Friday, September 16, 2005

Serotonin agonists and migraines

Migraines are a class of ferocious headaches, frequently with pain on only one side of the head, and often accompanied by nausea, visual illusions called aura, and a deep aversion to light or noise.

This month's Nature Reviews Drug Discovery has a review about progress in treating migraines. The most commonly chosen drugs, known as triptans, activate the Serotonin 1B and 1D receptors. This class of drugs has been the choice for persistent migraine cases since the late 80's. However, triptans (the best known is sumatriptan/Imitrex) act not only in the brain but also constrict blood vessels throughout the body, with potential cardiovascular side effects. The argument of this review is that pharma needs to design drugs that will disentangle the two effects.

The first section of the review explains the evidence that migraine is in the neurons of the brain and not the brain vasculature. (This is what brought me to the article. In fact the vascular actions of the drugs might have increased the confusion about which system mattered.) During attacks, brain activation is seen in specific areas which are associated with pain sensation in the head and the brain vasculature. (In fact the visual aura might be a blood flow effect.) But a specific electrical phenomenon known as a contingent negative variation (CNV) is altered before an oncoming attack and, if the attack is prevented with drugs, the CNV seems to become normalized. Thus migraine is associated with abnormal neuronal firing, and activation of specific brain regions associated with pain processing.

The author basically suggests that moving past the current therapy requires compounds targeting other, neuron specific, receptor systems. He runs down a pretty lengthy list of compounds which are in development. Of these the most interesting to me are the ones which are directly related to blocking nociception (the neuronal sense of "pain"). In any case, options for treating migraine will expand greatly in the near future.

A nice older review at NEJM is here .

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