Chronic daily headache (CDH), defined

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1 FINDING A FIT: STRATEGIES FOR CHRONIC MIGRAINE PROPHYLAXIS David W. Dodick, MD, FRCP(C), FACP ABSTRACT Chronic daily headache (CDH) affects approximately 4% to 5% of the population and is responsible for up to 8% of visits to headache specialty clinics. Chronic migraine, or transformed migraine, is among the most common type of CDH and significantly impacts quality of life. Therefore, preventive (prophylactic) therapy is essential to complement acute treatment in this population of patients. This article discusses the guidelines for initiation of preventive therapy in addition to establishing requirements for successful migraine prevention. The use of various established medications for migraine prevention is discussed. Chronic daily headache (CDH), defined as the presence of a headache for more than 15 days per month for longer than 3 months, 1 affects approximately 4% to 5% of the population. 2,3 Chronic migraine (CM), or transformed migraine (TM), is among the most common type of primary CDH, 3 and significantly impacts the quality of life (QOL) of these patients. 4-6 Therefore, preventive therapy is essential to complement acute treatment in this population of patients. The goals of preventive treatment include reducing attack frequency, severity, and duration, improving responsiveness to acute treatments, and This article is based on a roundtable symposium held in Los Angeles, California, on February 18, 26. Professor of Neurology, Mayo Clinic College of Medicine, Mayo Clinic, Scottsdale, Arizona. Address correspondence to: David W. Dodick, MD, FRCP(C), FACP, Professor of Neurology, Mayo Clinic College of Medicine, Mayo Clinic, 134 East Shea Boulevard, Scottsdale, AZ dodick.david@mayo.edu. improving the patient s ability to function in daily life without disability. Successful migraine prevention requires several components defined and collaborated on by the patient and physician. First, patients must be willing to commit to the treatment regimen, which may include not only prophylactic therapy for CM, but pharmacologically based acute and rescue strategies and behavioral or lifestyle modifications where appropriate. Clear and realistic expectations for preventive treatment must be established by the healthcare practitioner and patient. Patient education is essential for this component because frequently, patients may not understand the need for a lengthy trial of a medication at an adequate dose. Migraine prevention may take up to 6 to 8 weeks to begin to demonstrate efficacy and up to 6 months before full efficacy is established. It is also critical to engage the patient in a discussion about common and rare, but potentially serious, side effects. Patients must be made aware that none, one, some, or many side effects may be experienced, and there is no good way to predict the side effects that may occur in any given patient. Side effects are commonly self-limited, but when doselimiting side effects occur, the dose may have to be titrated down or at least halted until side effects attenuate. Headaches and migraine attacks should be monitored, and headache diaries are effective, objective tools to accomplish this. It is also necessary to identify and manage comorbid conditions. Choice of preventive agents may hinge on comorbid and coexistent conditions. For some patients, migraine with a specific comorbid or coexisting condition may be successfully treated with a single medication. For example, patients with tachycardia or hypertension may find β-adrenergic blockers helpful in reducing attack frequency and severity. Psychiatric conditions (in particular anxiety and depression 7 ) are highly prevalent among individuals with CDH and must be addressed to treat headache adequately. These patients may benefit from tricyclic antidepressants

