Clinical Pharmacokinetics

, Volume 10, Issue 4, pp 334–352 | Cite as

Clinical Pharmacokinetics of Ergotamine in Migraine and Cluster Headache

  • V. L. Perrin
Review Article


Ergotamine has been in use for the treatment of migraine for a century and is still considered to be the most effective therapeutic agent for acute attacks. Only during the last few years have assays been developed, enabling its pharmacokinetics to be studied. Appropriate assays for determining ergotamine concentrations in plasma are radio-immunoassay and high-performance liquid chromatography.

There is great interindividual variation in absorption of ergotamine in both patients and normal volunteers. Bioavailability is of the order of 5% or less by oral or rectal administration. After intramuscular or intravenous administration, plasma concentrations decay in a biexponential fashion. The elimination of half-life is 2 to 2.5 hours and clearance is about 0.68 L/h/kg. As yet, formal pharmacokinetics following oral dosing have not been determined. There is some evidence that ergotamine enters the cerebrospinal fluid. Metabolism occurs in the liver, and the primary route of excretion is biliary.

Up to 90% of migraine patients experience complete or partial symptom relief after ergotamine, providing the drug is given as early in their attack as possible. Efficacy is greatest after parenteral administration, although adverse effects may make the rectal or inhaled routes preferable. There is some evidence to suggest that good responses are associated with plasma concentrations of 0.2 ng/ml or above within one hour of administration.

The mode of action of ergotamine in migraine may be by means of selective arterial vasoconstriction on certain cranial vessel beds or, alternatively, by depression of central serotonergic neurons mediating pain transmission or circulatory regulation.

Principal adverse effects of ergotamine include nausea, vomiting, weakness, muscle pains, paraesthesiae and coldness of the extremities. Ergotamine dependence is not uncommon, resulting in an exacerbation of the above symptoms. Dosage must therefore be limited to no more than 10mg per week to minimise toxicity.


