The frequency with which migraine attacks

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1 STRATEGIES TO PREVENT MIGRAINE * Sheena K. Aurora, MD ABSTRACT Patients who suffer from daily or near-daily headaches may experience significant disability and interference in all aspects of their professional and personal lives. In this article, the pathophysiology of migraine (in particular, the genetic basis for migraine), the underlying mechanisms that may trigger migraine, disability issues, and how these aspects of the disorder translate into treatment planning will be addressed. The focus will be on prevention of migraine attacks in particular, on so-called chronic migraine/transformed migraine, a form of chronic daily headache. The goals for preventive treatment, recommendations for the initiation of prophylaxis, and evidence from clinical trials for specific therapies will be discussed. (Adv Stud Med. 26;6(9C):S891-S897) The frequency with which migraine attacks are suffered may vary from once in a lifetime to almost daily, which indicates that the degree of predisposition to migraine may vary. For individuals who suffer with daily or near-daily headaches, the degree of disability may be staggering, impacting on all aspects of their professional and personal lives. The current concept is of a threshold of susceptibility. To understand migraine, it is necessary to consider the factors that *This article is based on a roundtable symposium held in Miami, Florida, on March 18, 26. Director, Swedish Headache Center, Swedish Pain Service, Seattle, Washington. Address correspondence to: Sheena K. Aurora, MD, Director, Swedish Headache Center, Swedish Pain Service, 111 Madison, Suite 2, Seattle, WA sheena.aurora@swedish.org. influence the threshold of a person s susceptibility to a migraine attack, the mechanisms by which an attack is triggered, and the associated symptoms and headache that develop. In this article, the underlying pathophysiology of migraine (in particular, the genetic basis for migraine), the triggers for migraine, the degree of disability, and how these aspects of the disorder translate into practical, rational, lifestyle advice when planning treatment will be addressed. The focus will be on prevention of migraine attacks in particular, on socalled chronic migraine (CM)/transformed migraine, a form of chronic daily headache (CDH). UNDERSTANDING THE PATHOPHYSIOLOGY OF MIGRAINE Studies conducted on twins have confirmed the clinical observation that there is a genetic predisposition for migraines. 1 In addition, the identification of a variety of mutations on genes that code for voltagegated calcium channels, 2-5 sodium/potassium pumps, 6 and the dopamine D 2 receptor gene 7 all of which are associated with various types of familial migraine also lend additional evidence for a genetic foundation for migraine. Instability in pain control and sensitivity to changes in the central nervous system underlie migraine. Therefore, theories about pathophysiology must be based on the anatomy and physiology of the pain-producing structures within the cranium. Differences between the occipital cortex excitation threshold of patients with migraines and normal controls were evaluated in a 1998 study using transcranial magnetic stimulation. The investigators observed that the proportion of patients with migraine with phosphene generation was significantly greater than normal controls (P =.1), with the mean threshold level significantly lower in the migraine group. These results provide strong evidence that neuronal hyperexcitability predisposes individuals to migraine. 8 Many factors, alone or in combination, may result Johns Hopkins Advanced Studies in Medicine S891

2 in increased neuronal hyperexcitability. The amino acid glutamate has been speculated to promote hyperexcitability, particularly in the occipital cortex. Abnormal glutamate metabolism in the form of decreased glutamate turnover, increased release, poor reuptake, or incomplete enzymatic inactivation may account for the hyperactivity of glutamatergic neurons. Magnesium deficiency also has been implicated in hyperexcitability. This is based on the finding that glutamate-induced spreading depression can be inhibited by magnesium. In addition, intracellular magnesium levels are decreased in the brain of patients with migraine during an attack. 9 Hyperexcitability also may be attributed to the release of neurotransmitters secondary to opening of voltage-dependent calcium channels, with subsequent calcium ion accumulation in the cell. 9 Thus, if neuronal hyperexcitability predisposes to migraine, prevention may be attained by inhibition of excitatory neurotransmission or enhancement of inhibitory neurotransmitters that may reduce central neuronal hyperexcitability by suppressing abnormal cortical activity. 