2 (TCA) or selective serotonin reuptake inhibitors (SSRI). Patients with obesity and migraine may benefit from topiramate, because of its side effect profile (some patients experience weight loss). 8 However, sometimes a single drug is not optimal for the treatment of 2 conditions. For example, SSRIs and serotonin-norepinephrine reuptake inhibitors have fast become the first-choice drugs for treatment of depression, and the dose of a TCA required to achieve an antidepressant effect may be much higher than is necessary for an antimigraine effect. On the other hand, comorbid or coexisting conditions may limit the choices for preventive drugs. For example, a preventive drug that has a high potential for weight gain, such as divalproex or a TCA, would not be ideal choices for patients with obesity, hypertension, or diabetes all conditions that could be exacerbated by additional weight gain. GUIDELINES FOR INITIATION OF MIGRAINE PREVENTION Successful migraine prevention requires a detailed headache history to assess the appropriateness of preventive therapy, and, as previously mentioned, the monitoring of headache frequency (migraine and nonmigraine). The American Headache Society provides guidelines for the initiation of migraine preventive therapy. 9 According to these guidelines, the first indication for the necessity of preventive drug treatment is not frequency of attacks, but rather the use of acute medication more than 1 to 2 times per week. However, from the practical perspective of a neurologist, it may be more useful to examine frequency of attacks to determine necessity of prophylaxis. In a study by Scher et al, 1 potential cases (18+ headaches/year, n = 1134) and controls (2 14 headaches/year, n = 798) were interviewed 2 times over an average 11 months of followup. It was determined that once patients experienced more than 1 migraine attack per week, the incidence of CDH increased significantly (Figure 1). 1 Data from Katsarava et al 11 also indicates that headache frequency predicts progression to CDH; 14% (64) of 532 patients with episodic migraine (EM; 15 days/month) developed CDH over a 1-year period. If patients experienced 6 to 9 headaches per month (corresponding to approximately 1 headache/week), the odds ratio of 6.2 (95% confidence interval [CI], ) indicates that these individuals were 6 times more likely to develop CDH; more than 1 headaches per month yielded an odds ratio of 2.1 (95% CI, ), thus indicating 2 times the odds of transforming into CDH from EM attacks (Table 1). 11 Each situation must be considered individually. For example, if a patient has been experiencing 1 headache per week for 1 to 15 years and is obtaining relief using 1 to 2 triptans per week, it is unlikely that the patient will progress to CDH, and, therefore, may not require prevention. On the other hand, the patient who experiences 1 attack per week but requires 2 to 3 triptans along with other over-the-counter acute medications for relief is probably a candidate for preventive Figure 1. 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: Table 1. Progression to CDH from Episodic Migraine 14% of 532 patients with episodic migraine developed CDH over a 1-year period Risk Factors Odds Ratio 95% CI P Value Headache frequency <.5 Headache frequency <.1 >1 d/mo Analgesic overuse <.1 Multivariable analysis: adjusted for all other variables in the analysis. CDH = chronic daily headache; CI = confidence interval. Reprinted with permission from Katsarava et al. Neurology 24;62:

3 therapy. Other indications for prevention include situations where acute medications are contraindicated, not tolerated, or are ineffective; when recurring migraine significantly interferes with daily routine, despite acute treatment; when there is anticipatory use of acute therapies (as this may predispose patients to medication overuse headache); or when there is a patient preference to begin preventive drug therapy. COMMON PREVENTIVE THERAPIES FOR CDH Many therapies are currently used for migraine prevention. However, only 4 are approved by the US Food and Drug Administration: propranolol, timolol, divalproex, and topiramate. Methysergide is no longer available (Figure 2). Whereas medications from a broad range of classes have demonstrated efficacy in preventing migraine attacks, clinicians are most familiar with the data supporting use of β-adrenergic blockers, antidepressants, calcium channel antagonists, and valproate and topiramate, both antiepileptic drugs (AED). Until recently, the data from randomized, placebo-controlled trials of medications for CDH were scarce and not of particularly high quality. Among the AEDs studied, Spira et al evaluated 133 patients who experienced a 9.1% difference in headache-free rates for gabapentin compared to placebo (P =.5). 12 Another anticonvulsant medication demonstrating efficacy greater than placebo was topiramate, which reduced the mean number of days with headache to 8.1 for the treated group versus 2.6 for the placebo group (P <.7) in a small sample of 28 patients. 