Migraine Caffeine Cluster Headache Clinical Pharmacokinetic Migraine Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Achenbach, W. and Köhler, I.: Therapeutische Mitteilungen. Orale Behandlung des Migräneanfalls. Münchener Medizinische Wochenschrift 49: 1659–1660 (1955).Google Scholar
  2. Aellig, W.H. and Berde, B.: Studies of the effect of natural and synthetic polypeptide type ergot compounds on a peripheral vascular bed. British Journal of Pharmacology 36: 561–570 (1969).PubMedCrossRefGoogle Scholar
  3. Aellig. W.H. and Nüesch, E.: Comparative pharmacokinetic investigations with tritium-labelled ergot alkaloids after oral and intravenous administration in man. International Journal of Clinical Pharmacology and Biopharmacy 15: 106–112 (1977).PubMedGoogle Scholar
  4. Ala-Hurula. V.; Myllylä, V.V.; Arvela, P.; Heikkilä, J.; Kärki, N. and Hokkanen, E.: Systemic availability of ergotamine tartrate after oral, rectal and intramuscular administration. European Journal of Clinical Pharmacology 15: 51–55 (1979a).PubMedCrossRefGoogle Scholar
  5. Ala-Hurula, V.; Myllylä, V.V.; Arvela, P.; Kärki, N.T. and Hokkanen, E.: Systemic availability of ergotamine tartrate after three successive doses and during continuous medication. European Journal of Clinical Pharmacology 16: 355–360 (1979b).PubMedCrossRefGoogle Scholar
  6. Ala-Hurula, V.; Myllylä, V. and Hokkanen, E.: Ergotamine abuse: Results of ergotamine discontinuation with special reference to the plasma concentrations. Cephalalgia 2: 189–195 (1982).PubMedCrossRefGoogle Scholar
  7. Andersson, P.G.: Ergotamine headache. Headache 15: 118–121 (1975).PubMedCrossRefGoogle Scholar
  8. Bradfield, J.M.: A new look at the use of ergotamine. Drugs 12: 449–453 (1976).PubMedCrossRefGoogle Scholar
  9. Cabot, J.B.; Wild, J.M. and Cohen, D.H.: Raphe inhibition of sympathetic preganglionic neurons. Science 203: 184–186 (1979).PubMedCrossRefGoogle Scholar
  10. Chalmers, J.P. and Wing, L.M.H.: Central serotonin and cardiovascular control. Clinical and Experimental Pharmacology and Physiology 2 (Suppl.): 195–200 (1975).PubMedGoogle Scholar
  11. Clawson, T.A.: Treatment of severe migraine with Cafergot. Rocky Mountain Medical Journal 49: 1038–1039 (1952).PubMedGoogle Scholar
  12. Crooks, J.; Stephen, S.A. and Brass, W.: Clinical trial of inhaled ergotamine tartrate in migraine. British Medical Journal 1: 221–224 (1964).PubMedCrossRefGoogle Scholar
  13. Dubarry, J.J.; Dubarry, E. and Boucharenc, G.: Le tartrate d’ergotamine cafeiné, traitement de l’acces migraineux. Archives des Maladies de l’Appareil Digestif 44: 399–400 (1955).Google Scholar
  14. Eadie, M.J.: The use of ergotamine in migraine. Medical Journal of Australia (Suppl.): 26-29 (1972).Google Scholar
  15. Eckert, H.; Kieckel, J.R.; Rosenthaler, J.; Schmidt, R. and Schreier, E.: Biopharmaceutical aspects. Analytical methods, pharmacokinetics, metabolism and bioavailability; in Berde and Schild (Eds) Ergot Alkaloids and Related Compounds, Handbüch der Experimentellen Pharmakologie, vol. 49, pp. 719–803 (Springer-Verlag, Berlin 1978).CrossRefGoogle Scholar
  16. Edlund, P.O.: Determination of ergot alkaloids in plasma by high performance liquid chromatography and fluorescence detection. Journal of Chromatography 226: 107–115 (1981).PubMedCrossRefGoogle Scholar
  17. Ekbom, K.; Krabbe, A.A.; Paalzow, G.; Paalzow, L.; Tfelt-Hansen, P. and Waldenlind, E.: Optimal routes of administration of ergotamine tartrate in cluster headache patients. A pharmacokinetic study. Cephalalgia 3: 15–20 (1983).PubMedCrossRefGoogle Scholar
  18. Ekbom, K.; Paalzow, L. and Waldenlind, E.: Low biological availability of ergotamine tartrate after oral dosing in cluster headache. Cephalalgia 1: 203–207 (1981).PubMedCrossRefGoogle Scholar
