PHARMACODYNAMIC PRINCIPLES OF ANTI-MIGRAINE THERAPY A. FANCHAMPS, M.D. MIGRAINE, the main symptom of which is head pain, is not influenced as well by specific analgesics as it is by certain substances completely devoid of analgesic properties. In order to understand the mode of action of these substances, we must refer to the mechanism of this particular pain. PATHOGENESIS OF MIGRAINE PAIN The classic theory of the vascular mechanism of a migraine attack (Wolff41) - constriction of cranial arteries during the prodromal phase and passive dilatation of extracranial vessels during the painful phase-has been completed as a result of numerous studies which indicate the involvement of humoral mechanisms. Wolff41 had already concluded that two elements must be combined to produce migraine pain: -a loss of tone of extracranial arteries, leading to their passive distension (particularly if the capillaries are constricted at the same time) -an increased sensitivity of the pain receptors in the arterial walls. He attributed the reduction in the pain threshold to the local production of a plasmakinin, which he proposed to call neurokinin. Furthermore, many observations appear to demonstrate that serotonin is involved to a considerable extent in the phenomena which lead to a migraine, attack ( Hilton & Cumings,14 Kangasniemi et al.,15 Lance et al.,16 Sicuteri et al.31,34). Following its liberation by the blood platelets at the onset of the migraine, serotonin appears to play a double role: -on the one hand, the free serotonin increases permeability and lowers the pain threshold. -on the other hand, its increased excretion causes a reduction in blood levels, which contributes to a reduction in the tone of the extracranial vessels.
Figure 1 is an attempt to arrange the experimental findings in logical order leading up to the migraine headache (Fanchamps11). At the beginning of the attack, the blood platelets release serotonin,1 while the mast cells in the affected area release histamine and proteolytic enzymes which convert plasma-kininogens into plasmakinins.2 Free serotonin and histamine increase capillary permeability,3 thus promoting transudation4 of plasmakinin into the vascular walls and the perivascular tissue, The combined effect of plasmakinin5 and sero-
tonin6 on the receptors in the arterial walls lowers their pain threshold.7 On the other hand, the greater part of the released serotonin is excreted as 5-hydroxy-indolacetic acid by the kidneys,8 so that blood serotonin levels are reduced.9 Since serotonin has a constricting effect on the extracranial arteries and a dilatory effect on the capillaries, this reduction in plasma levels is accompanied by hypotonicity of these arteries and capillary constriction,10 leading to passive, pulse-synchronous distension of the arterial walls.11 Thus, the two factors required to produce the migraine headache12 are present: the reduced pain threshold and arterial distension. Even if still somewhat hypothetical, this interpretation of the experimental data helps us to understand how substances with the most varied pharmaco-dynamic properties can have an anti-migraine effect. TREATMENT OF THE MIGRAINE ATTACK The first thing which comes to mind to counter a headache is to administer an analgesic. However, the effect of conventional analgesics on a migraine attack is rather poor. Fortunately, it is not necessary to resort to strong analgesics such as morphine, since other drugs are available, capable of interfering effectively in the pathogenetic mechanism of the attack. The various modes of action possible are listed in Table 1. No known substance possesses all these desirable properties, though it is in fact an increase in the tone of the extracranial vessels which stands in the foreground. Accordingly, it is possible to abort a migraine attack with norepinephrine (Ostfeld et al.22), but the effect is very transient, so that intravenous infusion is necessary. Ergotamine is very superior in this respect, since its vasoconstricting effect is of a sufficient duration to definitively abort the majority of attacks (Wolff41). Ergotamine produces vasoconstriction if the tone of the vessel is low, but dilatation if the vessel is already hypertonic (Aellig TABLE I Desirable Properties For a Treatment of the Migraine Attack The Ideal Drug Should: A. Counteract hypotonus of cranial arteries 1. By direct vasoconstriction 2. By potentiating catecholamine induced constriction or restoring normal sensitivity of vessels to catecholamines 3. By restoring normal plasma serotonin level B. Counteract humoral disturbances and resulting lowering of pain threshold by interference with: 1. Serotonin 2. Histamine 3. Plasmakinins C. D.
