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Jerome S. Schwartz, Andrew Blitzer,
Nwanmegha Young, and Brian E. Benson

Headaches are one of the most common patient complaints presented to physicians in the United States and a major cause of disability worldwide. Nearly 27.9 million of Americans suffer from moderate to severe migraine headaches, accounting for nearly 10 million physician visits annually.1,2 The debilitating nature of these disorders can result in significant loss of productivity, reduced social engagement, and poorer quality of life. Other associated neuropsychiatric conditions such as depression and anxiety complicate the morbidity. The socioeconomic burden can be measured in the billions of dollars incurred both direct (health care utilization) and indirect costs attributable to disability. Although the overwhelming majority of headache disorders are benign in nature, the fear of a more significant pathology (e.g., brain tumor or aneurysm) impacts both patients and physicians. Not surprisingly, physicians, particularly those who are unfamiliar with headache management, request extensive and often unnecessary diagnostic examinations in search of organic pathology, adding to health care costs.

Management of migraine headache continues to evolve as many of the traditional therapeutics have failed to effectively treat the disorder. Compliance with prophylactic and abortive medications remains low because of inadequate efficacy and intolerable adverse effects. There exists a great demand for long-acting acute and prophylactic therapies that are effective, well tolerated, and devoid of significant systemic toxicities. Interest in the use of botulinum neurotoxin (BoNT) injection as an alternative therapy for migraine headache has gained popularity, and in 2010 BoNT/A was approved by the Food and Drug Administration (FDA) for the prophylactic treatment of chronic migraine. Although the basic pharmacologic activity of the BoNT molecule is fairly well understood, the mechanism of action in headache prevention remains unclear. This chapter discusses the pharmacologic activity, proposed mechanisms of action, safety, and dosing of BoNT therapy for migraine headache.

Cephalalgia, or headache, has plagued human beings since the beginning of time. The earliest available reference to a migraine-type headache was recorded among the Sumerian poems ca. 3000 BC, which described an individual as being “sick-headed.”3 The first reports of a patient describing altered visual perceptions, or aura, came from Hippocrates. During the second century AD, Aretaeus of Cappadocia delineated the symptom structure of what is commonly referred to as migraine with aura.⁴ More recently, scientific theories to explain the pathophysiology of migraine headaches have emerged. Liveing is credited with the origination of the neural theory, purporting that certain “disturbances” within the autonomic nervous system may account for the triggering and sustenance of the headache. Dey subsequently described the phenomenon of cyclical pituitary compression of the trigeminal nerve.³ In the 20th century, Harold Wolff, through experimental evidence, described a phenomenon of episodic extracranial vascular dilatation and constriction. His insights ultimately contributed to the formulation of the vasogenic theory of migraine.³

The word headache is used variously as a descriptive term, a symptom, and a disorder. The need for a formal headache classification schema arose to facilitate the diagnostic evaluation, communication and development of effective therapeutic modalities. The International Headache Society (IHS) published a classification system in 1988, the International Classification for Headache Disorders (ICHD-1), which categorized the major headache types, and distinguished primary from secondary headache disorders.⁵ Revised in 2003, the ICHD-2 defined a primary headache disorder as one for which no identifiable structural or organic cause is known (e.g., migraine and tension headaches). A secondary headache disorder required a known structural or systemic etiology as the cause of the headache symptom.⁶ Although the ICHD classification system has undergone much scrutiny, it nevertheless provides a basic structure upon which to initiate a rational approach to headache management.

The spectrum of migraine headache disorders has been coded by the IHS into six accepted subtypes, with notable sub-forms (Table 14.1). Migraine can be classified into two major subtypes, namely, with or without aura. Migraine without aura is the most prevalent migraine sub-type, and may involve a higher frequency of attacks and greater disability than migraine with aura. The majority of common migraine headache patterns are considered episodic, to differentiate from the complicated subform of chronic migraine (classification code 1.5.1). The diagnosis of chronic migraine requires that the diagnostic criteria for migraine are met, with at least 15 or more headache days per month, for at least 3 months, in the absence of medication overuse.

