The Pathophysiological and Pharmacological Basis of Current Drug Treatment of Migraine Headache

Doodipala Samba Reddy


Expert Rev Clin Pharmacol. 2013;6(3):271-288. 

In This Article

Ergot Alkaloids: Ergotamine (Ergomar) and Dihydroergotamine (Migranal)

Ergot alkaloids were the first antimigraine drugs available. Dihydroergotamine (DHE) is an ergotamine analog (Figure 3). DHE is administered as a nasal spray form (Migranal®, Valeant Pharmaceuticals, QC, Canada) or by injection. Ergotamine (Ergomar®, Rosedale Therapeutics, TN, USA) is available in oral and sublingual tablet formulation and rectal suppositories.

Figure 3.

Ergotamine and dihydroergotamine. Dihydroergotamine contains hydrogen atoms at C9 and C10.

Pharmacological Effects

The ergot alkaloids are nonspecific 5-HT agonists and vasoconstrictors (partial agonists or antagonists at adrenergic, dopaminergic and tryptaminergic receptors). The desirable and undesirable actions of ergot alkaloids used for migraine are related to the effects on smooth muscle. The drugs constrict arteries and veins by direct stimulation of cerebral vascular smooth muscle.[73–75]


The pharmacological effects of ergot alkaloids are complex and their precise mechanism of action is not very clear. The actions of ergot alkaloids at 5-HT1B/1D receptors likely mediate their acute antimigraine effects.[70] DHE is also an α1-adrenoceptor antagonist.


The use of ergot alkaloids for migraine should be restricted for patients having frequent, moderate migraines or infrequent, severe migraine attacks.[71,72] The drugs should be taken as soon as possible after the onset of a headache. Clinical studies have shown that oral ergotamine plus caffeine is less effective than triptans for acute migraine.


Ergot preparations for migraine therapy are listed in Table 3. Ergotamine is less widely used owing to the availability of triptans and its adverse side effect profile.[73,74] Only the rectal forms of ergotamine are superior to rectal triptans. Injected, oral and nasal spray forms are all inferior to the triptans. Ergotamine may still be helpful for patients with status migrainous or those with frequent recurring headaches. DHE is the currently used ergot preparation. An orally inhaled formulation of DHE delivered to the systemic circulation will be available in the near future.[75]

Side Effects & Contraindications

Nausea and vomiting occur in 10% of patients taking ergot alkaloids. They are contraindicated in patients with cardiovascular diseases.

Teratogenic Effects

Pregnancy category X (contraindicated in pregnancy). Ergot alkaloids are contraindicated in pregnant women because they cause uterine contractions, fetal distress, gastrointestinal atresia and miscarriage.

In March 2007, the FDA halted marketing of over 15 unapproved ergotamine products. The biggest concern was the absence of the 'black box warning' (on drug interactions and contraindications) on 15 unapproved ergotamine drugs.

Black Box Warning

Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of ergotamine with potent CYP3A4 inhibitors, including protease inhibitors and macrolide antibiotics. As CYP3A4 inhibition elevates the serum levels of ergotamine, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of these medications is contraindicated.