Is Migraine a Neuropathic Pain Syndrome?

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1 Is Migraine a Neuropathic Pain Syndrome? David M. Biondi, DO Corresponding author David M. Biondi, DO Headache Management Program, Spaulding Rehabilitation Hospital, 125 Nashua Street, Boston, MA 02114, USA. dbiondi@partners.org Current Pain and Headache Reports 2006, 10: Current Science Inc. ISSN Copyright 2006 by Current Science Inc. The understanding of migraine pathophysiology has evolved from the belief that migraine is a vascular disorder, to evidence that better defines migraine as a neurogenic disorder associated with secondary changes in brain perfusion. There is evidence to suggest that the early phase of migraine pain results from neurogenic inflammation affecting cranial blood vessels and dura. Allodynia, hyperalgesia, and expansion of nociceptive fields occur during most well-established migraine attacks. These clinical features of migraine are evocative of those traditionally associated with neuropathic pain. A hypothesis that defines migraine pain as a unique neuropathic pain disorder can imply the potential for neural plasticity and may provide insight into the mechanisms that underlie the transformation of episodic to chronic forms of migraine. The neuropathic pain model of migraine pathophysiology not only paves the way for mechanism-based treatment strategies that can improve the acute and preventive management of migraine attacks, but also opens the door for the discovery of novel therapeutic targets. It also lends momentum to an understanding of clinically intriguing topics such as opiate-induced hyperalgesia and medication-overuse headache (rebound headache), opioid resistance in the treatment of chronic headache, and disease modification in defending against the potential for migraine transformation. Introduction Migraine is a medical disorder that has a broad range of triggers, clinical manifestations, and treatment options. Migraine is a highly prevalent medical condition that affects approximately 13% of the general population and is approximately three times more prevalent in adult women [1]. A family history of migraine or similar headaches can be identified in more than 90% of cases [2]. Many migraineurs in the general population have not received proper diagnosis and either will self-medicate or use ineffective therapies [3]. Migraine is known to impose significant individual and societal burdens resulting from functional disability and loss of productivity. The condition has been estimated to account for more than 10 million physician office visits yearly and frequent use of emergency or urgent care facilities [4]. Migraine was estimated to cost employers more than 13 billion dollars each year because of absenteeism and decreased productivity [5]. Although migraine is associated with many clinical features, recognition that hyperalgesia and allodynia, which are well-accepted features of neuropathic pain, occur during most well-established migraine attacks has lent momentum to a better understanding of migraine mechanisms, mechanism-based treatment strategies, and the potential consequences of inadequately treated migraine attacks. Chronic daily headache (CDH) is an even more perplexing and disabling medical condition than episodic migraine. CDH is estimated to affect 4.1% of the general US population [6]. Chronic migraine, which makes up a large component of the CDH population, is estimated to affect 2% to 3% of the general population [6]. Evidence is mounting to implicate recurrent migraine attacks as a cause for structural and functional changes in the central nervous system [7,8 10]. It also is thought that prolonged nociceptive input may incite not only sensitization of central pain pathways, but also neural plasticity in these pathways, thereby promoting the transformation of episodic headache to a chronic head pain disorder [11 ]. This theory implies that achieving reductions in attack severity through aggressive abortive treatment of acute migraine attacks and reducing migraine attack frequency with prophylaxis may reduce the risk of neural plasticity and transformation to a more chronic, refractory, and disabling migraine pattern. Clinical observations and a growing body of evidence suggest that chronic migraine is associated with persistent hyperalgesia and allodynia even in between episodic migraine attacks [12 ]. Despite findings of clinical symptoms and signs that emulate neuropathic pain during migraine attacks, neither episodic migraine nor chronic migraine are recognized as neuropathic pain syndromes by most

2 168 Neuropathic Pain practicing clinicians and scientists involved in this field of study. This manuscript presents a neurobiologic model that may help to explain the clinical features of migraine attacks, including those attributed to neuronal sensitization and the phenomenon of transformation from episodic migraine to chronic daily headache. The proposed hypothesis is that migraine is a unique neuropathic pain disorder based on its clinical presentation, potential for progressive deterioration, and response to various pharmacologic treatments. The CDH nomenclature in this hypothesis is used to describe primary CDH that has migrainous features and would be classified in the revised International Classification of Headache Disorders (ICHD-II) as chronic migraine [13]. The references and information contained in this manuscript were gathered using a Medline search of literature through February The following search terms were employed: migraine, CDH, neuropathic pain, pathophysiology, opioid tolerance, and hyperalgesia. Because there is a general paucity of scientifically based evidence regarding the various clinical and diagnostic features of chronic migraine, clinical experience and expert consensus also are used in the development of this thesis. Clinical Presentation of Migraine Migraine is a paroxysmal neurologic disorder that generally is characterized by recurrent attacks of moderate to severe head pain accompanied by physical and cognitive impairment. The ICHD-II provides diagnostic criteria for the wide variety of headache disorders, including migraine and chronic migraine [13] (Table 1). The well-known clinical features of migraine include unilateral head pain, throbbing or pulsating pain quality, moderate to severe pain intensity, and several associated symptoms such as nausea, vomiting, photophobia, and