Migraine

Series Editor
Sid Gilman, M.D., F.R.C.P.
William J. Herdman Professor of Neurology
Chair, Department of Neurology
University of Michigan Medical Center

CONTEMPORARY NEUROLOGY SERIES

19 THE DIAGNOSIS OF STUPOR AND COMA, EDITION 3
Fred Plum, M.D., and Jerome B. Posner, M.D.
45 NEUROLOGIC COMPLICATIONS OF CANCER
Jerome B. Posner, M.D.
48 PAIN MANAGEMENT: THEORY AND PRACTICE
Russell K. Portenoy, M.D., and Ronald M. Kanner, M.D., Editors
50 MULTIPLE SCLEROSIS
Donald W. Paty, M.D., F.R.C.P.C., and George C. Ebers, M.D., F.R.C.P.C., Editors
51 NEUROLOGY AND THE LAW: PRIVATE LITIGATION AND PUBLIC POLICY
H. Richard Beresford, M.D., J.D.
52 SUBARACHNOID HEMORRHAGE: CAUSES AND CURES
Bryce Weir, M.D.
53 SLEEP MEDICINE
Michael S. Aldrich, M.D.
54 BRAIN TUMORS
Harry S. Greenburg, M.D., William F. Chandler, M.D., and Howard M. Sandier, M.D.
55 THE NEUROLOGY OF EYE MOVEMENTS, THIRD EDITION
R. John Leigh, M.D., and David S. Zee, M.D.
56 MYASTHENIA GRAVIS AND MYASTHENIC DISORDERS
Andrew Engel, M.D., Editor
57 NEUROGENETICS
Stefan M. Pulst, M.D., Editor
58 DISEASES OF THE SPINE AND SPINAL CORD
Thomas N. Byrne, M.D., Edward C. Benzel, M.D., and Stephen G. Waxman, M.D., Ph.D.
59 DIAGNOSIS AND MANAGEMENT OF PERIPHERAL NERVE DISORDERS
Jerry R. Mendell, M.D., David R. Cornblath, M.D., and John T. Kissel, M.D.
60 THE NEUROLOGY OF VISION
Jonathan D. Trobe, M.D.
61 HIV NEUROLOGY
Bruce James Brew, M.B.B.S., M.D., F.R.A.C.P.
62 ISCHEMIC CEREBROVASCULAR DISEASE
Harold P. Adams, Jr., M.D., Vladimir Hachinski, M.D., and John W. Norris, M.D., F.R.C.P.
63 CLINICAL NEUROPHYSIOLOGY OF THE VESTIBULAR SYSTEM, THIRD EDITION
Robert W. Baloh, M.D., and Vicente Honrubia, M.D.
64 NEUROLOGIC COMPLICATIONS OF CRITICAL ILLNESS, SECOND EDITION
Eelco F. M. Wrjdicks, M.D., Ph.D., F.A.C.P.
65 MIGRAINE: MANIFESTATIONS, PATHOGENESIS, AND MANAGEMENT,
SECOND EDITION
Robert A. Davidoff, M.D.
MIGRAINE
Manifestations,
Pathogenesis,
and Management
SECOND EDITION

ROBERT A. DAVIDOFF, M.D.

Professor of Neurology, Physiology and Biophysics,
and Molecular and Cellular Pharmacology
University of Miami School of Medicine

Chief, Neurology Service

Veterans Affairs Medical Center
Miami, Florida

OXFORD
UNIVERSITY PRESS
2002
OXFORD
UNIVERSITY PRESS

Oxford New York

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and an associated company in Berlin

Copyright 2002 by Oxford University Press, Inc.

Published by Oxford University Press, Inc.
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http://www.oup-usa.org
Oxford is a registered trademark of Oxford University Press.
All rights reserved. No part of this publication may be reproduced,
stored in a retrieval system, or transmitted, in any form or by any means,
electronic, mechanical, photocopying, recording, or otherwise,
without the prior permission of Oxford University Press.

Library of Congress Cataloging-in-Publication Data

Davidoff, Robert A., 1934-
Migraine : manifestations, pathogenesis, and management /
Robert A. Davidoff.2nd ed.
p. ; cm. (Contemporary neurology series ; 65)
Includes bibliographical references and index.
ISBN 0-19-513705-1
1. Migraine I. Title. II. Series.
[DNLM: 1. Migraine. WL 344 D249m 2002] RC392.D38 2002 616.8'57dc21 2001036606

The science of medicine is a rapidly changing field. As new research and clinical experience broaden our
knowledge, changes in treatment and drug therapy do occur. The author and the publisher of this work
have checked with sources believed to be reliable in their efforts to provide information that is accurate
and complete, and in accordance with the standards accepted at the time of publication. However, in
light of the possibility of human error or changes in the practice of medicine, neither the author, nor the
publisher, nor any other party who has been involved in the preparation or publication of this work
warrants that the information contained herein is in every respect accurate or complete. Readers are
encouraged to confirm the information contained herein with other reliable sources, and are strongly
advised to check the product information sheet provided by the pharmaceutical company for each drug
they plan to administer.

987654321
Printed in the United States of America
on acid-free paper
Preface to the Second Edition
The headache field has changed considerably since the first edition appeared in 1995.
Spurred by development of clinically effective 5-HT1B/1D agonists known as triptans,
new technologies in molecular biology and functional imaging, neuropharmacologic un-
derstanding of nociceptor function and pain pathways, and sophisticated epidemiologic
methodologies for studying large populations, migraine headaches have received pro-
gressively greater attention. An impressive number of refereed publications about mi-
grainebetween 475 and 620now appear yearly. This substantially increased amount
of new information necessitated significant updating of the previous edition. Almost all
sections have been rewritten, thoroughly revised, and expanded to reflect the develop-
ments of the past 7 years.
The first edition of Migraine: Manifestations, Pathogenesis, and Management com-
prised 12 chapters. The updated second edition contains 26. Much of the material in
the new or expanded sections was simply not known in 1995. In particular, new chap-
ters have been added about the genetics of migraine, its hormonal aspects, and the role
cerebral circulation plays in generating and sustaining headaches. The section on treat-
ment has been enlarged from three chapters into separate chapters on analgesics, er-
gots, triptans, and emergency department intervention. New chapters are also devoted
to beta and calcium-channel blockers, antidepressants, anticonvulsants, and antisero-
tonergics. The book's scope has been extended to include individual chapters about the
special problems of women, children, and the elderly. Special attention is also now paid
to the problem of intractable headaches. My aims in this new edition, however, remain
unchanged: to offer insights from both clinical and basic scientific points of view into
the complex biological subject of migraine. As before, the book begins with the epi-
demiology and genetics of migraine, describes migraine's clinical features in all their
variations, considers the basic aspects of migraine's pathophysiology, and offers a con-
temporary approach to managing migraineurs that includes an up-to-date discussion of
how to use pharmaceutical preparations to treat the disorder.
My wife Judith read the entire manuscript, and provided wisdom, generous sup-
port, encouragement, and an exceedingly sharp pen. She maintained her critical ap-
proach to scholarship throughout, and put up with my many imperfections. I owe her
profound thanks and gratitude. She already has my enduring devotion.

Miami, Florida R.A.D.

v
This page intentionally left blank
Preface to the First Edition

I have been intensely interested in the subject of headache for many years. This inter-
est doubtless reflects personal experience. Not only have I been a life-long victim of
migraine, but my wife and both children also suffer with the affliction. For many years
I have skewed my clinical practice toward headache, so that the vast majority of my pri-
vate patients are victims of migraine headaches. I am impressed not only with the in-
tense pain and overall misery that can be caused by migraine, but also by the social,
economic, and emotional morbidity that arise from a chronic disorder that can disable
a patient at any time without warning. It also troubles me that in addition to those who
actively seek treatment, migraine and associated headaches are a daily, weekly, or
monthly fact of life to nameless millions who endure pain and discomfort in silence.
Perhaps in response to the ubiquitous advertisements for over-the-counter preparations
that promise to ease pounding headaches accompanied by upset stomachs, I have the
suspicion that many migraineurs who could be helped instead believe that such head-
aches are a typical part of most people's lives.
Considering that headache pain may be the most common specific symptom for
which patients in the United States seek medical care, it discourages me that the ma-
jority of patients with this disorder receive unsatisfactory and largely inadequate care.
In part, this is a consequence of the relative neglect of the subject until the last 10 or
15 years. In part, it is a function of the great amount of the physician's time and en-
ergy that the care of a patient with migraine requires. Migraine does not fit into the
usual category of "high-tech" medicine practiced today. Most patients with migraine
need few, if any, laboratory or imaging procedures. The average physician is ill-equipped
either by his or her schooling or residency training to cope with patients whose prob-
lems require dialogue, compassion, and understanding rather than laboratory examina-
tions and procedures. Moreover, because migraine is a non-life threatening condition,
the physician can grow frustrated when patients return again and again, having failed
to benefit from attempted treatment. As a result of all these factors, an unfortunate,
but widespread, point of view prevails that migraine is merely a severe type of head-
ache which consumes far more of an active doctor's time than its importance warrants.
On the other hand, I have been heartened by the determined efforts of a variety
of clinical and bench scientists to understand migraine and its pathophysiology. Im-
mense strides have been made in understanding the pathogenesis of pain and the phar-
macology of various drugs which can benefit patients with migraine. Most physicians,
however, have read very little about these new developments. For example, because
the basic research findings on the subject are published in speciality journals or in jour-
nals largely inaccessible to most clinicians, the average neurologist is unaware of the
strides made in understanding head pain and its treatment. As a result, far too many
physicians lack comprehension of the complexities and variabilities of the condition.
The present volume has focused on migraine's myriad variations, its pathophysiol-
ogy, and its treatment. The pages offer insights into the complex biological subject of

VII
viii Preface

migraine from the point of view of an author who suffers from migraine headaches,
lives among a family of migraineurs, and is also a concerned, practicing physician, and
a basic scientist. Underlying much of the book is the idea that the clinical significance
of migraine and its treatment is intelligible only if the physician understands the anatom-
ical, physiological, pharmacological, and psychological factors underlying both head pain
and other manifestations of migraine.
Contents

Part I. Clinical Aspects of Migraine

1. EPIDEMIOLOGY 3
DEFINITION OF MIGRAINE 3
The International Headache Society Criteria Tension-type Headaches and
Migraine as a Continuum
DEMOGRAPHIC CHARACTERISTICS OF MIGRAINE 8
Prevalence of Migraine Migraine with Aura Gender Age
Socioeconomic Status, Intelligence, and Education Race
MIGRAINE IN CHILDREN AND ADOLESCENTS 15
Gender and Age Criteria Prognosis
MIGRAINE PERSONALITY 16
MIGRAINE, REHAVIOR, DISABILITY, AND QUALITY OF LIFE 18
COMORBIDITY 20
Psychiatric Disorders Epilepsy Hypertension Stroke
Raynaud's Phenomenon Mitral Valve Prolapse Systemic Lupus
Erythematosus Allergy Meniere's Disease
SUMMARY 25

2. GENETICS 31
TWIN STUDIES 32
MODE OF INHERITANCE 32
FAMILIAL HEMIPLEGIC MIGRAINE 33
Genetics of Familial Hemiplegic Migraine Voltage-gated Ca2+ Channels
CACNA1A Involvement in Other Neurological Disorders
IS MIGRAINE A CHANNELOPATHY? 36
CADASIL 36
MIGRAINE AND MITOCHONDRIAL DISORDERS 38
MELAS MERFF Ornithine Transcarbamylase Deficiency
HLA ANTIGENS 39
POLYMORPHISMS ASSOCIATED WITH MIGRAINE
SUSCEPTIBILITY 40
SUMMARY 40

IX
x Contents

3. CLINICAL MANIFESTATIONS 44
PHASES OF MIGRAINE ATTACKS 44
MIGRAINE WITHOUT AURA AND MIGRAINE WITH AURA 45
PATTERN OF MIGRAINE ATTACKS 46
PREMONITORY SYMPTOMS (PRODROMES) 47
MIGRAINOUS AURAS 48
Visual Symptoms Perceptual Alterations Non-visual Hallucinations
Somatosensory and Motor Symptoms Vertigo Cognitive and
Communicative Disturbances Combined Aura Symptoms
THE FREE INTERVAL 55
MIGRAINOUS HEAD PAIN 55
Intensity of Head Pain Location of Head Pain Lower-half Migraine
Idiopathic Stabbing Headache
SYMPTOMS ASSOCIATED WITH ATTACKS OF MIGRAINE 59
Photophobia, Phonophobia, and Osmophobia Gastrointestinal Complaints
Autonomic Changes Fluid Retention Neuro-otologic Symptoms
Changes in Emotions, Cognition, and Consciousness Acute Confusional
Migraine Syncope
BEHAVIOR DURING ATTACKS 62
TERMINATION OF ACUTE MIGRAINE ATTACKS AND
POSTDROMIC STATE 63
SUMMARY 63

4. UNUSUAL FORMS OF MIGRAINE, VARIANTS, AND

EQUIVALENTS 68
MIGRAINE AURA WITHOUT HEADACHE 68
COMPLICATED MIGRAINE 69
Migraine with Prolonged Aura Hemiplegic Migraine Basilar Migraine
Retinal Migraine Migrainous Infarction
POST-TRAUMATIC MIGRAINE 76
TRANSFORMED MIGRAINE 77
CLUSTER MIGRAINE 78
STATUS MIGRAINOSUS 78
MIGRAINE EQUIVALENTS AND PUTATIVE MIGRAINE
EQUIVALENTS 79
Migraine-related Vestibulopathy Benign Paroxysmal Vertigo of Childhood
Benign Recurrent Vertigo in Adults Benign Paroxysmal Torticollis in Infancy
Cyclic Vomiting Abdominal Migraine Transient Global Amnesia
Cardiac Migraine
OPHTHALMOPLEGIC MIGRAINE 83
ALTERNATING HEMIPLEGIA OF CHILDHOOD 84
 Contents xi

POSTICTAL HEADACHES 85
SUMMARY 85

5. INITIATORS, PRECIPITATORS, AND TRIGGERS 90

INITIATION OF MIGRAINE 90
PRECIPITATION OF INDIVIDUAL ATTACKS 91
PSYCHOSOCIAL STRESS 93
Types of Stressors Weekend Headaches and Let-down Migraine
DIETARY FACTORS 95
Vasoactive Amines Tyramine Chocolate Caffeine Citrus Fruits
Alcohol Monosodium Glutamate Nitrites Artificial Sweeteners
ALLERGY 102
HUNGER AND HYPOGLYCEMIA 102
SLEEP 104
EXERTION 104
Sexual Activity
PHYSICAL AND ENVIRONMENTAL FACTORS 105
Seasonal Factors and Changes in Weather Visual Stimuli Auditory Stimuli
Motion and Motion Sickness Olfactory Stimuli Smoking Ice Cream
Headache
HYPERSENSITIVITY TO ENVIRONMENTAL FACTORS 107
PRESCRIPTION DRUGS 108
ILLICIT DRUGS 109
TRAUMA-TRIGGERED MIGRAINE 109
DISORDERS OF THE NECK 109
Myofascial Trigger Points Extension-flexion (Whiplash) Injury
MEDICAL CONDITIONS 112
Chronic Fatigue Syndrome/Fibromyalgia Acquired Immunodeficiency
Syndrome Dialysis Platelet Disorders Eyestrain
SUMMARY 113

6. HORMONES 120
MENARCHE 120
MENSTRUATION 120
Premenstrual Syndromes and Menstrual Difficulties Menstrual Migraine
Menstrual Cycle Modulation of Pain Endocrinology of the Menstrual Cycle
Effects of Ovarian Hormones and Neurosteroids on the Brain and Vasculature
ORAL CONTRACEPTIVES 133
PREGNANCY 136
DELIVERY 136
xii Contents

LACTATION 136
Endocrinology of Lactation Migraine and Lactation
MENOPAUSE AND POSTMENOPAUSE 138
SUMMARY 140

7. EXAMINATION AND INVESTIGATION OF THE MIGRAINEUR 145

THE MIGRAINE HISTORY 147
CLINICAL EXAMINATION OF THE PATIENT WITH MIGRAINE 149
Interictal Examination Ictal Examination
IMAGING PROCEDURES 150
Computed Tomographic Scans Magnetic Resonance Imaging
ELECTROPHYSIOLOGICAL STUDIES 153
Electroencephalograms Visual Evoked Potentials The EEG and Visual
Evoked Potentials in the Evaluation of Patients with Migraine Somatosensory
and Auditory Evoked Potentials Event-related Potentials Habituation of
Evoked and Event-related Potentials
OTHER DIAGNOSTIC TESTS 156
Thermography Angiography Lumbar Puncture Neuropsychologic
Testing
SUMMARY 158

8. DIFFERENTIAL DIAGNOSIS 163

TENSION-TYPE HEADACHE 164
CLUSTER HEADACHE 167
Paroxysmal Hemicrania Hemicrania Continua
HEADACHES OF CERVICAL ORIGIN 169
Occipital Neuralgia and Related Problems
TEMPOROMANDIBULAR JOINT DYSFUNCTION 171
UNRUPTURED ARTERIOVENOUS MALFORMATIONS AND
MIGRAINOUS AURAS 172
EXPANDING INTRACRANIAL LESIONS 172
GIANT CELL ARTERITIS 173
TRIGEMINAL NEURALGIA 174
IDIOPATHIC INTRACRANIAL HYPERTENSION 174
LOW CEREBROSPINAL FLUID PRESSURE 175
HEADACHE WITH CEREBROSPINAL FLUID PLEOCYTOSIS 176
OPHTHALMOLOGICAL HEADACHES 176
SINUSITIS 177
HYPERTENSION 178
 Contents xiii

PHEOCHROMOCYTOMA 178
HEADACHES AS EMERGENCIES 178
Headaches Associated with Aneurysms and Arteriovenous Malformations
Thunderclap Headaches and Crash Migraine Headaches Associated with
Ischemic and Hemorrhagic Vascular Disease Carotid and Vertebral Artery
Dissection Toxic Vascular Headaches Headaches Secondary to
Meningeal Infection
SUMMARY 182

Part II. Pathophysiology

9. THE PRODROME AND THE AURA 189

PRODROMES 189
THE WOLFF HYPOTHESIS AND THE PRIMARY NEURONAL
HYPOTHESIS 190
CEREBRAL BLOOD FLOW 191
XENON (133XE) METHODS 191
INTERICTAL CEREBRAL BLOOD FLOW MEASUREMENTS 192
CHANGES IN CEREBRAL BLOOD FLOW DURING THE AURA 192
SERIAL REGIONAL CEREBRAL BLOOD FLOW
MEASUREMENTS 192
SPREADING DEPRESSION 196
Cerebral Blood Flow and Spreading Depression Mechanism of
Spreading Depression
MAGNETOENCEPHALOGRAPHY 198
POSITRON EMISSION TOMOGRAPHY 198
FUNCTIONAL MAGNETIC RESONANCE IMAGING 199
THE SPREADING DEPRESSION HYPOTHESIS AND MIGRAINE 201
CLINICAL OBSERVATIONS: AURAS AND CEREBRAL ISCHEMIA 202
SUMMARY 203
10. CONTROL OF THE CEREBRAL CIRCULATION 207
SYMPATHETIC INNERVATION 208
PARASYMPATHETIC INNERVATION 209
Cholinergic Parasympathetic Nerves Nitric Oxidean Atypical
Modulator/Transmitterand Parasympathetic Nerves Vasoactive
Intestinal Polypeptide
TRIGEMINOVASCULAR FIBERS AND CEREBRAL BLOOD
FLOW REGULATION 211
BRAIN STEM EFFECTS ON THE CRANIAL CIRCULATION 212
Locus Coeruleus Raphe Nuclei Serotonin Receptors Serotonin and
Intracranial Blood Vessels Brain Stem Activity and Migraine
xiv Contents

BASAL NUCLEUS 216

ENDOTHELIAL CONTROL OF CEREBRAL VESSELS 216
Nitric Oxide Arachidonic Acid Metabolites Endothelins
NITRIC OXIDE AND NEURONS 221
Nitric Oxide and Spreading Depression
OTHER FACTORS REGULATING CEREBRAL BLOOD FLOW 221
Protons and Carbon Dioxide Bradykinin Histamine Adenosine
SUMMARY 223

11. HEAD PAIN AND ASSOCIATED SYMPTOMS 228

LOCUS OF MIGRAINE PAIN 229
INTRACRANIAL SOURCES OF MIGRAINE PAIN 229
AFFERENT TRIGEMINAL AND CERVICAL SYSTEMS
(THE TRIGEMINOCERVICAL SYSTEM) 231
CENTRAL TERMINATIONS OF AFFERENT FIBERS 233
THALAMIC, SUBCORTICAL, AND CORTICAL PROJECTIONS 235
REFERRED PAIN 236
AFFERENT TRANSMITTERS 238
THREE THEORIES OF THE SOURCE OF MIGRAINOUS
HEAD PAIN 239
DILATATION OF PROXIMAL PARTS OF LARGE CEREBRAL
VESSELS 240
CEREBRAL BLOOD FLOW DURING MIGRAINOUS HEAD PAIN 241
NEUROGENIC INFLAMMATION AND VASCULAR PAIN 242
Neuropeptide Actions During Neurogenic Inflammation Neurogenic
Inflammation and Migraine
ACTIVATION OF THE TRIGEMINOVASCULAR SYSTEM AND
MIGRAINE ATTACKS 244
ACTIVATION OF NOCICEPTORS 247
Histamine Arachidonic Acid and Metabolites Bradykinin Serotonin
Protons Nerve Growth Factor Endothelins
NEURAL MECHANISMS OF MAINTAINED PAIN:
PERIPHERAL SENSITIZATION 253
NEURAL MECHANISMS OF MAINTAINED PAIN: CENTRAL
SENSITIZATION 253
ENDOGENOUS PAIN-MODULATING SYSTEMS 255
Periaqueductal Gray On- and Off-cells Monoamines and Nociception
Opioid Peptides Endorphins and Migraine
CENTRAL ACTIVATION OF PAIN-MODULATING SYSTEMS 260
NAUSEA AND VOMITING 262
 Contents xv

PHOTOPHOBIA 263
SUMMARY 263

12. THE SEROTONIN HYPOTHESIS AND OTHER THEORIES 274

CEREBRAL HYPEREXCITABILITY 274
SEROTONIN AND THE INITIATION OF MIGRAINE ATTACKS 275
Location of Serotonin Normal Platelet Function Platelet Activation,
Serotonin Metabolism, and Migraine Serotonin and Migraine
DOPAMINE HYPOTHESIS 283
MAGNESIUM 284
DECREASED MITOCHONDRIAL ENERGY RESERVE 285
THE SYMPATHETIC DYSFUNCTION THEORY 285
SUMMARY 286

Part III. Management of Acute Attacks

13. TRIGGER FACTORS AND NON-PHARMACOLOGICAL

APPROACHES 293
COMPLIANCE 295
THE PLACEBO RESPONSE 296
EVIDENCE-BASED MEDICINE 297
THE ROLE OF THE INTERNET, THE MEDIA, AND NATIONAL
ORGANIZATIONS 298
MANAGEMENT OF MIGRAINEURS 299
AVOIDANCE OF TRIGGER FACTORS 300
Headache Diary Dietary Changes Sleep and Eating Patterns
Discontinuation of Smoking Medications and Hormones Physical and
Environmental Factors
BEHAVIORAL TREATMENTS 303
Biofeedback Relaxation Therapy Cognitive-behavioral Training
Psychotherapy
OTHER NON-PHARMACOLOGICAL STRATEGIES 306
Exercise Physical Therapy and Modalities Ophthalmological Factors
Occlusal Adjustment Alternative/Unconventional Migraine Therapies
Hypnosis Acupuncture Transcutaneous Electrical Stimulation
Chiropractic
HERBAL REMEDIES 309
SUMMARY 309

14. ANTI-EMETICS, ANALGESICS, BARBITURATES,

AND OPIATES 314
ANCILLARY INTERVENTIONS 316
xvi Contents

HEADACHE RECURRENCE 316

CHOICE OF ANTI-MIGRAINE MEDICATION 316
Side Effects
RESCUE THERAPY 320
COST CONSIDERATIONS 320
MEDICATION OVERUSE 320
ANTI-EMETICS/PROKINETIC MEDICATIONS 321
ASPIRIN AND ACETAMINOPHEN 323
Side Effects and Contraindications
CAFFEINE 325
OTHER NON-STEROIDAL ANTI-INFLAMMATORY AGENTS 325
Side Effects Contraindications
BUTALBITAL-CONTAINING ANALGESIC DRUGS 327
Side Effects and Contraindications
ISOMETHEPTENE MUCATE 329
Side Effects and Contraindications
OPIOIDS/NARCOTICS 329
Side Effects
CORTICOSTEROIDS 331
MAGNESIUM 331
MECHANISMS OF ACTION OF MEDICATIONS FOR ACUTE
MIGRAINE ATTACKS 332
Anti-emetics Aspirin, Non-steroidal Anti-inflammatory Drugs, and
Acetaminophen Butalbital Opioids
SUMMARY 335
15. ERGOTS 339
ERGOTAMINE 339
Metabolism Pharmacokinetics and Clinical Use of Ergotamine
Ergotamine for Migraine with Aura, Migraine with Prolonged Aura, and
Complicated Migraine Adverse Reactions Contraindications
Ergotamine Overuse
DIHYDROERGOTAMINE 344
Pharmacokinetics and Metabolism Clinical Use of Dihydroergotamine
Adverse Events Contraindications
SUMMARY 346
16. TRIPTANS 349
SUMATRIPTAN 351
Subcutaneous Sumatriptan Oral Sumatriptan Intranasal Sumatriptan
SECOND-GENERATION TRIPTANS: TRIALS AND
COMPARATIVE TRIALS 354
HEADACHE RECURRENCE 357
 Contents xvii

ADVERSE SYMPTOMS 358

CHEST, NECK, AND THROAT SYMPTOMS 359
Serious Adverse Cardiac Events Actions on Coronary Circulation
CONTRAINDICATIONS 362
METABOLISM AND ITS CONSEQUENCES 362
COMPARISONS WITH OTHER TREATMENTS 363
EFFICACY AND LONG-TERM TRIPTAN USE 364
TRIPTAN OVERUSE 364
CLINICAL USE OF TRIPTANS 364
SUMMARY 366

17. MECHANISM OF ACTION OF ERGOTS AND TRIPTANS 373

ACTIVATION OF SEROTONIN RECEPTORS 373
PUTATIVE SITES OF ACTION 374
Prejunctional (Presynaptic) Inhibitory Effects on Trigeminovascular Fibers
Prejunctional 5-HT Receptor Subtypes Vasoconstriction of Intracranial
Arteries Vascular Locus of Action Vascular 5-HT Receptor Subtypes
Brain Stem/Spinal Cord Sites of Action
SUMMARY 380

18. EMERGENCY DEPARTMENT TREATMENT 385

NARCOTICS 387
TRIPTANS 387
DIHYDROERGOTAMINE 388
PHENOTHIAZINES, HALOPERIDOL, AND METOCLOPRAMIDE 388
PARENTERAL KETEROLAC 389
CORTICOSTEROIDS 389
OTHER MEDICATIONS 389
SUMMARY 389

Part IV. Prophylaxis

19. OVERVIEW OF INDICATIONS AND GUIDELINES 395

CRITERIA 395
DRUG EFFICACY 396
EFFICACY: INDIVIDUAL PATIENTS 397
PROPHYLACTIC AGENTS: OVERVIEW 397
SUMMARY 400
xviii Contents

20. /3-BLOCKERS AND CALCIUM-CHANNEL BLOCKERS 402

-ADRENERGIC RECEPTOR ANTAGONISTS ( -BLOCKERS) 402
Adrenergic Receptors Pharmacokinetics Guidelines for Use of
Propranolol Effectiveness of Propranolol Use of Other -Blockers
Side Effects Contraindications Mechanism of Action of -Blockers
CALCIUM-CHANNEL BLOCKERS 407
Side Effects Contraindications Verapamil Nifedipine and
Nimodipine Diltiazem Flunarazine Amlodipine Mechanism of
Action of Calcium-channel Blockers
SUMMARY 411

21. ANTIDEPRESSANTS 415

TRICYCLIC ANTIDEPRESSANTS 415
Guidelines Side Effects Contraindications
MONOAMINE OXIDASE INHIBITORS 419
Guidelines, Precautions, and Contraindications Side Effects Combined
Use of Monoamine Oxidase Inhibitors and Tricyclic Antidepressants
SELECTIVE SEROTONIN REUPTAKE INHIBITORS 422
MECHANISMS OF ACTION 422
SUMMARY 424

22. ANTICONVULSANTS 426

VALPROATE 426
Guidelines Side Effects Contraindications
GABAPENTIN 429
Guidelines Side Effects
TOPIRAMATE 429
LAMOTRIGINE 430
MECHANISMS OF ACTION 430
SUMMARY 431