Abort nausea and vomiting Relieve nervous tension
& Berde1). This bivalent action is also found with other alkaloids of ergot, but the inversion point may vary (figure 2). While the degree of vasoconstriction induced by dihydroergotamine is not so high as with ergotamine, the inversion point is the same with both substances: they induce vasodilatation only in very hypertonic vessels ( > 4 Resistance Units). Dihydroergocristine, on the other hand, one of the components of Hydergine, does not contract vessels unless their tone is extremely low, and has a dilatory effect as soon as the initial tone exceeds 2 Resistance Units. Tests in isolated canine and human veins (figure 3) show that the constriction evoked by ergotamine or dihydroergotamine is chiefly the result of alpha-adrenergic stimulation, since it is inhibited by alpha-blocking agents such as phentolamine ( figure 4 ), phenoxybenzamine or dibenamine (Stürmer,37 Müller-Schweinitzer and Stürmer20). Classical pharmacology places ergotamine in the. category of adreno-sympatholytic substances; actually it is a competitive alpha-blocking agent endowed with considerable intrinsic alpha-stimulant properties. This is the reason why, in the small dosages used in therapeutic prac-
tice, far from always blocking the effects of epinephrine and norepinephrine, it may frequently potentiate these (Weidmann and Taeschler,39 figure 5). The same holds for dihydroergotamine. In addition, these ergot derivatives also inhibit norepinephrine re-uptake after nerve stimulation ( Pacha and Salzmann,24 Salzmann et al.,26 figure 6) thus maintaining a high level of circulating norepinephrine.
They are only weak serotonin antagonists, but they do inhibit serotonin up-take by human platelets (Stacey,36 Lingjaerde17) and in the spleen of the cat (Owen et al.,23 figure 7). Thus, it may be speculated that ergotamine and dihydroergotamine are able to counteract the decrease in free blood serotonin, which is one of the pathogenetic factors leading to the headache. It is clear then that the effect of these drugs on the migraine attack is not limited to a direct vasoconstricting action, but is also partially attributable to humoral mechanisms involving catecholamines and serotonin. Both substances act quickly and effectively if administered by injection. However, their oral effectiveness is rather poor, unless they are combined with caffeine which increases and accelerates their intestinal absorption (Schmidt and Fanchamps28). PREVENTIVE INTERVAL TREATMENT Preventive treatment of migraine is only justified if the frequency and severity of the attacks is such as to seriously disturb the patient's life. Depending on the individual case, therapy may be directed against aetiological factors-hormonal, dietetic, gastro-enterological, allergic, orthopedic, psychological, etc. It may, however, be difficult to identify a well-defined cause for migraine. In this case, the physician still has the possibility of interfering with the mechanism producing the attack. Due to the multifactorial pathogenesis of migraine, several points of attack are available, as listed in table 2. It is along these lines that we shall attempt to identify the mode of action of some of the most important therapeutic agents. Some of the substances have an essentially vascular point of attack. Clonidine, a substance of which the mode of action-partly central and partly peripheral on the sympathetic nervous system-has yet to be fully elucidated, is well established as an effective treatment of arterial hypertension. Its use for the treatment of migraine has been suggested by Zaimis42 and Hanington et al.13 on the basis of its stabilizing effect on vascular reactions following stimulation of both alpha- and beta-adrenergic receptors. In the cat, 1 to 4 weeks' treatment with small oral doses of clonidine greatly reduced the constriction of the femoral artery induced by norepinephrine as well as dilatation induced by isoprenaline. This stabliziation of vascular tone is, without
TABLE 2 Possible Modes of Action For a Prophylactic Treatment of Migraine A. On arterial tonus 1. Reduce lability of vascular tonus 2. Prevent reduction of sensitivity to catecholamines 3. Prevent drop in plasma serotonin B. On pain threshold 1. Prevent disturbance in permeability by interfering with a. Histamine release and effect on receptors b. Serotonin release and effect on receptors 2. Prevent plasmakinin formation, transudation and effect on receptors 3. Prevent potentiation of plasmakinin induced pain by serotonin C. On basic personality of migraine patient 1. Relieve nervous tension 2. Counteract mood depression doubt, not the only mechanism of this substance, which appears to be particularly effective in migraines of dietary origin, responding to the tyramine loading test ( Wilkinson et al.40). Experiments in the cat spleen performed in our laboratories have shown that the substance has no effect on serotonin uptake (figure 