Migraine - Treatment & needs

People have been trying to treat migraine since medical records began. The Egyptians recommended tying a clay crocodile with herbs in its mouth to the patient's head. Other early remedies included blood-letting and drilling a hole in the skull to release evil spirits.

Ergot, extracted from a fungus, is just one of many naturally-occurring compounds that have given rise to modern medicines [JE Watkins].

Migraine treatment became more scientific in the 19th century when physicians began to use ergot. Ergot, which is extracted from a fungus, contains a mixture of chemicals. Some cause blood vessels to constrict and consequently turn off pain-producing nerves in the head. These properties gained ergot recognition as a useful treatment for migraine, albeit one with serious flaws. Its effects were unpredictable owing to the many biologically active compounds it contains: ergot, as well as treating migraine, can cause convulsions, gangrene, hallucinations and even death. Luckily, in the 1920s, chemists identified and isolated the chemical ergotamine from ergot. Ergotamine has the useful properties of ergot but fewer side effects. Since then several ergotamine variants have become available for the acute treatment of migraine and are still prescribed today.

In 1972, UK scientist Pat Humphrey initiated a migraine drug discovery project at Ware in Hertfordshire for the British pharmaceutical company Glaxo. His starting point was the observation that methysergide, an anti-migraine agent related to ergotamine, had the ability (amongst several others) to narrow only the blood vessels around the brain. It was selective, with little effect on other blood vessels.

In addition, it was already known that injections of serotonin could relieve migraines. Perhaps methysergide was acting on the same target proteins (receptors as they are known) in the blood vessels involved in migraine as did serotonin. The hunt was on to find these hitherto unknown receptors for serotonin. If they did, indeed, exist, it might then be possible to develop better anti-migraine drugs with fewer side-effects than the ergot-based compounds. These new drugs would be based on serotonin, not ergot. Serotonin itself will never make a good medicine, it plays too many roles in the body.

The researchers searched for - and found - the new serotonin receptors in isolated dog blood vessels, which were well-studied and easier to obtain than those from smaller animals like mice. Then, they made thousands of serotonin look-alike molecules and tried them to see if they would bind to the newly discovered targets. One, known as sumatriptan, hit the target, which was a good start but this alone did not mean it would have the desired effect on human migraine. Tests in anaesthetised dogs and cats were carried out to confirm that sumatriptan not only bound to the new receptors but that it really did lead to constriction of brain blood vessels without affecting circulation in other parts of the body.

This small molecule has greatly improved the quality of life for many people who suffer from migraine attacks.

Preclinical studies in other animals then established that sumatriptan was safe to be used in clinical trials with people – new drugs are always tested first in animals to protect the human volunteers and patients who participate in clinical trials. Subsequent clinical trials showed it was very effective in treating migraine, and sumatriptan was launched as a specific treatment for acute migraine in 1991. It has since been joined by other triptan drugs and life has been greatly improved for many migraine sufferers.

The development of triptans was a great leap forward in migraine therapy. But not all migraine sufferers respond to them. Also, even though these treatments are pretty specific for the brain blood vessels that cause migraine, they cannot be safely used in people who have heart disease or high blood pressure. The drugs used to prevent migraine are also only moderately effective. Thus, there is a need for further research, including research in animals, to find more effective drugs for treatment and prevention of migraine in all sufferers.

Future prospects