phonophobia. Patients with migraine often are hypersensitive to sensory stimuli other than light and sound, such as olfactory scents and tactile stimuli [14]. Other symptoms experienced during and sometimes between migraine attacks include nausea, diminished appetite, poor sleep quality, dizziness, disequilibrium, fatigue, cognitive inefficiency, mood alterations, and behavioral changes. Migraine pain often exhibits side-shift or alternating unilaterality of pain within or between attacks. The head pain associated with typical migraine attacks has a duration ranging between 4 and 72 hours and usually results in temporary impairment or disability. Notwithstanding the classic features of a migraine attack, migraine-related head pain could be bilateral in 40% of cases [15] and non-throbbing in approximately 30% [16]. The well-recognized visual auras of migraine, photopsia (flashing lights), or fortification spectra (angular prismatic visual hallucinations also called teichopsia) are experienced by only 15% to 20% of migraineurs and even then auras are not associated with every migraine attack [17]. Migraine auras are focal neurologic symptoms that most often are visual, but also can be sensory (ie, migrating paresthesiae) and occur before or early in the course of a migraine attack. Aura symptoms gradually develop over 5 to 20 minutes and resolve within 60 minutes [13]. Although nausea and vomiting are features that often contribute to migraine disability, they need not be present to establish a diagnosis of migraine in accordance with the ICHD-II. Other common but frequently overlooked or misidentified clinical features of migraine are sinus pressure, nasal congestion, rhinorrhea, and lacrimation, which are parasympathetic rhinomotor features of migraine attacks resulting from autonomic activation in the superior salivatory nucleus. The association of these sinus symptoms with headache can misdirect the diagnosis from migraine to sinus headache [18]. Neck pain, resulting from sensitization of neurons in the trigeminal nucleus caudalis, likewise is a common accompaniment of migraine and sometimes can mislead a clinician to establish a diagnosis of tension-type headache [19]. Sinus and tension-type headaches rarely are disabling; therefore, patients with recurrent, disabling headache regardless of associated symptoms require further evaluation and consideration for alternative headache disorders such as migraine. Many intrinsic and extrinsic circumstances such as cyclic hormonal changes (ie, estrogen), stress, hunger, physical exertion, illness, exposure to bright light or loud noise, strong odors, dramatic ambient temperature variations, or weather changes can exacerbate migraine-related pain and other associated symptoms. Despite a much greater prevalence in the general population, tension-type headache is rarely a primary complaint of patients in medical clinics [20]. It is the intense pain and disability associated with most migraine attacks that prompt migraineurs to seek medical attention. Clinical Presentation of Chronic Daily Headache Chronic daily headache is characterized by a pattern of 15 or more headache days each month. Primary CDH disorders are those headache conditions not associated with a structural or systemic pathology and include such diagnoses as chronic tension-type or chronic migraine headache. Secondary CDH disorders include those caused by structural, infectious, metabolic, or other systemic conditions such as cranial tumors, cerebrovascular disorders or malformations, intracranial or pericranial infection, disorders of cerebrospinal fluid pressure, medication side effects, cervicogenic headache, pericranial or facial muscular disorders, and head or neck trauma. The ICHD-II defines chronic migraine as a pattern of headaches occurring on 15 or more days per month, including 8 or more migraine days per month when the headache is present for at least 3 months in the absence of medication overuse and can not be attributed to another disorder [13]. Approximately 75% of patients

3 Is Migraine a Neuropathic Pain Syndrome? Biondi 169 Table 1. Diagnostic features of migraine and chronic migraine* Migraine without aura Recurrent headache disorder manifesting in attacks lasting 4 72 hours; typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea and/or photophobia and phonophobia Diagnostic criteria A. At least five attacks fulfilling criteria B through D B. Headache attacks lasting 4 to 72 hours (untreated or unsuccessfully treated) C. Headache has at least two of the following characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe pain intensity 4. Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) D. During headache, there is at least one of the following: 1. Nausea and/or vomiting 2. Photophobia and phonophobia E. Not attributed to another disorder Typical aura with migraine headache Typical aura consists of visual and/or sensory and/or speech symptoms; gradual development, duration no longer than 1 hour, a mix of positive and negative features, and complete reversibility associated with a headache fulfilling criteria for migraine without aura Diagnostic criteria A. At least two attacks fulfilling criteria B through D B. Aura consisting of at least one of the following, but no motor weakness: 1. Fully reversible visual symptoms, including positive features (ie, flickering lights, spots, or lines) and/or negative features (ie, loss of vision) 2. Fully reversible sensory symptom, including positive features (ie, pins and needles) and/or negative features (ie, numbness) 3. Fully reversible dysphasic speech disturbances C. At least two of the following: 1. Homonymous visual symptoms and/or unilateral sensory symptoms 2. At least one aura symptom develops gradually over > 5 minutes and/or different aura symptoms occur in succession over > 5 minutes 3. Each symptom lasts > 5 minutes and < 60 minutes D. Headache fulfilling criteria B through D for 1.1 Migraine without aura begins during the aura or follows aura within 60 minutes E. Not attributed to another disorder Chronic migraine Headache occurring on 15 or more days per month and at least 8 migraine days per month for more than 3 months in the absence of medication overuse Diagnostic criteria A. Headache fulfilling criteria C and D for migraine without aura B. Not attributed to another disorder *Data modified from Headache Classification of the International Headache Society [13].

