[Miles E. Drake]

Headache is in almost all cultures and countries among the most common health complaint, and was one of the first conditions to be commented on in ancient medical literature. The great majority of headaches requiring medical attention are manifestations of migraine, which is today the best understood of the headache disorders. The many recent advances in understanding of headache physiology, pharmacological treatment of headache and application of biotechnology to the treatment of headache have been mostly in the area of migraine, which also represents most of the historical cases of headache.

Some of the earliest treatment recommendations for headache involved decompressive skull surgery (trepanation) and evidence of such procedures has been found from as early as 7000 BCE.

The Ebers papyrus from about 1500 BCE contains clinical descriptions of headache syndromes consistent with migraine, and the ancient Egyptians developed an extensive pharmacopoeia of herbal medicines, some of them still recommended for migraine.

Egyptian therapies also included:

• Rubbing the affected side of the head with a fried fish, which is difficult to reconcile with current headache medicine
  
• Binding tightly to the head a clay crocodile containing invocations to the relevant gods.
  

The latter was reported to be effective for chronic headache, and it is possible that the pressure of the linen strips holding to the vessel had a beneficial effect on tension-type headaches [1].

History of Headaches | Details

Hippocrates and Headache

• The Hippocratic school of ancient Greek medicine also devoted much attention to headache treatment.
  
• The “father of medicine (Hippocrates)” himself described the prodrome of migraine and the nausea and vomiting that is often associated with migraines and sometimes relieves them.
  
• Hippocrates also described the visual scotoma and some other manifestations of the migraine aura and observed the correlation between migraine and exercise, including “Immoderate venery”.
  Note: Immoderate venery means: sexual indulgence
  

The occurrence of nausea with migraine and the frequent relief of headache with vomiting led Hippocrates to ascribe the disorder to vapors rising to the head from the stomach, which although incorrect was the ancestor of the neurohumoral theory of migraine pathogenesis that predominates today.

In addition to Hippocrates and his disciples, the philosopher Plato often commented on medical topics. Although he was usually wrong when he opined about medicine, Plato did contribute one observation that is germane to headache treatment and to psychosomatic medicine generally:

he suggested that in some cases head pain was due to excessive preoccupation with the body and its symptoms [2].

Temples of Asklepios | Therapeutic Sleep and Headache aversion
Headaches were among the chief symptoms addressed by the priests at the temples of Asklepios, and were often treated by the Enkoiemesis or induction of therapeutic sleep, probably by opium, followed by a medicinal diet, both of which may have presaged acute pain management and holistic headache treatments of the present day.

Roman Medicine and Headache
The other precursor of the Western medical tradition in classical antiquity was Roman medicine, epitomized by Galen of Pergamon even though he himself was Greek.

Galen took an active interest in headaches, and was the first to use the term Hemicranias, from which “migraine” was derived.

• He also identified for the first time the meninges and cerebral blood vessels as the source of head pain, and ascribed pulsatile headache with vomiting, particularly marked in children, to the accumulation of bile in the stomach, giving rise to the still-used term, “bilious attacks”.
  
• Arataeus of Cappadocia, another Greek physician in the Roman Empire, at about the same time summarized the features of what are today called classical or common migraine, and distinguished three types of headache: generalized cephalalgia, unilateral and usually migrainous hemicranias and cephalea, headache not in a nerve or blood vessel distribution. Arataeus also advocated cauterization of the scalp and scalp muscle division for refractory headache, modern equivalents of which have lately been used in headache treatment [3].
  

Hemicranias continua means a persistent unilateral headache, the term from which word  “Migraine” was derived.

The word "migraine" combines the word "hemicranias" (which means half the head) and megrim, which in the 18th century meant low feeling on a whim.

Headache also received attention in eastern medical traditions. The second-century surgeon Hua To identified acupuncture points useful in treating head pain, and according to legend used acupuncture needles to remove a bulging frontal lesion from a patient suffering from pain between his eyes, after which a canary flew out. Other techniques of ancient Chinese medicine used for headache, such as cupping, the application to the skin of heated glass vessels containing a vacuum to remove toxins, and moxibustion, the first direct and later indirect application of heat and herbal remedies to the skin to rebalance qi or life energy, may date from the 16 [th] century BCE, and their principles are reflected today in western energy medicine and detoxification treatments [4].