23. ANTISEROTONERGICS, NON-STEROIDAL

ANTI-INFLAMMATORY DRUGS, AND
MISCELLANEOUS MEDICATIONS 434
METHYSERGIDE 434
Guidelines Side Effects Fibrotic Disorders Contraindications
METHYLERGONOVINE 437
PIZOTIFEN 437
CYPROHEPTADINE 438
MECHANISMS OF ACTION OF ANTISEROTONERGICS 438
 Contents xix

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS 439

Side Effects Contraindications
LITHIUM 440
Guidelines Side Effects Contraindications Mechanisms of Action
MISCELLANEOUS PROPHYLACTIC TREATMENTS 442
Magnesium Riboflavin Botulinum Toxin Other Medications
SUMMARY 443

Part V. Special Topics

24. MIGRAINE IN WOMEN 449

MIGRAINE ASSOCIATED WITH MENSTRUATION 449
Therapy for Acute Attacks Preventative Medications Behavioral Therapy
Hormonal Therapy Treatment of Premenstrual Syndromes
ORAL CONTRACEPTIVES 452
THE PREGNANT MIGRAINEUR 454
Acute Migraine Attacks Prophylactic Medication
THE NURSING MIGRAINEUR 457
Pharmacokinetics Acute Migraine Attacks Prophylactic Medication
THE POSTMENOPAUSAL MIGRAINEUR 459
SUMMARY 460

25. INTRACTABLE HEADACHES AND MEDICATION OVERUSE 464

EXCESSIVE USE OF ANTI-MIGRAINE MEDICATION 464
Prevention of Drug-induced Headache Treatment Medications During
and After Withdrawal Success Rate After Medication Withdrawal
STATUS MIGRAINOSUS 469
Treatment
CHRONIC INTRACTABLE HEADACHES 470
SUMMARY 472

26. MIGRAINE IN CHILDREN AND THE ELDERLY 474

MIGRAINE IN CHILDREN 474
Acute Attacks Prophylactic Therapy Analgesic Rebound Headaches
Behavioral Therapy Migraine Equivalents
MIGRAINE IN THE ELDERLY 478
Guidelines Acute Attacks Prophylactic Therapy
SUMMARY 483

27. AFTERWORD 486

INDEX 491
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PART I

CLINICAL ASPECTS
OF MIGRAINE
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Chapter 1
Epidemiology
DEFINITION OF MIGRAINE
The International Headache Society
Criteria
Tension-type Headaches and Migraine as
a Continuum
DEMOGRAPHIC CHARACTERISTICS OF
MIGRAINE
Prevalence of Migraine
Migraine with Aura
Gender
Age
Socioeconomic Status, Intelligence, and
Education
Race
MIGRAINE IN CHILDREN AND
ADOLESCENTS
Gender and Age
DEFINITION OF MIGRAINE
What is migraine? Ideally, before we diagnose,
study, or try to understand migraine, it should
be accurately described. And yet, despite vo-
luminous publications, there is no totally satis-
factory definition with precise nomenclature.
The lack stems, in large measure, from a pri-
mary dependence upon clinical observations.
There is no biological marker for migraine. Un-
til recently, delineating it was the domain of
neurologists, internists, and other medical
practitioners who elicited histories about pat-
terns of head pain and associated symptoms
from patients who complained of headache.
The problem was that when clinicians describe
migraine they tend to cite typical attacks. But
migraine is a protean disorder, one whose at-
tacks not only vary markedly among individu-
Criteria
Prognosis
MIGRAINE PERSONALITY
MIGRAINE, BEHAVIOR, DISABILITY,
AND QUALITY OF LIFE
COMORBIDITY
Psychiatric Disorders
Epilepsy
Hypertension
Stroke
Raynaud's Phenomenon
Mitral Valve Prolapse
Systemic Lupus Erythematosus
Allergy
Meniere's Disease
SUMMARY
als but even in one person, whose particular
symptoms may occur in one attack, but not in
another, and whose characteristics are rarely
stable over a lifetime. Thus, when textbooks of-
fer clinical descriptions of representative bouts
of headache, they fail to convey migraine's
subtleand not so subtlevariations. Clini-
cally based accounts also suffer in that they are
drawn largely from patients self-selected by
virtue of their having sought medical attention.
This latter limitation is changing as data be-
come available from studies of the general
population.
Many formal studies of migraine have fo-
cused largely on patients chosen because they
conform to preconceived ideas about various
headache types. Research limited in this way
perpetuates existing biases in definition and di-
agnosis. The situation is made worse because
3
4 Clinical Aspects of Migraine

a number of older definitions are so stringent the World Federation of Neurology offered a
that they limit migraine to what would usually definition whose similarity to that of the Ad
be designated as "classic" migraine. Newer def- Hoc Committee is inescapable.206
initions are fuller and more accurate, but they,
[Migraine is] a familial disorder characterized by re-
too, adhere to stringent criteria, and so they current attacks of headache widely variable in in-
continue to exclude many patients who might tensity, frequency and duration. Attacks are com-
be reasonably diagnosed with migraine. monly unilateral and are usually associated with
To counteract these stringent criteria, some anorexia, nausea and vomiting. In some cases they
older authorities so expanded the concept of are preceded by, or associated with, neurological
migraine that nearly any recurrent, severe, in- and mood disturbances.
capacitating headache was included in the def-
Both the 1962 and the 1970 undertakings
inition. But because many of these "inclusive"
represented a considerable step forward in
definitions focused only on severe attacks, they
defining migraine, and were used for years by
omitted attacks with moderate levels of head
many who study headache. However, defini-
pain and minimal or modest activity limitations.
tions formulated solely by a consensus of sea-
Again, variations from person to person were
soned, expert clinicians whose opinions were
ignored, as were variations from mild-to-mod-
based on the limited proportion of the general
erate pain without impairment on one extreme
population that sought treatment in specialized
and intense pain with severe functional dis-
headache clinics are intrinsically unsatisfactory
ability on the other. It is quite conceivable that
because they offer short descriptions of char-
some of the "ordinary" headaches that almost
acteristic cases rather than precise definitions.
every person suffers from time to time, and at
They have been criticized as anecdotally de-
varying levels of intensity, are migrainous. Sur-
rived.14'27 Precise, unambiguous definitions
veys in the general population indicate that
would not include phrases like "commonly uni-
headaches with at least some characteristics as-
lateral," "usually associated with anorexia, nau-
sociated with migraine occur in a notable pro-
sea and vomiting," and "in some are preceded
portion of individuals.70'89 The many commer-
by a warning." Either of the two definitions is
cials for over-the-counter analgesics also testify
adequate to diagnose a case of migraine that
to a considerable market for products that re-
has all of the "characteristic" features, but fails
lieve "headache with upset stomach" for those
to address symptoms suffered by migraineurs
who are not impaired enough to seek medical
who have less typical patterns of head pain. Nor
intervention.
do the definitions provide specific criteria that
In 1962, the Ad Hoc Committee on Classi-
would allow the same patient to receive a reli-
fication of Headache, supported by the Na-
able diagnosis of migraine from different physi-
tional Institute of Neurological Diseases and
cians. And because they emphasize three
Blindness, made an attempt to inject order into
specific features generally attributed to
the subject of headache disorders.1 Their clas-
migrainewarning signs of impending head-
sification used clinical symptomatology to pro- ache, unilateral head pain, and nausea and
vide general categorizing guidelines. The com- vomiting, which, as we shall see in subsequent
mittee defined Vascular Headache of Migraine
chapters, are not invariably present in attacks
Type as
of migrainethese definitions are often inad-
recurrent attacks of headache, widely varied in in- equate to determine if a particular patient does
tensity, frequency, and duration. The attacks are or does not have migraine.
commonly unilateral in onset; are usually associated
with anorexia and, sometimes, with nausea and vom-
iting; in some are preceded by, or associated with,
conspicuous sensory, motor, and mood distur-
The International Headache
bances; and are often familial. Society Criteria
An additional purpose for the Ad Hoc Com- In 1988, the Headache Classification Commit-
mittee's classification criteria was to further tee of the International Headache Society
controlled research into the differential diag- (IHS) published an extensive classification
nosis and treatment of headache. In 1970, the scheme for various migraine syndromes and a
Research Group on Migraine and Headache of large number of other types of headaches.73

Table 1-1. Classification of Migraine
1. MIGRAINE
1.1 Migraine without aura
1.2 Migraine with aura
1.3 Ophthalmoplegic migraine
1.4 Retinal migraine
1.5 Childhood periodic syndromes that may be
precursors to or associated with migraine
1.6 Complications of migraine
1.7 Migrainous disorder not fulfilling above
criteria
From the Headache Classification Committee of the In-
ternational Headache Society.73
Their definitions were more precise than pre-
vious ones. According to this system, migraine
headaches are divided into seven subtypes
(Table 1-1). The first two types make up the
vast majority of cases of migraine: (1.1) mi-
graine without aura (formerly known as com-
mon migraine] and (1.2) migraine with aura
(formerly known as classic migraine). Attri-
butes judged to be the optimum indicators of
a migrainous headache are specified, as well as
the ones which must be present if the head-
ache is to be judged migrainous. The scheme
stipulates that a certain aggregate of charac-
teristic features must be present to establish a
diagnosis. These features include recurrence of
attacks; limited duration of each attack (from
4 to 72 hours); pain that has a unilateral loca-
tion, a pulsating quality, an intensity sufficient
to disrupt daily activities, and a sensitivity to
routine physical activities; and an association
with nausea, vomiting, photophobia, and pho-
nophobia (see Chapter 3). The criteria do not
contain equivocal terms such as "often," "usu-
ally," or "mostly." This system has the distinct
advantage that all definitions and diagnostic
criteria are operational and use information ac-
cessible to the practicing physician. The diag-
nosis of primary headache disorders rests pri-
marily upon clinical analysis and assessment of
symptoms, signs, and clinical course. Diagno-
sis by means of the IHS criteria thus depends
largely upon a headache history, and upon the
exclusion of secondary causes of headache by
means of physical and neurologic examinations
and any necessary laboratory investigations.
Laboratory studies are not used to support the
diagnosis directly.
Epidemiology 5
The IHS classification system has gained
broad acceptance. It represents an important
advance toward making headache diagnosis
more objective and is seen as a distinct im-
provement over past efforts at classification of
headaches. A number of reports have sup-
ported both its utility and validity.107'146 Re-
cent investigations have shown that the IHS
classification is a suitable tool for describing
headache in the general population.107'148 Re-
searchers using the IHS criteria are now capa-
ble of isolating a group of headache sufferers
with typical migraine, and can be reasonably
sure that these individuals represent a homo-
geneous (at least from a clinical point of view)
collection of patients who can be used for study
purposes.112
But operational criteria given for each head-
ache syndrome in this and all such classifica-
tion schema are liable either to be excessively
narrow (and suffer from unsubstantiated ex-
clusions) or, in the interests of including every-
thing, too broad (and suffer from erroneous in-
clusions). Because there is no biological marker
for migraine, diagnoses inevitably consist of
"typical combinations" of symptoms that fit
roughly into preconceived presumptions of the
working party or committee that issues the re-
sults of their deliberations. When symptoms
occur on a continuum, there is always subjec-
tivity in deciding where to "make the cut." This
also applies to decisions about which symptoms
grouped together are "in" and which are "out."
In other words, all definitional categories, no
matter how carefully drawn, are arbitrary in
some respects. As a result, analyses of data ob-
tained from population-based surveys have var-
ied as to the proportion of headache sufferers
in the study that could clearly be assigned
to a particular IHS headache diagnostic cate-
gory and the proportion that could
not 70,75,143,146,148
The IHS criteria were developed mainly for
research purposes, and have been used in vir-
tually all clinical drug trials and in most other
research on headache disorders since 1988.
Classification criteria such as the IHS criteria
work best in the study of groups of patients,
and work less well in the evaluation of indi-
vidual patients. In clinical settings, it is fre-
quently difficult to assign a single IHS diagno-
sis because the migraine definitions specify
only typical, homogeneous headache syn-
dromes, when in fact many transitional types
6 Clinical Aspects of Migraine

The criteria are also cumbersome in ordi-

Figure 1-1. The number of IHS diagnoses required to
classify headaches in 400 patients attending a headache
clinic. Dx, diagnoses. (Adapted from Sanin LC, Mathew
NT, Bellmeyer LR, and Ali S: The International Headache
Society (IHS) headache classification as applied to a head-
ache clinic population. Cepha-lalgia 14:443-446, 1994,
with permission of Blackwell Science Ltd.)
of headaches have migrainous features, but
may or may not be migrainous (Fig. 1-1 ).109>16
There is a tendency for the manifestations of
headaches to change across the lifespan of a
person. The IHS classification is designed only
to classify individual attacks, and does not take
into consideration the natural history or evolu-
tion of migraine over a period of time.
nary clinical practice, particularly when three
or four different diagnoses have to be given to
classify all the types of headaches in a specific
patient. A high proportion of patients attend-
ing headache clinics or hospital-based head-
ache referral centersespecially patients with
a chronic daily headacherequire multiple di-
agnoses.94'97'!09'162'173 when ^6 headaches of
these patients can be classified at all, they are
usually categorized as chronic tension-type
headaches. But such a diagnosis is inappropri-
ate when, as is often the case, the headaches
have evolved from episodic migraine. Thus the
many individuals who initially suffer from oc-
casional bouts of migraine, but also suffer from
mild, interictal headaches that ultimately
evolve into a chronic daily headache, do not fit
easily into the classification. In addition, the
criteria are sufficiently inflexible that some pa-
tients with migraine do not meet the criteria
even though they respond to anti-migraine
therapy (Fig. 1-2). In sum, meeting classifica-
tion criteria is not always equivalent to diag-
nosing an individual patient.
Because of all these definitional difficulties,
ways to revise the criteria have been proposed,
but whatever its limitations, the IHS system is
now accepted as a noteworthy improvement in
headache classification.139'168'173 It continues
to furnish the best diagnostic standard pres-

Figure 1-2. Venn diagram illustrating the relationships between self-reports of lifetime migraine, self-reports of
physician-diagnosed migraine, and migraine diagnosed by IHS criteria. The information was obtained from Canadian pa-
tients by means of a questionnaire developed for computer-assisted telephone interviewing. Note the small overlap be-
tween doctor-diagnosed migraine and migraine diagnosed by IHS criteria. (Adapted from O'Brien B, Goeree R, and
Streiner D: Prevalence of migraine headache in Canada: a population-based survey. Int J Epidemiol 23:1020-1026, 1994,
with permission of Oxford University Press.)

ently available to both the investigator and clin-
ician. The present monograph uses the termi-
nology of the IHS system whenever possible.
Older terms appear when they are appropriate
and still in general use.
Tension-type Headaches and
Migraine as a Continuum
Alternatives to a strict classification scheme
have been proposed for many years so as to un-
derstand the relationship between migraine and
tension-type headaches. Traditionally, migraine
and tension-type headaches (formerly tension
headaches, muscle contraction headaches) have
been considered distinct entities. Most early
classifications focused on symptoms supposedly
specific to the vasculature in migraine head-
aches and to the musculature in tension-type
headaches in order to differentiate these two
types. Although now regarded as inaccurate,
most clinicians are comfortable with this di-
chotomy and continue to regard migraine and
tension-type headaches as separate, indepen-
dent clinical entities with vascular and muscu-
lar mechanisms, respectively. The IHS classifi-
cation has formalized this distinction. Some
epidemiologists and many clinicians, however,
are skeptical about attempts to distinguish the
two headache categories because there are sev-
eral problems with differentiating them:
1. Neither factor analysis of adult and child
migraineurs' responses to detailed question-
naires nor analyses of headache clinic patients'
symptoms have generated any one cluster of
symptoms or set of variables frequently or
strongly deemed characteristic of migraine
headaches.48'49'52'193-212'213 Most of the clinical
variables customarily believed to distinguish
migraine from other types of recurrent head-
ache, such as nausea and vomiting, unilateral
head pain, visual symptoms before a headache,
and response to ergots, do not cluster together
in a population of individuals with severe head-
aches.
2. Excessive muscle contraction does not
play a critical role in tension-type headache. A
number of investigations have failed to dem-
onstrate either a consistent increase in muscle
tension or a correlation of muscle tension with
the severity of head pain in patients with this
complaint. >69 In sum, the balance of evidence
Epidemiology 7
does not favor muscular hypotheses in the gen-
esis of tension-type headaches.
3. Muscle tenderness and muscle pain are
at least as prominent in migraine as they are in
tension-type headache. Tenderness of pericra-
nial muscles is a common finding in tension-
type headache, but is also seen in patients
during bouts of migraine.51'56'78'161 Between
attacks, migraine patients often have tender
pericranial muscles.
4. Over the course of many attacks, symp-
toms claimed to characterize migraine head-
aches commonly coexist with symptoms
ordinarily associated with tension-type head-
aches.32'125 In fact, several authorities stress
the point that both migrainous and tension-
type headaches can occur during a particular
attack.125-185
5. A large number of patients with migraine
have tension-type headaches between their
attacks of migraine.77'125 These tension-type
headaches were previously called interval
headaches. Substantial numbers (possibly more
than 80%) of patients in random populations
have alternating migraine and tension-type
headache.146'148'178
6. Patients diagnosed as having tension-type
headaches by IHS criteria may have symptoms
commonly ascribed to migraine: namely, a
throbbing component of the head pain, nau-
sea, phonophobia, and photophobia. >146 These
symptoms are most common in severe attacks
of tension-type headache.
7. Finally, individuals with headaches that
meet all but one of the four IHS criteria (num-
ber of attacks, duration of attacks, quality of
pain, associated symptoms) required for the di-
agnosis of migraine are commonly seen in clin-
ical practice. This group of patients is some-
times referred to as migraine minus one
(borderline migraine, probable migraine) and
designated in the IHS classification as suffer-
ing from migrainous disorder. The prevalence
of migrainous disorder in the adult population
has been estimated to range between 2.5% and
16%.70>75 Pediatric patients also exhibit head-
aches with characteristics that would be classi-
fied as migrainous disorder.66'72'208 Migrainous
disorder headaches are variable in their clini-
cal presentation, and are less frequently asso-
ciated with the symptoms of nausea, vomiting,
and photophobia and less likely to be unilat-
eral than are headaches that fulfill all of the cri-
teria for migraine without aura. In addition,
8 Clinical Aspects of Migraine
Figure 1-3. The continuum of benign recurring headache from tension-type to classic migraine. (Adapted from Raskin
NH: Headache, 2nd ed. Churchill Livingstone, New York, 1988, with permission.)
migrainous disorder in adults is equally dis-
tributed by gender, a situation different from
the female preponderance of migraine. Some
feel that most migraine-minus-one patients
actually have tension-type headaches. Many
clinicians feel, however, that such patients have
migraine and should be treated in a manner
similar to that for migraineurs.
Data from a number of clinical and population-
based, descriptive studies, as well as from studies
that used varying statistical approaches, have
led several groups of researchers to question
whether migraine and tension headaches are dis-
crete headache entities at all.48'49'56'163'199'212'213
Instead, a number of investigators have con-
centrated on the severity of headache rather
than on a classification scheme that employs
separate categories with defined configurations
of symptoms.8'32'56'197 According to this con-
ception, migraine is considered one extreme in
a nosologic spectrum of headache ranging from
mild to severe and disabling (Fig. 1-3).85'95
When headache types are distinguished by the
level of attack severity rather than by any
unique constellation of symptoms, the symp-
toms associated with more severe, more
painful, and longer-duration headaches tend to
be those that traditionally characterize mi-
graine.32'199 One finds, for example, a positive
linear relationship between the severity of
headache and the number of symptoms gen-
erally accepted as migrainous. Thus, there may
be a continuum of headache symptoms rather
than discrete, identifiable, definable headache
types. In other words, idiopathic headaches
may constitute an affliction with a multiplicity
of symptoms that can occur in different com-
binations varying in severity.
Much current epidemiologic investigation
presupposes that migraine is a distinct disor-
der. If the continuum concept is valid, con-
temporary literature on migraine has largely
examined one end of a distribution of severity
rather than a clear-cut category of headache.
DEMOGRAPHIC
CHARACTERISTICS OF
MIGRAINE
Epidemiologic studies ascertain the distribu-
tion and correlates of headache-related phe-
nomena in populations to help identify partic-
ular headache syndromes. Such studies can
also suggest possible causes. Many of our pres-
ent conceptions of migraine, and of its rela-
tionships to other neurological and medical
afflictions, are based an extensive body of
epidemiologic literature. The investigations are
difficult to summarize, however, because their
findings are often inconsistent. Despite data
from more than 60 population-based studies,
one still has difficulties extracting precise epi-
demiologic information about how prevalent
migraine is. The following methodological ob-
stacles have impeded investigations of mi-
graine:
1. No objective pathology.
2. Lack of a diagnostic test. Although a
number of laboratory findings (abnormal
platelet aggregation, changes in platelet en-
zyme content, alterations in cerebral blood
flow, modifications in evoked potentials) have
been described in patients with migraine, none
are sufficiently precise to serve as biological
 Epidemiology 9

Figure 14. Diagnoses made by health-care providers (e.g., general practitioners, neurologists, ophthalmologists, oto-
laryngologists, pediatricians) for 414 patients who were then found by a headache specialist to have migraine or tension-
type headache. The headache specialists used IHS criteria to establish the diagnoses. Note the low rate of correct diag-
noses made by non-specialist physicicans. (Adapted from Vincent MB, de Carvalho JJ, and the Brazilian Headache Care
Cooperative Group: Primary headache care delivery by non-specialists in Brazil. Cephalalgia 19:520-524, 1999, with per-
mission of Blackwell Science Ltd.)

markers. Patients with migraine show no in-
variable physical signs and no diagnostic radi-
ologic or chemical abnormalities. In other
words, no objective tests can be used to con-
firm the diagnosis of migraine.
3. Differences in populations studied. Most
early studies of migraine included only those
individuals who sought treatment from physi-
cians or headache clinics. This was a skewed
population: in Denmark where epidemiologic
studies are frequent, only 56% of migraine pa-
tients visit a physician.14'' In the United States
as many as 50% of migraineurs have never even
consulted a physician, and fewer than 15% ever
consult a neurologist.91'92 It has been estimated
that 71% of male and 59% of female mi-
graineurs in the United States have never been
diagnosed by a physician as having migraine.92
Only 15% to 30% of active migraine sufferers
see a doctor each year.93'175 In addition, cor-
rect diagnoses are made by non-specialists in
only a minority of cases (Fig. 1-4). Although
the reasons for seeking, or failing to seek, med-
ical care are not well understood, data suggest
that those who do consult physicians are unlike
those who donot.75'88'148 For example, patients
who pursue medical care appear to have more
intense, protracted, or frequent headaches
than those who do not. The two groups als
differ in other significant variables such as ed-
ucation, income, psychological makeup, mari-
tal status, and gender.88'92'198 Women are more
likely to seek consultation for headaches than
men 31,93 jt seems probable that some groups
of migraineurs are significantly underrepre-
sented in epidemiologic surveys that consist
solely of patients who consult physicians for
headache. These include persons from lower
socioeconomic groups.89 As a result, much epi-
demiologic information found in clinical text-
books has been formed from the impressions
of clinicians who examined selected groups of
migraineurs.
Following the lead of a few early pioneers,
large numbers of investigators are now analyz-
ing migraine in random samples drawn from
10 Clinical Aspects of Migraine
the general population. Because such popula-
tion-based studies identify persons with mild
and severe migraine, regardless of whether
they seek or can afford medical care, they are
presumably unhampered by selection bias.
However, in some population investigations,
the study subjects continue to be selected for
certain characteristics and do not consist of a
random sample from the general population.24
4. Varying methods of data collection.
Questionnaires and clinical interviews have
been used to collect data. In some studies, the
interviews are conducted by physicians; in oth-
ers, by lay interviewers.75'143 Some use diag-
nostic headache diaries that incorporate the
IHS criteria; others use structured interviews
recorded on videotape.71'157 The validity of in-
formation collected in these various ways may
differ substantially.145 For questionnaires, the
respondents obviously must be capable of read-
ing, writing, and comprehending instructions.
Only easily understandable questions can be
used, with their obvious limitations. Other pos-
sible problems with questionnaires include
poor response rates and questions about how
representative the respondents are of the pop-
ulation being studied. The prevalence of mi-
graine may be overestimated when data are
collected by means of self-administered ques-
tionnaires completed by self-selected respon-
dents. In contrast, although interviews are
more flexible, preconceived notions may cause
unintentional interviewer bias.
Prevalence of Migraine
Prevalence refers to the proportion of the pop-
ulation affected by a particular problem dur-
ing a particular period of time. Estimations of
the prevalence of headaches in the general
population in the United States and Europe, as
well as other areas of the world, are that about
40% of men and about 50% of women have
had severe, disabling headaches at some time
in their lives (life-time prevalence).211 Accord-
ing to one study, only 4% of the total popula-
tion has never had a headache.148
A precise figure for the prevalence of mi-
graine, however, is difficult to obtain. Investi-
gators do not all have the same focus: some
study lifetime prevalence, others review dif-
ferent periods of time (period prevalence) or
specify no period of time. Studies that have
concentrated on younger age groups or on
women only cannot be extrapolated to the gen-
eral population. Variation among studies may
also reflect, in part or in full, sociodemographic
differences in their samples.180 Nor does every
study use the same definition of migraine. Per
haps as much as 70% of the variation in re-
ported prevalences can be attributed to defin-
itional differences and to the age and gender
distribution of the study samples.183 Given all
these variables, it is not surprising that the fig-
ures reported for the prevalence of migraine
vary dramatically.
In contrast, newer, population-based inves-
tigations have collected data that appear to be
more accurate. Because such studies pay at-
tention to IHS criteria and analyze data drawn
from a representative sample of migraineurs
who may or may not have consulted physicians
about their symptoms, the range of prevalence
has been narrowed. At present, 15% to 18% of
women and 6% to 7% of men are reasonable
estimates for the prevalence of all types of mi-
graine during the previous 1-year period; 12%
to 33% of women and 4% to 22% of men are
estimates for the lifetime prevalence of mi-
graine as defined by either IHS criteria or
slightly modified IHS criteria.70'75'83'121'143'148'159'180
Estimates of lifetime prevalence presumably
suffer from some inaccuracies, owing to the
faulty recall of individuals who may have had
migraine for only a limited period during their
lives.
The prevalence of headache including mi-
graine may be increasing according to several
studies. The prevalence ranged from 35% to
38% of the population in the 1960s to 1970s,
and climbed to 42% to 50% in the 1980s to
1990s.9'118'169'170'177 The reported incidence
of medically recognized migraine has also in-
creased.156 The increase is largest in women of
reproductive age (Fig. 1-5A). Incidence rate
are more stable in men over time (Fig. 1-5B).
The increased incidence is most pronounced
for migrainous disorder (Fig. 1-6). Increases in
awareness and health utilization for migraine
may account for the apparent increases, but en-
vironmental factors such as increasing use of
food additives and colorings could also be sig-
nificant.
Migraine with Aura
The IHS classification system uses separate di-
agnostic criteria to distinguish migraine with-
 Epidemiology 11

Figure 1-5. Trends in age-specific incidence rates of medically recognized migraine headache (new cases per 100,000
person years) in Olmsted County, Minnesota. Comparison of average rates during 1979-1981 with average rates during
1989-1990. (A) Average rates for females; (B) average rates for males. Note the increased incidence in both men and
women in 1989-1990 when IHS criteria were used to diagnose migraine. (Adapted from Rozen TD, Swanson JW, Stang
PE, McDonnell SK, and Rocca WA: Increasing incidence of medically recognized migraine headache in a United States
population. Neurology 53:1468-1473, 1999, with permission.)

out aura from migraine with aura. All investi-
gations agree that those who have auras com-
prise a substantially smaller proportion (be-
tween 18% and 36%) of all migraineurs than
those who do not have auras.83^49 But that is
about the only data they agree about. As ex-
pected, information derived from clinic-based
patients differs substantially from information
extracted from population-based studies, but
in addition, data from both groups range
widely.24'83'149'159 Such variation may result
from differences in definitions, methods of
case ascertainment, and age and gender dif-
ferences among samples. For example, most
clinical and several epidemiologic studies indi-
cate that a high proportion of patients suffer
from both migraine with and without aura, but
other studies disagree.38'83'149'158 In represen-
tative general populations, between 8% and
42% of individuals reportedly have both con-
ditions. Population-based surveys of migraine
with and without aura have found differences
between the two conditions as to age of onset,
influence of female hormones, and precipita-
tion by bright light.149'158
Gender
Adult women are clearly at greater risk for
developing migraine than are adult men. De-
terminations of the female-to-male ratios are