  19. Friedman, A.P. and Brenner, C.: Treatment of the migraine attack. American Practitioner 2: 467–470 (1948).Google Scholar
  20. Friedman, A.P. and Merritt, H.H.: Treatment of headache. Journal of the American Medical Association 163: 1111–1117 (1957).PubMedCrossRefGoogle Scholar
  21. Friedman, A.P. and Von Storch, T.J.C.: Recent advances in treatment of migraine. Journal of the American Medical Association 145: 1325–1329 (1951).PubMedCrossRefGoogle Scholar
  22. Fuchs, M. and Blumenthal, L.S.: Cafergot suppositories in migraine. Annals of Allergy 9: 616–620 (1951).PubMedGoogle Scholar
  23. Goodman, L.S. and Gilman, A.: In The Pharmacological Basis of Therapeutics, 6th edition, p.946 (Macmillan, New York/London 1980).Google Scholar
  24. Graham, A.N.; Johnson, E.S.; Persaud, N.P.; Turner, P. and Wilkinson, M.: Ergotamine toxicity and serum concentrations of ergotamine in migraine patients. Human Toxicology 3: 193–199 (1984a).PubMedCrossRefGoogle Scholar
  25. Graham. A.N.; Johnson, E.S.; Persaud, N.P.; Turner, P. and Wilkinson, M.: The systemic availability of ergotamine tartrate given by three different routes of administration to healthy volunteers; in Rose (Ed.) Progress in Migraine Research, Vol. 2. pp. 283–292 (Pitman, London 1984b).Google Scholar
  26. Graham, J.R.: Rectal use of ergotamine tartrate and caffeine alkaloid for the relief of migraine. New England Journal of Medicine 250: 936–938 (1954).PubMedCrossRefGoogle Scholar
  27. Graham, J.R.: Malvea, B.P. and Gramm, H.F.: Aerosol ergotamine tartrate for migraine and Horton’s syndrome. New England Journal of Medicine 263: 802–804 (1960).PubMedCrossRefGoogle Scholar
  28. Graham, J.R. and Wolff, H.G.: Mechanism of migraine headache and action of ergotamine tartrate. Archives of Neurology and Psychiatry 39: 737–763 (1938).CrossRefGoogle Scholar
  29. Graham, J.R. and Wolff, H.G.: Mechanism of migraine headache and action of ergotamine tartrate. Proceedings of the Association for Research in Nervous and Mental Disease 18: 638–669 (1937).Google Scholar
  30. Hakkarainen, H.; Gustafsson, B. and Stockman, O.: A comparative trial of ergotamine tartrate, acetyl salicylic acid and a dextropropoxyphene compound in acute migraine attacks. Headache 18: 35–39 (1978).PubMedCrossRefGoogle Scholar
  31. Hakkarainen, H.; Vapaatalo, H.; Gothoni, G. and Parantainen, J.: Tolfenamic acid is as effective as ergotamine during migraine attacks. Lancet 2: 326–328 (1979).PubMedCrossRefGoogle Scholar
  32. Heyck, H.: Pathogenesis of migraine. Research and Clinical Studies in Headache 2: 1–28 (1969).Google Scholar
  33. Hokkanen, E.; Myllylä, V.V. and Ala-Hurula, V.: Clinical aspects of pharmacokinetics of ergotamine; in Rose (Ed.) Advances in Migraine Research and Therapy, pp.181–186 (Raven Press, New York 1982).Google Scholar
  34. Horton, B.T.; Ryan, R. and Reynolds, J.L.: Clinical observation of the use of EC 110, a new agent for the treatment of headache. Proceedings of the Mayo Clinic 23: 105–108 (1948).Google Scholar
  35. Hovdal, H.; Syversen, G.B. and Rosenthaler, J.: Ergotamine in plasma and CSF after i.m. and rectal administration to humans. Cephalalgia 2: 145–160 (1982).PubMedCrossRefGoogle Scholar
  36. Ibraheem, J.J.; Paalzow, L. and Tfelt-Hansen, P.: Kinetics of ergotamine after intravenous and intramuscular administration to migraine sufferers. European Journal of Clinical Pharmacology 23: 235–240 (1982).PubMedCrossRefGoogle Scholar
  37. Ibraheem, J.J.; Paalzow, L. and Tfelt-Hansen, P.: Low bioavailability of ergotamine tartrate after oral and rectal administration in migraine sufferers. British Journal of Clinical Pharmacology 16: 695–699 (1983).PubMedCrossRefGoogle Scholar
