Monday, May 30, 2005

Migraine prophylaxis and drug design

Those of us with frequent migraine attacks want drugs that will prevent attacks before they even start. The list of drugs that sometimes work is motley: beta blockers, calcium channel blockers, anticonvulsants, a particular antihistamine, certain toxins from the ergot fungus, and so forth. Unfortunately it's rather hit-and-miss. What works for one person doesn't always work for another.

It was noticed that many of these drugs interact with serotonin receptors in the brain, in particular the 5HT-1B and -1D subtypes. For someone taking a beta blocker for high blood pressure this is a tiny side effect, but for a migraineur it is the main event and the blood pressure effects are unwanted. The ergots hit serotonin receptors like gangbusters, which is good for migraine, but bad for gangrene, so they can't be used for prophylaxis.

The drug companies sensed a major opportunity. Looking at the patient population, they found two major groups. Lots of people have infrequent migraines and would gladly pay $20 a pill for relief. Twenty dollars is cheap insurance against not having a brain meltdown at a business meeting, date, big exam, etc. The other group is a few people who have frequent migraines and need daily prophylaxis for a few dollars a day. They cannot afford $20×365 = $7200 a year.

And that is a problem. A drug company could design something that works for the second group, but then folks in the first group would just use it too and get relief for a couple of dollars a pop. Whereas if you make something for the first group, they'll pay $20/pill, and the second group will also pony up for quite a few $20 pills. Do the math and the $20 version is worth many billions of dollars more.

Naturally the drug companies went for the $20 pill. They put emphasis on drugs that were fast acting, and could be dosed to the gills without excessive side effects (sumatriptan is available in 100 mg tablets). Many drugs were discovered and approved: sumatriptan, naratriptan, etc. All of them but one (frovatriptan) leave the body within hours, so that prophylaxis would require multiple daily doses even if it was affordable. (One wonders if frovatriptan was an accident, from a discovery effort whose shorter half-life candidates bombed.)

I am not entirely complaining. The triptans are incredibly helpful, and have paid for loads of much-needed migraine research. It's just a drag to ask yourself "Is it worth $20 this time?" on a near-daily basis.

I should mention that there is some question as to whether triptans are safe and effective for prophylaxis. They are vasoconstrictors, so there is some theoretical risk of infarction, including stroke. However large studies have not found a worrisome stroke rate for occassional use, one small study found prophylactic efficacy and no bad effects with daily dosing (although the statistical power was small), and lots of people seem to use them heavily without stroking out.

Triptan Half-Lives
Compound Half-Life (hours) Brand Name U.S. Approval
Sumatriptan 2.5 Imitrex Dec. 1992
Zolmitriptan 3 Zomig Nov. 1997
Naratriptan 6 Amerge Feb. 1998
Rizatriptan 2–3 Maxalt Jun. 1998
Almotriptan 3–4 Axert May 2001
Frovatriptan 26 Frova Nov. 2001
Eletriptan 4 Relpax Dec. 2002


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