Figure 1-6. Trends in age-specific incidence rates of medically recognized migraine headache (new cases per 100,000
person years) in Olmsted County, Minnesota. Comparison of average rates during 1979-1981 with average rates during
1989-1990 for patients with (A) migraine without aura, (B) migraine with aura, and (C) migrainous disorder. (Adapted
from Rozen TD, Swanson JW, Stang PE, McDonnell SK, and Rocca WA: Increasing incidence of medically recognized
migraine headache in a United States population. Neurology 53:1468-1473, 1999, with permission.)
12 Clinical Aspects of Migraine
Figure 1-7. Prevalence ratio of female-to-male migraine sufferers by age. (Adapted from Stewart WF and Lipton RB:
Migraine headache: epidemiology and health care utilization. Cephalalgia 13(Suppl 12):41-46, 1993, with permission of
Blackwell Science Ltd.)
between approximately 2 to 1 and 3 to 1, de-
pending on the particular population-based
study.75'75'121'143'1*5'180 The female-to-male ra-
tio varies with age (Fig. 1-7). The ratio in-
creases from early adolescence to about age 40,
when it begins to decline.180 The ratio also
varies with migraine type: the female prepon-
derance is less pronounced for migraine with
aura compared to migraine without aura.31'89'177
In men, there is a nearly equal split between
the two major subtypes of migraine.
Women consistently report more frequent
attacks and more distress from their headaches
than men da31*75*91,180 Mild headaches are
more common in men, whereas women de
scribe headaches that are more severe and of
longer duration.31'75'211 They are more likely to
seek care for their headaches than men are, al-
though we do not know whether this is caused
by a greater intensity of their symptoms or
whether men have been socialized to restrain
from consulting physicians.31-178 Women are
also more likely to report a variety of both tem-
porary and persistent pains other than head-
ache.188 The dissimilarities between men and
women may lie in gender differences in re-
sponse to painful stimuli, but it also may a func-
tion of hormonal differences, cultural and psy-
chological dissimilarities, divergent social role
expectations, and situational factors. The pre-
vailing evidence indicates that in experimental
situations, women show a greater sensitivity to
noxious stimuli than men.68 The reason for this
gender difference in pain sensitivity is un-
known. Figure 1-8 represents a few of the con-
sequential biological, psychological, and social
adjustments that may influence male and fe-
male pain behavior.
Age
Migraine can develop at any age, but at least
90% of patients experience their first attack be-
fore the age of 40 (Fig. 1-9).144>158 Although
migraine rarely begins after 60, it is not im-
possible: the onset of migraine with and with-
out aura in elderly individuals is well docu-
mented.41 Many cases develop in childhood or
early adolescence.144'177 In developed coun-
tries, the onset (incidence) of migraine peaks
near, or shortly after, the age at which menar-
che is reported to occur.158 The connection be-
tween migraine and the menarche used to be
based largely upon the recall ability of adult
women. Recent studies of young women in-
dicate that between 14% and 18% of women
have their first attack during the year of menar-
che or the year after; this is especially true for
migraine without aura.
The incidence and the prevalence of mi-
graine vary significantly with age (Fig.
1-10).91-180 Migraine appears to be most preva-
lent between the second and fifth decades of
life for both men and women, but appears to
peak later in women than men.70>75'1^1>143'180
In general, the prevalence rate for men shows
less dependence upon age than does the rate
for women.121 In both sexes the prevalence
rate declines after age 40.180 It is not known
 Epidemiology 13

Figure 1-8. Some major life cycle events that may affect the experience of pain in men and women. (Adapted from
LeResche L: Gender considerations in the epidemiology of chronic pain. In Crombie IK, Croft PR, Linton SJ, LeRessche
L, and Von Korff M (eds): Epidemiology of Pain. IASP Press, Seattle, 1999, pp 43-52, with permission.)

whether the frequency truly wanes in groups Socioeconomic Status,

of older individuals, or whether the character-
istics of migraine undergo noticeable alter-
ations and the headaches metamorphose into
headaches resembling tension-type headaches
(see Chapter 4).45
Intelligence, and Education
There is disagreement about the prevalence of
migraine among different socioeconomic
classes. Some recent data suggest that in the

Figure 1-9. Age at onset of migraine in men and women in the general population. Data obtained by clinical interview
and examination from a cross-sectional study of headache in Denmark. Patients were diagnosed by IHS criteria. Note the
higher prevalence in males before puberty. (Adapted from Rasmussen BK: Migraine and tension-type headache in a gen-
eral population: precipitating factors, female hormones, sleep pattern and relation to lifestyle. Pain 53:65-72, 1993, with
permission.)
14 Clinical Aspects of Migraine

Figure 1-10. Incidence of migraine with and without aura in patients between 8 and 29 years of age. Data obtained
from a population-based telephone interview survey conducted in 1986-1987 among 12- to 29-year-old residents of Wash-
ington County, Maryland. A total of 392 men and 1018 women women were diagnosed as having migraine. (Adapted from
Stewart WF, Linet MS, Celentano DD, Natta MV, and Ziegler D: Age- and sex-specific incidence rates of migraine with
and without visual aura. Am J Epidemiol 134:1111-1120, 1991, with permission of Oxford University Press.)

United States migraine is more frequent in
lower income groups in adults and children.180
Information collected outside the United
States runs contrary to this.70'83'121-143'148'176
The differences may lie in the unequal distri-
bution of health care in the United States as
compared to in other countries with more uni-
versal health-care systems. Older clinical ob-
servations held that migraine was more fre-
quent among highly intelligent individuals,
executives, professionals, and the better edu-
cated. Overrepresentation in treatment sam-
ples collected from headache clinic patients
probably accounts for this. In other words, bias
resulted from the tendency of more intelligent,
better educated, affluent patients to consult
physicians for their migraine.197 Educational
level, occupational category, and employment
situation are no longer believed to be signifi-
cantly correlated with migraine. Furthermore,
the severity of migraine is not linked to either
urban or rural environment, or to a particular
region of the United States.180
Race
There may be race-related differences in vul-
nerability to migraine. For example, the preva-
lence rate is reported to be very low in parts
of Asia: in China and Hong Kong the preva-
lence is below that reported in most studies of
Western populations. 5>196.205>210 Taiwan and
Japan are also is in the low range, but the preva-
lence is much higher than in mainland China
or Hong Kong.0'195 In contrast, the preva-
lence in Korea is not lower than that found in
Western countries.153 Significantly, the preva-
lence of migraine among Asian-Americans is
50% to 60% of that observed in Caucasians.181
Migraine was also thought to be rare among
native Africans, but recent studies have shown
that figures for both adults and children from
Africa are lower than, but close, to those for
Europe and America.122'124'129 In addition, the
epidemiologic characteristics of migraine in
Africans are similar in most respects to those
in Caucasians.129 In the United States, how-
ever, migraine prevalence is higher in Cau-
casians than in African-Americans, a lower
prevalence among African-American males ac-
counting for the difference.177 However, be-
cause African-Americans are less likely to re-
spond to surveys, the sample studied may not
be representative.
It is unclear whether social acceptability of
migraine is an important issue in determining
its prevalence in certain areas of the world. Al-
ternatively, the variation may be the result of
real differences in genetic susceptibility. The
role of environmental factors in various regions
of the world has not been investigated.

MIGRAINE IN CHILDREN
AND ADOLESCENTS
Clinical patterns of migraine in children differ
from those in adult migraineurs. This discrep-
ancy complicates epidemiologic investigations
in children. Headache, for example, may be a
less prominent feature of childhood attacks,
and childhood migraine frequently has special
features such as episodic vertigo, abdominal
pain, and autonomic symptoms. In other
words, migraine variants and migraine equiva-
lents are more frequent and perhaps typical for
children. In addition, their migraine attacks are
relatively short in duration, and the pain is typ-
ically bilateral and non-pulsating.61'207 As a re-
sult, children are less likely to have their re-
current headaches diagnosed as migraine. An
often-delayed recognition of the disorder re-
sults in many children suffering recurrent
headaches for years without receiving appro-
priate care. Furthermore, many children are
brought for medical attention early in the
course of their affliction, before a recurring
pattern typical of migraine has been estab-
lished. But even when a recurrent pattern has
been established, many physicians are reluc-
tant to make the diagnosis in young children
because these children are thought to be "too
young" to have migraine. Migraine may go
undiscovered by unsuspecting physicians.89
Gender and Age
Epidemiologic investigations of children and
adolescents have shown that the prevalence of
migraine depends upon gender and age. Boys
typically develop migraine at an earlier age
than girls; before the age of 10, the prevalence
of migraine in males is slightly higher than in
females.9'110'118 In addition, boys may have
more severe migraine as measured by fre-
quency of attacks and medication use, but girls
appear to have headaches of longer dura-
tion.9'111 The prevalence of migraine without
aura invariably increases with age in child-
hood.9'45'179 Quite striking increases are noted
from preschool to adolescence. Various studies
estimate the childhood prevalence to be be-
tween 3.5% and 5.0% and to rise to between
3.5% and 17.6% in adolescents, depending
Epidemiology 15
upon the diagnostic criteria, the age distribu-
tion of the study sample, and other method-
ologic featuresA16>45'fll>118'169'179'189 During
and after adolescence, migraine becomes con-
siderably more prevalent in females than in
males.9'89'91
A child's first migraine headache is esti-
mated to happen most often between 5 and 11
years of age, although published data vary, be-
ing largely dependent upon how migraine is
defined.9'39 Children who subsequently de-
velop typical adult attacks have been observed
to have had previous bouts in very early child-
hood that were characterized mainly by nausea
and signs of autonomic dysfunction. The inci-
dence of migraine without aura peaks at 10 to
11 years of age in boys, but in girls the peak is
delayed to 14 to 17 years of age.179 In both
sexes, cases of migraine with aura are more in-
clined to develop at an earlier age than cases
without aura.9'45'179 Data vary as to whether
migraine with aura is more frequent in boys or
girls.118'209
Although unusual, migraine can occur in
toddlers and even in infants.10'142 Migraine
in very young children usually presents as
episodic vomiting, pallor, and behavioral
change. However, a number of infants indi-
cate that they are suffering from head pain by
gesture or by simple verbal utterance.
Criteria
More than 40 years ago, Vahlquist proposed a
set of criteria for the diagnosis of migraine that
is still being used widely.189 He defined mi-
graine as paroxysmal headaches separated by
symptom-free intervals and accompanied by at
least two of the following features: unilateral-
ity, nausea, visual aura, and family history of
migraine. Since then, a number of authors
have used similar criteria for pediatric mi-
graine.39'142
The IHS criteria for adult migraine repre-
sent a distinct advance over previous systems
used for adults, but the only concession made
for applying them to the pediatric population
was a single modification in headache duration,
from 4-72 to 2-48 hours for patients less than
15 years old. Several authorities have expressed
dissatisfaction with the IHS pediatric criteria
because expert clinical diagnosis and IHS-
16 Clinical Aspects of Migraine
Figure 1-11. The course of migraine in 73 school children with severe migraine followed for 40 years. (Adapted from
Bille B: A 40-year follow-up of school children with migraine. Cephalalgia 17:488^491, 1997, with permission of Black-
well Science Ltd.)
based diagnosis often disagree. Several recent
studies addressed the usefulness of the IHS cri-
teria to diagnose migraine in children and ado-
lescents. They concluded that strict use of IHS
criteria substantially reduced the frequency of
diagnosis of migraine without aura in chil-
dren.101'110-118'166'202'207'208 Between 44% and
60% of children diagnosed as suffering from mi-
graine on other grounds do not fulfill the overly
restrictive IHS criteria.29'61'72'101'166'202'203'207
The IHS criteria, primarily developed to clas-
sify headaches in adults, are less sensitive than
the criteria developed by Vahlquist and others,
who specifically addressed the differences in
presentation of headaches in pediatric and adult
clinical practice.166'202
Modifications have been proposed to in-
crease the sensitivity of the criteria to chil-
dren's migraine, particularly by propositions
reducing the minimum duration of migraine
still further.66'101'118'203'208 Migraine head-
aches last 2 hours or less in between one-fifth
and one-third of juvenile and adolescent pa-
tients.61'207 In addition, several studies have
demonstrated substantial differences in the lo-
cation of migraine pain in the pediatric and
adult populations.39*1'166 Migraine headaches
in children are frequently bifrontal and bitem-
poral. The criteria would be more sensitive if
the IHS criteria included these locations as
well as a unilateral location.61'203'207
Prognosis
The overall prognosis for children with mi-
graine is unclear. Some report an excellent
outcome, with 60% to 80% of patients im-
proved at follow-up.9'39 And indeed, the im-
mediate prognosis appears to be good: more
than 50% will improve in the 6-month period
following the initial consultation, regardless of
the particular treatment or lack of treat-
ment.9'142 Many times this improvement is
correlated with the end of the school year. It
is true that long remissions are common; the
long-term prognosis is less optimistic.9'10'39'102
During puberty and young adult life, a num-
ber of childhood migraineurs have remissions
for 2 years or longer, but in many children mi-
graine persists or returns.111 More than half
have migraine in middle age (Fig. 1-11).111
The prognosis is more unfavorable in girls than
boys.
MIGRAINE PERSONALITY
Clinicians have traditionally emphasized the
association of migraine with a distinctive con-
stellation of personality traits. For more than
50 years, the migraineur has been maligned
as a tense, compulsive, rigid, achievement-

driven, perfectionistic person with an inflex-
ible personality full of resentment and ag-
gression. This notion was fostered by Harold
G. Wolff and was accepted by many clinicians
enthusiastic about the psychoanalytic theo-
ries prevalent at the time. Wolff and others
contended that the migraineur maintained
excessive self-control over a store of inter-
nalized anger and was unable to express ag-
gressive feelings in a constructive manner.
Simply put, as a result of having a particular
migraine personality, an individual was hy-
pothesized to respond with a migraine attack
to certain environmental stresses and inter-
personal relationships. The attack itself was
hypothesized to be a psychophysiological ex-
pression of suppressed or repressed animos-
ity and resentment that could not be other-
wise resolved.
Many migraineurs unquestionably do have
intense, inflexible personalities, but so do many
people without migraine headaches. Early
studies that attempted to define a migraine
personality were flawed and biased. Most in-
vestigations concentrated on highly selected
subjects with severe migraine who sought spe-
cialist medical help at a migraine clinic or who
were referred by a community practitioner for
psychiatric intervention. Depictions of person-
ality were usually made on the basis of clinical
interviews alone and control groups were not
used for comparison. Individuals with the so-
called migraine personality are more likely to
consult physicians and are presumably more
committed to finding the cause of their dis-
comfort because of their basic temperament.
It is probable that these treatment-seeking
groups have a higher proportion of individuals
with traits of persistence, overconcern, and
perfectionism.
Systematic investigations of the association
between personality and migraine have em-
ployed several instruments to assess personal-
ity, including the Minnesota Multiphasic Per-
sonality Inventory (MMPI), the Eysenck
Personality Questionnaire, the Maudsley Per-
sonality Inventory, and Freiburg Personality
Inventory. The MMPI, the most frequently
used test, was not developed for the purpose
of studying patients with pain. Accordingly, no
normative data have been collected in this pop-
ulation. Moreover, because items concerning
somatic symptoms contribute to elevating the
Epidemiology 17
neurosis scales, there is a legitimate contention
as to whether MMPI profiles derived from
headache and other pain patients actually re-
flect neurotic traits. (Neuroticism is formulated
as an emotional instability and general overre-
activity to emotions that may lead to neurotic
symptoms when the person is stressed.) A
number of studies have demonstrated either
no differences or only modest differences in
MMPI results between patients with migraine
and control subjects or historical norms, but
the abnormalities in factor scores have been in-
consistent among studies.82'100'115-138-152 Other
personality inventories administered to both
population-based and clinic patients diagnosed
with migraine have shown that migraineurs
have greater levels of neuroticism than do mi-
graine-free individuals.17'20-21-106'137 No differ-
ences in extroversion or psychoticism were
noted. Nor were associations with other per-
sonality traits established: linkage between mi-
graine and neuroticism is not attributable to co-
existing major depression or anxiety. However,
because a connection between neuroticism and
tension-type headaches has been demon-
strated and because many patients with mi-
graine have coexisting tension-type headaches,
the high neuroticism score may be based on
the high proportion of migraineurs with coex-
isting tension-type headaches.
Some studies of the relationship between
migraine and personality have not controlled
for use or abuse of medications, frequency of
headaches, or disability caused by headaches.
These factors are especially important because
there are data to suggest that psychological
symptoms in migraineurs become increasingly
clifferent from controls as migraine persists
over time.105 The degree of putative emotional
disturbance and/or psychopathology is a func-
tion of the duration and severity of pain prob-
lems. Available evidence implies that many
personality features one finds in migraineurs
are a consequence of migraine pain, rather than
features that originally increased their vulner-
ability to migraine attacks.54
In sum, the research findings regarding per-
sonality characteristics in migraineurs do not
consistently establish abnormalities in specific
traits aside from neuroticism. In addition, the
question remains whether personality disor-
ders predispose to migraine or psychopathol-
ogy is instead a consequence of headache.
18 Clinical Aspects of Migraine

Figure 1-12. Interference with activities of daily living related to headache disability reported during previous year by
headache type. Data from a telephone survey of sample households in Kentucky. HA, headache. (Adapted from Kryst S
and Scherl E: Social and personal impact of headache in Kentucky. Frontiers in Headache Research 4:345-350, 1994,
with permission.)

MIGRAINE, BEHAVIOR, ceived more symptoms and greater emotional

DISABILITY, AND QUALITY
OF LIFE
Migraine has profound effects on one's func-
tional capacity in the work environment, at
school, and at home (Fig. 1_12).81'89>127 It nor-
mally affects individuals during their most pro-
ductive years. The deleterious effects of mi-
graine have been documented using a variety
of health-related quality-of-life questionnaires,
surveys, and inventories, which show that re-
current headache disorders are associated with
significant limitations of patient well-being,
functioning, and quality of life when compared
to the general population and to patients with
other common chronic illnesses such as hy-
pertension, osteoarthritis, diabetes, or depres-
sion.44'55'128'172 Migraine patients feel that
their subjective well-being and quality of life
are impaired even between attacks. Compared
with control subjects, migraine sufferers per-
distress, as well as disrupted sleep and reduced
energy.44 Individuals with frequent headaches
have more fear and anxiety about their health
than others.
A large proportion of chronic migraine suf-
ferers alter their behavior and lifestyle because
they cannot carry out normal tasks at home or
school or in the workplace.81'89'171 These
changes may be pervasive, disruptive, and
long-lasting. For example, migraineurs may
change their jobsor may stop working en-
tirelybecause the pain interferes with their
ability to function (Fig. 1-13). A number of in-
vestigations have shown how significantly mi-
graine contributes to reduced work perfor-
mance.53'164'182'194 It has been estimated that
female migraineurs, required 5.6 bed rest days
and male migraineurs, 3.8 days each year.76
Various estimates indicate that in European
and Canadian populations, 13% to 43% of pa-
tients miss work because of migraine in a
1-year period.120'143'147 In the United States, it

Figure 1-13. Percent unemployment as a function of
headache grade at baseline (B-L) and after 1 and 2 years
of follow-up. Grade I: low disability, low pain; Grade II:
low disability, high intensity; Grade III: high disability,
moderately limiting; Grade IV: high disability, severely
limiting. (Adapted from Lipton R, Stewart WF, and Von
Korff M: Migraine impact and functional disability. Cepha-
lalgia Suppl 15:4-9, 1995, with permission from Blackwell
Scientific Ltd.)
is estimated that 74% of women and 56% of
men with severe headaches have at least one
lost workday per year because of migraine (Fig.
1-14).182 Thirty percent of women and 17% of
men missed six or more workdays per year.
Predictors of lost work days include headache
duration (particularly if more than 24 hours),
pain level, and older age.182 In addition to ac-
tual missed workdays, reduced effectiveness at
work accounts for substantial indirect costs.
Migraineurs often stay at work during attacks
associated with severe pain and with consider-
ably reduced ability to function.143 It has been
estimated that migraine costs American em-
ployers about 13 billion dollars a year because
of missed workdays and impaired work func-
tion.76 Some patients with severe and recur-
rent headaches feel that headaches prevent
them from having an adequate income. How-
ever, despite these deleterious effects of mi-
graine on the ability to work, migraine is not a
major cause of compensated work disability,
and has been excluded as a potential cause of
work disability in reports estimating the con-
Epidemiology 19
tribution of chronic illness to disability. In ad-
dition, many migraine sufferers discontinue
specific leisure and recreational activities and
curtail social activities with family and friends.
The consequences of this retreat include de-
creased physical activity and fitness, reduced
social support, and loss of undertakings that
formerly furnished pleasure and feelings of
accomplishment.
A number of investigations have shown that
significant health service use is associated with
migraine: increased visits to physicians, trips to
hospital emergency departments, use of diag-
nostic facilities, and pharmacy costs (Fig.
1-15).36'89'127 An evaluation of Medicaid pa-
tients showed that total health-care costs for
migraineurs were 1.6 times higher than for
matched controls. Estimates of the annual di-
rect health costs of patients with headache in
the United States vary from $200 to just over
$800 per migraineur.127 Based on an estimated
10% prevalence in the population, economic
analyses have shown that headache-related
costs are between 0.4% and 1.7% of total na-
tional health-care spending in the United
States. Similar estimates have been arrived at
for other Western countries.42'190
Figure 1-14. The proportion of employed subjects with
headache who reported that they missed work for all or
part of the day because of headache in the past year, by
different types of headache defined by IHS criteria. Data
from Washington County, Maryland survey. (Adapted
from Schwartz BS, Stewart WF, and Lipton RB: Lost
workdays and decreased work effectiveness associated
with headache in the workplace. J Occup Environ Med
39:320-327, 1997, with permission.)
20 Clinical Aspects of Migraine
Figure 1-15. Cost of treating headache for 1 year as a function of headache grade. Grades defined as in Figure 1-13.
(Adapted from Lipton R, Stewart WF, and Von Korff M: Migraine impact and functional disability. Cephalalgia Suppl
15:4-9, 1995, with permission from Blackwell Science Ltd.)
Because migraine occurs more frequently in
women than in men and is most active during
childbearing and family care-giving years, pe-
riodic and recurrent disruption in the major
caregiver's ability to function often has major
undesirable and deleterious consequences for
normal family functioning and dynamics.171
Relationships with children and spouses are af-
fected, as are many other aspects of normal
family life, and household duties are commonly
postponed. Several studies show that family dis-
cord, instability, and disputes may be caused
by headaches/9'171 In addition, family mem-
bers share in the suffering of the migraineur
and often feel helpless because of their inabil-
ity to avert or terminate headaches. Migraine
can also significantly affect the frequency and
quality of sexual relations.171 Problems caused
by severe migraine in a spouse lead to separa-
tion or divorce in a substantial number of fam-
ilies. Migraine has been reported to cause
problems with interpersonal relationships in
70% of patients.53
Although there are no prospective studies, a
number of reports indicate that migrainous
children demonstrate frequent behavioral ab-
normalities.9-65 Data indicate that children
with headache avoid play or games more often
for fear of getting hurt than children without
migraine.6
COMORBIDITY
The term comorbidity is applied to situations
in which a greater than coincidental combina-
tion of two conditions occurs in the same set
of individuals. A large number of reports asso-
ciate migraine with other disorders, but many
are flawed by inadequate definitions of mi-
graine and the other condition, inadequate
methodology and analysis of data, disagree-
ment between clinical and epidemiologic data,
and inappropriate sampling or use of inappro-
priate populations. Because migraine is such a
common ailment, a proportion of migraine suf-
ferers will inevitably have other medical ill-
nesses during their lifetimes. Nonetheless, cer-
tain conditions occur in people with migraine
at a higher rate than would be expected by
chance alone. Migraine has been reported to
be comorbid with several medical, neurologic,
and psychiatric conditions, including depres-
sion, anxiety, epilepsy, stroke, mitral valve pro-
lapse, systemic lupus erythematosus, allergy,
hypertension, and Meniere's disease. Despite
 Epidemiology 21

association with a number of serious medical Table 1-2. Lifetime Prevalence of

conditions, increased mortality in migraine Psychiatric Illness in Individuals with
patients has not been convincingly demon- Migraine and Controls
strated.86'200
Migraineurs Controls
(0/n) (O/ )
\ 1) \ 'f
Psychiatric Disorders (N=128) (N = 879)

Data from clinical observations and uncon- Any anxiety 54 27

trolled studies, as well as systematic epidemi-
ologic investigations, consistently associate mi-
graine with major depression and specific
anxiety disorders (Table l_2).23-25,i04,ife The
lifetime prevalence of major depression in mi-
graineurs is threefold higher than that in indi-
viduals without a history of severe headache.26
Clinical studies indicate that children and ado-
lescents with migraine also have a higher
prevalence of depression.9'140 The relationship
between depression and migraine is, however,
complex. Some of the following factors must
be considered:
1. Depression is often mentioned as an af-
fective correlate of the headache itself; many
patients develop alterations in mood and affect
prior to an attack of migraine.13 Migraineurs
frequently note feelings of dejection, fatigue,
and lethargy, or may develop symptoms of
frank depression with weeping spells that ei-
ther precede the actual attack of head pain by
minutes, hours, or even days, or may accom-
pany a bout of migraine.
2. Patients who suffer from either headache
or depression may complain of a number of
similar somatic complaints such as insomnia,
appetite changes, irritability, and fatigue.
3. Some authorities believe that chronic
pain is likely to be psychological in origin and
that depression precedes the development of
pain. Most studies, however, have not found
evidence for this hypothesis.58
4. Other authorities contend that in many
chronic pain sufferers, emotional disturbance
is a result of living with pain.63 Convincing data
indicate that any chronic pain is able to pro-
duce a wide range of psychosocial distur-
bances, including anxiety and depression.58 In
fact, rates of depression in the range of 50%
to 65% are reported in patients with chronic
pain.59'80 In addition, it is generally accepted
that psychosocial symptomsincluding de-
pressionincrease the longer one is in pain
and the more severe and the more frequent the
pain is.58 The exact mechanisms by which mi-
Anxiety disorder 10 2
Generalized 10 2
anxiety disorder
Phobia 40 21
Major depression 35 10
Panic disorder 11 2
Obsessive 9 2
compulsive
disorder
From a random sample of young adults who were mem-
bers of an HMO in Michigan. Data from Breslau and Davis
(1993).23
graine might cause depression have not been
identified, but it is common for migraine pa-
tients and their relations to indicate that the
depression is secondary to the severe and per-
sistent head pain caused by repeated, disabling
bouts of migraine. In addition, some patients
become depressed as headache-related re-
strictions and the chronic incapacitation dis-
rupt normal daily living and social functioning.
5. Recent epidemiologic, community-based
studies have stressed a comorbid relationship
between migraine and major depression.24'26'105
Migraine with aura has been shown to be the
type of migraine most strongly associated with
depression.24'105'114
In contrast to the idea that a major depres-
sion in migraineurs is a psychologic response
to recurrent, disabling bouts of migraine, a
bidirectional relationship between migraine
and depression has been convincingly shown.25
Bidirectionality means that each disorder in-
creases the risk for developing the other af-
fliction. That major depression increases the
risk for migraine, and that migraine increases
the risk for major depression, supports the pos-
tulate that these problems have a shared etiol-
ogy.25 The specificity of the bidirectional asso-
ciation of migraine and depression is also
buttressed by findings that persons with dis-
abling headaches without migraine features
had a higher incidence of major depression, but
22 Clinical Aspects of Migraine
major depression did not predict a significantly
increased incidence of severe non-migraineous
headache.26 It should be noted that the risk of
suicide is increased among patients with coex-
isting migraine and major depression. When
the rate of suicide in such patients is compared
with the combined individual rates of patients
with migraine or depression alone, the risk of
suicide is much greater in the patients with
both problems.19'24'84
Many of those with a history of migraine are
more anxious than migraine-free subjects, or
actually have an anxiety disorder.24 In fact, mi-
graine and anxiety may be more closely linked
than migraine and depression.105 Evidence has
been presented that anxiety and depression oc-
cur more frequently together in migraine pa-
tients than one or the other alone.103 A high
proportion (84%) of individuals with a history
of migraine and major depression meet the cri-
teria for an anxiety disorder. Frequently, the
anxiety disorder is manifest as panic attacks,
but patients may also have phobias and gener-
alized anxiety.22'178'180 Children with migraine
also have significantly more anxiety than con-
trols.9
Epilepsy
A number of early studies reported both a
higher prevalence of all forms of epilepsy in a
population comprised of patients with migraine
as well as a higher risk of migraine in persons
with epilepsy. As with many early studies, the
data are difficult to interpret because of poorly
defined criteria for both epilepsy and migraine
and because most studies were uncontrolled.
Conflicting data from some other older inves-
tigations stressed the autonomous nature of
most forms of epilepsy and of migraine, and
considered the association of the two disorders
in individual patients largely fortuitous and
coincidental.
More recent epidemiologic data indicate
that the chance of developing migraine is more
than twice as high in individuals with epilepsy
than in those without epilepsy.130"132 The as-
sociation between epilepsy and migraine is in-
dependent of seizure type, cause, age of onset
of epilepsy, or family history of epilepsy. Envi-
ronmental risk factors such as head trauma,
which predisposes to both epilepsy and mi-
graine, contribute to the comorbidity, but
other factors must be operative because a pro-
pensity for migraine is also increased in per-
sons with idiopathic epilepsy. And because data
show a high likelihood of developing migraine
among epileptics both with and without a fam-
ily history of migraine, the comorbidity cannot
be explained simply by a genetic mechanism
that predisposes to both disorders.90'132
When individuals have both conditions,
epileptic seizures may occur spontaneously or
in association with a severe migraine at-
tack.4'119 Seizures induced by an aura have
been described.4 Although it has been esti-
mated that 3.0% of adult epileptic migraineurs
experience their seizures during or immedi-
ately after an attack of migraine, this phenom-
enon is seen more often in childhood and
adolescence.133
Epilepsy patients whose seizures that com-
mence with a migraine headache, or who have
complex migraine symptoms, have a high inci-
dence of intracranial pathology such as an ar-
teriovenous malformation or tumor. In addi-
tion, the MELAS syndrome (mitochondrial
encephalopathy, lactic acidosis, and stroke-like
episodes) may cause intense, extended mi-
graine symptoms and prolonged partial-status
epilepticus (see Chapter 2). It has also been
suggested that epilepsy may arise from a focal
cerebral lesion caused by an episode of com-
plicated migraine with infarction, but this se-
quence of events is rare.4
OCCIPITAL LOBE EPILEPSY
AND MIGRAINE
An unusual syndrome of children and adoles-
cents, designated childhood epilepsy with oc-
cipital paroxysms, is characterized by brief
seizures with mainly visual symptoms, such as
elementary visual hallucinations, illusions, or
amaurosis, paroxysmal occipital spike and slow-
wave abnormalities, and convulsions.2'64 Se-
vere, postictal migraine headaches occur in half
of the patients. And because the bilateral vi-
sual hallucinations and visual loss often ac-
company recurrent headaches associated with
nausea and vomiting, benign childhood occip-
ital seizures may be difficult to distinguish clin-
ically from migraine with aura or from basilar
migraine.5'134'135 However, unlike migraine,
the elementary visual hallucinations, which
may only occur in a minority of patients with
occipital seizures, are always on the same side,
are brief, lasting for 1 to 3 minutes at most, and
are predominantly multicolored, with circular

