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Migraine: a continuing problem
Migraine: a continuing problem Every neurologist's spirits must surely sink a little when facing yet a n o t h e r patient with headache. It is not that the p r o b l e m of headache lacks intrinsic interest, but rather that, after the patient has b e e n assessed, the diagnosis will so o f t e n p r o v e to b e t h a t o f m i g r a i n e . In t h a t case, sometimes the problem will be that of comparatively recent onset episodic headache, where there have b e e n fears, voiced or unvoiced, of a cerebral t u m o u r or o t h e r serious intracranial disorder. Reassurance as to the diagnosis of m i g r a i n e a n d o f its g e n e r a l l y b e n i g n n a t u r e , a n d organisation of a t r e a t m e n t r e g i m e n can then p r o d u c e a satisfying o u t c o m e for all c o n c e r n e d . However, m o r e often, t h e r e will be little d o u b t t h a t m i g r a i n e is the diagnosis and the real p r o b l e m will be that n u m e r o u s treatments have already b e e n tried and have failed to provide adequate relief, or to continue to provide it. T h e n the t h e r a p e u t i c i n g e n u i t y o f the n e u r o l o g i s t can be severely tested in trying to suggest a therapy that has some chance of success. This was a situation T h o m a s Willis 1 knew m o r e than 300 years ago w h e n he wrote: Some few years since I was called to see a Lady of Quality, troubled for about twenty years with a Head-ach, which at first was intermittent, but of late is almost continual...In order to the obtaining, or rather endeavouring a Cure, throughout the whole progress of the Disease, a great many Remedies, prescribed by most skilful Physicians, as well of our Country as foreigners, were used without any success, or ease: She tryed all the Great Remedies of every kind and form, but always in vain. M i g r a i n e is a c o m m o n d i s o r d e r . N o w t h a t t h e diagnostic criteria of the International H e a d a c h e Society are being- increasingly u s e d in h e a d a c h e p r e v a l e n c e studies, it appears that some 6% of adult males and 16% of adult females suffer from migraine. 2 The economic costs are clearly substantial though often not well quantified. 3 T h e m e c h a n i s m s responsible for the disorder are still not a d e q u a t e l y u n d e r s t o o d . N o n e of the h y p o t h e s e s concerning the pathogenesis of migraine seems capable of accounting for all the clinical features of the disorder. YVhether the p r i m a r y events are t h o u g h t to be neural, or vascular, it is difficult to explain why the pain may be
restricted to a limited area of the head, and why that area m a y c h a n g e f r o m o n e attack to the next. Until the biochemical mechanisms that p r o d u c e the manifestation of migraine are u n d e r s t o o d it will be difficult to develop new and rational treatments for the disorder. T h e great i m p e d i m e n t to the further study of migraine is that the critical investigations must be carried out in h u m a n s - there is no adequate and generally accepted animal model. In the middle years of the present century the investigations of Harold Wolff, 4 in New York, carried out in patients with migraine, threw considerable light on the physiological d i s t u r b a n c e s involved in attacks of the disorder, while biochemical studies using the m e t h o d s then available, d e m o n s t r a t e d the role of serotonin (5hydroxytryptamine: 5HT) in the pathogenesis of attacks. Unfortunately, the t e m p o of the advance in knowledge has since slowed, perhaps because the previously available technology had b e e n taken as far as it could be when used in an ethically acceptable way in humans. However the application of new dynamic m e t h o d s of studying living tissue chemistry, e.g. magnetic resonance spectroscopy, positron emission t o m o g r a p h y , may soon c o m e to be a p p l i e d to m i g r a i n e , a n d t h r o w f u r t h e r light on the situation. With the exception of sumatriptan, no significant new medication to treat or prevent attacks of migraine has b e c o m e available in the past two decades. T h e r e is little d o u b t that sumatriptan is the m o s t effective a g e n t yet p r o d u c e d to relieve migraine attacks. It acts as an agonist at certain 5 H T type 1 receptors, and presumably exerts its anti-migraine effects at this type of cranial vascular receptor, since it does not cross the n o r m a l blood-brain barrier. Its d e v e l o p m e n t has sparked a rapid expansion of knowledge of the varieties of 5 H T receptor, and an ever increasing a n d r a t h e r bewildering array o f types a n d s u b t y p e s o f 5 H T r e c e p t o r s is b e c o m i n g k n o w n , a Unfortunately, sumatriptan is not invariably successful in treating migraine attacks and, like every other drug, has its adverse effects, notably a peculiar discomfort or frank pain across the front of the chest and shoulders. This pain can be quite severe and, in the great majority of instances,