8, Salzmann and Kalberer27). Recently, beta-blocking agents, in particular propranolol, have been the subject of several positive studies as prophylactic treatment of migraine (Weber and Reinmuth,38 Malvea et al.18). Their effectiveness is probably attributable to the fact that stimulation of the beta-adrenergic receptors of the peripheral vessels produces vasodilatation, so that a blockage of these helps to maintain a certain level of vasoconstrictor tonus, counteracting the hypotonicity of extra-cranial arteries. These agents also appear to be capable of potentiating the effect of vasoconstricting drugs (Baumrucker5). It must be remembered, however, that some beta-blockers such as prindolol or practolol also have an intrinsic beta-stimulant effect which may mask their vasoconstricting potential. This may explain the varying results-sometimes positive (Anthony et al.4), sometimes negative (Ekbom et al.,10 Sjaastad et al.35 )-obtained with prindolol in this indication. Dihydroergotamine has properties similar, qualitatively, to those of ergotamine, though its vasoconstricting action is weaker. This is why higher doses have to be injected to abort an attack. However,
while daily administration of ergotamine in anti-migraine doses is not advisable, since in the long term this may cause undesirable peripheral vasoconstriction, the relatively weak vasoconstricting action of dihydroergotamine, especially when administered orally* , does permit long-term therapy. Used as an interval treatment, dihydroergotamine produces its prophylactic effect on the one hand by keeping the extracranial arteries at a certain level of tonicity and on the other hand by reinforcing the constricting effect of endogenous norepinephrine, as well as, perhaps, by maintaining useful levels of circulating norepinephrine ( figure 6 ) and free serotonin ( figure 9 ). Other no less-or even more-effective drugs have an effect not only on vascular, but also on humoral elements of the mechanism producing the headache. Methysergide is a semisynthetic derivative of ergot, though it is not related to ergotamine, as it possesses no polypeptide side-chain. In our tests, it shows no direct vasoconstricting effect, which explains its ineffectiveness in treating a migraine attack. It also has no influence on norepinephrine re-uptake (Berde6), while nevertheless having certain indirect effects on the blood vessels: reduction of the lability of arterial tone, as demonstrated in the cold pressor test (Wolff41 ), reinforcement of the vasoconstricting effect of norepinephrine in man (Dalessio8), normalisation of the response of the cranial vessels to norepinephrine in migraine sufferers ( Wolff41 ). However, the main sites of attack of methysergide are at the humoral level. It is a very powerful serotonin antagonist ( Fan-champs et al.12): strongly inhibiting the increase in permeability (Doepfner and Cerletti9), the potentiating effect of serotonin on induced pain in the mouse (Neuhold and Taeschler,21 Fanchamps,11 table 3) and the reinforcement by seroTABLE 3 Inhibiting Effect of Analgesics and Serotonin-Antagonists on Writhing Reaction to Intra-Peritoneal Injection of Acetic Acid in Mice ED 50 mg/kg s.c. 1 H before acetic acid Morphine 0.18 Aminopyrine 34.0 Methysergide 3.0 ( Sansert, Deseril ) According to Neuhold and Taeschler21 this writhing reaction requires the presence of serotonin.
tonin of the algesic effect of plasmakinins in humans (Sicuteri30). With regard to the blood serotonin level, methysergide has only a poor inhibitory effect on serotonin uptake in the cat spleen (Salzmann and Kalberer27), while in the rat in vivo it has been shown to reduce the serotonin releasing effect of reserpine on blood platelets (Owen et al.,23 figure 10). The events triggered off by reserpine with respect to blood serotonin-depletion of the platelets, increased excretion in the form of 5-hydroxy-indol-acetic acid (5-HIAA), reduction of the plasma serotonin level-are the same as those, that occur during migraine (figure 11). This explains why reserpine is able to provoke a typical attack in susceptible individuals and why such attacks can be aborted by injecting serotonin. The inhibitory effect of methysergide on the reserpine model permits the assumption that this substance might also prevent the spontaneous release of platelet serotonin, which is one of the first links in the chain of events leading up to the migraine headache. This property can be put in parallel with the inhibitory effect of methysergide on the release of histamine by the mast cells (Sicuteri et al.33 ). This broad spectrum of pharamcodynamic properties explains the relatively high percentage of success with methysergide as a preventive migraine treatment. However, it is not always well tolerated and the possibility of fortunately reversible reactions in the connective tissue, such as retroperitoneal fibrosis, following prolonged uninterrupted treatment must be kept in mind.
