Neurology Volume 72(5) February 3, 2009 Supplement 1

INTRODUCTION

Conventional management and novel modalities for improved treatment of chronic migraine Richard B. Lipton, MD Address correspondence and reprint requests to Richard B. Lipton, MD, Department of Neurology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 [email protected]

Neurology® 2009;72 (Suppl 1):S1–S2

Over the past decade, there has been remarkable progress in our understanding of chronic migraine (CM) and its classification, diagnosis, epidemiology, pathophysiology, and treatment. CM is one of the most disabling of the primary headache disorders and an enormous challenge in neurologic and headache practice. This supplement, focused on that progress, is based on the symposium, Conventional Management and Novel Modalities for Improved Treatment of Chronic Migraine, held at the American Headache Society Annual Scientific Meeting in June 2008. CM is now recognized as one of 4 types of primary chronic daily headache (CDH) of long duration, a syndrome defined by primary headaches 15 or more days per month for at least 3 months with attacks that last 4 hours or more per day on average.1,2 The other forms of CDH of long duration include chronic tension-type headache, new daily persistent headache, and hemicrania continua. With the exception of chronic tension-type headache, these disorders were new additions to the second edition of the International Classification of Headache Disorders (ICHDII).2 In defining CDH, it is useful to distinguish between conceptual and operational definitions. Conceptually, CM is a complication of migraine that arises as headache attacks increase in frequency, typically over months to years. This phenomenon of increasing headache frequency in people with migraine has been well known for many years based on

both observations in clinical practice3,4 and longitudinal population-based studies.5 The operational definition of CM has been debated and several alternative definitions have been proposed. There are 2 major issues: defining the link of CM to episodic migraine (EM) and distinguishing CM from EM with a co-occurring headache disorder (ie, tensiontype headache or medication overuse headache). The first operational definition for CM used the term transformed migraine instead and defined the link to migraine broadly.6 In contrast, the 2004 ICHD-II provided a very restrictive link to EM, requiring 15 or more headache days per month that met the criteria for migraine without aura. Diary studies showed that a limited number of patients met these criteria,7 and in response, several alternative case definitions were proposed and tested. The ICHD-II selected a definition that requires migraine without aura or response to migraine-specific medication 8 or more days per month; fortunately, this definition and several alternatives identify virtually identical groups of patients.7,8 With diagnostic criteria in place, a number of studies have examined the epidemiology of CM and its rate of onset among people with EM. These studies, reviewed in the article by Lipton in this supplement, provide several key findings. CM is a highly prevalent and disabling disorder, affecting about 2% of the general population.9,10 CM has a greater impact on the individual sufferer than EM, as reflected by higher migraine disability assess-

From the Department of Neurology, Albert Einstein College of Medicine, Bronx, NY. Jointly sponsored by the Annenberg Center for Health Sciences at Eisenhower and CogniMed Inc. This program is supported by an independent educational grant provided by Allergan, Inc. Disclosure: R.B.L. has participated on advisory boards for, consulted for, and received research support from Allergan, Inc., AstraZeneca, Bristol-Myers Squibb Company, GlaxoSmithKline, Novartis Pharmaceuticals Corporation, Ortho-McNeil Neurologics, Inc., and Pfizer Inc. Neurology® supplements are not peer-reviewed. Information contained in Neurology® supplements represents the opinions of the authors. These opinions are not endorsed by nor do they reflect the views of the American Academy of Neurology, Editor-in-Chief, or Associate Editors of Neurology®.

Copyright © 2009 by AAN Enterprises, Inc.

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ment scale scores, more lost productive time, greater direct medical costs and greater comorbidities. In addition, the rate of onset of CM in people with EM is about 2.5% per year in the population. Risk factors for the new onset of CM include medication overuse, headache frequency, obesity, allodynia, snoring, and head injury, among others.5 Recently, there has been an increasing hope that risk factor modification in people with EM may help prevent the onset of CM. There have also been a number of studies focused on the pathophysiology of CM, reviewed in the paper by Aurora in this supplement. Studies show that both allodynia and headache frequency are associated with CM and with changes in the brain.4,11 CM is associated impairment in the processing of sensory information. Functional imaging studies identify abnormalities in the periaqueductal gray (PAG) matter that increase with the number of migraine attacks. Building on seminal observations by Welch et al,12 Aurora proposes that repetitive migraine attacks may cause recurrent episodes of central sensitization which may generate free radicals that damage the PAG matter and contribute to migraine progression. Finally, therapeutic options for CM have been assessed at an accelerating rate with studies that are improving in quality. Mathew summarizes 3 categories of treatment studies in this supplement: studies of individual preventive treatments without an active comparator group, studies of preventive treatments with an active comparator group, and studies of combination preventive treatments. He summarizes and critiques studies of gabapentin, tizanidine, fluoxetine, amitriptyline, valproate, topiramate, and botulinum toxin type A, as well as novel nonpharmacologic ap-

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proaches including occipital nerve stimulation and closure of a patent foramen ovale. As of this writing, there are no FDAapproved treatment options for CM. The contributors to this supplement are heartened by the progress in the study of CM and look forward to an expansion of both the evidence base and the availability of treatment options with rigorous evidence for safety and efficacy in the treatment of CM. REFERENCES 1. Lipton RB, Bigal ME, Steiner TJ, Silberstein SD, Olesen J. Classification of primary headaches. Neurology 2004;63: 427– 435. 2. Olesen J, Steiner TJ. The international classification of headache disorders, 2nd edn (ICDH-II). J Neurol Neurosurg Psychiatry 2004;75:808 – 811. Editorial. 3. 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;69:1169 –1177. 4. Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 2003;106:81– 89. 5. Bigal ME, Lipton RB. Concepts and mechanisms of migraine chronification. Headache 2008;48:7–15. Review. 6. Silberstein SD, Lipton RB, Sliwinski M. Classification of daily and near-daily headaches: field trial of revised IHS criteria. Neurology 1996;47:871– 875. 7. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. The International Classification of Headache Disorders revised criteria for chronic migraine: field testing in a headache specialty clinic. Cephalalgia 2007;27:230 –234. 8. Olesen J, Bousser MG, Diener HC, et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia 2006;26:742–746. 9. Scher AI, Stewart WF, Liberman J, et al. Prevalence of frequent headache in a population sample. Headache 1998;38:497–506. 10. Castillo J, Mun˜oz P, Guitera V, Pascual J. Epidemiology of chronic daily headache in the general population. Headache 1999;39:190 –196. 11. Aurora SK, Barrodale PM, Tipton RL, Khodavirdi A. Brainstem dysfunction in chronic migraine as evidenced by neurophysiological and positron emission tomography studies. Headache 2007;47:996 –1003. 12. Welch KM, Nagesh V, Aurora SK, Gelman N. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache 2001;41:629 – 637.

ARTICLES

Tracing transformation Chronic migraine classification, progression, and epidemiology

Richard B. Lipton, MD

Address correspondence and reprint requests to Richard B. Lipton, MD, Department of Neurology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 [email protected]

ABSTRACT

Migraine attacks sometimes increase in frequency over time. Headache experts conceptualize this process with a model that envisions transition into and out of four distinct states: no migraine, low-frequency episodic migraine (⬍10 headaches per month), high-frequency episodic migraine (10 –14 headaches per month), and chronic migraine (CM, ⱖ15 headaches per month). Transitions may be in the direction of increasing or decreasing headache frequency and are influenced by specific risk factors. Overall, population studies estimate that patients who have low-frequency episodic migraine or high-frequency episodic migraine will transition to CM at the rate of about 2.5% per year. Two longitudinal population studies, the Frequent Headache Epidemiology study and the ongoing American Migraine Prevalence and Prevention (AMPP) study provide longitudinal population data that has defined the rates of and risk factors for transition. Launched in 2004, the AMPP study has followed a sample of ⬎10,000 migraine sufferers annually for 4 years. Cross-sectional data from the Frequent Headache Epidemiology study and the AMPP study show that patients with chronic daily headaches have lower levels of education and household income. In addition, epidemiologic profiles show that CM sufferers tend to be older and have higher body mass indexes. These studies have also assessed a number of potential risk factors associated with the transition to CM. These include baseline high attack frequency, obesity, stressful life events, snoring, and overuse of certain classes of medication. In particular, opiate and barbiturate combination products contribute to migraine progression, and nonsteroidal anti-inflammatory agents are protective in patients with ⬍10 headache days per month. The influence of medication is modified by both headache attack frequency and frequency of medication use. Although depression and anxiety are associated with an increased risk of new-onset CM, the influence of depression is accounted for by migraine disability assessment scale score, whereas the effect of anxiety may be independent of migraine disability assessment scale score. Emerging data on the longitudinal risk of CM suggest that, in a population at risk, CM may be a preventable disorder. NEUROLOGY 2009;72 (Suppl 1):S3–S7

Migraine is a common neurologic disorder that has a wide variety of subtypes, many comorbidities, and a variable prognosis.1 Because a broad range of disorders cause headache, a systematic approach to classification and diagnosis is essential for clinical management.2 Classification of very frequent headaches is a controversial subject.3 The International Classification of Headache Disorders (ICHD) is a comprehensive and hierarchical classification system for both primary and secondary headache disorders

developed by the International Headache Society.4 Its second edition, the ICHD-II, reflects improved understanding of some headache disorders and identifies new disorders.2 It is hoped that the ICHD-II will continue to help improve clinical diagnosis and management of headache.4 Although most people with primary headaches have two headache days per month or fewer, about 4% of adults experience headaches more days than not.2,3 Chronic daily headache (CDH) is one of the

From the Department of Neurology, Albert Einstein College of Medicine, Bronx, New York. Jointly sponsored by the Annenberg Center for Health Sciences at Eisenhower and CogniMed Inc. This program is supported by an independent educational grant provided by Allergan, Inc. Disclosure: R.B.L. has participated on advisory boards for, consulted for, and received research support from Allergan, Inc., AstraZeneca, Bristol-Myers Squibb Company, GlaxoSmithKline, Novartis Pharmaceuticals Corporation, Ortho-McNeil Neurologics, Inc., and Pfizer Inc. Neurology® supplements are not peer-reviewed. Information contained in Neurology® supplements represents the opinions of the authors. These opinions are not endorsed by nor do they reflect the views of the American Academy of Neurology, Editor-in-Chief, or Associate Editors of Neurology®.

