1. Advances in Migraine Alexander Mauskop, MD New York Headache Center

2. Potential Conflict of Interest Disclosure AllerganPozen AstraZenecaProcter & Gamble Bristol-Myers Squibb PR Osteo ElanRoyal Numico/GNC GlaxoSmithKlineUCB Pharma MerckWeber & Weber NovartisWinston Laboratories Ortho-McNeil Wyeth Pfizer

3. News in Migraine Pathophysiology CGRP antagonists PFO Classification Basilar migraine Chronic migraine Magnesium Botulinum toxin

7. Impact of Migraine on Quality of Life Adapted from Solomon GD et al. Headache 1994;34(3):143-147 Physical functioning Role functioning Social functioning Mental health Health perceptions Pain -1.2 -0.8 -0.6 -0.4 -0.2 0.2 0.4 0 No chronic conditions Diabetes Migraine Hypertension Angina Quality of Life Measure

8. Migraine Is a Neurovascular Disorder The genesis of migraine is neurologic Likely that hyperexcitability of CNS confers susceptibility to migraine attacks Migraine associated with regional reduction in cerebral blood flow and cortical spreading depression (CSD) Trigeminovascular system involved in production of migraine pain Aurora SK, Welch KMA. Curr Opin Neurol. 1998;11:205-209; Aurora SK, Welch KMA. Curr Opin Neurol. 2000;13:273-276.

9. Cause of Migraines A single gene is responsible for familial hemiplegic migraine Common migraine is polygenetic, which accounts for its variable expression Multiple triggers modify the frequency and the severity of attacks

10. Neuronal Hyperexcitability in Migraine Neuronal hyperexcitability predisposes individuals to migraine —Migraine patients visualized phosphenes following transcranial magnetic stimulation Increased neuronal hyperexcitability may be multifactorial —Abnormal calcium channels that influence presynaptic neurotransmitter release —Abnormal glutamate metabolism —Deficiency of systemic and brain magnesium Migraine may be prevented by reducing neuronal hyperexcitability —Inhibition of excitatory neurotransmission (eg, Na + channel) —Enhancement of inhibitory neurotransmission (eg, GABA) Welch, et al. Neurol Clin. 1990;8:817-828; Aurora SK, Welch KMA. Curr Opin Neurol. 1998;11:205-209; Cutrer, et al. Cephalalgia. 1997;17:93-100.

11. Early Intervention May Prevent Central Sensitization Clinical experience suggest that migraineurs are most-responsive to medications within the initial 30-60 minutes of an attack. The development of central hypersensitivity points to the need for the early use of anti- migraine drugs.

12. Benefits of Early Treatment Early pain-free response Less recurrence Prevents progression of attack Less disability Less need for multiple doses and rescue meds Effective early treatment may prevent chronic migraine

13. Migraine Is Often Overlooked Sinus headache is the most common misdiagnosis Symptoms include —Dull ache located near the nose —Pressure in the sinus cavities —Thick, colored nasal discharge —OTCs can sometimes relieve the pain Cady et al. Headache Free. 1993;36-38.

14. Sinus headache is the most common misdiagnosis Symptoms include: Dull ache located near the nose Pressure in the sinus cavities Thick, colored nasal discharge OTCs can sometimes relieve the pain Migraine Is Often Overlooked

16. Caffeine-containing Drugs Cafergot Wigraine Esgic Fiorinal Fioricet Norgesic Synalgos DC Rx

17. Caffeine-Containing Drugs Anacin Anacin Maximum Strength Aspirin Free Excedrin Excedrin Extra Strength Excedrin Migraine Maximum Strength Midol OTC

18. Caffeine “The analgesic effects of caffeine in headache” (Ward et al., Pain 1990) Caffeine (65 mg and 130 mg) equals to 650 mg of acetaminophen

19. Caffeine 52% moderate or severe headache 11% depression 11% low vigor 8% anxiety 8% fatigue 235 mg (2.5 cups) a day “Withdrawal syndrome after the double-blind cessation of caffeine consumption.” (Silverman et al. NEJM 1992)

20. Low brain magnesium in migraine N.M. Ramadan, H. Halvorson, A. Vande-Linde et al. Headache 1989;29:590-593. Magnesium and Migraine

21. Trauninger et al. Headache 42:114-119;2002 Oral magnesium load test in patients with migraine Oral magnesium load test in patients with migraine Conclusions: Magnesium retention occurs in patients with migraine after oral loading, suggesting a systemic magnesium deficiency

