Headache is a condition that affects 90% of the population at some point in their lives. The disorder is the seventh most common chief complaint in primary care offices and costs society more than $13 billion annually.1,2 Much of the pathophysiology of headache has remained unclear, but as additional research is compiled and the mechanisms underlying headache are identified, options for treating the disorder are improving.
Pathophysiology
While much of the pathophysiology of primary headaches remains a mystery, recent research has provided clinicians with the knowledge to more accurately diagnose and treat these disorders. Current understanding has moved beyond earlier theories that headaches are strictly vascular (migraine) or muscular (tension) in origin.3-6
The cause: Trigeminovascular stimulation
Recent studies support the concept that stimulation of the trigeminovascular system causes most headaches (see Figure 1). Peripheral stimulus activates the nerves entering the trigeminal nucleus claudalis (TNC), altering the sensitivity and lowering the threshold of activation of the trigeminal circuit. This process is referred to as central sensitization. Serotonin (5-hydroxytriptamine, or 5-HT) mediates homeostasis of the trigeminal system.3,4 Consequently, low levels of serotonin lead to central sensitization of the TNC, with several effects.
First, this stimulation causes activation of 5-HT1D receptors, causing a release of vasodilating neuropeptides such as substance P and calcitonin gene-related peptide (CGRP). Release of these vasopeptides results in the dilation of meningeal vessels via the 5-HT1B receptors.5,7,8 Dilation of the meningeal vessels causes tension and stretch on the nerves surrounding the vessels, producing depolarization and thus activation of these nerves, which the patient experiences as pain. The lowered stimulation threshold of the TNC also can cause stimulation of the trigeminal nerve. This nerve has three branches: ophthalmic (V1), maxillary (V2), and mandibular (V3). Trigeminal nerve stimulation explains the symptoms that are often associated with headaches, such as auras (V1), sinus pain and pressure (V2), and temporomandibular joint (TMJ) pain (V3). Finally, the TNC has upper cervical spine dermatome neurons that, when stimulated, can be perceived as neck pain, another common symptom associated with primary headaches.3,7
Convergence theory The mechanisms mentioned previously have been used specifically to describe the pathophysiology of migraine headaches, but many headache experts support the convergence theory, which hypothesizes that one underlying pathologic process exists for primary headache. This theory suggests that the difference in primary headache diagnosis depends on how far in the pathologic process the headache proceeds and to what degree the trigeminal system is activated before being stabilized by the brain's homeostatic mechanisms. At this point the convergence theory is not supported by research.2,3
Other etiologies
Other factors have also been associated with headache etiology, including estrogen, genetics, and environmental 
and behavioral factors. Experts think that estrogen is associated with headaches, specifically migraines, because observational studies show that the intensity and frequency of headaches in women typically increase after puberty and diminish after menopause. Additionally, the occurrence of headache is equal among males and females until puberty, after which women are about three times more likely to have migraine headaches than are men.4 As a result of these two observations, along with the ability of estrogen to affect serotonin-producing neurons, estrogen has been speculated to play a role in the etiology of headache.2,4
Genetics Children of parents who both suffer from migraine headaches are at a 75% greater risk of having migraines as compared to children whose parents do not have migraines. Even those persons with a distant relative who suffers from migraines have a 20% increased migraine risk.4
Finally, environmental and behavioral factors can trigger headaches (see Table 1). Triggers are not always obvious to the patient, and asking the person to keep a headache diary may be useful in identifying what they are.4