13 In a recently reported randomized, double-blind placebo control trial in patients with TM, 36 patients were randomized to receive topiramate or placebo. Topiramate was associated with a significant reduction in the mean number of days per month (± SD) with migraine or migrainous headache (6.41 ± [topiramate] vs 4.67 ± 6.77 [placebo]; P =.1), in addition to mean migraine-days per month (5.55 ± Table 2. Preventive Therapies for CDH Medication Class and Drug Target Daily Dose Titration Period Common Side Effect Antidepressants Tricyclic antidepressants (eg, amitriptyline) 5 1 mg 1 2 mo Weight gain, dry mouth, constipation, palpitation, drowsiness, dizziness, and fatigue Selective serotonin-reuptake inhibitors 2 6 mg 1 mo Anorexia, insomnia, anxiety, tremor, asthenia, dizziness, (eg, fluoxetine) and somnolence Anticonvulsants Divalproex wk Nausea, somnolence, dizziness, vomiting, tremor, alopecia, and weight gain Gabapentin 9 36 mg 1 2 mo Dizziness, somnolence, ataxia, abnormal thinking, peripheral edema, weight gain, and incoordination Topiramate 5 2 mg 1 2 mo Paresthesia, difficulty with word finding and concentration, and weight loss α 2 -adrenergic agonists Tizanidine 8 2 mg 1 2 mo Dry mouth, somnolence, asthenia, dizziness, constipation, hypotension, and bradycardia Neurotoxin Botulinum toxin type A U every 3 mo Injection every 3 moweakness of injected muscle, ptosis, and neck pain All the listed agents (except divalproex) have been studied in 1 randomized trial involving patients with a primary CDH (>15 d/mo). However, these were not studies specifically of patients with transformed migraine (TM) or medication overuse headache (MOH). Most of the patients in some studies and all the patients in other studies had a history of migraine; none of the studies evaluating these therapies uniformly used the definition of the International Headache Society for chronic migraine or the criteria of Silberstein et al for TM. Overuse of acute-headache medications was present in a substantial proportion of patients in several studies. This table is not intended to be exhaustive. No medications are approved by the US Food and Drug Administration for the prevention of headache in patients with TM or MOH. Silberstein SD, Lipton RB, Sliwinski M. Classification of daily and near-daily headaches: field trial of revised International Headache Society criteria. Neurology. 1996;47: CDH = chronic daily headache. Reprinted with permission from Dodick DW. N Engl J Med. 26;354:

4 Figure 2. Migraine Prevention Medications Antidepressants TCAs, SSRIs, MAOIs Amitriptyline, nortriptyline Cardiovascular medications Propranolol Timolol Verapamil Neurostabilizers Divalproex Gabapentin Topiramate Other NSAIDs 5-HT antagonists Methysergide Cyproheptadine Other Riboflavin (B 2 ) Feverfew Magnesium (Mg ++ ) Botulinum toxin Petasites hybridus ACE inhibitor Angiotensin II antagonist Coenzyme Q Quetiapine Currently holds US Food and Drug Administration-indication for migraine prevention. 5-HT = serotonin; ACE = angiotensin-converting enzyme; NSAID = nonsteroidal anti-inflammatory drug; MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin reuptake inhibitors; TCA = tricyclic antidepressant. Courtesy of Richard B. Lipton, MD. vs 4.8 ± 6.63 ; P =.32). The most common adverse events included paresthesia (29% [topiramate]; 7% [placebo]), upper respiratory tract infection (14% [topiramate], 12% [placebo]); and fatigue (12% [topiramate], 1% [placebo]). Eleven percent of patients receiving topiramate and 6% receiving placebo discontinued as a result of adverse events. No serious adverse events were reported. Other types of medications that have been studied include the muscle relaxant, tizanidine, and botulinum toxin A. In a study of 136 patients, the mean percentage improvement with tizanidine versus placebo was 54% versus 19% for the headache index (P =.144), 55% versus 21% for severe headache days (P =.331), and 3% versus 22% for total headache days (P =.593). 14 However, this study was an add-on study in which tizanidine was added to a preventive drug that the patient was taking before randomization and during the course of the study. Botulinum toxin type A was administered to patients in 3 randomized, placebo-controlled studies. 15,16 In the study by Ondo et al, 15 headache-free days were less in the twice botulinum toxin type A-injected group compared with the once-injected group (4 ± 26 vs 26 ± 19; P <.5; n = 6). 