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

Doodipala Samba Reddy

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

Migraine Prophylaxis (Preventive Antimigraine Therapy)

Patients with frequent or severe disabling migraine headaches and those who cannot take vasoconstrictors or are refractory to acute treatment should be given preventive therapy. There are several agents for prevention of migraine occurrence in susceptible patients (Table 4).^[63] Prophylactic therapy is indicated when attacks occur more than two- to three-times per month for more than 48 h, or cause significant functional impairment. It is also considered if symptomatic treatment provides inadequate relief or unacceptable side effects. Despite the unmet need for prophylaxis of migraine, there are few new drugs that are specifically developed for this indication.^[88–97]

Preventive antimigraine therapy (PAM) should probably not be considered until the headache frequency exceeds 1 per week. PAM is associated with significant side effects and often with tachyphylaxis over periods of 1–2 years. There are five drugs available in the USA with class-1 studies for PAM – propranolol, amitriptyline, topiramate, valproate and gabapentin. These all have efficacy in the class 1 studies; approximately 50% of subjects are at least 50% improved. In the clinic, with addition of the placebo effect, the 50% improvement rate is 60–70%. Studies suggest that flunarizine and sodium valproate might be effective prophylactic antimigraine agents.^[92] Onabotulinum toxin-A is approved for headache prophylaxis in adults with chronic migraine and has approximately the same rate of improvement. Side effects of PAM drugs should be reviewed prior to initiation of therapy. Sedation, autonomic effects, obesity, and alteration of sex drive, among others, are major factors that limit PAM use. Moreover, the preventive drugs discussed below are used for episodic migraine, since the level of evidence is different for chronic migraine.

Other potential PAM agents without class 1 data include levetiracetam, zonisamide, cyproheptadine, verapamil, amlodipine, oxcarbazepine, angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II-receptor-blocking drugs. These are potential 'second line' drugs.

β-Adrenoceptor Blockers

For continuous prophylaxis, β-blockers are commonly used.^[89,93–96] Propranolol and timolol are FDA approved for migraine prophylaxis. Propranolol (Inderal®, Akrimax Pharmaceuticals, NJ, USA) is a preferred drug for the prophylactic treatment of MA and MO. It putatively acts by blocking b-adrenergic-mediated cerebral vasodilation, or by the inhibition of catecholamine-induced platelet aggregation. However, there is little primary evidence that platelet aggregation is connected with migraine. Indeed, platelet aggregation causes transient ischemic attacks and these differ from migraine attacks. Timolol may also be useful for migraine prophylaxis. Other β-blockers such as metoprolol, nadolol and atenolol have also shown to be effective in migraine prophylaxis (but are not FDA-approved for this indication). Some β-blockers with intrinsic sympathomimetic activity (acebutolol, alprenolol, oxprenolol and pindolol) are ineffective. Side effects include fatigue, depression, nausea, dizziness and insomnia; however, symptoms appear to be fairly well tolerated.

Antiepileptic Drugs

Antiepileptic drugs are highly effective for migraine prophylaxis compared with placebo.^{[90,96–100]} They are increasingly used in many patients. Two drugs (valproate and topiramate) are FDA-approved for this indication. Sodium valproate is approved for migraine prophylaxis; however, the teratogenic potential of the compound limits its use. In addition, divalproex sodium (Depakote®, Abbott Laboratories, IL, USA) and topiramate (Topamax®, Janssen Pharmaceuticals) are also FDA-approved for prevention of migraine headaches. Gabapentin (Neurontin®, Pfizer) has been found to be effective in prevention of frequent migraine headaches (off-label use for migraine). Lamotrigine is another antiepileptic drug of choice for prophylaxis of MA.^[98] Nevertheless, many clinicians think antiepileptic drugs are generally ineffective, especially when one has to cope with their adverse events.

Antidepressants

Tricyclic antidepressants can prevent migraine in some patients.^[88,93,96] Amitriptyline, a tricyclic antidepressant, is an effective prophylactic agent. This effect is independent of the antidepressant effect. Although amitriptyline is a potent blocker of 5-HT transport, its mechanism of action in migraine prophylaxis is unknown. Tricyclic antidepressants often cause sedation, dry mouth and other anticholinergic side effects. Amitriptyline is widely used for prophylaxis (especially in patients who are also depressed), but it has not been approved by the FDA. However, its off-label use is common and has proved to be effective for migraine prevention.

Calcium Channel Blockers & ACE Inhibitors

Calcium channel blockers (e.g., verapamil) and ACE inhibitors (e.g., lisinopril) can prevent migraine attacks, but appear to be weak.^[101–104] However, these agents are not FDA indicated for migraine prophylaxis. Flunarizine, a nonspecific calcium-channel blocker, is approved for migraine prophylaxis in some European countries and is effective for this indication.

Other Prophylactic Agents

There are other pharmacological agents that are referred to as metabotropic drugs: riboflavin, coenzyme Q10 (CoQ10) supplementation and thioctic acid.^{[88,105–109]} CoQ10 is efficacious and well tolerated in children and adolescents with migraine.^[106] Riboflavin, which improves energy metabolism similarly to CoQ10, is effective in migraine prophylaxis.^[107] There is limited evidence that thioctic acid may be beneficial in migraine prophylaxis.^[108] It is thought that migraine is associated with a widespread metabolic abnormality of mitochondrial oxidative metabolism, leading to the use of riboflavin and CoQ10 as prophylactic therapy for migraine.^[109]

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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