HEADACHEAndrew Charles, M.D.

ProfessorDirector, Headache Research and Treatment Program

David Geffen School of Medicine at UCLA

COMMON TYPES OF HEADACHES

PRIMARY HEADACHESMIGRAINETENSION TYPE CLUSTER HEADACHE AND OTHER TRIGEMINAL AUTONOMIC CEPHALGIAS

SECONDARY HEADACHESHeadaches due to infectionHeadaches due to vascular causesHeadaches due to tumorsEtc., etc.

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

MIGRAINE – A MULTISYMPTOM COMPLEX

Sensory, Cognitive, Motor Symptoms

PATHOPHYSIOLOGICAL EVENTS

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. 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

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

-blockersInhibit neuronal adrenergic signaling

Calcium channel blockersInhibit neuronal calcium channels

CaffeineNeuronal/glial adenosine receptor antagonist

ErgotaminesModulate central 5-HT receptors

TriptansActivate neuronal 5-HT1 receptors in brainstem and thalamus

Olesen, et al. 1981 Hadjikhani et al., 2001

Cao et al., 1999

CORTICAL “WAVES” IN MIGRAINE WITH AURA

Bereczki et al., 2008

Woods et al., 1994

Chalaupka, 2008

Denuelle et al., 2008

Before sumatriptan2 to 4 h after the attack onset

After sumatriptan4 to 6 h after the attack onset

…AND MIGRAINE WITHOUT AURA

MIGRAINE – A MULTISYMPTOM COMPLEX

Cortical Activation

BrainstemActivation

Sensory, Cognitive, Motor Symptoms

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 vomitingPhotophobia and phonophobia

– At least 2 of the following criteriaUnilateral locationPulsating qualityModerate or severe intensityAggravated 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 = MigraineMigraine 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)

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.

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 migraineAdapted 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

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

CONSISTENCYTIMING OF MEALS, BALANCE OF DIET –- Don’t skip meals, mix of different food groupsSLEEP --- Don’t oversleep or undersleepCAFFEINE – “Minimum daily dose” of caffeine on a daily basisEXERCISE – 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

FREQUENT OPIOID OR BARBITURATE (BUTALBITAL) USE IS A RISK FACTOR

FOR MIGRAINE PROGRESSION

GROWING EVIDENCE THAT OVERUSE OF ANALGESIC MEDICATIONS LEADS TO WORSENING OF MIGRAINEAMPP 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 migraineTriptan use is neutral for progressionNonsteroidal 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 warrantedPeeters et al., JPET, 2007Charles, et al., Journal of Headache and Pain, 2007Bigal et al., Headache, 2008

MIGRAINE AND PREGNANCYTHE SIGNIFICANT MAJORITY OF WOMEN HAVE AN IMPROVEMENT IN MIGRAINE FREQUENCY DURING THE 2nd and 3rd TRIMESTERS OF PREGNANCYTHERE IS NO CONSENSUS OR EVIDENCED BASED APPROACH TO TREATMENT OF HEADACHE DURING PREGNANCYREGULAR SMALL AMOUNTS OF CAFFEINE, MAGNESIUM SUPPLEMENTATION ARE REASONABLE NON-PRESCRIPTION ALTERNATIVESTHE 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 THERAPIESCGRP Antagonist – Initial placebo controlled trials look very promising.Transcranial magnetic stimulation Inhaled ergotamines

PREVENTIVE THERAPIESPFO Closure – Multiple closure devices in clinical trialsMemantine – Initial uncontrolled results are promisingOcciptial nerve stimulationTonabersat

CGRP (Calcitonin Gene Related Peptide) IN MIGRAINE

CGRP IS RELEASED INTO JUGULAR VENOUS SYSTEM DURING A MIGRAINE ATTACKCGRP RECEPTOR ANTAGONISTS EFFECTIVELY ABORT A MIGRAINE ATTACKCalcitonin 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*

MODULATORS OF CERVICAL INPUT TO HEADACHE

Occipital Nerve Stimulation

INHIBITORS OF CORTICAL SPREADING DEPRESSIONMemantine, Tonabersat, Transcranial Magnestic Stimulation

POTENTIAL NEW THERAPIES FOR MIGRAINE

Adapted from Jones HR. Netter’s Neurology, St. Louis, MO; Saunders; 2005.

INHIBITORS OF CGRP RECEPTORTelcagepant

CIRCULATORY TRIGGERS TO BRAIN EXCITABILITY?

PFO Closure

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