These problems are not encountered with pizotifene (synonym: pizotyline, BC-105). This tricyclic substance has no direct vascular effect and does not potentiate catecholamines, though, unlike methysergide, it does reduce norepinephrine re-uptake following stimulation of the nerve (Berde6) and inhibits-very powerfully-serotonin uptake (Salzmann and Kalberer,27 figure 12). Thus, pizotifene may help to maintain high levels of circulating amines. The most specific properties of pizotifene are its very powerful antihistamine and antiserotonin effects (Roemer25). Among other things, it inhibits the permeability-increasing action of these amines and, furthermore, blocks histamine release by the mast cells (Sicuteri et al.32). On the, other hand, it does not interfere with serotonin release in the reserpine test. In somewhat higher concentrations, it inhibits some of the peripheral effects of bradykinin (Roemer25). In addition, pizotifene possesses certain sedative and antidepressant properties which, without interfering directly with the mechanism of the headache, may have a beneficial effect on the frequently tense and slightly depressive personality of migraine patients (Anselmi et al.,2 Müller et al.19). If we consider again the list of possible modes of action in prophylactic anti-migraine treatment, we can note down the sites of attack of the drugs which we have just been discussing (table 4). Clonidine, the beta-blocking agents and dihydroergotamine influence exclusively the vascular factors, by maintaining3/4by various mechanisms-a certain tonicity level of the extracranial arteries. Methysergide and pizotifene have only indirect and relatively weak vascular actions, whilst exerting a powerful effect-in different ways-on the humoral factors which lower the pain threshold. SUMMARY The pharmacodynamic profiles of the most important anti-migraine agents are discussed in the light of the modern theory of the pathogenesis of migraine
TABLE 4 Modes of Action of Various Prophylactic Treatments of Migraine A. On arterial tonus 1. Reduce liability of vascular tonus 2. Prevent reduction of sensitivity to catecholamines 3. Prevent drop in plasma serotonin B. On pain threshold 1. Prevent disturbance in permeability by interfering with a. Histamine: Release Effect on receptors b. Serotonin: Release Effect on receptors 2. Prevent plasmakinin formation Effect on receptors 3. Prevent potentiation of plasmakinin induced pain by serotonin
Clonidine
x
b Dihydroe Methys -Blocking rgotamine ergide Agents x
x x x
Pizotifene (BC-105)
x x x
x
x x
x x
x x
x
headache. This headache is produced when two elements-passive distention of the extracranial arteries and a lowering of the pain threshold of the receptors situated in the walls of the affected vessels-are present simultaneously. The main humoral factors involved in this phenomenon are the plasmakinins, serotonin and-to a lesser degree-histamine. The role played by serotonin which is released by the blood platelets at the onset of the attack is twofold: on the one hand, free serotonin increases the permeability of the capillaries, favouring transudation of plasmakinins, and lowers the pain threshold, while on the other hand, its increased excretion causes a reduction in its plasma concentration, promoting hypotonicity of the extracranial vessels. The drugs used to abort a migraine attack act essentially by direct vasoconstriction of the extracranial vessels. This is achieved by stimulating the alpha-adre-nergic receptors. In addition, ergotamine potentiates the vasoconstrictor effect of catecholamines and maintains useful levels of circulating norepinephrine and free serotonin. Among the substances used for prophylactic interval treatment, some, such as clonidine, the beta-blocking agents and dihydroergotamine, have a purely vascular site of action, maintaining-by various mechanisms-the tone of the extracranial arteries and thus reducing their lability. Methysergide and pizotifene have a chiefly indirect effect on the vessels, by potentiating the effect of catecholamines or helping to maintain free serotonin at a certain level. They act primarily against the humoral elements responsible for lowering the pain threshold: methysergide by inhibiting the release and blocking the effects of serotonin, by countering the potentiating effect of serotonin on the pain induced by plasmakinins and by inhibiting histamine release; pizotifene by inhibiting the release and blocking the effects of histamine, by blocking the effects of serotonin and by slightly inhibiting the peripheral effects of plasmakinins. Thus, the multifactorial pathogenesis of migraine helps to explain the effectiveness against migraine of substances possessing the most varied pharmacodynamic profiles.
