Chronic Migraine: Epidemiology and Disease Burden

Transcription

1 Curr Pain Headache Rep (2011) 15:70 78 DOI /s z Chronic Migraine: Epidemiology and Disease Burden Aubrey N. Manack & Dawn C. Buse & Richard B. Lipton Published online: 10 November 2010 # Springer Science+Business Media, LLC 2010 Abstract Chronic migraine is a common and disabling complication of migraine with a population prevalence of about 2%. Emerging evidence suggests that episodic migraine and chronic migraine differ not only in degree, but also in kind. Compared with patients with episodic migraine, those with chronic migraine have worse socioeconomic status, reduced health-related quality of life, increased headache-related burden (including impairment in occupational, social, and family functioning), and greater psychiatric and medical comorbidities. Each year, approximately 2.5% of patients with episodic migraine develop new-onset chronic migraine (ie, chronification). Understanding the natural disease course, improving treatment and management, and preventing the onset could reduce the enormous individual and societal burden of chronic migraine, and thus, have become important goals of headache research. This review provides a summary of the history of nomenclature and diagnostic criteria, as well as recent studies focusing on the epidemiology, natural history, and burden of chronic migraine. A. N. Manack (*) Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, USA manack_aubrey@allergan.com D. C. Buse Department of Neurology, Albert Einstein College of Medicine and the Montefiore Medical Center, 1575 Blondell Avenue, Suite 225, Bronx, NY 10461, USA R. B. Lipton Department of Neurology and Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1165 Morris Park Avenue, Rousso Building, Room 330, Bronx, NY 10461, USA Keywords Chronic migraine. Episodic migraine. Epidemiology. Burden. Prevalence. Natural history. Comorbidities. Health-related quality of life. Resource utilization. Headache impact Introduction Migraine is considered a chronic disorder with episodic attacks [1], with two major subtypes differentiated based on attack frequency. Episodic migraine is characterized by attacks that occur fewer than 15 days per month. Chronic migraine is broadly defined by the presence of migraine in a person with headaches on at least 15 days per month. Diagnosis of primary headache disorders is primarily based on the presence, frequency, and severity of clinical features used to create diagnostic boundaries. Diagnostic tests serve to exclude secondary causes of headache, and biological markers mainly serve to gain insight into mechanisms. As a consequence, the headache community has struggled to reach consensus on the optimal criteria for chronic migraine for application in clinical practice, clinical trials, and academic research [2 5]. Because of these controversies, there are a wide range of terms with a multiplicity of definitions applied to persons with very frequent headaches related to migraine. The most widely used terms have been transformed migraine and chronic migraine. In recent years, some degree of consensus has emerged. Several of the definitions identify groups that are largely overlapping. Using variants of these overlapping definitions, several large-scale epidemiologic studies have contributed to our understanding of chronic migraine [6 10, 11, 12, 13]. Guidelines have emerged for clinical trials in chronic migraine [14], and several studies have demonstrated beneficial effects for preventive treatments [5, 15].