4 170 Neuropathic Pain with chronic migraine originally had experienced episodic migraine without aura [21]. As chronic migraine develops, the headache tends to lose its episodic presentation and evolves into a constant headache pattern with characteristics of chronic tension-type headache. Superimposed upon the chronic tension-type headaches are episodic, but usually frequent headache attacks that have typical features of migraine [13]. Patients with chronic migraine often are sensitive to a variety of sensory stimuli such as light, sound, smell, and touch, even in between migraine attacks [22]. Other symptoms of chronic migraine include chronic nausea, diminished appetite, poor sleep, dizziness, disequilibrium, fatigue, cognitive inefficiency, and behavioral and mood changes. Similar to episodic migraine, many different intrinsic and extrinsic stimuli can exacerbate pain intensity and its associated symptoms, including cyclic hormonal changes, stress, strong emotions, hunger, physical exertion, illness, exposure to bright light or loud noise, strong odors, and dramatic variation of ambient temperature or weather change. Medication-overuse headache (MOH), informally called rebound headache, is a secondary CDH disorder that is a consequence of frequent symptomatic or analgesic medication use [13]. It is characterized by an insidious increase of headache frequency and intensity, inefficacy of alternative abortive or preventive medications in controlling headaches, predictable early morning awakenings because of headache, cyclical onset, worsening of headache intensity after the last dose of medication or before the next scheduled dose, and development of drug dependency or addiction. The frequent use of these medications causes a progressive worsening of headache activity that compels the patient to use more medication, thus setting up a vicious cycle of medication overuse. Medication use needs to be frequent, generally more than 2 days per week, and ongoing, generally over the course of several weeks or months. The International Headache Society defines MOH as a pattern of chronic headaches occurring 15 days or more each month induced by frequent or daily use of a medication for more than 3 months [13]. In addition, the headache must resolve or substantially improve within 1 month after withdrawal of the overused medication. Rebound headache has been studied primarily in the migraine population; migraineurs may be the primary headache population at risk for developing this syndrome. Rebound headache has been reported to occur after frequent use of various medications in different drug classes, including simple analgesics, combination analgesics containing butalbital and caffeine, opioid analgesics, ergot products, and the 5-HT 1 agonists (triptans) [23 26]. Prognosis and short-term benefits of treatment for CDH and MOH generally have been favorable for most patients who successfully complete inpatient, multidisciplinary headache management programs that combine pharmacologic and behavioral interventions. In an evaluation of 50 hospitalized patients who became headache-free after treatment with repeated dosing of intravenous dihydroergotamine, 72% demonstrated improvement in headache activity at 3 months and 87% continued to report improvement after 2 years [27]. A meta-analysis of 29 studies involving 2612 patients who had MOH revealed that the original primary headache was migraine in 65% and tension-type headache in 27% of the subjects [28]. The mean duration of frequent drug use was 10.3 years. In the 17 studies that provided outcomes after medication withdrawal, 72.4% of patients reported no headache or a greater than 50% improvement in the number of headache days within 1 to 6 months after withdrawing the overused medication. The long-term benefits of medication withdrawal for MOH have been variable. In the meta-analysis mentioned previously, the three studies that followed outcomes for more than 9 months (9 35 months) after medication withdrawal reported improvement of at least 50% that was maintained in 60%, 70%, and 73% of subjects, respectively [28]. Two other studies found that 35% to 43% of patients with MOH continued to experience CDH at 1 and 2 years after treatment, respectively [29,30]. Even among those who improved, a return to the baseline headache pattern was rare. In another study, 60% of migraine patients receiving treatment in a primary care setting continued to experience disability at 1 year and 20% continued to experience significant pain and disability at 2 years [31]. Patients with chronic migraine generally respond poorly to traditional migraine treatments, develop occupational and social impairment, and experience treatment-related complications or side effects. Factors that may improve treatment outcomes include lifetime headache experience of less than 10 years, duration of medication overuse less than 5 years, migraine as the primary headache disorder, long-term administration of appropriate prophylactic medications, and maintaining complete abstinence from the overused medication [32]. When psychologic disorders and behavioral conditions occur together with CDH, clinical manifestations of the disorder and treatment strategies become increasingly more complex [33]. Migraine appears to have a relapsing, remitting form defined by the episodic migraine diagnosis and a chronic, progressive form defined by the chronic migraine diagnosis. Describing the episodic and chronic forms of migraine with this nomenclature implies a continuum of migraine expression and potential for progressive deterioration that is suspected to be a consequence of neural plasticity, degeneration, or dysregulation, which are issues presented later in this manuscript. Based on clinical observations, the transformation of episodic migraine to chronic forms renders the headache condition more refractory to conventional treatment, thereby necessitating treatment strategies that employ rational