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Reprint requests to: Albert Fanchamps, M.D. Medical Counsel Pharmaceutical Research Department Sandoz Ltd. CH-4002 Basle, Switzerland
Figure 1 is an attempt to arrange the experimental findings in logical order leading up to the migraine headache (Fanchamps11). At the beginning of the attack, the blood platelets release serotonin,1 while the mast cells in the affected area release histamine and proteolytic enzymes which convert plasma-kininogens into plasmakinins.2 Free serotonin and histamine increase capillary permeability,3 thus promoting transudation4 of plasmakinin into the vascular walls and the perivascular tissue, The combined effect of plasmakinin5 and sero-
tonin6 on the receptors in the arterial walls lowers their pain threshold.7 On the other hand, the greater part of the released serotonin is excreted as 5-hydroxy-indolacetic acid by the kidneys,8 so that blood serotonin levels are reduced.9 Since serotonin has a constricting effect on the extracranial arteries and a dilatory effect on the capillaries, this reduction in plasma levels is accompanied by hypotonicity of these arteries and capillary constriction,10 leading to passive, pulse-synchronous distension of the arterial walls.11 Thus, the two factors required to produce the migraine headache12 are present: the reduced pain threshold and arterial distension. Even if still somewhat hypothetical, this interpretation of the experimental data helps us to understand how substances with the most varied pharmaco-dynamic properties can have an anti-migraine effect. TREATMENT OF THE MIGRAINE ATTACK The first thing which comes to mind to counter a headache is to administer an analgesic. However, the effect of conventional analgesics on a migraine attack is rather poor. Fortunately, it is not necessary to resort to strong analgesics such as morphine, since other drugs are available, capable of interfering effectively in the pathogenetic mechanism of the attack. The various modes of action possible are listed in Table 1. No known substance possesses all these desirable properties, though it is in fact an increase in the tone of the extracranial vessels which stands in the foreground. Accordingly, it is possible to abort a migraine attack with norepinephrine (Ostfeld et al.22), but the effect is very transient, so that intravenous infusion is necessary. Ergotamine is very superior in this respect, since its vasoconstricting effect is of a sufficient duration to definitively abort the majority of attacks (Wolff41). Ergotamine produces vasoconstriction if the tone of the vessel is low, but dilatation if the vessel is already hypertonic (Aellig TABLE I Desirable Properties For a Treatment of the Migraine Attack The Ideal Drug Should: A. Counteract hypotonus of cranial arteries 1. By direct vasoconstriction 2. By potentiating catecholamine induced constriction or restoring normal sensitivity of vessels to catecholamines 3. By restoring normal plasma serotonin level B. Counteract humoral disturbances and resulting lowering of pain threshold by interference with: 1. Serotonin 2. Histamine 3. Plasmakinins C. D.
Abort nausea and vomiting Relieve nervous tension
& Berde1). This bivalent action is also found with other alkaloids of ergot, but the inversion point may vary (figure 2). While the degree of vasoconstriction induced by dihydroergotamine is not so high as with ergotamine, the inversion point is the same with both substances: they induce vasodilatation only in very hypertonic vessels ( > 4 Resistance Units). Dihydroergocristine, on the other hand, one of the components of Hydergine, does not contract vessels unless their tone is extremely low, and has a dilatory effect as soon as the initial tone exceeds 2 Resistance Units. Tests in isolated canine and human veins (figure 3) show that the constriction evoked by ergotamine or dihydroergotamine is chiefly the result of alpha-adrenergic stimulation, since it is inhibited by alpha-blocking agents such as phentolamine ( figure 4 ), phenoxybenzamine or dibenamine (Stürmer,37 Müller-Schweinitzer and Stürmer20). Classical pharmacology places ergotamine in the. category of adreno-sympatholytic substances; actually it is a competitive alpha-blocking agent endowed with considerable intrinsic alpha-stimulant properties. This is the reason why, in the small dosages used in therapeutic prac-
tice, far from always blocking the effects of epinephrine and norepinephrine, it may frequently potentiate these (Weidmann and Taeschler,39 figure 5). The same holds for dihydroergotamine. In addition, these ergot derivatives also inhibit norepinephrine re-uptake after nerve stimulation ( Pacha and Salzmann,24 Salzmann et al.,26 figure 6) thus maintaining a high level of circulating norepinephrine.