J. Clin. Neuroscience
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is of uncertain cause though probably not due to coronary artery spasm. It is possible that new dosage forms of the drug, new routes of administration and the definition of a 'therapeutic range' of plasma concentrations, might help overcome some of the drug's current limitations, e.g. its incomplete oral bioavailability (circa 14% 6), and e n h a n c e its efficacy. Also, a modified release formulation which allowed p a r t o f the dose o f the d r u g to be available promptly, with the r e m a i n d e r b e c o m i n g available m o r e slowly, over several hours, m i g h t obviate a p r o b l e m with the c u r r e n t oral d o s a g e f o r m o f the drug. Because sumatriptan is eliminated quickly (half-life 2 hours), a migraine attack that has b e e n relieved can recur some 8 hours after the drug's intake, necessitating a further dose of sumatriptan. The other factor that limits the c o n t e m p o r a r y use of sumatriptan is its not insubstantial cost. The upsurge of interest in serotonin agonists in treating migraine attacks has b r o u g h t a b o u t an awareness that e r g o t a m i n e a n d d i h y d r o e r g o t a m i n e , t h e classical treatments for migraine attacks, act as agonists at the same 5 H T 1 like r e c e p t o r s o n which s u m a t r i p t a n exerts its effects. 7 Admittedly, these ergot derivatives are pharmacologically less specific agents than sumatriptan, a n d have very low oral bioavailabilities a n d d i f f e r e n t patterns of adverse effect. Ergotamine partly isomerises in aqueous solution to the inactive e p i m e r ergotaminine, 8 b u t m g f o r mg, it is r o u g h l y 50 t i m e s as p o t e n t as sumatriptan, has a longer duration of action, and is very m u c h c h e a p e r . T h e analytical m e t h o d o l o g y is n o w available to define the p h a r m a c o k i n e t i c s o f its active isomeric f o r m properly, 9 and on that basis to develop a m o r e rational and hopefully m o r e effective way of using it in migraine. No new a g e n t effective in migraine prevention has a p p e a r e d in m a n y years. T h e currently available drugs have a m o d e s t effectiveness, but what Edward Lieving wrote of the agents used to prevent migraine 120 years ago 1° could as well be said of the c o n t e m p o r a r y therapies: One circumstance common to the operation of pharmaceutical remedies in all this group of affections is the singular uncertainty of their curative influence. In a certain proportion of cases the administration of a particular drug is followed by well-marked and often immediate benefit: in others, which apparently differ but little if at all in their character, it will be perfectly inert.
106
J. Clin. Neuroscience
Volume 2
Number 2
While nearly all the drugs used in migraine prevention a p p e a r to a c t in s o m e way o r o t h e r o n s e r o t o n i n mechanisms, some as antagonists at 5 H T 9 receptors, their prophylactic activities are delayed and a p p e a r to persist for several weeks after drug intake ceases. This discrepancy between the course of the presence of the d r u g in the body, a n d of its effects, raises the possibility that the migraine preventives act indirectly, by p r o d u c i n g some t i m e - d e p e n d e n t reversible m o d i f i c a t i o n of s e r o t o n i n receptors. Thus current knowledge suggests some of the trails which research might follow in attempting to provide m o r e effective treatments for migraine, r e m e d i e s which the c o n t e m p o r a r y neurologist so badly needs if the n u m e r o u s patients in the c o m m u n i t y with therapeutically-refractory instances of the disorder are to be helped. MJ EADIE Co-Editor
References 1. Willis T. The London practice of physick. London: Bassett. 1685:384. 2. Stewart WF, Schecter A, Rasmussen BK. Migraine prevalence. A review of population based studies. Neurology 1994;44 (suppl. 4):$17-$23. 3. De Lissovoy G, Lazarus SS. The economic cost of migraine. Present state of knowledge. Neurology 1994;44 (suppl. 4) :$56-$72. 4. Wolff HG. Headache and other head pain. New York: Oxford University Press, 1963. 5. Hoyer D, Clark DE, FozardJR et al. The International Union of Pharmacology classification of receptors for 5hydroxytryptamine (serotonin). Pharmacological Reviews 1994;46:157-203. 6. Fowler PA, Lacey LF, Thomas M, Keene ON, Tanner RJN, Barber NS. The clinical pharmacology, pharmacokinetics and metabolism of sumatriptan. European Neurology 1991;31:282-90. 7. Humphrey PPA, Feniuk W, Marriott AS, Tanner RJN, Jackson MR, Tucker ML. Preclinical studies on the antimigraine drug sumatriptan. European Neurology 1991;31:291-94. 8. Eadie MJ. Ergotamine pharmacokinetics in man: an editorial. Cephalalgia 1983;3:135-58. 9. Sanders SW, Haering N, Mosberg H, Jaeger H. Pharmacokinetics of ergotamine in healthy volunteers following oral and rectal dosing. European Journal of Clinical Pharmacology 1986;30:331-34. 10. Lieving E. On megrim, sick-headache and some allied disorders. London: J & A Churchill. 1873:436-37.