5 Is Migraine a Neuropathic Pain Syndrome? Biondi 171 combinations of drugs integrated with nonpharmacologic therapies. In this way, the management of chronic migraine becomes analogous to the challenges faced in treating the traditional neuropathic pain disorders. It is unknown if the clinical manifestations of chronic migraine that result from these proposed neuroplastic changes could reach a state of irreversibility. Migraine Pathophysiology The contemporary model of migraine pathophysiology has evolved from the predominantly vascular theories promoted over several decades [34] to that of a complex neurovascular process involving cerebrocortical hypersensitivity, altered neurotransmitter activity, changes in pain modulation and nociceptor function, neurogenic inflammation in the dura and around cranial blood vessels, sensitization of peripheral and central trigeminal pain pathways, activation of various components of the autonomic nervous system, and altered brain perfusion [35,36,37 ]. Migraine can be described best as an episodic neurologic and neurovascular disorder. Clinical research supports the conclusion that migraine is genetically determined in most cases. Genetic studies have suggested the presence of a heterogeneous genotype, which gives rise to different phenotypic expressions [38]. The cerebral cortex of migraineurs generally is thought to exhibit lower activation thresholds for depolarization than that found in non-migraineurs [39]. The consequence of this neurophysiologic alteration is thought to initiate the complex cascade of neurologic events that result in the clinical features of a migraine attack. The trigeminal nerve is the primary sensory pathway for most headaches, although other nerves, such as the upper cervical sensory afferents, may be primarily involved in some types of headache. The pain of migraine is initiated by inflammation in or around pain-sensitive structures of the head, such as the meninges, dural vascular structures, and cranial blood vessels [40]. Although the presence of scalp sensitivity during a migraine attack has been observed in clinical practice [15], the recognition that this clinical feature of migraine is a form of allodynia [41 ], a clinical marker for central sensitization and a hallmark of neuropathic pain, changed the way that many scientists and clinicians conceptually understand migraine. The earliest clinical feature of a migraine attack, experienced by up to 70% of migraineurs, is a prodrome, which is a constellation of premonitory symptoms occurring up to 48 hours before the onset of a migraine aura or headache [42]. Prodromal symptoms can include feelings of fatigue, mood changes, food cravings, excessive yawning, vertigo, difficulty concentrating, and cognitive inefficiency. It is unknown what physiologic events underlie these symptoms, but prodrome is possibly related to early alterations in specific neurotransmitters (ie, dopamine) [43] or neurotransmitter receptor activity. In the aura phase of migraine, a wave of spreading cortical activation (depolarization) is thought to result in the clinical symptoms of aura that are experienced by some migraineurs [44]. Typical migraine auras are positive, transient, and migratory neurologic phenomena such as photopsia, spreading visual hallucinations, and migrating paresthesiae. In the wake of the depolarizing wave, there is suppression of spontaneous and evocable cortical activity, a phenomenon known as cortical spreading depression. The suppression of cortical excitability likely contributes to the negative clinical symptoms of migraine such as visual blind spots (scotoma), numbness, weakness, word finding difficulties, and cognitive inefficiency. Cortical recovery time or repolarization appears to be delayed in migraineurs [44], which may explain the persistence of neurologic migraine attack symptoms for several minutes to hours. If the migraine attack fails to progress to the next stage, the patient may experience migraine visual aura or other neurologic symptoms without associated headache, conditions also referred to as ophthalmic migraine, acephalgic migraine, or migraine equivalent [13]. If the attack progresses to the next stage, the trigeminal nerve is activated through an as yet unknown mechanism, which is thought to be directly activated by the spreading cortical depolarization or through a brainstem reflex [45]. Trigeminal activation incites the release of vasoactive, proinflammatory, and algogenic substances from trigeminal nerve terminals in the dura and around cranial blood vessels, thereby resulting in neurogenic inflammation and mast cell degranulation, vasodilation, and plasma protein extravasation [46]. If the neurogenic process fails to proceed beyond this stage or if its progression is arrested by an appropriate treatment, the head pain usually has qualities similar to those defined as tension-type headache. It is not unusual for migraineurs to experience tension-type and migraine headaches [47]. In migraine, most attacks are associated with throbbing pain, which likely occurs as the perivascular trigeminal nerve terminals become sensitized, thereby resulting in painful responses to previously innocuous stimuli such as blood vessel stretching and pulsations [48]. Ensuing activation of structures within central pain pathways such as the trigeminal nucleus caudalis and thalamus is thought to result in referred pain patterns and expansion of nociceptive sensory fields to involve regions of the neck and upper torso. Activation of parasympathetic fibers in the superior salivatory nucleus results in symptoms of nasal congestions, rhinorrhea, and tearing. In the next stage of migraine, protracted perivascular inflammation and peripheral trigeminal sensitization are hypothesized to incite sensitization of central pain pathways in the brainstem, upper spinal cord, thalamus, and cortex [41 ]. Work by Strassman et al. [49] and more recently by Burstein et al. [50 ] supports the hypothesis that central sensitization occurs in migraine. A common clinical feature of an

6 172 Neuropathic Pain untreated migraine attack is hyperalgesia and allodynia affecting the scalp, face, and contiguous regions of the neck and torso [47]. Cutaneous allodynia of the scalp has been demonstrated to occur in up to 75% of migraine attacks and usually is well established within 1 to 2 hours after the onset of throbbing head pain [47]. Some migraineurs develop allodynia as quickly as 20 minutes into a migraine attack. Sensitization, recruitment, and activation of brainstem structures, including autonomic pathways, result in several other well-known clinical features of migraine, including photophobia, phonophobia, nausea, nasal congestion, and rhinorrhea. Allodynia is not only a clinical marker for sensitization of central pain pathways, but it also appears to be an important marker for treatment efficacy [50 ]. During the resolution stage of a severe or prolonged migraine attack, many migraineurs will experience a postdrome that can last several hours to 1 day in duration. Common postdromal symptoms include fatigue, lassitude, irritability, myalgia, urinary frequency, and cognitive inefficiency. The pathogenesis and pathophysiologic mechanisms of CDH and chronic migraine have not been clearly identified. The risk of developing chronic migraine appears to be, at least partly, linked to heredity and genetics. The relative risk for developing CDH in first-degree relatives was found to be 2.1 to 3.9 times greater than the known risk for the general population [51]. Hypotheses for the pathogenesis of chronic migraine have included conditions of low central neuronal serotonin, dysregulation of neuronal 5-HT receptors, hyperexcitability of central pain pathways, low central β-endorphin levels, and dysfunction of N-methyl-D-aspartate (NMDA) receptors [52]. It can be hypothesized that frequent recurrent or prolonged nociceptive input at the level of the trigeminal nucleus results in supraspinal sensitization and central neuroplastic changes that may be