They are only weak serotonin antagonists, but they do inhibit serotonin up-take by human platelets (Stacey,36 Lingjaerde17) and in the spleen of the cat (Owen et al.,23 figure 7). Thus, it may be speculated that ergotamine and dihydroergotamine are able to counteract the decrease in free blood serotonin, which is one of the pathogenetic factors leading to the headache. It is clear then that the effect of these drugs on the migraine attack is not limited to a direct vasoconstricting action, but is also partially attributable to humoral mechanisms involving catecholamines and serotonin. Both substances act quickly and effectively if administered by injection. However, their oral effectiveness is rather poor, unless they are combined with caffeine which increases and accelerates their intestinal absorption (Schmidt and Fanchamps28). PREVENTIVE INTERVAL TREATMENT Preventive treatment of migraine is only justified if the frequency and severity of the attacks is such as to seriously disturb the patient's life. Depending on the individual case, therapy may be directed against aetiological factors-hormonal, dietetic, gastro-enterological, allergic, orthopedic, psychological, etc. It may, however, be difficult to identify a well-defined cause for migraine. In this case, the physician still has the possibility of interfering with the mechanism producing the attack. Due to the multifactorial pathogenesis of migraine, several points of attack are available, as listed in table 2. It is along these lines that we shall attempt to identify the mode of action of some of the most important therapeutic agents. Some of the substances have an essentially vascular point of attack. Clonidine, a substance of which the mode of action-partly central and partly peripheral on the sympathetic nervous system-has yet to be fully elucidated, is well established as an effective treatment of arterial hypertension. Its use for the treatment of migraine has been suggested by Zaimis42 and Hanington et al.13 on the basis of its stabilizing effect on vascular reactions following stimulation of both alpha- and beta-adrenergic receptors. In the cat, 1 to 4 weeks' treatment with small oral doses of clonidine greatly reduced the constriction of the femoral artery induced by norepinephrine as well as dilatation induced by isoprenaline. This stabliziation of vascular tone is, without
TABLE 2 Possible Modes of Action For a Prophylactic Treatment of Migraine A. On arterial tonus 1. Reduce lability of vascular tonus 2. Prevent reduction of sensitivity to catecholamines 3. Prevent drop in plasma serotonin B. On pain threshold 1. Prevent disturbance in permeability by interfering with a. Histamine release and effect on receptors b. Serotonin release and effect on receptors 2. Prevent plasmakinin formation, transudation and effect on receptors 3. Prevent potentiation of plasmakinin induced pain by serotonin C. On basic personality of migraine patient 1. Relieve nervous tension 2. Counteract mood depression doubt, not the only mechanism of this substance, which appears to be particularly effective in migraines of dietary origin, responding to the tyramine loading test ( Wilkinson et al.40). Experiments in the cat spleen performed in our laboratories have shown that the substance has no effect on serotonin uptake (figure 8, Salzmann and Kalberer27). Recently, beta-blocking agents, in particular propranolol, have been the subject of several positive studies as prophylactic treatment of migraine (Weber and Reinmuth,38 Malvea et al.18). Their effectiveness is probably attributable to the fact that stimulation of the beta-adrenergic receptors of the peripheral vessels produces vasodilatation, so that a blockage of these helps to maintain a certain level of vasoconstrictor tonus, counteracting the hypotonicity of extra-cranial arteries. These agents also appear to be capable of potentiating the effect of vasoconstricting drugs (Baumrucker5). It must be remembered, however, that some beta-blockers such as prindolol or practolol also have an intrinsic beta-stimulant effect which may mask their vasoconstricting potential. This may explain the varying results-sometimes positive (Anthony et al.4), sometimes negative (Ekbom et al.,10 Sjaastad et al.35 )-obtained with prindolol in this indication. Dihydroergotamine has properties similar, qualitatively, to those of ergotamine, though its vasoconstricting action is weaker. This is why higher doses have to be injected to abort an attack. However,
