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

Doodipala Samba Reddy

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

Pathophysiology of Migraine

The exact pathophysiology of migraine is unclear. It has been suggested that the characteristic pathophysiology of migraine is the cortical spreading depression (CSD) of neural impulses from a focal point of vasoconstriction followed by vasodilation. However, it is unlikely that vasoconstriction followed by vasodilation (spreading depression) or vasodilation alone accounts for the local edema and focal tenderness often observed in migraine patients.^[8,10] Lashley described the progressive nature of the visual aura in 1941.^[16] Leao described spreading depression in 1944.^[17] Milner connected these two developments in 1959.^[18] The work of Moskowitz and Olesen was seminal in our current understanding of spreading depression in migraine.^[19,20] The relation of migraine to arteries is still an important part of the pathophysiology. A central generator in the hypothalamus or periaqueductal gray has not been ruled out. In migraine patients, the spreading depression passing through nerve cells stimulates the release of several endogenous substances that cause inflammation, makes nerve fibers more sensitive to pain and causes vasodilation.^[21,22] There are at least two theories of migraine headaches, including vascular theory and neural theory (Figure 1).

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Figure 1.

An overview of the pathogenesis of migraine headache. According to vascular theory, vascular disturbances (vasodilatation–vasoconstriction) lead to migraine attacks through a cascade involving inflammation and the serotonin system. According to neural theory, hyperexcitability in the form of cortical spreading depression leads to migraine through a cascade involving inflammation and the sympathetic nervous system. There are alternative theories that may overlap with key mechanisms that may activate neural inflammation and lead to migraine pain.

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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

Pathophysiology of Migraine

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Figure 1.

Figure 1.

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