1 MIGRAINE THERAPIES BIOLOGIC BASIS FOR MIGRAINE PREVENTION Acute therapies for migraine attacks, such as triptans, target the trigeminal vasculature, with a goal of eliminating migraine symptoms and reducing attack duration. On the other hand, prophylaxis targets the brain with a goal of reducing attack frequency by limiting hyperexcitability. Hyperexcitability is controlled by increasing γ-aminobutyric acid neurotransmission and/or reducing glutamate neurotransmission. Norepinephrine and serotonin modulate hyperexcitability through secondary mechanisms, likely involving changes in protein phosphorylation. Controlling hyperexcitability tones down the migrainous brain, therefore, reducing the frequency of attacks. Agents for migraine prevention/reduced hyperexcitability may function through a variety of potential mechanisms, including raising the threshold for migraine activation and/or stabilizing a reactive nervous system. Raising the threshold for migraine activation may be accomplished by inhibiting migraine generation, enhancing antinociception, inhibiting cortical spreading depression, inhibiting sensitization, and/or blocking neurogenic inflammation. Stabilizing a more reactive nervous system may be executed by modulating sympathetic or serotonergic tone. Table 1 lists potential mechanisms for common migraine prophylactic agents. 11 GOALS AND GUIDELINES FOR MIGRAINE PREVENTION It is known that many patients are improperly diagnosed and/or undertreated for their migraine attacks, as indicated by measures of ongoing disability and treatment dissatisfaction For example, in a population-based survey conducted by Lipton et al 13 of 2 US households identifying 3577 individuals with severe headache meeting a case definition for migraine based on the International Headache Society (IHS) criteria, 37% of diagnosed and 21% of undiagnosed individuals with migraine reported 1 to 2 days of activity restriction per episode (P <.1); 38% of diagnosed and 24% of undiagnosed individuals with migraine missed at least 1 day of work or school in the previous 3 months (P <.1); 57% of diagnosed and 45% of undiagnosed individuals with migraine experienced at least a 5% reduction in work/school productivity (P <.1). The authors concluded that approximately 5% of individuals with migraine remain undiagnosed, with many being inadequately treated and experiencing severe pain and disability. In this investigation, 1 out of 3 individuals described their pain as extremely severe, and 47% rated their pain as severe (Figure 1). 14 In total, more than 8% of individuals with migraine report severe or extremely severe headache pain, and approximately 75% experi- Table 1. Agents for Migraine Prophylaxis and Their Potential Mechanisms Glutamate GABA Neurotransmission Neurotransmission NE 5-HT β blockers TCAs CCBs VPA GBP TPM 5-HT = serotonin; CCB = calcium channel blockers; GABA = γ-aminobutyric acid; GBP = gabapentin; NE = norepinephrine; TCA = tricyclic antidepressants; TPM = topiramate; VPA = valproate. Adapted with permission from Silberstein et al. Wolff s Headache and Other Head Pain. 7th ed. New York, NY: Oxford University Press; 21: S892 Vol. 6 (9C) October 26

3 Figure 1. Percentage of Patients with Migraine Who Experience Severe Pain and Disability Data from Lipton et al. 14 Mild 1% ence photophobia, phonophobia, or nausea in association with their attacks. The impact of severe pain as a result of migraine can be evaluated by assessing the patient s ability to function. Patients who are disabled by their migraine attacks cannot perform daily or routine activities and may retreat to a dark room to sleep. Lipton et al assessed disability in patients with migraine and found that 91% of patients experience some form of disability and 53% experience severe impairment and may require bed rest (Figure 1). 14 The pain and disability of migraine can have a substantial impact on work and productivity. Patients with migraine experience decreased work productivity, increased absenteeism, and increased rates of unemployment. 16 Despite this (53% of patients with migraine or approximately 7 million people meet frequency and disability criteria for prophylaxis), less than 5% of these individuals are receiving preventive therapy. 15 However, this may be overcome by a 3-pronged approach. In effect, strategies for migraine treatment optimally include acute and preventive therapies, in addition to preemptive treatment in certain circumstances, an example being when a patient knows of and preempts triggers, such as menstruation, stress, intake of certain foods, or sexual activity. In addition, preventive treatment, including the use of herbal therapies where appropriate, can assist in reducing overuse of acute medications and subsequent rebound that may lead to refractory headache or CM. Therefore, early intervention with preventive treatments is warranted when indicated. The goals of prophylaxis include a reduction in attack frequency, severity, and duration, in addition to improvement in treatment responsiveness when patients experience acute attacks, with the ultimate outcome of improved function and less disability. 