Migraine.(Pamphlet)

Migraine Research Shows No Cure but Many Advances

ACCORDING TO THE NATIONAL HEADACHE Foundation in Chicago, Americans spend more than $4 billion annually on drugs to stop migraine pain. Pharmaceutical companies had largely dismissed the headache market until Imitrex was released by Glaxo Wellcome in 1997, when it generated $840 million in worldwide sales. Since that time, there have been new scientific hypotheses about migraine pain that have fueled new research for migraines. CenterWatch has identified approximately 18 drugs in clinical testing for migraines and at least eight others close to entering early phases of clinical testing. It is estimated that pharmaceutical and biotech companies will spend between $45 million to $65 million to conduct clinical trials among the more than 100 million migraine suffers in 1998.

There are no known cures for migraine but only treatments for its symptoms and these treatments are not yet wholly effective. Furthermore, scientists do not understand all the causes of migraines. Most experts believe that migraine symptoms are the result of nerve, chemical or electrical changes in the brain. However, the nature of these changes and how they may interact to cause a migraine are still mostly unknown.

Several investigators are looking at areas of unusual activity within the brain. They are studying a part of the brain believed to start migraines, dubbed the "migraine generator." People afflicted with migraines appear to have blood vessels that over-react to various triggers from such things as stress, biological or environmental conditions. Scientists believe that nerve signals from this area travel to blood vessels in the head, face and spinal cord.

These triggers can set off an imbalance of naturally occurring chemicals in the brain, changing the levels of 5-HT (serotonin) and causing the blood vessels of the head to expand. The area surrounding these blood vessels becomes inflamed and irritates the nerve endings. This dilation and irritation may account for the throbbing pain one experiences in the temple and behind the eyes.

Conventional preventive therapies for migraines have been antidepressants, calcium channel blockers, methysergide, which had serious side effects, and divalproex sodium. However, the new medications called triptans target the specific receptors of serotonin. These new generation migraine drugs are all abortive they--stop migraine pain attack after it has started. Scientists have shown that migraines can strike in two locations; the dilating, blood vessels themselves or the nerve cells in the trigeminal nucleus.

These triptan medications are available in a variety of forms such as subcutaneous injections, nasal sprays, and oral tablets. Companies are trying to find the most beneficial therapies that provide rapid and prolonged relief.

Glaxo Wellcome's drug Imitrex (sumatriptan), which acts on 5-HT receptors in both areas and increases the amount of serotonin that nerve cells release, was one of the first successful triptans. Clinical trials show that sumatriptan reduces migraine pain in over 75% of patients within one hour and in over 80% of patients within two hours. Since then, three other triptans have been approved: Zeneca's Zomig (zolmitriptan), Glaxo Wellcome's Amerge (naratriptan) and Merck's Maxalt (rizatriptan). Each drug has benefits unlike the others and, for the most part, have been an improvement on each other by changing the levels of serotonin in the body. Similar drugs expected to be on the market soon are eletriptan, frovatriptan, and alniditan. However, common side effects still have occurred with triptans such as heart problems and chest tightness.

Due to these side effects, companies are working on improved compounds to relieve migraine symptoms while eliminating or minimizing the serious cardiovascular side effects. Zeneca is developing four other variations of Zomig for different types of migraines. According to the company Allelix, their product ALX-0646, which is currently in a phase II study, could allow physicians to prescribe a wider range of doses to treat migraine pain more effectively, and should reduce migraine recurrence rates. Also, it could be used in a wider variety of patients, including those with cardiovascular risk factors who cannot be treated effectively with current triptans.

VanGuard Medica Group/Elan Corporation's NDA submission for Frovatriptan is currently being reviewed. Results from their phase IIb trials showed Frovatriptan to be well tolerated in the treatment of acute migraine across a wide range of doses and the side effects were described as mild or moderate. At doses of 2.5mg and 5mg the compound had a side effect profile similar to the placebo. Pfizer has also completed regulatory filings for Relpax and recently received approval.

Eli Lilly/Synpatic were developing an anti-migraine compound they predicted would have no potential cardiovascular side effects. However, this phase II trial was stopped due to toxicity. This reinforces the difficulty companies are having in finding a new migraine treatment without side effects.

Other than triptans, a number of products are being developed for prophylaxis uses. CoCensy's product CCD-1042 (ganaxolone) and Mylan's product dotarizine are compounds that would ease the inflammation of blood vessels.

The Role of Genes

Researchers are also examining the role of genetics in migraines. Genes alone do not cause migraines, except in rare cases, but they may make people more susceptible to migraines. Both genes and environmental factors seem to cause common forms of migraines. Various studies have shown that a child has a 20% chance of developing migraines if an extended family member has the disorder, a 50% chance if one parent suffers from migraines, and a 75% chance if both parents have migraines.

Identifying the gene or genes involved in migraines could eventually lead to screening tests for people at greatest risk. Doctors could then take steps to prevent migraines from developing in those patients. The discovery of a migraine gene or genes also could lead to better treatments.

While all migraine sufferers require acute treatment, only those with frequent or severely disabling migraines require medicine to prevent migraines from developing. One of the more interesting preventive treatments being studied in migraine patients is Botox, a drug marketed by Allergan. Botox, is currently used to treat epilepsy because it reduces nerve activity. Results from clinical studies suggest that Botox prevents migraines for three to four months, although one study indicates the possibility of being headache-free for up to a year. Many large studies of Botox are being conducted across the country.

Unfortunately, there are no cures for migraine pain but the current treatments for migraines are quicker and are longer lasting. The main problem with current treatments is that a migraine that appears to be relieved by a dose of triptan, can often reoccur when the triptan wears off. Prevention of migraines remains a strong opportunity for pharmaceutical companies.

--KRISTINE ESCHMANN

Migraine and Headache Resources

 
American Academy of Head, 
Neck and Facial Pain                    817.282.1501 
www.aahnfp.org 
 
American Association for the 
Study of Headache                       609.423.0043 
www.aash.org 
 
American Council for Headache 
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