22. Magnesium glutamate angiotensin II potassium serotonin G proteins Known effects of IMg 2+ acetylcholine nitric oxide norepinephrine calcium enzyme complexes (325)

23. NMDA (N-Methyl-D-Aspartate) Receptor Complex Ca 2+ ZnGLY PCP MK801 Mg 2+ TCA NMDA Ca 2+ Mg 2+

24. Magnesium and Migraine Stress Alcohol and caffeine Genetics Low dietary intake Gastro-intestinal disorders Chronic illness Potential causes of magnesium deficiency Potential causes of magnesium deficiency

25. IV MgSO 4 for Acute Migraine IMg 2+ mmol/L IMg 2+ mmol/L 0.58 0.56 0.54 0.52 0.50 0.48 0.46 0.44 0.42 0.58 0.56 0.54 0.52 0.50 0.48 0.46 0.44 0.42 xxx o o oo o o x x xx x x x x xxxxxx oo ooooo ooo oooo oo o o x = non-responders o = responders A. Mauskop et al, Clin Science 1995;89:633-6

26. IV MgSO 4 for Cluster Headaches IMg 2+ mmol/L 0.60 0.58 0.56 0.54 0.52 0.50 0.48 0.46 0.44 0.60 0.58 0.56 0.54 0.52 0.50 0.48 0.46 0.44 0.76 o o o o o o o o ooo oooo o o o o ooo o o o o oo o o o o x x x x x x x x xxx x x x x x = non-responders o = responders Mauskop et al, Headache 1995;35:597-600.

27. Magnesium prophylaxis of menstrual migraine: Effects on intracellular magnesium. F. Facchinetti, G. Sances, A.R. Genazzani, G. Nappi. Cephalagia 1996; 16:257-263. Magnesium pyrrolidone carboxylic acid – 360 mg Days with migraine reduced 4.7 to 2.4 (p<0.01) Significant reduction in MDQ scores (p<0.05) Magnesium and Migraine

28. Prophylaxis of migraine with oral magnesium: results from a prospective, multicenter, placebo-controlled and double- blind randomized study. A. Peikert, C. Wilimzig, R. Kohne-Volland, Cephalagia 1996; 16:257-263. Trimagnesium dicitrate – 600 mg Attack frequency reduced41.6% vs 15.8%(p<0.05) Days with migraine reduced52.3% vs 19.5%(p<0.05) Magnesium and Migraine

29. Oral magnesium oxide prophylaxis of frequent childhood migraine Wang F, Van Den Eeden S, Ackerson L, et al. Cephalagia 2000;20:424 (abstract). Magnesium and Migraine

30. Magnesium in the prophylaxis of migraine: A double-blind, placebo-controlled study. Pfaffenrath V, Wessely P, Meyer C, et al. Cephalagia 1996; 16:436-440. Magnesium and Migraine

31. Effectiveness of High-dose Riboflavin in Migraine Prophylaxis J. Shoenen, J. Jacquy, M. Lenaerts. Neurology 1998; 50:466-440. * No. of Attacks per Month Month 4 3 2 1 1234 Placebo Riboflavin P=0.001 *

32. Botanical Remedies Feverfew Randomized double-blind placebo-controlled trial of feverfew in migraine prevention. Murphy JJ, Heptinsall S, Mitchell JRA. The Lancet, 23 July 1988, pp 189-192.

33. Feverfew Reduction in mean number of attacks – 3.6 vs 4.7 (p<0.005) Global assessment of improvement on VAS – 74 vs 60 (p<0.0001) Reduced severity of nausea and vomiting (p<0.02) Tendency toward milder intensity of pain No effect on duration of attacks Results

34. Natural Remedies Migraine is a multifactorial disease Any single pharmacologic agent has no more than 60% efficacy Single nutraceutical therapies may have no more than 50% efficacy The Case for Multi-Agent Therapies

35. Natural Remedies Migra-Lieve: Possible Combinations Riboflavin400 mg Magnesium300 mg Feverfew100 mg

36. Petasites hybridus Inhibits constriction of smooth muscle preparation induced by acetylcholine, histamine and potassium chloride Inhibits leukotriene synthesis Possible mechanisms of action:

37. Botanical Remedies Aromatherapy Topical preparations Oral preparations

38. Botanical remedies Double-blind, placebo-controlled, randomized cross-over design 32 healthy subjects Parameters tested: —EMG activity —Exteroceptive suppression periods —Contingent negative variation —Sensitivity to experimental pain —Current mood states Effect of Peppermint and Eucalyptus Oil

