1. New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD

2. Lecture outline Migraine diagnosis Migraine pathogenesis – research update Current and future abortive therapies Role of magnesium Migralex DrMauskop@NYHeadache.com

3. Number of Migraine Sufferers in the U.S. 1989 (Million) 1999 (Million) Overall23.627.9 Female18.020.9 Male 5.6 6.9 Lipton et al. 2001. American Migraine Study II.

4. Hu et al. Arch Intern Med.1999. Economic Impact of Migraine Migraine costs employers $13 billion annually —Missed work and reduced productivity Migraine produces 112 million bedridden days per year Most of the burden takes the form of reduced productivity

5. 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

9. Migraine Diagnosis Migraine is under-diagnosed 94% of patients presenting to a PCP with recurrent headache met IHS criteria for migraine or probable migraine Nearly 90% of “sinus headache” patients met IHS criteria for migraine or probable migraine Nearly 90% of “tension/stress” headache patients met IHS criteria for migraine or probable migraine

10. 1.1 Migraine Without Aura Diagnostic Criteria At least five attacks fulfilling the following criteria: Headache lasts 4 to 72 hours (untreated or unsuccessfully treated) Headache has at least 2 of the following characteristics: Unilateral location Pulsating quality Moderate or severe intensity (inhibits or prohibits daily activities) Aggravation by walking stairs or similar routine physical activity During headache at least 1 of the following occurs: Nausea and/or vomiting Photophobia and phonophobia

11. Migraine Diagnostic Questionnaire Has a headache limited your activities for a day or more in the last three months? Are you nauseated or sick to your stomach when you have a headache? Does light bother you when you have a headache? Sensitivity - 0.81 (95% CI, 0.77 to 0.85) Specificity - 0.75 (95% CI, 0.64 to 0.84) Positive predictive value - 0.93 (95% CI, 89.9 to 95.8). Test-retest reliability was good - kappa of 0.68 (95% CI, 0.54 to 0.82). R. Lipton et al. Neurology 2003;61:375-382

12. Hemiplegic migraine is overdiagnosed The International Classification of Headache Disorders 2nd Edition " distinction between migraine with aura and hemiparesthetic migraine is probably artificial and therefore not recognized in this classification" "Common mistakes (in diagnosing typical aura with migraine headache) are...mistaking sensory loss for weakness"

13. The myth of basilar migraine M. Kirchmann, L.L. Thomsen, J. Olesen. Basilar-type migraine: Clinical, epidemiologic, and genetic features. Neurology 2006; 66(6):880-886. Conclusions: Basilar-type aura seemingly may occur at times in any patient with migraine with typical aura. There is no firm clinical, epidemiologic, or genetic evidence that basilar migraine is an independent disease entity different from migraine with typical aura.

14. Causes 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

15. Hyperexcitability of Visual Cortex in Patients with Migraine Aurora SK et al. Cephalalgia. 2003;23:258–263. Probability of Phosphene Magnetic Stimulus Intensity (%) P=0.0001 (Logrank test) for difference in threshold levels.

16. Dysfunction of brain stem pain and vascular control centers Weiller C et al. Nat Med. 1995;1:658–660 –16 mm –18 mm CNS Activation During Migraine Pain Perception* Anterior cingulate cortex Migraine Generator* Raphe nuclei Locus coeruleus Periaqueductal gray *Areas of red indicate cerebral blood flow increases (P<0.001).

17. Trigeminovascular Migraine Pain Pathways Adapted with permission from Hargreaves RJ et al. Can J Neurol Sci. 1999;26(suppl 3):S12–S19. Trigeminal Activation Leading to Sterile Inflammation Pain Signal Transmission Trigeminal Nucleus Caudalis Trigeminal Ganglion Cranial Parasympathetic Activation Leading to Dural Vasodilation

18. 5-HT 1D CGRP 5-HT 1D /CGRP Human Trigeminal Tract: CGRP Fibers Co-express 5-HT 1D Receptors

19. Calcitonin Gene-Related Peptide Released from sensory nerves Potent vasodilator direct effects on smooth muscle vs nitric oxide mediated In migraineurs: CGRP levels are elevated in cranial venous effluent during an attack CGRP infusion can produce migraine-like symptoms Hargreaves RJ. Semin Headache Manag. 1999;4:10–15.