The ancient Indian Ayurvedic medical tradition, like the Greeks, postulated that disease was caused by imbalance of doshas or humors. The system derived its name from the Sanskrit for “science of life” or “life knowledge”, and from its beginnings approximately 5,000 years ago emphasized individual variations in disease susceptibility and the role of lifestyle and diet in the production of disease. Headache and pain in general was often ascribed to excess of vata, the energy of movement that is often associated with nervous disease. Headache treatment focused on diet and natural remedies, and some of these techniques are applied today in western holistic medicine as well as Ayurvedic practice [5]. The North and South American “Indian” medical traditions are similar in their approach to headache and other nervous disorders, although sometimes different in the herbal remedies used on account of geography, and appear to have used ritual and spirituality as well as natural medications for several millennia before the arrival of Europeans [6].

As in many areas of medicine, the Islamic world preserved and extended some important ancient insights during the western Dark Ages. The 8 [th] and 9 [th] century medical writers Muhammad al-Razi and Muhammad al-Tabari extensively reviewed the writings of Hippocrates and Galen in their books, and Sabet ibn al-Harani wrote a comprehensive pain textbook which dealt with headache at the start of the 10 [th] century. al-Tabari differentiated migraine from other types of headache, presciently ascribed it to vascular inflammation and described two medical methods of treatment as well as cauterizing the temporal artery for focal temporal pain that may have represented arteritis. Ibn Sina or Avicenna described methods for preparing and testing the efficacy of medicine in his influential Canon of Medicine about a century later, and emphasized the role of exercise in disease treatment and prevention [7].

Byzantine treatments for headache began with purging and bloodletting, preferably from the side opposite to hemicranial headache, often copious and from the the cranial circulation by way of incisions in the nose as well as from the arm. The 1500 medical aphorisms of Maimonides include many concerning headache management, particularly bleeding from palpable pulsating vessels, presumably those involved in the pathogenic events of migraine which were to be clarified centuries later. Beginning with Arataeus, these physicians independently developed the technique of cupping that was being used in Chinese medicine. More benign recommendations of the time included the advice of Oribasius, physician and friend to several late western Roman emperors, to inject soft oil into the ear on the involved side, and the 10 [th] century recommendation by ibn Isa to bind a dead mole tightly to the head, recapitulating the ancient Egyptian method [8].

St. Hildegard of Bingen wrote medical texts in addition to being a philosopher, dramatist, composer and Benedictine abbess. She experienced scintillating visions that are now felt to have been ocular migraines, and described these in writing as well as with drawings that remain classic illustrations of migrainous aura. Her medical works do not reflect her visionary experiences but result from her extensive experience in her abbey’s medicinal garden, and as one of few women schooled in Latin in that day, she was able to write about herbal medicine in a way that most of the women who mainly practiced it at that time could not, and provided the basis for subsequent compendia of medical herbalism. A particular innovation in her recommendations was the application to the scalp of poultices soaked in vinegar and impregnated with opium; it is thought that the vinegar opened the pores of the scalp and facilitated the absorption of the opium [9].

Headache came under the purview of “neurology” when Thomas Willis introduced that term in 1672, and proposed that migraine was the result of cerebral vasodilation, and suggesting that migraine symptoms were correlated with slowly ascending spasms beginning in peripheral nerves and extending centrally. Erasmus Darwin, grandfather of Charles, proposed at the end of the 18 [th] century that patients be spun in a centrifuge in order to redistribute blood from the head to the feet to reduce cerebral vasodilation and head pain. More detailed headache classification was attempted during the 18 [th] century, with the first description of what was later called cluster headache given by van Swieten in 1745, and the differentiation of primary or idiopathic headache from symptomatic headache secondary to an identificable cause and the delineation of 84 headache syndromes by Baur in 1787 [10]. The distinction between migraines with prodromal symptoms, usually visual (migraine ophthalmique), and those without ( migraine vulgaire) was first proposed in 1887 by Louis-Hyacinthe Thomas, by profession a librarian but also a migraineur with keen observational powers [10].

