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• Severe migraine attacks should be treated with a triptan, e.g. sumatriptan (below). In contrast to symptomatic treatments, triptans are best used during the established headache phase of the acute attack. Headache may return in 6-36 h in about one-third of patients, necessitating a second dose.

• Ergotamine 1-2 mg as a suppository is used if other treatments have failed, but not within 12 h of the last dose of a triptan; similarly a triptan should not be given until 24 h have elapsed after stopping ergotamine.

Sumatriptan

Sumatriptan (Imigran) selectively stimulates a subtype of 5-hydroxytryptaminej-receptors (called 5-HT1B/JD-receptors) which are found in cranial blood vessels, causing them to constrict. It is rapidly absorbed after oral administration and undergoes extensive (84%) presystemic metabolism; but bioavailability by the s.c. route is 96%. The t1/, is 2 h.

The oral dose is 50-100 mg, the 24 h total not to exceed 300 mg. The oral route may be avoided by sumatriptan 20 mg given intranasally, repeated once in not less than 2 h, with not more than 40 mg in 24 h. When a rapid response is required, sumatriptan 6 mg is given s.c., the dose to be repeated once if necessary after 1 h but the total should not exceed 12 mg in 24 h.

Sumatriptan is generally well tolerated. Malaise, fatigue, dizziness, vertigo and sedation are associated with oral use. Nausea and vomiting may follow oral or s.c. administration. The most important adverse effects are feelings of chest pressure, tightness and pain in about 5% of cases; these may be accompanied by cardiac arrhythmia and myocardial infarction and appear to be due to coronary artery spasm. Patients with ischaemic heart disease, unstable angina or previous myocardial infarction should not be given sumatriptan; use in relation to ergotamine (see above).

Almotriptan, naratriptan, rizatriptan and zol-mitriptan are similar.16

16 Ferrari M D et al 2001 Oral triptans (serotonim 5-HT D agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 358:1668-1675.

Ergotamine

Ergotamine is a partial agonist at a-adrenoceptors (vasoconstrictor) and also a partial agonist at serotonergic receptors. It must be used with special care.

Ergotamine constricts all peripheral arteries (an effect potentiated by concomitant (3-adrenoceptor block), not just those affected by the migraine process. Due to tissue binding, its effect on arteries persists as long as 24 h and repeated doses lead to cumulative effects long outlasting the migraine attack.

It is incompletely absorbed from the gastrointestinal tract; rectal administration may be preferred in the acute attack of migraine. Ergotamine is extensively metabolised in the liver (t'/2 2 h).

Tablets, 1 mg, may be crushed before swallowing with water. Initially 1-2 tablets should be taken and thereafter, not more than 4 tablets should be taken in 24 h, the sequence should not be repeated for 4 days, and not more than 8 tablets should be taken in a week. Suppositories, 2 mg, are now preferred as part of stepped therapy (above); they are subject to the same maximum dose restrictions. Caffeine enhances both the speed of absorption and peak concentration of ergotamine and is often combined with it (though it may prevent sleep).

Paraesthesiae in hands or feet give warning of peripheral ischaemia. Overdose can cause peripheral gangrene. Due to its complex actions on receptors, vasoconstriction is best antagonised by a nonselective vasodilator such as glyceryl trinitrate, nifedipine or sodium nitroprusside (rather than by an «-adrenoceptor blocker). Patients with vascular disease, coronary and peripheral, are particularly at risk.

Ergotamine is a powerful oxytocic and is dangerous in pregnancy. It may precipitate angina pectoris, probably by increasing cardiac pre- and afterload (venous and arterial constriction) rather than by constricting coronary arteries.

Ergotamine should never be used for prophylaxis of migraine.

Drug prophylaxis of migraine

This should be considered when, after adjustment of lifestyle, there are still two or more attacks per month. Benefit may be delayed for several weeks. Options (which may help up to 60% of patients) include:

• ^-adrenoceptor block by propranolol(dl); (the d-isomer, which lacks P-blocking action though it has membrane stabilising effect, also prevents migraine), as do other pure antagonists (atenolol, metoprolol) but not partial (ant)agonists, see page 474. It seems that ^-adrenoceptor block is not the prime therapeutic action. Note that if ergotamine (for an acute attack) is given to a patient taking propranolol for prophylaxis there is risk of additive vasoconstriction (block of P-receptor mediated dilatation with added a-receptor constriction).

• Calcium entry blockers, e.g. verapamil, flunarizine, may provide benefit.

• Pizotifen and cyproheptadine block serotonin (5-HT) receptors as well as having some Hj-antihistamine action; they can be effective.

• A tricyclic antidepressant, e.g. amitriptyline in low dose; start with 10 mg at night and increase to 50-75 mg.

• Methysergide (an ergot derivative) blocks serotonin receptors but it has a grave rare adverse effect, an inflammatory fibrosis, retroperitoneal (causing obstruction to the ureters), subendocardial, pericardial and pleural. Drug 'holidays', i.e. withdrawal for 1-2 months each 6 months, are a prudent safeguard. Because of this risk, methysergide cannot be a drug of first choice though it may be justified for a patient who is experiencing a sequence of severe attacks.

Cluster headaches may be treated with a 5HTj-receptor agonist, e.g. sumatriptan, as for migraine. Since bouts of headache tend to be of limited duration, e.g. a few weeks, short courses of methysergide are justified in intractable cases.

Premenstrual migraine may respond to mefenamic acid or to a diuretic. After six months it is worth trying slow withdrawal of the prophylactic drug.

Headache of raised intracranial pressure (cerebral oedema) responds to dexamethasone (10 mg i.v.; 4 mg 6-hourly, 2-10 d) which reduces the pressure; and to nonopioid analgesics (see also Palliative care).

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