  38. Kadish, A.H.: Clinical observations on the rectal and oral use of various ergot derivatives in headache. New England Journal of Medicine 242: 581–582 (1950).CrossRefGoogle Scholar
  39. Lennox, W.G.: Ergonovine versus ergotamine as terminator of headaches. American Journal of Medical Science 195: 458–468 (1938).CrossRefGoogle Scholar
  40. Lennox, W.G. and Von Storch, T.J.C.: Experience with ergotamine tartrate in 120 patients with migraine. Journal of the American Medical Association 105: 169–171 (1935).CrossRefGoogle Scholar
  41. Magee, K.R.; Westerberg, M.R. and De Jong, R.M.: Treatment of headache with ergotamine-caffeine suppositories. Neurology 2: 477–480 (1952).PubMedCrossRefGoogle Scholar
  42. Meyers, L. and Croft, G.S.: Effectiveness of aerosol administration of ergotamine tartrate in migraine headache. New York State Journal of Medicine 62: 2191–2193 (1962).PubMedGoogle Scholar
  43. Millen. F.J.: The treatment of headache with Cafergot suppositories. Wisconsin Medical Journal 53: 191–194 (1954).PubMedGoogle Scholar
  44. Müller-Schweinitzer, E.: Studies on the 5-HT receptor in vascular smooth muscle. Research and Clinical Studies in Headache 6: 6–12 (1978).PubMedGoogle Scholar
  45. Müller-Schweinitzer, E.: Vascular effects of ergot alkaloids: A study on human basilar arteries. General Pharmacology 14: 95–102 (1983).PubMedCrossRefGoogle Scholar
  46. Müller-Schweinitzer, E. and Weidmann, H.: Basic pharmacological properties; in Berde and Schild (Eds) Ergot Alkaloids and Related Compounds, Handbuch der Experimentellen Pharmakologie, vol. 49, pp. 87–232, (Springer-Verlag, Berlin 1978).Google Scholar
  47. Nimmerfall, F. and Rosenthaler, J.: Ergot alkaloids: Hepatic distribution and estimation of absorption by measurement of total radioactivity in bile and urine. Journal of Pharmacokinetics and Biopharmaceutics 4: 57–66 (1976).PubMedGoogle Scholar
  48. Norris, J.W.: Hachinski, V.C. and Cooper, P.W.: Changes in cerebral blood flow during a migraine attack. British Medical Journal 2: 676–677 (1975).CrossRefGoogle Scholar
  49. Orton, D.A. and Richardson, R.J.: Ergotamine absorption and toxicity. Postgraduate Medical Journal 58: 6–11 (1982).PubMedCrossRefGoogle Scholar
  50. Ostfeld, A.M.: A study of migraine pharmacotherapy. American Journal of Medical Science 241: 192–198 (1961).CrossRefGoogle Scholar
  51. O’sullivan, M.E.: Termination of one thousand attacks of migraine with ergotamine tartrate. Journal of the American Medical Association 107: 1208–1212 (1936).CrossRefGoogle Scholar
  52. Pichler, E.; Ostfeld, A.M.; Goodell, H. and Wolff, H.G.: Studies on headache: Central versus peripheral action of ergotamine tartrate and its relevance to the therapy of migraine headache. American Medical Association Archives of Neurology and Psychiatry 76: 571–577 (1956).PubMedCrossRefGoogle Scholar
  53. Piguet, G.: Les cephalees ‘vasculaires’ et leur traitement par une association d’ergotamine et de caféine. Revue Médicale de la Suisse Romande 73: 712–723 (1952).Google Scholar
  54. Puzich, R.; Girke, W.; Heidrich, H. and Rischke, M.: Assessment of extracranial cerebral vessels in patients with migraine after administration of ergotamine tartrate using Doppler ultrasound. Deutsche Medizinische Wochenschrift 108: 457–461 (1983).PubMedCrossRefGoogle Scholar
  55. Reinhard Jr, J.F.; Libemann, J.E.; Schlosberg, A.J. and Moskowitz, M.A.: Serotonin neurons project to small blood vessels in the brain. Science 206: 85–87 (1979).PubMedCrossRefGoogle Scholar
  56. Reisman, E.E.: The use of experimental suppositories in treating refractory migraine. American Practitioner and Digest of Treatment 3: 308–310 (1952).PubMedGoogle Scholar
  57. Rosenthaler, J. and Munzer, H.: 9, 10-Dihydroergotamine: Production of antibodies and radioimmunoassay. Experientia 32: 234–236 (1976).PubMedCrossRefGoogle Scholar