15 In the Mathew and Silberstein studies, the primary endpoints were not achieved. However, 5 of 6 secondary endpoints were positive, including a significant reduction in headache frequency, migraine/probable migraine frequency, and responder rates. This provided the rationale for 2 large pivotal, randomized, placebocontrolled, phase III international trials, which are currently under way. Mathew et al 16 noted a 54% versus 38% response rate in 355 patients who received botulinum toxin versus placebo. With several available options and no formal treatment guidelines determined as of yet, drug selection for each patient will depend on several factors, including migraine type, coexisting conditions, efficacy, side-effect profile, and patient preference (Figure 2). Table 2 lists the common preventive medications for CDH. The use of herbal remedies (eg, Petasites hybridus, coenzyme Q, and feverfew) for migraine prevention needs to be carefully considered because of the relative lack of evidence of efficacy and potential unknown long-term safety issues. BOTULINUM TOXIN TYPE A FOR CDH PROPHYLAXIS A recent injectable versus oral addition to the armamentarium for CDH is botulinum toxin type A. The largest published controlled studies in CDH have been conducted with botulinum toxin type A; there have been a total of 8 phase II studies 5 for patients with EM and 3 for patients with chronic headache disorders. The data from 1 particular phase II study, Mathew et al, 16 has provided the impetus to proceed with phase III testing. The patient population for this 11-month, placebo-controlled, randomized, doubleblind study was comprised of women (mean age approximately 43 years) with long-standing (14-year) history of disabling CDH (approximately 75% with severe Migraine Disability Assessment [MIDAS] scores). The patients had an average of 23 headache days per month with 13 attacks per month. Approximately 5% of the patients were overusing acute medications, and approximately 33% of the patients were taking prophylactic drugs. Of 355 patients, 4 withdrew for adverse events (ie, neck pain or weakness). The primary efficacy measure was the change from baseline in the frequency of headachefree days in a 3-day period for the placebo nonresponder group at day 18. The secondary efficacy measure was the proportion of patients with a decrease from baseline of at least 5% in the frequency of headache days per 3-day period for the placebo nonresponder group at day 18. The change from baseline in the frequency of headaches (per 3-day period), the

5 Table 3. Results of Phase II Mathew et al Study for BoNTA Efficacy Measures Outcome Measure Day 18 1º Headache-free d/mo, n Not significant 2º Percentage of patients with P =.27 5% decrease of headachedays/mo (4% vs 25%) Additional Headache frequency/mo P =.1 (-7.1 vs -3.7) Additional Patients with 5% decrease headaches/mo (54% vs 38%) P =.46 BoNTA = botulinum toxin type A. Data from Mathew et al. 16 Table 4. BoNTA: No Prophylaxis Subgroup (228; 64%) Efficacy Measures Outcome Measure Day 18 1º Headache-free d/mo, n P <.5 (-1 vs -6.7) 2º Percentage of patients with P <.5 5% decrease of headachedays/mo (46% vs 22%) Additional Headache frequency/mo P <.5 (-7.5 vs -3.6) Additional Acute headache medication P <.5 use (-7.8 vs -4.1) Additional Patients with 5% decrease Not significant of headaches/mo (52% vs 37%) BoNTA = botulinum toxin type A. Data from Dodick et al. 17 baseline of 5.2 headache-free days for placebo-treated patients. The between-group difference of 1.5 headache-free days favored botulinum toxin type A treatment, although the difference between the groups was not statistically significant. A significantly higher percentage of patients receiving botulinum toxin type A had a decrease of at least 5% in frequency of headache-days per 3-day period at day 18 (32.7% vs 15%; P =.27), and the mean change from baseline in the frequency of headaches per 3-day period at day 18 was -6.1 for patients treated with botulinum toxin type A compared to -3.1 for the patients receiving placebo (P =.13; Table 3). 16 A follow-up analysis was conducted to assess the efficacy and safety of botulinum toxin type A in patients with CDH without the confounding factor of concurrent prophylactic medications. 