Botulinum toxin type A is currently being

EMERGING PREVENTIVE OPTIONS FOR CHRONIC DAILY HEADACHE * David W. Dodick, MD, FRCP(C), FACP ABSTRACT Approximately 3% to 5% of the population is affected by headaches on a daily or almost daily basis. This often interferes with the quality of life for patients and requires them to take a variety of acute headache medications to manage their acute attacks. Over time, these treatments may wane in efficacy, cause adverse events, lead to their overuse, and ultimately increase the headache burden. Therefore, prevention of acute attacks for these patients is essential. Emerging therapeutic options for the prevention of headache include a variety of pharmacologic and nonpharmacologic agents. This article will focus on some of these agents, including evidence from clinical trials for use of botulinum toxin type A, herbal preparations, and the antiepileptic medication lamotrigine. (Adv Stud Med. 26;6(4D):S336-S342) *This article is based on a roundtable symposium held in New York, New York, on December 3, 25. 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 85259. E-mail: dodick.david@mayo.edu. Botulinum toxin type A is currently being studied as an emerging treatment for patients with migraine who suffer from chronic daily headache (CDH). In addition, various antiepileptic medications, vitamins, and herbal remedies are being explored as treatments for migraine. They include lamotrigine, coenzyme Q 1 (CoQ 1 ), and Petasites hybridus (butterbur). This article will focus on evidence from clinical trials for use of botulinum toxin type A, herbal preparations, such as butterbur, and the antiepileptic medication lamotrigine. USE OF BOTULINUM TOXIN TYPE A FOR EPISODIC MIGRAINE AND CHRONIC DAILY HEADACHE Two serotypes of botulinum neurotoxin (BoNT), type A (9 kd) and type B (5 kd), have been approved by the US Food and Drug Administration (FDA) since 1989 for a variety of therapeutic indications. 1 When used clinically, BoNT is delivered through intramuscular or local subcutaneous injection, where it binds preferentially to cholinergic terminals. BoNTs inhibit acetylcholine release at the neuromuscular junction. Specifically, type A cleaves the synaptosome-associated protein at different sites at the carboxyl-terminus, and this can be applied to the treatment of conditions characterized by a hyperfunction of cholinergic nerve terminals. 2 Although not yet US FDA sanctioned, evolving uses of the toxin include treatment of various pain syndromes, including headaches. Phase II studies of botulinum toxin type A for the treatment of episodic migraine and chronic tensiontype headache have been conducted since 2 with mixed results. 3-7 The literature for the use of botulinum toxin type A for CDH is sparse, although recent large randomized placebo-controlled studies by Silberstein et al and Mathew et al have yielded interesting findings in this rarely studied patient population. 8-1 The Silberstein et al study, which used a fixed-site, fixeddose approach, and the Mathew et al study, which used a modified, follow-the-pain approach, failed to achieve significance on their primary endpoints. However, sufficient information was obtained to warrant progressing to phase III investigations of botulinum toxin type A for use in patients with CDH. The late phase II study conducted by Mathew et al for the use of botulinum toxin type A for treatment of CDH was initiated in early 21. 9 The study design S336 Vol. 6 (4D) April 26

was an 11-month, randomized, double-blind, placebocontrolled investigation with 3-month treatment cycles. Patients were injected with botulinum toxin type A or placebo every 9 days and assessed every 3 days for 9 months. The primary efficacy measure was the change from baseline in the frequency of headache-free days in a 3-day period at day 18 the primary analysis time point. The secondary efficacy measure was the proportion of patients with a decrease from baseline of 5% or more in the frequency of headache-days per 3-day period at day 18. The change from baseline in the frequency of headaches (ie, per 3-day period), the proportion of patients with a decrease from baseline of at least 5% or greater in the frequency of headaches per 3-day period, days of acute medication use, and adverse events also were assessed (Figure 1). On a daily basis, patients used an electronic telephone diary to report headache characteristics, symptoms, and acute treatments. 