39. Results Analgesic effect Muscle relaxing effect Mentally relaxing effect Combination of Peppermint Oil and Ethanol

40. What to recommend? Natural Remedies Aerobic exercise, neck exercise Biofeedback / relaxation Magnesium, riboflavin, feverfew Acupuncture Massage, shiatsu, reflexology Dietary approaches

41. Candidates for Preventive Therapy Disabling primary headaches Chronic migraine Frequent migraine Chronic tension-type headache Medication overuse (“drug-induced headache”) Headaches refractory to routine treatment Contraindication to acute therapy

42. Currently Used Preventive Therapies MigraineTension-type Beta-blockersX Antidepressants X X AnticonvulsantsX Calcium channel blockersX MethysergideX NSAIDsXX Muscle relaxantsX

43. Potential Side Effects of Prophylactic Drugs Beta-blockersfatigue, dizziness, depression Antidepressantsdry mouth, drowsiness, weight gain, constipation, sexual dysfunction Anticonvulsantsweight gain, cognitive dysfunction, drowsiness, fatigue, constipation Calcium channel blockersconstipation, edema Methysergidefibrosis, water retention, leg cramps NSAIDsdyspepsia, peptic ulcers, renal disease Muscle relaxantssedation, dizziness

44. Prophylactic Drugs: Additional Drawbacks Work in minority of patients Compliance Fear of adverse events Drug-drug interactions

45. History of BTX-A Use in Migraine Anecdotal reports of reduced migraines from patients receiving BTX-A treatment for other indications A retrospective review of patient charts suggested migraine relief was associated with certain injection sites This information was used in designing early clinical studies

46. The Neuromuscular Junction

47. Botulinum Toxin Type A Mechanism of Action: Current Hypothesis

48. Botulinum Toxin Type A: Migraine Headache Study Binder WJ, et al. Otolaryngol Head Neck Surg 2000;123:669-676 Open-label study Dx: Migraine N=77 Variable dose Outcome measure: —Complete response —Partial response —No response

49. Botulinum Toxin Type A for Migraine Headache Silberstein S, et al. Headache. 2000;40:445-450. Double-blind, vehicle-controlled study Dx: Migraine (N=123) —Placebo (n=41) —25 U botulinum toxin type A (n=42) —75 U botulinum toxin type A (n=40) 3-month duration Outcome measure: —Reduction in migraine severity

50. Frontalis & Glabellar BTX-A Injection Sites: Fixed Sites, Fixed Dose Temporalis (Bilateral)

51. Proof-of-Concept Studies Two double-blind, vehicle-controlled studies —1-month baseline period, treatment, 3-4 month follow-up Study 1 (N=123) —2-8 moderate to severe migraines/month at baseline —Vehicle (n = 41); 25 U BTX-A (BOTOX ® ; n = 42); 75 U BTX-A (n = 40) Study 2 (N=418) —4-8 moderate to severe migraines/month at baseline —Vehicle (n = 106); 7.5 U BTX-A (n = 105); 25 U BTX-A (n = 101); 50 U BTX-A (n = 106)

52. Botulinum Toxin Type A for Migraine Silberstein S, et al. *P <.042 vs vehicle

53. Study 2

54. Safety Summary BTX-A was well tolerated All treatment-related adverse events were local and transient Most common were —Blepharoptosis —Injection site weakness —Skin tightness There were no serious treatment-related adverse events

55. Summary of Development Studies Results of initial studies using frontal injections are not definitive —Improvement from baseline in migraine frequency and acute medication use in one study —Patients perceived significant global improvement in both studies —Safe and well tolerated in both studies Future studies should employ alternative treatment approaches

56. Injection Sites: Glabellar and Frontal Regions X X X X X X X X X

57. Injection Site: Temporalis Muscle X X X X

58. Injection Site: Suboccipital Region Trapezius muscle Adapted with permission from: Netter FH. Atlas of Human Anatomy. Icon Learning Systems; Teterboro, NJ. 1997. X X Splenius capitis muscle X

59. Injection Site: Occipitalis Muscle XX

60. Botulinum Toxin Type A: Cost in Migraines A.M. Blumenfeld, Impact of Botulinum Toxin Type-A Treatemnt on Medication Costs and Usage in Difficult-to-Treat Chronic Headache: Case Studies. Headache Quarterly 2002;13(1):241-244. BTX-A-induced decreases in the frequency and/pr severity of chronic headaches led to decreased headache medication costs. A reduction in ED and office visits may provide further savings.