17 Additional treatment goals include reduction in the use of acute medication and potential for rebound headache, prevention of disease progression, and reduction in treatment costs. In one 18-month comparison study by Silberstein et al of acute versus preventive therapies, prophylaxis reduced office visits by 51%, emergency department visits by 82%, diagnostic imaging by 75% to 88% (computed tomography and magnetic resonance imaging scans), and monthly medication costs by $48 to $138 per patient. 18 The American Academy of Family Physicians and the American College of Physicians-American Society of Internal Medicine in collaboration with the American Headache Society (AHS) has issued recommendations for initiating preventive therapy. 19 These include frequency of headache as 2 or more attacks per month that produce disability more than 3 days per month; use of acute medication more than 1 or 2 times per week; contraindication to, poor tolerance of, or failure of acute treatments; the presence of uncommon migraine conditions, including hemiplegic migraine, migraine with prolonged aura, or migrainous infarction; and/or patient preference (Table 2). 19 Although not formally included in these guidelines, clinicians may want to consider other criteria for initiating prevention, such as an escalation in frequency and/or duration of headaches and an increasing pattern or anticipated increased use of acute medications to manage headaches. Patients with headache should be encouraged to keep diaries tracking the date, duration, intensity, associated symptoms and triggers, medication use, and other measures that may bring relief of their headaches. If an analysis of the patient s diary indicates that his or her headaches are getting worse, Table 2. Guidelines for Initiating Migraine Prophylaxis Frequency of headache >2/mo with disability >3 d/mo Use of acute medication >1 2 times/wk Acute medications contraindicated, not tolerated, or ineffective Presence of uncommon migraine conditions Hemiplegic migraine Migraine with prolonged aura or migrainous infarction Patient preference Data from Snow et al. 19 Johns Hopkins Advanced Studies in Medicine S893

4 Figure 2. Headache Frequency Predicts CDH Progression 1 year 798 controls (2 14 HA/yr) 23 (3%) CDH Predicted 1-year incidence Incident CDH (18+) Intermediate (15 179) > 1 attack/wk Baseline headache frequency CDH = chronic daily headache; HA = headache. Reprinted with permission from Scher et al. Pain. 23;16: preventive medication may be initiated preemptively, because there is now some evidence that headache frequency predicts progression to CDH. For example, in a study by Scher et al of 798 adults experiencing 2 to 14 headaches per year, those experiencing at least 1 headache per week were significantly more likely to progress to CDH (Figure 2). 2 In another investigation by Katsarava et al, 21 the authors followed 532 consecutive patients with episodic migraine (EM) to determine the likelihood of progression to CDH. The odds ratios for developing CDH were 2.1 (95% confidence interval [CI], ) comparing patients with a critical (1 14 days/month) versus low ( 4 days/month) headache frequency, 6.2 (95% CI, ) in patients with an intermediate (6 9 days/month) versus low headache frequency, and 19.4 (95% CI, ) comparing patients with and without medication overuse. Medication overuse and headache frequency of more than 1 days per month were significantly associated with the development of CDH (P <.1). 21 In counseling patients, these are important data to communicate in explaining the rationale for avoiding frequent use of abortive medications and initiating preventive therapy instead. TREATMENT STRATEGIES Therapies from a range of drug classes are currently used for migraine prevention. However, only 5 are approved or seeking approval from the US Food and Drug Administration, including methysergide, which was specifically designed for treatment of migraine, but is no longer available in the United States (Table 3). Other drugs include the cardiovascular drugs, propranolol and timolol, and the antiepileptic medications, divalproex and topiramate. Although the disadvantage of using a medication not originally designed for migraine treatment is the necessity for dosage adjustment, the advantage of using drugs from other categories is that they may be helpful in treatment of headache-associated comorbidities, such as depression. Furthermore, there are several emerging treatments for migraine prevention that include alternative therapies, such as butterbur (Petasites hybridus), feverfew, riboflavin, magnesium, and coenzyme Q 1. General principles of preventive therapy include initiating therapy with the lowest effective dose and titrating upward slowly to minimize adverse effects to give each therapy an adequate trial period because some may require 2 or 3 months to be effective. 