1. HEADACHE Andrew Charles, M.D. Professor Director, Headache Research and Treatment Program David Geffen School of Medicine at UCLA

2. COMMON TYPES OF HEADACHES PRIMARY HEADACHES MIGRAINE TENSION TYPE CLUSTER HEADACHE AND OTHER TRIGEMINAL AUTONOMIC CEPHALGIAS SECONDARY HEADACHES Headaches due to infection Headaches due to vascular causes Headaches due to tumors Etc., etc.

3. HEADACHE: Prevalence and Impact PREVALENCE 18-25 % women have migraine 6-10 % men have migraine 5% of women have headache more than 15 days per month 112 million bedridden days per year Cost to U.S. Employers -- $13 Billion per year The majority of patients with migraine have not received an appropriate diagnosis, and are not receiving appropriate therapy

4. MIGRAINE – A MULTISYMPTOM COMPLEX PATHOPHYSIOLOGICAL EVENTS

5. CHANGING CONCEPTS OF MIGRAINE PATHOGENESIS MIGRAINE IS A DISORDER OF BRAIN EXCITABILITY MIGRAINE IS A DISORDER OF BRAIN EXCITABILITY VASODILATION MAY OCCUR AS PART OF THE DISORDER, BUT IS NOT REQUIRED FOR MIGRAINE PAIN VASODILATION MAY OCCUR AS PART OF THE DISORDER, BUT IS NOT REQUIRED FOR MIGRAINE PAIN

6.  Penfield W. A contribution to the mechanism of intracranial pain. Assoc Res Nerv Ment Dis. 1935;15:399-416.  Ray BS, Wolff HG. Experimental studies in headache: Pain- sensitive structures of the head and their significance in headache. Arch Surg. 1940;41:813-856.

7. Issues with Studies of Ray and Wolff, Penfield Stimulation of vessels was focal external stimulation or mechanical dilation There is no evidence that physiological relaxation of smooth muscle and resultant dilation can cause pain Multiple areas of brain that could evoke pain were not stimulated: Cingulate cortex Brainstem – Stimulation or lesions in brainstem can cause migraine

8. Vasoactive Drugs Cause Migraine After Significant Delay (hours), Not Correlated with Vasodilation Nitric oxide donors PDE inhibitors HistamineCGRP Schoonman, et al. Migraine headache is not associated with cerebral or meningeal vasodilatation--a 3T magnetic resonance angiography study. Brain 131, 2192-2200, 2008. Kruus, et al. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain. 26:241-247, 2003. Rahman et al., Vasoactive intestinal peptide causes marked cerebral vasodilation but does not induce migraine. Cephalalgia. 28, 226-236, 2008.

9. Alternative Mechanisms of “ Vascular” Drugs  -blockers Inhibit neuronal adrenergic signaling Calcium channel blockers Inhibit neuronal calcium channels Caffeine Neuronal/glial adenosine receptor antagonist Ergotamines Modulate central 5-HT receptors Triptans Activate neuronal 5-HT1 receptors in brainstem and thalamus

10. Olesen, et al. 1981 Hadjikhani et al., 2001 Cao et al., 1999 CORTICAL “WAVES” IN MIGRAINE WITH AURA Bereczki et al., 2008

11. Woods et al., 1994 Chalaupka, 2008 Denuelle et al., 2008 Before sumatriptan 2 to 4 h after the attack onset After sumatriptan 4 to 6 h after the attack onset …AND MIGRAINE WITHOUT AURA

13. MIGRAINE – A MULTISYMPTOM COMPLEX CorticalActivation BrainstemActivation

14. MIGRAINE SHOULD BE IN DIFFERENTIAL DIAGNOSIS OF ANY EPISODIC NEUROLOGICAL DISORDER

15. Do most headache patients need an imaging study of the brain?

16. “I’ll want to get a few tests on you, just to cover my ass”

17. When Don’t You Need to Get a Scan? Patient with established history of episodic headache Current headache is consistent with previous headaches or is consistent with different manifestation of a primary headache. Current headache is consistent with previous headaches or is consistent with different manifestation of a primary headache. Normal neurological exam Normal neurological exam

18. When You Do Need to Get a Scan Extremely abrupt onset of headache Persistent unremitting headache Persistent unremitting headache New onset of headache in patient over age of 50 New onset of headache in patient over age of 50 Fever Fever Papilledema Papilledema Abnormal neurological examination Abnormal neurological examination

19. General Approach to The Headache Patient Make a diagnosis (or challenge the diagnosis that a patient has already been given) Identify and change exacerbating environmental factors and medications Establish regimen for acute therapy of headache Determine if preventive therapy is appropriate

20. IHS CRITERIA FOR MIGRAINE WITHOUT AURA At least 5 attacks fulfulling the following: Headaches lasting 4 to 72 hours During headache, at least one of the following: Nausea and/or vomiting Photophobia and phonophobia At least 2 of the following criteria Unilateral location Pulsating quality Moderate or severe intensity Aggravated by physical activity

