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

Treatment Consideration in Special Populations

Migraine & Pregnancy

Studies indicate a decreased frequency of headache activity (57%) in the first trimester and 85% in the second/third trimester of pregnancy. There is some controversy on triptan usage in pregnancy.[110–114] Some studies in Scandinavia suggested a link between triptans and early delivery/low birth weight; however, there are not sufficient numbers at this time to draw reasonable conclusions on safety during pregnancy.[111,112] These studies lack internal consistency in that there is no associated low birth weight.[113] In contrast, recent reports address this issue properly.[113,114] Ergot alkaloids are contraindicated in pregnancy. NSAIDs should not be used in the third trimester because they can cause birth defects. The triptans are classified as category C (risk cannot be ruled out) for use in pregnancy. Prophylactic therapy is generally not recommended in pregnancy.

Migraine & Epilepsy

Migraine and epilepsy are comorbid episodic disorders that have common pathophysiologic mechanisms (see ref.).[115] Migraine attacks, like epileptic seizures, may be triggered by excessive neocortical cellular excitability; in migraine, however, the hyperexcitability is believed to transition to CSD rather than to the hypersychronous activity that characterizes seizures.[115] Like epilepsy, some forms of migraine are linked to the channelopathies, which are diseases caused by disturbed function of ion channel subunits or the proteins that regulate them. Mutations in the calcium channel subunit genes can cause migraine or epilepsy. In some cases, the same gene is linked to both migraine and epilepsy. For example, FHM is an autosomal dominant migraine caused by mutations in a gene coding for the P/Q-type calcium channel α subunit, CACNA1A. There is clinical overlap in some FHM patients with epilepsy. This supports the notion that migraine, like epilepsy, is a fundamental disorder of altered neuronal excitability. The precise trigger for migraine attacks is enigmatic. Many clinical factors such as diet, alterations in sleep and stress are known to predispose individuals to attacks. It is particularly intriguing that photic stimulation can trigger both migraine attacks and epileptic seizures. Given the likely commonalities in the underlying cellular and molecular mechanisms, some antiepileptic drugs, including sodium valproate, topiramate and gabapentin, are effective for prophylaxis of migraine.

Migraine Management Guidelines

The US Headache Consortium completed a landmark evidenced-based review of the literature concerning the diagnosis and treatment of migraine.[116] The Consortium organizations include the American Academy of Neurology, the American Headache Society, the American Academy of Family Physicians, the American College of Emergency Physicians, the American College of Physicians–American Society of Internal Medicine, the American Osteopathic Association and the National Headache Foundation. Their recommendations are listed below:

  • For most migraine sufferers, NSAIDs are first-line therapy;

  • In patients whose migraine attack has not responded to NSAIDs, use migraine-specific agents (triptans, ergot products);

  • Select a nonoral route of administration for patients whose migraines present early with nausea or vomiting as a significant component of the symptom complex. Treat nausea and vomiting with an antiemetic;

  • Consider a self-administered rescue medication for patients with severe migraine who do not respond to (or 'fail') other treatments;

  • Guard against medication-overuse headache ('rebound headache' or 'drug-induced headache');

  • Migraine sufferers should be evaluated for use of preventive therapy;

  • Recommended first-line agents for the prevention of migraine are propranolol, timolol, amitriptyline, divalproex sodium and sodium valproate;

  • Educate migraine sufferers about the control of acute attacks and preventive therapy and engage them in the formulation of a management plan. Therapy should be re-evaluated on a regular basis;

  • Direct special attention to women who are pregnant or want to become pregnant. Preventative medications may have teratogenic effects. If treatment is absolutely necessary, select a treatment with the lowest risk of adverse effects to the fetus.