Effects of Ergotamine and Methysergide on Blood Platelet Aggregation Responses of Migrainous Subjects

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.5.593 on 1 May 1974. Downloaded from

Journal ofNeurology, Neurosurgery, and Psychiatry, 1974, 37, 593-597

Effects of ergotamine and methysergide on blood platelet aggregation responses of migrainous subjects

BARBARA P. HILTON AND K. J. ZILKHA From the Department ofNeurochemistry, Institute of Neurology, National Hospital, Queen Square, London

SYNOPSIS Platelet aggregation responses to 5-hydroxytryptamine (5-HT) were measured in plasma from migrainous subjects taking either methysergide maleate or ergotamine tartrate and were found to be reduced. Blood 5-HT levels of subjects free of headache were not affected by these drugs. The results support the hypothesis that methysergide and ergotamine act by occupying 5-HT uptake sites in vessel walls, leaving 5-HT molecules available to occupy receptors concerned with vasoconstriction.

Ergotamine tartrate is of proved value in the Ergotamine was taken in several different forms: Protected by copyright. relief of headache in an acute migraine attack (1) patients without headache took 1-2 mg daily, as (Graham, 1956), while methysergide maleate is a Migril, Cafergot suppositories, or Bellergal Retard; very effective prophylactic treatment for mi- (2) patients with migraine headache had taken 2 4 mg ergotamine within the previous six hours, as graine (Sicuteri, 1963; Curran and Lance, 1964; Cafergot tablets, Cafergot Q, Cafergot suppositories, Graham, 1964; Lance et al., 1970). In vitro tests or Migril. have shown that ergotamine and methysergide Whole blood for 5-HT estimation was collected suppress platelet aggregation responses to 5- into heparin and deep frozen (-20° C) immediately. hydroxytryptamine (5-HT) in plasma taken from The estimation was carried out using the method of control subjects (Cumings and Hilton, 1971). Ashcroft et al. (1964) and the 5-HT content was This paper reports on aggregation responses expressed per ml. blood, corrected to a theoretical and 5-HT levels in migrainous patients taking platelet count of 250,000 per cubic mm. either ergotamine tartrate or methysergide Platelet aggregation responses to 5-HT were maleate and the results obtained have been com- measured as previously described (Hilton and pared with those for patients not taking drugs. Cumings, 1971) using an EEL platelet aggregation http://jnnp.bmj.com/ meter linked to a Honeywell chart recorder, where The effect of headache on aggregation responses aggregation was expressed as the rate of aggregation and 5-HT levels has been noted. (R cm/min) shown on the chart paper. Values of R were corrected to a platelet count of 250,000 per METHODS cubic mm. Aggregation was induced using 5-HT (serotonin Blood was collected from patients with migraine creatinine sulphate, B.D.H.) 50 nmol in 0-1 ml. during and between migraine attacks. Patients with on September 30, 2021 by guest. migraine headache were asked to describe whether it was slight, moderate, or severe. Migrainous subjects RESULTS were included in the between headache group if they Blood 5-HT levels and had not suffered an acute migraine attack for three platelet aggregation days. Patients were questioned carefully about any responses of migrainous subjects who were free drugs or medication they were taking and were of headache but taking either ergotamine or divided into groups: (1) patients who had not taken methysergide regularly, are shown in Fig. 1. any drugs at all; (2) patients who had taken methyser- Results for migrainous subjects before the gide maleate (Deseril) 4-8 mg per day; and (3) institution of drug therapy and also for control patients who had taken ergotamine tartrate. subjects have been included for comparison. 593 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.5.593 on 1 May 1974. Downloaded from

594 Barbara P. Hilton and K. J. Zilkha

SUBJECTS ON DRUGS SUBJECTS NOT ON DRUGS

150 (142)

(37) i (17) (13) 100

Blood 5-HT (ng/ml) + S,E.M. 50 FIG. 1. Efjects of ergotamine and methysergide otn biochemical parameters of migrainous patients in the 0 absence of headache. The number of subjects in each group is shown in paren- i (180) theses. * See Hilton and Platelet .01. (17) Cumings (1971). Aggregation R (cm/ymin)

+ S.E.M. Protected by copyright. 0.5 i (8) j (28) 0 Ergotamine Methysergide Migrainous Conhtols

I(10) 150 (20) {(12) (37)

Blood 5-HT (13) http://jnnp.bmj.com/ } (6) (ng/ml) 100 JJ(22) + S.E.M. j (12)

50 on September 30, 2021 by guest.

