Migraine treatment and mistreatment: primum non nocere

Triptans can provide wonderful relief from migraine, but must not be overused as "pseudo-preventives"

MJA 2000; 172: 412-413

	If the 1990s was the decade of the brain for neuroscientists, then it was the decade of new treatments and renewed hope for sufferers of neurological diseases. Neurology, long the bastion of diagnosis, has become the specialty of the physician that we would all like to be -- one who is able to take a careful history and conduct a meticulous physical examination leading to a diagnosis and management plan. For headache patients, and perhaps neurological patients in general, it is the latter development in neurology, the move to more effective management of the conditions, that has been truly marvellous. We have started to identify the genes involved in causing the problem,1 and by so doing have begun to understand the episodic nature of the attacks in terms of ion-channel dysfunction. We have finally begun to image the primary headaches with functional/anatomical methods that have pointed to the brainstem, in migraine,2 and the posterior hypothalamus, in cluster headache,3 as likely candidates for the basic pathophysiological process.
	What is misuse and when is good medicine slipping into overtreatment?
	Best of all, from a clinical perspective, neurotherapeutics leapt ahead. The advent of the triptans (serotonin agonists) was to migraine and cluster headache almost the equivalent of penicillin to bacterial infection! It seems almost outrageous to liken the development of triptans to the discovery of penicillin, but this analogy has been used by at least three of my patients, themselves general practitioners who suffer migraines, to describe the change in their lives. Migraine never threatens life, but, as Professor Jim Lance, the Australian doyen of migraine, taught me, it simply "makes it hell". Disability is the key word to understanding the impact of migraine: inability to work effectively, care for dependants, enjoy recreation or participate in the myriad responsibilities that the non-migraineur takes for granted. What have we learnt from the developments of the past decade and what should we expect for the next decade in terms of therapeutics? The first triptan to be released was sumatriptan, developed in considerable part through the pioneering work of Lance and Anthony at Prince Henry Hospital in Sydney.4 This compound burst on to the clinical scene in the late 1980s,5 proving to be highly efficacious in clinical studies.6 Its development was marked by careful clinical trials methodology and spurred the widespread adoption of the International Headache Society Diagnostic Criteria7 for use in clinical studies. These criteria have been a boon for the clinical scientist and, if more widely used and adapted for primary care, could be useful for both doctors and patients more generally. As it became obvious that sumatriptan heralded a major advance in therapy, other researchers became interested in the field and triptan sons and cousins were soon in gestation. Naratriptan and zolmitriptan are now available in Australia and in Europe we also have rizatriptan; in late development or close to registration are almotriptan, eletriptan and frovatriptan. Do we have enough? For patients who respond to the triptans already available, obviously yes; for those who still suffer, confined like children to a room without a view for no sin other than their parents' genetic gifts, obviously not.8 Triptans are not perfect: a third of patients taking them have recurrence of headache within 24 hours; for some they do not work at all; and for those with significant risk factors for cardiovascular disease they are inappropriate. It has been at once heartening to find patients who show no improvement with one triptan yet respond to another, and disheartening that we have not been able to dissect what it is about the compounds9 that makes such profound differences in their clinical performance in individuals. In medicine almost every sunny day has a cloud on the horizon, and headache therapeutics is no exception. Ten years after the release of sumatriptan for clinical use, we have begun to appreciate the problems of mistreatment with triptans, reinforcing previous observations on mistreatment with other acute attack medications such as ergotamine or compound analgesics. In this context, "mistreatment" implies the inappropriate use of acute attack therapies by patients, either acting independently or under their doctors' instructions. This is referred to in the literature variously as "abuse", "overuse" or "misuse". Patients seldom misuse medications for any gain other than to attempt to function normally, to get to work or to look after their families. Given that acute medicines were designed for relatively infrequent use, and indeed that the triptans were studied explicitly in people having migraine frequencies of six or less per month, I believe that frequent use is a misuse of the