2 Curr Pain Headache Rep (2011) 15: Given the recent progress, a review of the epidemiology and burden of chronic migraine is timely. We will begin with a discussion of the emerging consensus on the diagnosis of chronic migraine. Using these definitions, we will review recent studies focusing on the epidemiology, natural history, and burden of chronic migraine. Classification and Nomenclature The term transformed migraine was first used in an indexed medical journal by Matthew et al. [16] in Several years later, Silberstein et al. [17, 18] proposed definitions for a group of chronic, frequent primaryheadache disorders, referred to as chronic daily headache (CDH). CDH was defined by headache on 15 or more days per month for at least 3 months. Transformed migraine was defined as primary CDH with a link to migraine. The presence or absence of medication overuse was defined as a modifier of transformed migraine. The criteria were tested, revised, and widely adopted, particularly in the United States (Table 1). After much debate, in 2004, chronic migraine for the first time was added to the International Classification of Headache Disorders, Second Edition (ICHD-II) as a complication of migraine [19]. The criteria required migraine without aura on 15 or more days per month for at least 3 months in the absence of medication overuse (Table 1). These criteria were tested in a subspecialty practice diary study, in which only 5% of patients with transformed migraine met criteria for chronic migraine [20]. These criteria were rapidly judged to be excessively restrictive, and revised criteria (referred to as chronic migraine revised or ICHD-2R) were proposed in June 2006 [3]. The new criteria required 15 or more days with headache per month for at least 3 months and migraine, or a response to migraine-specific treatment, at least 8 days per month, and again required the absence of medication overuse. The three sets of diagnostic criteria varied in their inclusiveness, with transformed migraine as the most inclusive, ICHD-2R being intermediate, and ICHD-II being the most restrictive (Table 1). The ICHD-2R criteria have gained traction within the headache community because they better identify those with chronic migraine seen in clinical practice [3, 4, 21 23]. The most controversial remaining point is the role of medication (analgesic) overuse in the classification of chronic migraine. Though it is clear that chronic migraine and medication overuse are associated and, indeed, relatively common in these patients [24], the causal sequence is uncertain. Medication overuse may be a response to frequent headache or headache frequency may escalate in the setting of medication overuse [2, 10, 25, 26]. To date, most research paradigms identify persons with chronic migraine and then identify those who do or do not meet revised criteria for medication overuse. We recommend this approach because it does not make assumptions about causal sequence and permits a useful approach to stratification both in clinical practice and in research. Prevalence of Chronic Migraine Estimates of chronic migraine prevalence in the population vary with case definition. A prevalence rate of approximately 2% for chronic migraine in the general population has been estimated when it is broadly defined as persons with migraine who experience headache on 15 or more days per month. Natoli et al. [27 ] performed a systematic review of the published literature to summarize populationbased studies reporting prevalence of chronic migraine among adults and to explore variation in definitions across studies. Identified were 16 publications representing 12 unique studies. The Silberstein and Lipton diagnostic criteria were most commonly used in these studies. Depending on the case definition, the prevalence of chronic migraine ranged from 0.9% to 5.1% in the general population, with estimates typically in the range of 1.4% to 2.2% [27 ]. Since the publication of this review in 2010, several new prevalence studies have emerged supporting the observation that prevalence varies with case definition. Katsarava et al. [28] used the German Headache Consortium (GHC) Study dataset to field test different chronic migraine definitions. The test sample was a population-based dataset comprising a random sample of 18, to 65-year-old patients in demographically diverse regions of Germany. Chronic migraine prevalence was estimated utilizing three case definitions (CM-I, CM-II, CM-III). The most restrictive definition (CM-I, defined as 15 headache days per month with 50% of headache days being migraine or probable migraine as defined by ICHD-II) had the lowest prevalence rate at 0.4% (95% CI, %). The CM-II definition ( 15 headache days/mo with 8 days with ICHD II defined migraine or probable migraine) yielded an intermediate prevalence estimate of 0.5% (95% CI, %). The CM-III definition ( 15 headache days/mo with reported migraine or probable migraine days as defined by ICHD-II) resulted in a prevalence of 2.0% (95% CI, %), which was most similar to estimates derived from studies using the transformed migraine definition proposed by Silberstein and Lipton [3]. Another German dataset, the Deutsche Migräne- und Kopfschmerzgesellschaft (DMKG) headache study, estimated the 6 month-period prevalence of chronic migraine

