Migraine and the pharmaceutical industry

The triptans – the migraine medicines of today

Among the most selective and useful medicines for acute treatment are the triptans. Their discovery arose from a search for a molecule which mimicked serotonin. This led scientists at Glaxo Wellcome to the discovery of GR43175, shown in 1988 to be effective in acute migraine treatment. This came to be known as sumatriptan, the first of a new class of anti-migraine medicines that have improved the lives of many patients. The innovative nature of this achievement was recognised in the UK when sumatriptan won the Queens Award for Technology in 1996.

Since then, three others have been introduced in the UK: naratriptan (Glaxo Wellcome), rizatriptan (Merck Sharp & Dohme), and zolmitriptan (Astra-Zeneca). Several others are in late-stage clinical trials, including almotriptan (Lundbeck), eletriptan (Pfizer), and frovatriptan (Vanguard).

It is difficult to make comparisons between the various triptans. Although those now available have been tested in extensive clinical trials and all are undoubtedly effective, they have not always been compared for the same effects. For example, various comparative studies use headache relief at 1 hour, 2 hours or even 4 hours as a benchmark, though in future the 2 hour time point may be adopted as the standard.

Comparisons are further complicated by the fact that the triptans each behave differently in the human body. For example, different amounts of each of these medicines are absorbed from the intestines when given as a tablet, and the speed of absorption differs. Further, all except sumatriptan cross from the blood stream into the brain, although this does not seem directly related to the effectiveness of the compounds. Yet again, some types of triptan such as naratriptan are slower to provide relief and yet may be more acceptable in specific individuals who suffer from an early return of their headache.

Also, some triptans should not be taken by people being treated with some other types of medicines. For example, only low dose rizatriptan should be given to patients taking the beta-blocker propranolol, because of an interaction that increases the blood level of rizatriptan, though this effect is not seen with other beta-blockers such as metoprolol, nadolol and timolol. Again, sumatriptan and rizatriptan are not appropriate for individuals taking monoamine oxidase inhibitors (MAOIs), used in the treatment of Parkinson’s and depression. In this case they interact with the MAOIs and modify the way they are cleared from the body. As a final example, zolmitriptan has been shown to interact with the anti-ulcer medicine, cimetidine.

The bottom line is that each triptan has its own particular attributes which commend its use in different individuals. While sumatriptan is often the therapy with which others are compared, there are real instances when an alternative would be preferable. This may be apparent from the patient’s medical history and/or symptoms, but often it is a matter of trial and error. If one compound does not suit, another one might. For instance, some people who do not respond adequately to sumatriptan may respond when switched to rizatriptan or zolmitriptan – a very important difference for that particular group.

The availability of the four triptans is, therefore, a considerable advantage, because without it patients and doctors would have less choice and fewer people would achieve acceptable control of their illness. As Professor Goadsby from the London Institute of Neurology has written, ‘...we must emphasise the principle of fitting the treatment or formulation to the patient, individualising care, not trying to insist that all patients fit into one treatment’.

There is a range of other triptans still in development. Early clinical trials carried out with eletriptan (Pfizer) have shown that it is effective and provides rapid pain relief. Other triptans in an advanced development stage are almotriptan (Lundbeck) and frovatriptan (Vanguard). The former appears to be very well absorbed and its effectiveness is in the range of the other triptans. Frovatriptan is less well absorbed, but both this and almotriptan appear to have a low relapse rate (i.e. return of headache) at 24 hours. An application to make frovatriptan available in Europe has now been made.

Although promising, the true significance of these new medicines in migraine and their performance against the existing triptans will only become clearer after greater experience in larger numbers of patients.

A related medicine at an earlier stage of development is the serotonin agonist, PNU-142633 (Pharmacia & Upjohn), which has completed its safety assessment in volunteers and has now entered clinical trials. Another related compound is ALX 1646 (Allelix Biopharmaceuticals), which is about to enter phase 2 trials in America. A third is SB220453 (SmithKline Beecham), which appears to have a different mechanism of action and to have a distinct binding site in the brain. It has completed Phase 1 studies and Phase 2 trials are planned for both prevention and treatment of migraine. Only time will tell, but it will clearly be some years before the triptan ‘seam’ has been fully mined out.