0 i Ergotamine Ergotamine Methysergide No Drugs Methysergide FIG. 2. Blood 5-HT levels in migrainous patients taking drugs. 0 Headache-free subjects; 0 subjects with migraine headache. The number of subjects in each group is shown in parentheses. * See Hilton and Cumings (1972). J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.5.593 on 1 May 1974. Downloaded from

Blood platelet aggregation responses of migrainous subjects 595

1 .50 . I(20) Platelet Aggregation 1 .00 4t(12) R (crn/min) + S.E.M.. (14) 0.50.

E (8) (28) § i (4) 0 Ergotamine Methysergide No Drugs FIG. 3. Platelet aggregation responses to 5-HT in plasma from migrainous patients taking drugs. 0 Headache-free subjects; 0 subjects with migraine headache. The Protected by copyright. number of subjects in each group is showsn in parentheses. * See Hilton and Cumings (1972).

Whereas there is no significant difference be- patients on drugs are significantly less than R for tween the blood 5-HT levels before and during either the no drug group or control subjects, at drug treatments, there is a highly significant drop the level P

2. The expected fall in 5-HT during headache http://jnnp.bmj.com/ (which is seen in subjects who had not taken drugs) was not found in subjects taking ergotamine or methysergide, but only in patients taking both ergotamine and methysergide. The N4umber rather high mean value for patients with head- of 5 ache who were taking methysergide is due mostly Subiects

to a high 5-HT content found for one patient. on September 30, 2021 by guest. The effect of headache on the platelet aggregation responses of migrainous patients taking drugs, can be seen in Fig. 3. The responses during headache, like those for headache-free patients, were reduced to values below those found for 0 patients not on drugs. Headache patients taking Slight Moderate ergotamine did not have such reduced responses. FIG. 4. Distribution of headache severity in patients on taking ergotamine or methysergide. IEa Ergotamine; It may be significant that, overall, patients methysergide. ergotamine suffered worse headaches than those J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.5.593 on 1 May 1974. Downloaded from

596 6Barbara P. Hilton and K. J. Zilkha

on methysergide, many of whom had slight jects less readily accept 5-HT or retain it, than do headaches, as can be seen in Fig. 4. those of control subjects. The effects of drugs on blood 5-HT levels during headache are difficult to evaluate since, as DISCUSSION shown in Fig. 4, groups of patients on ergot- The results clearly show that the aggregation amine or methysergide suffered headaches of responses of migrainous subjects are markedly differing severity. The reason may be twofold, reduced by taking ergotamine or methysergide. firstly, that methysergide, as a good prophylactic Platelet aggregation in response to 5-HT is de- treatment, reduced the incidence of headache, pendent on the availability of 5-HT uptake and, secondly, that patients were likely to resort sites on the platelet membrane (Baumgartner and to ergotamine when they realized a bad migraine Born, 1968). When the uptake site is empty, was starting. However, it does not appear that aggregation can occur, but if the uptake site is any part of these drugs' actions is due to raising already occupied by a molecule of 5-HT or an blood 5-HT levels. The one high blood 5-HT analogue, aggregation cannot take place. Thus, level for a patient on methysergide may have it is likely that the reduced responses after drug arisen by chance. This female patient, aged 30 treatment are due to ergotamine or methysergide years, had a blood 5-HT level of 260 ng/ml and occupying the 5-HT receptor sites. was suffering from a slight headache which had The similarity between results after ergotamine earlier been severe and had persisted about eight or methysergide ingestion is in agreement with hours in all. On one other occasion she had a earlier results found after in vitro pre-incubation blood 5-HT level of 116 ng/ml in a headache-Protected by copyright. of control plasma with those drugs, when both free interval. The high level could be due to were found to inhibit the aggregation response, recovery of 5-HT levels in the late stage of the and methysergide had a stronger effect than migraine headache, since fairly high 5-HT levels ergotamine (Cumings and Hilton, 1971). In this were noted in a few other subjects between six earlier paper, good agreement was reported be- and 14 hours after onset of headache. It should tween the anti-5-HT activities of ergotamine and also be borne in mind that high blood 5-HT methysergide on blood platelets and published levels during headache have been reported by results using isolated organ or neuronal prepara- other workers (Giacovazzo et al., 1965; Tretya- tions. It was suggested that the vascular effects of kova and Fets, 1969). Raised levels of urinary ergotamine are due to interactions with 5-HT 5-hydroxyindoleacetic acid (the main metabolite binding sites located on vessel walls. Thus 5-HT of 5-HT) have been reported after ergotamine uptake sites on blood platelets may resemble (Farris et al., 1967) and methysergide (Pokora, those found on other body surfaces and drug 1966; Curran et al., 1967); but no change was action on platelets may indicate action on, for found in blood 5-HT levels after methysergide http://jnnp.bmj.com/ example, vessel walls and neuronal surfaces. (Curran et al., 1965). The rise in urinary Recently, Salzmann and Kalberer (1973) have metabolite, with no change in blood levels of suggested that the efficacy of ergotamine in re- 5-HT, is consistent with the drug acting as lieving migraine is due to its occupying 5-HT competitive antagonist. uptake sites in the vessel walls, leaving 5-HT molecules available to occupy receptors con- We are grateful to Professor A. N. Davison for his