3 72 Curr Pain Headache Rep (2011) 15:70 78 Table 1 Chronic migraine diagnostic criteria Transformed migraine: Silberstein and Lipton criteria [3] Daily or near-daily headache with migraine that begins with episodic migraines and, as the headaches grow more frequent over months to years, the associated symptoms become less severe and less frequent A. Daily or almost daily (>15 d/mo) head pain for >1 mo B. Average headache duration of >4 h/d (if untreated) C. At least 1 of the following: 1. History of episodic migraine meeting any IHS criteria 1.1 to History of increasing headache frequency with decreasing severity of migrainous features over at least 3 months 3. Headache at some time meets IHS migraine criteria 1.1 to 1.6 other than duration D. Does not meet criteria for new daily persistent headache or hemicrania continua E. At least 1 of the following: 1. There is no suggestion of one of the disorders listed in groups Such a disorder is suggested, but it is ruled out by appropriate investigations 3. Such a disorder is present, but first migraine attacks do not occur in close temporal relation to the disorder Chronic migraine (original): ICHD-2 [18] Migraine headache occurring on 15 or more days per month in the absence of medication overuse A. Headache fulfilling criteria C and D for migraine without aura on 15 days per month for >3 mo B. Not attributed to another disorder Note: 1. History and physical and neurological examination do not suggest any of the disorders listed in groups 5 12; or history and/or physical and/or neurological examinations do suggest such disorder but it is not ruled out by appropriate investigations; or such disorder is present but headache does not occur for the first time in close temporal relation to the disorder. 2. When medication overuse is present and fulfills criterion B for any of the subforms of 8.2 (medication-overuse headache), it is uncertain whether criterion B for (chronic migraine) is fulfilled until 2 months after medication has been withdrawn without improvement. Chronic migraine (revised): ICHD-2 (revised) [19] Frequently occurring headache ( 15 days per month) with at least 8 days of migraine or probable migraine per month in the absence of medication overuse A. Headache (tension-type and/or migraine) on 15 or more days per month for at least 3 months B. Occurring in a patient who has had at least five attacks fulfilling criteria 1.1 (migraine without aura) C. On 8 or more days per month for at least 3 months, headache has fulfilled C.1 and/or C.2 below; that is, has fulfilled criteria for pain and associated symptoms of migraine without aura: 1. Has at least two of a d: a. Unilateral location b. Pulsating quality c. Moderate or severe pain intensity d. Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) And at least one of a or b below: a. Nausea and/or vomiting b. Photophobia and phonophobia 2. Treated and relieved by triptan(s) or ergot before the expected development of C.1 above D. No medication overuse and not attributed to another causative disorder ICHD International Classification of Headache Disorders, ICHD-2 International Classification of Headache Disorders, Second Edition, IHS International Headache Society according to the original and highly restrictive ICHD-II definition. Straube et al. [29] reported that, when stratified by medication-overuse headache (MOH) criteria, prevalence was 0.28% in those with chronic migraine regardless of MOH and 0.09% in those without MOH. In this study, MOH was derived from International Headache Society (IHS) 8.1 criteria and based on the reported symptom frequency and the frequency of medication intake specifically for headache during the previous month with a reported 6-month prevalence of 0.98%. Because differences in standard medical practice along with environmental and societal risk factors can contribute to variation in disease prevalence, results from two recent population-based studies conducted in the Republic of Georgia and Brazil are of particular interest. Katsarava et al. [30 ] conducted a study to estimate the 1-year