21. Simplified Diagnostic Criteria: ID Migraine Light sensitivity with headache Nausea with headache Decreased ability to function with headache Any 2 out of 3 = Migraine Migraine should be the default diagnosis for any headache that is brought to the attention of a health care provider

22. Migraine: Other Features Perimenstrual timing Stereotypical prodromal symptoms Characteristic triggers Abatement with sleep Childhood precursors (motion sickness, somnambulism, episodic vomiting, episodic vertigo) Osmophobia Diarrhea during attack

23. Landmark: How Likely Is it That “Headache” Is Migraine? In a prospective, open-label study of 1203 patients with episodic headache 94% (of 377 evaluable patients) had migraine or probable migraine 25% with migraine were not diagnosed by their physician Headaches had a severe impact (HIT–6 score 64) Migraine (n=288) 76% Probable migraine (n=67) 18% Episodic tension-type (n=11) 3% Unclassifiable (n=11) 3% Adapted from Tepper SJ et al. Headache. 2004;44:856–864.

24. Landmark: Patient and Physician Diagnoses Self-report or physician diagnosis of migraine was almost always correct Self-report or physician diagnosis of non-migraine was almost always later found out to be migraine Adapted from Tepper SJ et al. Headache. 2004;44:856–864. Patient If patient self-reports migraine, 99.5% chance migraine or probable migraine If patient self-reports non-migraine, 86% chance migraine or probable migraine Physician If physician diagnoses migraine, 98% chance migraine or probable migraine If physician diagnoses non-migraine, 82% chance migraine or probable migraine In a prospective, open-label study of 1203 patients with episodic headache

25. MIGRAINES ARE OFTEN MISDIAGNOSED SINUS HEADACHES SIMILAR DISTRIBUTION OF PAIN MIGRAINES CAN BE SEASONAL DECONGESTANTS CAN “TAKE THE EDGE OFF” OF MIGRAINE WITHDRAWAL FROM DECONGESTANTS CAN PRECIPITATE MIGRAINES

26. “SINUS HEADACHE”

27. OTHER COMMON MIGRAINE MISDIAGNOSES TENSION HEADACHE/CERVICOGENIC HEADACHE NECK PAIN IS A SYMPTOM OF MIGRAINE MIGRAINE COMMONLY ASSOCIATED WITH NECK PAIN NECK PAIN MAY OCCUR BEFORE, DURING, OR AFTER HEADACHE

28. ARE THERE MIGRAINE TRIGGERS?

30. COMMON HEADACHE TRIGGERS IRREGULAR MEALS IRREGULAR CAFFEINE, CHOCOLATE, NUTS, BANANAS, ETC. IRREGULAR SLEEP (PARTICULARLY EXCESSIVE SLEEP) STRESS OR “LET-DOWN” FROM STRESS AIR TRAVEL, CHANGE IN BAROMETRIC PRESSURE MENSTRUAL PERIOD

31. THE MIGRAINE LIFESTYLE CONSISTENCY TIMING OF MEALS, BALANCE OF DIET –- Don’t skip meals, mix of different food groups SLEEP --- Don’t oversleep or undersleep CAFFEINE – “Minimum daily dose” of caffeine on a daily basis EXERCISE – The more aerobic exercise the better

32. MEDICATIONS THAT MAY MAKE MIGRAINES WORSE ORAL CONTRACEPTIVES HORMONE REPLACEMENT SSRI ANTIDEPRESSANTS STEROIDS (TAPERING) DECONGESTANTS SHORT ACTING SEDATIVES (e.g. Ambien (?) BONE DENSITY MEDICATIONS (?) BOTOX

33. FREQUENT OPIOID OR BARBITURATE (BUTALBITAL) USE IS A RISK FACTOR FOR MIGRAINE PROGRESSION GROWING EVIDENCE THAT OVERUSE OF ANALGESIC MEDICATIONS LEADS TO WORSENING OF MIGRAINE AMPP DATA (Bigal et al., Neurology 2008) Frequent use of opioids or butalbital (more than 8 days/month) is a risk factor for progression to chronic migraine Triptan use is neutral for progression Nonsteroidal use is protective

34. ACUTE THERAPIES TRIPTANS – Selective 5HT 1b 1d agonists SUMATRIPTAN (IMITREX TABLETS, NASAL SPRAY, INJECTION), SUMATRIPTAN NAPROXEN COMBINATION RIZATRIPTAN (MAXALT “MELTABS”, TABLETS) NARATRIPTAN (AMERGE TABLETS) ZOLMITRIPTAN (ZOMIG) ALMOTRIPTAN (AXERT) FROVATRIPTAN (FROVA) ELETRIPTAN (RELPAX) DHE NASAL SPRAY (MIGRANAL), INJECTION NSAIDSMETACLOPRAMIDE

35. TRIPTAN NEWS TRIPTANS ARE NOW AVAILABLE WIDELY WITHOUT A PRESCRIPTION IN EUROPE. SUMATRIPTAN WILL SOON BE AVAILABLE AS A GENERIC IN MULTIPLE PREPARATIONS. SUMATRIPTAN/NAPROXEN COMBINATION TABLET (TREXIMET) IS NOW AVAILABLE.