Copyright © 2009 by AAN Enterprises, Inc.

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Figure

Epidemiologic cycle. Reproduced with permission5

more common headache presentations to headache specialty care centers.2 There is much to be learned about the biologic mechanisms that lead to progressively worse headache symptoms, and the epidemiologic literature provides insight into factors that affect the risk of headache progression.3 It is now possible to design trials to explore the prevention of migraine progression.1 The epidemiologic cycle provides a framework for linking risk factors discovered in epidemiologic studies to clinical trials and clinical practice (figure).5 Clinical observations can be used to create hypotheses that support the development of analytic epidemiologic studies.1 Potential risk factors can be identified from these studies.1 Risk factor modification, or treatment intended to modify the course of the disease, can then be tested.1 Ideally, repetition of this cycle will contribute to continued improved care of patients with headache. Migraine is considered to be in remission when symptoms cease over a prolonged period, often 1 year. Persistent migraine is defined by relative clinical stability with no markers of progression. Migraine that undergoes progression clinically evolves to highfrequency episodic migraine or chronic migraine (CM). Functional changes may accompany migraine progression, including the development of allodynia, and changes in the periaqueductal gray matter. Anatomically, lesions occur both in and outside of the brain as a result of migraine progression.1,6,7 CDH comprises disorders characterized by a high frequency of headaches per month (ⱖ15), including medication-overuse headaches.8 CDH can be subdivided into primary and secondary. Primary CDH is unrelated to a structural or systemic illness and can be grouped into long- or short-duration disorders, whereas secondary CDH has an underlying cause, such as medication overuse, head trauma, cervical spine disorders, or vascular disorders. A headache duration of ⬍4 hours, or short-duration CDH, includes differential diagnoses of cluster headache, paroxysmal hemicrania, idiopathic stabbing headS4

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ache, hypnic headache, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. A long-duration CDH is defined as a headache duration exceeding 4 hours. Its primary attributable disorders, with diagnostic criteria defined by ICHD-II, are CM, hemicrania continua, chronic tension-type headache, and new daily persistent headache. Long-duration CDH is a prevalent problem, with ⬃3% to 5% of the worldwide population experiencing daily or near-daily headaches. Most patients with long-duration primary CDH have CM. One of the important new changes in ICHD-II was the inclusion of CM, which is defined as pain and symptoms associated with migraine without aura for 15 days or more per month for longer than 3 months, without medication overuse.2,4 CM causes significant disability, resulting in a negative impact on quality of life and mental health and impairing physical, social, and occupational function.8,9 Although the terms CM and transformed migraine (TM) were used synonymously in the past, ICHD-II does not recognize TM as separate.2 One reason CM is now used in place of TM is that a history of transformation often was missing for patients in this subset.8 MIGRAINE PROGRESSION OR ESCALATION

Migraine can be a progressive disease in some patients and can transform into CM.1,10 Many clinical observations have been made regarding migraine and CDH. CM is common and may emerge, remit, and re-emerge. Although ICHD-II does not include medication overuse in the definition of CM, CM is associated with medication overuse, as well as depression and other comorbidities. Further, medication overuse has been demonstrated to coexist in most patients with CDH, and improvement can occur once the overused headache medication is withdrawn.11 In some studies, CM developed faster in patients who overused triptans and used fewer single dosages than patients who overused ergots or analgesics.11 Patients with an intermediate headache frequency of 6 to 9 days per month were at greater risk for headache chronicity, and this risk was even higher for patients with the critical frequency of 10 to 14 headache days per month.11 Migraine shares common features with episodic pain disorders, such as postoperative pain or posttraumatic pain, and with chronic pain disorders, such as osteoarthritis or painful neuropathy.1 Consequently, migraine can be considered a chronic disorder with episodic attacks.1,12 Progression may be physiologic, anatomic, or clinical, which leads to CM.1,13 Progression may be activated by mecha-

nisms that produce migraine attacks, such as cortical spreading depression, or by the results of the attacks, such as lesions in the periaqueductal gray matter.13 Because migraine does not progress in most patients, applying risk factors to identify individuals at high risk for progression has become an important goal in public health research.1,14 Risk factors can be divided into those that are easily modifiable and those that are not.1 Age and gender are nonmodifiable risk factors, for instance, whereas socioeconomic status and head injury are not easily modified.1 Easily modifiable risk factors for migraine progression include headache frequency, allodynia, obesity, acute medication overuse, depression, stressful life events, caffeine consumption, and snoring.1 Attack frequency and obesity are among the most important risk factors for migraine progression.1 Headache frequency and medication overuse act in concert as risk factors for chronicity of headache.11,12 However, because some patients can experience CM without medication overuse and others overuse medication without experiencing chronic headache, medication overuse is not the sole determinant of migraine progression.11 Important approaches that may reduce the risk of developing CDH include decreasing headache frequency with behavioral and pharmacologic interventions, weight loss and maintenance of ideal body weight, avoiding medication and caffeine overuse, treating sleep disturbances and snoring, and screening for depression and other psychiatric comorbidities.15 In clinic-based samples, the prevalence and severity of somatic symptoms were greater in patients with chronic headache and in those with severe headacherelated disability.16 Chronic headache, severe disability, and high somatic symptom severity were associated with major depressive disorder. Major depression may increase pain perception, and painful symptoms may be a manifestation of major depression. Recognizing risk factors for CDH is an important step toward identifying methods to manage CDH more effectively and determining preventive strategies.17 Head and neck injuries have long been associated with headache.17 A recent study suggested that headache related to head and neck injuries may be a unique subclassification of CDH, based on increased frequency of migraine with aura and the significant increase in frequency of daily headache (⬎30 per month).17 Sleep disorders may result from or may cause headache.18 Chronic headache and depression may cause disturbed sleep, and sleep deprivation or excessive sleep may cause migraine attacks.18 Sleepdisordered breathing has also been strongly associated with cluster headache.18 Frequent snoring, even

in the absence of sleep apnea, has been associated with headache.18 Correcting obstructive sleep apnea has been reported to decrease or eliminate headache for some patients.18 Women are approximately twice as likely as men to be affected by CDH.3 Individuals with migraine or frequent headache are more likely to have coexistent nonheadache pain, especially related to musculoskeletal pain or arthritis, compared with those without headache.19 Lower socioeconomic status is a risk factor for CDH incidence and is also associated with a poorer prognosis.3 RESULTS FROM THE AMERICAN MIGRAINE PREVALENCE AND PREVENTION STUDY Mi-

graine affects ⬃12% of adults in Western countries, and its prevalence in the United States is about 18% in women and 6% in men.20 The American Migraine Prevalence and Prevention (AMPP) 2004 study was undertaken to reassess the prevalence of migraine in the United States and further investigate the need for and use of preventive headache treatment. The epidemiology, burden, and patterns of migraine treatment were assessed using methods that permitted comparisons with the results of the American Migraine Studies (AMS)-I and AMS-II. Questionnaires were mailed to a representative sample of 120,000 US households.20 The survey included questions about use of health care, preventive medication use, and the migraine disability assessment scale to determine the level of impairment. A panel of headache experts defined operational criteria for preventive treatment, which resulted in three groups being identified in terms of their need for preventive treatment. The first group was offered preventive treatment, the second group was considered for preventive treatment, and prevention was not indicated for the third group. These recommendations were based on reported headache days per month and degree of impairment during headache attacks. The group offered preventive treatment comprised migraine patients who reported headache 6 days or more per month, 4 days or more with at least some impairment, or 3 days or more with severe impairment or impairment requiring bed rest. Prevention was considered for migraine patients with four or five migraine days per month with normal function, three migraine days with some impairment, or two migraine days with severe impairment. Preventive treatment was not offered if there were ⬍4 headache days per month and no impairment or if there were ⱕ1 headache day per month regardless of impairment level. In concert with previous studies, the AMPP 2004 study demonstrated that the epidemiologic profile of migraine has remained stable in the United States Neurology 72 (Suppl 1)

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Table 1

MIDAS in CM and EM: lost days per 3 months9 CM

Missed work or school, d

2.4

EM 0.54

ⱖ50% Reduced productivity at work or school, d

10.4

1.7

Incomplete household work or chores, d

21.4

3.5

ⱖ50% Reduced productivity in household work or chores, d

18.7

2.6

Missed time with family, social, or leisure activities, d

10.5

1.7

Total

63.4

10.0

MIDAS ⫽ migraine disability assessment scale; CM ⫽ chronic migraine; EM ⫽ episodic migraine; d ⫽ days.

