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

Doodipala Samba Reddy

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

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.

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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]

Mechanism

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-HT_1B/1D receptors likely mediate their acute antimigraine effects.^[70] DHE is also an α1-adrenoceptor antagonist.

Indications

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.

Products

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.

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Abstract and Introduction
Pathophysiology of Migraine
Vascular Theory
Neural Theory
Other Theories
Migraine Genetics
Inflammation & Pain Pathway
Diagnosis of Migraine
Treatment of Migraine
Symptomatic Treatment of Migraine: Mild-to-Moderate Migraine
STM: Moderate-to-Severe Migraine
Ergot Alkaloids: Ergotamine (Ergomar) and Dihydroergotamine (Migranal)
Triptans: Selective Serotonin 5-HT₁-Receptor Agonists
Migraine Prophylaxis (Preventive Antimigraine Therapy)
Treatment Consideration in Special Populations
Expert Commentary
Five-year View
References
Sidebar

Table 1. Migraine subtypes according to the International Classification of Headache Disorders (ICHD-2).
Migraine subtype	IHS description
1.1 MO	Recurrent headache disorder manifesting in attacks lasting 4–72 h. Typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity and association with nausea and/or photophobia and phonophobia. Previously it was called common migraine
1.2 MA	Recurrent disorder manifesting in attacks of reversible focal neurological symptoms that usually develop gradually over 5–20 min and last for less than 60 min. Headache with the features of migraine without aura usually follows the aura symptoms. Less commonly, headache lacks migrainous features or is completely absent. Previously it was called classic migraine Typical aura with migraine headache Typical aura with nonmigraine headache Typical aura without headache FHM Sporadic hemiplegic migraine Basilar-type migraine
1.3 Childhood periodic syndromes that are commonly precursors of migraine	Recurrent episodic attacks, usually stereotypical in the individual patient, of vomiting and intense nausea. Attacks are associated with pallor and lethargy. There is complete resolution of symptoms between attacks Cyclical vomiting Abdominal migraine Benign paroxysmal vertigo of childhood
1.4 Retinal migraine	Repeated attacks of monocular visual disturbance, including scintillations, scotomata or blindness, associated with migraine headache
1.5 Complications of migraine	Complications of migraine (for coding purpose):
	• Chronic migraine
	• Status migrainosus
	• Persistent aura without infarction
	• Migrainous infarction
	• Migraine-triggered seizure

FHM: Familial hemiplegic migraine; IHS: International Headache Society; MA: Migraine with aura; MO: Migraine without aura.

Table 2. Over-the-counter analgesics and NSAID combinations for migraine.
Drug/class	Trade name(s)	Dosage
*OTC analgesics and NSAIDs*
Aspirin		650 mg, q4h (max 4000 mg daily)
APAP	Tylenol®, others	650 mg, q4h (max 4000 mg daily)
Ibuprofen	Advil® migraine^†, Motrin® migraine^†	200–400 mg, q4–6h (max 2400 mg daily)
Naproxen sodium	Aleve®, Anaprox®	220 m, q6–8h (max 660 mg daily)
*NSAID combinations*
Aspirin 400 mg + caffeine 32 mg	Anacin®	As above, see aspirin dosage
Acetaminophen 250 mg + aspirin 250 mg + caffeine 65 mg	Excedrin® migraine^†	As above, see aspirin–APAP dosage
Acetaminophen 325 mg + isometheptene 65 mg + dichloralphenazone 100 mg	Midrin®^‡	As above, see APAP dosage
*Barbiturate/NSAID combinations*
Aspirin 650 mg + butalbital 50 mg	Axotal®	1 tablet, q4h (max 6 tablets daily)
Aspirin 300 mg + butalbital 50 mg + caffeine 50 mg	Fiorinal®	1–2 tablets, q4h (max 6 tablets daily)
Acetaminophen 325 mg + butalbital 50 mg + caffeine 50 mg	Fioricet®	1–2 tablets, q4h (max 6 tablets daily)

^†US FDA-approved for migraine; all other agents and combination products are not FDA-indicated for migraine
^‡Combination of butalbital (a 5-allyl-5-isobutyl-barbituric acid, used for tension headaches), isometheptene (a sympathomimetic amine with vasoconstriction properties) and dichloralphenazone (a sedative-hypnotic used for tension headaches).
APAP: Acetaminophen; max: Maximum; OTC: Over-the-counter; q4h: Every 4 h; q4–6h: Every 4–6 h; q6–8h: Every 6–8 h.

