Anti-epileptic Reduces Migraines, Weight

April 04, 2003

Larry Schuster

April 4, 2003 (Honolulu) — In the largest trials of prophylactic use of a drug for migraine prevention, the anti-epileptic topiramate (Topamax) reduced the number of monthly migraine episodes by nearly 50%, and — in contrast to other migraine drugs — caused up to 5% weight loss.

In two parallel, randomized, double-blind, placebo-controlled studies involving a total of about 1,000 patients, the results were nearly the same in both studies on all key measures. Both studies were released here at the American Academy of Neurology 55th annual meeting.

In the study known as MIGR-002, which involved 483 patients, Jan Brandes, MD, from the Nashville Neuroscience Center in Tennessee, reported in a poster presentation that as early as one month into treatment, the average number of migraines was reduced by half for 49% of patients receiving topiramate at either 100 or 200 mg per day and 39% of patients taking 50 mg per day.

The mean number of migraines decreased from 5.8 to 3.5 per month for patients receiving 100 mg of topiramate ( P= .008) and from 5.1 to 2.9 for patients receiving 200 mg ( P = .001) compared with a decrease from 5.6 to 4.5 for those receiving placebo. Patients also experienced significant weight loss: 2.4%, 3.5%, and 4.75% for those receiving 50 mg, 100 mg, and 200 mg per day, respectively ( P = .001 for all).

No deaths occurred and no serious adverse events were considered by the study investigators to be related to topiramate. The most common adverse effects for withdrawing from the study were parasthesia, fatigue, nausea, and abdominal pain.

In the MIGR-001 study, reported by Ninan Mathew, MD, from the Houston Headache Clinic in Texas, the efficacy was similar. The most common adverse events resulting in discontinuation included parasthesia, anxiety, difficulty sleeping, and hypoesthesia.

In a phone interview with Medscape, Dr. Brandes said they "had more patients in the [topiramate] trials than any other drug that's been used for prevention. Most of the trials of those that have received [Food and Drug Administration] (FDA) approval have had as few as 96 patients."

The other three drugs on the market for migraine prevention are two hypertension medications, propranolol (Inderal) and timolol (Blocadren), and an anticonvulsant, divalproex (Depakote). Topiramate entered the market for epilepsy in 1997.

Part of the mechanism that causes migraine is that the gray matter is more excitable, Dr. Brandes said. "This hyperexcitability can be moderated by drugs classified [as] antiepileptics. They act as a neuromodulator in patients who have migraine."

Ideal candidates for the drug are people who have at least three or four disabling migraine episodes a month, he said. The drug also appears to reduce the severity of the remaining migraines, which then can be treated with acute therapy, preferably by one of the triptans.

"One of the most exciting things is the effect on weight loss," Dr. Brandes said of topiramate. "That's a very significant advantage for this drug."

Weight gain can be a huge problem with some migraine drugs, such as tricyclic antidepressants.

The weight-loss benefit of topiramate is particularly important, he noted, if the patient is above the normal weight body mass index and additional weight gain would put the patient at increased risk for type 2 diabetes. The issue is especially important for those who already have diabetes.

The most common adverse effect in the MIGR-002 study was parasthesis, which Dr. Brandes called benign and which usually resolves. Researchers advised doctors to tell their patients that this is a normal and transient effect of the drug. In addition, patients should be advised not to go for long periods without food. Tell them, Dr. Brandes said, to "remember to eat carefully."

Also, the drug can make anything carbonated taste odd. Not everyone will have that adverse effect, but if so, that might be an indication to adjust the dosage. One advantage of that adverse effect is that it may help patients decrease their intake of caffeinated carbonated beverages. Overuse of caffeine, Dr. Brandes said, may result in rebound headaches.

"The real concern are the cognitive side effects," said Dr. Rothrock, who noted the effect seems dose-dependent. Problems with memory and finding words show up in about 15% of patients receiving 200 mg, 10% of those receiving 100 mg, 8% of those receiving 50 mg, and 4% of those who received placebo.

To minimize that effect, the researchers advised physicians to start their patients at low doses, perhaps even less than 50 mg a day, and slowly increase the dose. For some patients, 50 mg may be enough, although for most patients, the target dose might be 100 mg.

Physicians also need to be aware of patients' history regarding renal stones and glaucoma, both rare adverse effects that have been reported with this drug, Dr. Brandes said. She advised physicians to have patients treated for any disposition to develop stones prior to placing them on the drug. At the least, patients should be monitoring for this and report any discomfort as it happens, she said.

Dr. Brandes does not place patients on the drug who have glaucoma, but she noted that no patient of hers developed glaucoma while receiving topiramate, and the type of glaucoma that might come from its use would be resolved upon stopping the drug.

But whether a patient's migraines are more likely to be prevented by topiramate or divalproate, for example, can only be determined by patient experience, Drs. Rothrock and Brandes told Medscape. With both drugs, about 50% of patients respond.

"We just don't know," Dr. Rothrock said. So far, there have been no head-to-head trials that might answer that question.

Although older anticonvulsive drugs that were used for migraine interfered with birth control pills and caused bone loss, this has not been found with topiramate, Dr. Brandes said. Dr. Rothrock said he also has not seen "breakthrough pregnancy" due to interference by the drug with birth control drugs, but "it remains a theoretical possibility," he said.

The researchers also noted that the drug began working within the first four weeks, while some drugs tend to take longer to have an effect.

Suzanne Simons, executive director of the National Headache Association in Chicago, Illinois, told Medscape that with these positive results, "You now have another medication to offer patients," and the drug represents another opportunity for the prevention of migraines.

Drs. Brandes, Rothrock, and Mathew's research was supported by Johnson & Johnson Pharmaceutical Research and Development.

AAN 55th Annual Meeting: Abstracts PO3.155, PO3.156, S42.001. Presented April 2, 2003.

Reviewed by Gary D. Vogin, MD

Larry Schuster is a freelance writer for Medscape.


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