Historical Overview

Perhaps one of the oldest medical conditions afflicting mankind, migraine headaches, were first recorded during the Mesopotamian Era in about 3,000. B.C.. A few notable migraine sufferers throughout history include Thomas Jefferson, Julius Caesar, Cervantes, Sigmund Freud, Ulysses S. Grant, Lewis Carroll and Vincent Van Gogh.

Historically, migraines have been treated with trial-and-error approaches, based upon the prevailing medical knowledge of the time, or with primitive methods based upon superstitions. Some of the treatments prescribed by early physicians such as Galen and Hypocrites, included:

  • Drilling a hole in the skull to free "evil spirits"
  • Purges and bloodletting
  • Applying a hot iron to the site of pain
  • Inserting a clove of garlic through an incision in the temple.

Milestones in Migraine Research

As medical science replaced superstition and crude "medical procedures," scientists began to look into the physiology of migraine. Researchers have long believed that migraine involves some type of interaction between cranial blood vessels and the brain.

Two theories are associated with this connection. The older theory suggests that migraine involves an initial momentary stage of vessel constriction followed by a more prolonged period of vessel dilation, resulting in the characteristic, throbbing pain. A newer theory suggests that the initial stimulus for migraine occurs within the brain itself, causing major semi-hemispherical cranial vasodilatation, while a sequence of events initiates the release of serotonin.


Serotonin -- also called 5-hydroxytryptamine, or 5-HT, is a naturally-occurring chemical that is widely distributed in the body. Serotonin has a broad spectrum of effects in the cardiovascular, respiratory, gastrointestinal and central nervous Systems. It influences the tissues in which it is stored by stimulating and interacting with various types of receptors on the individual tissues.

Receptors -- are specific proteins on the tissue surface to which the serotonin binds, thus triggering certain biological responses in the body. Several types of 5-HT receptors have been identified throughout the body. The body's reaction to serotonin is directly related to the nature of the specific type of serotonin receptor activated. For example, serotonin can cause nausea and pain in the head. Medications that are non-selective can affect all 5-HT receptors and, for instance, cause nausea while reducing migraine pain.

Note: Serotonin research has lead to the development of medications that are selective, designed to activate (agonists) or block (antagonists) serotonin's effect on a particular serotonin receptor.

Note: 5-HT1, the specific receptor thought to be involved in migraine, is found primarily in the cranial blood vessels and the nerves. During a migraine attack, it is thought that the serotonin level decreases, allowing blood vessels to dilate. This sequence causes surrounding tissues to swell, including nerve endings, which transmit impulses to the brain, resulting in the throbbing pain of migraine.

Breakthroughs in Migraine Treatment

While certain biological mechanisms of Migraine are still being studied, scientists do know much about what biological mechanisms initiate migraine attacks and ways to treat pain and associated symptoms. Significant treatment milestones have occurred within the past 50 years -- each new treatment having distinct advantages, as well as some limitations due to side effects. For example, because some treatments have vessel-constricting properties, they are not recommended for use by patients with cardiovascular conditions. In addition, over use of many medications can also cause drug rebound headache, a phenomenon that occurs when the medication itself actually causes or prolongs the duration of the headache.

The first treatment used specifically for migraine, ergotamine tartrate (ergot), was introduced in the 1940s and represented the first real relief for many sufferers. It acts by constricting blood vessels. Though it works on the serotonin system, it is non-selective in the receptors targeted, and as a result can cause nausea and vomiting. It does not treat the migraine associated symptoms. In some patients, it can also cause dependence.

The next treatment milestone came with dihydroergotamine mesylate (DHE), introduced in the 195Os. DHE is related to ergotamine, but does not cause dependence. It acts upon the serotonin system and constricts blood vessels. However, it is also non-selective and may affect other serotonin receptors, such as those in the gastrointestinal tract, causing diarrhea in approximately 50 percent of patients. DHE does not treat the associated symptoms of migraine.

It was not until the early 1990s that the next migraine medication, Imitrex, sumatriptan succinate (or sumatriptan), became available. It is the only selective agonist specifically targeted for the 5-HT1 receptor. As a 5-HT1 agonist, it mimics the action of serotonin at the 5-HT1 receptor site, constricting the dilated blood vessels, relaxing the pain and associated symptoms. Imitrex is indicated for the acute treatment of migraine attacks. It should only be used where a clear diagnosis of migraine has been established.


Information offered at this Web site by either a lay person or a health professional should not be interpreted as giving a diagnosis or a treatment recommendation. These can only be provided by a physician who has had an opportunity to interact with a patient in person and at length, with access to the patient's previous records and appropriate follow-up.