20. CGRP antagonists in migraine Olesen, Diener, Husstedt et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 2004;350(11):1104-10. Response rate: 2.5-mg - 66% placebo - 27% (P=0.001).

21. CGRP antagonists in migraine MK-0974 Pain relief at 2 hours Pain free 300 mg n=38 68.1% 45.2% 400 mg n=45 48.2% 24.3% 600 mg n=40 67.5% 32.1% rizatriptan n=34 69.5% 33.4% placebo n=115. 46.3% 14.3%

22. CGRP and Botulinum Toxin Meng J, Wang J, Lawrence G, Dolly JO Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by botulinum toxins reflects their anti-nociceptive potential. J Cell Sci. 2007;120(16):2864-74

23. Acute Treatment Goals Rapidly relieve attack Consistently relieve attack No recurrence Restore ability to function Minimize need for backup medications Optimize self-care (prevent ER/physician visits) Cost-effective Minimize or avoid adverse events US Headache Consortium: 2000

24. Prescription Drugs Cafergot, Wigraine Migranol Midrin Fioricet, Fiorinal, Esgic NSAIDs, COX-2 codeine, hydrocodone Stadol NS Non-triptans

25. Prescription Drugs Imitrex - sumatriptan Zomig - zolmitriptan Maxalt - rizatriptan Amerge - naratriptan Axert - almotriptan Frova - frovatriptan Relpax - eletriptan Triptans

26. Partial or no response Recurrence Risk of CV side effects Risk of other side effects Very high cost Restrictions by HMOs Limited frequency of use Limitations

27. Triptans Ischemic heart disease Coronary vasospasm Multiple risk factors for CAD Hemiplegic or basilar migraine Uncontrolled hypertension Use within 24 hours of ergot or another triptan Pregnancy: Category C Contraindications

28. OTC Drugs Excedrin Migraine Advil Migraine Motrin Migraine Bayer Aspirin Anacin Tylenol

29. OTC Drugs Gastro-intestinal side effects, liver and kidney toxicity Presence of caffeine can cause rebound headaches, insomnia, anxiety Lack of efficacy for a large percentage of sufferers Limitations

30. Migralex A new paradigm in the treatment of migraines Aspirin – 500 mg Magnesium oxide – 75 mg A new paradigm in the treatment of migraines Aspirin – 500 mg Magnesium oxide – 75 mg

31. Low-dose aspirin for migraine prophylaxis. Buring JE, Peto R, Hennekens CH, JAMA 1990;264(13). Physicians’ Health Study (n=22,071) Aspirin, 325 mg every other day migraines 661 (6.0%) Placebo818 (7.4%) 20% reduction (statistically significant) Aspirin in Migraine

32. Effervescent metoclopramide and aspirin (Migravess) versus effervescent aspirin or placebo for migraine attacks: a double-blind study Peer Tfelt-Hansen, Jes Olesen, Cephalalgia 1984(4):107. Aspirin, 650 mg with metoclopramide 10 mg vs Aspirin 650 mg vs Placebo (n=118 patients) Both active groups were statistically better (p<0.01) than placebo for pain with no difference between the two active groups Aspirin in Migraine

33. Acetylsalicylic acid effervescent 1000 mg (Aspirin) in acute migraine attacks; a multicentre randomized, double-blind, single-dose, placebo- controlled parallel group study. Lange R, Schwartz J, Hohn M. Cephalalgia, 2000;20(7):663-667 Aspirin in Migraine Relief at 2 hours (n=343 patients): Aspirin 55% Placebo36% P<0.001

34. Mouth-dispersible aspirin in the treatment of migraine: A placebo-controlled study. MacGregor EA, Dowson A, Davies TG. Headache 2002;42(4)249-255 Aspirin in Migraine Relief at 2 hours (n=71 patients): Aspirin (900 mg) 48% Placebo19% P=0.0005