during the past 15 years.20 It also confirmed major findings of the AMS-I and AMS-II: migraine prevalence was higher in whites than in blacks, higher in women compared with men, and higher in individuals with lower family income.20 The negative impact of migraines on quality of life was also confirmed, because ⬎50% of all individuals who reported migraines experienced severe impairment during attacks (table 1).9 Another finding of the 2004 study was the underutilization of preventive treatment, such that only 12.4% of respondents were using preventive treatment though 38.8% were potentially candidates for it.20 Although the levels of disability caused by migraine in France and Latin America are similar to that in the United States, only 6% of migraine patients in France and 2% in Latin America received preventive treatment, illustrating the variable application of preventive treatment in different parts of the world. Strengths of this AMPP 2004 study include the sample size, its representativeness of the US population with respect to demographic characteristics, and the use of questionnaires that were compatible with the AMS-I and AMS-II. The AMPP 2004 study was followed up with the 24,000 surveys of the AMPP 2005

Table 2

study.9 This study compared the prevalence, characteristics, and comorbidity of CM and episodic migraine (EM). The CM group had lower educational levels and lower household incomes than the EM group. Major depression, anxiety disorder, and other chronic pain disorders were more likely to occur with CM than with EM. CM was also more likely to have a greater negative impact on quality of life and cause impairment. The AMPP 2006 study involved 20,639 surveys and attempted to reach all available headache sufferers from 2005.21 On the basis of the updated information, the rate of new onset TM/CM was determined to be 2.5%. Interestingly, the use of barbiturates and opiates in 2005 predicted CM in 2006. Other significant risk factors for CM in the longitudinal analysis included obesity, migraine disability assessment scale score, allodynia, anxiety, and depression (table 2). The results from the AMPP 2006 study also suggested that risk factors vary by transition.22 Age, sex, depression, and anxiety were implicated in the transition from no migraine to EM, and obesity, allodynia, and anxiety were determined to be risk factors when EM transitions to CM (table 3). REMEDIABLE RISK FACTORS FOR CDH FROM FREQUENT HEADACHE CDH was found to be

more prevalent in women, individuals with lower educational and socioeconomic levels, white patients, and those who were previously married.23 Risk of CDH was increased in individuals with lifetime injuries to the head or neck, even if the injuries were remote to the onset of CDH.3 CDH was also associated with diabetes, arthritis, and obesity.23 Obesity, which is defined as a body mass index 30 or higher, has been shown to be predictive of 1-year CDH incidence.3 Headache remission was more likely to occur in non-white patients, individuals with higher education, and those who are married.23 Ultimately, the identification of individuals at higher risk of head-

Use of barbiturates and opiates in 2005 predicts CM in 200621 Women Unadjusted OR (95% CI)

Acetaminophen

Men Adjusted OR (95% CI)

Unadjusted OR (95% CI)

Adjusted OR (95% CI)

Overall Adjusted OR (95% CI)

1.0 (reference)

1.0 (reference)

1.0 (reference)

1.0 (reference)

1.0 (reference)

Prescribed medication ⫹ NSAIDs

0.88 (0.62–1.26)

0.97 (0.67–1.41)

0.85 (0.46–1.55)

0.93 (0.46–1.88)

0.96 (0.69–1.34)

Triptans

1.11 (0.76–1.63)

0.93 (0.62–1.40)

2.37 (1.20–4.71)

2.11 (0.97–4.63)

1.05 (0.73–1.50)

Barbiturate compounds

2.29 (1.44–3.64)

1.97 (1.21–3.23)

1.42 (0.43–4.72)

1.29 (0.38–4.37)

1.73 (1.10–2.73)

Opiates

1.74 (1.15–2.63)

1.28 (0.81–1.97)

3.48 (1.74–6.96)

2.76 (1.20–6.38)

1.44 (1.10–2.08)

Isometheptene compounds

0.94 (0.41–2.16)

0.85 (0.36–2.02)

1.64 (0.38–7.09)

1.60 (0.34–7.54)

0.93 (0.44–1.98)

CM ⫽ chronic migraine; OR ⫽ odds ratio; CI ⫽ confidence interval; NSAID ⫽ nonsteroidal anti-inflammatory drug. S6

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8. Table 3

Risk factors for new onset of M (␭1) and progression of EM (␭2) vary by transition22 ␭1 ␭2 No migraine 3 EM 3 CM ␭1 No migraine 3 migraine

␭2 EM 3 CM

Age

⫹

⫺

Sex

⫹

⫺

Obesity

⫺

⫹

MIDAS score

?

⫹

Allodynia

⫺

⫹

Depression

⫹

⫺

Anxiety

⫹

⫹

9.

10.

11.

12.

M ⫽ migraine; ␭ ⫽ transition rate; EM ⫽ episodic migraine; CM ⫽ chronic migraine; MIDAS ⫽ migraine disability as.sessment scale

ache progression may improve the treatment of CDH.23 Such individuals may be advised to lose weight, avoid or limit barbiturates and opiates, modify stress, and seek treatment for snoring, if needed. REFERENCES 1. Lipton RB, Bigal ME. Looking to the future: research designs for study of headache disease progression. Headache 2008;48:58 – 66. 2. Lipton RB, Bigal ME, Steiner TJ, Silberstein SD, Olesen J. Classification of primary headaches. Neurology 2004;63: 427– 435. 3. Scher AI, Midgette LA, Lipton RB. Risk factors for headache chronification. Headache 2008;48:16 –25. 4. Olesen J, Steiner TJ. The international classification of headache disorders, 2nd edn (ICDH-II). J Neurol Neurosurg Psychiatry 2004;75:808 – 811. Editorial. 5. Lipton RB, Bigal ME. Looking to the future: research designs for study of headache disease progression. Headache 2008;48:58 – 66. 6. Welch KM. Concepts of migraine headache pathogenesis: insights into mechanisms of chronicity and new drug targets. Neurol Sci 2003;24(suppl 2):S149 –S153. 7. Welch KM, Nagesh V, Aurora SK, Gelman N. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache 2001;41:629 – 637.

13. 14. 15.

16.

17.

18.

19.

20.

21.

22.

23.

Silberstein SD. Chronic daily headache. J Am Osteopath Assoc 2005;105(4 suppl 2):S23–S29. Bigal ME, Serrano D, Reed M, Lipton RB. Chronic migraine in the population: burden, diagnosis, and satisfaction with treatment. Neurology 2008;71:559 –566. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. The International Classification of Headache Disorders revised criteria for chronic migraine: field testing in a headache specialty clinic. Cephalalgia 2007;27:230 –234. Katsarava Z, Schneeweiss S, Kurth T, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004;62:788 –790. Haut SR, Bigal ME, Lipton RB. Chronic disorders with episodic manifestations: focus on epilepsy and migraine. Lancet Neurol 2006;5:148 –157. Bigal ME, Lipton RB. Concepts and mechanisms of migraine chronification. Headache 2008;48:7–15. Review. Bigal ME, Lipton RB. Modifiable risk factors for migraine progression. Headache 2006;46:1334 –1343. Bigal ME, Lipton RB. Modifiable risk factors for migraine progression (or for chronic daily headaches): clinical lessons. Headache 2006;46(suppl 3):S144 –S146. Tietjen GE, Brandes JL, Digre KB, et al. High prevalence of somatic symptoms and depression in women with disabling chronic headache. Neurology 2007;68:134 –140. 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;69:1169 –1177. Scher AI, Lipton RB, Stewart WF. Habitual snoring as a risk factor for chronic daily headache. Neurology 2003;60: 1366 –1368. Scher AI, Stewart WF, Lipton RB. The comorbidity of headache with other pain syndromes. Headache 2006;46: 1416 –1423. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF; AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 2007;68:343–349. Bigal ME, Serrano D, Buse D, et al. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache 2008;48: 1157–1168. Bigal ME, Lipton RB. Clinical course in migraine: conceptualizing migraine transformation. Neurology 2008;71: 848 – 855. Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 2003;106:81– 89.

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Spectrum of illness Understanding biological patterns and relationships in chronic migraine

Sheena K. Aurora, MD

Address correspondence and reprint requests to Sheena K. Aurora, MD, Swedish Pain and Headache Center, 1101 Madison Street, Suite 200, Seattle, WA 98104 [email protected]

ABSTRACT

Chronic migraine (CM) typically evolves from episodic migraine (EM) over months to years in susceptible individuals. Headaches increase in frequency over time, becoming less intense but more disabling and less responsive to treatment. The results of electrophysiologic and functional imaging studies indicate that CM is associated with abnormalities in the periaqueductal gray matter that may be progressive. In addition, CM is associated with a greater degree of impairment in cortical processing of sensory stimuli than EM, perhaps because of more pervasive or persistent cortical hyperexcitability. These findings fit with the model of migraine as a spectrum disorder, in which the clinical and pathophysiologic features of migraine may progress over time. This progression is postulated to result from changes in nociceptive thresholds and ensuing central sensitization caused by recurrent migraine in susceptible individuals, for whom risk factors have been described. Also, progression may lead to changes in baseline neurologic function between episodes of headache, evident in electrophysiologic and functional imaging studies and as an increase in depression, anxiety, nonhead pain, fatigue, gastrointestinal disorders, and other somatic complaints that may occur after years of EM. From the available research and migraine models, a concept of CM is emerging that identifies relatively permanent and pervasive central changes warranting novel, tolerable treatments. This model also implies that prevention of CM is an important goal in the management of EM, particularly for individuals who exhibit risk factors for chronic transformation. NEUROLOGY 2009;72 (Suppl 1):S8 –S13