While developing his system of homeopathic medicine in which substances causing a particular symptoms were used in great dilution to cure it, Samuel Hahnemann found that many vasodilatory compounds such as nitroglycerin (Glonoinum) were effective homeopathic remedies for migraine. This supported the predominant vascular theory, but that concept was challenged in 1863 by Edward Living’s treatise on “Megrim and Sick Headache”, which suggested that these represented brain dysfunction due to “nerve storms” that were related to epilepsy. Gowers’ first comprehensive English neurology text in 1888 endorsed this neu1rogenic view, and differentiated between intermittent treatments aimed at aborting attacks and continuous treatment intended to prevent them. He introduced the “Gowers solution” of nitroglycerin in alcohol that was one of the first examples of vasoactive therapy, along with the alkaloid of the ergot fungus that was first used in 1868. Gowers also advocated prophylactic treatment with Cannabis indica, presumably having a neural effect [11].

Headache research became more active and systematic in the 20 [th] century, beginning with the isolation of the therapeutically active ergot ingredient (ergotamine) in 1918 and the demonstration by Wolff and colleagues that the migraine aura corresponded to extracranial vasoconstriction and the headache to vasodilatation. The demonstration in 1941 that blood vessels and meninges were pain-sensitive but the brain itself was not supported the vascular theory, while Lashley’s description of his own migrainous scotomata in 1941 and the identification of cortical spreading depression by Leão in 1944 put in place crucial supports of the present view of the neural origin of migraine. The discovery of serotonin and the effects of a variety of serotoninergic drugs, particularly the demonstration in 1959 of the efficacy of methysergide against migraine, indicated the relationship between a particular neurotransmitter and what were still often called vascular headaches, and it became clear during this period that the correspondence of vasoconstriction with aura and vasodilatation with headache was not sufficient to explain migraines entirely. Spreading cerebral oligemia was demonstrated in migraine with aura by newer methods for measurement of cerebral blood flow in 1981, and oligemia was correlated with cortical spreading depression in animal models the following year. This led to the combination of the vascular and neurogenic theories in 1987 in order to explain migraine on the basis of “neurogenic inflammation”. This is the present consensus, and positron and functional MRI imaging has led to the identification of a probable brainstem migraine generator that sets this in motion. Recent interest has focused on the possibility that migraine may represent an ion channel disorder (channelopathy), and on the role of calcitonin gene-related peptide (CGRP) in the initiation of migraine attacks, while the identification and characterization of serotonin receptors has led to the development of sumatriptan and a dramatic expansion of the armamentarium for effective headache treatment [12].

EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF MIGRAINE

Migraine, which represents about 85 per cent of headaches requiring medical attention , and is ranked 19 [th] among diseases causing disability throughout the world by the World Health Association. In the United States, migraine is thought to affect about 30 million people, many of whom do not seek medical attention for this. The disorder is a particular source of impaired domestic function and workplace productivity, as it predominates during the productive years of 25 to 50, and is 3 times as common in women as among men. A recent study estimated that medical costs for migraine evaluation and treatment approach 2 billion dollars annually, while 13 billion dollars in productivity are lost on account of migraine.

As mentioned earlier, it was suggested in ancient times that the pain of migraine arose from the meningeal coverings and blood vessels of the brain. Harold Wolff elaborated a vascular theory of migraine in the 1940s, based in part on his personal experience with the disorder: he was apparently in the habit of massaging his temples, particularly when he felt the prodromal symptoms of a migraine attack, and noticed that the usually palpable temporal pulse disappeared when he was having a migraine aura but was bounding during the migraine itself, and coincided with the pulsing headache that he experienced. As the technique of cerebral angiography was more frequently used for headache evaluation, constriction of arteries was suggested before the onset of headache, while dilated vessels were seen during the migraine attack. Although most of the brain is insensitive to pain, its blood vessels are richly supplied with pain-sensitive nerve fibers. It was therefore suggested that constriction of the cerebral blood vessels and reduction of cerebral blood flow caused symptoms of migraine aura such as numbness, tingling or visual disturbance, and then led to compensatory dilation resulting in headache, either from edema or inflammation around the affected blood vessels that activated the surrounding nerve fibers [14] . This theory explained the initial premonitory symptoms and subsequent pulsatile headache of the migraine attack, as well as the effectiveness of caffeine, ergotamine and other therapies that constrict blood vessels. Two problems remained, however: most migraine sufferers do not have auras before their attacks, and newer methods of measuring cerebral blood flow have not shown the expected decrease in blood flow during pre-migraine symptoms and increase in blood flow with headache in those who do [15].