17 Of the original patient population for the Mathew et al study, 228 (64%) were not taking prophylactic medication and were included in this analysis (117 patients received botulinum toxin type A and 111 received placebo injections). They had similar demographic characteristics to the original study population. After 2 injection sessions, the maximum change in the mean frequency of headaches per 3 days was -7.8 in the botulinum toxin type A group compared to only -4.5 in the placebo group (P =.32) a statistically significant Figure 3. Change in Medication Overuse in Patients Using BoNTA proportion of patients with a decrease from baseline of at least 5% in the frequency of headaches per 3-day period, acute medication use, and adverse events also were assessed. Although the primary outcome measure (number of headache-free days) was not met, secondary outcomes (percentage of patients with 5% reduction in headache-days/month) and 2 of the a priori sub-analyses (headaches/month and headache frequency/ month) were all significant in favor of botulinum toxin treatment. At day 18, placebo nonresponders treated with botulinum toxin type A had an improved mean change from baseline of 6.7 headache-free days per 3-day period compared to a mean change from Mean change in n of headaches % overusing acute headache pain medications (ICHD-II definitions) Pooled (n = 355) P < BoNTA (n = 173) Placebo (n = 182) Baseline: BoNTA = 13.5, Placebo = Medication Overusers (n = 168) 4.5 P BoNTA (n = 91) Placebo (n = 77) Baseline: BoNTA = 15.2, Placebo = 14.9 BoNTA = botulinum toxin type A; ICHD-II = International Classification of Headache Disorders (second edition). Data from Saper et al. 18

6 between-group difference of 3.3 headaches. The between-group difference favoring botulinum toxin type A treatment continued to improve to 4.2 headaches after a third injection session (P =.23). In addition, botulinum toxin type A treatment at least halved the frequency of baseline headaches in over 5% of patients after 3 injection sessions compared to Figure 4. Headache Duration in Patients Using BoNTA BoNTA = botulinum toxin type A. Data from Elkind et al 19 and Aurora et al. 2 P.44 baseline. Statistically significant differences between botulinum toxin type A and placebo were evident for the change from baseline in headache frequency and headache severity for most timepoints from day 18 through day 27 (Table 4). 17 Other important data from analysis of the phase II studies included a significant reduction in the number of headaches experienced by patients who overused acute medications of 4.5 (n = 168; P.44; Figure 3) 18 and the duration of headache (Figure 4). 19,2 A mean change in the number of headaches of at least 4 hours was observed; at day 18, botulinum toxin type A was -4.6 versus placebo -2.2 (P.5) Perhaps of greatest importance clinically because of its effects on patients most disabling headaches (migraines) were the results of a subgroup analysis of the data from a Mathew et al study of 177 patients with frequent headache (>4 headaches/ month) who were not using concomitant headache prophylaxis. These data indicated that botulinum toxin type A treatment resulted in a significant decrease (P <.5) in the frequency of migraine or probable migraine episodes among sufferers of frequent headache, with 6% to 65.5% of patients receiving botulinum toxin type A reporting at least a 5% reduction in migraine or probable migraine attacks compared to 33.3% to 5% with placebo (P <.5; Figures 5 and 6). 21 CONCLUSIONS Figure 5. Change in M/PM Episodes (BoNTA vs Placebo) Mean change in n of M/PM episodes M/PM Headache Episodes per 3-day Period Days after treatment P <.5 P =.1 BoNTA (n = 9) Placebo (n = 87) P <.5; P =.1; TM = headaches 15 d/mo, lasting 4 hours and >5% are M/PM. BoNTA = botulinum toxin type A; M/PM = migraine/probable migraine; TM = transformed migraine. Reprinted with permission from Aurora et al. Cephalalgia. 25;25: The treatment of CDH presents challenges to the practicing neurologist. Millions of individuals suffer from headache, and 7% to 8% of patients who seek treatment at headache specialty centers are suffering from daily or near-daily headaches. 22 For clinicians and patients, it is uncertain at the onset of treatment which therapies will be most effective in each case. Prophylactic therapy is necessary for patients at either end of the acute treatment spectrum: those unable to tolerate acute medications or those overusing acute medications intended for episodic attacks. Until recently, the evidence from randomized, clinical trials has been less than optimal, and treatment choices are often experiencebased. Clinical trial guidelines for patients with CDH are being developed, and over the next decade, patients with CDH will represent a research priority and be the focus of preventive drug trials.

