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Headaches are estimated to affect over 90% of the general population at some time in their lives1 and may be encountered by physicians in a wide variety of clinical settings. The overwhelming majority of recurrent headaches occur in the context of what are known as primary headache disorders, in which no identifiable underlying cause can be found. Some headaches, however, classified as secondary headache disorders, are symptomatic of an underlying abnormality that may include anything from transient viral illness, to intracranial tumor, aneurysm, or drug withdrawal (for differential diagnosis of secondary headache disorder, see Cutrer2). Prevalence studies indicate that a benign process, such as a mild febrile illness or alcohol withdrawal, usually causes secondary headaches and that the lifetime prevalence of headache resulting from more ominous intracranial structural lesions is less than 2%.3


Head pain occurs when nociceptive neurons within the trigeminal, vagus, or glossopharyngeal cranial nerves or within the upper cervical roots become depolarized. Information from procedures involving intracerebral electrode implantation suggests that direct electrical or mechanical activation of areas within the brain involved in pain processing may also cause head pain.4 The causes of head pain vary widely and include not only direct mechanical, chemical, or inflammatory stimulation of pain-generating structures but also less well-characterized events that occur in primary headache disorders. Once initiated, the transmission and processing of the painful information is likely to be quite similar regardless of the inciting cause. In this chapter, we first review the anatomy involved in generating generic head pain and then discuss current theories of the pathophysiology of the major primary headache disorders, including migraine, cluster headache, and tension-type headache.


Under normal physiologic conditions, the brain is largely insensate. This has been demonstrated in neurosurgical procedures in which stimulation of the brain parenchyma in awake patients caused no pain.5,6 Head pain is mediated by projections from the trigeminal and upper cervical dorsal root ganglia, which innervate the pial, dural, and extracranial blood vessels. In general, these pseudounipolar neurons innervate the vessels on the same side, which can explain the unilateral distribution of pain in certain headache types, but some of the cells project bilaterally to innervate midline vessels. On activation, these unmyelinated C fibers transmit nociceptive information from perivascular terminals through the trigeminal ganglia7 to project centrally to synapses on second-order neurons within the trigeminal nucleus caudalis. The primary neurotransmitter for the C fibers is glutamate, but the primary afferents also co-store substance P, calcitonin gene–related peptide and neurokinin A, as well as other neurotransmitters and neuromodulators, in their central and peripheral (e.g., meningeal) axons.


Activity in the trigeminal nucleus caudalis can be modulated by projections from rostral trigeminal nuclei,8 the periaqueductal gray matter, and the nucleus raphe magnus,9 as well as by descending cortical inhibitory systems.9,10 From the trigeminal nucleus caudalis, second-order neurons transmit the nociceptive information, projecting to numerous subcortical ...

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