Pathophysiology of Medication Overuse Headache—An Update

Authors

  • Anan Srikiatkhachorn MD,

    Corresponding author
    1. Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
    • Address all correspondence to A. Srikiatkhachorn, Faculty of Medicine, Chulalongkorn University, Physiology, Rama IV Road, Pathumwan, Bangkok 10330, Thailand.

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  • Supang Maneesri le Grand PhD,

    1. Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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  • Weera Supornsilpchai PhD,

    1. Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
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  • Robin James Storer PhD

    1. Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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  • Conflict of Interest: None.

Abstract

The pathogenesis of medication overuse headache is unclear. Clinical and preclinical studies have consistently demonstrated increased excitability of neurons in the cerebral cortex and trigeminal system after medication overuse. Cortical hyperexcitability may facilitate the development of cortical spreading depression, while increased excitability of trigeminal neurons may facilitate the process of peripheral and central sensitization. These changes may be secondary to the derangement of central, probably serotonin (5-HT)-, and perhaps endocannabinoid-dependent or other, modulating systems. Increased expression of excitatory cortical 5-HT2A receptors may increase the susceptibility to developing cortical spreading depression, an analog of migraine aura. A reduction of diffuse noxious inhibitory controls may facilitate the process of central sensitization, activate the nociceptive facilitating system, or promote similar molecular mechanisms to those involved in kindling. Low 5-HT levels also increase the expression and release of calcitonin gene-related peptide from the trigeminal ganglion and sensitize trigeminal nociceptors. Thus, derangement of central modulation of the trigeminal system as a result of chronic medication use may increase sensitivity to pain perception and foster or reinforce medication overuse headache.

Overuse of symptomatic medications is a common problem observed in patients with primary headaches, especially migraine and tension-type headache. In addition to other adverse effects, prolonged use of these abortive compounds can produce the paradoxical effect of deteriorating the underlying headache pathophysiology. This results in a clinical syndrome known as “medication overuse headache” (MOH). According to the International Classification of Headache Disorders (2nd edition), MOH refers to the frequent headache condition (15 days per month or more) that occurs in patients with primary headaches who regularly use 1 or more acute and/or symptomatic drugs for more than 3 months.[1] This clinical syndrome is common. Population-based studies report the 1-year prevalence rate of MOH to be from 1% to 2%.[2] The relative frequency is much higher in secondary and tertiary care centers.[3] This disorder strongly affects the quality of life of patients and causes substantial economic burden.

There is no clear explanation of how chronic abortive drug exposure can increase headache frequency and result in MOH. Some possible mechanisms have been summarized in recent reviews.4-6 In this article, we review the recent studies, both clinical and preclinical, investigating the pathogenesis of this condition. Possible mechanisms underlying the process of medication-induced headache transformation are also proposed.

Some Clinical Clues

Some clinical features of MOH provide clues about its pathogenesis. First, MOH occurs mostly in patients with primary headaches. Chronic analgesic consumption rarely induces MOH in nonheadache patients.[7] This condition also occurs in headache-prone patients who regularly take analgesics for other indications. For instance, Wilkinson et al showed that migraine patients who regularly took opiates to control bowel motility developed chronic headache, while those without a history of migraine did not.[8] These observations suggest 2 things. Analgesic overuse is the cause of chronic headache, not the consequence; and MOH results from an interaction between an excessive use of abortive medication and a susceptible patient.

Second, MOH usually occurs in patients with migraine or tension-type headache. Although the pathogenesis of these 2 primary headaches has not yet been completely understood, it is widely accepted that both conditions are the result of an increase in excitability of neurons in the central nervous system. By contrast, MOH rarely occurs in patients with cranial neuralgias, a condition in which abnormalities in neuronal excitability of the peripheral nervous system play a major role. These observations imply that the mechanism underlying MOH is more likely to be an alteration of the central control system that modulates pain perception than an alteration in its peripheral nociceptive counterpart, although it could be that there are contributions from both peripheral and central systems.

