New treatment alternatives for migraines

Want to get instant attention from a patient with migraines? Tell her (female migraineurs outnumber male sufferers three to one) there is no such thing as a migraine headache.

"Migraine is the disease, and headache is the most common symptom," explained Michael John Coleman, executive director of MAGNUM, a migraine advocacy and support organization. "The biggest problem is that sufferers, their partners, and their physicians try to treat the symptom and don't recognize the disease."

For most sufferers, migraine is characterized by intense, throbbing head pain, usually localized to one side of the head. The blinding headaches are often accompanied by nausea, with or without vomiting, and sensitivity to light or sound. Attacks occur periodically and can last up to 72 hours. Mild migraine brings attacks two or three times a year. Severe cases can mean two or three attacks every week.

More than 90% of sufferers report that migraines significantly interfere with their ability to function in everyday life, according to Fred Sheftell, M.D., founder and director of the New England Center for Headache.

"A migraine is a hell of an enemy," Coleman said. "You don't know when your next one is going to come. You can be in an incredible degree of pain and put on a happy face. Then, when people leave the room, you collapse into a fetal ball on the floor."

What causes migraines remains unclear, although the disease appears to be associated with a malfunction within the brain itself. Once an attack begins, pain and other symptoms result from an inflammatory cascade involving the trigeminal nerve. Perivascular nerve activity results in the release of calcitonin gene-related peptide (CGRP), nitric oxide, and other substances that produce vasodilation and sterile inflammation.

Serotonin (5-hydroxytryptamine, or 5-HT) plays a role in the inflammation. Products that inhibit specific types of 5-HT receptors halt or reduce the severity of an attack.

Migraine treatments fall into two basic categories: abortive, to stop an ongoing or impending attack, and preventive, for chronic management to reduce or prevent acute attacks.

The newest abortive treatment is Relpax (eletriptan, Pfizer). Relpax has been available in Europe and other areas for several years and was approved by the Food & Drug Administration in late December 2002. It is the seventh triptan to reach U.S. patients.

"Right now, triptans are the best treatment for acute migraine and Relpax is the best triptan available," claimed Ninan Mathew, M.D., director of the Houston Headache Clinic. "In three head-to-head studies of Relpax and Imitrex [sumatriptan, GlaxoSmithKline], Relpax came out ahead on every endpoint we looked at. Relpax will become the new gold standard for acute migraine," he predicted. Imitrex, the first triptan approved for use in the United States, is currently the reference treatment, he added.

But Mathew's enthusiasm is not universal. At the Diamond Headache Clinic in Chicago, pharmacist Richard Wenzel agreed that Relpax is another useful agent. But he thinks it is not significantly better than sumatriptan or newer competitors Zomig (zolmitriptan, AstraZeneca), Amerge (naratriptan, GlaxoSmithKline), Maxalt (rizatriptan, Merck), Axert (almotriptan, Pharmacia), and Frova (frovatriptan, Elan).

"Relpax is an effective agent," Wenzel said. "But an individual patient's response to a specific triptan cannot be predicted. The similarities between the oral triptans are arguably greater than their differences in terms of efficacy and adverse effects, thus cost becomes a chief difference between the products." That could mean trouble for patients. Response to different triptans can vary dramatically, he said. A drug that works well in one patient may be ineffective in another.

Wenzel likened triptans to selective serotonin reuptake inhibitors (SSRIs), another category with highly variable patient reactions to different products. Idiosyncratic reactions mean patients and physicians must have access to several products to find the one that is most effective for each patient. "There are patients who respond well to one triptan but not at all to another," he said. "You need multiple products available to try in patients who have failed one or more agents."

More choices are on the way, according to the Pharmaceutical Research & Manufacturers of America. PhRMA's annual New Medicines in Development lists a dozen new migraine drugs or indications in human trials. Most build on the initial discovery of 5-HT_1B/1D agonists that led to the development of triptans.

Epitome Pharmaceuticals, in Halifax, Nova Scotia, has a 4% aminophylline topical gel, tentatively named HAGel, in early clinical trials. NPS Pharmaceuticals, based in Salt Lake City, has a new triptan, ALX-0646, in phase I/II trials.

Pozen Pharmaceuticals, in Chapel Hill, N.C., is working on three products. MT100 is a combination antiemetic and nonsteroidal anti-inflammatory drug in tablet form. MT300 is an injectable ergotamine-related compound. Both are in phase III trials. MT400, a triptan and NSAID combo tablet, is in phase II trials.