These problems and the increasingly-recognized association between migraine and central nervous system conditions like epilepsy and mood disorder have led to a neural theory of its cause. The experimental psychologist Karl Lashley suffered from migraine preceded by one of the most common auras, slow progression and then resolution of decreased vision, and in 1941 carefully mapped his visual loss and suggested that it represented slow inactivation spreading over his visual cortex at a rate of 3 to 5 mm per minute. Two years later, the Brazilian neurophysiologist A. A. P. Leão observed waves of neural hyperactivity followed by suppressed activity moving across the rabbit cerebral cortex at 3 to 4 mm per minute, and termed this “spreading depression”. It was suggested a decade later that the slowly-evolving migraine aura might be due to slowly-progressing spreading depression of the cerebral cortex, preceded by increased neural activity during the migraine headache [16].

The most prevalent view of the cause of migraine today is that genetically susceptible people may have or develop generator sites in the hypothalamus or brainstem (the periacqueductal gray matter of the midbrain) that cause or accentuate waves of spreading depression that may inactivate areas of cerebral cortex and cause auras. The rapid neural firing that occurs at the start of spreading stimulate the release of substances which cause a cascade of inflammation, dilation of cerebral blood vessels and activation of the autonomic nervous system. This makes nerve fibers, particularly branches of the trigeminal nerve which supplies the face and head, more sensitive to pain, and can result in nausea, vomiting and other associated symptoms of migraine. Spreading depression is attended by opening of potassium channels and outward flow of potassium, with a compensatory inward flow of sodium through sodium channels. The associated excitation of neurons results in the inflow of calcium through calcium channels and release of the excitatory transmitter glutamate. The increased neuronal activity also affects the release and reuptake of serotonin. This sequence of events would explain why migraine may be prevented by drugs which affect sodium and potassium channels and glutamate (anticonvulsants), medications which influence serotonin reuptake or bind to serotonin receptors (antidepressants and the migraine-specific triptans) and calcium channel- blocking drugs, as well as those which constrict cerebral blood vessels (ergots) [17].

The susceptibility to migraine is clearly inherited, but the inheritance is complex, with several genes and multiple other factors probably involved. Cortical spreading depression may be due to the abnormal function of ion channels in the cell membranes of neurons, and a number of rare “channelopathies” have been found, causing muscle disorders, seizure disorders, periodic paralysis and some forms of migraine. Familial hemiplegic migraine (FHM) causes migraine headaches with paralysis and is an autosomal dominant disorder (the gene is not carried by the sex chromosomes, and more or less everyone who inherits the gene gets the disorder): attacks of FHM are very similar to some kinds of migraine aura, and 3 causative gene mutations have been identified that result in malfunctioning sodium, potassium and calcium channels [18]. When more than one gene may be involved and the disorder in question is not dominantly inherited, so that some family members will have the gene but not have the disorder, the traditional genetic studies cannot be done, and this is the case for garden variety migraine, particularly migraine without aura. Such disorders can now be studied because the human genome has been essentially deciphered: the Human Genome Project completed the sequencing of human DNA in 2003, and the International HapMap project identified the common patterns of human genetic variation around 2005. The genomes of people with various diseases can be scanned with various markers and compared to the genomes of people without those diseases, in order to identify genetic variants that may be associated with the disease of interest. This is termed a genome-wide association study, and such studies in migraine have suggested 3 genes that regulate the excitatory neurotransmitter glutamate and one that codes for a protein involved in pain perception [19].

It is still uncertain how the molecular alterations of migraine result in inflammation and headache, but it may develop as follows. Cortical spreading depression, responsible for migraine aura, activates pain receptors (nociceptors) such as the protein described above, and this causes the release of chemical factors which dilate blood vessels and initiate inflammation. The trigeminal nerve, subserving sensation in the face and head, is particularly sensitive, and becomes more so as an attack progresses (“central sensitization”). Activation of trigeminal nerve C-fibers, the type which primarily transmit pain, results in the release of substance P (for pain), which causes aggregation of platelets and release of serotonin and thromboxane A2. Clumped platelets, serotonin and thromboxane then activate the production of prostaglandin and kinins (“neurogenic inflammation”) and result in the swelling of the brain’s dural lining, which stretches the pain-sensitive nerve fibers that surround the dural blood vessels and result in the characteristic throbbing pain [20].

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