4 Curr Pain Headache Rep (2011) 15: prevalence of both migraine and tension-type headache in the general population of the Republic of Georgia, and reported chronic migraine prevalence as 1.4% (95% CI, %) and chronic tension-type headache prevalence as 3.3% (95% CI, %). A population-based, crosssectional study conducted in a rural area of Brazil concluded that the 1-year prevalence of CDH was 3.6%, with chronic migraine being the most common subtype at 36.8% of those with CDH [31 ]. These rates are comparable to rates summarized in the previously published systematic review of chronic migraine prevalence. Incidence and Risk Factors for Onset of Chronic Migraine The incidence or new onset of chronic migraine within the general population has not been studied [27 ]. However, based on results from the American Migraine Prevalence and Prevention (AMPP) study, among persons with episodic migraine in the general United States population, the incidence of chronic migraine in a subsequent year was 2.5% [10]. In a prospective study from Germany, the incidence of chronic headache was 14% [32]. In this study, attack day frequency and medication use were major risk factors for chronification. In a long-term, retrospective, clinic-based study of persons with one to six attacks per month of episodic migraine, 1.6% had developed chronic migraine at 10 years postassessment [33]. The terms progression and chronification have been used to describe the evolution from episodic to chronic migraine. Risk factors for chronification can be divided into three categories: nonmodifiable, modifiable, and putative [31]. Nonmodifiable risk factors include older age, female sex, Caucasian race (in a US sample), low education level, worse socioeconomic status, and genetic factors. Modifiable factors are important because they provide targets for intervention and include attack frequency, obesity, medication overuse, snoring, stressful life events, depression, and anxiety. Putative factors, or factors currently being investigated, include proinflammatory states and prothrombotic states [34]. Recent publications have provided supportive data for some previously identified modifiable risk factors and evidence for the role of depression from episodic to chronic migraine. Ashina et al. [35] conducted a cross-sectional and longitudinal population study to investigate the relation of clinical characteristics of chronic headaches (ie, new-onset or persistent chronic headache) to poor outcome. During the 12-year follow-up and within a population with migraine, univariate analysis concluded that both daily use of acute headache medications and use of migraine prophylactic medications were significant risk factors for poor outcome (eg, chronification to 15 headache days per month) [35]. Migraine and depression are highly comorbid and their relationship is bidirectional, thus is difficult to determine if depression is a risk factor or a consequence of migraine [36]. Additionally, patients with chronic migraine have a greater risk of depression than those with episodic migraine [11, 37 ]; therefore, the AMPP study dataset was utilized to elucidate the impact of depression on migraine chronification [42]. Among those with episodic migraine, depression was a significant predictor of the new onset of chronic migraine. Moreover, the risk of new-onset chronic migraine increased with the severity of depression. In fully adjusted models that included adjusting for headache frequency (average days/mo), moderate, moderately severe, and severe depression were significant independent predictors of chronic migraine onset. Data strongly suggest that depression is a risk factor for chronification to chronic migraine [38]. Because chronification to chronic migraine does not occur in all those with migraine, identifying risk has become an important goal in headache research [39 41]. Particularly in a heterogeneous patient population that is not easily treated, recognizing risk factors can help identify targets for pharmacologic and nonpharmacologic intervention to prevent chronification and in effect, more successfully manage those with episodic migraine [40, 43]. Chronic Migraine Remission Data are limited on the remission of chronic migraine. However, one important goal in treatment is reducing attack frequency so that chronic migraine remits to episodic migraine [14]. Manack et al. [38] utilized the longitudinal AMPP study dataset to estimate remission rates in a population-based sample of persons with chronic migraine; to identify potential predictors of chronic migraine remission; and to assess the influence of chronic migraine remission on headache-related disability. Results concluded that approximately one fourth of those with chronic migraine remitted to episodic migraine or other headache types over the course of 2 years. In multivariate models, predictors of remission included headache frequency (average days/mo) and the absence of allodynia. Furthermore, those who continued to have chronic migraine (ie, the persistent group) demonstrated increased headacherelated disability over the course of 2 years, while those who remitted (eg, average headache frequency decreased to <10 days/mo) demonstrated decreased headache-related disability. These findings provide evidence of the natural course of chronic migraine. We now have evidence from the general population that chronic migraine remission does