Primary chronic daily headache (CDH) may be classified into four different headache types according to duration of the attack.1 Short-duration headaches, which last ⬍4 hours, include chronic cluster headache, chronic paroxysmal hemicrania, and hypnic headache. Long-duration headaches include chronic tension-type headache, new daily persistent headache, hemicrania continua, and chronic migraine (CM), which was previously called transformed migraine. In patients who have frequent headaches, CDH develops from episodic headache disorder ⬎92% of the time, usually originating from migraine (72% of the cases) but occasionally developing from episodic tension-type headache. Overuse of analgesics, opioids, ergotamine, and triptans can also lead to frequent headaches. The pathophysiology of

migraine pain has a neural basis and is not caused by a primary vascular event.1,2 Migraine is a form of neurovascular headache, in which neural events cause the dilation of blood vessels, subsequently resulting in pain and additional nerve activation.2 It has been proposed that CDH may involve central sensitization, which results from increased spontaneous impulse discharges, and increased sensitivity to peripheral stimuli.1 Enhanced neuronal responses are characteristic of a state of central sensitization, and the enhanced cardiovascular responses represent both intracranial hypersensitivity and cutaneous allodynia.1 There may also be a correlation between age and sensitization, because patients with allodynia tend to be significantly older than those who did not have allodynia.1 Other possible factors associated

From the Swedish Pain and Headache Center, Seattle, Washington. Jointly sponsored by the Annenberg Center for Health Sciences at Eisenhower and CogniMed Inc. This program is supported by an independent educational grant provided by Allergan, Inc. Disclosure: S.K.A. has received grants and research support from Advanced Bionics Corporation, Alexza Pharmaceuticals, Inc., Allergan, Inc., GlaxoSmithKline, MAP Pharmaceuticals, Inc., Merck & Co., Inc., Neuroalieve Inc., and Ortho-McNeil Pharmaceutical, Inc. She has served as a consultant for Allergan, Inc., GlaxoSmithKline, MAP Pharmaceuticals, Inc., Merck & Co., Inc., Neuroalieve Inc., Ortho-McNeil Pharmaceutical, Inc., and Pfizer Inc. She has received honoraria from GlaxoSmithKline, Merck & Co., Inc., Neuroalieve Inc., Ortho-McNeil Pharmaceutical, Inc., and Pfizer Inc. Neurology® supplements are not peer-reviewed. Information contained in Neurology® supplements represents the opinions of the authors. These opinions are not endorsed by nor do they reflect the views of the American Academy of Neurology, Editor-in-Chief, or Associate Editors of Neurology®.

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Figure 1

Headache frequency predicts progression to CDH

days/year)

Estimates were calculated using multinomial logistic regression (p ⬍ 0.005). CDH ⫽ chronic daily headache. Adapted with permission.4

with CDH include medication overuse and head trauma.3 Headache frequency has been demonstrated to predict progression to CDH. The risk of new-onset CDH increases nonlinearly with baseline headache frequency (figure 1).4 Because migraine frequency increases over time for some individuals, identifying patients at high risk for frequent headache would help prevent progression to CDH.5 Risk factors associated with frequent headache include attack frequency, obesity, acute medication overuse, caffeine overuse, depression, sleep disorders, and stressful life events.5 CM typically evolves from episodic migraine (EM).6 Although routine clinical imaging for CM usually shows no evidence of structural abnormality with a normal neurologic examination result, there is Figure 2

Correlation of iron in PAG matter with longevity of migraine

p ⬍ 0.006, r ⫽ 0.80, and y ⫽ 0.0016x ⫹ 5.6213. PAG ⫽ periaqueductal gray; R2⬘ ⫽ transverse relaxation rates. Adapted with permission.7

increasing evidence that nociceptive pathways are involved in CDH and migraine.6 A positive correlation between the duration of headache and the increase in magnetic resonance imaging index of tissue iron levels in the periaqueductal gray (PAG) matter has been demonstrated in patients with CDH6 (figure 2). In an effort to further elucidate the pathophysiology of CM, studies measuring cortical excitability using transcranial magnetic stimulation have been performed with CM patients.6 The metabolism of the brain was also studied using positron emission testing (PET), paying particular attention to the brainstems of CM patients to determine whether there was a correlation with areas of activation and inhibition. Decreased inhibition in CM was observed, when compared with normal control participants and EM patients. Patients with CM were distinguished by a reduction in visual suppression that correlated with high cortical excitability. Hyperexcitability of the occipital cortex in migraine, as well as activation of the brainstem as measured by blood flow, has been confirmed in a subset of CM patients. The higher frequency of attacks in CM patients might be due to high cortical excitability, which may increase susceptibility to external or internal triggers of migraine. Previously, research concerning the mechanisms involved in migraine focused primarily on cranial vasodilation as a source of pain.8 The mechanisms of peripheral trigeminal activation, the localization and physiology of second-order trigeminovascular neurons, and the mechanisms of cortical spreading depression are other areas of interest that are being studied extensively.8 Observations using PET have demonstrated that the rostral brainstem, particularly the contralateral midbrain PAG matter, is essential in migraine pathophysiology.8 These findings suggest that brainstem regions play a pivotal role in either initiation or termination of the acute attack of migraine, such that migraine likely results from a dysfunction of the brainstem or diencephalic nuclei that are involved in the sensory modulation of craniovascular afferents.2 Development of a treatment for acute migraine attacks with exclusively neural action, with no vascular effects, would be a crucial improvement.2 Migraine attacks are episodic and may vary from person to person or from attack to attack.2 This variability may be explained in part by the dysfunction of an ion channel in the aminergic brainstem nuclei that normally modulates sensory input and provides neural control of cranial vessels. The release of calcitonin gene-related peptide (CGRP) is triggered by peripheral trigeminal activation in migraine via an unknown mechanism. The resulting pain has been suggested to be a combination of an altered percepNeurology 72 (Suppl 1)

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Figure 3

Relaxation rates: PAG matter7

Group-wise comparison: one-way ANOVA. ap ⬍ 0.05 vs CDH. ANOVA ⫽ analysis of variance; CDH ⫽ chronic daily headache; EM ⫽ episodic migraine; PAG ⫽ periaqueductal gray; R2⬘ ⫽ transverse relaxation rates.

tion of craniovascular input that is not usually painful, likely caused by peripheral or central sensitization. Elevated tissue iron is a marker of disturbed neuronal function.7 Iron homeostasis in the PAG matter has been studied for its suitability as an indicator of function in patients with EM between attacks and in patients with CDH during headache. Using high-resolution magnetic resonance imaging techniques, the transverse relaxation rates R2, R2*, and R2⬘ were mapped in the PAG matter, red nucleus, and the substantia nigra. These measures are sensitive to shifts in the paramagnetic properties of free iron in brain tissue and blood. Tissue iron levels were reported to be increased in the PAG matter of patients with EM or CDH (figure 3). MIGRAINE TRANSFORMATION In a study of 450 patients, headache chronicity developed during a period of 1 year in 64 (14%) of the patients.9 Patients who overused headache medication were at high risk for chronicity of headache.9 The shift from episodic to chronic headache has been suggested to involve progressive change in the central nociceptive system.10 Repeated migraine attacks lead to free radical formation in the PAG matter, which has been proposed to cause repetitive damage and structural alteration, resulting in a lowered threshold for additional migraine attacks.10 Neuroimaging of women who experienced a high frequency of migraines suggested that they were at higher risk for subclinical brain lesions.10 Although CM is thought to evolve from a complication of EM, the mechanism by which it occurs has not yet been fully elucidated.11 The long-term effects of CM on the brainstem have been studied much S10

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more than the pathophysiologic mechanisms in the cortex. One theory to explain the progression to CM is that exposure to sustained large doses of analgesics causes attacks. A second theory proposes that CM shares pathophysiologic mechanisms with EM. A third possibility is that CM results from a combination of additional and shared mechanisms. Recent advances in noninvasive techniques for studying components of migraine pathophysiology allow further studies to investigate the theory that CM and EM have common mechanisms involving reduced cortical inhibition.11 The use of magnetic suppression of perceptual accuracy (MSPA) provides an objective and reliable method to demonstrate excitability differences between migraine patients and control participants.11 During the MSPA protocol, a series of trigrams is flashed briefly on a computer screen. Each trigram is followed by a short interval of 40 to 190 milliseconds, after which a single magnetic pulse is delivered by a stimulation coil held against the occipital skull. Results with control participants exhibit a characteristic U-shaped function, because accuracy of reporting letters is good at both short (40 milliseconds) and long (190 milliseconds) intervals, but not better than chance for medium (100 milliseconds) intervals.11 However, patients with EM have MSPA profiles that are shallower, indicating it is harder to suppress perception at the medium intervals.11 The difference in profiles is proposed to be due to an increased baseline cortical excitability, as a consequence of impaired intracortical inhibitory mechanisms in these EM patients.6,11 Because patients with CM have very frequent attacks, it is possible that their baseline cortical excitability is higher than that of patients with EM.11 It may also mean that a reduction in cortical excitability with pharmacologic treatment of CM could reduce headache frequency.11 Patients with probable CM who were tested in this MSPA protocol had profiles that were significantly shallower than EM patients, such that virtually no perception suppression occurred.11 A possible explanation for this observed difference is that cortical excitability is raised further by pharmacologic treatment in patients with CM than in patients with EM.11 Patients with CM may be exceptionally susceptible to external or intrinsic triggers of migraine because of their high cortical excitability.11 The use of a ␥-aminobutyric acid agonist, such as topiramate, reduces cortical excitability, consequently decreasing attack frequency.11 Cutaneous allodynia is defined as the perception of pain when a non-noxious stimulus is applied to normal skin, and its underlying mechanism is believed to be central sensitization, that is, sensitization of second-order neurons in the trigeminal nucleus