9 After a single-blind placebo injection, patients were reassessed 1 month later to determine the responsiveness to placebo. Patients were stratified as placebo responders (ie, >3% reduction in headaches) or placebo nonresponders. These 2 groups were then randomized to receive placebo or botulinum toxin type A in a double-blind fashion. Study subjects then received 2 subsequent double-blind injections of active drug or placebo every 12 weeks. Injection sites were as indicated in Figure 2. All patients received injections into the following muscles: frontal/glabellar, temporalis, occipitalis, trapezius, semispinalis capitis, and splenius capitis. The dosages were modified according to the pain experienced by the patient. Twenty-three to 58 injection sites were used per patient with a total dosage between 15 and 26 U used per treatment in each patient. 9 Demographic characteristics for this patient population were similarly matched between the groups who received botulinum toxin type A and placebo. Most of the subjects were female with a mean age of approximately 43 years (age range, 18 65 years). These patients were long-term sufferers of CDH, averaging nearly 15 years, with Migraine Disability Assessment questionnaire scores in the severe range (ie, >2) for those patients receiving botulinum toxin type A treatments and those patients receiving placebo (ie, 78% and 72%, respectively). They suffered with headache for 23 days on average, whereas the actual frequency of headache attacks was approximately 13. The discrepancy owes to the fact that 1 attack may last longer than 1 day. There was no significant difference between treatment groups for the headache frequency per 3 days (during baseline) or for migraine/probable migraine frequency per 3 days (during baseline). Every headache reported by the patient during the study was classified into migraine, probable migraine, or nonmigraine (eg, tension-type headache) using the International Criteria of Headache Disorders (second edition). It was determined that 1% of the patients experienced at least 1 migraine or probable migraine headache during the baseline period. 9 Figure 1. Use of in the Treatment of CDH Baseline Single-blind placebo Tx nonresponder responder Late Phase II Studies Common Design Doubleblind Tx Interim analysis Doubleblind Tx Primary analysis Doubleblind Tx Final analysis Day Day -3 Day Day 9 Day 18 Day 27 = botulinum toxin type A; CDH = chronic daily headache; Tx = treatment. Figure 2. Injection Sites for Phase II Clinical Studies of Frontal/ glabellar Masseter reconstituted with 2 ml/vial (5 U/mL) 23 58 total injection sites = botulinum toxin type A. Semispinalis Temporalis Occipitalis Trapezius MUSCLE AREA # Units Bilateral? Total Dose Frontal/glabellar 25 4 No 25 4 Occipitalis 1 Yes 2 Temporalis 1 25 Yes 2 5 Masseter (optional) 25 Yes 5 Trapezius 1 3 Yes 2 6 Semispinalis 5 1 Yes 1 2 Splenius capitis 5 1 Yes 1 2 TOTAL DOSE RANGE = 15 26 U Splenius capitis Johns Hopkins Advanced Studies in Medicine S337

Half (53%) of the subjects in the botulinum toxin type A group were overusing acute headache medications, whereas 42% in the placebo group were overusing acute headache medications (total use of all headache medications, 1 days/month for >3 months). These patients were permitted to remain in the study at the discretion of the investigator if they believed that the patients were not experiencing medication overuse headaches. Approximately one third of patients (ie, 32% and 39%, respectively for botulinum toxin type A and placebo subjects) were using concurrent preventive headache medications at baseline. 9 A total of 76.9% (273/355) of patients completed the study, including 132 patients who completed the original protocol requiring only 1 postrandomization treatment. Of the 22.8% (81/355) of patients who discontinued early, 5.1% (18/355) of these patients discontinued for lack of efficacy, 1.4% (5/355) for adverse events,.3% (1/355) for inability to follow study instructions, 1.1% (4/355) for personal reasons, and 2.8% (1/355) were lost to follow-up. Of the patients who discontinued because of adverse events, the specific adverse events were neck pain in 2 subjects and neck weakness in 2 other patients. 9 Table 1 lists the primary and secondary endpoints: number of headache-free days and patients with at least a 5% decrease in headache-days per month, respectively. 9 In terms of the primary outcome measure, there was no significant difference between botulinum toxin type A and placebo. The placebo nonresponders and the placebo responders improved, but there was no statistical difference between the 2 groups, and therefore, the data could be pooled for greater statistical power. The secondary endpoint the proportion of patients with at least a 5% decrease in headache-days per month in the placebo-nonresponder group was significantly in favor of botulinum toxin type A treatment at day 18 (32.7% for those receiving botulinum toxin type A and 15% in patients receiving placebo). When examining headache frequency, there was a significant difference at most time points favoring botulinum toxin type A in the pooled population. On average, patients receiving botulinum toxin type A injections had 7 fewer headaches per month compared to approximately 4 fewer headaches per month among those patients receiving placebo injections at day 18. 9 Because patients were experiencing an average of 13.5 headaches per month at baseline, this has true relevance to clinical practice, especially as these patients have traditionally been considered to be largely recalcitrant to treatment. A specific subpopulation of these patients (n = 228) who were not using concurrent headache-preventive medications achieved statistical significance for most study endpoints at day 18, including the number of headache-free days (1 vs 6.7; P =.38), percentage of patients with at least a 5% decrease in headache-days per month (46% vs 22%; P =.5), headache frequency per month (-7.5 vs -3.6; P.5), and days using acute headache medication (-7.8 vs.1; P =.15). Patients with at least a 5% reduction in headaches per Table 1. Outcome Measures for Treatment Versus Efficacy Measures Outcome Measure Day 18 1º Headache-free days/month, n Not significant 2º Percentage of patients with 5% P =.27 decrease headache-days/month (4% vs 25%) Additional Headache frequency/month P =.1 (-7.1 vs -3.7) Additional Patients with 5% decrease P =.46 headaches/month (54% vs 38%) = botulinum toxin type A. Data from Mathew et al. 9 Table 2. : No Prophylaxis Subgroup (228; 64%) Efficacy Measures Outcome Measure Day 18 1º Headache-free days/month, n P <.5 (-1 vs.7) 2º Percentage of patients with 5% P <.5 decrease headache-days/month (46% vs 22%) Additional Headache frequency/month P <.5 (-7.5 vs -3.6) Additional Acute headache medication use P <.5 (-7.8 vs.1) Additional Patients with 5% decrease Not of headaches/month significant (52% vs 37%) = botulinum toxin type A. Data from Dodick et al. 11 S338 Vol. 6 (4D) April 26

month did not achieve statistical significance (52% for botulinum toxin type A vs 37% for placebo; Table 2). 11 Specific populations that appear to respond well to botulinum toxin type A treatments include particularly challenging patients, such as those who overuse acute headache medications (Figure 3) 4,12 and patients who experience moderate-to-severe headaches of at least 4 hours in duration (Figure 4). 5,6 For the population of patients who overuse acute headache medications, a significant difference in headache episodes was observed at nearly all time points favoring botulinum toxin type A (P.5). In the population of patients who experienced headaches for more than 4 hours, there was a significant difference favoring botulinum toxin type A at all time points (P <.5). For this study, there was no dose response observed, adverse events were dose and injection-site dependent, there was an incremental response after the second injection, and the duration of response correlated with the biologic activity of the toxin (approximately 3 months). The conclusions from this phase II study were that repeat treatments with botulinum toxin type A are safe and well tolerated at doses up to 26 U and that there were significant, clinically meaningful improvements compared to placebo in headache frequency, responder rates, and days and number of acute headache medication used. Furthermore, these findings were confirmed among patients with headache who did not use concurrent headache prophylaxis and among patients who overused acute headache medications. COENZYME Q 1 AND VITAMIN B 2 (RIBOFLAVIN) Mitochondrial dysfunction resulting in impaired oxygen metabolism may play a role in migraine pathogenesis. 13 Vitamin B 2 (riboflavin) and CoQ 1 are known to improve abnormalities in mitochondrial encephalomyopathies. Vitamin B 2 (randomized controlled trials) and CoQ 1 (open-label) have been studied in migraine prophylaxis. 14-16 Schoenen et al compared riboflavin (4 mg) and placebo in 55 patients with migraine in a randomized trial of 3 months duration. 14 Patients who took riboflavin had significantly fewer attacks and headache-days compared to the placebo group (reduced attack frequency, P =.5; headache-days, P =.12). Furthermore, the proportion of patients who improved by at least 5% was 15% for placebo and 59% for riboflavin (P =.2) and the number-needed-to-treat for effectiveness was 2.3. Three minor adverse events occurred: 2 in the riboflavin group (diarrhea and polyuria) and 1 in the placebo group (abdominal cramps). 14 A randomized controlled trial by Sandor et al of 42 patients reported that significantly more patients taking 1 mg 3 times daily of CoQ 1 had at least a 5% reduction in their migraine than patients who took placebo Figure 3. Late CDH Study: No Prophylaxis and Overusing Acute Pain Medications Mean change in n of headaches -8 * * 47% overusing acute headache pain medications (ICHD-II definitions) Pooled (n = 355) 3.4 * * * * -1 * P <.35-12 3 6 9 12 15 18 21 24 27 * (n = 173) (n = 182) Baseline: * = 13.5, = 12.7-8 -1 Medication Overusers (n = 168) * 4.5 * * * * * * * * P.44-12 3 6 9 12 15 18 21 24 27 * (n = 91) (n = 77) Baseline: * = 15.2, = 14.9 = botulinum toxin type A; CDH = chronic daily headache; ICHD-II = International Classification of Headache Disorders (second edition). Data from Saper et al. 12 Figure 4. Late CDH Study: Headaches 4 or More Hours Mean change in n of headaches -1-3 -5 >7% of all headaches were >4 hours in duration Day 18. *.6 vs placebo.2 (P <.5). <4 hours 3 6 9 12 15 18 21 24 27 * (n = 173) (n = 182) -1-3 -5 4 hours *P.44 * * ** 2.4 * * * * * 3 6 9 12 15 18 21 24 27 * (n = 173) (n = 182) Baseline: * = 3.9, = 3.5 Baseline: * = 9.6, = 9.2 = botulinum toxin type A; CDH = chronic daily headache. Data from from Elkind et al 5 and Aurora et al. 6 Johns Hopkins Advanced Studies in Medicine S339

Figure 5. Efficacy of CoQ 1 Versus Verum (n = 21) (n = 21) P Value* N of migraine -.9 ± 1.9-1.19 ± 1.9.5 attacks/mo N of days with -1.4 ± 3.6-1.9 ± 3.9.8 headache/mo Mean severity of.3 ± 1.4 -.4 ± 1.2.25 migraine/day N of days with.8 ± 2.2 -.9 ± 1.8.2 nausea/vomiting Mean n -.2 ±.5.4 ±.9.71 tablets/day Mean duration -.5 ± 4.1.6 ± 5.9.11 of migraine/day 5% responder 3 (14.3%) 1 (47.6%).2 rate for attack frequency (47.6% vs 14.3%) after 3 months. 16 Although this is a small study, large-scale clinical trials may be in order to establish whether this is of benefit for patients with chronic migraine (Figure 5). 16 PETASITES HYBRIDUS (BUTTERBUR) 4.4 Petasites hybridus (butterbur) is a perennial shrub used medicinally for 2 years. The active ingredients, petasine and isopetasine, block leukotriene synthesis and have anti-inflammatory effects. An extract of the root stock (Petadolex) is available in Germany where it is sold as an herbal preventative medication for migraine. A small, placebo-controlled trial (n = 6) was positive at dosages of 5 mg twice daily, indicating that butterbur may be effective and well tolerated in the prophylaxis of migraine. Following a 4-week baseline phase, 33 patients were randomized to treatment with 2 capsules of 25-mg butterbur twice a day and 27 patients were randomized to placebo. The mean attack frequency per month decreased from 3.4 at baseline to 1.8 after 3 months (P =.24) in the verum group and from 2.9 to 2.6 in the placebo group. The responder rate (ie, improvement of migraine frequency 5%) was 45% in the verum group and 15% in the placebo group. 17 Lipton et al conducted a larger, 3-arm, parallelgroup, randomized trial comparing Petasites extract 75 mg twice daily, Petasites extract 5 mg twice daily, or Attacks/month (95% CI) 6 5 4 3 2 CoQ 1 Baseline (1) 2 3 4 Months Change from baseline (month 1) to month 4. Values are means ± SD. *Mann-Whitney U test; 2 test for responder rate. CI = confidence interval; CoQ 1 = coenzyme Q 1. Reprinted with permission from Sandor et al. Neurology. 25;64:713-715. 