maintained, leading to the transformation of episodic to chronic headaches. This concept appears to be supported by recent epidemiologic and clinic-based studies that sought to identify risk factors for this phenotypic transformation. Headache attack frequency was found to be an important and substantial risk factor for headache transformation [52,53]. In these studies, an average headache frequency of 4 to 5 headache days per month is a point at which the risk for transformation to chronic migraine increases exponentially. The mechanisms of chronic tension-type headache are even more obscure and less well understood. Potential Neuronal Injury as a Consequence of Migraine There are several lines of evidence to suggest that repeated episodes of migraine headache are associated with changes in central nervous system structure or function. Through specialized brain imaging techniques, Welch et al. [7 ] demonstrated abnormal nonheme iron deposition in the periaqueductal gray matter of the rostral brainstem in migraineurs, but not in non-migraine control subjects. The amount of iron deposited was positively correlated with the subjects lifetime duration of migraine. It was hypothesized that this change occurs through iron-catalyzed free radical cell damage accentuated by repeated episodes of hyperoxia during migraine attacks. This finding might suggest that repeated attacks of migraine result in iron accumulation in the antinociceptive systems of the brainstem, potentially causing or acting as a marker for impaired pain modulation. Chronicle and Mulleners [54] suggested that cerebral ischemia during attacks of migraine with aura causes changes in the primary visual cortex, which results in impaired visual function. Similarly, Khalil et al. [55] concluded that repeated migraine auras caused damage to the visual system, most likely at the cortical level, and suggested that NMDA-associated neurotoxicity, repeated transient hypoxia, or ischemia were possible causes for injury to cortical tissue. High migraine frequency, especially in cases of migraine with aura, has been linked to white matter lesions of the cerebral and cerebellar hemispheres [8]. The nature of these white matter lesions has been debated regarding whether they represent ischemic or metabolic injury. Others findings that suggest plasticity of or injury to neuronal tissue as a consequence of migraine include interictal abnormalities in cognitive function [56], subclinical cerebellar dysfunction [57], and abnormalities at the neuromuscular junction [58]. What is Neuropathic Pain? The definition of neuropathic pain has undergone change and remains an issue of controversy [59]. The International Association for the Study of Pain (IASP) originally had defined neuropathic pain as pain initiated or caused by a primary lesion of the nervous system. Controversy developed after revision of this definition also defined dysfunction of the nervous system as a potential etiology of neuropathic pain. It has been suggested that dysfunction of the pain systems may result from inflammatory mechanisms, traditionally recognized as an etiology for nociceptive pain, that cause sensitization of peripheral and central pain pathways [60] or a loss of descending pain modulation. The clinical features of neuropathic pain that are well accepted by the medical and scientific communities include stimulus-independent or spontaneous pain, hyperalgesia, allodynia, and expansion of sensory fields. Neuropathic pain generally is intense (moderate to severe) and often is described as dull, burning, shooting, pinching, drilling, and cutting [61]. Burning appears to be a more common descriptor for neuropathic pain of central origin. Other clinical features include paresthesia and dysesthesia. A study that sought to identify sensitive clinical features that accurately indicated the diagnosis of neuropathic pain from a bedside sensory examination found that subjective sen-

7 Is Migraine a Neuropathic Pain Syndrome? Biondi 173 sory abnormalities (increased or decreased) of the skin in the affected region and mechanical hypersensitivity to light brushing of the skin were most predictive [61]. Other indicators that were suggestive but had a lower diagnostic sensitivity included pinprick- and cold-evoked pain. Throbbing, a classic feature of migraine, was found to be a common pain descriptor in cases of nontraditional neuropathic pain, which includes conditions such as complex regional pain syndrome, atypical facial pain, chronic low back pain, and chronic musculoskeletal pain, among others. On the other hand, burning was a more commonly reported pain descriptor in cases of traditional neuropathic pain syndromes such as painful diabetic neuropathy, postherpetic neuralgia, trigeminal neuropathy, and spinal root compression. Neurodiagnostic features of neuropathic pain include a lower pain threshold for mechanical and thermal stimuli [62]. Conditions of the central nervous system that are thought to be associated with neuropathic pain include segmental sensitization, changes in descending antinociceptive modulatory mechanisms, changes in the activities of astrocytes and microglia, and reorganization of spinal, thalamic, or cerebral cortical sensory receptive fields (neuroplasticity) [63 65]. Intense inflammatory pain can result in sensitization of peripheral and central pain pathways, resulting in hyperalgesia [66]. If quickly and appropriately treated, it generally is thought that the potential neuronal consequences of inflammatory pain (neuronal sensitization and other forms of neuroplasticity) can be attenuated or avoided. The traditional model of chronic neuropathic pain requires some type of injury to the peripheral or central nervous systems that is partly associated with inflammation and facilitation of neuronal sensory transmission. Clinical experience and scientific experimentation have demonstrated that pain processing involves a dynamic and complex interaction of inflammation, physiologic pain transduction, sensitization of various peripheral and central pathways, autonomic activation, descending central neuronal modulation (antinociceptive), endocrinologic involvement, and various psychobiologic influences mediated through limbic nervous system pathways [67]. These processes are prone to neuroplasticity, which then can result in chronic, potentially irreversible pain disorders. Because of the controversy surrounding the definitions of clinical pain disorders, Backonja [68 ] suggested that the definitions of pain disorders be revised to reflect pathophysiologic mechanisms and specific clinical features of the pain disorder. The proposed classification would include two specific groups of pain disorders: neuropathic pain and hypersensitivity pain. In this system, neuropathic pain would be associated with three principal characteristics: 1) pain and sensory symptoms that persist beyond the healing of injured tissue; 2) presence, in variable degrees, of neurologic sensory signs manifesting as negative and