Third, all classes of symptomatic medications, both migraine-specific (such as ergots and triptans) and nonspecific analgesics (such as opiates and non-narcotic analgesics), are able to cause MOH if they are used excessively.[9] Clinical features of MOH caused by these abortive agents are quite similar, but not necessarily identical. Because these drugs have different pharmacological actions, it is unlikely that MOH is caused by the specific action of any single causative agent. The more likely, but as yet unproven, explanation is that all drugs share some common mechanism in generating this phenomenon.

Finally, in addition to headache, patients with MOH also suffer from other clinical symptoms. These include depressed mood, sleep disturbance, and noncephalic body pain. MOH patients tend to have poor general health and poor quality of life.[10] These nonheadache manifestations imply that chronic analgesic consumption not only affects nociceptive and pain perception processes, but also alters neural pathways that control vegetative functions.

The clinical observations described above lead to the hypothesis that chronic medication may alter the central modulating system that controls nociception and other vegetative functions. This alteration may further affect the already vulnerable nervous systems of those with underlying primary headaches.

Possible Mechanisms Leading to MOH

Activation of the trigeminal system is an essential step in generating all forms of primary headaches. The primary afferents of trigeminal nociceptive fibers innervate pain-sensitive structures, including cranial vessels, meninges, and pericranial muscles and fascias. Activation of trigeminal nociceptive terminals stimulates the release of calcitonin gene-related peptide (CGRP). This neuropeptide can increase the sensitivity of perivascular nociceptors and dilate cranial vessels. Central axons of the trigeminal ganglionic (TG) neurons terminate onto second-order neurons in the trigeminocervical complex (TCC), which includes the trigeminal nucleus caudalis (TNC), and CGRP release here can facilitate neurotransmission of nociceptive trigeminovascular input.[11] Both TG and TCC neurons are highly plastic, physiologically and anatomically. Their responses can change according to the patterns of their input. Chronic activation modulates the transcription of several proteins that are involved in nociceptive transduction. These modifications result in long-lasting changes in neuronal activity. The increases in response of TG neurons (known as peripheral sensitization) and TCC neurons (known as central sensitization) play major roles in the development of throbbing headache and cutaneous allodynia developed during the attacks of migraine.[12]

The second-order neurons in the TCC convey intracranial nociceptive information to the ventral posteromedial nucleus of thalamus, which is proposed to act as a relay center conveying the nociceptive information to higher cortical pain processing regions, where it is interpreted.[13] Ascending trigeminal fibers also terminate in several brainstem areas, including the periaqueductal gray (PAG), brainstem reticular formation, and nucleus raphe. These brainstem structures form the complex network of the endogenous pain modulating system. The descending projections from these nuclei have a strong influence on nociceptive perception, while the ascending projections control the execution of several pain responsive behaviors via functional modification of several cortical and subcortical areas.

Alteration of various components of the trigeminal nociceptive system could contribute to an increase in headache frequency as seen in MOH. These alterations could include increased sensitivity of the peripheral and central trigeminal nociceptive neurons, increased excitability of cortical neurons, and derangement of the central endogenous control system.

Pathophysiological Changes in MOH—Clinical Evidence

Several lines of clinical evidence suggest the hypothesis of neuronal hyperexcitability as a mechanism underlying MOH. The conclusion arises from neurophysiological, functional imaging, and neurochemical studies, as described following. It should be noted that the number of patients in most of these studies was rather small. The interpretation and generalization of results must be considered cautiously.

Neurophysiology

Studies using clinical electrophysiological techniques indicate an increase in the neuronal excitability, at least in somatosensory and visual cortices, in patients with MOH.[14] For example, Ayzenberg et al showed that, in patients with MOH, sensory-evoked cortical potentials in response to electrical simulation on the forehead or limb were increased and became normalized after drug withdrawal.[15] Because this transient facilitation was found in both trigeminal and somatic nociceptive systems, it is more likely to be controlled by supraspinal mechanisms. The dysfunction of supraspinal diffuse noxious inhibitory controls was supported by the finding of a decrease in augmentation of nociceptive threshold induced by a cold pressor test.[16]

