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.

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

VISUAL SYMPTOMS

PAIN

Sensory, Cognitive,
Motor Symptoms

PATHOPHYSIOLOGICAL EVENTS

Nausea/Vomiting

PAIN

VESTIBULAR SYMPTOMS

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: Painsensitive 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
-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

Bereczki et al., 2008

Cao et al., 1999

AND MIGRAINE WITHOUT AURA

Woods et al., 1994

Before sumatriptan
2 to 4 h after the attack onset

After sumatriptan
4 to 6 h after the attack onset

Chalaupka, 2008
Denuelle et al., 2008

MIGRAINE A MULTISYMPTOM COMPLEX

VISUAL SYMPTOMS

PAIN

Sensory, Cognitive,
Motor Symptoms

Cortical
Activation
Brainstem
Activation

Nausea/Vomiting

PAIN

VESTIBULAR SYMPTOMS

MIGRAINE SHOULD BE IN
DIFFERENTIAL DIAGNOSIS
OF ANY EPISODIC
NEUROLOGICAL DISORDER

Do most headache patients need an

imaging study of the brain?

Ill want to get a few tests on you, just to cover my ass

When Dont 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 (HIT6 score 64)

Probable migraine (n=67)

18%
Migraine (n=288)

76%

Episodic tension-type (n=11)

3%
Unclassifiable (n=11)
3%

Adapted from Tepper SJ et al. Headache. 2004;44:856864.

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

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;44:856864.

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 Dont skip meals, mix of different food
groups
SLEEP --- Dont 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

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 NONPRESCRIPTION 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

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 GeneRelated 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*

POTENTIAL NEW THERAPIES FOR

MIGRAINE
INHIBITORS OF CORTICAL SPREADING DEPRESSION
Memantine, Tonabersat, Transcranial Magnestic Stimulation

CIRCULATORY TRIGGERS
TO BRAIN EXCITABILITY?

INHIBITORS OF CGRP RECEPTOR

Telcagepant

PFO Closure

MODULATORS OF CERVICAL
INPUT TO HEADACHE
Occipital Nerve Stimulation

Adapted from Jones HR. Netters Neurology, St. Louis, MO; Saunders; 2005.

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