Clinical pharmacokinetics of ergotamine in migraine and cluster headache

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 radioimmunoassay 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.