The finding of evoked-potential facilitation in MOH was confirmed by several subsequent studies. Coppola et al showed that patients with MOH had larger amplitude somatosensory-evoked potentials (SEP) than nonheadache controls, and lacked SEP habituation.[17] Using laser-evoked potentials to study habituation to nociceptive simulation, Ferraro et al showed that the deficient habituation was partly restored after successful treatment of MOH.[18] The observation of decreased magnetic suppression of perceptual accuracy implies an impairment of the cortical inhibitory process and may explain the increase in cortical excitability.[14] These findings suggest that sensory cortices become sensitized in patients with MOH. The patterns of SEP changes were determined by the type of causative drugs. Overconsumption of nonsteroidal anti-inflammatory drugs caused more pronounced effect on cortical inhibition as compared with triptans. Drug-induced changes in central serotonergic transmission have been proposed to underlie this change.[17, 19]

It should be noted that diminished inhibition causing a lack of habituation and increased cortical excitability has also been reported in patients with chronic migraine without medication overuse. Aurora et al compared phosphene thresholds and magnetic suppression of perceptual accuracy profiles among patients with episodic migraine, probable chronic migraine, and normal controls.[20] They found that patients with chronic migraine had the highest cortical excitability. Subsequent study using a magnetoencephalographic technique confirmed that, in chronic migraine patients, there was an increase in excitability of the visual cortex, which was normalized after successful treatment with topiramate.[21] Therefore, cortical hyperexcitability may reflect the increased tendency of having headache attacks. However, this change can be caused by a variety of influences and is not solely confined to medication overuse.

Imaging Studies

Functional imaging studies also lend support to the hypothesis of alteration in cortical excitability in MOH. Using fludeoxyglucose (F18) position emission tomography, Fumal et al demonstrated several areas of hypometabolism, including the bilateral thalamus, orbitofrontal cortex, anterior cingulate gyrus, insula/ventral striatum, and right inferior parietal lobule, in patients with MOH.[22] The metabolism of all areas normalized after medication withdrawal, except for the orbitofrontal cortex. This finding probably reflects the role of orbitofrontal cortex, a part of the limbic circuit, in medication dependence. Altered activities in several cortical areas in patients with MOH have been demonstrated by functional magnetic resonance imaging studies. MOH patients showed reduced pain-related activity across the primary somatosensory cortex, inferior parietal lobule, and supramarginal gyrus, as well as in regions of the lateral pathway of the pain matrix.[23, 24] Activity recovered to almost normal, 6 months after drug withdrawal. Anatomical study demonstrated changes in gray matter volume in many cortical and subcortical structures. The gray matter volume was found to be increased in the PAG, bilateral thalamus, and ventral striatum, and decreased in the frontal regions, including the orbitofrontal cortex, anterior cingulate cortex, the left and right insula, and the precuneus.[25] Because these areas are involved in pain perception, these observed abnormalities suggest an alteration in pain modulatory networks in patients with MOH.

Functional imaging studies also provide some information regarding the mechanisms underlying cortical excitability alteration. Patients with MOH had reduced task-related activity in the substantia nigra/ventral tegmental area complex and increased activity in the ventromedial prefrontal cortex when compared with controls.[26] The ventral tegmental area is a part of the brain reward circuit and might play a role in drug dependence. The alteration in brainstem activities has also been demonstrated in patients with chronic migraine. Welch et al reported an abnormal iron homeostasis in the PAG in chronic migraine patients.[27] Aurora et al demonstrated an increase in metabolism in the brainstem, while metabolism in the medial frontal, parietal, and the somatosensory cortex was decreased.[28] Connectivity between the PAG and several brain areas within nociceptive and somatosensory processing pathways is stronger in migraine patients. The strength of the connectivity increases as the headaches worsen. By contrast, connectivity between the PAG and brain regions with a predominant role in pain modulation (prefrontal cortex, anterior cingulate, and amygdala) decreases.[29] It is known that brainstem nuclei, especially the PAG and nucleus raphe, are parts of a central modulating system that has a strong influence on nervous system function. Therefore, alteration of these structures may alter the activity of cerebral cortices, and underlie the development of cortical hyperexcitability and the facilitation of the trigeminal nociceptive process. Noteworthy is that changes in brainstem activity have been demonstrated during the attacks of migraine.[30]

