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

Doodipala Samba Reddy

Disclosures

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

In This Article

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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