Medical School, researchers discussed the role of anticonvulsants—including divalproex sodium, gabapentin, lamotrigine, tiagabine, and topiramate—in migraine prevention.

While other drugs may be used "off label," only four have been approved by the Food and Drug Administration (FDA) for migraine prevention. These include methysergide (a serotonin receptor antagonist), propranolol and timolol (both ß-adrenergic receptor blocking agents), and divalproex sodium (a GABAergic agent). Since the approval of divalproex sodium in 1996, headache specialists have begun to investigate whether other available anticonvulsants could benefit patients with migraine.

DIVALPROEX SODIUM—FDA APPROVED

A three-year open prospective safety study of divalproex sodium for migraine prevention found that treated patients experienced a reduction in headache frequency and that this effect could be maintained over time. A total of 163 patients with migraine were recruited from 24 participating headache centers. Divalproex sodium was given in doses ranging from 500 to 2,500 mg/day, with 1,000 mg/day as the most frequently administered dose.

After three months of divalproex sodium treatment, the mean number of monthly headaches decreased from a baseline of 5.3 to 3.11, according to Alan M. Rapoport, MD, Director of the New England Center for Headache, Stamford, Connecticut. During study months 13 to 18, the mean number of monthly headaches in 73 patients decreased from a baseline of 5.43 to 2.41. During study months 31 to 36, the mean number of monthly headaches in 27 patients decreased from a baseline of 6.1 to 2.5.

Although divalproex sodium was generally well tolerated, 34 patients (21%) discontinued the study. Patients treated with divalproex sodium for at least 18 months reported tremor, asthenia, alopecia, somnolence, abdominal pain, dyspepsia, nausea, and diarrhea. The incidence of adverse events decreased to a steady level for many patients, Dr. Rapoport noted.

Hepatotoxicity in treated patients is a rare, idiosyncratic event, said Dr. Rapoport. When used as monotherapy, divalproex sodium has a hepatotoxicity rate of 1:118,000. He recommended liver function testing at two and six months, particularly if the patient is on polytherapy. Divalproex sodium may produce neural tube defects in the fetus, he added, and benefits in pregnant patients must be weighed against the risk of injury to the fetus.

GABAPENTIN FOR MIGRAINE PROPHYLAXIS

The safety and efficacy of gabapentin also has been tested for migraine prevention, Dr. Rapoport said. In the Gabapentin Migraine Prophylaxis Study Group trial, 145 patients were randomized in a 2:1 ratio to receive either gabapentin or placebo, Dr. Rapoport reported. The patients (ages 16 to 75) met the International Headache Society criteria for migraine and had experienced three to eight migraine episodes per month prior to study enrollment. Patients who received the drug initially received 300 mg of gabapentin daily; the dose was then titrated to 2,400 mg/day in three doses. The study consisted of a four-week single-blind baseline period, a four-week titration period, and an eight-week stable dosing period. Seventy-eight percent of patients completed the study.

The gabapentin-treated patients (77) had a median of 2.7 headaches during the last four weeks of the study, Dr. Rapoport said. The placebo group, in comparison, had a median of 3.4 headaches. Forty percent of the treated patients had a 50% or greater reduction in headache compared with only 19% of the patients who received placebo, he said. When the number of headache days per four weeks was analyzed, the median number of headaches was lower in the gabapentin-treated group (3.6) when compared with the placebo group (4.7). The final stable dose was 2,400 mg/day in most of patients (75%); about 18% received 1,800 mg/day, he added.

The results indicated that gabapentin was superior to placebo, based on the four-week reduction in migraine, Dr. Rapoport said. Most adverse events that occurred were of mild to moderate intensity, he added. The adverse events leading to study discontinuation included somnolence, dizziness, asthenia, and vasodilation.

ANTICONVULSANTS IN MIGRAINE—THE NEXT GENERATION

According to Dr. Rapoport, experience in migraine prevention with the newer antiepileptic drugs—including lamotrigine, tiagabine, and topiramate—has been limited. In 1997, a double-blind trial with lamotrigine found that it was not effective over placebo for migraine prevention. Two subsequent trials, however, found that lamotrigine was effective in decreasing migraine with aura. However, Dr. Rapoport noted, if the dose is rapidly increased, a rash may develop. "When we administer lamotrigine, we start with a very low dose (25 mg) and maintain that dose for two weeks," Dr. Rapoport said. "We then increase the dose by 25 mg every two weeks. We have never had patients develop a rash; however, the efficacy of the drug is low and some patients actually get worse," he said.

A recent open-label study suggested that tiagabine may be highly effective in migraine prophylaxis, according to Dr. Rapoport. However, tiagabine has produced mixed results, he said, referring to his personal experiences. He noted that he starts patients with 4 mg and slowly increases the dose. Some patients with chronic daily headache reported they slept better after beginning tiagabine treatment, he noted.

Topiramate also may aid in migraine prevention, Dr. Rapoport said. A double-blind study of 40 patients presented at the 52nd Annual Meeting of the American Academy of Neurology demonstrated efficacy. Many positive anecdotal reports also have been noted from around the country. In patients with cluster headaches, for example, topiramate has been reported to work very well at very low doses (25 mg tid). Dr. Rapoport said he starts patients on 12.5 mg topiramate taken at night. The average dose is 25 mg administered three times daily, he said, which can be increased to 50 mg three times daily. If a high dose is prescribed, such as 200 mg and over, patients may experience weight loss, memory problems, and become confused, he cautioned.

"We always titrate drugs slower in patients with headache than in patients with epilepsy because those with headache do not do well when the doses are titrated too rapidly; they are much more sensitive to medications than patients with epilepsy," he pointed out. The choice of preventive medications, he added, depends on the drugs' efficacy, the side-effect profile, and especially the comorbidity. In patients who have both hypertension and migraine, for example, one drug to treat both disorders is the desired treatment approach, he said.

—Lynda Charters
Contributing Writer

Suggested Reading
Hering R, Kuritzky A. Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia. 1992;12:81-84.

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