while daily administration of ergotamine in anti-migraine doses is not advisable, since in the long term this may cause undesirable peripheral vasoconstriction, the relatively weak vasoconstricting action of dihydroergotamine, especially when administered orally* , does permit long-term therapy. Used as an interval treatment, dihydroergotamine produces its prophylactic effect on the one hand by keeping the extracranial arteries at a certain level of tonicity and on the other hand by reinforcing the constricting effect of endogenous norepinephrine, as well as, perhaps, by maintaining useful levels of circulating norepinephrine ( figure 6 ) and free serotonin ( figure 9 ). Other no less-or even more-effective drugs have an effect not only on vascular, but also on humoral elements of the mechanism producing the headache. Methysergide is a semisynthetic derivative of ergot, though it is not related to ergotamine, as it possesses no polypeptide side-chain. In our tests, it shows no direct vasoconstricting effect, which explains its ineffectiveness in treating a migraine attack. It also has no influence on norepinephrine re-uptake (Berde6), while nevertheless having certain indirect effects on the blood vessels: reduction of the lability of arterial tone, as demonstrated in the cold pressor test (Wolff41 ), reinforcement of the vasoconstricting effect of norepinephrine in man (Dalessio8), normalisation of the response of the cranial vessels to norepinephrine in migraine sufferers ( Wolff41 ). However, the main sites of attack of methysergide are at the humoral level. It is a very powerful serotonin antagonist ( Fan-champs et al.12): strongly inhibiting the increase in permeability (Doepfner and Cerletti9), the potentiating effect of serotonin on induced pain in the mouse (Neuhold and Taeschler,21 Fanchamps,11 table 3) and the reinforcement by seroTABLE 3 Inhibiting Effect of Analgesics and Serotonin-Antagonists on Writhing Reaction to Intra-Peritoneal Injection of Acetic Acid in Mice ED 50 mg/kg s.c. 1 H before acetic acid Morphine 0.18 Aminopyrine 34.0 Methysergide 3.0 ( Sansert, Deseril ) According to Neuhold and Taeschler21 this writhing reaction requires the presence of serotonin.
tonin of the algesic effect of plasmakinins in humans (Sicuteri30). With regard to the blood serotonin level, methysergide has only a poor inhibitory effect on serotonin uptake in the cat spleen (Salzmann and Kalberer27), while in the rat in vivo it has been shown to reduce the serotonin releasing effect of reserpine on blood platelets (Owen et al.,23 figure 10). The events triggered off by reserpine with respect to blood serotonin-depletion of the platelets, increased excretion in the form of 5-hydroxy-indol-acetic acid (5-HIAA), reduction of the plasma serotonin level-are the same as those, that occur during migraine (figure 11). This explains why reserpine is able to provoke a typical attack in susceptible individuals and why such attacks can be aborted by injecting serotonin. The inhibitory effect of methysergide on the reserpine model permits the assumption that this substance might also prevent the spontaneous release of platelet serotonin, which is one of the first links in the chain of events leading up to the migraine headache. This property can be put in parallel with the inhibitory effect of methysergide on the release of histamine by the mast cells (Sicuteri et al.33 ). This broad spectrum of pharamcodynamic properties explains the relatively high percentage of success with methysergide as a preventive migraine treatment. However, it is not always well tolerated and the possibility of fortunately reversible reactions in the connective tissue, such as retroperitoneal fibrosis, following prolonged uninterrupted treatment must be kept in mind.
