HEADACHE CURRENTS—BASIC SCIENCE REVIEW

Pathophysiology of Medication Overuse Headache—An UpdateAnan Srikiatkhachorn, MD; Supang Maneesri le Grand, PhD; Weera Supornsilpchai, PhD; Robin James Storer, PhD

The pathogenesis of medication overuse headache is unclear.Clinical and preclinical studies have consistently demonstratedincreased excitability of neurons in the cerebral cortex andtrigeminal system after medication overuse. Corticalhyperexcitability may facilitate the development of corticalspreading depression, while increased excitability of trigeminalneurons may facilitate the process of peripheral and centralsensitization. These changes may be secondary to thederangement of central, probably serotonin (5-HT)-, andperhaps endocannabinoid-dependent or other, modulatingsystems. Increased expression of excitatory cortical 5-HT2A

receptors may increase the susceptibility to developing corticalspreading depression, an analog of migraine aura. A reduction ofdiffuse noxious inhibitory controls may facilitate the process ofcentral sensitization, activate the nociceptive facilitating system,or promote similar molecular mechanisms to those involved inkindling. Low 5-HT levels also increase the expression andrelease of calcitonin gene-related peptide from the trigeminalganglion and sensitize trigeminal nociceptors. Thus, derangementof central modulation of the trigeminal system as a result ofchronic medication use may increase sensitivity to painperception and foster or reinforce medication overuse headache.

Keywords: medication overuse headache, serotonin, trigeminal system, sen-sitization, endogenous pain control system, diffuse noxious inhibitory control

Overuse of symptomatic medications is a common problemobserved in patients with primary headaches, especially migraineand tension-type headache. In addition to other adverse effects,prolonged use of these abortive compounds can produce theparadoxical effect of deteriorating the underlying headachepathophysiology. This results in a clinical syndrome known as“medication overuse headache” (MOH). According to the Inter-national Classification of Headache Disorders (2nd edition),MOH refers to the frequent headache condition (15 days permonth or more) that occurs in patients with primary headacheswho regularly use 1 or more acute and/or symptomatic drugs formore 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 muchhigher in secondary and tertiary care centers.3 This disorderstrongly affects the quality of life of patients and causes substan-tial economic burden.

There is no clear explanation of how chronic abortive drugexposure can increase headache frequency and result in MOH.Some possible mechanisms have been summarized in recentreviews.4-6 In this article, we review the recent studies, bothclinical and preclinical, investigating the pathogenesis of thiscondition. Possible mechanisms underlying the process ofmedication-induced headache transformation are also proposed.

SOME CLINICAL CLUESSome clinical features of MOH provide clues about its patho-genesis. First, MOH occurs mostly in patients with primaryheadaches. Chronic analgesic consumption rarely induces MOHin nonheadache patients.7 This condition also occurs inheadache-prone patients who regularly take analgesics for otherindications. For instance, Wilkinson et al showed that migrainepatients who regularly took opiates to control bowel motilitydeveloped chronic headache, while those without a history ofmigraine did not.8 These observations suggest 2 things. Analgesicoveruse is the cause of chronic headache, not the consequence;and MOH results from an interaction between an excessive use ofabortive medication and a susceptible patient.

Second, MOH usually occurs in patients with migraine ortension-type headache. Although the pathogenesis of these 2primary headaches has not yet been completely understood, it iswidely accepted that both conditions are the result of an increasein excitability of neurons in the central nervous system. By con-trast, MOH rarely occurs in patients with cranial neuralgias, acondition in which abnormalities in neuronal excitability of theperipheral nervous system play a major role. These observationsimply that the mechanism underlying MOH is more likely to bean alteration of the central control system that modulates painperception than an alteration in its peripheral nociceptive coun-terpart, although it could be that there are contributions fromboth 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 causeMOH if they are used excessively.9 Clinical features of MOHcaused by these abortive agents are quite similar, but not necessar-ily identical. Because these drugs have different pharmacological

From the Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok,Thailand (A. Srikiatkhachorn and R.J. Storer); Department of Pathology, Faculty of Medicine,Chulalongkorn University, Bangkok, Thailand (S.M. le Grand); Department of Physiology,Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand (W. Supornsilpchai).Address all correspondence to A. Srikiatkhachorn, Faculty of Medicine, Chulalongkorn Univer-sity, Physiology, Rama IV Road, Pathumwan, Bangkok 10330, Thailand.Accepted for publication August 18, 2013..............Headache© 2013 American Headache Society

.............Conflict of Interest: None.