17 Clinicians also need to assess coexisting conditions and avoid treating migraine with a drug contraindicated for another condition that the patient may have. Conversely, it is important not to use a drug for other conditions that exacerbate migraine and to be aware of drug interactions. If a patient is a woman of childbearing potential, clinicians must exercise caution in Table 3. Prophylactic Therapies for Migraine Antidepressants TCAs, SSRIs, MAOIs Amitriptyline, nortriptyline Cardiovascular medications Propranolol* Timolol* Verapamil Antiepileptic drugs Divalproex* Gabapentin Topiramate* Other NSAIDs 5-HT antagonists Methysergide* Other Riboflavin (B 2 ) Feverfew Magnesium (Mg ++ ) Botulinum toxin Petasites hybridus ACE inhibitor Angiotensin II antagonist Coenzyme Q 1 Quetiapine 5-HT = serotonin; ACE = angiotensin-converting enzyme; MAOI = monoamine oxidase inhibitor; NSAID = nonsteroidal anti-inflammatory drug; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant. *Currently holds US Food and Drug Administration indication for migraine prevention. S894 Vol. 6 (9C) October 26

5 drug treatment choice. A listing of select agents and their recommended doses is available from the AHS 22 based on evidence-based guidelines available from the American Academy of Neurology. 23 CLINICAL TRIAL DATA FOR MIGRAINE AND CDH PROPHYLAXIS Clinical trials for various migraine preventive agents have been conducted since the 1962 approval of methysergide. However, before 1991, when the IHS established rigorous guidelines for conducting these trials, standards were not as stringent. For example, in the largest clinical trial of timolol and propranolol for migraine prevention, less than 5% of patients receiving timolol or propranolol obtained at least a 5% reduction in headache frequency. Forty-four percent and 48% of patients treated with timolol and propranolol, respectively, responded to treatment, as did 24% of patients receiving placebo. This difference between the active agents and placebo was statistically significant (P <.1). 24 In 1979, Couch et al 25 published the results of the efficacy of amitriptyline for migraine prophylaxis. Of the 1 patients who completed week 8 of the trial, 26 (55%) patients had at least a 5% response to amitriptyline (as compared to their values at the end of the placebo run-in period), and 18 (34%) patients had a similar response while receiving placebo (P <.5). At the end of week 12, only 72 patients remained in the trial (37 amitriptyline and 35 placebo); of these patients, 2 receiving amitriptyline and 13 receiving placebo had at least a 5% response. It is important to note that this was an interim analysis (for completers) of amitriptyline in migraine and is not an intent-to-treat analysis and it is not evaluating the endpoints of the study. 25 More recent studies have been conducted on neuromodulator/antiepileptic medications, such as gabapentin, divalproex, and topiramate. Gabapentin resulted in at least a 5% reduction in the rate of migraines over 4 weeks for 36% of patients (n = 56) compared to 16% of patients (n = 31) taking placebo (P =.8). 1 Responder rates for divalproex range from 3% to 48% compared to placebo response rates of 14% to 24% in several studies conducted by Klapper, 26 Mathew et al, 27 and Freitag et al. 28 Finally, responder rates for topiramate as an agent of migraine prevention are doserelated, with patients with migraine experiencing at least a 5% reduction in monthly migraine frequency for doses ranging from 1 mg to 2 mg daily, compared to 14% to 21% of patients receiving placebo having the same reduction in frequency. 29 The evidence base for CDH prevention is less extensive than for EM or migraine prevention therapies (Table 4) Studies have been conducted for topiramate, 31 tizanidine, 32 gabapentin, 33 fluoxetine, 34 and botulinum toxin type A. 35 It is difficult to compare these head-to-head or to know how to interpret these data, because the studies did not have the same endpoints, the sample populations were heterogeneous, and the results, such as small differences in the numbers of headache-free days, may not be of real clinical importance. However, all demonstrated evidence of possible efficacy for the treatment of CDH. For example, in the case of botulinum toxin type A, although phase II investigations failed to meet their primary endpoints (3 additional headache-free days at day 18 for botulinum toxin type A vs placebo), secondary endpoints were met, and positive data from the subanalysis was sufficient to prompt phase III trials, which are currently under way. Specifically, there was a decrease in the number of headaches in patients who were treated with botulinum toxin type A versus placebo on days 3, 6, and 12 to 27 (eg, at day 18 the difference was 3.4). More than 7% of all headaches in the study were at least 4 hours in duration, and 64% of patients were not using prophylactic headache medication. For these 2 populations, there was improvement in the number of headaches in patients treated with botulinum toxin type A at every time-point (eg, a difference of 2.4 headaches at day 18) as illustrated in Figures 3 and In summary, the conclusions of the late phase II study were that repeat treatment with Table 4. Evidence Base for CDH Prevention Topiramate Silvestrini et al. Cephalalgia. 