Table 14.1 Classification of Migraine Headache Disorders

Headaches account for 1 to 2% of all emergency room visits, with migraine making up nearly 40% of headache-related visits.7 Nearly 18% of women and 6% of men are affected in the United States; however, these estimates may underreport the true incidence of disease as many patients go undiagnosed. The disorder most commonly affects individuals between the ages of 25 and 55.⁸ Migraine is among the leading causes for missed days at work. Lost productivity at work or school, decreased quality of life, and familial and social dysfunction increase the risk of affective disorders among these patients.^9,10

Migraine is a paroxysmal headache disorder, with periods of relative quiescence between acute headache episodes. The International Headache Society put forth the criteria for diagnosis of migraine without aura (Table 14.2). Headaches typically manifest with moderate to severe throbbing head pain lasting hours to days, in a hemicranial, fronto-temporal distribution; however, bilateral and posterior cervical pain can occur. Associated symptoms may include nausea, vomiting, anorexia, malaise, photo-or phonophobia, and blurred vision. Peculiar, transient neurosensory perceptions prior to or concomitant with the pain phase occur in migraine with aura. Headaches have been associated with in-take of certain foods (meats and cheeses [high nitrites], nuts, chocolate), alcohol ingestion, caffeine withdrawal, menstruation, bright lights, and exercise. Patients often seek a dark, quiet environment for symptom relief.

Table 14.2 Criteria for Diagnosis of Migraine Without Aura

According to the vasospasm–vasodilatation theory, changes in both intra- and extracranial arterial diameter mediate the symptoms of migraine. Oligemia through extracranial vessels (e.g., the frontal branch of superficial temporal artery) becomes evident during the headache’s prodrome and persists into the early headache phase. As the pain phase begins, vessel diameters and cerebral blood flow increase. The resulting hyperemia may persist throughout the duration of the pain phase. Compression of the superficial temporal or carotid artery during this phase has occasionally provided mild pain relief. This headache model prompted trials of peripheral vasoconstricting agents as a pharmacologic means to control migraine-induced pain. Vasoconstrictors and antiplasma extravasation agents such as caffeine, serotonergic 5-HT1B/1D receptor agonists (triptans), and the nonselective serotonergic agonists (ergot alkaloids) have all been used acutely with variable success in treating migraine.

Autonomic pathways via the facial nerve efferents, mediated through the pterygopalatine and otic ganglia, may alter both intra- and extracranial vascular tone, resulting in vasodilation. Numerous neuropeptides released from parasympathetic nerve terminals are believed to affect vascular smooth muscle contraction. Of these, vasoactive intestinal polypeptide (VIP) has been histologically demonstrated within the terminal nerve endings associated with extracranial vessels supplying the tongue, salivary gland, and nose.11,12 Antibodies directed against VIP appear to block the neurogenic vasodilatory response following electrical stimulation of the locus ceruleus or pterygopalatine ganglion. In addition, VIP release into the extracranial circulation has been observed following trigeminoneurovascular stimulation.¹³

Neuromodulators have also been found in the cell bodies of trigeminal nerve afferents, particularly near the trigeminal ganglion. The neurogenic inflammation theory attributes ongoing pain to peripheral sensitization and chemosensitization. These inflammatory events appear to be regulated by neuropeptide release from trigeminal afferents. Substance P and calcitonin gene-related peptide (CGRP) are among those that have been studied.¹⁴ Serum levels of CGRP taken from the external jugular vein during the headache phase of migraine are elevated.¹⁵ Similarly, stimulation of the trigeminal ganglion as well as the superior sagittal sinus (both of which induce headache when stimulated) releases CGRP into plasma.¹⁶ These inflammatory mediators, along with histamine and neurokinin A, may subsequently create a cascade of events including plasma extravasation, mast cell degranulation, and further vasodilation.

Central pain modulators in the central nervous system (CNS) also appear to exert influence on headache. Although the exact mechanisms are unclear, it appears that neurotransmitter release may affect pain thresholds by increasing or decreasing responses to afferent nociceptive signals. Clinical evidence also suggests that serotonergic hyperactivity in the CNS modulates pain processing in the brainstem.¹⁷ Astrocytes and glial supportive cells have been purported to affect central pain transmission. It is likely that a combination of complex interactions, both peripherally and centrally, yield a final common pathway of neurovascular irritation and CNS signal modification.

Table 14.3 Important Headache Descriptors to be Elicited

The correct diagnosis of patients presenting with chronic head and facial pain requires a systematic approach to obtaining the necessary information. At times this may be difficult because the patient’s global anxiety, feelings of helplessness, and other mood disorders may complicate the physician’s findings. A careful interview and documentation of the complete headache history and examination can aid in reaching the correct diagnosis and classification. Table 14.3 highlights important headache descriptors to be elicited.

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