16 4.3 3.2 placebo to be taken twice daily in 245 patients with migraine. 18 The main outcome measure was the decrease in migraine attacks per month calculated as percentage change from baseline over a 4-month treatment period. The authors found that migraine attack frequency was reduced by 48% for Petasites extract 75 mg twice daily (P =.12 vs placebo), 36% for Petasites extract 5 mg twice daily (P =.127 vs placebo), and 26% for the placebo group. The proportion of patients with at least a 5% reduction in attack frequency after 4 months was 68% for patients in the 75-mg arm and 49% for the placebo arm (P <.5; Figure 6). 18 Results also were significant in favor of Petasites 75 mg as early as 1 month into therapy, but lower dosages (ie, 5 mg twice daily) did not seem effective. Secondary endpoints also achieved statistically significant improvements over baseline, including at least a 5% reduction in attack frequency, reduction in attack intensity, and mean number of attackdays per month. Petasites extract was well tolerated with 87% of participants reporting good/excellent tolerability. The most frequently reported adverse reactions considered possibly related to treatment were mild gastrointestinal events (ie, burping, nausea, or vomiting) and, rarely, neurologic symptoms (ie, exacerbation of migraine attacks or sleep interruption). 18 Figure 6. Efficacy of Petasites Versus Mean change from baseline 1% % -1% % -3% % -5% % Reduction in Migraine Attack Count (3 months) (n = 63) Petasites 5 mg (n = 71) Petasites 75 mg (n = 68) 6% P =.7-34% P <.1 P =.4 8% Reprinted with permission from Lipton et al. Neurology. 24;63:224244. 18 S34 Vol. 6 (4D) April 26

LAMOTRIGINE Lamotrigine inhibits voltage-gated sodium channels and prevents release of glutamate. Glutamate is considered pivotal for the initiation and propagation of cortical spreading depression the underlying physiological substrate for migraine aura. Evidence in favor of lamotrigine for the prevention of migraine with aura is conflicting. For example, there have been 3 open-label trials suggesting efficacy in patients with migraine with aura, 191 including a trial by D Andrea et al that studied the effects of 1 mg of lamotrigine per day in 24 patients affected by migraine with aura and a high frequency of attacks. 19 Following a 1-month run-in period, the patients took lamotrigine for 3 months. Mean attack number per month was reduced from 6.1 ± 4.1 during the run-in period to.7 ± 1.3 at the third month of treatment (P <.1). According to the authors, in 13 out of 21 patients who completed the study the attacks were completely abolished, whereas only 1 patient was completely unresponsive to the drug. 19 However, a randomized controlled study demonstrated no difference in reducing migraine frequency in 77 patients who had migraine with aura. 22 In this study, Steiner et al compared the safety and efficacy of lamotrigine and placebo for migraine prophylaxis in a double-blind randomized parallel-groups trial; 37 patients were treated with lamotrigine and 4 were treated with placebo for up to 3 months. 22 Initially, lamotrigine therapy was commenced at the full dosage of 2 mg per day, but because of the development of rashes in study patients, a gradually increasing dosage schedule was introduced as follows: 25 mg per day for 2 weeks, 5 mg per day for 2 weeks, and then 2 mg per day. Migraine attack rates were reduced from baseline means of 3.6 per month on lamotrigine and 4.4 on placebo to 3.2 and 3. respectively during the last month of treatment. Improvements were greater on placebo and these changes, although not statistically significant, indicated that lamotrigine was ineffective for migraine prophylaxis. CONCLUSIONS Chronic daily headache is a condition that continues to plague millions of individuals worldwide. Treatments to date include mainly analgesics to cope with acute attacks, and these may wane in their efficacy or cause adverse effects over time. Efforts also have been focused on developing therapeutic options for prophylaxis, including nontraditional pharmaceutical agents and alternative therapies. There is now evidence from randomized, double-blind, placebo-controlled clinical trials that botulinum toxin type A may be an effective treatment for patients with migraine suffering with CDH. 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