Figure 4

Central sensitization: sensitization of second-order neurons in the trigeminal nucleus caudalis mediates cutaneous allodynia. Adapted with permission14

caudalis12,13 (figure 4). Central sensitization may be associated with a diminished response to treatment with triptans and may play a role in the progression of migraine.13 Repeated episodes of central sensitization may be associated with permanent neuronal damage at the level of or close to the PAG matter, with resultant poor modulation of pain, reduced effectiveness of preventive treatment, and migraine progression.13 Approximately 60% of patients experience cutaneous allodynia during migraine episodes, especially in the periorbital region of the painful side.15 A significantly higher frequency of allodynia was reported during headache episodes by patients with CM (66%) or migraine with aura (65%) vs migraine without aura (41%).15 To better explain the pathophysiology of CM, the prevailing theories are summarized here. Modulation of trigeminovascular nociception by the brainstem, especially the PAG matter, is important in migraine. A central source was proposed to be re-

sponsible for migraine pain based on the ability to develop migraine-like headaches after implantation of a stimulating electrode into the PAG matter.8 Activation of the brainstem regions appears to be specific to migraine because the brainstem does not seem to be involved in experimentally induced facial pain, atypical facial pain, acute cluster headache, or short-duration unilateral neuralgiform pain with conjunctival injection and tearing. In a correlative case history, a patient with no significant history of headache presented with CM symptoms. It was determined that a left-sided contralateral dorsal vascular lesion involving the midbrain PAG matter had developed, which is in the same region re-

ported to be associated with migraine, as determined with PET. This case further supports the theory that midbrain dysfunction may be important in the pathophysiology of migraine. The concept of centrally mediated pain hypersensitivity is well established, and PAG matter dysfunction would explain the abnormal sensation often reported in nontrigeminal areas. Missense mutations in the

gene encoding the ␣1A subunit of the P/Q type voltage-gated calcium channel are present for ⬃55% of families with familial hemiplegic migraine.8 Injection of a P/Q channel blocker into the PAG matter facilitates trigeminal neuron responses to stimulation of the superior sagital sinus. An inherited defect in calcium channels in the PAG matter consequently would be predicted to facilitate trigeminovascular nociceptive transmission, likely causing episodic throbbing pain. Increased trigeminovascular activation may also explain the medication overuse commonly observed with migraine patients. Elevated levels of interictal CGRP are observed in migraine patients, and CGRP has been demonstrated to facilitate morphine tolerance. Progression of migraine may result from dysfunction of the brainstem involved in modulation of craniovascular afferents and may be associated with increased levels of iron in the PAG matter. Dysfunction of

brainstem areas involved in the modulation of craniovascular afferent fibers most likely results in migraine.16 Brainstem activation may also result in activation of ascending and descending pathways, which can cause perimeningeal vasodilation and neurogenic inflammation.16 During a migraine attack, neural events lead to the dilation of meningeal blood vessels, Neurology 72 (Suppl 1)

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which then causes pain, additional nerve activation, and inflammation.16 PET studies during spontaneous migraine without aura reported increased blood flow in mesencephalic regions, which also possibly indicated activation of the PAG matter, dorsal raphe nuclei, and locus ceruleus, and suggested the involvement of the brainstem in migraine attacks.7 Because tissue iron levels are associated with cellular function, subsequent studies of iron homeostasis in the PAG matter of migraine patients were performed.7 Highly elevated PAG matter iron levels were observed in patients with either EM or CDH, with the highest tissue iron levels measured in those patients who had prolonged illness with severe and frequent EM or CDH. Repetitive migraine attacks can cause repetitive central sensitization. Many types of chronic pain are associ-

ated with long-lasting activation and sensitization of peripheral nociceptors or central nociceptive neurons in the dorsal horn.14 Central sensitization can be activity dependent, when it occurs because of incoming signals from peripheral nociceptors, or it can be activity independent, when it is self-sustained without peripheral inputs. However, once central sensitization is established, sensitization of the second-order trigeminovascular neurons becomes largely activity independent. Central sensitization generates free radicals that damage the PAG matter, which facilitates migraine progression. Repeated episodes of hyperoxia of

brainstem structures activated during migraine attacks could render these areas at risk for ironcatalyzed free radical damage.7 Specific analysis of tissue iron in the PAG matter has provided evidence that iron homeostasis is constantly and progressively impaired by iron-catalyzed free radical injury from repeated migraine attacks. Iron accumulates in the PAG matter during headaches and with the increasing burden of migraine attacks. Transferrin receptors, which transport iron in and out of the PAG matter, are at highest density in the PAG matter compared with other brain regions. Transferrin receptor density may be an indicator of the cellular requirements for iron during oxidative metabolism and may be affected by nociceptive function. Elevated iron levels may suggest that the PAG matter is abnormally metabolically active with migraine, even between EM attacks, or it has a higher density of metabolically active neurons. Neurons with high resting iron levels have the potential for iron-induced oxidative stress and may be selectively susceptible to damage by free radicals. Iron homeostasis in the PAG matter is persistently and progressively impaired as a result of iron-catalyzed free radical injury from repeated migraine attacks. S12

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Cutaneous allodynia is a marker for central sensitization. The skin hypersensitivity associated with cuta-

neous allodynia is typically found in the periorbital area on the side of the migraine headache.14 Central trigeminovascular neurons are chronically sensitized in patients who have ⬎15 headache days per month.12 Although allodynia in migraine is typically established in cephalic areas, it may also be found in extracephalic regions, which suggests that the trigeminovascular neurons that process sensory information originating from the skin are sensitized.12 Allodynia results from neuronal sensitization in pain pathways that generate headaches.12 Cutaneous allodynia is not reversible with late triptan treatment (4 hours after onset of migraine in allodynic patients), and the high incidence of allodynia in patients with CM may explain the dramatic reduction in the effectiveness of triptans often observed with these patients.12,14 Because triptans cannot block ongoing sensitization in second-order trigeminovascular neurons, treatment of migraine is more complicated in the presence of allodynia.14 Consequently, identification of allodynia may facilitate optimal treatment selection for migraine patients.12

REFERENCES 1. Silberstein SD, Lipton RB. Chronic daily headache. Curr Opin Neurol 2000;13:277–283. 2. Goadsby PJ, Lipton RB, Ferrari MD. Migraine: current understanding and treatment. N Engl J Med 2002;346: 257–270. Review. 3. Silberstein SD. Chronic daily headache. J Am Osteopath Assoc 2005;105(4 suppl 2):S23–S29. 4. Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 2003;106:81– 89. 5. Bigal ME, Lipton RB. Modifiable risk factors for migraine progression. Headache 2006;46:1334 –1343. 6. Aurora SK, Barrodale PM, Tipton RL, Khodavirdi A. Brainstem dysfunction in chronic migraine as evidenced by neurophysiological and positron emission tomography studies. Headache 2007;47:996 –1003. 7. Welch KMA, Nagesh V, Aurora SK, Gelman N. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache 2001;41:629 – 637. 8. Goadsby PJ. Neurovascular headache and a midbrain vascular malformation: evidence for a role of the brainstem in chronic migraine. Cephalalgia 2002;22:107–111. 9. Katsarava Z, Schneeweiss S, Kurth T, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004;62:788 –790. 10. Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C; BOTOX CDH Study Group. Botulinium toxin type A (BOTOX®) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebocontrolled trial. Headache 2005;45:293–307. 11. Aurora SK, Barrodale P, Chronicle EP, Mulleners WM.

Cortical inhibition is reduced in chronic and episodic migraine and demonstrates a spectrum of illness. Headache 2005;45:546 –552. 12. Ashkenazi A, Sholtzow M, Shaw JW, Burstein R, Young WB. Identifying cutaneous allodynia in chronic migraine using a practical clinical method. Cephalalgia 2007;27:111–117. 13. Bigal ME, Lipton RB. When migraine progresses: transformed or chronic migraine. Expert Rev Neurotherapeutics 2006;6:297–306. Review.

14.

15.

16.

Burstein R, Jakubowski M. Implications of multimechanism therapy: when to treat? Neurology 2005;64(10 suppl 2):S16 –S20. Lovati C, D’Amico D, Rosa S, et al. Allodynia in different forms of migraine. Neurol Sci 2007;28(suppl 2):S220 – S221. Bigal ME, Krymchantowski AV. Emerging drugs for migraine prophylaxis and treatment. Med Gen Med 2006;8: 1–16.

