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

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.

MIGRAINE: Prevalence and Impact LIFETIME CUMULATIVE INCIDENCE 43% of women 18% of men Stewart et al., Cephalagia, 2008 5% of women have headache more than 15 days per month – Migraine likely represents a significant component for these patients. The majority of patients with migraine have not received an appropriate diagnosis, and are not receiving appropriate therapy

HEADACHE MIGRAINE – A MULTISYMPTOM COMPLEX AURA PATHOPHYSIOLOGICAL SENSORY SYMPTOMS LANGUAGE SYMPTOMS VISUAL SYMPTOMS MOTOR DYSFUNCTION COGNITIVE PATHOPHYSIOLOGICAL MECHANISMS FATIGUE, MOOD CHANGE YAWNING, POLYURIA NAUSEA, VOMITING DIZZINESS, VERTIGO HEADACHE

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

Penfield W. A contribution to the mechanism of intracranial pain 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.

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

Nitric oxide donors PDE inhibitors Histamine CGRP Vasoactive Drugs Cause Migraine After Significant Delay (hours), Not Correlated with Vasodilation Nitric oxide donors PDE inhibitors Histamine CGRP 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.

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

CORTICAL “WAVES” IN MIGRAINE WITH AURA Olesen, et al. 1981 Hadjikhani et al., 2001 So by now we see that events c temporal, spatial, blood flow characteristics of CSD appear to occur in migraine pts, correlate with aura sx. Bereczki et al., 2008 Cao et al., 1999

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

The image on this slide is a PET scan from one individual in the Weiller et. al. study. The red area or locus of activity is located in the brain stem. The authors of this study identified the raphe nuclei, the locus ceruleus, and the peri-aqueductal gray as brain stem regions that are selectively activated during a migraine attack. These regions are thought to be involved in the generation of headache pain. Reference: Weiller C, May A, Limmroth V, et. al. Brain stem activation in spontaneous human migraine attacks. Nat Med. 1995;1:658-660.

Hypothalamic Activation in Migraine (Denuelle et al., Headache, 2007)

Sensory, Cognitive, Motor Symptoms MIGRAINE – A MULTISYMPTOM COMPLEX PAIN Sensory, Cognitive, Motor Symptoms VISUAL SYMPTOMS Cortical Activation Brainstem Activation Nausea/Vomiting VESTIBULAR SYMPTOMS PAIN

MIGRAINE SHOULD BE IN DIFFERENTIAL DIAGNOSIS OF ANY EPISODIC NEUROLOGICAL DISORDER

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

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

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. Normal neurological exam

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

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

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

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

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

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) Probable migraine (n=67) 18% Migraine (n=288) 76% Episodic tension-type (n=11) 3% The Landmark Study evaluated the diagnosis of patients consulting their primary care physicians with headache, and was conducted in 128 practices (93% primary care) in 15 countries. This prospective, open-label study included patients (aged 18–65 years) who consulted their physician with headache as a primary or secondary complaint. Patients were excluded if they had chronic daily headache or if they had a known or suspected secondary headache disorder. A total of 1203 patients were included. During the screening visit, patients self-reported a headache diagnosis, and were then assigned a headache diagnosis by their physician following his or her usual practice. Patients with a physician diagnosis of migraine or non-migraine primary headache completed diaries to record headache symptoms for 3 months or 6 attacks, whichever occurred first. Members of an expert panel (Carl Dahlöf, Sweden; Andrew Dowson, UK; and Lawrence Newman and Stewart Tepper, US), who were unaware of the physician diagnosis, then used the diary data to assign a headache diagnosis according to IHS criteria. The expert panel reviewed diary data for 448 patients (306 with a new physician diagnosis of migraine and 142 with a diagnosis of non-migraine primary headache). Of these, 377 diaries were evaluable for making a headache diagnosis. Of the 377 patients, 355 (94%) were assigned a diagnosis of migraine (76%) or probable migraine (18%) by the expert panel. The Landmark Study found that if a patient presents to their physician with complaint of headache, there is a 94% likelihood it is migraine or migrainous headache. Unclassifiable (n=11) 3% Adapted from Tepper SJ et al. Headache. 2004;44:856–864.

Landmark: Patient and Physician Diagnoses In a prospective, open-label study of 1203 patients with episodic headache 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 Of the 206 patients in the Landmark study who self-reported migraine at the screening visit, almost all (99.5%) were confirmed as having migraine or probable migraine by the expert panel (88% migraine, 11.5% probable migraine). No patient who self-reported migraine was subsequently diagnosed with episodic tension-type headache. Of the 272 patients who were given a new diagnosis of migraine by their physician, 98% were diagnosed with migraine or probable migraine by the expert panel. Therefore, a patient or a physician diagnosis of migraine is likely to be accurate, according to this study. However, if the patient or the physician diagnosed non-migraine, there was a high probability that the patient actually had migraine. Of the 148 patients who self-reported non-migraine headache, 86% were diagnosed by the expert panel with migraine or probable migraine. Likewise, of the 105 patients diagnosed by their physicians as having non-migraine headache, 82% were assigned a diagnosis of migraine or probable migraine by the expert panel. A self-report or physician diagnosis of migraine was almost always correct. On the other hand, a self-report or physician diagnosis of non-migraine was almost always later found out to be migraine. It may be helpful to provide such tools as migraine diaries for patients, and request them to fill it out over several migraine attacks before asking the patient to return to the clinic. During this followup visit, the physician can review the diary and refer to the I.H.S. diagnostic criteria in order to help reach a final diagnosis. 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.

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

“SINUS HEADACHE”

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

ARE THERE MIGRAINE TRIGGERS?

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

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

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

AMPP DATA (Bigal et al., Neurology 2008) 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

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 NSAIDS METACLOPRAMIDE

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.

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)

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

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

MIGRAINE AND PREGNANCY THE SIGNIFICANT MAJORITY OF WOMEN HAVE AN IMPROVEMENT IN MIGRAINE FREQUENCY DURING THE 2nd and 3rd 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

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

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