New York Headache Center Headache Update Alexander Mauskop, MD

Lecture outline Headache diagnosis Migraine pathogenesis – research update Abortive therapies Botox and other prophylactic therapies Magnesium and alternative therapies DrMauskop@NYHeadache.com Anything else we could show to support economic benefit of Imitrex or 100 mg? Every minute the cost to employers. Cost to have one of their assistants out with migraine for a year. Delete here - since moved to # 36 - what do you think ?

Number of Migraine Sufferers in the U.S. 1989 1999 (Million) (Million) Overall 23.6 27.9 Female 18.0 20.9 Male 5.6 6.9 Lipton et al. 2001. American Migraine Study II.

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

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

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

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

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"

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.

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 Anything else we could show to support economic benefit of Imitrex or 100 mg? Every minute the cost to employers. Cost to have one of their assistants out with migraine for a year. Delete here - since moved to # 36 - what do you think ?

CNS Activation During Migraine Dysfunction of brainstem pain and vascular control centers Pain Perception* Anterior cingulate cortex Migraine Generator* Raphe nuclei Locus coeruleus Periaqueductal gray The development of migrainelike episodes in patients undergoing surgery to implant electrodes in the periaqueductal gray and the raphe nuclei for the treatment of chronic pain generated the hypothesis that dysfunction in the central nervous system early in a migraine attack could provoke changes in these brain stem nuclei.3 Weiller and colleagues4 used positron emission tomography to examine the changes in regional cerebral blood flow, an index of neuronal activity, during spontaneous migraine attacks. The left panel in the above slide is a positron emission tomography scan from an individual during a migraine attack treated acutely with sumatriptan. The scan depicts neuronal activity in a section through the brain stem. The authors of this study report that monoaminergic brain stem regions (raphe nucleus [serotonergic neurons] and locus coeruleus [noradrenergic neurons]) and periaqueductal gray are selectively activated during a migraine attack. When this patient used subcutaneous sumatriptan to acutely relieve his headache pain, the brain stem centers continued to appear active on follow-up positron emission tomography scans. By contrast, the anterior cingulate cortex (right panel), a region thought to be involved in processing affective components of pain, was also activated during spontaneous migraine attacks, and this activation was reduced concomitant with headache pain relief after administration of sumatriptan. Taken together, these observations suggest that the raphe nucleus, the locus coeruleus, and the periaqueductal gray are regions that may be involved in the generation of headache pain and associated symptoms during a migraine attack.4 –16 mm –18 mm *Areas of red indicate cerebral blood flow increases (P<0.001). Weiller C et al. Nat Med. 1995;1:658–660

Human Trigeminal Tract: CGRP Fibers Co-express 5-HT1D Receptors Immunofluorescent studies of sensory trigeminal nerve fibers have shown evidence of colocalization of CGRP and 5-HT1D receptors.9 This lends support to the theory of neurogenic vasodilatation and the inhibition of CGRP release via presynaptic activation of the inhibitory 5-HT1D receptor. CGRP 5-HT1D 5-HT1D /CGRP

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

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%

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

Medication-Overuse Headache (MOH) New to IHS Classification Common cause of headaches 15 days/month Headache has developed or is markedly worse with regular overuse of opioids or caffeine-containing drugs Diagnosis important: patients often do not respond to preventive Rx until the overused medication is withdrawn Discontinuation of acute medication usually results in Withdrawal symptoms (increased headache) Later improvement Previously used terms: rebound headache, drug-induced headache, medication-misuse headache

Migralex A rapidly dissolving combination of: Aspirin – 500 mg Magnesium oxide – 75 mg

Prescription Drugs Triptans Imitrex (Treximet) – sumatriptan (+naproxen) Zomig - zolmitriptan Maxalt - rizatriptan Amerge - naratriptan Axert - almotriptan Frova - frovatriptan Relpax - eletriptan

Triptans Contraindications 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

Consider Prevention When: Migraine significantly interferes with patient’s daily routine despite acute treatment Frequency attacks >2/week with risk of acute medication overuse Contraindication to, failure, adverse events, or acute medication overuse Patient preference