  58. Rosenthaler, J.; Munzer, H.; Voges, R.; Andres, H.; Gull, P. and Bolliger, G.: Immunoassay of ergotamine and dihydroergotamine using a common 3H-labelled ligand as tracer for specific antibody and means to overcome experienced pitfalls. International Journal of Nuclear Medicine and Biology 11: 85–89 (1984).PubMedCrossRefGoogle Scholar
  59. Rothlin, E.: Historical development of the ergot therapy of migraine. International Archives of Allergy 7: 205–209 (1955).CrossRefGoogle Scholar
  60. Sakai, F. and Meyer, J.S.: Regional cerebral haemodynamics during migraine and cluster headaches measured by the 133Xe inhalation method. Headache 18: 122–132 (1978).PubMedCrossRefGoogle Scholar
  61. Schmidt, R. and Fanchamps, A.: Effect of caffeine on intestinal absorption of ergotamine in man. European Journal of Clinical Pharmacology 7: 213–216 (1974).PubMedCrossRefGoogle Scholar
  62. Shofstall, C.K. and Shofstall, W.H.: A clinical report on the relief of headaches non-responsive to analgesics. Journal of the Kansas Medical Society 52: 366–367 (1951).PubMedGoogle Scholar
  63. Smits, J.F. and Struyker-Boudier, H.A.: Intrahypothalamic serotonin and cardiovascular control in rats. Brain Research 111: 422–427 (1976).PubMedCrossRefGoogle Scholar
  64. Sofia, R.D. and Vassar, H.B.: The effect of ergotamine and methysergide on serotonin metabolism in the rat brain. Archives Internationales de Pharmacodynamie et de Therapie 216: 40–50 (1975).PubMedGoogle Scholar
  65. Speed, W.G.: Ergotamine tartrate inhalation: A new approach to the management of recurrent vascular headaches. American Journal of Medical Science 240: 327–331 (1960).CrossRefGoogle Scholar
  66. Spierings, E.L.H. and Saxena, P.R.: The action of ergotamine on the distribution of carotid blood flow — the migraine shunt theory revisited. Headache 20: 143–145 (1980).PubMedCrossRefGoogle Scholar
  67. Sutherland, J.M.; Hooper, W.D.; Eadie, M.J. and Tyrer, J.H.: Buccal absorption of ergotamine. Journal of Neurology, Neurosurgery and Psychiatry 37: 1116–1120 (1974).CrossRefGoogle Scholar
  68. Swirsky, M.Y.: Ergotamine tartrate and caffeine (EC112) in migraine headaches. Connecticut State Medical Journal 18: 121–123 (1954).PubMedGoogle Scholar
  69. Symonds, C.P.: A particular variety of headache. Brain 79: 217–232 (1956).PubMedCrossRefGoogle Scholar
  70. Tfelt-Hansen, P.; Ibraheem, J.J. and Paalzow, L.: Clinical pharmacology of ergotamine studied with a high performance liquid Chromatographic meihod; in Rose (Ed.) Advances in Migraine Research and Therapy, pp. 173–179 (Raven Press, New York 1982).Google Scholar
  71. Tfelt-Hansen, P.; Kanstrup, I.L.; Christensen, N.J. and Winkler, K.: General and regional haemodynamic effects of intravenous ergotamine in man. Clinical Science 65: 599–604 (1983).PubMedGoogle Scholar
  72. Wainscott, G.; Volans, G. and Wilkinson, M.: Ergotamine-induced headaches. British Medical Journal 2: 724 (1974).PubMedCrossRefGoogle Scholar
  73. Waters, W.E.: Controlled clinical trial of ergotamine tartrate. British Medical Journal 2: 325–327 (1970).PubMedCrossRefGoogle Scholar
  74. Wilkinson, M. and Wall, W.C.: Ergotamine tartrate in the treatment of migraine. Archives of Neurobiology 37: 317–319 (1974).Google Scholar
  75. Yuill, G.M.; Swinburn. W.R. and Liversedge, LA.: A double-blind crossover trial of isometheptene mucate compound and ergotamine in migraine. British Journal of Clinical Practice 26: 76–79 (1972).PubMedGoogle Scholar

Copyright information

© Adis Press Limited 1985

Authors and Affiliations

  • V. L. Perrin
    • 1
  1. 1.Medical DivisionGlaxo Group Research Ltd, WareHertfordshireUK

Personalised recommendations