or spherical patterns.134'135 Epileptiform activ-
ity is present when the eyes are closed and is
markedly attenuated when the eyes are
opened.33 The interictal electroencephalo-
grams (EEGs) of these patients maybe normal
or may show prominent, repetitive epilepti-
form spike-wave activity confined to the pos-
terior regions of one or both hemispheres.
In contrast, seizures have been observed in
association with basilar migraine. The ictal
EEC of some patients with this condition dem-
onstrates transient posterior slow-wave activity
during attacks. Occipital spike-wave complexes
have also been described in patients with basi-
lar migraine.46
ROLANDIC (CENTROTEMPORAL)
EPILEPSY AND MIGRAINE
Benign rolandic epilepsy is generally a disease
of childhood. Seizures typically occur during
sleep, usually shortly after falling asleep, but
sometimes before awakening. The disorder is
characterized by simple, partial seizures that
produce unilateral paresthesias affecting the
tongue, lips, gum, and cheeks, followed by
unilateral tonic contractions or clonic jerks in
the same areas as the paresthesias, and by
dysarthria and drooling. The patients do not
lose consciousness, the symptoms occurring ei-
ther during drowsiness or arousal. The diag-
nosis is confirmed by the EEG features: slow,
diphasic, high-voltage, pseudorhythmic, unilat-
eral spikes or sharp waves in the rolandic or
temporal area. They can be unilateral, but are
often bilateral and independent. The syndrome
is called benign because it diminishes over
time. Many children with this form of epilepsy
either have an unusually high prevalence of mi-
graine in their families and/or suffer intense
migrainous headaches themselves during child-
hood, Their migraine prevalence has been es-
timated at between 63% and 80%.12-165
Hypertension
Much of the case-control and epidemiologic
data on the prevalence and significance of hy-
pertension in patients with migraine is equiv-
ocal. The general conclusion is that the associ-
ation between mild-to-moderate migraine and
hypertension is probably coincidental.98 Hy-
pertension may, however, amplify the fre-
quency and intensity of migraine. Moreover,
Epidemiology 23
hypertension may be one of the factors that
transforms episodic migraine into a chronic
daily headache."
Stroke
Although without doubt, migraine and cere-
brovascular disease are associated, the rela-
tionships between them are intricate and com-
plicated, because of the following factors:
1. Headaches, some of them resembling mi-
graine, frequently accompany acute ischemic
stroke as preictal, ictal, and postictal phenom-
ena.96'191 In most patients, however, this type
of headache is nonspecific and varies in sever-
ity (see Chapter 7).
2. Although migraine-induced stroke is a
relatively rare phenomenon, long-lasting or
permanent neurological sequelae with evir
dence of ischemic infarction of the cerebrum
or brain stem can occur during or following an
attack of migraine (see Chapter 4).15>40>50
3. Ischemic strokes unrelated to specific
migraine attacks are more common in mi-
graineurs than in controls.28-30'186'187-201
A number of investigations do, however,
support the idea that a history of migraine sig-
nificantly increases the risk of stroke and that
migraine is an independent risk factor for
stroke, especially for ischemic stroke (Table
!_3) 30,33,3V,97,154U86,187 The predse risk of
stroke in migraineurs is difficult to assess, how-
ever, because in the age and gender group with
the highest prevalence of migraine, women un-
der 45 years of age, stroke is a rare disorder
and migraine is a common one. Although sev-
eral different investigations have considered
Table 1-3. Studies of the Relationship
between Migraine and Stroke in
Young Women
Risk of
Ischemic Stroke
Study (Odds Ratio)
Collaborative Group (1975)37 2.0
Tzourio et al. (1993)186 4.3
Tzourio et al. (1995)187 3.5
Lidegaard (1993)87 2.8
Carolei et al. (1996)30 1.9
Chang et al. (1999)33 3.5
24 Clinical Aspects of Migraine
the premise that migraine is a potential cause
of stroke in young individuals, their conclusions
vary widely, but ischemic stroke seems to be
increased between two- and fourfold in pa-
tients with migraine.
Certain subpopulations of migraineurs ap-
pear to be at particular risk. Data indicate that
the association between migraine and cerebral
ischemia is largely restricted to women below
the age Of 45.30'186'187 A female migraineur who
smokes and uses contraceptive pills appears
particularly at risk for stroke.187 The associa-
tion between migraine and stroke is more fre-
quent in patients who have migraine with aura
and in patients with posterior circulation
strokes. >184 Although disputed, a history of
migraine may also be relevant for increasing
the risk of stroke in older men and women.28'113
Raynaud's Phenomenon
Raynaud's phenomenon is a pathological vaso-
motor reaction of the digital blood vessels to
cold exposure. Several studies have reported
an association between migraine with and with-
out aura and Raynaud's phenomenon.47'123'151
In fact, estimates show that the prevalence of
migraine in patients with Raynaud's phenom-
enon is as high as 42% to 47%.123'141'204
Mitral Valve Prolapse
Mitral valve prolapse (MVP) is a highly vari-
able, clinical entity resulting from dysfunction
of the mitral valve. It is reportedly a widespread
cardiac abnormality, but estimates of its preva-
lence vary among the populations studied and
according to the criteria and methods used to
diagnose it. Nonetheless, there is some con-
cordance: the results of both clinical and post-
mortem investigations have indicated that
MVP has a prevalence of at least 5% to 10%
and is more common in women.74
A substantially higher proportion of mi-
graineurs are reported to have MVP than non-
migraineursbetween a fifth and a third of pa-
tients.3'62'174 Conversely, half of the patients
with MVP are estimated to have migraine.62
The possible association between migraine and
MVP will have to be reevaluated, however, in
view of recent data obtained using strict crite-
ria that demonstrated a lower prevalence
(2.4%) of MVP than is usually reported in
community-based samples.60
Systemic Lupus Erythematosus
Headache, especially migraine, has been
thought to be a common symptom in the acute
phases of systemic lupus erythematosus (SLE)
and was reported to occur in the majority of
patients.7 It has even been reported to be the
first manifestation of the disease and to occur
in the absence of renal dysfunction, hyperten-
sion, and active central nervous system (CNS
involvement.18 Many SLE patients are said to
experience throbbing headaches that have the
qualities typical of a migraine attack and that
some are preceded by scintillating sco-
tomas.7'16'18 Recent studies, however, have dif-
fered with regard to the presence or type of
chronic or recurrent headache diagnosed using
IHS criteria.57'67'167 It is also unclear whether
or not the severity and frequency of headaches
in patients with SLE are related to either the
expression or severity of the disease or to seri-
ous organ involvement.18'155'167 In sum, the re-
lationship of migraine to underlying SLE is un-
certain.
Allergy
Numerous anecdotal reports and several
case-control and epidemiologic studies have
shown that large numbers of migraine patients
suffer from allergic disorders, and that there
appears to be a higher prevalence of allergy
sufferers in the migraine than in the non-mi-
graine population. These allergic disorders in-
clude vasomotor rhinitis, asthma, hay fever,
hives, and eczema.34'104'116'117 Despite the
claims of many allergists, however, allergy may
not be a major factor in the genesis of migraine.
Because allergy is such a widespread condition,
one would expect significant numbers of mi-
graineurs to suffer from one or another aller-
gic condition. At least 80% of migraineurs are
free of any allergic disease.108
Meniere's Disease
For many years, authorities have speculated
about the relationship between migraine and

Meniere's disease, because in many patients it
may not be possible to separate the two con-
ditions on clinical grounds alone. For example,
fluctuating low-frequency sensorineural hear-
ing loss and vertigo are considered key parts of
the clinical picture of Meniere's disease, but
such hearing loss and vertigo also occur in mi-
graineurs.43'126 Most reports indicate an in-
creased prevalence of migraine in patients with
Meniere's diseaseperhaps more than twice
as high as in the general population or in nor-
mal controls.136'150 Prospective studies with
adequate follow-up are needed to investigate
this association further.
SUMMARY
Most older epidemiologic data on the preva-
lence and demographics of migraine are im-
perfect because they depend largely upon
inexact nomenclature and incomplete defini-
tions. The new classification of headache dis-
orders published by the IHS represents a ma-
jor step toward making headache diagnosis
more objective. Many of our epidemiologic
data, particularly that dealing with comorbid-
ity, must be reanalyzed using this classification.
And more important, there needs to be con-
tinued investigation of the hypothesis that
headache is a continuum of symptoms with mi-
graine at one end and tension-type headaches
at the other, rather than a collection of discrete,
identifiable, definable headache types.
Nonetheless, bearing in mind die problems
of definition, certain generalities about mi-
graine are agreed upon. Migraine is a frequent
cause of pain and dysfunction in all societies.
Objective data have now confirmed older ob-
servations that migraine has profound effects
on the functional capacity of sufferers, both at
work and in the home. All observers agree that
adult women suffer more frequently from mi-
graine than adult men do. It has been clearly
shown that the prevalence of migraine in both
children and adults varies considerably with
age. If the frequency of diagnosis of migraine
in children is to be accurate, the IHS defini-
tions for childhood migraine require revision.
Whether or not migraine with aura and mi-
graine without aura represent the same entity
or different entities has to be decided. Mi-
graine appears to be comorbid with several
Epidemiology 25
medical, neurologic, and psychiatric condi-
tions, including depression, anxiety, epilepsy,
stroke, and mitral valve prolapse. The basis for
this comorbidity requires study. Clearly, epi-
demiologic data about migraine are important
for clinical studies of pathophysiology and eti-
ology.
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Chapter 2
Genetics
TWIN STUDIES
MODE OF INHERITANCE
FAMILIAL HEMIPLEGIC MIGRAINE
Genetics of Hemiplegic Migraine
Voltage-gated Ca2+ Channels
CACNA1A Involvement in Other
Neurological Disorders
IS MIGRAINE A CHANNELOPATHY?
CADASIL
It is a clinical commonplace that migraine has
a strong tendency to run in families. A major-
ity of migraineurs describe migraine histo-
riesoften very similar to their ownfor sev-
eral family members, histories that often span
several generations. Early investigations re-
ported a very high percentage of positive fam-
ily histories (between 65% and 91%).13>25 The
clinical idea of a "family history" has been so
compelling that both the Ad hoc Committee
on Classification of Headache in 1962 and the
Research Group on Migraine and Headache in
1970 included family history as a criterion for
the diagnosis of migraine.1'*01 Its inclusion, of
course, produced bias toward hereditary fac-
tors so that studies to determine the prevalence
of familial migraine became suspect.
Information provided by a patient about
headache in relatives is often inaccurate.79 Sta-
tistical evidence gathered in recent years pro-
vides a much more variable picture of the fa-
milial migraine pattern, the relative risk of
migraine in family members ranging from 1.5
tO 19 3 2,3,5,17,48,55,59,61,63,67,86,90,91,99,104 jjjis
wide variation reflects differences among
studies as to migraine definitions, estimates of
family aggregation, methods used to identify
MIGRAINE AND MITOCHONDRIA!.
DISORDERS
MELAS
MERFF
Ornithine Transcarbamylase Deficiency
HLA ANTIGENS
POLYMORPHISMS ASSOCIATED WITH
MIGRAINE SUSCEPTIBILITY
SUMMARY
migraine in relatives, and source of patients.
Often, relatives of patients were not directly
questioned. In addition, because the preva-
lence of migraine in the general population is
high, familial occurrence may result from sim-
ple chance alone.
When International Headache Society
(IHS) criteria were applied to the diagnosis of
migraine and direct family interviews used,
data analysis indicated that fewer than half the
migraine cases in the population result in some
way from familial factors.91 Another investiga-
tion that also used IHS criteria and direct in-
terviews of family members found that first-
degree relatives of probands suffering from mi-
graine without aura had a significantly in-
creased risk of migraine both with and without
aura.86 The data from two carefully done pop-
ulation studies are shown in Table 2-1. The rel-
ative risk for migraine in first-degree family
members of migraine patients ranges from a
nonsignificant 1.42 for migraine without aura
to a modestly increased 3.8 for migraine with
aura.84'91 In sum, remarkably little reliable
family data are available, but what have been
collected indicate that a hereditary component
is present in migraine.81
31
32 Clinical Aspects of Migraine
Table 2-1. Relative Risk of Migraine
Headache Type
in Proband
Migraine with aura84
Migraine without aura
Migraine with aura91
Migraine without aura
"Relative risk is the risk above the prevalence in the population of developing migraine in
first-degree (1) family members of proband. A relative risk of 1 means that migraine does not
occur more frequently in relatives than it does in the general population. (Adapted from Gard-
ner K: The genetic basis of migraine: how much do we know? Can J Neurol Sci 26(Suppl
3):S37-S43, 1999, with permission.)
TWIN STUDIES
Of paramount importance in establishing the
relative importance of genetic factors and en-
vironmental influences is data on concordance
rates of migraine in monozygotic and dizygotic
twins. Higher concordance in monozygotic than
in dizygotic twin pairs favors a genetic basis for
the disorder. Unfortunately, many of the stud-
ies are flawed by problems with clinical defi-
nitions of zygosity or by inappropriate criteria
for the diagnosis of migraine. In all twin stud-
ies, monozygotic twins reportedly have higher
concordance ratios for migraine with without
aura than dizygotic twins.27^'37'47'53'55-60'95-104'105
Even so, the concordance in most monozygotic
twin studies is not very high, an indication that
a simple inheritance is unlikely and that genetic
factors do not explain all of the variance in
migraine.^
CCQ
Data obtained from twin studies, as well as
from spouse, family, and complex segregation
analysis studies, strongly support the idea of a
multifactorial model, including environmental
as well as genetic factors.17'27'48>59>83'96 In
other words, migraine is a disorder in which
environmental factors and triggers have a ma-
jor impact on genetically predisposed individ-
uals (see Chapters 5 and 6). Analysis of the data
from twin studies has led to estimates that
perhaps 40% to 50% of the liability to migraine
is attributable to genetic effects and the re-
mainder to non-genetic, environmental fac-
tors.37'53'59'105 A reasonable hypothesis is that
a genetic predisposition renders an individual
more or less vulnerable to develop the afflic-
Headache Type Relative
in 1 Relatives Risk*
Migraine with aura 3.8
Migraine without aura =1.0
Migraine with aura 1.4
Migraine without aura 1.9
Migraine 1.95
Migraine 1.42
tion in response to a combination of environ-
mental and internal trigger factors. What is
probably inherited is a lowered biologic
threshold to a variety of external and internal
stimuli.
MODE OF INHERITANCE
The search for genetic risk factors for multi-
factorial disorders, particularly ones without a
biological marker, is complicated by numerous
clinical, genetic, and statistical problems. It is
not surprising, therefore, that family studies
and segregation analyses have produced con-
flicting results about the mode of migraine in-
heritance.63'85'91'96 Over the years, several ge-
netic models have been proposed, including
autosomal dominant transmission with partial
penetrance and autosomal recessive transmis-
sion. The findings that there is an unequal sex
distribution (with female preponderance of 2
or 3 to 1) and that maternal transmission is
more than twice as frequent as paternal trans-
mission may imply involvement of either an
X-linked susceptibility gene or extranuclear
factors. But because cases of father-child trans-
mission are not uncommon, exclusive maternal
inheritance based on the transmission of X-
linked or mitochondrial DNA is moot.3'63
The idea of migraine inheritance based on a
single gene has largely been discarded. If a sin-
gle gene were the cause of migraine, the mi-
graine "gene" would be more widespread than
any other known disease-producing gene.81
That migraine could be a polygenic disorder,

however, in which variation is caused by the ef-
fects of multiple genes at different loci with
varying penetrances, or that migraine could re-
sult from genetic heterogeneity, a situation
where the same or similar phenotypes result
from different genetic mechanisms, is possible.
FAMILIAL HEMIPLEGIC
MIGRAINE
Familial hemiplegic migraine (FHM), a rare
subtype of migraine, is characterized by recur-
rent episodes of headache and hemiparesis.
The age of onset varies from 5 to 30 years with
a predominance during youth. Attacks are usu-
ally stereotyped throughout the patient's life,
so that the hemiparesis typically affects the
same side of the body in all attacks. Charac-
teristically, the neurological symptoms last for
30 to 60 minutes, followed by a unilateral
throbbing headache. The aura, however, can
be prolonged and severe, and the hemiparesis
may accompany or follow, rather than precede,
the headache. The hemiparesis nearly always
resolves without sequelae. The motor deficit is
usually associated with other symptoms in-
cluding hemianesthesia or paresthesia and
hemianopic visual field disturbances. Aphasia,
variable degrees of drowsiness, confusion, or
even coma occasionally accompany attacks.100
The headache is, however, characteristic of mi-
graine and is associated with nausea and pho-
tophobia. The idea that the attacks of hemi-
paresis and headache are typical of migraine is
buttressed by findings that attacks of non-
hemiplegic migraine without aura can occur in
FHM patients. In addition, different individu-
als in FHM families can suffer either from
hemiplegic or non-hemiplegic migraine. These
observations have been used to argue that
FHM is part of the spectrum of migraine, and
that the genes involved in FHM are candidate
genes for other types of migraine as well.93
In approximately 20% of families with FHM,
members develop a mild, but progressive,
cerebellar disturbance with nystagmus and
ataxia, the presumed result of cerebellar atro-
phy.43'78'93 Symptoms of cerebellar ataxia may
occur prior to the first attack of hemiplegic mi-
graine and progress independently of the fre-
quency or severity of these attacks. Members
of other FHM families have developed tremor,
Genetics 33
retinal degeneration, sensorineural deafness,
or recurrent episodes of acute paranoid psy-
chosis.43'45'78'89^
Genetics of Familial
Hemiplegic Migraine
In most families, FHM is inherited as an au-
tosomal dominant characteristic.31'74 Because
some pedigrees contain asymptomatic gene
carriers, penetrance is probably not com-
plete.21 Approximately half of the FHM fami-
lies, including all with progressive cerebellar
ataxia, show genetic linkage to chromosome
19pl3.20'43'45'78'92 On that chromosome, mis-
sense mutations in a gene (CACNA1A) that en-
codes a neuronal voltage-gated P/Q-type Ca2+
channel CKIA subunit (see below) have been hy-
pothesized as being responsible for the disor-
der.4'9'20'76'77 Even though a role for the chro-
mosome 19pl3 locus has been shown in a
number of FHM families, additional genes
must presumably be specified to explain the
disorder's full clinical spectrum. Evidence
against a linkage to chromosome 19 has been
found in approximately 40% of the FHM fam-
ilies, indicating non-allelic genetic heterogene-
ity.45'78 Two separate regions have been found
on the long arm of chromosome 1 in these fam-
ilies.22'26 French families have been linked to
chromosome lq21-23.23 Some patients linked
to the chromosome lq21-23 locus also have
seizures. The other chromosome 1 locus has
been localized at chromosome Iq31. And at
least one other gene must be involved, because
in some families the disorder is not linked ei-
ther to the CACNA1A gene on chromosome
19p or to chromosome 1, yet the characteris-
tics of attacks are similar. A comparison be-
tween chromosome 19-linked FHM families
and families not linked to this chromosome has
revealed that patients from the former group
are more likely to have attacks triggered by mi-
nor head trauma or associated with uncon-
sciousness than are patients from unlinked
families.92
Voltage-gated Ca2+ Channels
Voltage-gated (voltage-sensitive, voltage-
dependent) Ca2+ channels are transmembrane
34 Clinical Aspects of Migraine

Figure 2-1. Structural organization of the voltage-gated Ca2+ channel. The i subunit is composed of four hydropho-
bic domains (I-IV), each containing six transmembrane segments. It forms the central pore of the channel. The ft sub-
unit is entirely cytoplasmic. The az8 subunit is anchored in the plasma membrane by means of the transmembrane seg-
ment of the 8 subunit. (Adapted from De Waard M, Gurnett CA, and Campbell KP: Structural and functional diversity
of voltage-activated calcium channels. In Narahashi T (ed): Ion Channels, Volume 4. Plenum Press, New York, 1996, pp
41-87, with permission.)

proteins that are normally closed at the hyper-
polarized level that characterizes the resting
membrane potential. They open in response to
membrane depolarization to allow Ca2+ ions to
enter the cell from the extracellular space.
Ca2+ channels are multiunit protein complexes
consisting in most cases of i, ft, and a^S sub-
units (Fig. 2-1). The a\ subunit is the central
functional component of the complex; it con-
fers ion selectivity and also regulates the volt-
age sensitivity of die Ca2+ channel. The a\ sub-
unit consists of four domains or motifs (I to IV),
each of which consists of six a-helical segments
that span the membrane. The 24 transmem-
brane segments form a square array around a
central transmembrane pore through which
Ca2+ ions travel. The fourth helix (S4) of each
domain acts as a voltage sensor containing a
positively charged amino acid in every third or
fourth position.
The other Ca2+ channel subunits modify the
characteristics of the a\ component. The /3
subunit, which lacks a helixes capable of span-
ning the membrane, is thought to be entirely
intracellular in location. It is capable of mod-
ulating current amplitude, activation and inac-
tivation kinetics, and voltage dependence when
coexpressed with 0.1 subunits. The a%8 subunit
consists of two glycosylated 2 and 8 polypep-
tides linked together by a disulfide bond. It ap-
pears to influence current amplitude and inac-
tivation of the channel. The 8 subunit traverses
the membrane, while the component is en-
tirely extracellular.
Five different specific subtypes or classes of
voltage-gated Ca2+ channelsL, N, P/Q, and
Rhave been defined on the basis of their bio-
physical and pharmacological properties. The
differences among the different types of chan-
nels are thought to be caused by different iso-
forms of one or more of the subunits. It is the
IA subunit in the P/Q channel that is associ-
ated with FHM (Fig. 2-2). In humans, the ex-
pression of aiA subunits is particularly high in
the cerebellum. Almost all of the Ca2+ current
of Purkinje cells and a large fraction of the
Ca2+ current of cerebellar granule cells are
carried by P/Q channels. P/Q channels are
present in many other central neurons as well.
P/Q channels are located in presynaptic nerve
terminals where they control the depolarization-
induced Ca2+ influx that is tightly coupled to,
and necessary for, neurotransmitter release.
Their additional localization in dendrites and
cell bodies indicates supplementary postsynap-
tic roles.
Direct analysis of the changes in Ca2+ chan-
nel properties in samples of human tissue from

Figure 2-2. Detailed membrane topology of the aiA subunit of the P/Q calcium channel. The locations of the amino
acid substitutions are indicated for some of the mutations that cause familial hemiplegic migraine (FHM) and familial
hemiplegic migraine with cerebellar ataxia (FHM/PCA). , R192Q; 4, V714A; , T666M; A, I1811L; *, D715E.
(Adapted from Ducros A, et al.: Am J Hum Genet 64:89-98, 1999, with permission from University of Chicago Press.)
patients with FHM is not feasible. But muta-
tions corresponding to those in patients with
the disorder can be produced in IA subunits
and, after heterologous expression in other
cells, the biophysical properties of the mutant
channels can be analyzed. The mutations of
IA subunits reported in FHM patients affect
the kinetic properties, the channel density, the
unitary conductance (a measure of the current
that flows through the open channel in re-
sponse to the electrochemical driving force),
and the voltage dependence of Ca2+ channel
activation.34'5*'52 It does appear, however, that
altered channel gating represents the common
pathophysiological mechanism in FHM. De-
pending upon the amount of activity and the
type of neuron, mutations produce both loss-
and gain-of-function in human P/Q Ca2+
channels. The pathophysiological and clinical
consequences of such alterations in channel
function are still unknown, but may result in
disturbed neurotransmitter release. 2
CACNA1A Involvement in Other
Neurological Disorders
The CACNA1A gene is also involved in two
other diseases: episodic ataxia type 2 and spino-
cerebellar ataxia type 6.
Episodic ataxia type 2 (EA2; acetazolamide-
responsive hereditary paroxysmal cerebellar
ataxia; paroxysmal vestibulocerebellar ataxia;
hereditary paroxysmal cerebellar ataxia) is also
an autosomal dominant disorder. Although
there is great intra- and interfamilial variabil-
ity both for the episodic and permanent symp-
Genetics 35
toms, paroxysmal attacks of cerebellar ataxia
lasting from a few minutes to several days char-
acterize the disease.15'76'98 They may start in
childhood or early adulthood. The attacks may
be precipitated by emotional or physical stress,
alcohol, or coffee, but not by startle. Less fre-
quent symptoms include vertigo, nausea,
diplopia, confusion, and generalized sweating.
Attacks of ataxia may be accompanied by head-
ache; patients often develop migraine after
ataxic symptoms have begun.66 They may also
have interparoxysmal migraine attacks. Pa-
tients with EA2 may show a dramatic response
to acetazolamide, which substantially reduces
the frequency of paroxysmal ataxic symptoms.
Some patients develop permanent ataxia with
gait unsteadiness, limb incoordination, and
dysarthria. Interictal nystagmus is common.
Cerebellar atrophy affecting primarily the an-
terior vermis has been demonstrated on imag-
ing studies.
Truncating mutations producing deletions of
part of the O!IA subunit and expanded trinu-
cleotide (GAG) repeats (encoding repeat
polyglutamine units) have been found associ-
ated with EA2.15'41'102 The large phenotypic
variability, however, suggests that environ-
mental or genetic factors other than the
CACNA1A mutation are important.
Point mutations and expansion of GAG re-
peats within the open reading frame of
CACNA1A are found in patients with autoso-
mal dominant spinocerebellar ataxia type 6
(SCA6).40'76'103 Patients with this disorder suf-
fer from a late-onset, mild, but progressive
ataxia affecting the limbs and gait, dysarthria,
nystagmus, and cerebellar atrophy. Several
36 Clinical Aspects of Migraine
groups have reported episodic features in
SCA6 patients with many of the features of
EA2, suggesting that SCA6 and EA2 represent
a clinical continuum.28'40'42 It appears that dif-
ferent mutations in CACNA1A cause a spec-
trum of disorders, with overlapping symptoms
that make a strict genotype-phenotype corre-
lation difficult.
Interestingly, mutations in the aiA subunit
gene have also been identified in the tottering
(tg) and leaner (t^a) mice, two strains of epilep-
tic mice with seizures remarkably similar to
those in human absence epilepsy.19'24 The tot-
tering mutation results in spike-and-wave dis-
charges, mild ataxia, and intermittent convul-
sions. The leaner mutation displays ataxia,
stiffness, retarded motor activity, and signs of
absence seizures.
IS MIGRAINE A
CHANNELOPATHY?
Inherited voltage-dependent ion-channel mu-
tations (channelopathies) are the cause of sev-
eral neurologic disorders in humans. As exam-
ples, mutations in K + channels underlie the
symptoms in episodic ataxia type 1, mutations
in Cl~ channels are responsible for myotonia
congenita, mutations in Na + channels produce
hyperkalemic periodic paralysis and paramyo-
tonia congenita, and mutations in Ca2+ chan-
nels result in hypokalemic periodic paralysis.
These disorders are largely characterized by
paroxysmal events. It is not understood how al-
tered ion permeability could precipitate pro-
longed central nervous system (CNS) dysfunc-
tion. Nonetheless, it is intriguing to speculate
that the symptoms of migraine may be pro-
duced at least in part by a channelopathy in-
volving Ca2+ permeability. It has been sug-
gested that migraine is a disease of altered
neural excitability whose threshold for the trig-
gering of attacks is set by the function of Ca2+
channels (see Chapter 12).65
The discovery that FHM is linked to muta-
tions in a gene located on chromosome 19p that
encodes a neuronal Ca2+ channel IA subunit
has spurred attempts to define the putative role
of this genetic locus in individuals suffering
from more common forms of migraine. Data
conflict as to whether nonhemiplegic migraine
with or without aura is associated with the
chromosome 19p locus, but it does appear that
some families with migraine are linked to the
chromosome 19p locus.38>49)58>64'71'93 Data in-
dicate that the IA subunit gene is involved in
some families with migraine both with and
without aura; its contribution to patients with
aura, however, appears strongest. Migraine
presumably is a heterogeneous disorder; and
one gene for typical migraine may be located
at the chromosome 19p locus.
CADASIL
Cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalop-
athy (CADASIL) is a rare hereditary disorder
characterized by migraine, stroke or transient
ischemic attacks, and dementia. Although the
clinical picture varies among families, smaller
case series and meta-analyses have convinc-
ingly shown that migraine with and without
aura constitute a distinctive feature of the dis-
ease.16'54 For example, migraine defined by
IHS criteria was present in 38% of individuals
in a series encompassing nine families with
CADASIL.18 Several studies have shown that
migraine may be the earliest manifestation of
CADASIL, and that its prevalence increases to
about age 50 (Figs. 2-3, 2-4).10'11'16'39'97 Most
patients with CADASIL have attacks of mi-
graine without aura, but migraine with aura,
migraine aura without headache, migraine with
prolonged aura, hemiplegic migraine, and basi-
lar migraine have all been described.18 Patients
with CADASIL typically experience recurrent,
subcortical ischemic events leading to a step-
wise decline in function. The disease leads to
death in 20 to 25 years after a period of de-
mentia associated with pseudobulbar palsy, gait
disturbance, and bilateral pyramidal signs.1 >18
One of the hallmarks of the disease is the
presence of striking abnormalities in the white
matter on magnetic resonance imaging (MRI).
More or less diffuse white matter hyperinten-
sities predominating in periventricular regions
are typical. Some lesions resemble those seen
in typical cases of migraine (see Chapter 7). In
CADASIL, however, the white matter changes
are usually associated with small lacunar in-
farctions in the thalami, basal ganglia, and
pons. Abnormalities on MRI may be demon-
strated early in the course of the disease. They
may be found not only in symptomatic patients
 Genetics 37