April 1995
restricted to a limited area of the head, and why that area m a y c h a n g e f r o m o n e attack to the next. Until the biochemical mechanisms that p r o d u c e the manifestation of migraine are u n d e r s t o o d it will be difficult to develop new and rational treatments for the disorder. T h e great i m p e d i m e n t to the further study of migraine is that the critical investigations must be carried out in h u m a n s - there is no adequate and generally accepted animal model. In the middle years of the present century the investigations of Harold Wolff, 4 in New York, carried out in patients with migraine, threw considerable light on the physiological d i s t u r b a n c e s involved in attacks of the disorder, while biochemical studies using the m e t h o d s then available, d e m o n s t r a t e d the role of serotonin (5hydroxytryptamine: 5HT) in the pathogenesis of attacks. Unfortunately, the t e m p o of the advance in knowledge has since slowed, perhaps because the previously available technology had b e e n taken as far as it could be when used in an ethically acceptable way in humans. However the application of new dynamic m e t h o d s of studying living tissue chemistry, e.g. magnetic resonance spectroscopy, positron emission t o m o g r a p h y , may soon c o m e to be a p p l i e d to m i g r a i n e , a n d t h r o w f u r t h e r light on the situation. With the exception of sumatriptan, no significant new medication to treat or prevent attacks of migraine has b e c o m e available in the past two decades. T h e r e is little d o u b t that sumatriptan is the m o s t effective a g e n t yet p r o d u c e d to relieve migraine attacks. It acts as an agonist at certain 5 H T type 1 receptors, and presumably exerts its anti-migraine effects at this type of cranial vascular receptor, since it does not cross the n o r m a l blood-brain barrier. Its d e v e l o p m e n t has sparked a rapid expansion of knowledge of the varieties of 5 H T receptor, and an ever increasing a n d r a t h e r bewildering array o f types a n d s u b t y p e s o f 5 H T r e c e p t o r s is b e c o m i n g k n o w n , a Unfortunately, sumatriptan is not invariably successful in treating migraine attacks and, like every other drug, has its adverse effects, notably a peculiar discomfort or frank pain across the front of the chest and shoulders. This pain can be quite severe and, in the great majority of instances,
J. Clin. Neuroscience
Volume 2
Number 2
April 1995
105
is of uncertain cause though probably not due to coronary artery spasm. It is possible that new dosage forms of the drug, new routes of administration and the definition of a 'therapeutic range' of plasma concentrations, might help overcome some of the drug's current limitations, e.g. its incomplete oral bioavailability (circa 14% 6), and e n h a n c e its efficacy. Also, a modified release formulation which allowed p a r t o f the dose o f the d r u g to be available promptly, with the r e m a i n d e r b e c o m i n g available m o r e slowly, over several hours, m i g h t obviate a p r o b l e m with the c u r r e n t oral d o s a g e f o r m o f the drug. Because sumatriptan is eliminated quickly (half-life 2 hours), a migraine attack that has b e e n relieved can recur some 8 hours after the drug's intake, necessitating a further dose of sumatriptan. The other factor that limits the c o n t e m p o r a r y use of sumatriptan is its not insubstantial cost. The upsurge of interest in serotonin agonists in treating migraine attacks has b r o u g h t a b o u t an awareness that e r g o t a m i n e a n d d i h y d r o e r g o t a m i n e , t h e classical treatments for migraine attacks, act as agonists at the same 5 H T 1 like r e c e p t o r s o n which s u m a t r i p t a n exerts its effects. 