These problems are not encountered with pizotifene (synonym: pizotyline, BC-105). This tricyclic substance has no direct vascular effect and does not potentiate catecholamines, though, unlike methysergide, it does reduce norepinephrine re-uptake following stimulation of the nerve (Berde6) and inhibits-very powerfully-serotonin uptake (Salzmann and Kalberer,27 figure 12). Thus, pizotifene may help to maintain high levels of circulating amines. The most specific properties of pizotifene are its very powerful antihistamine and antiserotonin effects (Roemer25). Among other things, it inhibits the permeability-increasing action of these amines and, furthermore, blocks histamine release by the mast cells (Sicuteri et al.32). On the, other hand, it does not interfere with serotonin release in the reserpine test. In somewhat higher concentrations, it inhibits some of the peripheral effects of bradykinin (Roemer25). In addition, pizotifene possesses certain sedative and antidepressant properties which, without interfering directly with the mechanism of the headache, may have a beneficial effect on the frequently tense and slightly depressive personality of migraine patients (Anselmi et al.,2 Müller et al.19). If we consider again the list of possible modes of action in prophylactic anti-migraine treatment, we can note down the sites of attack of the drugs which we have just been discussing (table 4). Clonidine, the beta-blocking agents and dihydroergotamine influence exclusively the vascular factors, by maintaining3/4by various mechanisms-a certain tonicity level of the extracranial arteries. Methysergide and pizotifene have only indirect and relatively weak vascular actions, whilst exerting a powerful effect-in different ways-on the humoral factors which lower the pain threshold. SUMMARY The pharmacodynamic profiles of the most important anti-migraine agents are discussed in the light of the modern theory of the pathogenesis of migraine
TABLE 4 Modes of Action of Various Prophylactic Treatments of Migraine A. On arterial tonus 1. Reduce liability of vascular tonus 2. Prevent reduction of sensitivity to catecholamines 3. Prevent drop in plasma serotonin B. On pain threshold 1. Prevent disturbance in permeability by interfering with a. Histamine: Release Effect on receptors b. Serotonin: Release Effect on receptors 2. Prevent plasmakinin formation Effect on receptors 3. Prevent potentiation of plasmakinin induced pain by serotonin
Clonidine
x
b Dihydroe Methys -Blocking rgotamine ergide Agents x
x x x
Pizotifene (BC-105)
x x x
x
x x
x x
x x
x
headache. This headache is produced when two elements-passive distention of the extracranial arteries and a lowering of the pain threshold of the receptors situated in the walls of the affected vessels-are present simultaneously. The main humoral factors involved in this phenomenon are the plasmakinins, serotonin and-to a lesser degree-histamine. The role played by serotonin which is released by the blood platelets at the onset of the attack is twofold: on the one hand, free serotonin increases the permeability of the capillaries, favouring transudation of plasmakinins, and lowers the pain threshold, while on the other hand, its increased excretion causes a reduction in its plasma concentration, promoting hypotonicity of the extracranial vessels. The drugs used to abort a migraine attack act essentially by direct vasoconstriction of the extracranial vessels. This is achieved by stimulating the alpha-adre-nergic receptors. In addition, ergotamine potentiates the vasoconstrictor effect of catecholamines and maintains useful levels of circulating norepinephrine and free serotonin. Among the substances used for prophylactic interval treatment, some, such as clonidine, the beta-blocking agents and dihydroergotamine, have a purely vascular site of action, maintaining-by various mechanisms-the tone of the extracranial arteries and thus reducing their lability. Methysergide and pizotifene have a chiefly indirect effect on the vessels, by potentiating the effect of catecholamines or helping to maintain free serotonin at a certain level. They act primarily against the humoral elements responsible for lowering the pain threshold: methysergide by inhibiting the release and blocking the effects of serotonin, by countering the potentiating effect of serotonin on the pain induced by plasmakinins and by inhibiting histamine release; pizotifene by inhibiting the release and blocking the effects of histamine, by blocking the effects of serotonin and by slightly inhibiting the peripheral effects of plasmakinins. Thus, the multifactorial pathogenesis of migraine helps to explain the effectiveness against migraine of substances possessing the most varied pharmacodynamic profiles.
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Reprint requests to: Albert Fanchamps, M.D. Medical Counsel Pharmaceutical Research Department Sandoz Ltd. CH-4002 Basle, Switzerland