Figure 2-3. Initial symptoms of CADASIL, sorted by decade of age of onset. Filled bars, stroke or transient ischemic
attack; hatched bars, migraine; open bars, depression; striped bars, other. (Adapted from Desmond DW, Moroney JT,
Lynch T, et al.: The natural history of CADASIL. A pooled analysis of previously published cases. Stroke 30:1230-1233,
1999, with permission)

but also in presymptomatic individuals with the
mutated gene.
CADASIL has been linked to mutations of
the NotchS gene, which lies in close proximity
to the CACNA1A Ca2+ channel gene on chro-
mosome 19pl3 that carries one of the muta-
tions causative of FHM.44'46 All CADASIL
families are apparently linked to this locus.
Multipoint linkage data suggest that the ge-
netic loci responsible for the two conditions re-
side within an interval of about 30 centimor-
gans on chromosome 19.94 The NotchS gene

Figure 2-4. Kaplan-Meier graph for migraine in patients with CADASIL. Cumulative frequency for migraine in 102 pa-
tients with CADASIL (separated by gender). (From Dichgans M, Mayer M, Uttner I, et al.: The phenotypic spectrum of
CADASIL: clinical findings in 102 cases. Ann Neurol 44:731-739, 1998, with permission.)
38 Clinical Aspects of Migraine
encodes a transmembrane protein with a re-
ceptor and cell signal transduction function.
How alterations in NotchS lead to the
CADASIL phenotype is not understood.
MIGRAINE AND
MITOCHONDRIA!. DISORDERS
The role of mitochondria! dysfunction in sev-
eral diseases associated with attacks of mi-
graine is being increasingly investigated. Such
dysfunction can result from changes in mito-
chondria! DNA (mtDNA) or from nuclear
DNA defects. Mitochondria contain their own
DNAa genetic code that is different from the
DNA code found in the nucleusand a tran-
scriptional and translational machinery uncon-
nected to that in the nucleus. The human mi-
tochondrial genome is a 16,569 base-pair circle
of double-stranded DNA. Because mitochon-
drial DNA is transmitted exclusively from
mothers to their children, diseases caused by
point mutations of the mitochondria! genome
have a maternal inheritance. In contrast to nu-
clear genes, which are present in two copies
per cell, each cell can incorporate hundreds of
mitochondria each with several copies of the
mitochondria! genome. Frequently, mutant
mtDNA and normal mtDNA in different mi-
tochondria may coexist in varying proportions
within the same cell. This phenomenon ac-
counts for some of the variability in the clini-
cal expression of mtDNA mutations.
There are at least three inherited mitochon-
dria! problems that are associated with migraine-
like attacks. Two of thesemitochondria! en-
cephalopaihy, lactic acidosis, and stroke-like
episodes (MELAS) and myoclonic epilepsy
with ragged red fibers (MERFF)are caused
by point mutations of mtDNA and involve de-
fects in energy transduction in the respiratory
chain. A third, ornithine transcarbamylase de-
ficiency, is produced by a nuclear DNA muta-
tion. It is characterized by a defect in the urea
cycle owing to abnormalities in an enzyme lo-
cated in mitochondria.
MELAS
MELAS constitutes a distinct syndrome that
affects the CNS and skeletal muscle. Migrain-
ous phenomena are frequent and prominent in
the majority of patients.36 The recurrent at-
tacks of severe pulsatile headache with nausea
and vomiting seen in almost 75% of patients
with MELAS resemble, or are identical to,
bouts of migraine.36 Such migraine, however,
is often complicated, and may result in pro-
tracted, frequently permanent, neurological
deficits.75
Although the disease can be quite heteroge-
neous, most patients with MELAS appear nor-
mal at birth and during early childhood. Symp-
toms typically start before age 15. By age 40,
almost all affected individuals suffer from
stroke-like occurrences that produce focal neu-
rologic deficits such as hemiparesis and apha-
sia. These infarcts occur frequently in the
occipital region, leading to homonymous hemi-
anopias in more than half the patients. Some
develop cortical blindness. Mitochondria! an-
giopathy characterized by accumulations of ab-
normal mitochondria in vascular smooth mus-
cle and endothelial cells cause the infarcts.73
Other symptoms and signs include ataxia, fo-
cal or generalized seizures, ophthalmoplegia,
visual and hearing loss, and dementia in vary-
ing combinations. Muscle biopsies show ragged
red fibers.
Some patients with MELAS lack the com-
plete clinical picture.68 As an example, moth-
ers of affected individuals have mild but defi-
nite symptoms in keeping with the maternal
inheritance of the disease. In addition, some
other relatives often have incomplete clinical
expression of the MELAS phenotype or may
be asymptomatic. These latter individuals dem-
onstrate ragged red fibers on muscle biopsy or
have elevated lactic acid levels. Migraine may
be a major feature in patients with the incom-
plete syndrome or in relatives of MELAS pa-
tients.
The MELAS phenotype is associated with
six mitochondrial DNA mutations, although
most cases result from point mutations at base
pair 3243 or 3271 in the mtDNA gene for
tRNAleu(UUR).32
MERFF
MERFF can begin at any age from late child-
hood to adulthood. Episodic hemicranial head-
ache is an attribute of MERFF, even though
the other manifestations of the disease may

vary. The range of clinical features in a single
family extends from severe CNS dysfunction
with deafness, ataxia, spasticity, generalized
seizures, myoclonus, dementia, and myopathy
with weakness in a limb-girdle distribution to
asymptomatic myopathy with ragged-red fibers
in muscle biopsy specimens.87 Most cases are
caused by a point mutation in the tRNALys
gene at position 8344.88
Ornithine Transcarbamylase
Deficiency
The enzyme ornithine transcarbamylase (OTC)
is incorporated into the mitochondria! matrix
attached to the inner mitochondrial mem-
brane. The structural gene encoding for OTC
has been mapped to the short arm of the X
chromosome. OTC deficiency is therefore in-
herited with an X-linked recessive pattern.
More than 100 mutations have been described
in families with OTC deficiency: large dele-
tions in 8% of patients; small deletions/inser-
tions in a further 10%; and the remaining mu-
tations confined to single base substitutions.62
Deficiency of OTC, an enzyme in the Krebs-
Henseleit urea cycle responsible for catalyzing
the formation of citrulline from ornithine and
carbamyl phosphate, results in hyperammone-
mia (Fig. 2-5). Ammonia is highly toxic to the
brain where it interferes with energy produc-
tion and with the normal metabolism of neu-
rotransmitters. Because of severe ammonia in-
toxication, males with the deficiency rarely
survive the neonatal period. The partial defi-
ciency seen in heterozygous females produces
a variable clinical course that depends upon the
level of residual enzyme and the degree of hy-
perammonemia. The phenotypic variability
ranges from apparent normality to the same se-
vere onset with the profound neurologic im-
pairment observed in hemizygous males.
Migraine-like headaches accompanied by nau-
sea and vomiting are frequent after protein in-
gestion in adult women with a partial OTC de-
ficiency.30 A few patients have an altered level
of consciousness accompanying the headache.
The history of these patients usually reveals
protein intolerance, self-restriction of high
protein-containing foods, and severe vomiting
with lethargy during viral infections. The diag-
nosis of OTC deficiency can be established by
enzyme analysis of liver or intestinal tissue.
Genetics 39
Fumarate
Figure 2-5. Schematic diagram of the urea cycle show-
ing the role of ornithine transcarbamylase (OTC) in the
detoxification of ammonia.
HLA ANTIGENS
Human leukocyte antigen, or histocompatibil-
ity leukocyte antigen (HLA) genes encode in-
tegral membrane proteins essential in the pre-
sentation of antigens to T lymphocytes. Genes
in the HLA system have a marked effect on
susceptibility to a variety of diseases, especially
autoimmune ones. Although they show famil-
ial recurrence, such diseases have uncertain
but presumably multifactorial etiologies so that
the relation with HLA alleles identifies only
one of the genetic factors that predispose the
disorder to appear. The emerging picture is
that HLA-complex genes are necessary, but not
sufficient, for even the most strongly HLA-
associated diseases to develop. As to migraine
and HLA alleles, we have only fragmentary in-
formation. Some data show an increase of
shared HLA haplotypes in families with mem-
bers who suffer from migraine with aura.29 A
study of Italian migraine patients showed no
alteration in the distribution of HLA class I A,
B, and C antigen frequency. HLA class II DR2
antigen, however, was found to have a de-
creased frequency in Italian migraineurs with
aura when compared either to control patients
or to patients with migraine without aura.57
40 Clinical Aspects of Migraine
POLYMORPHISMS ASSOCIATED
WITH MIGRAINE
SUSCEPTIBILITY
As noted above, a migraine susceptibility locus
may have been localized to chromosome 19pl3
not only in the rare FHM but also in the
more common forms of familial typical mi-
graine.38'58'93 A second locus in such families
may be present on chromosome Xq.70 Several
searches have been made for mtDNA muta-
tions in migraine, with varying results.6>33'50'56'82
Association studies assess the frequency of
certain genetic markers in migraine patients
when compared to individuals from a control
population. The results of such studies have
been interesting, even though definitive data
have not been forthcoming. Because altered
monoaminergic neurotransmission has been
hypothesized to be involved in the pathogene-
sis of migraine, dysfunctional genes for sero-
tonin (5-HT) and dopamine (D) systems have
been sought. Studies using linkage and associ-
ation analyses have excluded mutations in the
5-HT1B, 5-HTiD, 5-HT2A, and 5-HT2C recep-
tor genes.7'8'64'69 As for the allelic distribution
of the serotonin transporter gene, differences
have been described between individuals who
have migraine either with or without aura and
unaffected controls.72
Two groups of investigators have found data
that implicate changes in dopamine receptors
in migraineurs. The Ncol polymorphism in the
gene encoding the D2 receptor (DRD2) has
been found more frequently in patients with
migraine with aura than in controls or in pa-
tients with migraine without aura.80 In other
words, susceptibility to migraine with aura is
significantly modified by DRD2 Ncol Al alle-
les. In addition, the distribution of allele 1 at
the DRD2 locus differed significantly from
controls in a subgroup of migraineurs with pu-
tatively enhanced dopamine sensitivity (based
on the presence of both nausea and yawning
during the migraine attack).14
SUMMARY
Clinicians have long thought that migraine oc-
curs in certain families and have postulated
that susceptibility to migraine has a genetic
component. Concordance of migraine in
monozygotic as compared to dizygotic twins
provide cogent evidence for such a genetic
component, but also indicate that only 40% to
50% of the probability of developing migraine
is attributable to genetic effects. In other
words, the mode of inheritance of migraine is
presumably multifactorial.
Advances in molecular biology, however,
have led to some exciting insights into the ge-
netics of migraine. It is now clear that at least
50% of the families with familial hemiplegic
migraine show genetic linkage to mutations in
a neuronal voltage-gated P/Q-type Ca2+ chan-
nel ctiA subunit gene (CACNA1A) located on
chromosome 19pl3. The same gene is involved
in episodic ataxia type 2 and spinocerebellar
ataxia type 6, and may be implicated in some
families with more common types of migraine.
Progress has also been made in describing and
characterizing the clinical picture and genetic
bases of several other genetic disorders in
which migraine is a part. These include
CADASIL, MELAS, MERFF, and ornithine
transcarbamylase deficiency. In sum, the pat-
terns of typical migraine inheritance appear
complex. The exact mode of migraine inheri-
tance and the precise role of genetic factors in
the pathogenesis of the disorder are yet to be
clarified.
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1. Ad Hoc Committee on Classification of Headache:
Classification of headache. JAMA 179:717-718.1962.
2. Alonso Vilatela ME, Garcia Pedroza F, Ziegler DK,
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Chapter 3
Clinical Manifestations
PHASES OF MIGRAINE ATTACKS
MIGRAINE WITHOUT AURA AND
MIGRAINE WITH AURA
PATTERN OF MIGRAINE ATTACKS
PREMONITORY SYMPTOMS
(PRODROMES)
MIGRAINOUS AURAS
Visual Symptoms
Perceptual Alterations
Non-visual Hallucinations
Somatosensory and Motor Symptoms
Vertigo
Cognitive and Communicative
Disturbances
Combined Aura Symptoms
THE FREE INTERVAL
MIGRAINOUS HEAD PAIN
Intensity of Head Pain
Location of Head Pain
Migraine is characterized by the periodic
emergence of attacks with a constellation of
signs and symptoms of almost infinite variety.
Most investigators of migraine have concen-
trated on headache as the defining variable, but
head pain is only one component of a complex
malady whose many features clearly comprise
a generalized disorder. The systemic, neuro-
logic, cognitive, affective, gastrointestinal, and
autonomic symptoms that can accompany the
headache indicate disturbed function of the
cerebrum, brainstem, hypothalamus, eye, in-
tracranial and extracranial vasculature, and au-
tonomic nervous system. The nature of an in-
dividual attack can range from a few symptoms
to a major siege in which all aspects of the dis-
order are manifest. As will become evident
44
Lower-half Migraine
Idiopathic Stabbing Headache
SYMPTOMS ASSOCIATED WITH
ATTACKS OF MIGRAINE
Photophobia, Phonophobia, and
Osmophopia
Gastrointestinal Complaints
Autonomic Changes
Fluid Retention
Neuro-otologic Symptoms
Changes in Emotions, Cognition, and
Consciousness
Acute Confusional Migraine
Syncope
BEHAVIOR DURING ATTACKS
TERMINATION OF ACUTE MIGRAINE
ATTACKS AND POSTDROMIC STATE
SUMMARY
from the diverse clinical manifestations de-
scribed in this chapter, migraine cannot be
viewed simply as an intermittent annoyance.
That may be the case for individuals who suc-
cessfully treat themselves with over-the-
counter analgesics and who never seek a physi-
cian's care. But for a tremendous number of
people, migraine must be thought of as a prob-
lem that can lead to profound, striking, and
sometimes frightening alterations in their qual-
ity of life.
PHASES OF MIGRAINE ATTACKS
The typical attack of migraine consists of a se-
quence of events that Harold G. Wolff, the pi-

Table 3-1. Classification of Migraine
1. MIGRAINE
1.1 Migraine without aura
1.2 Migraine with aura
1.2.1 Migraine with typical aura
1.2.2 Migraine with prolonged aura
1.2.3 Familial hemiplegic migraine
1.2.4 Basilar migraine
1.2.5 Migraine aura without headache
1.2.6 Migraine with acute onset aura
1.3 Ophthalmoplegic migraine
1.4 Retinal migraine
1.5 Childhood periodic syndromes that may be
precursors to or associated with migraine
1.5.1 Benign paroxysmal vertigo of childhood
1.5.2 Alternating hemiplegia of childhood
1.6 Complications of migraine
1.6.1 Status migrainosus
1.6.2 Migrainous infarction
1.7 Migrainous disorder not fulfilling above
criteria
From the Headache Classification Committee of the In-
ternational Headache Society.72
oneer American investigator of headache, di-
vided into three phases: (1) preheadache, (2)
headache, and (3) postheadache.158 Blau, the
most careful and precise contemporary clinical
investigator of migraine phenomena, has pro-
vided cogent evidence that attacks of migraine
could be further subdivided into five stages: (1)
prodrome, (2) aura, (3) headache, (4) resolu-
tion, and (5) postdrome.14 An additional phase
might be included: the "free interval" between
the aura and the onset of headache.16 In the
individual mlgraineur, an attack can consist of
any or all of these phases.32 Some bouts, for
example, exclude the head pain, but consist of
a prodrome, aura, and postdrome.
MIGRAINE WITHOUT AURA
AND MIGRAINE WITH AURA
The presence or absence of an aura, an episode
of focal transient neurological dysfunction, in
the preheadache phase of a migraine attack has
historically been used to separate migraine into
two subtypes that before 1988 were designated
classic migraine and common migraine. The
Clinical Manifestations 45
term common merely implies that migraine
without an aura is the most frequent variety.
Today, common migraine and classic migraine
have been replaced by migraine without aura
and migraine with aura in the scheme of the
International Headache Society (IHS) (Tables
3-1, 3-2, and 3-3). According to this scheme,
migraine with aura also includes the subcate-
gories migraine with prolonged aura, familial
hemiplegic migraine, hasilar migraine, mi-
graine aura without headache, and migraine
with acute-onset aura. By definition, well-
defined episodes of focal neurological dys-
function do not precede or accompany attacks
of migraine without aura. In contrast, attacks
of migraine with aura are associated with strik-
ing neurological manifestations that are usually
visual, but at times are sensory, motor, vestibu-
lar, or cognitive.
Although the absence or presence of the
aura serves to separate individual attacks of mi-
graine without aura from attacks of migraine
with aura, whether they are discrete entities,
disparate expressions of the same disorder,
or pieces of a continuum is controver-
sialte.43,100,128,133,155During & person's Hfe-
time, one type of migraine may evolve, progress,
or metamorphose into another, or a person
may have both types with equal or different
frequencies. The aura sometimes disappears as
patients age. Migraine without aura may be
converted to migraine with aura by the use of
Table 3-2. Diagnostic Criteria for
Migraine without Aura
(Common Migraine)
At least five attacks lasting 4 to 72 hours
Headache has at least two of the following
characteristics:
Unilateral location
Pulsating quality
Moderate or severe intensity
Aggravation by routine physical activity
At least one of the following occurs during
headache:
Nausea and/or vomiting
Photophobia and phonophobia
Normal neurological exam and no evidence of
organic disease that could cause headaches
Adapted from the Headache Classification Committee
of the International Headache Society.72
46 Clinical Aspects of Migraine
Table 3-3. Diagnostic Criteria for
Migraine with Aura (Classic Migraine)
At least two attacks
Aura must exhibit at least three of the following
characteristics:
Is fully reversible and indicative of focal
cerebral cortical and/or brain stem dysfunction
Has gradual onset
Lasts less than 60 minutes
Is followed by headache with a free interval of
less than 60 minutes, or headache may begin
before or simultaneously with the aura
Normal neurological exam and no evidence of
organic disease that could cause headaches
Adapted from the Headache Classification Committee
of the International Headache Society.72
oral contraceptives.8 The head pain in both
types of migraine responds in a similar manner
to abortive medication, and both have pro-
dromes and postdromes.
Despite such similarities, the clinical im-
pression remains that migraine with and with-
out aura differ in a number of respects, even
though no agreement exists as to the differ-
ences.100'128'^-39 Women do seem more likely to
have migraine without aura than migraine with
aura; there is no such difference among
men.128 Patients suffering from migraine with-
out aura are often thought to have more fre-
quent and longer lasting attacks, but not all in-
vestigations have demonstrated this.43'100'128
Similarly, migraine attacks without aura were
believed to be associated more often with pho-
tophobia and vomiting and accompanied by bi-
lateral head pain. Recent population-based
epidemiologic data do not sustain this be-
lief.100'128 The relationship between migraine
attacks and female hormonal fluctuations (in-
cluding menstrual precipitation and the effect
of oral contraceptives) appears stronger in pa-
tients who suffer from migraine without aura
than in migraineurs with aura.38'128-133 Mi-
graine attacks that occur for the first time dur-
ing pregnancy are likely to occur with aura.33'38
And in patients with migraine without aura, we
are uncertain whether attacks are more likely
to be precipitated by environmental situations,
emotional states, and psychological stresses
than attacks in patients with migraine with
aura.100'128 Epidemiologic data indicate that
bright lights are a precipitating factor for pa-
tients with aura, but not for patients without
aura.133 Clinical experience is, however, at vari-
ance with this conclusion. In sum, the clinical
differences between the two types of migraine
remain unclear.
MIGRAINE
PATTERN OF MIGRAINE
ATTACKS
Attacks of migraine can show themselves in
countless ways.86'113'139 An episode may begin
at any time of the day or night. Some patients
are awakened from sleep with an intense
pounding headache. Not infrequently, patients
awaken in the morning to discover that a head-
ache is developing. Other headaches begin
early in the day and slowly increase in inten-
sity. Overall, however, there appears to be a
circadian variation in the onset of migraine at-
tacks; most seem to develop early in the morn-
ing (Fig. 3-1).61
Similarly, the frequency of attacks varies
greatly among individuals. More than half of
the adult patients who visit neurological clinics
have between one and four attacks a month.139
One or more severe headaches per month are
reported by 59% of females and 50% of
males.149 About 15% suffer more than 10 at-
tacks a month. Among migrainous children, the
frequency of headaches varies from once
monthly to two or three times a week.10'37
Population studies indicate a frequency that
is somewhat lower than reports from headache
clinics.120'127'149 Stewart and colleagues have
estimated that the median attack rate for ac-
tive migraine sufferers in different investiga-
tions ranges from 0.4 to 1.5 attacks per
month.149 The median attack rate is lower for
men than for women. Various other accounts
have indicated that only 2% of patients have
more than three attacks per week, that only
2.1% of subjects suffered from 0.6 to 3.5 at-
tacks per week, and that 13.8% of patients had
between three and six attacks per week.73'120-149
Daily migraine attacks are rarely reported.106
In a large German population study, a mean
attack rate of 2.82 days per month was de-
scribed (Fig. 3-2).65 In a similar study in The
Netherlands, migraineurs experienced a me-
dian of 12 attacks per year and more than 25%
of migraineurs experienced an attack at least
twice a month.87

Figure 3-1. Circadian periodicity in the time of onset of 3582 migraine headaches endured by 1698 patients. Zero rep-
resents midnight. Note the peak in the early morning hours. (Adapted from Fox AW and Davis RL. Migraine chronobi-
ology. Headache 38:436-441, 1998, with permission.)
35
Figure 3-2. Number of migraine headache days per
month in migraine patients diagnosed by IHS criteria and
surveyed in a large German population study. (Adapted
from Gobel H, Petersen-Braun M, and Soyka D. The epi-
demiology of headache in Germany: a nationwide survey
of a representative sample on the basis of the headache
classification of the International Headache Society.
Cephalalgia 14:97-106, 1994, with permission of Blackwell
Science Ltd.)
Clinical Manifestations 47
Some individuals have had only two or three
episodes in their entire lives. Moreover, the
frequency of migraine attacks may vary signif-
icantly throughout a patient's lifetime. Some
patients have periods of remission that last for
months or even years. Other patients' attacks
take on a cyclical pattern.105 For such individ-
uals, headaches occur almost daily for a few
weeks, after which there is a headache-free or
relatively headache-free interval. The cycle
may be repeated many times a year. Many of
these patients complain of depression during
cycles.
PREMONITORY SYMPTOMS
(PRODROMES)
A proportion of migraineurs experiences a va-
riety of early systemic, mental, and/or psycho-
logical premonitory symptoms that precede the
aura (if any) and the headache phase of a mi-
graine attack. Although it has been suggested
that premonitory symptoms are specific for
bouts of migraine, similar symptoms may pre-
cede tension-type headaches. 27 Premonitory
symptoms are often very subtle and can antic-
ipate the aura or head pain by several hours,
or even by days.2'12'14'127'152 Such symptoms
are designated "premonitory" symptoms or
"prodromes," but there is confusion because
48 Clinical Aspects of Migraine
the term prodrome has been used by some as
a synonym for the term aura.
Prodromes and auras, however, have differ-
ent characteristics. Auras develop relatively
rapidly and generally last minutes, and the
symptoms indicate significant neurological dys-
function with abnormalities of visual, so-
matosensory, motor, speech, or brain stem
function. Prodromal symptoms begin insidi-
ously, may last several hours to days, and char-
acteristically involve changes in mood, ap-
petite, and energy levels. Prodromes occur
more frequently than auras, although their pre-
cise frequency is unknown. Figures vary
widely: they are reported to occur in between
7% and 88% of migrameurs.12'14'78'128'135'152'153
Presumably the lower figures are low because
many patients have not been taught to recog-
nize often vague prodromal symptoms for what
they are. Prodromes are more common in pa-
tients with migraine with aura than in patients
with migraine without aura, and are more com-
mon in women than in men.2
Many prodromes go unrecognized because
they duplicate incidental discomforts that are
part of ordinary life and are passed off with
comments such as, "It's one of those days," or
"I got up on the wrong side of the bed." Many
patients fail to associate prodromes with mi-
graine attacks until the relationship between
prodrome and headache is called to their no-
tice. Furthermore, in a given migraineur, head-
aches do not consistently follow every pro-
drome. In other words, migraineurs may have
prodromal symptoms as the only manifestation
of some of their migraine attacks.
Prodromal symptoms vary widely among pa-
tients. Individuals may experience discrete sets
of symptoms on different occasions. As seen in
Table 3-4, prodromes may include changes in
mood and behavior; symptoms suggestive of
nervous system involvement; fatigue; symp-
toms referable to the cervical musculature; and
gastrointestinal manifestations.12'69'135'139'152 A
feeling of depression coupled to a sense of las-
situde is the most consistent prodrome. Irri-
tability and moodiness also occur frequently.
Some patients may develop symptoms often as-
sociated with the headache phase, such as pho-
tophobia and ill-defined blurring of vision. But
other patients experience a sense of well-being
with increased energy and lucidity of thought,
an increased appetite especially for sweets, and
an unusual capacity for work. Some patients
Table 3-4. Migraine Prodromes:
Premonitory Symptoms and Signs
Changes in Mood or Behavior (mental state)
Irritability, difficulty thinking, overactivity,
euphoria, excitement, depressive feelings,
sluggishness, withdrawal, obsessional behavior,
anxiety, apathy
Neurological Symptoms
Excessive yawning, trembling hands, phonophobia,
photophobia, hyperosmia, blurred vision,
accommodation disturbances, dysphasia,
impaired concentration, dizziness, tinnitus
General Symptoms
Excessive physical fatigue (or the opposite: an
unusual capacity for work), pallor, gooseflesh,
shivering, aching muscles, increased urinary
frequency, fluid retention
Symptoms Related to Head
Cervical muscle stiffness or pain, heavy-
headedness
Gastrointestinal Symptoms
Hunger, craving for food, bulimia, swollen or
painful epigastrium, nausea, anorexia,
constipation, increased bowel frequency
Data from Amery et al. (1986),2 Blau (1987),14 and
Waelkens (1985).152
become unusually talkative the evening before
attacks. Except for yawning and irritability, a
prodrome is said to be unusual in childhood
migraine. 89
MIGRAINOUS AURAS
It is not known how frequently episodes of
well-defined, transient, focal neurological dys-
function, or auras, accompany headaches in
adult migraineurs (see Chapter 1), but it is
thought that auras are more common in adult
than in childhood migraine.10'37'76'122'128 In
some individuals, an aura is present before
each and every migraine attack but in other pa-
tients, it accompanies only a small proportion
of attacks.155 Some patients may have only a
few auras during their lifetimes. The intensity
of auras also varies among attacks; sometimes
the aura is vivid and impressive, sometimes it
is nearly indiscernible. Usually the focal neu-
 Clinical Manifestations 49

rological disturbance develops before the head

pain commences, but on occasion an aura may
appear or recur at the height of the headache.
Some patients have identical neurological dis-
turbances without an ensuing headache.
By far the most frequently encountered
auras consist of disturbances of vision, but an
aura may consist of virtually any neurological
symptom (Table 3-5) .80>128 The symptoms may
remain constant from attack to attack, or they
may vary in successive attacks. Some patients,
for example, have only visual auras preceding
bouts; others may have a visual aura preceding
one attack and a somatosensory aura preced-
ing another. In addition, patients not infre-
quently report progression of symptoms from
one type of aura to another.80 Thus, a patient
may have a visual aura preceding the develop-
ment of paresthesias in the hand and face. Only
visual auras typically occur in isolation (Fig.
3-3).
An aura generally takes between 5 and 40
minutes to develop to its peak and usually lasts
between 5 and 60 minutes.131 It lasts more than
an hour in 6% to 12% of cases.100'132 In rare
cases, the aura, particularly if it is visual, may
reach its peak of intensity abruptly.58'59'131'132
Table 3-5. Types of Migraine Auras
Visual, Sensory, and Perceptual Disturbances
Visual (scotomas, scintillating scotomas, photopsias)
Somatosensory (cheiro-oral numbness/paresthesias)
Olfactory
Auditory
Gustatory
Visual hallucinations
Metamorphopsia
Alice-in-Wonderland phenomena
Vertigo
Motor Abnormalities
Hemiparesis
Dysarthria
Aphasia
Behavioral Alterations
Dreamy states
Delirium
Dejd vu/jamais vu
Depersonalization
Figure 33. Venn diagram illustrating the distribution of
various aura symptoms and the overlap in patients who had
two or more symptoms. (Adapted from Russell MB and
Olesen J: A nosographic analysis of the migraine aura in a
general population. Brain 119:355-361, 1996, with per-
mission of Oxford University Press.)
For the most part, such auras with acute onset
occur in individuals who have aura without
headache.58-59'93 The duration and additional
characteristics of auras with abrupt onset are
otherwise typical of migraine with aura.
Visual Symptoms
As noted above, visual auras constitute by far
the most frequent type of aura.132 Most are
unilateral (i.e., involving one hemianopic field
of vision), but approximately 30% are reported
to be bilateral (i.e., involving both fields of vi-
sion).132 Visual disturbances can be divided
into two main types: positive visual phenom-
ena with hallucinations, and negative visual
phenomena (scotomas}, characterized by par-
tial obliteration, or complete loss of vision, in
a portion or the whole of the visual field. Both
positive and negative visual symptoms can arise
from disturbances located in the retina or in
the occipital lobes. However, retinal distur-
bances that produce symptoms are rare com-
pared to visual disturbances caused by cerebral
dysfunction.
Photopsias are the simplest type of visual
hallucination, and one of the most common
(Fig. 3-4).122 Photopsias are white or colorless
small spots or dots, stars, sparks, unformed
50 Clinical Aspects of Migraine