7 Figure 6. Responder Rate for Patients with CDH: M/PM Episodes (BoNTA vs Placebo) Patients, % % Patients with > 5% Decrease in M/PM Episodes DISCUSSION Days after treatment P <.5 BoNTA (n = 9) Placebo (n = 87) P <.5; TM headaches 15 d/mo lasting 4 hours and >5% are M/PM. BoNTA = botulinum toxin type A; M/PM = migraine/probable migraine; TM = transformed migraine. Reprinted with permission from Aurora et al. Cephalalgia. 25;25: Dr Dodick: In terms of monitoring headache attacks, do you think we need to use a headache diary to know whether a patient is responsive to prophylactic therapy? Dr Mondell: One can assess patient satisfaction and response to treatment without a diary. However, I strongly encourage patients to keep a written record. Using a diary to monitor headache attacks is useful to the patient and the practitioner and generally provides an unambiguous view of headache frequency, severity, and duration, as well as the amount of acute treatment required. Dr Dodick: Does what patients report in their headache diaries affect your decision making in terms of whether you bump up the dose, switch to another medication, or add another medication? Dr Mondell: Both the patient s subjective report and the patient s objective diary recordings are required for clinical decision making and therapeutic choices. Dr Dodick: Does it ever disagree or does it ever conflict with what they tell you subjectively? Dr Mondell: Many patients have real difficulty telling you if they are better or not. By looking at the diary, I can quantify how many mild, moderate, and severe headaches the patient is having. A diary is also an excellent way to monitor the use of acute therapy, because it is so easy for patients to lose track of how much they really are taking. An added benefit of diary keeping comes from engaging patient responsibility to actively participate in the care of his or her headaches, shifting the locus of control. Dr Saxton: Initially, patients usually have a problem keeping the diary, because they cannot see the usefulness of it. But once they see that they are being educated about their own headaches, then they can accept it. If they do not want to keep a headache diary, alternately, they can fill out a MIDAS questionnaire or a Headache Impact Test. Dr Dodick: With regard to the Mathew et al 16 phase II study on botulinum toxin type A among patients with chronic headache, although the investigators did not meet their primary endpoint, what do you feel as very experienced clinicians who see patients day-to-day? Do you think the results are clinically relevant? Dr Schim: I think that this is a difficult group of people, and to cut from 23 days of headache and reduce that by 1 or 11 days is very meaningful for most patients. The severity of the headaches that they experience often tends to decline. I also think it is useful in terms of getting patients off of the medicines that they are overusing. Plus, it flies right in the face of the notion that if someone is overusing medicine, they are going to fail preventives. Dr Dodick: There is an article published in the February 26 issue of the European Journal of Neurology that is critical of the Mathew et al data. 23 I think what critics of the study are doing is they are drawing on the difference between placebo and active drug response and saying it is not clinically meaningful. However, these patients were systematically excluded for randomized, controlled trials the past 15 or 2 years because they were thought to be intractable. I would never have predicted this in this population a 54% response rate. Therefore, I think it is quite impressive if you can take a patient who on average is experiencing 13 attacks per month and drop the attacks by 7; that is pretty significant in this type of population. Dr Schim: Even in the context of a 38% placebo response rate, a 54% response rate is a therapeutic gain of 16%. Dr Dodick: The data from the no prophylaxis subgroup looked essentially the same, except that this primary endpoint number of headache-free days was now