5 74 Curr Pain Headache Rep (2011) 15:70 78 occur, but rates are variable, and that benefits of remission go beyond symptom reduction translating to marked decreases in headache-related disability [42]. Sociodemographic and Comorbidity Profiles of Episodic and Chronic Migraine As with other primary headache disorders, migraine is subtyped by attack frequency into an episodic and a chronic form based on the average number of headache days per month ( 15 headache days/mo versus <15 headache days/ mo, respectively) over the previous 3 months [3, 19, 40]. Recent data suggests that episodic migraine and chronic migraine differ not only in the degree of headache attack frequency but also in biological type [44]. Distinguishing related disorders in the absence of a diagnostic gold standard is a well-recognized challenge. Epidemiologic data are critical to making these distinctions. Buse et al. [11 ] used the large longitudinal dataset of migraine sufferers, the AMPP study, to assess differences in sociodemographic and comorbidity profiles between chronic migraine and episodic migraine within the general population. Compared with episodic migraine, respondents with chronic migraine had statistically significant lower levels of household income, were less likely to be employed full time, and were more likely to be occupationally disabled. Those with chronic migraine were approximately twice as likely to have depression, anxiety, and chronic pain. Respiratory disorders (including asthma, bronchitis, and chronic obstructive pulmonary disease) and cardiac risk factors (including hypertension, diabetes, high cholesterol, and obesity) also were significantly more likely to be reported by those with chronic migraine [11 ]. Also within the AMPP study dataset, Bigal et al. [45] evaluated the differences in cutaneous allodynia between the two migraine populations and concluded that cutaneous allodynia is more common and more severe in chronic migraine than in episodic migraine. Table 2 summarizes key sociodemographic and comorbidity differences between chronic and episodic migraine. Yalug et al. [46 ] conducted a clinic-based study in Turkey to investigate whether patients suffering from episodic migraine differ from those with chronic migraine in regards to measures of depression, anxiety, and alexithymia. A total of 165 patients with episodic migraine and 135 patients with chronic migraine were studied. The Beck Depression Inventory, State Trait Anxiety Inventory, and Toronto Alexithymia Scale (TAS) were administered. Compared to patients with episodic migraine, the patients with chronic migraine had significantly higher scores on measures of depression but not alexithymia and anxiety. There was a positive correlation between TAS scores and age and education in both migraine groups, but there was no correlation between TAS scores and other demographic variables. Depression and anxiety were significantly correlated with alexithymia in both migraine groups. Results support population-based research that patients with chronic migraine are considerably more likely to be depressed than those with episodic migraine [46 ]. Katsarava et al. [28] assessed differences in the demographic profiles of chronic migraine, low-frequency episodic migraine (LFEM: 0 8 headache days/mo), and high-frequency episodic migraine (HFEM: 9 14 headache days/mo) with the GHC study dataset. Women predominated in each of the migraine groups and ranged between 67% and 72% of the respective populations. Compared to those with LFEM and HFEM, those with chronic migraine were significantly older, had significantly higher body mass index (BMI), were significantly more likely to report lower levels of education, and were significantly more likely to be current smokers [28]. A recent publication from Blumenfeld et al. [37 ] offers a rare comparison of chronic migraine and episodic migraine in nine countries across North America, Europe, and the Asia/Pacific region. The International Burden of Migraine Study (IBMS) utilized web-based surveys to assess differences in sociodemographic profiles, headache characteristics, comorbidities, and burden between the two migraine disorders and between regions. Data support the findings of other population-based studies, in that those with chronic migraine are more likely than those with episodic migraine to be overweight, unemployed, more depressed, and more anxious. Additionally, the IBMS data support that the clinical presentation differs between chronic migraine and episodic migraine. Those with chronic migraine reported longer headache duration (hours) and greater