Figure 3-4. Characteristic types of visual auras. Upper row depicts different types of photopsias: (left) diffuse, flickering
spots or dots; (middle) similar spots, but denser in the left hemifield of vision; (right) so-called grouped dysopsias. Lower
row: (left) fortification spectrum with scotoma in the right hemifield of vision and diffuse flickering spots in the left hemi-
field field of vision; (middle) fortification spectrum with scotoma involving both fields of vision; (right) complete right-
sided homonymous hemianopia. (Adapted from Bucking H and Baumgartner G: Klinik und Pathophysiologie der initialen
neurologischen Symtome bei fokalen Migranen (Migraine ophthalmique, Migraine accompagnee). Arch Psychiatr Ner-
venkr 219:37-52, 1974, with permission of Springer-Verlag.)

flashes of light, streaks of light, wavy lines, or spread to the center, and in rare cases spread
simple geometric forms and patterns.84 They to the contralateral visual field. A negative sco-
frequently flicker, glisten, sparkle, or shimmer. toma may completely escape observation even
Their margins are usually sharp. Only a few or by a careful observer unless it blurs or obscures
many hundreds of dots or spots may be pres- a target to which attention has been addressed.
ent at a time. Reports of colored photopsias are
rare.30 Photopsias may be restricted to one part
of the visual field, often arising in the central
portion. In other cases they are noted in the
temporal fields of vision or scattered through-
out the entire visual field. They generally last
from seconds to several minutes. Simple pho-
topsias may also occur during the headache
phase of the attack.
Migraine sufferers may develop almost any
type of negative scotoma. They may have hom-
onymous hemianopic or quadrantic field de-
fects, central scotomas, tunnel vision, altitudi-
nal visual defects, or even complete blindness.
In some patients a central scotoma appears, but
as it enlarges the central field clears (Fig. 3-5).
In some cases a partial or complete loss of vi-
sion begins in the center and gradually in-
creases in size, spreading outward to the pe-
riphery of the visual field. Some patients report
that only central vision is depressed or lost.
Figure 3-5. Drawing of a progressive central scotoma
Many migraineurs report patchy scotomas with with a serrated edge. The scotoma progressively enlarges
irregular contours. In a small number of pa- to occupy most of the central field of vision. Vision is in-
tients, scotomas appear in the periphery and tact outside the edge, but is lost within it. (From Gowers.66)

The loss of vision may materialize as the visual
hallucinations subside, or visual loss may be
present from the onset. Other patients describe
their vision as blurred, opaque, or foggy. Oth-
ers state that their vision is distorted as if they
were viewing shimmering or flickering objects
though heated air or through a film of rippling
water.
Scintillating scotomas are regarded as the
most characteristic visual hallucination, yet
they are described by only 20% of patients with
visual auras.122 Such scotomas consist of an ab-
sent arc or band of vision (negative scotoma)
with a shimmering or glittering zigzag bor-
der.130 The border usually oscillates in bright-
ness at a fast rate. It may be white, gray, or
colored, although most scintillations are un-
colored. Many migraineurs note that the visual
abnormality begins in the center of the visual
field with an ill-defined loss of vision or per-
ception similar to that seen following the dis-
charge of a photographic flashbulb. During
the next few minutes, the area of disturbed vi-
sion slowly expands laterally over a period of
10 to 30 minutes and develops a bright border.
This gradual expansion has been termed build-
up, and usually leaves an area of impaired or
obscured vision behind it.59 In some instances
there is no scotoma, but only a scintillating bor-
der. Not all scintillating scotomas begin near
the fixation point. A few patients invariably ex-
perience scintillating scotomas that start pe-
ripherally in their visual fields. Patients per-
ceive scintillating scotomas with their eyes
opened or closed. Of interest in this regard is
the report of a patient with scintillating sco-
tomas that occurred after enucleation of both
eyes.1 All authorities accept the idea that hemi-
anopic scintillating scotomas are the result of
occipital cortical events.
Scintillating scotomas can assume diverse
geometric designs, but are usually perceived as
semicircular, crescent-shaped, or horseshoe-
shaped visual defects bordered by moving,
shiny streaks of light (Fig. 3-6). The streaks of
light may have a jagged or serrated outline. The
hallucinations frequently resemble the pattern
formed by the bastions of a fort or of a me-
dieval fortified town observed from above. (It
does not have the right-angled, crenelated ap-
pearance of a battlement.) Accordingly, the
term fortification spectrum is used (spectrum
from the Latin spectare, to look or see; in this
context, spectrum is not used to mean a col-
ored band of light). Scintillating scotomas are
Clinical Manifestations 51
Figure 3-6. Diagrams of two types of fortification spec-
tra. In each case the black area represents a region of tran-
sient loss of vision. The dot is the point of fixation. (From
Richards W: The fortification illusions of migraines. Sci
Am 224:88-96, 1971. Copyright 1971 by Scientific Amer-
ican, Inc. All rights reserved.)
also referred to as teichopsias (from the Greek
teikhos, fortification or town wall, and opsis, vi-
sion). Most of our descriptions and text illus-
trations of elaborate scintillating scotomas are
the result of drawings made by physicians and
other trained observers of their own scotomas.
A large proportion of scintillating visual auras
are, however, simple in nature. They typically
consist of flickering, colored or uncolored, uni-
lateral or bilateral zig-zag lines or patterns,
semicircular or arcuate patterns, wavy lines, or
irregular patterns.131
As emphasized by Daroff, not all unformed
simple visual hallucinations are migrainous.41
For example, phosphenes are photopsias and
may be produced by vitreal, retinal, optic nerve
or chiasmal disease, or in normal individuals by
eye trauma. They can also be produced by elec-
trical stimulation of the visual pathways from
the eye to the occipital lobe. One of the most
common causes is detachment or separation of
the posterior vitreous resulting from changes
in the properties of the vitreous that occur with
aging. Vitreous adhesions exert traction on the
retina causing recurrent episodes of photop-
sias.3 Monocular photopsias, usually of a fleet-
ing nature, are described by patients with com-
pressive, inflammatory, demyelinating, and
vascular disease of the optic nerve and chiasm,
and by patients with a variety of ocular prob-
lems such as retinal detachment or tear, reti-
nal emboli, and inflammation or infection of
the retina or choroid. In contrast, photopsias
that develop in a hemianopic pattern are al-
most always considered migrainous in etiology.
Subclinical visual impairment is not uncom-
mon in migraineurs between headaches. It is
52 Clinical Aspects of Migraine

usually not apparent to the patient and requires

perimetric, psychophysical, or electrophysio-
logical testing to uncover.34'140'142

Perceptual Alterations
In addition to photopsias and teichopsias,
achromatopsia (absence of color) and palinop-
sia (visual perseveration) have been re-
ported.4'139 Migraineurs also describe formed,
complex visual hallucinations and disturbances
of visual perception. Such hallucinations may
be exceedingly intricate, although geometric
shapes far outnumber the formed visions. On
very rare occasions, the hallucinations consist
of bizarre and elaborate apparitions of people
in detailed scenarios that have distorted spatial
relationships.27 A twelfth century nun, Hilde-
gard of Bingen, had countless visions that some
now consider migrainous in nature (Fig. 3-7).
In the Middle Ages, visions were thought to
have otherworldly origins, so Hildegard could
freely describe them in her mystical writings.
Today, however, many patients may be reluc-
tant to introduce the subject because of ap-
prehension that the bizarre characteristics of
their symptoms will cause attending physicians
to regard them as irrational or even deranged.
Metamorphopsia is another well-described
visual perceptual abnormality that occurs as an
aura.84 Patients with metamorphopsia describe
distortions and alterations of the shape and
contours of objects. They may also have the il-
lusion that objects or persons are altered in
size, position, or color. The most common type Figure 3-7. "Vision of the Fall of the Angels" from Hilde-
of illusions are of changes in sizemicropsia gard of Bingen manuscript Scivias (c. 1180) possesses an
impressive similarity to the visual phenomena associated
and macropsiawhere all or part of the sur- with an attack of classic migraine.
roundings abruptly and momentarily appear ei-
ther incongruously larger or smaller than their
actual size.1'68 Objects may also be perceived or small, are rare symptoms described by mi-
as farther away (telopsid). graineurs. Other patients may have illusions of
Bizarre subjective perceptual alterations of shrinking or elongation of the entire body, or
the body shape or image also occur.27 They are the body may feel as if it is distorted in shape.
called "Alice-in-Wonderland phenomena" in Patients have described feeling as if a part of
the neurological literature because during her the body such as the neck, the ear, or die hip
travels in Wonderland, Alice occasionally be- 'balloons out,' or the head feels as if it were en-
comes notably tall or short, or distorted in larged and floating toward the ceiling.96
shape (Fig. 3-8). As an aside, there is debate
as to whether the distorted figures in the story
are related to the migraine suffered by Lewis Non-visual Hallucinations
Carroll, the author of Alice in Wonderland.20
Macro- and microsomatognosia, perceptions Although visual hallucinations are common
that a part of their body is anomalously large among migraineurs, hallucinations of the other
 Clinical Manifestations 53

Somatosensory and Motor

Symptoms

Somatosensory symptoms are frequent auras,

second in frequency to visual symptoms, and
occur in approximately 20% to 35% of patients
who have migraine with aura.30'80'100'1^52 Most
Somatosensory auras are associated with visual
auras.131'132 They consist of feelings of numb-
ness or sensations of tingling or of pins and nee-
dles in circumscribed parts or in all parts of one
half of the body. The distribution of symptoms
varies among patients and, on occasion, in the
same patient during different attacks.
One common type of Somatosensory distri-
bution involves die hand, face, and tongue
(cheiro-oral or digito-lingual paresthesias}
(Fig. 3-9).74'80'100 Involvement of the tongue
is very typical. The radial or ulnar digits may
be involved, and the paresthesias may ascend
to include the entire hand and forearm. The
paresthesias may march up an extremity, pass-
ing from one finger to another to subsequently
involve the whole hand, but most often the area

Figure 3-8. Drawing from the original edition of Alice in

Wonderland. It illustrates the complex distortion in shape
that can be associated with the auras of migraine.

special senses are unusual, but not unheard of.

Auditory hallucinations generally consist of
hissing, growling, or rumbling noises that, on
occasion, are accompanied by dullness of
sound or by diminished auditory acuity.134
More highly organized auditory hallucinations
such as music are extremely rare. Migrainous
olfactory hallucinations are also infrequent, but
have been described in 1% to 13% of clinic pa-
tients.4'109 The hallucinated smell is typically
strong and usually, but not always, unpleasant.
Hallucinations of burning rubber, decaying an-
imal flesh, and bacon frying have been de- Figure 3-9. Cheiro-oral type of sensory loss involving the
side of the mouth and the entire hand. (Adapted from
scribed by patients. These olfactory phenom- Bruyn GW: Cerebral cortex and migraine. Adv Neurol
ena can last anywhere from 5 minutes to 24 33:151-172, 1982, with permission from copyright holder
hours 62,109,137,156 Lippincott Williams & Wilkins, Inc.)
54 Clinical Aspects of Migraine

Figure 3-10. Drawings of a sensory aura recorded every 5 minutes by a 23-year-old woman. The sensory symptoms (tin-
gling) were preceded by a visual aura. Left-sided tingling started in the hand and then gradually progressed to the arm,
body, leg, foot, face, and tongue. The paresthesias reached their maximum development in 25 minutes and lasted 60 min-
utes. The attack was also accompanied by speech disturbance and left hemiparesis. (Adapted from Russell MB, Iversen
HK, and Olesen J: Improved description of the migraine aura by a diagnostic aura diary. Cephalalgia 14:107-117, 1994,
with permission of Blackwell Science Ltd.)

of abnormal sensation begins in the fingers and
then bypasses the arm and shoulder to involve
the angle of the mouth, one-half of the lips and
tongue, the buccal mucosa, and the cheek. On
occasion, paresthesias or numbness are felt in
the foot and the leg. The cheiro-oral pattern of
sensory disturbance can be caused by dysfunc-
tion located in the cortex of the parietal lobe,
but there is also evidence that lesions of the
ventrobasal thalamus and brain stem or of the
operculum can cause this remarkable pat-
tern.24'83 Some patients describe loss of sensa-
tion in various distributions that resemble
those commonly seen in patients with stroke or
transient ischemic episodes (Fig. 3-10). In
some cases, the numbness may be bilateral and
extend to both hands, all four limbs, the circu-
moral region, and both sides of the tongue.29'74
The somatosensory symptoms may be brief,
persisting only for several seconds to minutes,
but they typically take up to 30 minutes to de-
velop fully. Some patients report that the
paresthesias appear at all sites simultaneously.
The leisurely expansion of most sensory symp-
toms is analogous to the build-up of visual
teichopsias. Paresthesias in a forelimb may be
accompanied by subjective feelings of heavi-
ness or clumsiness of the arm or hand and usu-
ally implies mild, transient motor weakness.
Quite often paresis is associated with impaired
coordination, but severe paresis is rare. Disor-
ders of speech (dysarthria) may also accom-
pany paresthesias in some patients. Their
speech may be slow, slurred, faltering, or even
stammering. The dysarthria is presumed to be
secondary to sensory abnormalities of the
tongue and/or mouth.
Limb pain has been described accompany-
ing attacks of migraine.67'129 Its frequency in
clinic patients may vary from 3.2% to 4.4%.
Some individuals have unilateral pain that may
alternate sides in different attacks. The upper
extremities are more affected than the lower.
The pain may vary in severity. The clinical fea-
tures suggest that it is of central origin.
Vertigo
True vertigo, the illusion of rotational envi-
ronmental movementalone or associated
with nausea and vomitingnot infrequently
constitutes a migraine aura.84'139 Such vestibu-
lar symptoms usually last only a few minutes,
but can persist for an hour. About one-third of
children with migraine describe attacks of ver-
tigo or dizziness just before the onset of a bout
of migraine or during the headache phase.154
In some individuals, the vestibular symptoms
are accompanied by dysarthria, diplopia, and
other symptoms of brain stem dysfunction, but
in other patients the symptoms presumably
originate in the labyrinth and are unaccompa-
nied by evidence of brain stem involvement.
Cognitive and Communicative
Disturbances
On occasion, during more prolonged migrain-
ous auras, patients become confused and dis-
oriented as a result of major alterations of cere-
bral integrative functions.134 Dreamy states,
delirium, intense feelings of dejd vu orjamais

vu of extended duration, and transient states of
depersonalization have been noted, although
most of the reports are not well documented.
The mental symptoms may continue well into
the headache phase.
Aphasia is well described as an aura of a mi-
graine attack. Difficulties with word-finding
(Broca's aphasia] appear to be the most com-
mon type.4 The aphasic symptoms tend to be
mild. Some patients describe paraphasias or
impaired comprehension of language. Dysar-
thria is present in about one-half of patients
with aphasic auras.132 Alexia with and without
agraphia can also occur as an aura, as can
acalculia.4
Combined Aura Symptoms
Visual auras are the only types of auras that reg-
ularly occur by themselves. Although it is pos-
sible for them to occur alone, most other
typessomatosensory, motor, speech, cogni-
tive, and communicative symptomscom-
monly follow visual auras.74'80'132 When two or
more aura symptoms occur in a single attack,
they regularly occur in succession, not concur-
rently. The most common pattern is for visual
symptoms to be followed by somatosensory
symptoms, and then hemiparesis.
THE FREE INTERVAL
The free interval is the period between the end
of an aura and the onset of headache (not to
be confused with the headache-free, or inter-
ictal, interval between attacks).16 Most patients
describe alterations in mood, detachment from
the environment or other people, fears, dis-
turbances of speech or thought, or somatic
symptoms such as lethargy, light-headedness,
and nausea.16
MIGRAINOUS HEAD PAIN
Headache is generally considered the hallmark
of the migraine attack. However, it must be
stressed that headache is never the only symp-
tom of a migraine attack. Indeed, presence of
headache pain is not even characteristic for
some individuals. The feature of migrainous
head pain most often emphasized is its throb-
Clinical Manifestations 55
bing or pulsatile nature. Despite this empha-
sis, most attacks do not begin with throbbing
pain. In their initial phases, the discomfort of
many migraine attacks is characterized as a
mild or dull, deep, steady ache or sensation of
pressure. The pain generally becomes more in-
tense over a period of minutes to hours. It may
then develop the throbbing quality described
by patients as "pounding," "hammering,"
"beating," or "banging." Between 47% and
82% of patients indicate that their head pain
has a pulsating quality.77'113'126 In those pa-
tients who do have such a throbbing compo-
nent, the throbbing character of the pain is sig-
nificantly correlated with its intensity. Pain of
this kind frequently reverts to a constant dis-
comfort as the attack progresses. Patients who
complain of a steady nonpulsatile type of head
pain find that Valsalva maneuvers or bending
over to pick an object from the floor may pro-
duce a pulsating quality.32 Patients with steady
head pain describe it as a "pressing," "squeez-
ing," "splitting," or "vise-like" sensation and,
less often, as a "sharp" or "sickening" pain.
Whatever the quality, the duration of the
head pain can vary from a few hours to several
days. The IHS criteria require a headache du-
ration of between 4 and 72 hours, but 12% to
27% of patients experience pain for less than
4 hours. >77'139 It lasts for less than a day in
two-thirds of patients.127'139 Some patients,
however, have extended attacks lasting several
days. In general, the duration of headaches is
longer in women than in men.149 Migrainous
head pain frequently has a much shorter dura-
tion in children than in adults (see Chapter I).90
Intensity of Head Pain
It is typical for the intensity of the head pain
to vary from attack to attack in the same pa-
tient. Sometimes the pain is so subtle that its
existence is only perceived when the head is
rapidly moved or when the patient bends over.
During other attacks, the pain may be of such
intolerable intensity that die patient is totally
incapacitated. In addition, the head pain usu-
ally fluctuates during a migraine attack. Some
patients experience pain waxing and waning in
slow cycles for the duration of the attack. For
others the pain may come on rapidly, or build
up gradually to a peak and stay at that level for
the duration of the attack.
56 Clinical Aspects of Migraine
Figure 3-11. Severity of headaches in patients with mi-
graine, episodic tension-type, and chronic tension-type
headaches surveyed in a large German population study
(see Fig. 3-2). (Adapted from Gobel H, Petersen-Braun
M, and Soyka D. The epidemiology of headache in Ger-
many: a nationwide survey of a representative sample on
the basis of the headache classification of the International
Headache Society. Cephalalgia 14:97-106, 1994, with per-
mission from Blackwell Science Ltd.)
Although quantification of pain intensity is
subjective, the majority of migraine patients
describe their headache as severe (Fig.
3-11).73'94'127 Less than 20% of patients, how-
ever, describe the pain as terribly severe or al-
most unbearable. However, approximately
80% of migraineurs state that their pain has an
intensity of 7 or greater on a scale of 1 to 10
(0, no pain; 10, pain as severe as it can be).73
During bouts of headache, the severity of pain
is significantly greater in patients with migraine
than in patients diagnosed with tension-type
headaches. Pain intensity is a substantial de-
terminant of the disability produced by a par-
ticular migraine attack. However, some mi-
graineurs without intense pain may be disabled
by significant vomiting, photophobia, phono-
phobia, or other symptoms, or because they re-
quire bed rest. In contrast, other patients may
have severe pain without being disabled.
Attempts have been made to define the
severity of attacks. Varying definitions of sever-
ity lead to varying estimates of how frequent
severe migraine attacks occur. It has been
found, however, that when severe bouts of mi-
graine are defined as (1) lasting more than 12
hours; (2) associated with disability (very re-
duced working capacity or bed rest); and (3)
unresponsive to medication, they are found to
constitute less than 1% of all attacks.108 The
data may be inadequate, however, because
physicians and patients often fail to discuss
headache-related disability during consulta-
tion. Disability is an influential factor deter-
mining perceptions of headache severity.
Location of Head Pain
The word migraine is a French word derived
from the Latin hemicrania, which in turn came
from the Greek hemikranios, a term intro-
duced by Galen. Put simply, the word's ety-
mology implies the presence of hemicranial or
unilateral symptoms and, as a result, undue
emphasis has been placed on the necessity of
a unilateral distribution of headache for diag-
nosis. Indeed, most definitions have stressed
the unilateral nature of the head pain in mi-
graine attacks. In actuality, migrainous head
pain is strictly unilateral only in 56% to 68% of
adult patients and in 22% to 31% of childhood
migraineurs.10'37'86'113'126'133'145 A bilateral
pain distribution is more characteristic in chil-
dren (see Chapter 1).
If the pain is unilateral, the side involved in
successive attacks may vary, or the pain may
recur consistently on the same side in each at-
tack. Between 15% and 20% of patients with
migraine with aura or migraine without aura
report that the same side of the head is involved
throughout lifeso-called side-locked unilat-
erality.40'92'145 Some patients have a relative
proclivity for one side. For others the pain in-
volves one side for months, then switches to
the opposite side, alternates sides, or becomes
bilateral. Additionally, some patients state that
headaches are consistently more painful and
severe when a particular side of the head is in-
volved. It is also possible for the pain to change
from one side to the other during the course
of a single attack. Many patients say that the
pain is always bilateral and symmetrical, or that
the pain involves the entire head. For others,

an initial hemicrania often develops into a
holocranial headache.
One would expect that the head pain in mi-
graine with aura would be invariably localized
over the cerebral hemisphere from which the
focal neurological symptoms emanated, yet
one-third to one-half of patients with visual and
sensory auras, when questioned after their at-
tacks, indicate that they have ipsilateral head-
aches.80'101'118'122'139 However, when patients
are questioned during attacks, the vast major-
ity indicate that the headaches are located on
the side of the cerebral hemisphere responsi-
ble for their aura symptoms.132
Migrainous head pain in both adults and
children most often involves the frontotempo-
ral region of the head or is located in, around,
or behind an eye. However, any region of the
head or face may be affectedthe parietal re-
gion, the base of the nose, the upper or lower
jaw or teeth, the malar eminence, the upper
anterior neck, and the postauricular region.
The occiput and the vertex are less common
loci of pain, particularly at the onset of the at-
tack. The pain may persist in one sharply de-
fined area such as the medial wall of the orbit,
or it may radiate to involve one-half of the
head. As a migraine attack continues, the pro-
cess often involves the cervical paraspinal mus-
culature and the trapezius muscles. Some pa-
tients, however, comment that their migraine
attacks begin with a dull, aching pain in the
neck and shoulders, which then radiates ante-
riorly to involve the temple or eye.
The scalp as well as the pericranial and cer-
vical muscles often become tender during
acute attacks.50'113 These areas are more ten-
der in patients with frequent headaches than
they are in patients with a few days of head-
ache per month.50 The sternocleidomastoid,
posterior cervical, and trapezius muscles are
most frequently affected. During unilateral
bouts of migraine, tenderness on the side of
the head pain is more pronounced than on the
contralateral side. The scalp is frequently ten-
der in the forehead, the temples, and the oc-
ciput, but is generally most severe at the locus
of the headache.50'139 It may prevent the pa-
tient from lying on the affected side. Residual
scalp and muscle tenderness may persist for a
day or more after the acute attack has termi-
nated.50 The muscle and scalp tenderness has
traditionally been ascribed to dilatation of ex-
tracranial arteries, but this idea is suspect be-
Clinical Manifestations 57
cause the temporal muscle blood flow does not
significantly change during migraine attacks.79
Another hypothesis suggests that muscle pain
and tenderness are caused by reflex muscle
spasm as a result of the migraine pain, although
no data support this supposition. Recorded
electromyograph (EMG) levels during attacks
are not high.6'35
Patients with migraine may also have tender
carotid and superficial temporal arteries on the
same side as a hemicranial headache.124 Some
patients find that manual compression of the
superficial temporal artery produces transient
abatement of pain.21'54 A rare patient may even
compress the ipsilateral carotid artery to pro-
cure some Tf 1 '~ r for a few minutes. Placing an
ice pack on the scalp or neck decreases pain
intensity for some migraineurs, although oth-
ers favor the application of heat to the head.
Still others may gain some pain reduction from
a hot shower or bath.
Lower-half Migraine
Some patients find that their the migrainous
pain is limited to structures located below the
level of the eyes; accordingly, this type of at-
tack has been named lower-half or facial mi-
graine. The pain of lower-half migraine is usu-
ally unilateral, involving the nostril, cheek,
gums, and teeth. This syndrome has features
such as nausea, vomiting, and photophobia
usually associated with migraine headache lo-
cated in cranial structures. Lower-half mi-
graine is an unusual affliction that may be con-
founded with atypical facial pain, trigeminal
neuralgia, or cluster headache. Its identifica-
tion and differentiation from these other enti-
ties are necessary, because lower-half migraine
responds to the usual therapies for migraine.
Migrainous pain is also said to originate from
the extracranial carotid artery in the neck.47'124
The term carotidynia is sometimes used to re-
fer to this rare problem, although it is uncer-
tain if carotidynia is an acceptable nosological
entity. The pain is described as throbbing and
is located either in the neck, at the angle of the
jaw, or in the jaw itself. It may radiate to the
ipsilateral side of the face and ear, and may be
associated with headache. The pain is charac-
teristically aggravated by head movements,
swallowing, chewing, coughing, yawning, and
sneezing. Attacks last for hours or days, recur-
58 Clinical Aspects of Migraine
ring several times a week or a month over a pe-
riod of years. Conspicuous carotid pulsations,
tenderness, or swelling of the neck are some-
times present on the side of the pain.
Idiopathic Stabbing Headache
Superimposed on a rm'grainous headache or oc-
curring during interictal periods may be ultra-
short, severe, discrete, jabbing, sharp pains that
have been compared to an ice pick, needle,
knife, or nail. Various terms have been used for
them: idiopathic stabbing headaches, ice
pick-like pains, sharp short-lived head pains,
jabs and jolts, needle-in-the-eye syndrome, and
ophthalmodynia periodica.104'1'6'125'148 The
pains seem to occur spontaneously, character-
istically around the orbit or the temple, and less
frequently in the occipital and parietal areas
(Fig. 3-12).116 If there is a preferred site for
their customary headache, patients often ex-
perience them at that site. Although charac-
teristically located on the side of the headache,
they may be bilateral. Most patients experience
only single jabs, although some have volleys of
jabs. Although unusual, episodes may occur up
to 50 times a day. Each jab lasts only 1 to 2
seconds; several or multiple jabs usually last
Figure 3-12. Areas of pain produced by the jabs of idio-
pathic stabbing headache in a group of 38 patients so af-
fected. (Adapted from Pareja JA, Ruiz J, de Isla C, al-Sab-
bah H, and Espejo J: Idiopathic stabbing headache (jabs
and jolts syndrome). Cephalalgia 16:93-96,1996, with per-
mission from Blackwell Science Ltd.)
Figure 3-13. Age of onset of symptoms in a group of 38
patients with idiopathic stabbing headache. (Adapted from
Pareja JA, Ruiz J, de Isla C, al-Sabbah H, and Espejo J:
Idiopathic stabbing headache (jabs and jolts syndrome).
Cephalalgia 16:93-96, 1996, with permission from Black-
well Science Ltd.)
from 5 to 10 seconds. There is great variabil-
ity in the frequency, and an unpredictable long-
term pattern. They tend to develop later in life
than migraine headaches (Fig. 3-13).
The prevalence of this type of headache in
migraine patients is high42% in one study.125
Ice pick-like pains have also been reported as
an isolated headache problem with a lifetime
prevalence of 2%.128 They are also present in
some patients with cluster headaches, tension-
type headache, chronic paroxysmal hemicrania,
hemicrania continua, and temporal arteritis.
Trigeminal neuralgia and short-lasting uni-
lateral neuralgiform headache attacks with
conjunctival injection, tearing, sweating, and
rhinorrhea (SUNCT) are differential diagnos-
tic possibilities that may be confused with id-
iopathic stabbing headache. In the case of
trigeminal neuralgia, the existence of trigger
points and response to carbamazepine are
valuable distinguishing characteristics. Patients
with SUNCT complain of unilateral headache
with frequent (5 to 30 times per hour), short-
lasting (15 to 60 seconds) attacks of pain.64'115
The pain occurs in and around one eye and is
accompanied by ipsilateral conjunctival injec-
tion that is frequently intense, often with im-
pressive lacrimation and (subclinical) forehead