23. (n = 28) 31 Tizanidine Saper et al. Headache. 22. (n = 136) 32 Gabapentin Spira et al. Neurology. 23. (n = 133) 33 Fluoxetine Saper et al. Headache (n = 64) 34 Botulinum toxin type A Ondo et al. Cephalalgia. 24. (n = 6) 35 None of these studies have the same endpoints Heterogenous samples Clinical significance of results dubious CDH = chronic daily headache. Data from Dodick 3 ; Silvestrini et al 31 ; Saper et al 32 ; Spira et al 33 ; Saper et al 34 ; and Ondo et al. 35 Johns Hopkins Advanced Studies in Medicine S895

6 botulinum toxin type A is safe and well tolerated at doses up to 26 U; there were significant improvements observed following botulinum toxin type A treatment compared to placebo in headache frequency, headache days (no prophylaxis data), and days and number of acute headache medications used; and lastly, these findings were confirmed in the no prophylaxis and medication overuser subpopulations. 36,37,391 SELECTION, ASSESSMENT, AND LONG-TERM MONITORING OF MIGRAINE PROPHYLAXIS The initial assessment of migraine type and illness severity, along with coexisting conditions, drug efficacy, Figure 3. CDH Study Data for Headache of at Least 4 Hours Mean change in n of headaches Figure 4. Data from CDH Study (Medication Overuse)* Mean change in n of headaches * * <4 hours BoNTA* (n = 173) Placebo (n = 182) Number of Headaches Mean Change/3-Day Period Pooled (n = 355) * * * * -1 * P < BoNTA* (n = 173) Placebo (n = 182) Baseline: BoNTA* = 13.5, Placebo = Medication Overusers (n = 168) * * * * * * * * * P < BoNTA* (n = 91) Placebo (n = 77) Baseline: BoNTA* = 15.2, Placebo = 14.9 *No concomitant prophylactic medication and overusing acute pain medications. BoNTA = botulinum toxin type A; CDH = chronic daily headache. Data from Saper et al hours *P.5 * * ** * * * * * BoNTA* (n = 173) Placebo (n = 182) Baseline: BoNTA* = 3.9, Placebo = 3.5 Baseline: BoNTA* = 9.6, Placebo = 9.2 BoNTA = botulinum toxin type A; CDH = chronic daily headache. Data from from Aurora et al 36 and Elkind et al. 37 and adverse effects, directs treatment choice and the longterm management plan. However, continued follow-up in the clinic and the home is needed to ensure that medications or doses are adjusted, comorbid conditions are managed appropriately, and the impact of illness improves. Headache pain and associated symptoms can routinely be recorded in headache diaries, thus clinician and patient may monitor headache response to specific treatments, track response times, and note recurrence issues. Headaches also need to be monitored for changing frequency and improving or deteriorating disability. The Migraine Disability Assessment Questionnaire 42 can be used to measure the impact of migraine on work, school, household work, and social or leisure activities. A quantifiable score helps assess the severity of illness and can be recorded and monitored during the long-term care of the patient. Migraine often is associated with comorbid conditions. As these coexisting conditions change, so too does the likelihood of migraine frequency or intensity. For example, migraine has a documented comorbidity with depression, and clinicians may try to find a single medication that works to treat both. Underlying these practical considerations is the continued quest for a better understanding of the pathophysiology of migraine that may in turn lead to concrete biomarkers and/or diagnostic imaging techniques that may, based on or in conjunction with genetic information from patients, specifically tailor migraine treatment to the individual. Although there is currently no cure for migraine, prophylactic pharmacotherapy and lifestyle changes offer a vast improvement in the quality of life for patients that suffer with chronic headaches. View highlights from panel discussion that followed this presentation: REFERENCES 1. Honkasalo ML, Kaprio J, Winter T, et al. Migraine and concomitant symptoms among 8167 adult twin pairs. Headache. 1995;35: Knight YE, Bartsch T, Kaurbe H, Goadsby PJ. J Neurosci. 22;22:RC May A, Ophoff RA, Terwindt GM, et al. Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura. Hum Genet. 1995;96: Nyholt DR, Lea RA, Goadsby PJ, et al. Familial typical migraine: Linkage to chromosome 19p13 and evidence for genetic heterogeneity. Neurology. 1998;5: Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996;87: S896 Vol. 6 (9C) October 26

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