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Deepen Your Understanding of Headache

By Stephen D. Silberstein, MD

The current consensus is that the term chronic daily headache (CDH) refers to headache disorders experienced very frequently (15 or more days a month), including headaches associated with medication overuse. CDH can be divided into primary and secondary varieties.1 Studies in the United States, Europe and Asia suggest that four to five percent of the general population have primary CDH,2-4 and 0.5 percent have severe headaches daily.5-7

Once secondary headache, including medication overuse headache (MOH), has been excluded, frequent headache sufferers are subdivided into two groups, based on headache duration. When the duration is greater than four hours, the major primary disorders to consider are chronic migraine (CM), hemicrania continua (HC), chronic tension-type headache (CTTH) and new daily persistent headache (NDPH). CM, NDPH, and HC are primary CDH disorders that are now included in the 2nd IHS classification.8 Transformed migraine (TM) is similar, but not identical, to CM. Understanding and identifying the multifarious presentations that fall under the rubric of CDH is further complicated by its rather esoteric pathophysiology. In this article, we will look more closely at the mechanisms at work beneath the surface.

Pathophysiology Of Chronic Daily Headache

The trigeminal nucleus caudalis (TNC) of the trigeminal complex, the major relay nucleus for head and face pain, receives nociceptive input from cephalic blood vessels and pericranial muscles (via the trigeminal and upper cervical nerves)^A, as well as inhibitory and facilitatory suprasegmental input. The trigeminal nerve has three divisions: ophthalmic, mandibular and maxillary. Anterior pain-producing structures are innervated by the ophthalmic (first) division.^B  Posterior regions are subserved by the upper cervical nerves.9

Afferent processes of the trigeminal nerve converge to form the sensory root, entering the brain stem at the pontine level and terminating in the trigeminal brain stem nuclear complex, which is composed of the principal and the spinal trigeminal nuclei (subdivided into the nucleus oralis, the subnuclear interpolaris, and the nucleus caudalis). The brain stem spinal trigeminal nucleus is analogous to the dorsal horn of the spinal canal, the first synapse in the central nervous system.

Most spinothalamic and trigeminothalamic tract neurons that originate from the dorsal horn and project to ventroposterior lateral and ventroposterior medial nuclei have wide dynamic-range characteristics.10 The trigeminothalamic tract is analogous to the spinothalamic tract. Second-order neurons from the trigeminal spinal nuclei form the trigeminothalamic tract and project to other midbrain structures, as well as to the thalamic tract. Most ventroposterior medial nuclei, some with wide dynamic-range characteristics, respond to low-threshold stimuli.9 Recent evidence suggests that central pain facilitatory neurons (on-cells) are present in the ventromedial medulla. In addition, neurons in the TNC can be sensitized as a result of intense neuronal stimulation.

Pain has three spatiotemporal characteristics: (1) as intensity increases, the area in which it is experienced often enlarges (radiation); (2) pain may outlast the evoking stimulus; and (3) repeated nociceptive stimuli ^D may increase the perceived pain intensity, even without increased input (sensitization).11 Pain has both sensory and affective dimensions. In addition to being physically unpleasant, pain is associated with negative emotional feelings shaped by context, anticipations and attitudes.10 Pain unpleasantness is in series with pain sensation intensity.

Headache Pathophysiology
Pain in Migraine

Migraine most likely results from a dysfunction of the trigeminal nerve^E  and its central connections that normally modulate sensory input. Components involved include: (1) the cranial blood vessels and meninges; (2) the trigeminal innervation of the vessels and meninges; (3) the reflex connections of the trigeminal system with the cranial parasympathetic outflow; and (4) local and descending pain modulation.^F   The key pathway for the pain is trigeminovascular input from the meningeal vessels. Brain imaging studies suggest that important modulation of the trigeminovascular nociceptive input stems from the dorsal raphe nucleus, locus coeruleus and nucleus raphe magnus.12

Although the source of pain in CDH is unknown and may depend on the subtype, recent work suggests several mechanisms:

(1) increased peripheral nociceptive activation (perhaps due to chronic neurogenic inflammation) ^G and activation of silent nociceptors; (2) peripheral sensitization; (3) altered sensory neuron excitability due to changes in ion-channel expression/ phosphorylation/accumulation in primary afferents; (4) central sensitization of TNC neurons due to posttranslational changes in ligand- and voltage-gated ion-channel kinetics, altering excitability and strength of their synaptic inputs; (5) phenotype modulation due to alterations in the expression of receptors/transmitters/ion channels in peripheral and central neurons; (6) synaptic reorganization modification of synaptic connections caused by cell death or sprouting; (7) decreased pain modulation due to loss of local and descending input;11 or (8) a combination of these.