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Dynamic optimization of chronic migraine treatment Current and future options

Ninan T. Mathew, MD

Address correspondence and reprint requests to Ninan T. Mathew, MD, FRCPC, Houston Headache Clinic, 1213 Hermann Drive, Houston, TX 77004

ABSTRACT

Comparator studies that assess treatment effects in a clinical setting have improved the understanding of the efficacy and tolerability of prophylactic treatments for chronic migraine (CM). It is premature to recommend device-based treatments, such as occipital nerve stimulation, vagal nerve stimulation, and patent foramen ovale closure for CM, because clinical trials are in the preliminary stages. Physical therapy techniques, like applying heat or cold packs, ultrasonography, and electrical stimulation, have been shown to lessen pain. Nonpharmacologic treatments, including cognitive behavioral therapy, stress management, and biofeedback, have been investigated and proved effective in some areas of pain management, including migraine. However, pharmacologic interventions may be necessary for effective, long-term prophylaxis. Several medications under investigation, including topiramate, gabapentin, tizanidine, and amitriptyline, have proved efficacious in reducing the number of migraine episodes and the pain associated with migraine, although adverse events may prevent continued use of some agents. Evidence supports the use of botulinum toxin type A (BoNT-A) for CM, with or without medication overuse, to achieve a significant reduction in headache episodes. Efficacy of BoNT-A for CM is comparable with or better than that of valproate and topiramate, with better tolerability. Predictors of response to BoNT-A for CM appear to include predominantly unilateral location of the headache and the presence of cutaneous or muscle allodynia. BoNT-A has been demonstrated to be safe and well tolerated, with rare discontinuations due to adverse events. Recent clinical trials indicate that rational combination therapy may have a place in treating refractory CM. Well-controlled multicenter trials are awaited. NEUROLOGY 2009;72 (Suppl 1):S14 –S20

NONPHARMACOLOGIC

MIGRAINE

TREAT-

Treating chronic daily headache (CDH) can be difficult, especially if medication overuse and comorbid depression are present.1 Once secondary headache disorders have been excluded, the specific primary CDH disorder needs to be diagnosed and comorbid medical and psychiatric conditions and exacerbating factors, especially medication overuse, need to be identified. Because it is assumed that the brain of a patient with migraine is more reactive to sensory stimuli, avoidance of adverse stimulation or triggers is recommended.2 Migraine patients typically do not easily adapt to changes in their internal or external MENT

environments, so it is beneficial to maintain routine day-to-day activities, including regulation of eating habits, exercise, and sleep.1,2 Various types of physical therapy, including heat, cold packs, ultrasound, electrical stimulation, improvement of posture, stretching, and exercise, can also be beneficial in treating migraine.1 Migraine can be effectively managed with behavioral therapy, including biofeedback, counseling, stress management, and relaxation therapy, which are the most commonly used nonmedication treatments.1,3 A study showed improvement in 39% to 94% of its patients using relaxation techniques alone, and in addition with biofeedback, efficacy rates rose to 56%.3 Results maintained efficacy for up to

From the Houston Headache Clinic, Houston, Texas. Jointly sponsored by the Annenberg Center for Health Sciences at Eisenhower and CogniMed Inc. This program is supported by an independent educational grant provided by Allergan, Inc. Disclosure: N.T.M. has received research support from Allergan, Inc., ENDO, GlaxoSmithKline, Merck & Co., Inc, Ortho-McNeil Pharmaceutical, Inc., Pfizer Inc, and POZEN, Inc. He is a consultant for Allergan, Inc., Merck & Co., Inc., and Ortho-McNeil Pharmaceutical, Inc., and is on the speakers bureaus for Allergan, Inc., ENDO, GlaxoSmithKline, Merck & Co., Inc., Ortho-McNeil Pharmaceutical, Inc., and Pfizer Inc. Neurology® supplements are not peer-reviewed. Information contained in Neurology® supplements represents the opinions of the authors. These opinions are not endorsed by nor do they reflect the views of the American Academy of Neurology, Editor-in-Chief, or Associate Editors of Neurology®.

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Figure 1

Gabapentin in CDH: primary end point

Gabapentin increases HFR over placebo by 9.1%. Minimum mean clinically relevant ⫽ 7.5%. aPrerandomization vs placebo, p ⬍ 0.001. bPrerandomization vs gabapentin, p ⬍ 0.0001. cPlacebo vs gabapentin, p ⬍ 0.0005. CDH, chronic daily headache; HFR, headache-free rate. Adapted with permission.11

5 years in another smaller study when relaxation was used in conjunction with electromyographic biofeedback.3 Smaller trials indicate 50% improvement of symptoms with a combination of cognitive psychotherapy and behavioral treatment.3 Intractable CDH can be improved by treating painful trigger areas in the neck.1 PROPHYLACTIC MIGRAINE TREATMENT Goals of migraine prophylaxis should include reducing migraine frequency, severity, duration, and disability; reducing reliance on ineffective acute headache medication; improving responsiveness to the treatment of acute attacks; and improving the patient’s quality of life and ability to function.4 Preventing disease progression in migraine is another important goal of preventive treatment and may be accomplished using such strategies as risk factor modification, the use of preventive therapies, and the use of triptans as early as possible during a migraine attack.5 A preventive drug should be chosen based on its proven efficacy, the patient’s preferences and headache profile, the drug’s side effects, and the presence of any coexisting disease.5

Classes of agents used to treat CDH prophylactically include ␤-adrenergic antagonists, calcium-channel blockers, ␣2-adrenergic agonists, serotonin antagonists, antidepressants, nonsteroidal anti-inflammatory drugs, and antiepileptic drugs.6,7 Unfortunately, the usefulness of these agents is limited because of poor compliance resulting from intolerable side effects, daily dosage administration requirements, and inadequate efficacy.6 Other than topiramate, no drug to date has received regulatory approval for patients with migraine.8,9 Few of the prePHARMACOLOGIC THERAPY

ventive agents typically used to prevent migraine have been evaluated for their effectiveness in treating chronic migraine (CM).10 The efficacy of these agents for the prevention of CM has not been evaluated in large, multicenter, controlled clinical trials.10 Consequently, there is a great need for further research to develop effective treatments.6 Gabapentin. Gabapentin is an antiepileptic medication used for a variety of painful disorders.11 It is an analog of ␥-aminobutyric acid (GABA) and may stimulate the release of GABA, which blocks pain signaling. Gabapentin also binds to voltage-gated calcium channels.9 Gabapentin has been demonstrated to increase the percentage of headache-free days over placebo by 9.1% ( p ⫽ 0.0005) (figure 1).11 Headache severity, disability, and quality of life also showed some improvement, as did headache duration when compared with prerandomization.11 The amount of analgesic use was reduced as a consequence of treatment with gabapentin.11 Tizanidine. Tizanidine is an ␣2-adrenergic agonist

that inhibits the release of norepinephrine in both the brainstem and the spinal cord. It acts as a central muscle relaxant and also has antinociceptive effects.7 The effectiveness of tizanidine over placebo in a study on patients with CDH was assessed by headache index (calculated as the sum of the products of the number of headache days, average intensity, and duration of each headache during each 4-week interval, divided by 28 days), the primary end point.7 Tizanidine was shown to reduce the overall headache index compared with placebo and to reduce the average number of headache days per week, severe headache days per week, average headache intensity, peak headache intensity, and mean headache duration. Fluoxetine. Fluoxetine is a selective serotonin reuptake inhibitor that downregulates serotonin receptors, thereby increasing synaptic serotonin.9 Fluoxetine has been demonstrated to be moderately effective in treating CDH, such that it caused a significant improvement in overall mood and a modest decrease in headache frequency.12 Amitriptyline. Amitriptyline downregulates serotonin receptors, increases the levels of synaptic norepinephrine, and enhances endogenous opioid receptor actions.9 Although amitriptyline is used to treat CDH, adverse effects may limit its use or prevent increasing the dose to a therapeutic level.13 The efficacy of combining amitriptyline and fluoxetine compared with amitriptyline alone was assessed in patients with CDH.13 Although amitriptyline alone, as well as in combination with fluoxetine, caused an overall decrease in the reported headache indexes at Neurology 72 (Suppl 1)

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Figure 2

Change from baseline in monthly (28 days) rate of migraine/migrainous and migraine days

N ⫽ 153 for topiramate and placebo groups. p value based on analysis of covariance models, including treatment and center as main effect and baseline monthly migraine/migrainous or migraine days as covariates. Reproduced with permission.10

the end of the study, no significant improvement over the effect of amitriptyline was observed by combining it with fluoxetine.13 This lack of difference may be due to the small number of study participants and the relatively short duration of the study.13 Valproate. Although the mechanism by which val-

proate improves migraine symptoms is unclear, previous studies have demonstrated its effectiveness in migraine prophylaxis.14 The efficacy and tolerability of valproate on CDH was assessed in a prospective, double-blind, randomized, placebo-controlled study. Valproate reduced the level and frequency of pain in patients with CDH compared with placebo. In addition, when comparing two of the subgroups of CDH, 500 mg twice daily of valproate was more effective in treating CM than chronic tension-type headache (CTTH). The incidence of adverse effects in this study was lower than previously reported for valproate. Topiramate. Topiramate blocks voltage-sensitive sodium channels and voltage-activated calcium channels, inhibits glutamate release, and increases GABA levels.9 Extensive studies have demonstrated that topiramate is a safe, effective, and well-tolerated drug for migraine prophylaxis and the challenge of treating CM.4 A reduction in headache days and in the use of acute headache medication was observed with topiramate in patients with CM.4 Topiramate is associated with a wide range of side effects, including paresthesia, fatigue, anorexia, nausea, diarrhea, weight loss, dizziness, taste perversion, and difficulty with memory and concentration.4 In another study, topiramate treatment resulted in a significant reducS16

