Pharmacologic treatment of Migraine. Part 1: pathophysiology and clinical features

This is the introduction to a series of three posts on the pharmacological treatment of migraine. Part 2 will explore agents used in the prevention of attacks, while in part 3 drugs like triptans and ergot derivatives will be discussed.

Introduction: classification of headaches

Headache is one of the most common medical complaints in clinical practice, most clinicians of a wide range of medical specialties will often hear their patients complain about this clinical disorder.

As an introduction, below is a PowerPoint discussing the latest headache classification.

Download PPT: Headache Classification

Migraine Pathophysiology

During the interval between attacks, various disturbances (genetically determined) may be observed, e. g., cerebral hypomagnesemia, elevated concentration of excitatory amino acids (glutamate, aspartate), and increased reactivity of cranial blood vessels. The cumulative effect of these disturbances is a heightened sensitivity to nociceptive stimuli (migraine pain threshold).

Impulses from the cortex, thalamus, and hypothalamus activate the so-called migraine center (shown in the image) responsible for the generation of migraine attacks, putatively located in the brain stem(serotonergic raphe nuclei, locus ceruleus).


Source: Fauci AS, Kasper DL, Braunwald E, Hauser SL, Longo DL, Jameson JL, LOscalzo J: Harrison’s Principles of Internal Medicine, 17th Ed.

The migraine center triggers cortical spreading depression (suppression of brain activity across the cortex) accompanied by oligemia, resulting in an aura. Trigeminovascular input from meningeal vessels is relayed to the brain stem, via projecting fibers to the thalamus and then, by the parasympathetic efferent pathway, back to the meningeal vessels (trigeminal autonomic reflex circuit).

Perivascular trigeminal C-fiber endings (trigeminovascular system) are stimulated to release vasoactive neuropeptides such as substrate P, neurokinin A, and calcitonin gene-regulated polypeptide (CGRP), causing a sterile inflammation. Researchers are focusing their attention on the development of calcitonin gene-regulated polypeptide antagonists.


Modified from: 1999a Eur.J.Pharmacol. 375: 61-74.

Vasoconstriction and vascular hyperesthesia with subsequent vasodilatation spread via trigeminal axon reflexes. The perception of pain is mediated by the pathway from the trigeminal nerve to the nucleus caudalis, thalamus and cortex. Trigeminal impulses also reach autonomic centers.

Pharmacologic and other data point to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT; also known as serotonin) in migraine.  The triptans are designed to selectively stimulate subpopulations of 5-HT receptors; at least 14 different 5-HT receptors exist in humans. The triptans are potent agonists of 5-HT1B, 5-HT1D, and 5-HT1F receptors and are less potent at the 5-HT1A receptor. A growing body of data indicates that the antimigraine efficacy of the triptans relates to their ability to stimulate 5-HT1B/1D receptors, which are located on both blood vessels and nerve terminals.

The following video integrates pathophysiology of migraine in a very appealing and clear way.

Clinical features of migraine and diagnosis

Migraine can be subdivided into two types:

  • Migrane with aura (classic migraine).
  • Migraine without aura (common migraine): this is the most frequent clinical presentation.

As the image shows, a classic migraine attack has 4 phases: prodromal, aura, headache and resolution.


Source: Rohkamm, R “Color atlas of Neurology” , 1st edition. Thieme:2004.

Prodromal phase. The migraine attack may be preceded by a period of variable prodromal phenomena lasting a few hours to two days. Most patients complain of sensitivity to smells and noise, irritability, restlessness, drowsiness,fatigue, lack of concentration, depression, and polyuria. In children, the chief complaints are abdominal pain and dizziness.

Aura. Some patients experience attacks without an aura (common migraine), while others have attacks with an aura (classic migraine) that develops over 5–20 minutes and usually lasts less than one hour, but may persist as long as one week (prolonged aura). Auras typically involve visual disturbances, which can range from undulating lines (resembling hot air rising), lightning flashes, circles, sparks or flashing lights (photopsia), or zig-zag lines (fortification figures, teichopsia, scintillating scotoma).  Unilateral paresthesiae (tingling or cold sensations) may occur. Emotional changes (anxiety, restlessness, panic, euphoria, grief, aversion) of variable intensity are relatively common.

Headache phase. Most patients (ca. 60%) complain of pulsating, throbbing, or continuous pain on one side of the head (hemicrania). Others have pain in the entire head, particularly behind the eyes (“as if the eye were being pushed out”), in the nuchal region, or in the temples. Migraine headache worsens on physical exertion and is often accompanied by anorexia, malaise, nausea, and vomiting.

Resolution phase. This phase is characterized by listlessness, lack of concentration, and increased pain sensitivity in the head.

Simplified Diagnostic Criteria for Migraine

The International Headache Society elaborated diagnostic criteria for the diagnosis of migraine. These are as follows:

Repeated attacks of headache lasting 4–72 h in patients with a normal physical examination, no other reasonable cause for the headache, and:

At least 2 of the following features: Plus at least 1 of the following features:
Unilateral pain Nausea/vomiting
Throbbing pain Photophobia and phonophobia
Aggravation by movement
Moderate or severe intensity

The following video is targeted to a general audience. However, it is very useful to review the differential diagnosis with tension type headache.


Fauci, Anthony S., Braunwald, Eugene, Kasper,Dennis L. “Harrison’s Principles of Internal Medicine”, 17 edition. Mc Graw Hill: 2008.

Rohkamm, R “Color atlas of Neurology” , 1st edition. Thieme:2004.

Villalón CM et al. Migraine: Pathophysiology, Pharmacology, Treatment and Future Trends. Curr Vasc Pharmacol. 2003 Mar;1(1):71-84.

Illustrated Psychopharmacology Lectures in Your Inbox

  • Mechanisms of action, adverse effects and indications of psychotropic medications.
  • Concise and illustrated presentations. 
  • Practical tips for mental health professionals.




Are you a visual learner interested in learning psychopharmacology? Click here to get our videos