Peripheral Mechanisms

Although the brain itself is largely insensate, pain can be generated by large cranial vessels, proximal intracranial vessels or dura mater. The central convergence of the ophthalmic division of the trigeminal nerve and the branches of C2 nerve roots explain the typical distribution of migraine pain over the frontal and temporal regions and the referral of pain to the parietal, occipital and high cervical regions.12

During a migraine attack, an inflammatory process occurs in the meninges, at the site of the nerve terminal. Trigeminal nerve activation is accompanied by the release of vasoactive neuropeptides, including CGRP, substance P (SP) and neurokinin A from the nerve terminals. These mediators produce mast cell activation, sensitization of the nerve terminals and extravasation of fluid into the perivascular space around the dural blood vessels. Intense neuronal stimulation causes induction of c-fos (an immediate early gene product) in the TNC of the brainstem. SP and CGRP further amplify the trigeminal terminal sensitivity by stimulating the release of bradykinin and other inflammatory mediators from nonneuronal cells.13

Inflammatory mediators increase the responsiveness of and turn on silent, or sleeping, nociceptors. Neurotropins, such as nerve growth factor, are synthesized locally and can also activate mast cells and sensitive nerve terminals.14 Bradykinin and kallidin, both acting through the B1 and B2 receptors, can activate primary afferent nociceptors.15 Prostaglandins and nitric oxide (a diffusible gas that acts as a neurotransmitter)16 are both endogenous mediators that can be produced locally and can sensitize nociceptors. Cortical spreading depression (the cause of the aura) can activate the trigeminal system. Repeated episodes of neurogenic inflammation may chronically sensitize the pain pathways and contribute to the development of daily headache.

Sarchielli et al.17 measured CSF levels of nerve growth factor (NGF), CGRP and SP in patients with TM both with and without medication overuse. Higher NGF, CGRP and SP levels were found in CSF in both groups of patients compared with controls. A correlation was found between NGF and SP levels. All levels correlated with the duration of the disorder. This study suggests the involvement of NGF and chronic activation of the trigeminal vascular system in TM. NGF production could arise from peripheral trigeminal nerve terminals as well as the TNC and pain facilitating pathways. A study by Ashina et al.18 strongly suggests that patients with an elevated CGRP level had TM and that the trigeminal vascular system is activated as part of the process of TM.

Lance observed that during migraine attacks patients complain of increased pain with stimuli that would ordinarily be non-nociceptive. These stimuli include hair-brushing, wearing a hat and resting the head on a pillow. This phenomenon of pain being produced by non-painful stimuli is referred to as allodynia. In a series of now-classic experiments, Burstein et al.19 explored allodynia development in patients with migraine. He measured pain thresholds for hot, cold and pressure stimuli, both within the region of spontaneous pain and outside it. He found that as an attack progressed in a selected group of migraine sufferers, cutaneous allodynia developed in the region of pain and then outside it (extracephalic locations). He found that 33 of 42 patients (79 percent) developed allodynia. Allodynia began over the first half of the attack in those who eventually developed it.

Peripheral Sensitization. Sensitization of nociceptors results in an increased spontaneous neuronal discharge rate. Neurons show increased responsiveness to both painful and non-painful stimuli. The receptor fields expand and, as a result, pain is felt over a greater part of the dermatome. This results in hyperalgesia (increased sensitivity to pain) and cutaneous allodynia. An example of this is sunburn, with increased sensitivity to temperature (i.e., a warm shower feels painfully hot).

How does sensitization occur? Tissue injury^J  and inflammation result in the release of inflammatory mediators, such as prostaglandin E2, bradykinin and NGF. These substances act on G-protein-coupled receptors or tyrosine kinase receptors expressed on nociceptor terminals.^K  This activates intracellular signaling pathways, resulting in phosphorylation of receptors and ion channels. Phosphorylation changes the threshold and kinetics of the nociceptor terminals, producing increased sensitivity and excitability that results in peripheral sensitization.20 Transcriptional or translational regulation can also contribute to peripheral sensitization. NGF-induced activation of p38 mitogen-activated protein kinase in primary sensory neurons after peripheral inflammation increases the expression and peripheral transport of TRPV1 (a member of the transient receptor potential family), exacerbating heat hyperalgesia.21