sweating. The syndrome may be identified by
a lack of response to carbamazepine and by its
significant autonomic concomitants.143'144
SYMPTOMS ASSOCIATED WITH
ATTACKS OF MIGRAINE
Headache is typically the most dramatic oc-
currence in a migraine attack, but it is only one
of a host of oppressive symptoms associated
with the attack.
Photophobia, Phonophobia,
and Osmophobia
Intolerance of light and noise are among the
most frequent symptoms associated with mi-
grainous head pain. During an attack, between
66% and 88% of patients are believed to
develop an amplified and usually unpleasant
sensitivity to light (photophobia).49'113'126'139
Quantitative investigations have shown that
the threshold for visual and auditory discom-
fort falls substantially during migraine at-
tacks.49'55'150'159 Of interest are findings that
migraineurs also have a lowered threshold
for light discomfort between attacks when
compared to control individuals (Fig. 3-
14) 98,99,150,159 interictal photophobia appears
to be a common and troublesome symptom.111
Photophobia may thus be an intrinsic property
of migraineurs. The extreme intolerance to
light usually consists of a combination of two
quite different sensations: photophobia is eye
pain, induced, or exacerbated, by exposure to
bright light; dazzle is an uncomfortable or in-
tolerably exaggerated sense of brightness or
glare.88
1 OQ
An excessive sensitivity to and intolerance of
noise involving a feeling of discomfort or pain
(phonophobia) is present in between 70% and
83% of migraine patients during attacks.82
Sounds of moderate intensity such as conver-
sational speech, the noise of traffic, or the
sound of a television may seem unacceptably
loud to a migraineur in the throes of an attack.
During bouts of migraine, patients fre-
quently complain of a heightened sense of
smell (hyperosmia) and an aversion to some
odors (osmophobia). Perhaps as many as 40%
of patients have these symptoms.23 Patients
may develop an exaggerated dislike for odors
Clinical Manifestations 59
Figure 3-14. Visual discomfort in migraineurs and con-
trol subjects. The visual discomfort threshold was lower in
migraineurs than in controls during the interictal period
and fell significantly during bouts of migraine. (Adapted
from Woodhouse A and Drummond PD. Mechanisms of
increased sensitivity to noise and light in migraine head-
ache. Cephalalgia 13:417-421,1993, with permission from
Blackwell Science Ltd.)
that are usually offensive but frequently toler-
able, such as cigarette smoke or diesel exhaust,
and they may also experience an increased
awareness of smells ordinarily perceived as
pleasant, such as subtle perfumes.23 Strong
perfumes or colognes and heavily scented sta-
tionery or magazine advertisements may cause
great distress. Food aromas may induce or ac-
centuate nausea. Some patients feel that all
smells acquire an intense and often foul qual-
ity. It is unclear, however, whether olfactory
thresholds are lower or higher in migraine suf-
ferers than in controls between attacks.75'146
Gastrointestinal Complaints
In the course of a migraine attack, the major-
ity of patients complain of problems with their
gastrointestinal tracts. Gastrointestinal distur-
bances are thought to be more common or
more prominent in children, but this claim is
difficult to confirm from published data.76 The
symptoms usually begin after the inception of
the pain, but may sometimes precede the head-
60 Clinical Aspects of Migraine
ache. Whether the attacks of migraine are in-
consequential or overwhelming, approximately
90% of patients report that they experience
nausea.8"'113'133 Nausea accompanied by vom-
iting affects more than half of adult mi-
graineurs.86'113'139 Emesis may develop within
an hour of the onset of the head pain, but it
can also occur late in the course of an attack.
For some migraine sufferers, the onset of vom-
iting ushers in a noticeable decline in the sever-
ity of the headache and even its conclusion.
Some patients intentionally induce vomiting to
obtain respite from the head pain. In contrast,
other patients suffer from prolonged, severe at-
tacks of vomiting. Their vomiting constitutes a
potentially harmful aspect of a migraine attack.
Such vomiting must be treated vigorously, for
it is the principal reason, in company with ex-
cessive sweating and diarrhea, for intense fluid
and electrolyte depletion that can cause pros-
tration.
Gastrointestinal symptoms other than nau-
sea are common. Diarrhea coexists with nau-
sea and vomiting in between 10% and 20% of
migraineurs.113 Some patients complain of
constipation and abdominal distension. Attacks
may also be accompanied by a sense of heavi-
ness in the epigastric region, belching, and flat-
ulence. Gastric emptying is delayed during mi-
graine attacks even in those patients who do
not complain of vomiting.25 The delayed gas-
tric emptying may be accompanied by gastric
dilatation or prolonged contraction.
Eating during a migraine attack is rarely re-
ported.18 However, some few migraineurs do
eat, have cravings for specific foods, or even
have an increased appetite.
Autonomic Changes
Structures innervated by the autonomic ner-
vous system often malfunction during the
course of an acute migraine attack. Most pa-
tients become pale.21 Sometimes the face de-
velops localized edema, which is most promi-
nent in the temporal and periorbital regions.
Dilatation of the superficial temporal artery is
observed during the height of the pain in ap-
proximately one-third of patients. On occasion,
the forehead may become flushed and hot on
the side of the hemicranial pain as a result of
extracranial vasodilatation. Injection of the
conjunctiva and lacrimation may be seen on the
side of the headache. Rarely, this process may
be profound, and result in extravasation of
blood sufficient to produce subconjunctival
hemorrhages, epistaxis, or periorbital ecchy-
moses.36'45'147 The strain of vomiting can also
contribute to the hemorrhage. At least 20% of
migraineurs complain of nasal congestion dur-
ing migraine attacks.15 The turbinates may be
engorged and may lead both patient and physi-
cian to an erroneous diagnosis of sinus head-
ache. Some patients with frequent migraine
headaches are so disturbed by the nasal con-
gestion that they overuse, and may be become
addicted to, nose sprays containing nasal de-
congestants.
Ptosis and miosis (Homer's syndrome} have
been observed during the height of attacks of
migraine with or without aura an attack.46'51"53
The Homer's syndrome usually appears dur-
ing the headache phase and is almost always on
the side of the headache if the pain is hemi-
cranial. It usually subsides when the headache
is over, but may remain for hours or even days.
A permanent Horner's syndrome may develop.
During attacks of migraine without aura, the
mean pupil diameter is smaller in patients than
in non-headache control subjects. l The cause
of the pupillary change is unknown. Pharma-
cologic tests used to assess sympathetic pupil-
lary function have produced contradictory con-
clusions, linking pupillary responses to central
adrenergic hypofunction, adrenoceptor hyper-
sensitivity, or peripheral postganglionic peri-
carotid sympathetic involvement.4"'53'57 Some-
times the pupil dilates on the side of the head
pain and on rare occasions may even become
insensitive to light.85 Adie's tonic pupil has
been described during bouts of migraine.121
Many patients complain of cold, clammy
hands and feet and may feel cold all over or
suffer from chills. In contrast, profuse sweat-
ing is a complaint in some patients, and fever
occasionally occurs during attacks.91'157 Tachy-
cardia is present in about 3% of patients dur-
ing migraine attacks.26 Hypertension, which is
thought to be related to the pain, is frequently
present, although hypotension and bradycardia
may also occur.
Fluid Retention
Before an attack approximately 50% of mi-
graineursmore often women than menre-

tain fluid and sodium. During a period lasting
hours to days, there may be a weight gain of
2 to 10 pounds, so that shoes, belts, and rings
may feel tight.114 Some patients may note ol-
iguria as a prodromal symptom, and then ex-
perience polyuria immediately after the in-
ception of the head pain or during the
recession of the headache. In the pre-
headache phase, the serum sodium rises.31
Decreased excretion of sodium and water is
usually observed prior to and during the early
phase of a migraine attack.136 As the attack
subsides, sodium and water excretion in-
creases. In addition, the serum osmolality is
usually elevated just before a migraine attack
and decreases during an attack.112 Because
administration of diuretics does not typically
prevent or modify the headache, retention of
fluid and sodium is presumably not a cause of
migraine attacks.
Neuro-otologic Symptoms
Patients who suffer from migraine frequently
complain of what they call "dizziness" during
attacks of otherwise typical migraine. Perhaps
three-quarters of migraineurs attending a mi-
graine clinic have vague, transitory periods of
giddiness, lightheadness, heavy-headedness, or
unsteadiness associated with some or all of
their attacks.139 These symptoms are often ini-
tiated or augmented by changes in posture or
head position, such as from sitting to lying or
more often rising from a horizontal or stooped
position.82 These symptoms occur more fre-
quently during the headache phase than dur-
ing the prodrome or aura and may last from
minutes to several hours, sometimes persisting
as long as the headache does. In addition, some
patients complain of true vertigo during an at-
tack.39
The potential for migraine to cause hearing
loss is low, but fluctuating low-frequency hear-
ing loss without progression has been noted in
patients with migraine-related dizziness and in
patients with basilar migraine.81'95'117 Migraine
has also been implicated as the cause of sud-
den hearing loss that persists.95'151 Such pa-
tients report the abrupt onset of a profound
hearing loss over a period of seconds to min-
utes. They may show some gradual improve-
ment, but are often left with a severe unilat-
eral sensorineural hearing loss.
Clinical Manifestations 61
Changes in Emotions, Cognition,
and Consciousness
A number of studies have investigated the rela-
tionship between headaches and mood.5'69'70'102
Many migraineurs feel discontented, discour-
aged, or even profoundly depressed during an
attack. Others feel anxious, irascible, irritable,
and hostile. A loss of control is common, and
verbal stimuli that would under normal cir-
cumstances evoke little or no emotional re-
sponse may trigger verbal outbursts. Many pa-
tients are well aware that they are behaving
unreasonably, yet they are helpless to change
their behavior. Most migraine sufferers are
sensible and defensive enough to crave isola-
tion, seclusion, and darkness, and to reject in-
timacy or even the presence of others. Yet al-
though most patients feel listless, apathetic,
weak, and fatigued during an attack, some
notably stubborn and obsessional individuals
make no compromises with an attack and con-
tinue to work, with or without the help of
analgesics. If an attack is severe enough, how-
ever, most migraineurs do retire to their beds,
darken their rooms, decrease the ambient tem-
perature, and lie still. Many are lethargic,
drowsy, or even irresistibly sleepy.
Cognitive changes are frequent during mi-
graine attacks. Patients complain of reduced
ability to concentrate, decreased capacity to
comprehend the meaning and significance of a
text or conversation, slow thinking (bradyphre-
nia), impairment of memory and attention, and
an inability to think or express themselves
clearly.11'110 Many migraineurs report mental
"fuzziness" or "cloudiness."107 Those mi-
graineurs who persist in working often find that
work performed during the course of a mi-
graine attack has to be carefully checked the
next day for grammatical, arithmetical, and log-
ical errors. Cognitive impairment may persist
for several hours after the end of an attack.
Some patients develop a more severe or-
ganic mental syndrome during the headache
phase of the attack. The problem, referred to
as dysphrenic migraine by European clini-
cians,28 is characterized by problems with ab-
stract thought and orientation. Some patients
have difficulty with word-finding, construct
paraphasias with the usage of incorrect, inap-
propriate, or unintelligible words, make
spelling errors, and suffer from dyscalculia. Mi-
62 Clinical Aspects of Migraine
grainous inability to read without loss of abil-
ity to write (alexia without agraphia) has been
documented during attacks. '60 Severe mem-
ory lapses may cause a total inability to re-
member conversations or discussions. Patients
may suffer major alterations in consciousness
that include twilight states, dreamy states,
delirium, and even stupor.89 Many of the lat-
ter problems have been associated with basilar
migraine or hemiplegic migraine. Even psy-
chosis with visual and auditory hallucinations
has been reported during or following a bout
of migraine. '63>84'97
Acute Confusional Migraine
Unlike the minor cognitive changes and the
more dysphrenic migraine, other patterns of
mental confusion during migraine have been
described for many years.86 An unusual con-
fusional state (acute confusional migraine] oc-
curs in children and in adolescents.44'56'141
The syndrome is more frequent in males than
in females. Episodes are characterized by the
acute onset of inattention, disorientation, dis-
tractibility, bewilderment, and severe mem-
ory difficulties. These symptoms are often as-
sociated with agitation, and purposeless,
irrational behavior. Some patients are violent
enough to require physical restraint. In oth-
ers, a stuporous state may develop. Episodes
of confusional migraine are usually brief, last-
ing 30 minutes to 6 hours, but they can per-
sist up to 12 or 24 hours. Symptoms may wax
and wane. Such a state may occur in the ab-
sence of head pain or in the presence of in-
significant head pain, but usually occurs after
the onset of a throbbing headache. The head-
ache may be accompanied by nausea and vom-
iting and other usual symptoms associated
with attacks of migraine. Patients recover with
no lasting sequelae but are frequently amnes-
tic for the episode. Although some cases oc-
cur after relatively trivial head trauma, the di-
agnosis of the first episode of acute
confusional migraine is typically made in ret-
rospect, when other causes such as acute
toximetabolic encephalopathy and encephali-
tis have been excluded.56 Recurrent episodes
are seen in 25% of patients with acute confu-
sional migraine.
Syncope
Syncope is estimated to occur during bouts of
migraine headache in approximately 5% of
adult patients and less frequently in chil-
dren.86'119 The incidence is higher for individ-
uals with basilar migraine (see Chapter 4). Syn-
cope most often occurs when patients arise
from bed. The loss of consciousness is tran-
sient, rarely lasting more than a minute. It is
thought to be a consequence of postural hy-
potension caused by vasomotor instability com-
bined with fluid and electrolyte depletion from
vomiting.71 The finding that many migraineurs
have orthostatic symptoms between attacks is
in support of this hypothesis.123
BEHAVIOR DURING ATTACKS
Withdrawal is the typical behavior pattern for
migraineurs.22'103 During attacks almost all pa-
tients, if they can, seek solace and respite in a
quiet, dark room where they can be alone and
lie or sit still. Stillness characteristically atten-
uates migrainous pain. Sometimes, however,
an intense headache is made worse by a supine
position, so that sitting upright or reclining with
elevated head and shoulders provides relief.18
Some recline in bed with more than the usual
number of pillows.103 Some patients lie on the
painful side, while others find that they are
more comfortable lying on the non-painful
side.17 In almost all patients the pain of a mi-
graine headache is increased in intensity by any
physical activity or effort, by active or passive
head movement, and by the transmitted im-
pulse of coughing, sneezing, or vomiting. The
pain may even be increased by the slightest
movement of the bed or by the vibration
caused by steps of others in the room. Many
patients have observed that a dull, steady head-
ache may develop an intense, pulsatile quality
when they bend forward, suddenly move their
head, or perform a Valsalva maneuver.32 Phys-
ical exertion or lowering of the head may also
result in the appearance of vertigo or photop-
sias. Queckenstedt's maneuver (application of
pressure on the internal jugular veins by press-
ing the lateral aspect of the neck), which raises
intracranial venous pressure, worsens migraine
headache pain in 25% of patients.42