headache pain intensity. When evaluating headache features, participants with chronic migraine reported greater frequency of moderate to severe pain, throbbing, photophobia, and phonophobia compared to those with episodic migraine [37 ]. Given the evaluation of multiple dimensions across three robust datasets, it is becoming evident that chronic migraine and episodic migraine differ in important ways and that epidemiologic data support a biological distinction. Headache-related Burden and Impact of Chronic Migraine Chronic migraine is a disabling, underdiagnosed, unrecognized, and undertreated disorder [47]. Those with chronic migraine spend at least half their days suffering from debilitating pain and associated symptoms (eg, nausea, vomiting, photophobia, phonophobia). This nearly constant

6 Curr Pain Headache Rep (2011) 15: Table 2 Summary of sociodemographic and comorbidity differences between chronic and episodic migraine Variable Chronic migraine Episodic migraine Mean age, y (SD) 47.7 (14.0) 46.0 (13.8) Race a, % Employment 1 in 5 reported being occupationally disabled 1 in 10 reported being occupationally disabled Household income b, % 29.9% 24.9% Mean BMI, n (SD) 29.8 (8.3) 29.2 (7.9) Cutaneous allodynia, % Comorbid conditions More likely to report or meet criteria for psychiatric, pain, respiratory, and cardiovascular comorbid conditions Less likely to report or meet criteria for psychiatric, pain, respiratory, and cardiovascular comorbid conditions Significantly different finding reported in published AMPP study data [10, 11 ] AMPP American Migraine Prevalence and Prevention, BMI body mass index, SD standard deviation a Reported percent of Caucasian respondents b Reporting less than $22,500/y interference in the predictability of normal life activities affects the ability to work, perform routine chores, and build and maintain functional family, social, and community relationships [47]. Thus, patients with chronic migraine have been recognized as one of the segments suffering most from headache [3]. However, migraine clinical trial studies generally have excluded patients with chronic migraine. The exclusion is a combined result of the evolution of the diagnostic criteria and considerable discussion around the biological nature of those with frequent headaches, especially when there is presence of medication overuse [5]. With little controlled empirical trial data on the treatment of the chronic migraine population, there is little evidence available to help physicians care for these patients [3]. Consequently, those with chronic migraine continue to suffer from this disabling headache disorder. Recent studies have aimed to quantify the burden that frequent migraine attacks pose on patients, their families and employers, and health care systems. Bigal et al. [47] evaluated the disability profile and patterns of treatment and health care use for chronic migraine in the general population and in contrast to episodic migraine. They reported that, according to evaluations of the Migraine Disability Assessment (MIDAS), chronic migraine is more disabling than episodic migraine and chronic migraine does not appear to be adequately managed, as less than one third of chronic migraine sufferers received migraine-specific acute therapies and less than half reported satisfaction with their acute therapies. While most patients with chronic migraine (87.6%) had previously sought care to discuss their headaches with a health professional, less than half visited a neurologist, and only 26% reported visiting a pain specialist. Despite most of those with chronic migraine meeting Headache Consortium Guidelines for Prevention, just 33.3% were currently using preventive medications [47]. In 2001, Wang et al. [48] established that when comparing patients with episodic migraine to those with chronic headache conditions (either chronic migraine or chronic tension-type headache), and after controlling for the Hospital Anxiety and Depression Scale, age, sex, education, and other chronic illnesses, the patients with chronic migraine had the worst Medical Outcome Study-Short Form profiles; whereas the patients with chronic tensiontype headache and migraine had compatible results [48]. Blumenfeld et al. [37 ] recently compared headacherelated disability, health-related quality of life (HRQoL), healthcare costs, and resource utilization between patients with episodic migraine and those with chronic migraine in the IBMS. These global results concluded that, compared to patients with episodic migraine, those with chronic migraine reported significantly more severe disability as assessed by MIDAS, lower HRQoL as assessed by the Migraine-Specific Quality of Life questionnaire, higher levels of anxiety and depression as assessed by to the Patient Health Questionnaire-4, and greater health care resource utilization. These findings were consistent between country-specific findings and with previous clinicand population-based studies [37 ]. Given the substantial burden and resource utilization, it is not surprising that chronic migraine exacts a significantly higher economic toll on patients and health care systems compared with other forms of migraine. Munakata et al. [49 ] utilized longitudinal data from the AMPP study to evaluate the impact of incident chronic migraine on health care resource utilization, medication use, and productivity loss, and provided estimates of the total direct and indirect costs