Preventive Treatment Choice is based on: Patient’s preferences Headache type Drug side effects Presence of coexisting conditions

Principles of Preventive Drug Treatment Start with low dose and increase slowly Need adequate trial (1 to 2 months) Avoid drug overuse and interfering drugs Evaluate therapy Use calendar Taper (and stop?) if headaches well controlled

Currently Used Preventive Drugs High efficacy  -blockers: propranolol, timolol TCAs: amitriptyline Divalproex Topiramate Moderate efficacy -blockers: atenolol, metoprolol, nadolol ARBs: candesartan Some NSAIDs SNRIs: duloxetine Gabapentin

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 History of BTX-A Use in Headache 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. 25

The Neuromuscular Junction This slide illustrates the mechanism of neurotransmitter release in the neuromuscular junction. As you can see, stored within the synaptic vesicles is the neurotransmitter acetylcholine (seen in green). To facilitate docking of vesicles and subsequent release of acetylcholine, a complex of SNARE proteins, consisting of syntaxin, synaptobrevin, and SNAP-25, are employed. These proteins act in concert to promote vesicular docking and neurotransmitter release. Once released into the neuromuscular junction, the acetylcholine binds its receptor on the muscle cell and muscle contraction ensues. Note: This illustration simplifies the process of exocytosis and does not depict the other soluble proteins involved. Reference Arnon SS, Schechter R, Inglesby TV, et al. Botulinum toxin as a biological weapon: medical and public health management. JAMA. 2001;285:1059-1070. 26

Botulinum Toxin Type A Mechanism of Action Botulinum Toxin Type A Mechanism of Action: Current Hypothesis Exposure to botulinum toxin inhibits vesicular docking and subsequent acetylcholine release at the neuromuscular junction, leading to chemodenervation and reduced muscular contractions. First, the neurotoxin (seen in purple) binds to specific receptors on the neuronal cell membrane that are located outside the synaptic cleft (shown here inside for the sake of illustration). It then enters the cell by a process known as receptor-mediated endocytosis. Once inside, the light chain of botulinum toxin proteolytically cleaves sites on its respective target SNARE proteins. This prevents synaptic fusion by disruption of the synaptic fusion complex. In the absence of vesicle assembly, the membranes fail to fuse and acetylcholine is not released. Different botulinum toxin serotypes have different SNARE protein targets. Botulinum type A, the subject of this presentation, targets SNAP-25, as does C and E; B, D, F, and G target synaptobrevin. Type C also targets syntaxin. Despite their different molecular targets, the different serotypes all share the same general mechanism of action — inhibition of vesicular docking and acetylcholine release at the neuromuscular junction. Reference Arnon SS, Schechter R, Inglesby TV, et al. Botulinum toxin as a biological weapon: medical and public health management. JAMA. 2001;285:1059-1070. 27

CGRP and Botulinum Toxin Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by botulinum toxins reflects their anti-nociceptive potential. Meng J, Wang J, Lawrence G, Dolly JO. J Cell Sci. 2007;120(16):2864-74 28

Botox for chronic migraine: Phase III trials Aurora SK, Schim JD, Cutrer FM, et al. Botulinum neurotoxin type A for treatment of chronic migraine: PREEMPT 1 trial double-blind phase. Cephalalgia 2009;29 (suppl 1):29. Dodick DW, Smith TR, Becker WJ, et al. Botulinum neurotoxin type A for treatment of chronic migraine: PREEMPT 2 trial double-blind phase. Cephalalgia 2009;29 (suppl 1):29. Considering placebo-subtracted pain free at 2 hour rates, rizatriptan 10 mg and eletriptan 80 mg maintain their higher rates relative to sumatriptan 100 mg (mean 19%). The other triptans are comparable to the reference.

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

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

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

Magnesium and Migraine Known effects of IMg2+ glutamate angiotensin II potassium serotonin G proteins acetylcholine nitric oxide norepinephrine calcium enzyme complexes (325)

NMDA (N-Methyl-D-Aspartate) Receptor Complex Ca2+ Mg2+ Zn GLY Ca2+ NMDA PCP MK801 Mg2+ TCA

IV MgSO4 for Acute Migraine IMg2+ mmol/L 0.58 0.56 0.54 0.52 0.50 0.48 0.46 0.44 0.42 xxx o oo x xx xxxxxx ooooo ooo oooo x = non-responders o = responders A. Mauskop et al, Clin Science 1995;89:633-6

IV MgSO4 for Cluster Headaches x 0.76 x 0.60 0.58 0.56 0.54 0.52 0.50 0.48 0.46 0.44 o x x o xxx o x = non-responders xxx o o = responders xxx ooo IMg2+ mmol/L oooo x o x o ooo o o oo Mauskop et al, Headache 1995;35:597-600. o o

Magnesium and Migraine 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 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 reduced 41.6% vs 15.8% (p<0.05) Days with migraine reduced 52.3% vs 19.5% (p<0.05)

Magnesium and Migraine 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 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 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 reduced 41.6% vs 15.8% (p<0.05) Days with migraine reduced 52.3% vs 19.5% (p<0.05)

Magnesium and Migraine 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 Potential causes of magnesium deficiency Stress Alcohol & caffeine Genetics of absorption and renal excretion Low dietary intake Gastro-intestinal disorders (IBS, colitis, celiac) Chronic illness

Coenzyme Q10 Efficacy of coenzyme Q10 in migraine prophylaxis: A randomized controlled trial P. S. Sándor, L. Di Clemente, G. Coppola Neurology 2005;64:713-715 Double-blind, randomized, placebo-controlled trial 42 patients; CoQ10 100 mg TID vs placebo 50% responder rate for attack frequency 14.4% for placebo and 47.6% for CoQ10

Coenzyme Q10 Coenzyme Q10 deficiency and response to supplementation in pediatric and adolescent migraine Hershey AD, et al. Headache 2007;47:73-80 1550 patients – 32.9% deficient Supplementation with 1-3 mg/kg/day CoQ10 levels improved, p<.0001 HA frequency improved from 19.2 to 12.5, p<.001 HA disability improved from 47.4 to 22.8, p<.001

Mind-body therapy Progressive relaxation Imagery & visualization Behavioral therapy Cognitive therapy Social support Therapeutic touch Hypnotherapy Meditation Biofeedback Prayer Reiki

Botanical Remedies Feverfew Efficacy and safety of 6.25 mg t.i.d. feverfew CO2--extract (MIG-99) in migraine prevention – a randomized, double-blind, multicenter, placebo-controlled study. Diener HC, Pfaffenrath V, Schnitker et al. Cephalalgia 2005;25:1031-1041 N=170, 89 - feverfew, 81 - placebo, 4 - 6 attacks/month No prophylactic drugs

Feverfew (Diener) Results Reduction in number of attacks in 28 days– 1.9 vs 1.3 (p<0.0456) Global assessment of efficacy – statistically significant difference No difference in averse events (25.2% active, 26.6% – placebo) No effect on duration of attacks

Petasites hybridus- butterbur (Petadolex®) Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Lipton RB, Gobel H, Einhaupl KM, Wilks, K and Mauskop A. Neurology 2004;63:2240-2244 245 patients Three groups: placebo, 100 mg and 150 mg Main outcome measure: attack frequency

Petasites hybridus- butterbur (Petadolex®) Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Lipton RB, Gobel H, Einhaupl KM, Wilks, K and Mauskop A. Neurology 2004;63:2240-2244 Attack frequency reduced by: 48% in 150 mg group (p=0.0012) 36% in 100 mg group (p=0.127) 26% in placebo

Approach to migraine patients at the NYHC aerobic exercise, neck exercise biofeedback / meditation / yoga magnesium, riboflavin, feverfew (MigreLief ®) CoQ10, butterbur (Petadolex ®) acupuncture dietary approaches botulinum toxin medications: abortive, prophylactic 53

Parenteral treatment of acute migraines Goal: Keep patients out of the ER 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