Neurochemical Changes

Several neurotransmitter systems are altered in patients with MOH. These include 5-HT, endocannabinoids, corticotrophin-releasing factor, and orexinA. In patients with MOH, platelet serotonin is decreased, and the density of 5-HT2A receptors on platelets was increased.[31, 32] This receptor upregulation was normalized after drug withdrawal.[33] Activity of the platelet serotonin transporter was increased in patients with analgesic- and triptan-induced MOH.[34] These findings suggest a suppression of 5-HT function in MOH.

The endocannabinoid system plays an important role in endogenous antinociception. This system antagonizes the development of neuronal sensitization in nociceptive pathways.[35] Activation of cannabinoid receptors inhibits neuronal transmission in the trigeminovascular system that has a primary role in primary head pain.36-38 Derangement in the endocannabinoid transmitter system has been reported in patients with MOH. Platelet levels of 2 endogenous cannabinoids, anandamide and 2-acylglycerol, were decreased and correlated with a reduction in 5-HT level.[39] The activity of the anandamide membrane transporter and fatty acid amide hydrolase, 2 proteins controlling the level of anandamide, was significantly reduced in MOH.[40] The change in endocannabinoid levels correlated with the facilitation of spinal cord pain processing. The enzymatic activity and pain facilitation were normalized after withdrawal treatment.[41] These findings support the potential involvement of a dysfunctioning of the endocannabinoid and serotonergic systems in the pathology of MOH.

Biochemical analysis of cerebrospinal fluid (CSF) found increased concentrations of orexinA and corticotropin-releasing factor in patients with MOH. The levels of both hormones correlated with the amount of monthly drug intake.[42] Patients overusing triptans had CSF glutamate levels lower than those in patients with chronic migraine without medication overuse, but higher than those in nonheadache controls.[43]

The anatomical, functional, and biochemical studies described above demonstrate the dysfunction of the endogenous pain control system, probably 5-HT- or endocannabinoid-dependent, in patients with MOH. Alteration of this control system may increase cortical excitability and facilitate pain perception. However, because several changes are also observed in chronic migraine patients without medication overuse, these changes may simply reflect the worsening of headache and may not imply much about the pathogenesis of MOH.

Effect of Chronic Medication on the Trigeminal Nociceptive System—Preclinical Evidence

The primary objective of preclinical studies is to determine how chronic medication affects the trigeminal nociceptive system and other brain areas involved in headache pathogenesis.

Effect on the Trigeminal Nociceptive System

Preclinical evidence shows that chronic exposure to opiates can facilitate the nociceptive process. Upregulation of CGRP has been observed in dorsal root ganglia after prolonged exposure to morphine.[44, 45] Sustained morphine exposure affects spinal glutamatergic transmission. Enhancement of glutamate release[46] and downregulation of spinal glutamate transporters[47] has been found after sustained morphine exposure. Expansion of cutaneous receptive fields and lower thresholds of dura-sensitive medullary dorsal horn neurons was observed in rats receiving sustained infusion of morphine.[48] Another mechanism underlying chronic opiate-mediated nociceptive exacerbation has been proposed as the activation of a toll-like receptor-4 on glial cells, resulting in a proinflammatory state.[49] This evidence indicates that chronic opiate exposure can lead to a persistent pronociceptive trigeminal neural adaptation.[50]

Prolonged exposure to triptans produces comparable changes in the sensory system. Enhancement of the CGRP and NO systems has been observed in animals treated with triptans. Chronic sumatriptan exposure produces long-lasting cutaneous tactile allodynia. This change corresponds with an increased number of CGRP-positive dural afferent neurons in the TG. Exposure to triptans increases CGRP levels in the blood after challenge by a nitric oxide donor.[51] CGRP can increase expression of the TRPV1 receptor, thus facilitating the nociceptive process.[52] In addition to increasing CGRP levels, chronic triptan exposure can increase the expression of neuronal nitric oxide synthase (nNOS) in the TG neurons innervating the dura in rats. The involvement of nNOS in generating allodynia was confirmed by the observation that cutaneous allodynia was reversed by NXN-323, a selective nNOS inhibitor.[53]