7 Admittedly, these ergot derivatives are pharmacologically less specific agents than sumatriptan, a n d have very low oral bioavailabilities a n d d i f f e r e n t patterns of adverse effect. Ergotamine partly isomerises in aqueous solution to the inactive e p i m e r ergotaminine, 8 b u t m g f o r mg, it is r o u g h l y 50 t i m e s as p o t e n t as sumatriptan, has a longer duration of action, and is very m u c h c h e a p e r . T h e analytical m e t h o d o l o g y is n o w available to define the p h a r m a c o k i n e t i c s o f its active isomeric f o r m properly, 9 and on that basis to develop a m o r e rational and hopefully m o r e effective way of using it in migraine. No new a g e n t effective in migraine prevention has a p p e a r e d in m a n y years. T h e currently available drugs have a m o d e s t effectiveness, but what Edward Lieving wrote of the agents used to prevent migraine 120 years ago 1° could as well be said of the c o n t e m p o r a r y therapies: One circumstance common to the operation of pharmaceutical remedies in all this group of affections is the singular uncertainty of their curative influence. In a certain proportion of cases the administration of a particular drug is followed by well-marked and often immediate benefit: in others, which apparently differ but little if at all in their character, it will be perfectly inert.
106
J. Clin. Neuroscience
Volume 2
Number 2
While nearly all the drugs used in migraine prevention a p p e a r to a c t in s o m e way o r o t h e r o n s e r o t o n i n mechanisms, some as antagonists at 5 H T 9 receptors, their prophylactic activities are delayed and a p p e a r to persist for several weeks after drug intake ceases. This discrepancy between the course of the presence of the d r u g in the body, a n d of its effects, raises the possibility that the migraine preventives act indirectly, by p r o d u c i n g some t i m e - d e p e n d e n t reversible m o d i f i c a t i o n of s e r o t o n i n receptors. Thus current knowledge suggests some of the trails which research might follow in attempting to provide m o r e effective treatments for migraine, r e m e d i e s which the c o n t e m p o r a r y neurologist so badly needs if the n u m e r o u s patients in the c o m m u n i t y with therapeutically-refractory instances of the disorder are to be helped. MJ EADIE Co-Editor
References 1. Willis T. The London practice of physick. London: Bassett. 1685:384. 2. Stewart WF, Schecter A, Rasmussen BK. Migraine prevalence. A review of population based studies. Neurology 1994;44 (suppl. 4):$17-$23. 3. De Lissovoy G, Lazarus SS. The economic cost of migraine. Present state of knowledge. Neurology 1994;44 (suppl. 4) :$56-$72. 4. Wolff HG. Headache and other head pain. New York: Oxford University Press, 1963. 5. Hoyer D, Clark DE, FozardJR et al. The International Union of Pharmacology classification of receptors for 5hydroxytryptamine (serotonin). Pharmacological Reviews 1994;46:157-203. 6. Fowler PA, Lacey LF, Thomas M, Keene ON, Tanner RJN, Barber NS. The clinical pharmacology, pharmacokinetics and metabolism of sumatriptan. European Neurology 1991;31:282-90. 7. Humphrey PPA, Feniuk W, Marriott AS, Tanner RJN, Jackson MR, Tucker ML. Preclinical studies on the antimigraine drug sumatriptan. European Neurology 1991;31:291-94. 8. Eadie MJ. Ergotamine pharmacokinetics in man: an editorial. Cephalalgia 1983;3:135-58. 9. Sanders SW, Haering N, Mosberg H, Jaeger H. Pharmacokinetics of ergotamine in healthy volunteers following oral and rectal dosing. European Journal of Clinical Pharmacology 1986;30:331-34. 10. Lieving E. On megrim, sick-headache and some allied disorders. London: J & A Churchill. 1873:436-37.
April 1995