cerned with vasoconstriction. helpful criticism and guidance. One of us (B.P.H.) on September 30, 2021 by guest. The similar results obtained for aggregation thanks the Migraine Trust for support. responses during and between headaches support the hypothesis that a permanent difference exists in the platelet membrane of migrainous subjects REFERENCES (Hilton and Platelets from Ashcroft, G. W., Crawford, T. B. B., Bins, J. K., and Cumings, 1972). MacDougall, E. J. (1964). Estimation of 5-hydroxy- migraine sufferers more readily aggregate with tryptamine in human blood. Clinica Chimica Acta, 9, 364- 5-HT after one minute's pre-incubation with 369. Baumgartner, H. R., and Born, G. V. R. (1968). Effects of 5-HT than do platelets from controls, which im- 5-hydroxytryptamine on platelet aggregation. Nature, 218, plies that platelet uptake sites of migrainous sub- 137-141. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.5.593 on 1 May 1974. Downloaded from

Blood platelet aggregationi responses of mnigrainous subjects 597

Cumings, J. N., and Hilton, B. P. (1971). Effects of methy- platelet aggregation induced by 5-hydroxytryptamine. sergide on platelets incubated with reserpine. British Journal of Clinical Pathology, 24, 250-258. Journal of Pharmacology, 42, 611-619. Hilton, B. P., and Cumings, J. N. (1972). 5-Hydroxy- Curran, D. A., Hinterberger, H., and Lance, J. W. (1965). tryptamine levels and platelet aggregation responses in Total plasma serotonin, 5-hydroxyindoleacetic acid and subjects with acute migraine headache.Journal offNeirology, p-hydroxy-m-methoxymandelic acid excretion in normal Neurosurgery, and Psychiatry, 35, 505-509. and migrainous subjects. Brain, 88, 997-1010. Lance, J. W., Anthony, M., and Somerville, B. (1970). Curran, D. A., and Lance, J. W. (1964). Clinical trial of Comparative trial of serotonin antagonists in the manage- methysergide and other preparations in the management of ment of migraine. British Medical Jolurnal, 2, 327-330. migraine. Journal of Neutrology, Neurosurgery, and Pokora, J. (1966). Effect of serpasil, niamid and deseril on Psychiatry, 27, 463-469. the excretion of 5-hydroxyindoleacetic acid in diurnal I. del Farris, F., Rappelli, A., and Mathis, (1967). Effetto urine and on oxidase activity of ceruloplasmin in human tartrato di ergatamina sull'escrezione urinaria di acido serum. Polish Medical Journal, 5, 716-722. 5-irossiindolacetico. Bollettino della Societa Italiana di Biologia Sperimentale, 43, 308-310. Salzmann, R., and Kalberer, F. (1973). Anti-migraine drugs Giacovazzo, M., Butti, A., and Santis, R. de (1965). La and storage of serotonin. In Background to Migraine, pp. 'soglia di sensibilita alla serotonina' in condizioni normali 63-72. Fifth Migraine Symposium, 1972. Edited by J. N. Cumings. Heinemann: London. e patologiche. Nota preliminare. Folia Allergolica, 12, 37- 48. Sicuteri, F. (1963). Prevention de la migraine par les derives Graham, J. R. (1956). Ergot preparations. In Treatmetnt of de I'acide lysergique. Triangle, 6, 116-125. Migraine, pp. 43-76. Little, Brown: Boston. Tretyakova, K. A., and Fets, A. N. (1969). Total blood Graham, J. R. (1964). Methysergide for prevention of head- serotonin concentration in patients with migraine during ache. Newv England Journal of Medicine, 270, 67-72. and between attacks. (Trans.) Zhurnal Nevropatologii Hilton, B. P., and Cumings, J. N. (1971). An assessment of Psikhiatrii imenii S.S. Korsakavo (Moskra), 69, 831-835. Protected by copyright. http://jnnp.bmj.com/ on September 30, 2021 by guest.