positive phenomena; and 3) presence, in variable degrees, of other neurologic signs, including motor dysfunction manifesting as negative or positive motor phenomena or autonomic signs. Postherpetic neuralgia, central pain syndrome, painful diabetic neuropathy, causalgia, and painful radiculopathy were offered as examples of neuropathic pain disorders as defined within this paradigm. The second group of pain disorders, those defined as hypersensitivity pain disorders, would be associated with less specific symptoms and signs that are suggestive of neuropathic pain, such as hyperalgesia and allodynia, but without apparent neuronal injury. These conditions would include those neuropathic pain disorders resulting from a dysfunction of the nervous system as defined in the IASP definition. Examples of these conditions include fibromyalgia and chronic low back pain. Based on clinical and neurophysiologic testing, episodic and chronic migraine also may be included in the hypersensitivity pain disorder category. Although more deliberation similar to the proposed revision of neuropathic pain definitions and diagnostic criteria is needed, distinction between the proposed classifications of neuropathic pain and hypersensitivity pain disorder remain vague and will not likely distract from the controversy surrounding the operational definitions for various pain disorders. The difficulty in achieving a consensus on this issue is arguably the result of an incomplete understanding of anatomic and cellular pain mechanisms and their complex interactions. Adding to the difficult task of reaching consensus is the general lack of comparable clinical, neurodiagnostic, and scientific data across different pain disorders, especially migraine and other headache disorders. Is Migraine a Neuropathic Pain Syndrome? Based on a synthesis of clinical and preclinical evidence that is currently available, migraine is an episodic or chronic pain disorder that is the result of both peripheral neurogenic inflammation resulting in nociceptive pain and, in most cases, central sensitization resulting in clinical symptoms that are typical of neuropathic pain disorders. Inflammatory nociceptive pain usually is well localized, aching or throbbing in quality, and effectively relieved by acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or opioid analgesics. Scientific evidence suggests that the initial pain of a migraine attack is caused by trigeminal nociceptor activation as a consequence of neurovascular inflammation in the meninges and around cranial blood vessels [35]. In this early stage of the migraine attack, the head pain most often is unilateral and generally well localized, aching or throbbing in quality, and often responsive to NSAIDs and opioids if used as early as possible to the onset of head pain. As peripheral trigeminal nociceptors within the dura and surrounding cranial blood vessels become sensitized, most migraineurs

8 174 Neuropathic Pain experience spontaneous throbbing pain, pain exacerbation during Valsalva, cough, or bending, and exacerbation of pain incident to physical exertion. It can be argued that these clinical features of a migraine attack are manifestations of allodynia resulting from peripheral neuronal sensitization. Neuropathic pain is caused by injury to or dysfunction of neural pain pathways resulting in sensitization of peripheral nociceptors and central nociceptive pathways [36]. The clinical characteristics of pain from this process are described as being more diffuse, burning or jabbing in quality, and generally unresponsive to simple analgesics. In classic definitions, neuropathic pain also is characterized by spontaneous or stimulus-independent pain, hyperalgesia, and allodynia. In the later stages of a migraine attack, the clinical features often include diffuse head pain that is moderate to severe in intensity. The sensation of pain often spreads from cranial regions to involve the neck and upper torso, which is a clinical manifestation of sensory field expansion. The intense, throbbing pain during a migraine attack often is accompanied by jabbing or sharp paroxysmal pain, hyperalgesia and allodynia of the face and scalp, and poor responsiveness to NSAIDs and opioid analgesics [69]. Also conforming to clinical and diagnostic features of neuropathic pain, migraine often is associated with positive and negative sensory phenomena such as paresthesia and numbness, in addition to hyperalgesia and allodynia. Furthermore, positive and negative autonomic nervous system features are common during migraine attacks and include physical signs and symptoms such as ashen skin color, rhinorrhea, lacrimation, gastroparesis, and diarrhea. In rare forms of migraine, motor paralysis affecting eye movements or hemiparesis can be observed. Similarly, the clinical features of CDH emulate the traditional neuropathic pain disorders because of its association with constant pain, scalp hyperalgesia, scalp allodynia, and exacerbation of pain intensity by a variety of physical, emotional, and environmental triggers. CDH most often presents as a diffuse head pain with a sharp or sometimes burning quality and paroxysmal attacks of jabbing, shooting, or shock-like pain. Hyperalgesia and allodynia of the scalp, neck, and shoulder have been demonstrated [47]. Patients frequently report constant sensitivity to sensory stimuli that are not typically painful or unpleasant, such as light, sound, and olfactory scents [14]. When classifying migraine as a neuropathic pain disorder, an important question to consider is whether the anatomic changes that have been demonstrated in the brainstem and cortical white matter are representative of neuronal injury [7,8]. If these structural changes indeed are representative of neuronal injury, episodic and chronic migraine disorders would not only fit current IASP definitions for neuropathic pain based on both nervous system dysfunction and having primary lesions of the nervous system, but also would conform to the definitions of neuropathic pain disorders and hypersensitivity pain disorders in the revised pain classifications proposed by Backonja [68 ]. When clinical observations and scientific evidence are examined, the clinical features and neurodiagnostic study results for migraine are compatible with the various current and proposed diagnostic schemas defining neuropathic pain. In cases of episodic migraine, these signs of neuropathic pain occur and resolve spontaneously, which is a unique presentation when compared with traditional neuropathic pain disorders. Implications of the Neuropathic Pain Model for Migraine Treatment When administering triptans for the abortive management of acute migraine, efficacy outcomes demonstrated a greater likelihood to achieve a pain-free result and greater likelihood to achieve a sustained pain-free result (pain-free at 2 hours without pain recurrence in the 24-hour period following treatment) when the triptan was administered at mild pain intensity. In experimental