7 76 Curr Pain Headache Rep (2011) 15:70 78 associated with chronic migraine. Direct and indirect headache-related costs were estimated using unit cost assumptions from the PharMetrics Patient-Centric database (IMS, Norwalk, CT), wholesale acquisition costs (Red Book), and wage data from the US Bureau of Labor Statistics. Average per-person annual total costs, including direct and indirect costs, were 4.4-fold greater for patients who developed chronic migraine ($7750) compared with those who remained episodic ($1757). Munakata et al. [49 ] reported that patients who developed chronic migraine reported significantly more primary care visits, neurologist or headache specialist visits, pain clinic visits, and emergency room visits compared with those whose migraine remained episodic; however, differences in hospital overnight stays and urgent care visits did not reach statistical significance. Because migraine attacks may necessitate complete bed rest and interfere with occupational and educational functioning [37, 50, 51], the potential economic consequences go beyond direct health care costs. The impact of chronic migraine on lost productive time (LPT), which sums absenteeism and presenteeism, only recently has been explored. Stewart et al. [52] compared the work impact of chronic migraine versus episodic migraine in the AMPP study dataset. Approximately one in five patients with chronic migraine compared to one in ten patients with episodic migraine reported being occupationally disabled [11, 52]. When assessing LPT for those working with migraine, those with chronic migraine were less likely to be working for pay compared with migraine with 3 or more headache days per month. On average, those with chronic migraine lost 4.6 h per week from headache compared with 1.1 h for those with 3 or less headache days/mo. Those with 10 to 14 headache days per month or with chronic migraine accounted for 9.1% of employed migraineurs, 20.8% of work-related LPT, and 35% of the overall lost work time when considering medical leave and unemployment [52]. Conclusions Chronic migraine is a common and disabling complication of migraine with a population prevalence of about 2%. Episodic migraine and chronic migraine differ not only in degree but also in kind. Operational definitions of chronic migraine have provided a foundation for epidemiologic studies that reveal the prevalence, risk factors, and burden of chronic migraine. Success in chronic migraine treatment trials also is a reflection of the utility of the current case definition. Despite this progress, the term chronic migraine most likely encompasses a biologically heterogeneous set of disorders that may be better defined as robust longitudinal clinical phenotypes and biomarkers emerge [4]. Chronic migraine imposes a substantial burden on individuals who have it and a substantial economic burden on society. Data support the need to prevent new onset of chronic migraine or chronification and to provide appropriate management and treatment for chronic migraine, thereby reducing the considerable unmet medical need. As we learn to better identify patients, communicate disease awareness, define risk factors, and develop therapies to effectively manage both episodic and chronic migraine, the ultimate reward will be a significant reduction in the impact of migraine. Disclosures Dr. Aubrey N. Manack is a full-time employee of Allergan, Inc. Dr. Dawn C. Buse has served as a consultant to Allergan, and has received grants or has grants pending with Allergan, Merck Pharmaceuticals, Endo Pharmaceuticals, OrthoMcNeil Pharmaceuticals, and GlaxoSmithKline. Dr. Richard B. Lipton is a member of the advisory boards of Allergan, Merck, and MAP Pharmaceuticals, Inc.; has served as a consultant for Allergan; has received grants or has grants pending with Allergan, Merck Pharmaceuticals, GlaxoSmithKline, and Bristol-Myers Squibb; has received payment for manuscript preparation from Allergan; has received payment for the development of educational presentations from Allergan; and has received travel expense compensation from Allergan and Merck. References Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Haut SR, Bigal ME, Lipton RB: Chronic disorders with episodic manifestations: focus on epilepsy and migraine. Lancet Neurol 2006, 5: Manack A, Turkel C, Silberstein S: The evolution of chronic migraine: classification and nomenclature. 