Effect on the Cerebral Cortex

Chronic medication can affect cerebral cortical activity. In rats, chronic exposure to acetaminophen increases the frequency of cortical spreading depression (CSD), an analog of migraine aura.[54] CSD-evoked increases of 5-HT2A serotonin receptor expression and c-Fos-immunoreactivity in the cerebral cortex and TNC have been found in rats after chronic acetaminophen treatment.[55] Increased CSD development and increased TNC c-Fos immunoreactivity were also shown in rats chronically treated with dihydroergotamine.[56] These findings suggest that chronic exposure to either antimigraine drugs or nonspecific analgesics can increase the excitability of cortical neurons, thus increasing susceptibility to develop CSD, facilitating the trigeminal nociceptive process.

Effect on Central Modulating System

Preclinical studies support clinical findings of an altered 5-HT system in patients with MOH. Chronic administration of acetaminophen resulted in the upregulation of 5-HT2A receptors in the cerebral cortex.[57] Changes in the expression of 5-HT receptors and transporters in several subcortical areas, including the PAG and the locus coeruleus, were also reported in animals after chronic triptan exposure.[58, 59]

A derangement in the endogenous 5-HT-dependent control system may underlie the cortical hyperexcitation and pain facilitation seen in MOH. Animals with decreased 5-HT levels show an increase in CSD susceptibility and CSD-evoked c-Fos expression in the TNC.[60] Inhibition of NO production can attenuate this cortical hyperexcitability.[61] Low levels of 5-HT may subsequently upregulate the expression of pronociceptive 5-HT2A receptors in the cortex and trigeminal system. Activation of this pronociceptive receptor can upregulate NOS expression[62] and increase susceptibility to CSD. Dysfunction of the 5-HT system also facilitates the trigeminal nociceptive process. The expression of c-Fos and phosphorylation of the NR1 NMDA-receptor subunit in TNC neurons evoked by meningeal inflammation is increased in animals with levels of 5-HT depleted by tryptophan hydroxylase inhibition.[63] Animals with depleted 5-HT levels also showed an increase in CGRP expression in the TG and an increase of CGRP release evoked by CSD.[64, 65]

The evidence presented above shows that the central modulating control has a strong influence on the function of the trigeminal system. Derangement of this control system, either decreasing nociceptive inhibition or increasing nociceptive facilitation, may enhance the process of central sensitization.

Conclusion: Pathogenesis of MOH—A Hypothesis

The clinical and preclinical studies described above indicate an increased excitability of neurons in the cerebral cortex and trigeminal system after chronic headache medication. The cortical hyperexcitability may increase the probability of developing CSD, while increased excitability of trigeminal neurons may facilitate peripheral and central sensitization. These changes may be secondary to the derangement of central, especially 5-HT-dependent, nociception modulating systems. The relative depletion of 5-HT by headache medication overuse subsequently upregulates the 5-HT2A receptor and changes intracellular signaling. Increased expression of cortical 5-HT2A receptors may increase susceptibility to CSD. Reduction of diffuse noxious inhibitory controls may facilitate the process of central sensitization, activate the nociceptive facilitating system, or promote the same molecular mechanisms that are involved in kindling.[66, 67] Low 5-HT levels increase the expression and release of CGRP from the TG and sensitize trigeminal nociceptors. Thus, derangement in the central pain modulating system as a result of chronic medication use may increase sensitivity to pain perception and foster or reinforce MOH.

Acknowledgments

This study was supported by the Neuroscience of Headache Research Unit, “Integrated Innovation Academic Center: IIAC”: 2012 Chulalongkorn University Centenary Academic Development Project, Chulalongkorn University, and the Ratchadapiseksompotch Fund from the Faculty of Medicine, Chulalongkorn University.

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