models, triptans have not demonstrated efficacy in reversing clinical features of central sensitization possibly related to the finding that central (second-order) trigeminal neurons do not express a high density of 5-HT 1D receptors, a principal site for the pharmacologic action of triptans. Correspondingly, in clinical use, triptan efficacy is diminished when allodynia is present during a migraine attack [70]. Several prospective trials have demonstrated substantial improvement of efficacy outcomes when the patient was instructed to treat at a mild level of migraine pain intensity [71 75]. Presumably, mild pain implies that treatment took place prior to the development of cutaneous allodynia, but this cannot be certain. Cumulative outcome results generally have demonstrated a doubling of the pain-free efficacy outcomes for oral triptans when they are administered during a mild level of pain intensity. Morphine generally has demonstrated low efficacy in the acute treatment of migraine [69,76]. Neuropathic pain traditionally has been considered poorly responsive to opioid analgesics, although clinical studies have demonstrated variable outcomes. Several clinical studies have demonstrated a lack of potency and low efficacy for opioid analgesics in the treatment of neuropathic or central pain syndromes [76 79], whereas others demonstrated opioid analgesic efficacy, but larger-than-expected dosages were required [80,81]. A systematic review of published randomized clinical trials was conducted to assess the efficacy of opioid analgesics for the treatment of non-cancer neuropathic pain [82]. Short-term trials (< 24 hours) demonstrated equivocal evidence. Intermediate-term trials (median time, 28 days; range, 8 56 days) demonstrated significantly better opioid analgesic efficacy compared with placebo (14-point reduction on a scale; 95% CI, -10 to -18; P < 0.001). A potential concern, especially

9 Is Migraine a Neuropathic Pain Syndrome? Biondi 175 given the relatively short duration of active treatment in the clinical drug trials, is the observation that opioid tolerance can be associated with elevated pain sensitivity, a condition commonly known as opioid-induced hyperalgesia [84 85]. This phenomenon has been well described in the general pain literature and may be identical to the many descriptions of analgesic rebound or MOH found in the headache literature. Although opioid analgesics have demonstrated efficacy in some studies for the treatment of acute, episodic migraine [86], other medications such as dihydroergotamine and ketorolac have been at least equally effective and generally caused fewer side effects [69,87]. A clinical trial and a case series using long-term, scheduled opioid analgesics for the treatment of CDH and chronic migraine did not demonstrate significant analgesic efficacy or substantial improvement in functional capacity in most cases, although a subpopulation of subjects reported pain reductions [88 90]. The variable analgesic responses of chronic migraine to opioid analgesics appears to parallel the variable outcomes observed in trials using opioid analgesics for the treatment of neuropathic pain. The relative lack of chronic headache responsiveness to opioid analgesics appears to parallel the general reduction of potency and efficacy for opioid analgesics in the treatment of neuropathic pain. If the pathophysiologic models previously described are valid, migraine and chronic migraine are neuropathic pain syndromes; therefore, the variable responsiveness of migraine disorders to opioid analgesics should not be unexpected. Furthermore, because the chronic administration of opioids to migraineurs has been observed to incite the transformation of intermittent migraine to CDH, the use of opioids in CDH may potentiate and perpetuate chronic headache patterns by a process similar to that suspected in the development of opioid-induced hyperalgesia observed in patients who have non-headache, non-cancer chronic pain disorders. A final example of migraine treatment implications for the neuropathic model of migraine is clinical observations that suggest greater efficacy of antiepileptic drugs such as topiramate or divalproex sodium compared with β-adrenergic blockers for the prophylactic management of chronic migraine. In clinical practice, antiepileptic drugs are prescribed alone or in combination with other medications such as tricyclic antidepressants (ie, amitriptyline or nortriptyline) or selective serotonin/norepinephrine-reuptake inhibitors (ie, venlafaxine or duloxetine) for the palliative management of chronic migraine. This treatment strategy is similar to that used and found most effective for the management of various neuropathic pain syndromes [90]. Most clinical drug trials are aimed at establishing the safety and efficacy of a single drug compared with placebo in the preventive or palliative management of migraine, chronic migraine, or neuropathic pain, rather than establishing the efficacy of combination therapy. However, clinical experience has demonstrated that patients who do not respond to a single, appropriately dosed medication often can achieve greater benefit from combining medications with different but complementary pharmacologic mechanisms of action, which is presumed to provide additive or synergistic effects. As knowledge of migraine mechanisms improves, so shall the opportunity to discover and develop mechanism-based treatment strategies by exploiting translational research strategies. These treatments will specifically target one or more steps in the cascade of events that compose the migraine attack, including the development of peripheral and central sensitization during episodic migraine attacks and in chronic forms of migraine. Candidate pharmacologic targets continue to expand, but there is enthusiasm for agents that act as calcitonin gene-related peptide antagonists [91], nitric oxide synthase inhibitors [92], AMPA-kainate receptor antagonists [93], NMDA receptor antagonists [94], adenosine A1 receptor agonists [95], and cannabinoid receptor agonists [96]. Conclusions The hypothesis that migraine is a neuropathic pain disorder can be upheld and confirmed by means of several diagnostic guidelines, but it is certain that debate over this issue will continue. Preclinical, clinical, and longitudinal epidemiologic studies are crucial for addressing current concerns regarding the premise that neuroplasticity and neurodegeneration underlie the transformation of episodic to chronic headache and whether these functional or structural neuronal consequences are reversible once established. Improved understanding of these processes and of pain mechanisms in general will help to establish the importance of aggressive and appropriate headache treatment as well as the potential role for neuroprotection and disease modification in the life-long management of migraine and other headache disorders. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Lipton RB, Stewart WF: Prevalence and impact of migraine. Neurol Clin 1997, 15: Peroutka SJ: Genetic basis of migraine. Clin Neurosci 1998, 5: Lipton RB, Stewart WF, Diamond ML, Reed M: Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001, 41: Hu XH, Markson LE, Lipton RB, et al.: Burden of migraine in the United States. Arch Intern Med 1999, 159: Lipton RB, Stewart WF, Simon D: Work-related disability: results from the American Migraine Study. Cephalalgia 1996, 16: Scher AI, Stewart WF, Liberman J, Lipton RB: Prevalence of frequent headache in a population sample. Headache 1998, 38:

10 176 Neuropathic Pain 7. Welch KM, Negesh V, Aurora SK, Gelman N: Periaqueductal gray matter dysfunction in migraine: Cause or the burden of illness? Headache 2001, 41: Using a specialized MRI protocol, this paper reports the finding of nonheme iron deposition in periaqeductal gray neurons of migraineurs, but not control subjects. This finding may suggest injury to or degeneration of this rostral brainstem region that is an integral part of the intrinsic pain modulation systems. 8. Kruit MC, van Buchem MA, Hofman PAM, et al.: Migraine as a risk factor for subclinical brain lesions. JAMA 2004, 291: Khalil NM, Legg NJ, Anderson DJ: Long-term decline of P100 amplitude in migraine with aura. J Neurol Neurosurg Psychiatry 2000, 69: Lee H, Lopez I, Ishiyama A, Baloh RW: Can migraine damage the inner ear? Arch Neurol 2000, 57: Welsh KM, Goadsby PJ Chronic daily headache. Curr Opin Neurol 2002, 15: This paper is a thorough review of the pathogenesis and cellular mechanisms that underlie CHD and the transformation of episodic migraine to chronic forms of migraine. 12. Kitaj MB, Klink M: Pain thresholds in daily transformed migraine versus episodic migraine headache patients. Headache 2005, 45: This paper reports the results of a clinical study that demonstrated the development of persistent hyperalgesia and allodynia in cases of chronic migraine. 13. Headache Classification of the International Headache Society: The International Classification of Headache Disorders, edn 2. Cephalalgia 2004, 24(suppl 1): Vingen JV, Sand T, Stover LJ: Sensitivity to various stimuli in primary headaches: a questionnaire study. Headache 1999, 39: Selby G, Lance JW: Observation on 500 cases of migraine and allied vascular headaches. J Neurol Neurosurg Psychiatry 1960, 23: Stewart WF, Schechter A, Lipton RB: Migraine heterogeneity: disability, pain intensity, attack frequency, and duration. Neurology 1994, 44:S24 S Rasmussen BK, Olesen J: Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia 1992, 12: Cady R, Dodick DW, Levine HL, et al.: Sinus headache: a neurology, otolaryngology, allergy, and primary care consensus on diagnosis and treatment. Mayo Clin Proc 2005, 80: Kaniecki RG: Migraine and tension-type headache: an assessment of challenges in diagnosis. Neurology 2002, 58(supp16):S15 S Tepper SJ, Dahlof CG, Dowson A, et al.: Prevalence and diagnosis of migraine in patients consulting their physician with a complaint of headache: data from the Landmark Study. Headache 2004, 44: Rapoport AM, Stang P, Gutterman DL, et al.: Analgesic rebound headache in clinical practice: data from a physician survey. Headache 1996, 36: Vingen JV, Sand T, Stover LJ: Sensitivity to various stimuli in primary headaches: a questionnaire study. Headache 1999, 39: Mathew NT, Stubits E, Nigam M: Transformation of migraine into daily headache: analysis of factors. Headache 1982, 22: Linton-Dahlof P, Linde M, Dahlof C: Withdrawal therapy improves chronic daily headache associated with longterm misuse of headache medication: a retrospective study. Cephalalgia 2000, 20: Fritsche G, Eberl A, Katsarava Z, et al.: Drug-induced headache: long-term follow-up of withdrawal therapy and persistence of drug misuse. Eur Neurol 2001, 45: Katsarava Z, Fritsche G, Muessig M, et al.: Clinical features of withdrawal headache following overuse of triptans and other headache drugs. Neurology 2001, 57: Silberstein SD, Silberstein JR: Chronic daily headache: prognosis following inpatient treatment with repetitive IV DHE. Headache 1992, 32: Diener HC, Dahlof CG: Headache associated with chronic use of substances. In The Headaches, edn 2. Edited by Olesen J, Tfelt-Hansen P, Welch KM. Philadelphia: Lippincott Williams & Wilkins; 2000: Scher AI, Lipton RB, Stewart WF: Natural history and prognostic factors for chronic daily headache: results from the Frequent Headache Epidemiology Study. Neurology 2002, 58(suppl 3):A Lu SR, Fuh JL, Chen WT, et al.: Chronic daily headache in Taipei, Taiwan: prevalence, follow-up, and outcome predictors. Cephalalgia 2001, 20: VonKorff M, Stewart WF, Simon DJ, Lipton RB: Migraine and reduced work performance: a population-based diary study. Neurology 1998, 50: Diener HC, Dichgans J, Scholz E, et al.: Analgesic-induced chronic headache: long-term results of withdrawal therapy. J Neurol 1989, 236: Verri AP, Cecchini P, Galli C, et al.: Psychiatric comorbidity in chronic daily headache. Cephalalgia 1998, 18: Graham JR, Wolff HG: Mechanisms of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry 1938, 39: Moskowitz MA: The neurobiology of vascular head pain. Ann Neurol 1984, 15: Goadsby PJ, Zagami AS, Lambert GA: Neural processing of craniovascular pain: a synthesis of the central structures involved in migraine. Headache 1991, 31: Pietrobon D, Streissnig J: Neurobiology of migraine. Nat Rev Neurosci 2003, 4: This paper provides a thorough review of migraine pathophysiology based on available preclinical and clinical evidence. Neurogenic and cellular mechanisms of the migraine attack including neurogenic inflammation, peripheral sensitization, and central sensitization are succinctly summarized. 38. Ferrari MD: Migraine. Lancet 1998, 351: Aurora SK, Welch KM, Al-Sayed F: The threshold for phosphenes is lower in migraine. Cephalalgia 2003, 23: Peroutka SJ: Neurogenic inflammation and migraine: implications for the therapeutics. Mol Interv 2005, 5: Burstein R, Yarnitsky D, Goor-Aryeh I, et al.: An association between migraine and cutaneous allodynia. Ann Neurol 2000, 47: This paper provided the original evidence that allodynia is associated with acute migraine attacks. 42. Kelman L: The premonitory symptoms (prodrome): a tertiary care study of 893 migraineurs. Headache 2004, 44: Peroutka SJ: Dopamine and migraine. Neurology 1997, 49: Hadjikhani N, Sanchez del Rio M, Schwartz D, et al.: Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A 2001, 98: Bolay H, Reuter U, Dunn AK, et al.: Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002, 8: Goadsby PJ: Migraine pathophysiology. Headache 2005, 45(suppl 1):S14 S Burstein R, Cutrer FM, Yarnitsky D: The development of cutaneous allodynia during a migraine attack: clinical evidence for sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain 2000, 123: Williamson DJ, Hargreaves RJ: Neurogenic inflammation in the context of migraine. Microsc Res Tech 2001, 53: Strassman AM, Raymond SA, Burstein R: Sensitization of meningeal sensory neurons and the origin of headaches. Nature 1996, 384: