Preventive medication for migraine is PROCEEDINGS PREVENTIVE THERAPY FOR MIGRAINE: FOCUS ON 2 NEW TREATMENTS *

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1 PREVENTIVE THERAPY FOR MIGRAINE: FOCUS ON 2 NEW TREATMENTS * Based on a presentation by Stephen D. Silberstein, MD, FACP ABSTRACT There are 7 classes of preventive migraine drug therapy: antiepileptic drugs (AEDs), antidepressants, beta blocking agents, calcium channel blocking agents, nonsteroidal anti-inflammatory drugs, serotonin antagonists, and a general eclectic group of other drugs. Most of these drugs were originally designed or discovered to treat other disorders. All 7 classes of migraine preventive therapies are used off label on a regular basis, with varying levels of scientific evidence to support their use. AEDs are one of the most common first-line agents used in migraine prophylaxis. Good scientific evidence supports the use of gabapentin, valproate, and carbamazepine for this indication based on recommendations from the US Headache Consortium. Topiramate is the most recently developed AED and, to date, shows positive results in migraine prevention. Botulinum toxin A (Btx-A) is classified under other and has shown benefit as both acute and preventive migraine therapy. The most recent safety and efficacy data for these 2 drugs are discussed in this article. Topiramate appears to be a safe and effective migraine preventive treatment with relatively mild-to-moderate side effects, and 2 more serious side effects (acute myopia and secondary angle-closure glaucoma, and treatment-emergent depression) appear to *Based on a presentation by Dr Silberstein at the American Headache Society Scottsdale Headache Symposium. Director, Jefferson Headache Center, Professor of Neurology, Thomas Jefferson University; Clinical Professor of Neurology, Temple University, Philadelphia, Pennsylvania. be rare and apparently reversible with treatment discontinuation. The efficacy of Btx-A in tensiontype headache is not yet unequivocal, but in migraine prevention, it appears to offer some benefit. Further work to identify appropriate injection sites, doses, and treatment duration is needed to optimize the potential for this therapy. (Adv Stud Med. 2003;3(3B):S153-S158) Preventive medication for migraine is designed to decrease frequency, severity, and duration of migraine headaches. There are 7 classes of preventive migraine drug therapy: antiepileptic drugs (AEDs), antidepressants, beta blocking agents, calcium channel blocking agents, nonsteroidal anti-inflammatory drugs, serotonin antagonists, and a general eclectic group of other drugs. Most of these drugs were originally designed or discovered to treat other disorders. Methysergide, a serotonin antagonist, was the only rationally developed migraine preventive drug, based on the concept that migraine was caused by excess serotonin. Antidepressants downregulate serotonin and beta-adrenergic receptors; AEDs decrease glutamate and enhance gamma amino butyric acid (GABA). All 7 classes of migraine preventive therapies are used off label on a regular basis and have varying levels of scientific evidence to support their use. Numerous classes of drugs are used to prevent migraine, none of which is effective in every Advanced Studies in Medicine S153

2 migraineur, strongly suggesting multiple mechanisms are involved in the manifestation of a migraine headache. As we have the epilepsies, we are most likely also treating the migraines. Migraine preventive therapies are thought to be effective by one of several mechanisms that raises the threshold to migraine activation (ie, inhibiting the migraine generator, enhancing antinociception, or inhibiting cortical spreading of depression) they appear to stabilize a more reactive nervous system. Figure 1. Topiramate Responder Rate: MIGR-001* PRINCIPLES OF PREVENTIVE MIGRAINE THERAPY Before the availability of triptans, most treatment recommendations (as a guideline for preventive therapy use) focused on the number of attacks occurring each month to determine if preventive therapy was warranted. Given the wide choices for therapy available, however, preventive treatment guidelines must also consider patients response to acute medication, patients needs or preferences, and characteristics of migraine attacks. Patients needs and preferences include the degree to which the migraine attacks interfere with daily routine despite appropriate acute therapy as well as any comorbid or coexisting conditions or concomitant medications. Overall, the goals of preventive migraine therapy are to reduce attack frequency, severity, and duration; improve responsiveness to acute treatment; and improve function and reduce disability. The US Headache Consortium has evaluated the scientific evidence for all drugs in each class of preventive therapy. AEDs are one of the most common firstline agents used in migraine prophylaxis. Good scientific evidence supports the use of gabapentin, valproate, and carbamazepine for this indication. Topiramate is the most recently developed AED and, to date, shows positive results in migraine prevention. Botulinum toxin A (Btx-A) is classified under other and has shown benefit as both acute and preventive migraine therapy. The most recent safety and efficacy data for these 2 drugs are discussed below. TOPIRAMATE Topiramate is a structurally unique AED it is an analog of a fructose-1-6-diphosphate but devoid of hypoglycemic activity. Its resemblance to acetazolamide prompted its evaluation as an AED in epilepsy *Results as of November P =.039. P <.001. TPM = topiramate. Table 1. AED Efficacy in Migraine Prevention Responder Rate (%) AED Type Drug Placebo Difference Gabapentin Mathew Divalproex Mathew Klapper Topiramate Silberstein AED = antiepileptic drug. Data from Mathew et al 12,13 ; and Klapper. 14 S154 Vol. 3 (3B) March 2003

3 models. It is approved for the treatment of epilepsy as adjunctive therapy in adults and children aged 2 to 16 years with partial onset seizures or generalized primary clonic-tonic seizures, or seizures associated with Lennox- Gastaut syndrome (in patients older than 2 years). 1 Topiramate affects several neurological pathways. Those believed to be involved in migraine prevention include blocking calcium channels, sodium channels, AMPA/kainate receptors, and GABA channels, and inhibiting carbonic anhydrase. 2 Its broad activity among cell membrane receptors is thought to be due to inhibition of protein kinase A phosphorylation. 2 In small studies, topiramate has demonstrated solid efficacy in migraine prophylaxis with relatively minor side effects. 3-7 It has also shown efficacy in cluster headache Topiramate is under evaluation in 3 large, international clinical trials (MIGR-001, -002, and -003) and a large US study (CAPSS-155). MIGR-001 is a randomized, double-blind, placebo-controlled, parallel-group study comparing topiramate (50 mg, 100 mg, and 200 mg) vs placebo in 469 patients. After a 14-day washout period, a 28-day baseline period, and an 8-week titration phase, patients received their maintenance doses for 18 weeks. To date, results show the best response (defined as at least 50% reduction in migraine periods) were observed with the 100-mg and 200-mg doses (Figure 1), although the 50-mg dose also produced a significant response. The responder rate of topiramate is comparable to that observed with the 2 other most commonly used AEDs (Table 1) Topiramate is also known for its effect on weight loss, and study results from MIGR-001 support this finding. The higher doses of topiramate have produced almost 4% decreases in mean body weight (P <.004) after 18 weeks of treatment. The 50-mg dose was associated with a 2.6% decrease in mean body weight (P <.004). Investigators have also noted a correlation between body weight at study onset and loss of body weight (ie, those who are heavier tend to lose the most weight). For any migraine preventive agent, treatmentemergent adverse events are important, especially if the primary goal is to reduce disability and if migraineurs are taking other medications. In MIGR- 001, the most common adverse events included paresthesias, taste change, loss of appetite, nausea, diarrhea, memory difficulty, and dizziness (Table 2). Rates of dizziness and nausea were not largely different from placebo; diarrhea was predominantly seen with higher Table 2.Treatment-Emergent Adverse Events: MIGR-001* Topiramate, n (%) Placebo, n (%) 50 mg 100 mg 200 mg Event (n = 116) (n = 118) (n = 126) (n = 113) Paresthesias 8 (7) 43(36) 59 (47) 53 (47) Taste change 2 (2) 23 (19) 13 (10) 16 (14) Loss of appetite 5 (4) 13 (11) 16 (13) 16 (14) Nausea 14 (12) 8 (7) 20 (16) 16 (14) Diarrhea 8 (7) 8 (7) 14 (11) 17 (15) Memory difficulty 3 (3) 11 (9) 9 (7) 14 (12) Dizziness 13 (11) 9 (8) 10 (8) 14 (12) *Results as of November Figure 2. Btx-A and Number of Moderate-to-Severe Migraine Attacks per Month *P<.042 vs the vehicle group. Btx-A = botulinum toxin A. Adapted with permission from Silberstein et al. 22 Advanced Studies in Medicine S155

4 doses. Paresthesias were the most common adverse event. It has been our clinical experience that potassium chloride (20-40 meq per day) can alleviate paresthesias in most of these patients. 14 RECOMMENDATIONS FOR USE The best starting dose of topiramate for migraine prevention is 25 mg, increasing by 15 to 25 mg each week. The start low, go slow strategy is useful for topiramate as well as other AEDs; benefit with topiramate can be seen at doses as low as 50 mg. The optimal dose appears to be 50 mg to 100 mg per day. If treatment-emergent adverse events are reported, 2 options are available: restart therapy at 7.5 to 15 mg daily; or decrease the dose to a slightly lower dose, wait until the symptoms resolve, then increase slowly by smaller amounts (eg, 7.5 mg per week). Acute myopia and secondary angle-closure glaucoma have also been reported with topiramate use Typically, the myopia and glaucoma are observed very early in treatment (mean onset, 7 days; range, 1 49 days) with acute onset, do not resolve with lowered doses, and are reversible with drug discontinuation. 19 In these rare cases (54 cases in 1.25 million treated as of March 2002), treatment with topiramate should be discontinued. Anecdotally, depression, if it occurs and is related to topiramate, also appears early in treatment and does not respond to lower doses. Treatment should also be discontinued if this occurs. BOTULINUM TOXIN A Several studies have suggested the efficacy of Btx-A in treating tension-type headache, but the data are not conclusive The rationale behind Btx-A therapy in tension-type headache was based on its effect on muscle pain and the hypothesis that increased muscle tension may contribute to tension-type headaches. Btx-A reduces muscle tenderness and pain in many diseases associated with myofascial pain. The moderate or missed effects of Btx-A in tension-type headache may be due to incorrect or suboptimal choice of injection sites, dose of botulinum toxin, or duration of treatment. 22 Only 1 randomized, placebo-controlled study of pericranial injection of Btx-A for migraine prevention has been published. 22 In this study, 123 subjects with a history of 2 to 8 moderate-to-severe migraine attacks per month, with or without aura, were randomized to Table 3. US Headache Consortium: Migraine Prevention Quality of Scientific Clinical Adverse Drug Evidence* Effect Impression Effects Antiepileptic Divalproex A Occasional to frequent Gabapentin B Occasional to frequent Topiramate A Occasional to frequent Antidepressants Amitriptyline A Frequent Nortriptyline C? +++ Frequent Fluoxetine B + + Occasional Beta blockers Propranolol A Infrequent to occasional Timolol A Infrequent to occasional Atenolol B Infrequent to occasional Calcium channel blockers Diltiazem C? 0 Infrequent to occasional Verapamil B + ++ Infrequent to occasional NSAIDs Aspirin B + + Infrequent Ibuprofen C? + Infrequent Naproxen B + + Infrequent Serotonin antagonists Cyproheptadine C + + Frequent Methysergide A Frequent Other Feverfew B ++ + Infrequent Riboflavin B Infrequent *A = Multiple well-designed randomized clinical trials, directly relevant to the recommendation, yielded a consistent pattern of findings; B = Some evidence from randomized clinical trials supported the recommendation, but scientific support was not optimal. Either few randomized trials existed, the trials that did exist were somewhat inconsistent, or the trials were not directly relevant to the recommendation. An example of the last point would be the case where trials were conducted using a study group that differed from the target group for the recommendation; C = The US Headache Consortium achieved consensus on the recommendation in the absence of relevant randomized clinical trials. NSAIDs = nonsteroidal anti-inflammatory drugs. Adapted with permission from Silberstein et al. 24 S156 Vol. 3 (3B) March 2003

5 receive single administrations of vehicle or Btx-A, 25 U or 75 U, injected into multiple sites of pericranial muscles at the same visit. Efficacy was based on patients daily diaries, in which they recorded migraine frequency, migraine severity, and occurrence of migraine-associated symptoms. Results from 3-month follow-up postinjection show 50% reduction in the number of moderate-tosevere migraine attacks per month by the second month in patients receiving 25 U Btx-A (Figure 2). Unexpectedly, patients responded better to the 25-U dose than to the 75-U dose. As with the tension-type headache studies, the cause of this paradox may lie partly in the choice of injection sites. In this study, 6 sites were chosen but were not necessarily related to location of pain. Greater experience with optimal injection sites may improve the efficacy findings. 22 An open-label study of 77 migraineurs also showed important positive responses to Btx-A for migraine prevention. With a mean 4.1 months duration of response, 51% (95% confidence interval, 39% to 62%) reported complete response (symptom elimination); 38% reported partial response ( 50% reduction in headache frequency or severity), with a mean response duration of 2.7 months. Of 10 migraineurs treated with Btx-A as acute treatment, 70% reported complete response with improvement 1 to 2 hours after treatment. No adverse effects were reported. 23 As with other migraine preventive therapies, the exact mechanism of Btx-A in migraine as acute or preventive therapy is not fully known. The prevailing hypothesis is that Btx-A is an antinociceptive, with reduction of muscle spasm related to pain, direct inhibition of nociceptive fibers with reduced peripheral pain sensation, and indirect modulation of the central nervous system. Further work is now being done to more precisely characterize the mechanism of action of Btx- A in migraine prevention. MIGRAINE PREVENTIVE DRUGS: SCIENTIFIC EVIDENCE The US Headache Consortium guidelines examined all 7 classes of migraine preventive drugs based on their scientific efficacy. Topiramate is considered a high-efficacy drug for migraine prevention based on the quality of evidence, scientific effect, and clinical impression (Table 3). Topiramate may also be used to treat epilepsy and possibly mania as coexisting conditions with migraine, with relatively few side effects (Table 4). 24,25 Btx-A does not appear to have any relative contraindications and may be preferred by some patients who want more natural Table 4. Migraine Prevention and Coexisting Conditions Comorbid Condition Side Relative Relative Drug Efficacy Effects Contraindication Indication Anticonvulsants Divalproex Liver disease, Mania, epilepsy, bleeding disorders anxiety disorders Gabapentin Epilepsy, mania? Topiramate Kidney stones Epilepsy, mania? Antidepressants Tricyclics Mania, urinary Other pain disorders, retention, heart depression, anxiety block disorders, insomnia SSRIs Mania Depression, OCD MAOIs Unreliable patient Refractory depression Antiserotonin Methysergide Angina, PVD Orthostatic hypotension Beta blockers Asthma, depression, Hypertension, angina CHF, Raynaud s disease, diabetes Calcium channel blockers Verapamil Constipation, Migraine with aura, hypotension hypertension, angina, asthma NSAIDs Naproxen Ulcer disease, Arthritis, other gastritis pain disorders Other Riboflavin Preference Feverfew for natural Btx-A products SSRIs = selective serotonin reuptake inhibitors; OCD = obsessive-compulsive disorder; MAOIs = monoamine oxidase inhibitors; PVD = peripheral vascular disease; CHF = congestive heart failure; NSAIDs = nonsteroidal anti-inflammatory drugs; Btx-A = botulinum toxin A. Adapted with permission from Silberstein et al. 25 Advanced Studies in Medicine S157

