Migraine and the pharmaceutical industry

Early leads and possible future directions

The idea that migraine aura and the spread of the headache phase may be caused by a slowly moving wave of electrical activity suggested a relationship with epilepsy. The possibility of such a link is borne out by the benefits of anti-epileptic medicines in various kinds of brain-centred pain (neuropathic pain), including migraine. The earliest reports date back to the late 1960s, but recently sodium valproate (for the treatment of epilepsy, from Sanofi-Synthélabo and Pharmacia & Upjohn) has shown activity in migraine prevention, apparently by blocking inflammation of the membrane covering the brain (the meninges). Abbott in the USA has developed a slow-release form.

A newer medicine used for epilepsy, vigabatrine (Aventis) has also been studied in migraine. A publication in 1999 showed that it improved migraine in patients treated with it. However, there was no clear link between the blood levels of the medicine and its effect, which suggests a complex mechanism of action. So far the clinical trials have not been double blind and placebo controlled, but on the basis of these data, there is a justification for more controlled studies.

Other potential targets in migraine and some other disorders affecting the brain are substances called peptides – calcitonin gene-related peptide (CGRP) and neurokinins – released in the blood vessel walls after trigeminal nerve stimulation.

Chemicals that block the action of some of the peptides have already been prepared. For example, both Pfizer and Merck Sharp & Dohme have research programmes in this area while Glaxo Wellcome has an active pre-clinical research programme in medicines based around CGRP. Boehringer Ingelheim has one, BIBN 4096BS, in phase 2 trials for the treatment of acute migraine.

An unrelated compound which may share some of these activities is ganoxolone (CoCensys, USA). It seems to block the action of some of the peptides released at nerve endings attached to brain blood vessels. Some benefit in migraine was shown in preliminary clinical trials.

Recent genetic studies have suggested that calcium transport into brain cells may be defective in people who suffer from migraine. This may explain the interest in calcium channel blockers such as flunarazine and dotarizine (Mylan Pharmaceuticals). If deficient calcium transport contributes to the low trigger threshold of migraineurs, it might point to a mechanism for preventing the attacks altogether.

A completely different, unusual and somewhat unexpected approach for migraine prevention is the use of a toxin from a bacterium called Clostridium botulinum. Reports from the USA stated that people with migraine who were receiving injections of the toxin for cosmetic facial surgery experienced an improvement in their migraines lasting for several months. This result was checked in a larger study of 100 people with migraine who received toxin injections into the skin of their foreheads and neck. Several months later, about half of them said that their migraines had stopped and another 37 per cent said they were getting migraines half as often or were experiencing a reduction in severity.

A modified form of the botulinum toxin called NC-164 has been developed by the Centre for Applied Microbiology & Research (CAMR) in the UK as a long-acting analgesic. The compound exhibits a similar efficiency to analgesics, but without their side effects. It appears to work by targeting the neurones responsible for pain transmission and can prevent the release of neurotransmitters from their terminals and hence block pain signals. The compound is under pre-clinical investigation for chronic pain and though it is too soon to say whether it will be useful in migraine, it represents an interesting future lead.

A second approach to migraine prevention has led Glaxo Wellcome to a new compound called GV196771, now in Phase 2 clinical trials. This belongs to a class of medicine called the glycine antagonists. It acts at the NMDA receptor, a different brain neurotransmitter site to other anti-migraine compounds. Though it is early days, the compound is thought to decrease central sensitisation and may therefore stop impending migraines from developing.

Finally, Glaxo Wellcome has an active research programme aimed at defining new targets for the design of both acute treatments for migraine and for its prevention. These include inhibitors of inflammation of the dura mater and, in the longer term, leads based on the genes which predispose people to migraine and which may therefore provide further targets for its prevention.