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New York Headache Center Advances in Migraine Alexander Mauskop, MD Potential Conflict of Interest Disclosure Allergan Pozen AstraZeneca Procter & Gamble Bristol-Myers Squibb PR Osteo Elan Royal Numico/GNC GlaxoSmithKline UCB Pharma Merck Weber & Weber Novartis Winston Laboratories Ortho-McNeil Wyeth Pfizer News in Migraine Pathophysiology CGRP antagonists PFO Classification Basilar migraine Chronic migraine Magnesium Botulinum toxin Impact of Migraine on Quality of Life No chronic conditions Diabetes Migraine 0.4 Hypertension Angina Quality of Life Measure 0.2 0 -0.2 -0.4 -0.6 -0.8 -1 -1.2 Physical functioning Role functioning Social functioning Mental health Health perceptions Adapted from Solomon GD et al. Headache 1994;34(3):143-147 Pain 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. 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 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. 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 antimigraine drugs. 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 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 Caffeine-containing Drugs Rx Cafergot Wigraine Esgic Fiorinal Fioricet Norgesic Synalgos DC Caffeine-Containing Drugs OTC Anacin Anacin Maximum Strength Aspirin Free Excedrin Excedrin Extra Strength Excedrin Migraine Maximum Strength Midol 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 Caffeine 235 mg (2.5 cups) a day 52% moderate or severe headache 11% depression 11% low vigor 8% anxiety 8% fatigue “Withdrawal syndrome after the double-blind cessation of caffeine consumption.” (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 Known effects of IMg2+ glutamate acetylcholine angiotensin II nitric oxide potassium norepinephrine serotonin calcium G proteins enzyme complexes (325) NMDA (N-Methyl-D-Aspartate) Receptor Complex Ca2+ Mg2+ Zn GLY Ca2+ NMDA PCP MK801 Mg2+ TCA Magnesium and Migraine Potential causes of magnesium deficiency Stress Alcohol and caffeine Genetics Low dietary intake Gastro-intestinal disorders Chronic illness IV MgSO4 for Acute Migraine 0.58 0.56 0.54 xxx x xx x xx xxxxxx 0.52 IMg2+ mmol/L 0.50 0.48 x xx o oo oo ooooo ooo oooo x = non-responders o = responders oo o 0.46 0.44 0.42 o A. Mauskop et al, Clin Science 1995;89:633-6 IV MgSO4 for Cluster Headaches 0.76 x x o 0.60 0.58 x x 0.56 0.54 IMg2+ mmol/L xxx xxx xxx 0.52 0.50 0.48 0.46 0.44 x x o o o ooo oooo o o ooo o o oo o o x = non-responders o = responders Mauskop et al, Headache 1995;35:597-600 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 doubleblind 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 childhood migraine Wang F, Van Den Eeden S, Ackerson L, et al. Cephalagia 2000;20:424 (abstract). Effectiveness of High-dose Riboflavin in Migraine Prophylaxis 4 No. of Attacks per Month 3 Placebo Riboflavin 2 * * 1 1 2 3 4 Month J. Shoenen, J. Jacquy, M. Lenaerts. Neurology 1998; 50:466-440. P=0.001 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. Feverfew Results 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 Natural Remedies The Case for Multi-Agent Therapies 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 Natural Remedies Possible Combinations Migra-Lieve: Riboflavin 400 mg Magnesium 300 mg Feverfew 100 mg Petasites hybridus Possible mechanisms of action: Inhibits constriction of smooth muscle preparation induced by acetylcholine, histamine and potassium chloride Inhibits leukotriene synthesis Natural Remedies What to recommend? Aerobic exercise, neck exercise Biofeedback / relaxation Magnesium, riboflavin, feverfew Acupuncture Massage, shiatsu, reflexology Dietary approaches 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 Currently Used Preventive Therapies Migraine Beta-blockers X Antidepressants X Anticonvulsants X Calcium channel blockers X Methysergide X NSAIDs X Muscle relaxants Tension-type X X X Potential Side Effects of Prophylactic Drugs Beta-blockers fatigue, dizziness, depression Antidepressants dry mouth, drowsiness, weight gain, constipation, sexual dysfunction Anticonvulsants weight gain, cognitive dysfunction, drowsiness, fatigue, constipation Calcium channel blockers constipation, edema Methysergide fibrosis, water retention, leg cramps NSAIDs dyspepsia, peptic ulcers, renal disease Muscle relaxants sedation, dizziness Prophylactic Drugs: Additional Drawbacks Work in minority of patients Compliance Fear of adverse events Drug-drug interactions 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 The Neuromuscular Junction Botulinum Toxin Type A Mechanism of Action: Current Hypothesis 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 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 BTX-A Injection Sites: Fixed Sites, Fixed Dose (Bilateral) Frontalis & Glabellar Temporalis 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) Botulinum Toxin Type A for Migraine Silberstein S, et al. Months Postinjection 0 1 2 3 Mean Change from Baseline 0 -0.4 -0.8 -1.2 * -1.6 -2 -2.4 75U BTX-A 25U BTX-A Vehicle * *P <.042 vs vehicle Study 2 Months Postinjection 0 1 2 3 4 Mean Change From Baseline 0 50U BTX-A -0.4 -0.8 -1.2 -1.6 -2 -2.4 25U BTX-A 7.5U BTX-A Vehicle 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 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 Injection Sites: Glabellar and Frontal Regions X X X X X X X XX Injection Site: Temporalis Muscle X X X X Injection Site: Suboccipital Region Trapezius muscle X X Splenius capitis muscle X Adapted with permission from: Netter FH. Atlas of Human Anatomy. Icon Learning Systems; Teterboro, NJ Injection Site: Occipitalis Muscle X X 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.