GlaxoSmithKline has a combination migraine/epilepsy treatment dubbed SB204269 in phase II trials.

A third-generation of 5-HT agonists similar to the first two waves of triptans is being developed by The Medicines Co., Basel, Switzerland. A nasal triptan, IS-159, has shown positive results in phase II trials, but may be less effective than current products.

There is also growing interest in the use of CGRP antagonists, nitric oxide synthase inhibitors, and other compounds that target different receptors in the cascade leading to migraine. A CGRP antagonist, BIBN4096, has shown substantial preclinical activity. The compound is in clinical trials at the Institute of Neurology in London, but no results have been released. Another CGRP inhibitor, GR79236, also appears to have antimigraine action in a pilot study at Cambridge University.

Nitric oxide plays an important role in cardiovascular systems and also acts as a neuronal messenger molecule. Early GlaxoSmithKline trials with an NO-synthase inhibitor showed promising results, but more human data are needed.

Civamide (Winston Laboratories), the cis-isomer of capsaicin, has also shown potential. Capsaicin provides the fire in hot chili peppers by activating vanilloid receptors on sensory nerve endings. A nonplacebo-controlled trial with Civamide suggested that the drug is 55% effective in severe migraine. But more than 90% of patients complained of nasal burning. Tearing was another common side effect. "This is all very preliminary," Wenzel cautioned. "If these meds ever get approved, it is years away."

But even the most potent abortive agents are not enough for patients with frequent migraines. None of the triptans or other current rescue drugs can be taken on a daily basis because of rebound headaches. Patients who get more than occasional migraines should be taking preventive agents on a regular basis, Wenzel said.

Just which preventive to use is an open question. The FDA has approved propranolol (Inderal LA, AstraZeneca), timolol (Blocadren, Merck), methysergide (Sansert, Novartis), and divalproex (Depakote ER, Abbott), said Amelito Malapira, M.D., assistant professor of neurology at the University of South Alabama. According to the American Council for Headache Education (ACHE), there is no way to predict which med will be most effective for any given patient, so other conditions often dictate which products to try first. Beta-blockers are obvious candidates for a migraine patient with high blood pressure, a tricyclic antidepressant is a really bad idea for somebody with a history of coronary disease, and SSRIs might be appropriate for somebody with mood problems (or maybe not, depending on whether you view depression as a contributing factor to migraine or an effect of migraine). Then there are other factors, such as drug cost, Rx benefit coverage, and so on.

Off-label use of other products is common, said ACHE, which lists beta-blockers, anticonvulsants, tricyclic antidepressants, calcium-channel blockers, NSAIDs, serotonin antagonists, and a serotonin-plus-histamine antagonist as used to prevent migraine attacks.

More products are in the pipeline. Ortho-McNeil has Topamax (topiramate), an anticonvulsant approved for epilepsy, in phase III trials for migraine prophylaxis. Pozen is developing a novel serotonin receptor antagonist, MT500, to prevent migraine attacks. Allergan is testing Botox (botulinum toxin) to prevent migraine as well as tension-type headaches.

The Norwegian University of Science and Technology in Trondheim has reported a yearlong trial with the angiotensin II receptor candesartan (Atacand, AstraZeneca). The drug reduced migraine attacks for more than 50% of patients with no more adverse events than placebo.

"The bottom line is that this is a disease you can manage and live with," Coleman said. "There are no sliver bullets against migraine, but there is no shortage of treatments. Migraineurs need that knowledge just like diabetics need to know the range of treatments for their disease. Pharmacists could work wonders for millions of patients if they just help them recognize that migraine is a disease that can be managed."

Fred Gebhart

FOR MORE INFORMATION

• American Council for Headache Education (ACHE), 19 Mantua Rd., Mt. Royal, NJ 08061, (800) 255-2243, www.achenet.org

MAGNUM, 113 S St. Asaph St., Suite 100, Alexandria, VA 22314, (703) 739-9384, www.migraines.org

• National Headache Foundation (NHF), 820 N Orleans, Suite 217, Chicago IL 60620, (888) 643-5552, www.headaches.org

• World Headache Alliance, 208 Lexington Rd., Oakville, Ontario, Canada L6H 6L6, (905) 257-6229, www.w-h-a.org

• GlaxoSmithKline and other drugmakers also maintain migraine-related Web sites. Sites listed on Google include www.migrainehelp.com (GlaxoSmithKline) and www.Excedrin.com (Bristol-Myers Squibb)

 

Fred Gebhart. New treatment alternatives for migraines. Drug Topics Women's Health Supplement;147:37s.