6 treatments for their headaches (Table 4). Btx-A has not yet been evaluated by the US Headache Consortium. CONCLUSION Topiramate appears to be a safe and effective migraine preventive treatment with relatively mild-tomoderate side effects; 2 more serious side effects (acute myopia and secondary angle-closure glaucoma, and treatment-emergent depression) appear to be rare and apparently reversible with treatment discontinuation. The efficacy of Btx-A in tension-type headache is not yet unequivocal, but it appears to offer some benefit in migraine prevention. Further work to identify appropriate injection sites, doses, and duration of treatment is needed to optimize the potential for this therapy. REFERENCES 1. Topiramate prescribing information. Available at: tpamax.pdf. Accessed February 3, Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia. 2000;41(suppl 1):S3-S9. 3. Hershey AD, Powers SW, Vockell AL, LeCates S, Kabbouche M. Effectiveness of topiramate in the prevention of childhood headaches. Headache. 2002;42: Von Seggern RL, Mannix LK, Adelman JU. Efficacy of topiramate in migraine prophylaxis: a retrospective chart analysis. Headache. 2002;42: Young WB, Hopkins MM, Shechter AL, Silberstein SD. Topiramate: a case series study in migraine prophylaxis. Cephalalgia. 2002;22: Storey JR, Calder CS, Hart DE, Potter DL. Topiramate in migraine prevention: a double-blind, placebo-controlled study. Headache. 2001;41: Mathew NT, Kailasam J, Meadors L. Prophylaxis of migraine, transformed migraine, and cluster headache with topiramate. Headache. 2002;42: Forderreuther S, Mayer M, Straube A. Treatment of cluster headache with topiramate: effects and side effects in five patients. Cephalalgia. 2003;23: Forderreuther S, Mayer M, Straube A. Treatment of cluster headache with topiramate: effects and side-effects in five patients. Cephalalgia. 2002;22: Wheeler SD, Carrazana EJ. Topiramate-treated cluster headache. Neurology. 1999;53: Mathew NT, Rapoport A, Saper J, et al. Efficacy of gabapentin in migraine prophylaxis. Headache. 2001;41: Mathew NT, Saper JR, Silberstein SD, et al. Migraine prophylaxis with divalproex. Arch Neurol. 1995;52: Klapper J. Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia. 1997;17: Silberstein SD. Control of topiramate-induced paresthesias with supplemental potassium. Headache. 2002;42: Thambi L, Kapcala LP, Chambers W, et al. Topiramate-associated secondary angle-closure glaucoma: a case series. Arch Ophthalmol. 2002;120: Rhee DJ, Goldberg MJ, Parrish RK. Bilateral angle-closure glaucoma and ciliary body swelling from topiramate. Arch Ophthalmol. 2001;119: Sankar PS, Pasquale LR, Grosskreutz CL. Uveal effusion and secondary angle-closure glaucoma associated with topiramate use. Arch Ophthalmol. 2001;119: Banta JT, Hoffman K, Budenz DL, Ceballos E, Greenfield DS. Presumed topiramate-induced bilateral acute angle-closure glaucoma. Am J Ophthalmol. 2001;132: Keates EU. Identifying a rare and reversible ocular syndrome in topiramate-treated patients: acute myopia and secondary angle closure glaucoma. Adv Studies Med. 2002;2: Rollnik JD, Dengler R. Botulinum toxin (DYSPORT) in tensiontype headaches. Acta Neurochir Suppl. 2002;79: Schmitt WJ, Slowey E, Fravi N, Weber S, Burgunder JM. Effect of botulinum toxin A injections in the treatment of chronic tension-type headache: a double-blind, placebocontrolled trial. Headache. 2001;41: Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. For the BOTOX Migraine Clinical Research Group. Headache. 2000;40: Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM. Botulinum toxin type A (BOTOX) for treatment of migraine headaches: an open-label study. Otolaryngol Head Neck Surg. 2000;123: Silberstein SD, US Headache Consortium. Practice Parameter. Evidence-based guidelines for migraine headache (an evidence-based review). Available at the American Academy of Neurology Web site ( Accessed February 3, Silberstein SD, Lipton RB, Goadsby PJ, eds. Headache in Clinical Practice. 2nd ed. London: Martin Dunitz Ltd; 2002:93. S158 Vol. 3 (3B) March 2003