Table 3. Triptans and ergot alkaloids for acute migraine therapy.
Drug	Formulations	Usual dosage
*Ergot alkaloids*
Dihydroergotamine mesylate – generic, DHE 45®	1 mg/ml ampules	1 mg im. or sc.; can be repeated at 1 h intervals (max 3 mg/24 h, 6 mg/week)
Migranal® nasal spray	4 mg/ml nasal spray	One spray (0.5 mg) into each nostril, repeated 15 min later (2 mg/dose; max 3 mg/24 h)
Ergotamine tartrate – Ergomar®	2 mg sublingual tabs	2 mg sublingually; can be repeated q30min PRN (max 6 mg/24 h, 10 mg/week)
Ergotamine/caffeine – Cafergot®	1 mg/100 mg tabs, 2 mg/100 mg rectal suppositories	Two tablets p.o., then 1 q30min × 4 PRN (max six tablets/attack), one rectal suppository; can be repeated once 1 h later
*Triptans*
Almotriptan – Axert®	6.25, 12.5 mg tablets	12.5 mg p.o.; can be repeated once after 2 h (max 2 doses/day)
Eletriptan – Relpax®	20, 40 mg tablets	20 or 40 mg p.o.; can be repeated after 2 h (max 80 mg/day)
Frovatriptan – Frova®	2.5 mg tablets	2.5 mg p.o.; can be repeated after 2 h (max 7.5 mg/day)
Naratriptan – Amerge®	1, 2.5 mg tablets	2.5 mg p.o.; can be repeated once after 4 h (max 5 mg/day)
Rizatriptan – Maxalt®	5, 10 mg tablets; 5, 10 mg OD tablets	5 or 10 mg p.o.; can be repeated after 2 h (max 30 mg/day)
Sumatriptan – Imitrex®	25, 50, 100 mg tablets 5, 20 mg nasal spray, 4, 6 mg/0.5 ml cartridges; 6 mg/0.5 ml vials	50 or 100 mg p.o.; can be repeated after 2 h (max 200 mg/day), 5, 10 or 20 mg intranasally; can be repeated once after 2 h (max 40 mg/day), 6 mg sc.; can be repeated once after 1 h (max 12 mg/day)
Zolmitriptan – Zomig®, Zomig® ZMT	2.5, 5 mg tablets; 2.5, 5 mg orally disintegrating tablets 5 mg/100 mcl nasal spray	2.5 or 5 mg p.o.; can be repeated after 2 h (max 10 mg/day), 5 mg intranasally; can be repeated once after 2 h (max 10 mg/day)

im.: Intramuscular; OD: Orally dispersible; p.o.: Orally; PRN: As needed; q30min: Every 30 min; sc.: Subcutaneously.

Table 4. Pharmacological agents for prophylaxis of migraine.
Drug	Formulations	Usual dosage
β–blockers
Metoprolol – generic^†, Lopressor®^†	25, 50, 100 mg tablets	50–100 mg b.i.d.
Metoprolol ER – generic^†, Toprol-XL®^†	25, 50, 100, 200 mg tabs	100–200 mg q.d.
Propranolol – generic, Inderal®	10, 20, 40, 60, 80 mg tablets	160–240 mg q.d. divided b.i.d., t.i.d. or q.i.d.
Propranolol ER – generic, Inderal LA®	60, 80, 120, 160 mg caps	160–240 mg q.d.
Timolol – generic	5, 10, 20 mg tablets	10–15 mg b.i.d. or 20 mg q.d.
*Antiepileptic drugs*
Divalproex sodium – Depakote®, Depakote® ER	125, 250, 500 mg tablets; 125 mg sprinkle caps, 250, 500 mg tablets	250–500 mg b.i.d., 500–1000 mg q.d.
Topiramate – Topamax®	25, 50, 100, 200 mg tablets; 15, 25 mg caps	50 mg b.i.d.
*Tricyclic antidepressants*
Amitriptyline^† – generic	10, 25, 50, 75, 100, 150 mg tabs	30–150 mg q.d.

^†Not approved by the US FDA for this indication.
b.i.d.: Twice-daily; q.d.: Every day; q.i.d.: Four-times daily; t.i.d.: Three-times daily.

Table 5. Overview of future new drugs for migraine.
Name	Pharmacological properties
Olcegepant	CGRP-receptor antagonist (intravenous)
Telcagepant	CGRP-receptor antagonist (oral)
BI-44370 TA	CGRP-receptor antagonist (oral)
Lasmiditan	5-HT_1F-receptor agonist (oral)
Onabotulinum toxin A	Mechanism unknown (injection)
SB-705498	TRPV1 antagonist

5-HT_1F: 5-hydroxytriptamine_1F; CGRP: Calcitonin gene-related peptide.

Box 1. Migraine case report.
A 31-year-old woman consults a pharmacist seeking headache medications. She says her headaches occur 1 to 2 times each month; right-sided pulsatile pain; she cannot function at her full capacity; such headaches started 6 months ago and the worst headache happened 2 months ago. She describes that her headaches begin with visual changes, flashes of light along with sensations of dizziness; she experiences nausea/vomiting sensation during the headache. She has tried acetaminophen/ibuprofen without much relief. How should she be evaluated and treated? What is the probable migraine type and the drug of choice for its treatment and long-term management?

Box 2. International Headache Society classification of headaches.
Migraine headache diagnostic requirements
At least two of the following features: Unilateral location Throbbing character Worsening pain with routine activity Moderate-to-severe intensity At least one of the following features: Nausea and/or vomiting Photophobia and phonophobia Tension headache diagnostic requirements At least two of the following features: Pressing, tightening or nonpulsatile character Mild-to-moderate intensity Bilateral location Both of the following features: No nausea or vomiting No photophobia and phonophobia Cluster headache diagnostic requirements Following features: Five attacks, with a frequency of one to eight attacks on any given day Severe unilateral, bilateral, supraorbital or temporal pain lasting 15–180 min With at least one of the following features on the same side as the pain: Lacrimation Nasal congestion Rhinorrhea Forehead and/or facial sweating Ptosis Miosis Eyelid edema

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

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

Pharmacological Effects

Mechanism

Indications

Products

Side Effects & Contraindications

Teratogenic Effects

Black Box Warning

Tables

Tables

Tables

Tables

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

Sidebar

Sidebar

Key Issues

Figure 3.

Figure 3.

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