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actions, it is unlikely that MOH is caused by the specific action ofany single causative agent. The more likely, but as yet unproven,explanation is that all drugs share some common mechanism ingenerating this phenomenon.

Finally, in addition to headache, patients with MOH alsosuffer from other clinical symptoms. These include depressedmood, sleep disturbance, and noncephalic body pain. MOHpatients tend to have poor general health and poor quality oflife.10 These nonheadache manifestations imply that chronicanalgesic consumption not only affects nociceptive and painperception processes, but also alters neural pathways that controlvegetative functions.

The clinical observations described above lead to the hypoth-esis that chronic medication may alter the central modulatingsystem that controls nociception and other vegetative functions.This alteration may further affect the already vulnerable nervoussystems of those with underlying primary headaches.

POSSIBLE MECHANISMS LEADING TO MOHActivation of the trigeminal system is an essential step in gener-ating all forms of primary headaches. The primary afferents oftrigeminal nociceptive fibers innervate pain-sensitive structures,including cranial vessels, meninges, and pericranial muscles andfascias. Activation of trigeminal nociceptive terminals stimulatesthe release of calcitonin gene-related peptide (CGRP). This neu-ropeptide can increase the sensitivity of perivascular nociceptorsand dilate cranial vessels. Central axons of the trigeminal gangli-onic (TG) neurons terminate onto second-order neurons in thetrigeminocervical complex (TCC), which includes the trigeminalnucleus caudalis (TNC), and CGRP release here can facilitateneurotransmission of nociceptive trigeminovascular input.11

Both TG and TCC neurons are highly plastic, physiologicallyand anatomically. Their responses can change according to thepatterns of their input. Chronic activation modulates the tran-scription of several proteins that are involved in nociceptivetransduction. These modifications result in long-lasting changesin neuronal activity. The increases in response of TG neurons(known as peripheral sensitization) and TCC neurons (known ascentral sensitization) play major roles in the development ofthrobbing headache and cutaneous allodynia developed duringthe attacks of migraine.12

The second-order neurons in the TCC convey intracranialnociceptive information to the ventral posteromedial nucleus ofthalamus, which is proposed to act as a relay center conveying thenociceptive information to higher cortical pain processingregions, where it is interpreted.13 Ascending trigeminal fibers alsoterminate in several brainstem areas, including the periaqueduc-tal gray (PAG), brainstem reticular formation, and nucleus raphe.These brainstem structures form the complex network of theendogenous pain modulating system. The descending projec-tions from these nuclei have a strong influence on nociceptiveperception, while the ascending projections control the execution

of several pain responsive behaviors via functional modificationof several cortical and subcortical areas.

Alteration of various components of the trigeminal nociceptivesystem could contribute to an increase in headache frequency asseen in MOH. These alterations could include increased sensi-tivity of the peripheral and central trigeminal nociceptiveneurons, increased excitability of cortical neurons, and derange-ment of the central endogenous control system.

PATHOPHYSIOLOGICAL CHANGES IN MOH—CLINICAL EVIDENCESeveral lines of clinical evidence suggest the hypothesis of neu-ronal hyperexcitability as a mechanism underlying MOH. Theconclusion arises from neurophysiological, functional imaging,and neurochemical studies, as described following. It should benoted that the number of patients in most of these studies wasrather small. The interpretation and generalization of resultsmust be considered cautiously.