36. EVIDENCE-BASED NON-PRESCRIPTION APPROACHES TO MIGRAINE Magnesium (300-500 mg. per day) Riboflavin (400 mg. per day) CoQ10 (300 -1200 mg. per day) Melatonin (3 mg. qhs) Petasites (Butterbur 75 mg. BID)

37. THERAPEUTIC OPTIONS FOR MIGRAINE PROPHYLAXIS BETA BLOCKERS TRICYCLICS CALCIUM CHANNEL BLOCKERS VALPROIC ACID (Depakote) TOPIRAMATE (Topamax) ?? MEMANTINE

38. MEMANTINE FOR MIGRAINE PREVENTION? Activity dependent blocker of NMDA receptors Identified as a blocker of CSD in rodents Appears to be effective as a migraine preventive therapy for significant percentage of patients with frequent migraine who had failed other preventive therapies It is generally very well tolerated Well designed studies are warranted Peeters et al., JPET, 2007 Charles, et al., Journal of Headache and Pain, 2007 Bigal et al., Headache, 2008

39. MIGRAINE AND PREGNANCY THE SIGNIFICANT MAJORITY OF WOMEN HAVE AN IMPROVEMENT IN MIGRAINE FREQUENCY DURING THE 2 nd and 3 rd TRIMESTERS OF PREGNANCY THERE IS NO CONSENSUS OR EVIDENCED BASED APPROACH TO TREATMENT OF HEADACHE DURING PREGNANCY REGULAR SMALL AMOUNTS OF CAFFEINE, MAGNESIUM SUPPLEMENTATION ARE REASONABLE NON-PRESCRIPTION ALTERNATIVES THE ONLY ADVERSE EVENT THAT HAS BEEN IDENTIFIED WITH TRIPTANS AND PREGNANCY IS A SLIGHTLY INCREASED RISK OF PREMATURE DELIVERY….i.e. OK TO USE TRIPTANS IN SEVERE CASES

40. NEW THERAPIES ON THE HORIZON ACUTE THERAPIES CGRP Antagonist – Initial placebo controlled trials look very promising. Transcranial magnetic stimulation Inhaled ergotamines Inhaled ergotamines PREVENTIVE THERAPIES PFO Closure – Multiple closure devices in clinical trials Memantine – Initial uncontrolled results are promising Occiptial nerve stimulation Tonabersat

41. CGRP (Calcitonin Gene Related Peptide) IN MIGRAINE CGRP IS RELEASED INTO JUGULAR VENOUS SYSTEM DURING A MIGRAINE ATTACK CGRP RECEPTOR ANTAGONISTS EFFECTIVELY ABORT A MIGRAINE ATTACK Calcitonin Gene–Related Peptide Receptor Antagonist BIBN 4096 BS for the Acute Treatment of Migraine. NEJM, 350: 1104-1110, 2004. Jes Olesen, M.D., Hans-Christoph Diener, M.D., Ingo W. Husstedt, M.D., Peter J. Goadsby, M.D., David Hall, Ph.D., Ulrich Meier, Ph.D., Stephane Pollentier, M.D., and Lynna M. Lesko, M.D., for the BIBN 4096 BS Clinical Proof of Concept Study Group Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 70: 1304-1312, 2008. T. W. Ho, MD, L. K. Mannix, MD, X. Fan, PhD, C. Assaid, PhD, C. Furtek, BS, C. J. Jones, MS, C. R. Lines, PhD, A. M. Rapoport, MD On behalf of the MK-0974 Protocol 004 study group *

42. MODULATORS OF CERVICAL INPUT TO HEADACHE Occipital Nerve Stimulation INHIBITORS OF CORTICAL SPREADING DEPRESSION Memantine, Tonabersat, Transcranial Magnestic Stimulation POTENTIAL NEW THERAPIES FOR MIGRAINE Adapted from Jones HR. Netter’s Neurology, St. Louis, MO; Saunders; 2005. INHIBITORS OF CGRP RECEPTOR Telcagepant CIRCULATORY TRIGGERS TO BRAIN EXCITABILITY? PFO Closure

43. TAKE HOME MESSAGES MIGRAINE IS A COMPLEX DISORDER OF BRAIN EXCITABILITY AND NOT SIMPLY A “VASCULAR HEADACHE” MIGRAINE IS EXTRAORDINARILY COMMON AND UNDERDIAGNOSED. THE MAJORITY OF MIGRAINE PATIENTS CAN BE EFFECTIVELY AND SAFELY TREATED WITH AN ORGANIZED PLAN OF LIFESTYLE MANAGEMENT, ACUTE THERAPY, AND PREVENTIVE THERAPY IF NEEDED PROMISING NEW THERAPIES ARE ON THE HORIZON