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This article concludes that the prevalence of chronic daily headache in rural area of Brazil is similar to previously published data in South America, and that psychiatric conditions often are comorbid. 32. Katsarava Z, Schneeweiss S, Kurth T, Kroener U, Fritsche G, Eikermann A, Diener HC, Limmroth V: Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004, 62: Dahlöf CG, Johansson M, Casserstedt S, Motallebzadeh T: The course of frequent episodic migraine in a large headache clinic population: a 12-year retrospective follow-up study. Headache 2009, 49: Bigal M: Migraine chronification concept and risk factors. Discov Med 2009, 8: Ashina S, Lyngberg A, Jensen R: Headache characteristics and chronification of migraine and tension-type headache: A population-based study. Cephalalgia 2010, 30: Breslau N, Lipton RB, Stewart WF, Schultz LR, Welch KM: Comorbidity of migraine and depression: investigating potential etiology and prognosis. Neurology , 60: Blumenfeld AM, Varon SF, Buse DC, Kawata AK, Manack A, Goadsby PJ, Lipton RB: Disability, HRQOL and Resource Use Among Chronic and Episodic Migraineurs: Results from the International Burden of Migraine Study (IBMS). Cephalalgia 2010, doi: / This study is the only multicountry, international study of migraine epidemiology, impact, and burden. The study utilized a web-based survey with items that parallel the United States AMPP study questionnaires. Results of this article compare persons with episodic migraine and chronic migraine on headache features, headache-related disability, health-related quality of life, health care resource

9 78 Curr Pain Headache Rep (2011) 15:70 78 utilization, and medical and psychiatric comorbidities across nine countries. 38. Ashina S, Buse DC, Manack AN, Serrano D, Maizels M, Turkel C, Lipton RB. Depression: a risk factor for migraine chronification: results from the American Migraine Prevalence and Prevention (AMPP) Study. Neurology 74(Suppl 2):A113, Presented at the Annual Meeting of the American Academy of Neurology, April 13, Bigal ME, Lipton RB: Modifiable risk factors for migraine progression. Headache 2006, 46: Lipton RB: Tracing transformation: chronic migraine classification, progression, and epidemiology. Neurology 2009, 72:S3-S Lipton RB, Bigal ME: Looking to the future: research designs for study of headache disease progression. Headache 2008, 48: Manack A, Buse DC, Serrano D, Turkel CC, Lipton RB: Rates, predictors, and consequences of remission from chronic migraine to episodic migraine. Neurology 2010, In press. 43. Couch JR, Lipton RB, Stewart WF, Scher AI: Head or neck injury increases the risk of chronic daily headache: a population-based study. Neurology 2007, 69: Lipton RB, Chu MK: Conceptualizing the relationship between chronic migraine and episodic migraine. Expert Rev Neurother 2009, 9: Bigal ME, Ashina S, Burstein R, Reed ML, Buse D, Serrano D, Lipton RB: Prevalence and characteristics of allodynia in headache sufferers: a population study. Neurology 2008, 70: Yalug I, Selekler M, Erdogan A, Kutlu A, Dundar G, Ankarali H, Aker T: Correlations between alexithymia and pain severity, depression, and anxiety among patients with chronic and episodic migraine. Psychiatry Clin Neurosci 2010, 64: This article explored the unclear but hypothesized correlation between alexithymia and the severity of pain, depression, and anxiety among patients with migraine and concluded that depression and anxiety were significantly correlated with alexithymia in both episodic and chronic migraine. Additionally, there was a positive association between depression, anxiety, and alexithymia in both subsets of patients with migraine. 47. Bigal ME, Serrano D, Reed M, Lipton RB: Chronic migraine in the population: burden, diagnosis, and satisfaction with treatment. Neurology 2008, 71: Wang SJ, Fuh JL, Lu SR, Juang KD: Quality of life differs among headache diagnoses: analysis of SF-36 survey in 901 headache patients. Pain 2001, 89: Munakata J, Hazard E, Serrano D, Klingman D, Rupnow MF, Tierce J, Reed M, Lipton RB: Economic burden of transformed migraine: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache 2009, 49: This article highlights the economic burden that chronic migraine imposes on society in the United States. 50. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M: Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001, 41: Stewart WF, Lipton RB, Dowson AJ, Sawyer J: Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology 2001, 56:S20-S Stewart WF, Wood GC, Manack A, Varon SF, Buse DC, Lipton RB: Employment and Work Impact of Chronic Migraine and Episodic Migraine. J Occup Environ Med 2010, 52:8 14.