NeurophysiologyStudies using clinical electrophysiological techniques indicate anincrease in the neuronal excitability, at least in somatosensory andvisual cortices, in patients with MOH.14 For example, Ayzenberget al showed that, in patients with MOH, sensory-evoked corticalpotentials in response to electrical simulation on the forehead orlimb were increased and became normalized after drug with-drawal.15 Because this transient facilitation was found in bothtrigeminal and somatic nociceptive systems, it is more likely to becontrolled by supraspinal mechanisms. The dysfunction of supra-spinal diffuse noxious inhibitory controls was supported by thefinding of a decrease in augmentation of nociceptive thresholdinduced by a cold pressor test.16

The finding of evoked-potential facilitation in MOH wasconfirmed by several subsequent studies. Coppola et al showedthat patients with MOH had larger amplitude somatosensory-evoked potentials (SEP) than nonheadache controls, and lackedSEP habituation.17 Using laser-evoked potentials to study habitu-ation to nociceptive simulation, Ferraro et al showed that thedeficient habituation was partly restored after successful treat-ment of MOH.18 The observation of decreased magnetic sup-pression of perceptual accuracy implies an impairment of thecortical inhibitory process and may explain the increase in cor-tical excitability.14 These findings suggest that sensory corticesbecome sensitized in patients with MOH. The patterns of SEPchanges were determined by the type of causative drugs. Over-consumption of nonsteroidal anti-inflammatory drugs causedmore pronounced effect on cortical inhibition as compared withtriptans. Drug-induced changes in central serotonergic transmis-sion have been proposed to underlie this change.17,19

It should be noted that diminished inhibition causing a lack ofhabituation and increased cortical excitability has also beenreported in patients with chronic migraine without medication

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overuse. Aurora et al compared phosphene thresholds and mag-netic suppression of perceptual accuracy profiles among patientswith episodic migraine, probable chronic migraine, and normalcontrols.20 They found that patients with chronic migraine hadthe highest cortical excitability. Subsequent study using a mag-netoencephalographic technique confirmed that, in chronicmigraine patients, there was an increase in excitability of thevisual cortex, which was normalized after successful treatmentwith topiramate.21 Therefore, cortical hyperexcitability mayreflect the increased tendency of having headache attacks.However, this change can be caused by a variety of influences andis not solely confined to medication overuse.

Imaging StudiesFunctional imaging studies also lend support to the hypothesis ofalteration in cortical excitability in MOH. Using fludeoxyglucose(F18) position emission tomography, Fumal et al demonstratedseveral areas of hypometabolism, including the bilateral thalamus,orbitofrontal cortex, anterior cingulate gyrus, insula/ventral stria-tum, and right inferior parietal lobule, in patients with MOH.22

The metabolism of all areas normalized after medication with-drawal, except for the orbitofrontal cortex. This finding probablyreflects the role of orbitofrontal cortex, a part of the limbic circuit,in medication dependence. Altered activities in several corticalareas in patients with MOH have been demonstrated by func-tional magnetic resonance imaging studies. MOH patientsshowed reduced pain-related activity across the primary somato-sensory 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 with-drawal. Anatomical study demonstrated changes in gray mattervolume in many cortical and subcortical structures. The graymatter volume was found to be increased in the PAG, bilateralthalamus, and ventral striatum, and decreased in the frontalregions, including the orbitofrontal cortex, anterior cingulatecortex, the left and right insula, and the precuneus.25 Because theseareas are involved in pain perception, these observed abnormalitiessuggest an alteration in pain modulatory networks in patients withMOH.

Functional imaging studies also provide some informationregarding the mechanisms underlying cortical excitability altera-tion. Patients with MOH had reduced task-related activity in thesubstantia nigra/ventral tegmental area complex and increasedactivity in the ventromedial prefrontal cortex when comparedwith controls.26 The ventral tegmental area is a part of the brainreward circuit and might play a role in drug dependence. Thealteration in brainstem activities has also been demonstrated inpatients with chronic migraine. Welch et al reported an abnormaliron homeostasis in the PAG in chronic migraine patients.27

Aurora et al demonstrated an increase in metabolism in the brain-stem, while metabolism in the medial frontal, parietal, and thesomatosensory cortex was decreased.28 Connectivity between the

PAG and several brain areas within nociceptive and somatosensoryprocessing pathways is stronger in migraine patients. The strengthof the connectivity increases as the headaches worsen. By contrast,connectivity between the PAG and brain regions with a predomi-nant role in pain modulation (prefrontal cortex, anterior cingu-late, and amygdala) decreases.29 It is known that brainstem nuclei,especially the PAG and nucleus raphe, are parts of a centralmodulating system that has a strong influence on nervous systemfunction. Therefore, alteration of these structures may alter theactivity of cerebral cortices, and underlie the development ofcortical hyperexcitability and the facilitation of the trigeminalnociceptive process. Noteworthy is that changes in brainstemactivity have been demonstrated during the attacks of migraine.30