35. Aspirin is efficacious for the treatment of acute migraine. Lipton RB, Goldstein J, Baggish JS et al. Headache 2005;45(4):283-92 Aspirin in Migraine Relief at 2 hours (n=401 patients): Aspirin (1000 mg) 52% Placebo34% P<0.001

36. Aspirin in Migraine Efficacy of 1,000 mg Effervescent Acetylsalicylic Acid and Sumatriptan in Treating Associated Migraine Symptoms H.C. Diener et al. European Neurology 2004;52:50-56 433 patients Relief Pain-free 1,000 mg effervescent ASA 49.3% 25.3% 50 mg sumatriptan 48.8% 24.4% placebo 32.9% 14.5% All active treatments were superior to placebo (p < 0.05).

37. Caffeine CNS side effects: anxiety, jitteriness, tremor, insomnia Other side effects: palpitations, stomach pain/GERD Potential for causing rebound headaches The case against caffeine as an ingredient in a migraine product

38. 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)

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

40. 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

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

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

43. 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

44. 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.

45. Efficacy of intravenous magnesium sulfate in the treatment of acute migraine attacks. Demirkaya S, Vural O, Dora B, et al. Headache 2001;41:171-177 Randomized, single-blind, placebo controlled trial 15 patients – 1 g of MgSO 4 ; 13 complete relief, 2 - partial 15 patients – placebo, followed by 1 g MgSO 4 ; 4 – partial relief, 11 – none; after 1 g MgSO4 14 – complete relief. Magnesium and Migraine

46. Parenteral treatment of acute migraines magnesium sulfate – 1 gram IV sumatriptan – 4-6 mg SC ketorolac – 60 mg IV dexamethasone – 8 mg IV metoclopramide – 10 mg IV dihydroergotamine – 1 mg IV valproate sodium – 500 mg IV droperidol – 2.5-5 mg IV Goal: Keep patients out of the ER

47. 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

48. 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-u-aspartate-hydrochloride-trihydrate – 20 mmol No relief of headaches – interim analysis of 69 patients. Diarrhea: 45.7% on magnesium, 23.5 on placebo Magnesium and Migraine

49. 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

50. Oral magnesium oxide prophylaxis of frequent migrainous headache in children: A randomized, double-blind, placebo-controlled trial. Wang F, Van Den Eeden S, Ackerson L, et al. Headache 2003;43:601-610. Magnesium oxide 9 mg/kg 86 of 118 completed; “statistically significant downward trend in HA frequency over time in MgO but not placebo group” Magnesium and Migraine

51. Stress Alcohol Genetics Low dietary intake Gastro-intestinal disorders Chronic illness Potential causes of magnesium deficiency Potential causes of magnesium deficiency

52. Migralex A new paradigm in the treatment of migraines Aspirin – 500 mg Magnesium oxide – 75 mg A new paradigm in the treatment of migraines Aspirin – 500 mg Magnesium oxide – 75 mg

53. Migralex Both ingredients relieve all migraine symptoms, but through different mechanisms, which may result in superior efficacy due to synergistic effect Low recurrence rate due to the sustained effect of magnesium and antiplatelet effect of aspirin Magnesium facilitates absorption and reduces potential GI side effects of aspirin Rapidly absorbed Advantages

54. Migralex Can be effective for “overindulgence headaches” Effective for “sinus” and tension headaches May have lasting preventive effect Caffeine-free Magnesium is potentially beneficial in asthma, stroke, neonates, cardiac arrhythmias, PMS, etc. Aspirin has many other potential benefits and lacks the stigma of other NSAIDs (cardiovascular risks) Advantages

55. Migralex and Acute Treatment Goals Rapidly relieve attack Consistently relieve attack No recurrence Restore ability to function Minimize need for backup medications Optimize self-care/prevent ER/MD visits Cost-effective Minimize or avoid adverse events US Headache Consortium: 2000

56. New York Headache Center Magnesium, Migralex and Migraine Alexander Mauskop, MD