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tion in the number of monthly migraine days in the medication overuse subpopulation, although medication use did not decrease in the topiramate group compared with the placebo group. This study suggests that it may not be necessary to withdraw patients with CM from medication overuse before initiating preventive treatment.15 A different study demonstrated that topiramate had a very good tolerance profile when doses lower than those typically used in epilepsy management were given to patients with CM.16 A dose of daily topiramate 50 mg reduced, with significant difference, the 28-day headache frequency compared with placebo, demonstrating that low doses of topiramate can be effective at reducing headache frequency in patients with CM with medication overuse.16 Higher doses of topiramate (approximately 100 mg per day) have also been shown to be effective at reducing the average monthly migraine headache days in patients with CM (figure 2).10 Botulinum toxin type A. Botulinum toxin type A (BoNT-A) is a focally acting protein that inhibits the release of acetylcholine from presynaptic nerve endings and blocks the release of nociceptive mediators, such as substance P, glutamate, and calcitonin generelated peptide.9 Reduction of peripheral nociceptive mediators may cause a reduction in central sensitization by reducing inflammatory signals to sensitized regions of the brain. The biologic effects of BoNT-A are reversible and last for approximately 3 months. The ability of BoNT-A to treat migraine effectively has been evaluated in many studies with different subsets of migraine patients. The effectiveness of BoNT-A in the treatment of CM without medication overuse has been evaluated.17 Patients were excluded from the study if they were taking triptans more than 3 days per week, ergotamine more than 2 days per week, dihydroergotamine more than 2 days per week, or any combination of these medications for more than 3 days per week. Analgesic use was restricted to 2 opioids and 10 simple analgesic tablets per week or 9 combination analgesics per week. Caffeine consumption in excess of 500 mg per day was another criterion for exclusion from the study. The injection of 100 U of BoNT-A into 5 sites (glabella, temporal, frontal, suboccipital, and trapezius) using a fixed dose resulted in significant reductions in migraine episodes in the patients with CM receiving BoNT-A, without the complication of medication overuse. The high level of safety and tolerability of BoNT-A as a preventive CM therapy was demonstrated by the low number of adverse events in this study. The effectiveness of BoNT-A injection for patients with refractory CM was assessed in a different study. The patient-selection criteria required the participants to have tried 3 classes of prophylactic medi-

Figure 3

BoNT-A in CDH without concomitant prophylaxis

p ⬍ 0.05. BoNT-A, botulinum toxin type A; CDH, chronic daily headache. Reproduced with permission.19

a

cations for at least 1 year with no improvement.18 Doses of 250 U of BoNT-A were injected into 15 sites, and patients were followed for 4 months. Pain intensity and frequency of headaches decreased during the study, demonstrating the effectiveness of BoNT-A to treat refractory migraine. A 2005 study to assess BoNT-A in patients with CDH did not discriminate any specific CDH subtype but included any combination of migraines, with or without aura, migrainous/probable migraine, and episodic migraine (EM)/CTTH.6 In addition, many patients in the study were overusing acute medications and/or taking concurrent prophylactic headache treatments. BoNT-A use in this study did not statistically meet the predetermined primary efficacy measure of the number of headache days per month. However, a statistically significant higher percentage of BoNT-A patients, compared with placebo patients, had at least a 50% decrease in frequency of headache days by day 180. This exploratory study suggested that the number of headache-free days per 30-day period may not be the optimal end point for detecting a treatment response for patients in this headache population. When the effectiveness of BoNT-A in CM was assessed without concomitant prophylaxis, BoNT-A decreased by at least half, compared with baseline, the frequency of headaches in more than 50% of the patients after three injection sessions.19 Statistically significant decreases in headache frequency and headache severity were observed between BoNT-A and placebo for most time points from day 180 through day 270. Consequently, this subgroup analysis demonstrated that BoNT-A is an effective treat-

ment for patients with CDH who are not taking other preventive headache medications (figure 3). Predictors of response to BoNT-A were evaluated in a recent study of patients with CDH, specifically with CM and CTTH. It has been reported previously that patients with imploding (pain is felt from the outside to the inside of the head) or ocular (pain is localized around or behind the eye) headaches responded to BoNT-A, whereas patients with exploding (painful buildup inside the head) headaches did not.20 To isolate factors that might predict response to BoNT-A in CDH, patients with CM or CTTH, which form the majority of CDH disorders, received at least two injections of BoNT-A 100 U at 12- to 15-week intervals, using fixed-sites, fixed-dose, and “follow-the-pain” approaches.21 Patients were divided into responders (ⱖ50% reduction in both headache frequency and migraine disability assessment scale scores compared with baseline) and nonresponders (⬍50% reduction).21 A larger proportion of patients with CM (76.1%) responded to BoNT-A than did patients with CTTH (36.4%).21 In CM, treatment response was associated with a high incidence of unilateral headache and allodynia, such that scalp and muscle allodynia were seen in 82% and 61% of treatment responders, respectively. Nonresponders had 12% and 18% scalp and muscle allodynia, respectively.21 Specifically, the presence of scalp allodynia, muscle allodynia, and unilateral headache appeared to be predictors of response to BoNT-A in patients with CM, whereas muscle allodynia in patients with CTTH may be a predictor of responsiveness to BoNT-A.21 The objectives of an exploratory phase 2 trial were to identify a treatment-responsive population for BoNT-A, evaluate the safety and efficacy of different BoNT-A doses compared with placebo using a fixedsite protocol, and assess BoNT-A dose response in the prophylactic treatment of CDH.22 The primary efficacy end point was determined to be the average change from baseline in the frequency of headachefree days for the 30-day period ending on day 180 for the placebo nonresponding group. Although the primary end point was not met, all three groups responded to treatment, with the 225-U and 150-U groups showing the greatest decrease in headache frequency compared with placebo at day 240. A higher percentage of patients in the placebo group used acute pain medications throughout the study, and this may have contributed to the higher-than-expected placebo response, thus confounding the results. B O NT-A VS TOPIRAMATE IN 2008 CM STUDY

In a recent study to assess the effectiveness of BoNT-A vs topiramate to treat CM, patient selection Neurology 72 (Suppl 1)

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included those individuals with CM, no medication overuse, and age between 18 and 65 years.23 After randomization, one group received either a BoNT-A injection (maximum 200-U dose at baseline visit and at month 3 only) or an oral placebo, and the other group received topiramate (100 mg/day, with an optional 4-week titration to 200 mg/day) or a placebo injection. Both groups were assessed at intervals of 1, 3, 6, and 9 months. The percentage improvement was reported as marked, moderate, or mild, and all treatments had a similar effect. At month 6, both groups had significantly fewer headaches compared with baseline, with BoNT-A showing a larger decrease than topiramate. By month 9, however, both treatment groups demonstrated an equivalent reduction in headache days per month. B O NT-A VS DIVALPROEX IN 2005 HEADACHE STUDY Inclusion criteria for this study involved

men and women aged 18 to 65 years with EM (between 3 and 15 migraine days/month) or CM (⬎15 migraine days/month), with stable headache severity and pattern.24 The overall duration of the study was 10.5 months, including 1 month of baseline screening, one 3-month treatment cycle, one 6-month treatment cycle, and a final safety visit. Following the baseline period, eligible patients were randomized (1:1) to receive either BoNT-A or divalproex. The BoNT-A group received a total of 100 U of BoNT-A injections and placebo-divalproex tablets orally. Eleven muscle areas were injected by the “follow-thepain” approach: the procerus, corrugators, frontalis, temporalis, splenius capitis, sternocleidomastoid, trapezius, occipitalis, cervical paraspinalis, semispinalis capitis, and masseter. Injection sites and dosages were determined on an individual basis, depending on each patient’s symptom profile. Patients in the divalproex group received 250 mg twice a day orally and a series of saline injections (placebo-BoNT-A). After the first week, the divalproex dose was increased up to 500 mg twice a day if deemed necessary and tolerable. This study demonstrated that prophylactic treatment with either BoNT-A or divalproex in patients with EM or CM significantly reduced disability associated with these types of headaches.24 Both treatments showed significant improvements in migraine disability scores and reductions in headache days and headache index. A possible trend in decreased headache severity was also observed with BoNT-A. Compared with divalproex, BoNT-A had a more favorable tolerability profile, with fewer reported adverse events and a lower percentage of patients discontinuing treatment. ADVERSE EVENTS DURING TRIALS When the effectiveness of BoNT-A and topiramate were comS18

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pared in a recent study, a higher percentage of patients receiving topiramate discontinued the study because of adverse events (53% with topiramate vs 25% with BoNT-A).23 In a study comparing BoNT-A and divalproex for prophylactic treatment of EM or CM, significantly fewer adverse events possibly related to treatment were reported for the patients receiving BoNT-A injections compared with the divalproex group.24 The most frequently reported adverse events for the BoNT-A group were eyelid (26.7%) and/or eyebrow (16.7%) drooping (blepharoptosis), and the divalproex group reported nausea/gastrointestinal discomfort (41.2%), hair loss (17.2%), and fatigue/ sleepiness (31.0%). A significantly greater proportion of the divalproex group (27.6%) discontinued the study because of adverse events compared with the BoNT-A group (3.3%). Although the majority of adverse events were transient and no more than moderate in severity for both treatment groups, the adverse events leading to leaving the study in the BoNT-A group were nausea and irregular breathing, whereas hair loss, fatigue, tiredness, tinnitus, disorientation, nausea, weight gain, edema, numbness, tremors, decreased appetite, and elevated liver enzymes were the adverse events leading to discontinuation in the divalproex group. COMBINATION THERAPY: RATIONALE AND TRIALS To investigate whether combining therapies