Neurochemical ChangesSeveral neurotransmitter systems are altered in patients withMOH. These include 5-HT, endocannabinoids, corticotrophin-releasing factor, and orexinA. In patients with MOH, plateletserotonin is decreased, and the density of 5-HT2A receptors onplatelets was increased.31,32 This receptor upregulation was nor-malized after drug withdrawal.33 Activity of the platelet serotonintransporter was increased in patients with analgesic- and triptan-induced MOH.34 These findings suggest a suppression of 5-HTfunction in MOH.

The endocannabinoid system plays an important role inendogenous antinociception. This system antagonizes the devel-opment of neuronal sensitization in nociceptive pathways.35 Acti-vation of cannabinoid receptors inhibits neuronal transmission inthe trigeminovascular system that has a primary role in primaryhead pain.36-38 Derangement in the endocannabinoid transmittersystem has been reported in patients with MOH. Platelet levels of2 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 fattyacid amide hydrolase, 2 proteins controlling the level of ananda-mide, was significantly reduced in MOH.40 The change in endo-cannabinoid levels correlated with the facilitation of spinal cordpain processing. The enzymatic activity and pain facilitation werenormalized after withdrawal treatment.41 These findings supportthe potential involvement of a dysfunctioning of the endocan-nabinoid and serotonergic systems in the pathology of MOH.

Biochemical analysis of cerebrospinal fluid (CSF) foundincreased concentrations of orexinA and corticotropin-releasingfactor in patients with MOH. The levels of both hormonescorrelated with the amount of monthly drug intake.42 Patientsoverusing triptans had CSF glutamate levels lower than those inpatients with chronic migraine without medication overuse, buthigher than those in nonheadache controls.43

The anatomical, functional, and biochemical studies describedabove demonstrate the dysfunction of the endogenous paincontrol system, probably 5-HT- or endocannabinoid-dependent,in patients with MOH. Alteration of this control system may

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increase cortical excitability and facilitate pain perception.However, because several changes are also observed in chronicmigraine patients without medication overuse, these changesmay simply reflect the worsening of headache and may not implymuch about the pathogenesis of MOH.

EFFECT OF CHRONIC MEDICATION ON THETRIGEMINAL NOCICEPTIVE SYSTEM—PRECLINICAL EVIDENCEThe primary objective of preclinical studies is to determine howchronic medication affects the trigeminal nociceptive system andother brain areas involved in headache pathogenesis.

Effect on the Trigeminal Nociceptive SystemPreclinical evidence shows that chronic exposure to opiates canfacilitate the nociceptive process. Upregulation of CGRP hasbeen observed in dorsal root ganglia after prolonged exposure tomorphine.44,45 Sustained morphine exposure affects spinal gluta-matergic transmission. Enhancement of glutamate release46 anddownregulation of spinal glutamate transporters47 has beenfound after sustained morphine exposure. Expansion of cutane-ous receptive fields and lower thresholds of dura-sensitive med-ullary dorsal horn neurons was observed in rats receivingsustained infusion of morphine.48 Another mechanism underly-ing chronic opiate-mediated nociceptive exacerbation has beenproposed as the activation of a toll-like receptor-4 on glial cells,resulting in a proinflammatory state.49 This evidence indicatesthat chronic opiate exposure can lead to a persistent pronocicep-tive trigeminal neural adaptation.50

Prolonged exposure to triptans produces comparable changesin the sensory system. Enhancement of the CGRP and NOsystems has been observed in animals treated with triptans.Chronic sumatriptan exposure produces long-lasting cutaneoustactile allodynia. This change corresponds with an increasednumber of CGRP-positive dural afferent neurons in the TG.Exposure to triptans increases CGRP levels in the blood afterchallenge by a nitric oxide donor.51 CGRP can increase expres-sion of the TRPV1 receptor, thus facilitating the nociceptiveprocess.52 In addition to increasing CGRP levels, chronic triptanexposure can increase the expression of neuronal nitric oxidesynthase (nNOS) in the TG neurons innervating the dura in rats.The involvement of nNOS in generating allodynia was con-firmed by the observation that cutaneous allodynia was reversedby NXN-323, a selective nNOS inhibitor.53

Effect on the Cerebral CortexChronic medication can affect cerebral cortical activity. In rats,chronic exposure to acetaminophen increases the frequency ofcortical spreading depression (CSD), an analog of migraine aura.54

CSD-evoked increases of 5-HT2A serotonin receptor expressionand c-Fos-immunoreactivity in the cerebral cortex and TNC havebeen found in rats after chronic acetaminophen treatment.55

Increased CSD development and increased TNC c-Fos immuno-reactivity were also shown in rats chronically treated with dihy-droergotamine.56 These findings suggest that chronic exposure toeither antimigraine drugs or nonspecific analgesics can increasethe excitability of cortical neurons, thus increasing susceptibilityto develop CSD, facilitating the trigeminal nociceptive process.

Effect on Central Modulating SystemPreclinical studies support clinical findings of an altered 5-HTsystem in patients with MOH. Chronic administration of acet-aminophen resulted in the upregulation of 5-HT2A receptors inthe cerebral cortex.57 Changes in the expression of 5-HT recep-tors and transporters in several subcortical areas, including thePAG and the locus coeruleus, were also reported in animals afterchronic triptan exposure.58,59

A derangement in the endogenous 5-HT-dependent controlsystem may underlie the cortical hyperexcitation and pain facili-tation seen in MOH. Animals with decreased 5-HT levels showan increase in CSD susceptibility and CSD-evoked c-Fos expres-sion in the TNC.60 Inhibition of NO production can attenuatethis cortical hyperexcitability.61 Low levels of 5-HT may subse-quently upregulate the expression of pronociceptive 5-HT2A

receptors in the cortex and trigeminal system. Activation of thispronociceptive receptor can upregulate NOS expression62 andincrease susceptibility to CSD. Dysfunction of the 5-HT systemalso facilitates the trigeminal nociceptive process. The expressionof c-Fos and phosphorylation of the NR1 NMDA-receptorsubunit in TNC neurons evoked by meningeal inflammation isincreased in animals with levels of 5-HT depleted by tryptophanhydroxylase inhibition.63 Animals with depleted 5-HT levels alsoshowed an increase in CGRP expression in the TG and anincrease of CGRP release evoked by CSD.64,65

The evidence presented above shows that the central modu-lating control has a strong influence on the function of thetrigeminal system. Derangement of this control system, eitherdecreasing nociceptive inhibition or increasing nociceptive facili-tation, may enhance the process of central sensitization.

CONCLUSION: PATHOGENESIS OF MOH—A HYPOTHESISThe clinical and preclinical studies described above indicate anincreased excitability of neurons in the cerebral cortex and tri-geminal system after chronic headache medication. The corticalhyperexcitability may increase the probability of developingCSD, while increased excitability of trigeminal neurons mayfacilitate peripheral and central sensitization. These changes maybe secondary to the derangement of central, especially 5-HT-dependent, nociception modulating systems. The relative deple-tion of 5-HT by headache medication overuse subsequentlyupregulates the 5-HT2A receptor and changes intracellular signal-ing. Increased expression of cortical 5-HT2A receptors mayincrease susceptibility to CSD. Reduction of diffuse noxious

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inhibitory controls may facilitate the process of central sensitiza-tion, activate the nociceptive facilitating system, or promote thesame molecular mechanisms that are involved in kindling.66,67

Low 5-HT levels increase the expression and release of CGRPfrom the TG and sensitize trigeminal nociceptors. Thus, derange-ment in the central pain modulating system as a result of chronicmedication use may increase sensitivity to pain perception andfoster or reinforce MOH.

Acknowledgments: This study was supported by the Neuroscienceof Headache Research Unit, “Integrated Innovation AcademicCenter: IIAC”: 2012 Chulalongkorn University Centenary Acade-mic Development Project, Chulalongkorn University, and theRatchadapiseksompotch Fund from the Faculty of Medicine,Chulalongkorn University.

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