medicine and a mistreatment of migraine. Reports of triptan misuse10,11 come as no surprise given the problems with ergotamine over the years,12 and this has sparked renewed interest in the subject of analgesic misuse.13 While the extent to which analgesics, particularly compound analgesics such as those containing codeine, can induce headache is not yet established, it seems clinically plausible that they block the frequency-reducing benefits of headache preventive therapy. What is misuse and when is good medicine slipping into overtreatment? With regard to ergotamine, a recent European consensus statement recommends, with some clearly stated exceptions, that the maximum usage should be 4-6 times a month.14 The tool with which to define this problem is the diary: a simple record of the number of days on which headache is experienced, and which prescription or over-the-counter medications are taken, will soon reveal whether excess medication is being consumed and whether management, including neurological referral, is appropriate. What are the prospects for the future? An understanding of migraine neurobiology will build on what has been done; more genes will be identified; functional imaging will better define and elaborate on the brain areas responsible for the disorder; and experimental laboratory work will put these observations under the modern anatomical and physiological microscope, returning more questions to the clinical scientists. In terms of treatment we need to do both more and less. We need to treat more patients who could benefit from medication but are not receiving adequate treatment. We need to develop new preventives to treat the sufferer of frequent headache whose disability load is truly dreadful, while at the same time guarding against using medications designed for intermittent acute use (triptans, ergotamine and analgesics) as pseudo-preventives -- primum non nocere! Lastly, we must spread the message that migraine is a genetically determined problem which is reasonably well characterised neurobiologically. Migraine involves dysfunction of brainstem and diencephalic areas normally involved in controlling pain and other sensory information and results in activation of very specific trigeminovascular pain pathways which are well defined and understood. The future is bright -- a good history, meticulous physical examination, clear diagnosis and explanation, and management directed at restoring ability to function is exactly what we can offer and, I think, exactly what patients want. Peter J Goadsby Professor of Clinical Neurology, Institute of Neurology University Department of Clinical Neurology National Hospital for Neurology and Neurosurgery Queen Square, London, UK Disclosure statement: In recent times the author has advised, collaborated with, and spoken at meetings organised by various companies, including Allergan, Almiral-Prodesfarma, AstraZeneca, BristolMyersSquibb, GlaxoWellcome, MSD, Pfizer, Pharmacia-Upjohn, Sandoz, and SmithKlineBeecham, which manufacture compounds referred to in this article or have an interest in developing compounds for the treatment of various primary headache syndromes. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNLA4. Cell 1996; 87: 543-552. Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med 1995; 1: 658-660. May A, Bahra A, Buchel C, et al. Hypothalamic activation in cluster headache attacks. Lancet 1998; 351: 275-278. Anthony M, Hinterberger H, Lance JW. Plasma serotonin in migraine and stress. Arch Neurol 1967; 16: 544-552. Doenicke A, Brand J, Perrin VL. Possible benefit of GR43175, a novel 5-HT1-like receptor agonist, for the acute treatment of severe migraine. Lancet 1988; 1: 1309-1311. Ferrari MD. The Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. N Engl J Med 1991; 325: 316-321. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(Suppl 7): 1-96. Goadsby PJ. A triptan too far. J Neurol Neurosurg Psychiatry 1998; 64: 143-147. Goadsby PJ. 5-HT1B/1D agonists in migraine: comparative pharmacology and its therapeutic implications. CNS Drugs 1998; 10: 271-286. Kaube H, May A, Diener HC, Pfaffenrath V. Sumatriptan misuse in daily chronic headache. BMJ 1994; 308: 1573-1574. Limmroth V, Kazarawa S, Fritsche G, Diener HC. Headache after frequent use of new serotonin agonists zolmitriptan and naratriptan. Lancet 1999; 353: 378. Friedman AP, Brazil P. Ergotamine tolerance in patients with migraine. J Am Med Assoc 1955; 157: 881-884. Diener HC. A personal view of the classification and definition of drug dependence headache. Cephalalgia 1993; 13: 68-71. Tfelt-Hansen P, Saxena PR, Dahlof C, et al. Ergotamine in the acute treatment of migraine - a review and European consensus. Brain 2000; 123: 9-18. ©MJA 2000 Make a comment Home | Issues | eMJA shop | Terms of use | Classifieds | More... | Contact | Topics | Search The Medical Journal of Australia    eMJA   Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> © 2000 Medical Journal of Australia. We appreciate your comments.