will result in improved outcomes for migraine patients, an open-label study that combined a ␤-blocker (nadolol or propranolol) and valproate was performed.25 Patients who had EM with or without aura and who were previously unresponsive to ␤-blockers and valproate in monotherapy were included in the study. Combination therapy with a ␤-blocker and valproate was effective in preventing migraines in more than 50% of previously resistant migraine cases. However, combining drugs can increase the risk of adverse events, and in this study, almost 20% of the participating patients were unable to tolerate even typically low doses of these medications. Another open-label study tested the combination of a ␤-blocker (nadolol or propranolol) and topiramate in migraine patients who previously did not respond to either treatment as monotherapy.26 Approximately 60% of these patients with refractory migraine observed at least a 50% reduction in the number of headache days in the third month of treatment as a result of combining therapy. However, 17% of patients who had previously tolerated each medication as monotherapy discontinued the study early because of adverse events, which included cognitive impairment, paresthesia, depression, and gas-

trointestinal symptoms. Although monotherapy is the first line of defense in migraine treatment, drug combinations are often used to treat refractory migraine. It is possible that compounds acting at different levels of migraine pathophysiology have additive effects in preventive therapy. The use of tricyclic antidepressant medication, stress management therapy, and the combination of these two therapeutic approaches were evaluated for their ability to treat CTTH.27 Although CTTH is primarily treated with tricyclic antidepressants, some trials have reported little or no improvement in CTTH with the tricyclic antidepressant amitriptyline. Amitriptyline (up to 100 mg/day) or nortriptyline (up to 75 mg/day) was administered either as monotherapy or in combination with stress management therapy. The stress management therapy used in the study taught both relaxation and cognitive coping skills for preventing and managing stress and headaches. Tricyclic antidepressant medication and stress management therapy each produced larger reductions in headache activity, analgesic medication use, and headache-related disability than placebo, with more rapid improvement observed with antidepressant medication. Combining therapies increased the likelihood of producing significant reductions (at least 50%) in headache index scores. OTHER THERAPIES: DEVICE-BASED TREATMENT IN EARLY TESTING To further address the

unmet needs of patients with CDH, other methods to treat migraines are being investigated. Although migraine carries a small but significant risk of stroke, especially for women who smoke and take oral contraceptives, the mechanisms of this association have not been fully elucidated.28 One possibility is the involvement of a paradoxical embolism through a patent foramen ovale (PFO); this abnormality has been observed in up to 48% of patients with migraine with aura. The right-to-left shunt (RLS) that results from PFO could exacerbate migraine by permitting neuromediators that are normally inactivated by the pulmonary filter to initiate the migraine attack. In this study, the severity of migraines was monitored in a group of patients undergoing transcatheter closure of PFO for cryptogenic stroke. Closure of the PFO resulted in the prevention of migraine in 29% of patients, as well as substantial improvement in all the features of migraine in 59% of the patients. Although some patients did not respond to PFO closure, there is a clear link with RLS and migraine. Additional studies are needed to assess whether RLSassociated migraine can be clinically identified. Peripheral nerve stimulation in the occipital region has been successfully used in the management

of intractable headaches, including CDH, and may affect the trigeminocervical complex neurons.29 Implantation of occipital nerve stimulation may be beneficial to patients with frequent, intense, and debilitating headaches that do not respond to conservative treatments. Refining the implantation techniques and improving the equipment technology are required to improve the utility of this approach. Vagal nerve stimulation (VNS) is another technique being explored for its possible use to alleviate headache pain. VNS is used to treat seizures and may provide an activating or inhibiting effect downstream of the nucleus tractus solitarius, which projects to the trigeminal nucleus caudalis.30 The results of a small study suggested that VNS may have a prophylactic effect on migraine, with 8 of 10 patients showing at least a 50% reduction of monthly headache frequency. Larger and more accurate studies are needed to further assess the usefulness of this technique as a preventive migraine treatment. Finally, another study using transcranial direct current stimulation has demonstrated that shortterm homeostatic plasticity is altered in patients with visual aura between attacks.31 REFERENCES 1. Silberstein SD. Chronic migraine: diagnosis and management strategy [case review]. Rev Neurol Dis 2004;1:155– 160. 2. Saper JR, Dodick D, Gladstone JP. Management of chronic daily headache: challenges in clinical practice. Headache 2005;45(suppl 1):S74 –S85. 3. Millea PJ, Brodie JJ. Tension-type headache. Am Fam Physician 2002;66:797– 804. 4. Fontebasso M. Topiramate for migraine prophylaxis. Expert Opin Pharmacother 2007;8:2811–2823. 5. Bigal ME, Lipton RB. When migraine progresses: transformed or chronic migraine. Expert Rev Neurother 2006; 6:297–306. Review. 6. Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C; BOTOX CDH Study Group. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebocontrolled trial. Headache 2005;45:293–307. 7. Saper JR, Lake AE III, Cantrell DT, Winner PK, White JR. Chronic daily headache prophylaxis with tizanidine: a double-blind, placebo-controlled, multicenter outcome study. Headache 2002;42:470 – 482. 8. Bigal ME, Krymchantowski AV. Emerging drugs for migraine prophylaxis and treatment. MedGenMed 2006;8: 1–16. 9. Mathew NT. The prophylactic treatment of chronic daily headache. Headache 2006;46:1552–1564. 10. Silberstein SD, Lipton RB, Dodick DW, et al. The Topiramate Chronic Migraine Study Group. Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial. Headache 2007;47:170 –180. 11. Spira PJ, Beran RG; Australian Gabapentin Chronic Daily Headache Group. Gabapentin in the prophylaxis of Neurology 72 (Suppl 1)

February 3, 2009

S19

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

S20

chronic daily headache: a randomized, placebo-controlled study. Neurology 2003;61:1753–1759. Saper JR, Silberstein SD, Lake AE III, Winters ME. Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache 1994;34:497–502. Krymchantowski AV, Silva MT, Barbosa JS, Alves LA. Amitriptyline versus amitriptyline combined with fluoxetine in the preventative treatment of transformed migraine: a double-blind study. Headache 2002;42:510 – 514. Yurekli VA, Akhan G, Kutluhan S, Uzar E, Koyuncuoglu HR, Gultekin F. The effect of sodium valproate on chronic daily headache and its subgroups. J Headache Pain 2008;9:37– 41. Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ; TOPMAT-MIG-201(TOPCHROME) Study Group. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia 2007;27:814 – 823. Silvestrini M, Bartolini M, Coccia M, Baruffaldi R, Taffi R, Provinciali L. Topiramate in the treatment of chronic migraine. Cephalalgia 2003;23:820 – 824. Freitag FG, Diamond S, Diamond M, Urban G. Botulinum toxin type A in the treatment of chronic migraine without medication overuse. Headache 2008;48:201–209. Menezes C, Rodrigues B, Magalha˜es E, Melo A. Botulinum toxin type A in refractory chronic migraine: an openlabel trial. Arq Neuropsiquiatr 2007;65:596 –598. Dodick DW, Mauskop A, Elkind AH, DeGryse R, Brin MF, Silberstein SD; BOTOX CDH Study Group. Botulinum toxin type A for the prophylaxis of chronic daily headache: subgroup analysis of patients not receiving other prophylactic medications: a randomized double-blind, placebo-controlled study. Headache 2005;45:315–324. Jakubowski M, McAllister PJ, Bajwa ZH, Ward TN, Smith P, Burstein R. Exploding vs. imploding headache in migraine prophylaxis with Botulinum Toxin A. Pain 2006; 125:286 –295. Mathew NT, Kailasam J, Meadors L. Predictors of response to botulinum toxin type A (BoNTA) in chronic daily headache. Headache 2008;48:194 –200.

Neurology 72 (Suppl 1)

February 3, 2009

22.

23.

24.

25.

26.

27.

28.

29. 30.

31.

Silberstein SD, Stark SR, Lucas SM, Christie SN, DeGryse RE, Turkel CC; BoNTA-039 Study Group. Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebocontrolled trial. Mayo Clin Proc 2005;80:1126 –1137. Mathew NT. A double-blind comparison of botulinum toxin type A (BoNTA) and topiramate for the prophylactic treatment of transformed migraine headaches: a pilot study. Presented at the 12th Congress of the European Federation of Neurological Societies; August 23–26, 2008; Madrid, Spain. Blumenfeld AM, Schim JD, Chippendale TJ. Botulinum toxin type A and divalproex sodium for prophylactic treatment of episodic or chronic migraine. Headache 2008;48: 210 –220. Pascual J, Leira R, La´inez JM. Combined therapy for migraine prevention? Clinical experience with a ␤-blocker plus sodium valproate in 52 resistant migraine patients. Cephalalgia 2003;23:961–962. Pascual J, Rivas MT, Leira R. Testing the combination beta-blocker plus topiramate in refractory migraine. Acta Neurol Scand 2007;115:81– 83. Holroyd KA, O’Donnell FJ, Stensland M, Lipchik GL, Cordingley GE, Carlson BW. Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial. JAMA 2001;285:2208 – 2215. Morandi E, Anzola GP, Angeli S, Melzi G, Onorato E. Transcatheter closure of patent foramen ovale: a new migraine treatment? J Interv Cardiol 2003;16:39 – 42. Jasper J, Hayek S. Implanted occipital nerve stimulators. Pain Physician 2008;11:187–200. Review. Lenaerts ME, Oommen KJ, Couch JR, Skaggs V. Can vagus nerve stimulation help migraine? Cephalalgia 2008; 28:392–395. Antal A, Lang N, Boros K, Nitsche M, Siebner HR, Paulus W. Homeostatic metaplasticity of the motor cortex is altered during headache-free intervals in migraine with aura. Cereb Cortex 2008;18:2701–2705.