8 significant. But the responder rate was not significant only insofar as the placebo response rate came up. What are your thoughts about these data from the no prophylaxis subgroup? Dr Aurora: I think statistically it is a better population to look at because you are not having any additive effects. Dr Saxton: When you talk about headache frequency, it does not tell you anything about how severe the attacks are. Dr Frishberg: That is one of the issues when you use the primary endpoint of headache-free days. If patients have headaches with severity measuring 9 out of 1 on a 1-point scale 3 days of the month, and after treatment they have headaches that are described as a 1 out of 1 points 3 days of the month, this is not reflected as no difference in headache-free days, despite a profound change in their QOL. Dr Dodick: One of the things I learned from these phase II data, is that 1 injection cycle does not seem to be enough. There is an incremental improvement in these patients over time. Just as we explain to people on oral prophylaxis regarding how their response initially is not necessarily what it will be at 6 months, maybe this is the same with botulinum toxin. If there is even a hint of improvement over the course of 3 months, those patients should be reinjected. Dr Schim: I agree. If they had zero effect at all, I am a little bit more dubious, but if they have had some improvement, I am going to encourage them to treat a second time, and potentially change perhaps push the dosing or shift the treatment pattern some. Dr Saxton: Do you treat sooner than 3 months? Dr Schim: Generally not. Dr Frishberg: I would say I do things a little differently in that I do not usually increase my typical dose unless there are unusual circumstances, such as a change in pain character or associated dystonia. In most patients who have no response, I personally do not suggest they use it again. Dr Rosenberg: I do not think one response of anything is meaningful. The problem we have with all of these preventive medicines is that patients do not stay on them for a very long period of time, and perhaps it has not had a chance to work. Thus, it would make sense here that you could not expect botulinum toxin necessarily to work in 1 treatment. Dr Saxton: In these patients who are not responding, have you seen that the medication actually took effect that their foreheads are not wrinkled? Should we check for antitoxin antibody levels? Dr Schim: I have never seen that doing so is clinically useful. True primary nonresponse is very rare. Secondary response is also very rare, and current toxin has a substantially reduced chance of development of antibodies and thus of secondary resistance. In terms of assessing resistance, I have rarely checked for resistance through mouse protection assay. One can typically see reduced frontalis and corrugator effect by observation. Lack of this would make me concerned about resistance. Dr Dodick: Here is where monitoring diary data is important, because patients expectations are high. And if they get, for example, a 3% or 2% response to botulinum toxin, they perceive that the treatment did not work. Dr Schim: Educating the patient so that they have appropriate expectations regardless of whether we are talking about botulinum toxin or another preventive or acute medicine is vital. Dr Dodick: How about predicting response to botulinum toxin and other preventive medications based on whether the patient is an imploder or an exploder? Dr Schim: How about triptan responsivenesss in exploders versus imploders? Dr Dodick: Yes, that is being worked on. Dr Rosenberg: This has the potential for really changing the approach to migraine for the general, primary care physician, because this is something you can get your hands on pretty quickly and easily. We will have to see how it holds up in the other treatments. REFERENCES 1. Dodick DW. Clinical practice. chronic daily headache. N Engl J Med. 26;354: Scher AI, Stewart WF, Liberman J, Lipton RB. Prevalence of frequent headache in a population sample. Headache. 1998;38: Castillo J, Munoz P, Guitera V, Pascual J. Epidemiology of chronic daily headache in the general population. Headache. 1999;39: D Amico D, Usai S, Grazzi L, et al. Quality of life and disability in primary chronic daily headaches. Neurol Sci. 23;24:S97-S1. 5. Guitera V, Munoz P, Castillo J, Pascual J. Quality of life in chronic daily headache: a study in a general population. Neurology. 22;58: Wang SJ, Fuh JL, Lu SR, Juang KD. Quality of life differs among headache diagnoses: analysis of SF-36 survey in 91 headache patients. Pain. 21;89:

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