TERMINATION OF ACUTE
MIGRAINE ATTACKS AND
POSTDROMIC STATE
Many migraine attacks are terminated by
sleep.13'14 Some patients find their pain may
be eradicated or substantially reduced by even
a brief period of sleep; for others, several hours
of deep sleep is necessary. The period of sleep
may be during the day or night. As already
noted, vomiting can terminate some patients'
attacks. For most migraineurs, however, the
pain gradually diminishes over a period of
hours or a day or two.13
The majority of migraineurs also experience
a postdromal period after the acute headache
subsides. It can last for several hours to several
days.13'138 Many patients claim to feel "differ-
ent." Most are extremely fatigued. Some feel
weak, listless, or lethargic, this being particu-
larly true if there has been much vomiting and
diarrhea. Others are depressed. Many are in-
capable of performing imaginative or skilled
activities because of impaired concentration,
difficulty reading, weariness, and irritability
during the postdromal period. Some patients
cannot exert themselves and must limit their
physical activities. In contrast, some patients
feel normal after attacks, and some even feel
ebullient and enthusiastic.
SUMMARY
The material in this chapter has reviewed a va-
riety of clinical phenomena that have been
called "migrainous." The phenomena are var-
iegated, many of them falling far afield from
the "ordinary" cases of migraine commonly
seen in practitioners' offices. It is difficult to
classify much of this material. The classifica-
tion of headache disorders published by the
IHS represents a considerable improvement
in the diagnosis of headaches. But that classi-
fication still does not do justice to the extended
array of migrainous manifestations. Even the
entities of migraine with aura and migraine
without aura, which are thought to be rela-
tively well defined, clearly consist of several
stages or phases that can overlap with other
types of migraine or even occur as isolated
entities.
Clinical Manifestations 63
It is important to remember that migraine
can be a "shape shifter," with an impressive and
truly broad array of manifestations. And be-
cause a headache need not be present, and
symptoms can vary from attack to attack or
from one stage of life to another, migraine can
be a real diagnostic challenge. A clinician must
eschew preconceived notions of what consti-
tutes "typical" migraine, and must sympathet-
ically ask the kind of questions that will elicit
from a patient symptoms that a patient may not
consider connected to an attack or may feel are
too embarrassingly bizarre to report. Diagno-
sis of migraine comes from perceptive obser-
vation and careful historiesnot from charts
or questionnaires that, by their very nature,
must simplify matters.
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Chapter 4
Unusual Forms of Migraine, Variants,
and Equivalents
MIGRAINE AURA WITHOUT HEADACHE
COMPLICATED MIGRAINE
Migraine with Prolonged Aura
Hemiplegic Migraine
Basilar Migraine
Retinal Migraine
Migrainous Infarction
POST-TRAUMATIC MIGRAINE
TRANSFORMED MIGRAINE
CLUSTER MIGRAINE
STATUS MIGRAINOSUS
MIGRAINE EQUIVALENTS AND
PUTATIVE MIGRAINE EQUIVALENTS
Migraine-related Vestibulopathy
There are migrainous conditions, such as mi-
graine aura without headache and several kinds
of complicated migraine, whose uncommon
characteristics differentiate them from ordi-
nary migraine attacks. These must be Recog-
nized and diagnosed. Unfortunately^ the
nomenclature of many of these conditibns is
ambiguous. Many older terms have been dis-
carded, but synonyms and some definitional
problems have not been appropriately, dealt
with by the International Headache Society
(IHS) criteria. Another group of neurological
problems (and also syndromes with mainly sys-
temic symptoms) have been considered mi-
grainous, or associated with migraine, although
their present status is ambiguous. There is con-
fusion about whether they are truly related to
the routinely accepted migrainous syndromes
of migraine with aura and migraine without
68
Benign Paroxysmal Vertigo of Childhood
Benign Recurrent Vertigo in Adults
Benign Paroxysmal Torticollis in Infancy
Cyclic Vomiting
Abdominal Migraine
Transient Global Amnesia
Cardiac Migraine
OPHTHALMOPLEGIC MIGRAINE
ALTERNATING HEMIPLEGIA OF
CHILDHOOD
POSTICTAL HEADACHES
SUMMARY
aura. Ophthalmoplegic migraine, transient
global amnesia, benign recurrent vertigo, be-
nign paroxysmal torticollis in infancy, abdomi-
nal migraine, and cardiac migraine fall into this
group.
MIGRAINE AURA
WITHOUT HEADACHE
Some individuals have migraine aura without
any headache at all (acephalgic migraine,
migraine sine hemicrania, migrame-sans-
migraine, abortive migraine, migraine disso-
ciee). They can experience any of the visual,
sensory, motor, vestibular, or cognitive symp-
toms that commonly occur as an aura, but these
patients do not develop accompanying or sub-
sequent head pain. If carefully questioned,
 Unusual Forms of Migraine, Variants, and Equivalents
however, some patients are aware of a bilateral
head pressure lasting up to 2 hours after the
aura. Some have postdromal symptoms in-
cluding photophobia, inappropriate tiredness,
or depression that correspond to symptoms re-
ported after more typical migraine headaches.
The lifetime prevalence of migraine aura
without headache in an unselected population
is reported to be 0.95%.12 Looking at the pro-
belm from another perspective, among adult
individuals suffering from migraine with aura,
approximately 40% have also had migraine
aura without headache.128 Acephalgic migraine
occurs both in patients with a well-established
history of migraine and in individuals with a
strong family history of migraine but who have
never experienced more typical migraine with
head pain. Attacks without headache may also
alternate with episodes accompanied by head-
ache. But whereas migraine headaches com-
monly begin in the first three decades of life,
acephalgic migraine typically starts during or
after middle age, becoming increasingly fre-
quent with advancing age. It has a male pre-
ponderance, unlike the well-described preva-
lence of the more common types of migraine
in women.5 Some patients develop episodic
neurologic dysfunction that resembles an
auraand may be migrainous in originfor
the first time after the age of 45 (late-life mi-
grainous accompaniments) (see below). Mi-
graine aura without headache is a rare condi-
tion in childhood.138'172 Familial cases have
been reported.179
Almost any neurological symptom can recur
in a migrainous pattern and yet be unaccom-
panied by headache. Visual symptoms, such as
scintillations, scotomas, and photopsias, are the
most frequent.5 Less frequently, patients com-
plain of repeated episodes of paresthesias of
the face and hand, hemiparesis, dysphasia, or
symptoms such as dysarthria and ataxia that in-
dicate involvement of the brain stem. Others
have repetitive vertiginous episodes (benign re-
current vertigo) (see below).
In the 1980s, Fisher described a large group
of patients who appeared to have developed
acephalgic migraine or migraine with aura for
the first time after age 45.52-53 They had
episodes of neurologic dysfunction that in-
cluded scintillating scotomas, paresthesias,
dysarthria, aphasia, brain stem symptoms, and
motor weakness. Although only half the pa-
69
tients had a history of recurrent migraine with
or without aura, and although the episodes of
neurologic dysfunction were often unaccom-
panied by headache, Fisher labeled these
epispdes migrainous accompaniments. Suitable
investigations eliminated embolic and occlu-
sive cerebrovascular disease as a factor and an-
giograpjiy jWas normal. Permanent neurologi-
cal sequelae were rarely observed in Fisher's
patients, but detailed follow-up was not pro-
videpl.
Fisher's major objective was to differentiate
these symptoms from those seen during tran-
sient iseheifnic attacks (TIAs) caused by cere-
brovasculaf disease. Fisher set forth a number
of clinical criteria that could be used to sup-
port his diagnosis of migrainous accompani-
ments: (1) the presence of visual symptoms
such as a scintillating scotoma; (2) a gradual
build-up or progressive expansion and en-
largement of a scintillating visual scotoma over
a period of 5 to 30 minutes; (3) a slow march
of paresthesias from one area of the body to
another; (4) the succession of consecutive ac-
companiments, as, for example, from visual to
sensory; (5) the occurrence of two or more
identical spells; and (6) a generally benign
course without permanent neurologic seque-
lae. Some qf these phenomena are uncommon
in cerebrovascular disease, but all are unique
to migrainqus attacks.
Fisher's ! approach to these problems has
heuristic value. However, from a practical
point of view, the diagnosis of new-onset,
acephalgic tnigraine in an older individual can
only be macfe after rigorous and exhaustive at-
tempts, I|av been made to exclude cerebral
thrombosis,/ embolism, arterial dissection, sub-
clavian steal, angiitis, thrombocythemia, poly-
cythemia, hyperviscosity syndromes, and epi-
lepsy. Few neurologists would consider the
diagnosis unless the patient had a history of suf-
fering without sequelae from virtually identical
occurrences over a period of several years.
COMPLICATED MIGRAINE
Complicated migraine is an imprecise term
that has been used to refer both to rare types
of migraine with significant focal neurological
deficits and to attacks of migraine whose neu-
rological deficits persist well beyond the con-
70 Clinical Aspects of Migraine
elusion of the head pain, even becoming per-
manent. Definitions in the literature are often
ambiguous: many different names are used for
the same condition with different terms often
describing equivalent or analogous phenom-
ena. For example, French authors use mi-
graine accompagnee and migraine associee in-
terchangeably to refer to migraine with
significant and long-lasting neurological
deficits.25 The terms, however, also refer to
migraine with acute aura and to migraine at-
tacks whose neurological signs begin after the
onset of the headache. Most clinicians accept
the terms hemiplegic migraine, basilar mi-
graine, and retinal migraine to describe dis-
tinct types of migraine that may be compli-
cated by prolonged neurological deficits. The
IHS classification appears to complicate mat-
ters by designating complicated migraine as
migraine with prolonged aura; this term is
used by many clinicians to refer to a prolonged
(days, weeks, or even months) visual aura, a
very rare condition. The IHS classification also
includes migrainous infarction as a complica-
tion of migraine.
Attempts to diagnose the various types of
complicated migraine in individual patients is
confounded by more than inconsistent termi-
nology. The clinician must be constantly mind-
ful that non-migrainous conditions such as
ischemic cerebral events can produce a syn-
drome of transient headache followed by per-
sistent neurological deficiteven in young in-
dividuals.
Migraine with Prolonged Aura
Migraine with prolonged aura is defined by the
IHS as migraine in which the aura symptoms
last more than 60 minutes, but less than a week.
Neuroimaging is normal.66 Again, the term is
imprecise. Omitted from the definition are
auras that follow one another rapidly for sev-
eral hours, days, or even weeks (migraine aura
status] and visual auras that reportedly persist
for months to years in the absence of evidence
for infarction.60-61'94'96'125 Patients with mi-
graine aura status endure a considerable num-
ber of mostly visual auras, often without an
accompanying headache. Most of these pro-
tracted auras appear to be simple, positive vi-
sual phenomena that involve a hemifield or the
entire visual field. They may consist of diffuse,
small particles such as snow, dots, rain, or TV
static. 4 Others have described scintillating
geometric figures.
Hemiplegic Migraine
The association of headache with prolonged
unilateral sensory or motor deficits is a rela-
tively uncommon syndrome that can be either
sporadic or familial in origin. (The familial form
is described in Chapter 2.) The sporadic form
of hemiplegic migraine typically starts in the
teens or early twenties.21 Most patients also ex-
perience attacks of migraine with and without
aura more frequently than the hemiplegic
ones.70 When a hemiplegic migraine strikes, a
hemisensory deficit and/or hemiparesis usually
precedes the headache and persists through-
out the headache phase of the attack. As the
headache abates, the neurological signs and
symptoms may disappear, but, on occasion, the
neurological disturbances extend well beyond
the headache itself, persisting for days or even
for weeks. Complete recovery of motor and
sensory function is the rule, although occa-
sionally a degree of residual hemiparesis re-
mains.21'35 It is common dogma that the same
side of the body is affected in each attack in a
particular individual, but, in fact, the hemi-
paresis and hemisensory deficits may alternate
sides from one attack to another. Long-lasting,
unilateral sensory and motor symptoms may
occur only once or may recur in subsequent at-
tacks. The question of cerebral infarction al-
ways arises when neurological signs persist for
longer than 24 hours. It is difficult to evaluate
patients in whom appropriately timed com-
puted tomography (CT) scans or magnetic res-
onance imaging (MRI) have not been per-
formed. This is of course true for cases
described in the older literature.
Although some authorities restrict the term
hemiplegic migraine to attacks with severe,
long-lasting hemiparesis, descriptions of the af-
fliction range from relatively brief unilateral
paresthesias, through modest numbness and
weakness, to profound hemiplegia. Sensory
disturbances are the most frequent symptom
in hemiplegic migraine and, as a rule, precede
other symptoms. 1'70 Paresthesias that consist
of tingling, numbness, or formication are com-
mon and invariably involve the hand. The arm
may also feel heavy or clumsy; it is also possi-
 Unusual Forms of Migraine, Variants, and Equivalents
ble for the lower limb to be affected. A cheiro-
oral or digito-lingual distribution is frequently
seen. Weakness of one side of the body is pres-
ent in almost two-thirds of patients/1 It may
come on rapidly, although seldom as suddenly
as the hemiparesis caused by cerebral em-
bolism, and it may advance to become a fully
developed hemiplegia.
Disturbances of speech and communication
are frequent when the right side of the body is
involved. Aphasia and/or dysarthria accompany
the hemiparesis in more than half the clinic pa-
tients, but is less frequent in patients culled
from the general population.21'7"-120 The apha-
sia is typically of a mixed type, with difficulties
of both expression and comprehension. Visual
disturbances such as teichopsias or hemi-
anopias in the appropriate homonymous fields
are frequently noted. Indeed, visual symptoms
in the ipsilateral field of vision may herald an
attack.70 An alteration in consciousness that
varies from mild confusion to coma may also
be an attribute of an attack, especially when it
occurs in a child. The headache component of
an attack of hemiplegic migraine has all of the
characteristics expected of migrainous head
pain; it can consist of severe, throbbing pain,
intensified by exertion and by bending over
and, at times, accompanied by nausea and vom-
iting. It may last from a few hours to a few days.
On rare occasions, the headache is inconspic-
uous or never develops at all. In a large pro-
portion of young individuals with hemiplegic
migraine, the frequency and severity of attacks
decline with age, and bouts of hemiplegia are
often replaced by other forms of migraine.
It is difficult to make a diagnosis of hemi-
plegic migraine during the first attack because
sometimes there is little to distinguish it from
syndromes produced by cerebral lesions
caused by occlusive cerebral vascular disease,
cardiac emboli, carotid dissection, cerebral
hemorrhage, neoplasm, or vascular anomalies
such as small intracerebral arteriovenous mal-
formations (AVMs). Only when there is a his-
tory of several attacks, especially if the affected
side of the body alternates, is the diagnosis ap-
parent. Patients with the first attack require a
full evaluation, particularly if the hemiplegia
lasts 24 hours or longer.
Cerebral angiography performed during
hemiparetic episodes usually revealed no ab-
normalities. Computed tomography scanning
and MRI also ordinarily display no abnormali-
71
ties. However, if permanent weakness occurs,
neuroimaging may show an hypodense area of
infarction. Regional Cerebral blood flow
(rCBF) studies have demonstrated a modest
reduction in the blood flow of the hemisphere
contralateral to the hemiparesis.
Basilar Migraine e
The term basilar migraine (basilar artery mi-
graine, Bickerstaffs migraine] refers to a par-
ticular type of complicated migraine whose
aura symptoms unquestionably arise from dys-
function of the brain stem and/or both occipi-
tal lobes (Table 4I).15 Although the sequence
in which symptoms evolve during attacks of
basilar migraine varies greatly among different
patients, most bouts are inaugurated by visual
symptoms.14 They are frequently bilateral, con-
sisting of visual impairment or visual halluci-
nations in the temporal and nasal fields of both
eyes. Some patients may lose vision completely
or report its dimming or graying. Other pa-
tients describe dramatic visual hallucinations of
unformed images, or photopsias involving the
whole of the visual fields. No matter what kind
of visual symptoms occur, they become distinct
from the usual case of migraine with visual
aura, because even if the onset is hemianopic
in basilar migraine, the symptoms eventually
occur concurrently in both left and right visual
fields.72
Table 4-1. Diagnostic Criteria for
Basilar Migraine
Fulfills the criteria for migraine with aura
Two or more of the following aura symptoms
are present:
Visual phenomena in temporal and nasal fields
of both eyes
Dysarthria
Vertigo
Tinnitus
Decreased hearing
Double vision
Ataxia
Bilateral paresthesias
Bilateral pareses
Decreased level of consciousness
Adapted from the Headache Classification Committee
of the International Headache Society.66
72 Clinical Aspects of Migraine
Bilateral paresthesias and/or numbness of
the extremities, the perioral region, and occa-
sionally the tongue customarily follow the vi-
sual disturbances. Sensory abnormalities affect
the hands and feet to just above wrists and an-
kles. Varying combinations of vertigo, ataxia of
gait, diplopia, dysarthria, difficulty with hear-
ing, and tinnitus are usually present. These
phenomena commonly last from 10 to 60 min-
utes, but can persist for hours or even days.152
They are followed by a severe, bilateral, throb-
bing headache, predominantly in the occipital
region. The pain may even extend down into
the neck or radiate forward toward the vertex.
During some attacks, it spreads to become
holocephalic. The headache may last several
hours or longer. Nausea and vomiting are com-
mon and frequently prostrating.14'72 Some pa-
tients in childhood or their early teens may en-
dure the visual, sensory, and ataxic features of
the syndrome without subsequently develop-
ing a headache.
As might be expected from a condition in
which the brain stem is affected, conscious-
ness can be altered, but only a minority of pa-
tients are affected.72'152 Disturbed conscious-
ness ordinarily ranges from mild drowsiness
to extended coma, but prolonged amnesia,
confusion, somnolence, stupor, or even syn-
cope have been reported. The clinical picture
may resemble sleep from which the patient
can be aroused by vigorous stimulation. A cu-
rious, dream-like, confusional state some-
times develops. In such cases, the symptoms
generally occur just when the premonitory
r ptoms are subsiding and the headache is
to start. The abnormalities in sensorium
are more common in children and adoles-
cents. The symptoms are usually transient, but
have been known to last for days. Drop at-
tacks have also been reported in patients with
basilar migraine. Even though these patients
have intact sensoria, they suddenly lose pos-
tural tone and fall. Drop attacks, like the al-
tered consciousness of basilar migraine, usu-
ally occur at the point when the visual and
brain stem symptoms are receding and the
headache is slated to begin. Although not fea-
tured in the original reports of the syndrome,
focal or generalized seizures are reported to
develop during episodes of basilar migraine,
especially in children. It is difficult to deter-
mine whether these cases represent a variety
of basilar migraine or are a coincidence of
epilepsy and migraine.
Permanent, albeit mild, complications can
follow attacks of basilar migraine. It is uncom-
mon, however, for major neurological symp-
toms to outlast the headache, and it is excep-
tionally uncommon for a major neurological
deficit to be fixed (even though there have
been a few case reports of lateral medullary
and cerebellar infarctions following typical at-
tacks).35'146'152 Cochleovestibular abnormali-
ties are frequent between attacks. Routine au-
diometry demonstrates a mild, low-frequency
hearing loss in many patients.114 A few patients
have significant hearing loss. Positional nystag-
mus is seen on electronystagmographic testing
in a number of patients, and many have caloric
abnormalities.114
It was originally thought that basilar mi-
graine predominantly affected adolescent girls.
Then, a number of reports stressed its fre-
quency among children. 7>72 Current thought,
however, recognizes that the affliction, while
usually starting in the teenage years, occurs in
all age groups and in both sexes.152 Most cases
have a family history of migraine, although not
necessarily the basilar kind. Basilar attacks tend
to become less common with time and, in the
majority of patients, are eventually replaced by
other, more common, varieties of migraine.
Basilar migraine must be distinguished from
conditions that produce vertebrobasilar arte-
rial insufficiency. The youth of most patients
renders unlikely a diagnosis of occlusive cere-
brovascular disease resulting from atheroscle-
rosis and angiitis. Congenital malformations at
the base of the brain such as Arnold-Chiari
malformation, platybasia, and basilar impres-
sion could be responsible for episodic head-
ache with alterations in brain stem and visual
function. Patients with posterior fossa tumors,
however, usually do not have an episodic
course. An MRI or CT scan should rule these
out possibilities. Patients who suffer from com-
plex partial seizures may have recurrent attacks
of visual and sensory disturbances accompa-
nied by vertigo and followed by an alteration
of consciousness and postictal headache. Such
attacks are of much briefer duration than are
bouts of basilar migraine, and the headache is
not a prominent feature of each attack. The di-
agnosis of basilar migraine in a particular pa-
tient is suggested by a family history of mi-
 Unusual Forms of Migraine, Variants, and Equivalents
graine coupled with an attack that is isolated
or interspersed with more typical episodes of
migraine, with or without aura.
Retinal Migraine
Retinal migraine is a rare form of complicated
migraine characterized by repeated episodes of
unilateral visual impairment or monocular sco-
toma or blindness associated with headache
(Table 4-2). A more precise designation of the
condition would be ocular migraine or anterior
visual pathway migraine, because either the
ciliary or the retinal circulations can be in-
volved, and the visual symptoms characteristic
of attacks result from either optic nerve or reti-
nal dysfunction. The term ophthalmic migraine
has also been used, but such a phrase can cause
confusion, as some authorities use the term to
characterize any migrainous visual disturbance,
whether it results from ocular or from cerebral
changes.
Retinal migraine is an unusual disorder,
seen most often in young adults. Patients ex-
perience sudden monocular episodes of visual
loss or photopsias. These recurrent episodes
of sudden visual loss or impairment are fre-
quently described as "blackouts," "greyouts,"
or "whiteouts." The visual deficit may develop
as a progressive concentric constriction of the
monocular visual field proceeding from pe-
riphery to center. Vision may be completely
lost, or some normal central vision may re-
Table 4-2. Diagnostic Criteria for
Retinal Migraine
At least two attacks
Monocular scotoma or blindness
Completely reversible
Lasts less than 60 minutes
Confirmed by examination during attack or by
patient's drawing of monocular field defect
Headache preceding or following visual
symptoms
Normal ophthalmological examination after an
attack
Embolism ruled out by appropriate studies
Adapted from the Headache Classification Committee
of the International Headache Society.66
73
main. But patients with this condition do not
usually complain of a "curtain" dropping over
the vision as do patients with amaurosis fugax.
Patients describe photopsias as little sparkles
of light in one eye, which may precede the dis-
turbed vision. The visual abnormalities range
from seconds to hours but, in most cases, last
less than 30 minutes.30
The visual symptoms can accompany a mi-
graine attack or they may develop at other
times in individuals with strong histories of mi-
graine.161 When they accompany a migraine at-
tack, the visual phenomena may occur before,
during, or after the headache; they may also
follow migrainous sensory symptoms. The
headache may be a typical migrainous one or
may consist of a dull ache. The pain is charac-
teristically retro-orbital and ipsilateral to the af-
fected eye. Patients have been described who
have monocular visual loss unaccompanied by
headache but who have a personal or family
history of migraine. These cases do not satisfy
the IHS criteria for retinal migraine and have
been called vasospastic amaurosis fugax by
neuro-ophthalmologists.173
Examination of the fundi during attacks has
demonstrated constriction of retinal arterioles
and venous narrowing. It may be that the ve-
nous narrowing is caused by active venous con-
traction or is secondary to diminished arterio-
lar inflow.27 Migrainous attacks of monocular
visual loss may result in serious sequelae.36'157
Migrainous infarction of the anterior visual
pathways can cause permanent visual field de-
fects with central or centrocecal scotomas, al-
titudinal defects, constriction of the visual field,
or even complete loss of vision in the affected
eye. Ischemic optic neuropathy, central retinal
artery or retinal artery branch occlusion, reti-
nal vein occlusion, retinal pigmentary changes,
and intraocular hemorrhage have been re-
ported as rare complications of this condi-
tion.12'79'88
Patients with monocular visual alterations
ascribed to migraine comprise a younger pop-
ulation than that with amaurosis fugax caused
by atherosclerotic carotid artery disease. Even
so, the clinical presentation of amaurosis fugax
from embolic or atherosclerotic vascular dis-
ease is sufficiently inconsistent to prevent a
conclusive distinction from retinal migraine.36'49
Points in favor of the diagnosis of retinal mi-
graine include youth, a clear-cut personal and
74 Clinical Aspects of Migraine
family history of migraine, no evidence of con-
genital or acquired valvular heart disease, lack
of potential sources of emboli, and an absence
of bruits or cardiac murmurs.
Migrainous Infarction
The IHS Headache Classification Committee
defines migrainous infarction as "one or more
migrainous symptoms not fully reversible
within 7 days and/or associated with evidence
of ischemic infarction on neuroimaging stud-
ies."66 Although the number of well-described
cases of cerebral infarction or stroke during or
immediately following attacks of migraine is
relatively small, documentation supporting a
causal link between a migraine attack and mi-
grainous infarction has included the following
factors:
1. Clinical observations. Patients recognize
that the headache preceding or at the onset of
a stroke is identical to that experienced in pre-
vious attacks of migraine unaccompanied by
stroke.8'51
2. CT scan and MRI examinations. The CT
and MRI abnormalities similar to those seen in
patients with non-migrainous stroke are noted
in some patients whose strokes are associated
with attacks of migraine.41'46'77'133 However,
similar lesions have been seen in the CT scans
of migraineurs after attacks unaccompanied by
neurological deficits.77'133 These latter lesions
presumably represent subclinical strokes. Evi-
dence that the abnormalities are indeed in-
farcts is based on the general contour and
topography of the affected regions. Low-
density lesions are the most common abnor-
mality, although cerebral edema has also been
reported.29'50
3. Angiographic studies. Occlusion, or ir-
regular narrowing suggestive of vasospasm of
an appropriate intracranial artery, has been
noted on angiographic studies in a few patients
whose strokes occurred during a migraine at-
tack.32'46'50'101'150 The most common occlu-
sions have been of the posterior cerebral or
middle cerebral arteries, or one of their small
branches.24'46 Most migrainous infarcts, how-
ever, are unaccompanied by angiographic evi-
dence of arterial occlusion.19'12'
4. Pathological assessments. Rare cases of
putative migrainous cerebral infarction have
been fatal; pathological examination showed ei-
ther severe ischemia or infarction of brain tis-
sue.26'59'91
Patients who have migraine with aura are
more prone to migrainous infarction. A num-
ber of reports have also described migrainous
infarction associated with migraine attacks
without aura, but the risk is greatest for those
with migraine with aura.50,68,111,127,130,171 jn
one study, long-lasting migraine attacks have
also been found to increase the risk of infarc-
tion.19 In addition, patients with a history of
one migrainous stroke are at significantly in-
creased risk for recurrent stroke.126
The risk for stroke among persons with mi-
graine is elevated across all ages (Fig. 4-1). Most
cases of infarction develop in women.19'24'145
This preponderance presumably reflects in
part the gender distribution of migraineurs, but
it contrasts with observations that the majority
of cerebral infarctions in non-migraineurs less
than 50 years of age occur in men. Migrainous
infarction has been described in childhood but
is rare.47'124'174 Major factors that increase the
probability that a migrainous patient will de-
velop an infarction during an attack of migraine
include the use of oral contraceptives, smok-
ing, and discontinuation of preventative mi-
graine therapy.50'65 The majority of strokes that
take place during migraine attacks occur sud-
denly, but some patients experience a gradual
or incremental onset, with a build-up of symp-
toms over 90 minutes to several days.50'75
A considerable proportion of migrainous in-
farcts involves areas of the brain supplied by the
posterior cerebral artery.24'67'130 The occipital
lobes are affected more than other sites, which
accounts for the findings that the most typical
permanent neurological defectshomonymous
field defectsare visual ones.19'24'75'130 Hemi-
paresis is also a common enduring deficit and
may be combined with an ipsilateral sensory
deficit or aphasia.50
The diagnosis of migrainous infarction is dif-
ficult because headaches so frequently accom-
pany ischemic or thromboembolic cerebrovas-
cular events, an incidence reported between
25% to 44%.48'106 Many of these headaches
have clinical features suggestive of migraine
and can be confused with migraine.49 In addi-
tion, recent clinical reports of patients with
carotid disease and reduced blood flow suggest
that ischemia may contribute to the develop-
ment of migraine attacks both with and with-
out aura.113'139 Furthermore, some patients
 Unusual Forms of Migraine, Variants, and Equivalents 75

Figure 4-1. Cumulative incidence of stroke as a function of migraine status measured in 5-year intervals. Data obtained
from a national probability sample (20,729 individuals, 25 to 74 years of age) of the civilian noninstitutionalized popula-
tion of the United States. A standardized medical examination and a sreies of questionnaires were administered between
1971 and 1974. Closed circles, individuals with migraine; open circles, individuals without migraine. (Adapted from
Merikangas KR, Fenton BT, Cheng SH, Stolar MJ, and Risch N: Association between migraine and stroke in a large-scale
epidemiological study of the United States. Arch Neurol 54:362-368, 1997. Copyrighted 1997, American Medical Associ-
ation.)

thought to have strokes related to acute attacks
of migraine have had later clinical events or
autopsies that established non-migrainous
mechanisms for the cerebral infarction.123'139
Finally, there are conditions that predispose
to migraine or migraine-like headaches that
also cause stroke. These conditions include
CADASIL and MELAS (see Chapter 2). Mi-
graineurs with cerebral infarction require a
comprehensive assessment that includes hema-
tologic, cardiologic, and arteriographic investi-
gation. Cerebral infarction should not be at-
tributed to migraine until all other diagnostic
possibilities have been excluded.
ANTIPHOSPHOLIPID ANTIBODIES
Anticardiolipin antibodies and lupus anticoag-
ulant are antiphospholipid antibodies, a het-
erogeneous group of circulating polyclonal im-
munoglobulins that include immunoglobulin G
(IgG), IgM, and IgA types. The presence of
these antibodies has been implicated in the
pathogenesis of migraine, but recent evidence
refutes an unambiguous relationship.69'159'163'166
Antiphospholipid antibodies have been
strongly associated with arterial and venous
thrombosis, thrombocytopenia, and fetal loss.
In particular, an association between the de-
velopment of ischemic stroke and the presence
of antiphospholipid antibodies has been
posited for young patients.6 The significance of
this association has been controversial because
of flaws in the following study factors: the
populations investigated (most studies have in-
cluded a preponderance of patients with sys-
temic lupus erythematosus), study methodol-
ogy, antiphospholipid assay techniques, and
categories of strokes studied. In contrast, sev-
eral well-controlled studies have found little or
no evidence to link antiphospholipid antibod-
ies to the pathogenesis of stroke in either
younger or older individuals.110'160'163 An-
tiphospholipid antibodies have also been im-
plicated in a predisposition to stroke in mi-
graineurs. Cases of migrainous infarction with
76 Clinical Aspects of Migraine
circulating antiphospholipid antibodies have
been reported. 2'14 However, the results of
studies designed to determine the presence of
antiphospholipid antibodies in cases of stroke
in migraineurs have been inconsistent.23'76'159
POST-TRAUMATIC MIGRAINE
Between one-third and one-half of all patients
who suffer mild or minor head or neck trauma
develop headaches.58 According to IHS crite-
ria, the onset of acute traumatic headaches oc-
curs less than 14 days after the injury (or after
regaining consciousness). In actuality, head-
aches typically emerge within 24 hours of the
head injury but can develop some days, weeks,
or months afterward.40 The relationship of the
headache to the preceding trauma in such
cases is problematic. Most of the headaches be-
come more intense for a period of days to
weeks, and then progressively improve. Many
patients are left with head pain that lasts for
years or even decades.
No matter what the type, post-traumatic
headaches are often, but far from always, ac-
companied by a group of assorted symptoms
that are relatively consistent, although they
may vary considerably in severity among pa-
tients. The syndrome may develop even if
loss of consciousness, increased intracranial
pressure, or electroencephalographic (EEC)
changes during or following the original head
trauma do not occur. The collection of symp-
toms is either referred to as the post-traumatic
syndrome or as the postconcussive syndrome.
Symptoms include true vertigo, nonspecific
dizziness, tinnitus, personality disturbances,
depression, anxiety, irritability, apathy, cogni-
tive symptoms such as impairment of memory
and reduced attention span, insomnia, daytime
sleepiness, easy fatiguability, decreased libido,
blurred vision, and intolerance to alcohol. Such
symptoms usually develop within 24 to 48
hours after the trauma, but they may be de-
layed for many days. In most individuals the
symptoms gradually disappear with resolution
over a period of 1 to 3 months. Unfortunately,
sometimes the symptoms persist for months or
even years.
Counterintuitively, the severity of the head
injury does not determine the severity of the
headache. Severe headache can follow even
trivial head injury. Paradoxically, some author-
ities indicate that there is an inverse relation-
ship between the severity of head trauma
and the incidence of post-traumatic head-
aches.116'178 Injuries related to the onset of
headaches often result from motor vehicle ac-
cidents. Rear-end injuries appear to be partic-
ularly pernicious, with neck injury frequently
being more consequential than head trauma.
Recurrent migraine attacks are also reported
to occur after abrupt, forceful extension-
flexion movements of the neck (so-called
whiplash injuries).62 Sometimes, immediately
following the accident only neck pain is pres-
ent. Over days or weeks, the neck problem pro-
gresses into headaches.
Post-traumatic headache does not constitute
a single entity.117 It can take one of several
forms:
1. Tension-type headache. The most fre-
quent post-traumatic headache resembles
tension-type headaches, characterized by non-
throbbing, but constant, dull, diffuse, or bilat-
eral discomfort.40'62
2. Migraine. Although controversy exists as
to its incidence, some patients' post-traumatic
headaches have the features of migraine head-
aches, satisfy the criteria of the IHS, and re-
spond to anti-migraine medications.11'62'170
Post-traumatic migraine may occur more fre-
quently than originally suspected. Moreover,
head or neck injuries may increase the sever-
ity of headaches in patients with preexisting mi-
graine. Most cases of post-traumatic migraine
consist of migraine without aura, although
some cases of migraine with aura have been re-
ported.11'170 A number of individuals who suf-
fer from recurrent bouts of migraine are con-
vinced they can identify an episode of head
trauma that preceded their first attack.16
3. Mixed headaches. A proportion of pa-
tients may develop the combined symptoms of
a daily tension-type headache with superim-
posed, distinct episodes of migraine.
4. Cluster headaches. About 10% of patients
have a syndrome that seems to have all of the
characteristics of cluster headache.121
5. Localized discomfort. There are individ-
uals who suffer from post-traumatic head
pain characterized by localized discomfort that
has a jabbing or neuralgic quality. At times,
throbbing can occur. It is assumed that some
of these problems result from entrapment of
afferent nerve endings in scar tissue at the site
of injury.
 Unusual Forms of Migraine, Variants, and Equivalents
TRANSFORMED MIGRAINE
The course of migraine over years or decades
can be very variable. The majority of mi-
graineurs have a relatively stable frequency of
migraine attacks and may not develop other
types of headaches. In the intervals between
bouts of migraine, however, some patients be-
gin to experience more and more attacks that
resemble tension-type headaches. Still other
patients gradually find that their episodic pat-
tern disappears and is replaced by daily head-
aches.99'^ The typical migraine headaches in
another subset of migraineurs start to occur
several times a week, or even every day.
Episodic migraine headaches can thus be
transformed into a chronic daily headache
so-called transformed migraine. Other desig-
nations have included chronic daily headache
syndrome, chronic daily headache evolved
from migraine, transformational migraine, evo-
lutive migraine, migraine with interparoxysmal
headache, mixed tension-vascular headache,
and daily mixed headache.98,103,140,149
The IHS classification does not consider
chronic daily headache to be a distinct clinical
entity. And indeed, many, if not most, patients
with chronic daily headache are difficult to fit
into the present IHS scheme. Yet a substantial
number of patients referred to specialty head-
ache clinics suffer from daily or near-daily
headache and have been doing so for months
or years. Between 34% and 77% of these
chronic daily headache patients are reported to
have transformations of what was originally
episodic migraine.99'103'148 One epidemiologi-
cal investigation has estimated that patients
with transformed migraine constitute 2.4% of
the general population.33
The transformation from episodic migraine
headache to chronic daily headache usually
takes place gradually over years. Sudden
change occurs in a small minority of patients,
and it is not impossible for chronic daily head-
ache to develop after only a few years or even
months of episodic headaches. Most patients
with transformed migraine are women whose
past history of episodic migraine without aura
meets IHS criteria. Their migraine typically be-
gan in their teens or twenties.102'140 Headache
frequency gradually increased and, as it did,
the associated symptoms of photophobia,
phonophobia, and vomiting may have de-
creased. For about half of those patients with
77
aura, the disorder metamorphoses first into mi-
graine without aura and then to chronic daily
headache. Some patients develop a daily head-
ache in parallel with the onset of migraine;
these patients never experienced only inter-
mittent migraine attacks. Chronic daily head-
ache has also been reported in children and
adolescents.56
Patients usually complain of a continuous,
diffuse, dull discomforta constant aching,
pressure, or tightness around the head that re-
sembles chronic tension-type headache. The
daily pain may be bilateral or unilateral, and
frequently it is frontal or frontotemporal in lo-
cation.148 Very often, it involves the neck. If
the daily pain is unilateral, it tends to be on the
side and at the same site as the migrainous at-
tacks.
For the majority of patients, the headache is
already present when they awaken, although
some develop it during the course of the morn-
ing.150 Most commonly, the headache gradu-
ally increases in severity as the day progresses,
reaching a peak in the afternoon or evening.
Patients are typically never free from head-
aches during the day. Moreover, nocturnal
awakening by headache is not infrequent. Most
patients with transformed migraine continue to
have periodic episodes of throbbing pain typi-
cal of migraine.' 150
Although both syndromes are characterized
by daily head pain, the term chronic daily
headache is not synonymous with the term
chronic tension-type headache (see Chapter
g) 102,148,149 Compared to chronic tension-type
headaches in non-migraineurs, chronic daily
headaches in migraineurs are
1. More severe and last longer119'164
2. More often associated with photophobia,
phonophobia, and nausea80'151
3. Exacerbated by physical activity and
bending over80'151
4. More often unilateral102
5. Frequently precipitated by trigger factors
such as alcohol, aged cheese, chocolate,
and overexertion151'164
6. Worsened by menstruation, and fre-
quently alleviated during pregnancy
7. Commonly associated with a family his-
tory of migraine
8. More likely to respond to sumatriptan.28
Transformed migraine very commonly
emerges in patients who overuse analgesic
medication.102'168 Analgesic abuse is the most
78 Clinical Aspects of Migraine
important factor in between 50% and 82% of
cases referred to specialized headache cen-
ters.99'103'104'148 It appears to be a factor in
slightly more than 30% of patients with a
chronic daily headache in the general popula-
tion.33 Analgesic abuse and analgesic rebound
headaches have also recently been described in
pediatric and adolescent migraineurs.154'165
The majority of patients who develop this prob-
lem use excessive amounts of over-the-counter
anti-pyretic and anti-inflammatory analgesics
(aspirin, acetaminophen, non-steroidal antiin-
flammatory medications), prescribed butalbital-
containing analgesic drugs, narcotic medica-
tions, or ergots.104 Any of these drugs taken
daily and/or in excessive amounts can cause and
sustain headache. Chronic daily headache suf-
ferers using excessive, daily analgesics note (1)
habituation to the acute, pain-reducing prop-
erties of the analgesics; (2) worsening of head-
aches a few hours after an analgesic is taken;
and (3) a marked increment in both the fre-
quency and intensity of headaches after anal-
gesic medication is discontinued. The issue of
drug-induced headache is complex and impor-
tant (see Chapters 14 and 25).
Patients with drug-induced, chronic daily
headache frequently complain of asthenia, anx-
iety, restlessness, and fatigue. Approximately
80% of patients are depressed.102 These symp-
toms accompany the development of constant
pain. Sleep disorders are common and include
difficulty in' initiating and maintaining sleep
and awakening in the early morning with se-
vere headache. Patients often complain of irri-
tability and difficulties with memory and con-
centration.
At least 20% of patients with a daily head-
ache resulting from transformed migraine
never took analgesic medication in excessive
amounts or too frequently. There may be a nat-
ural progression of their clinical course, with
more frequent interictal headaches appearing
between their migraine attacks. Eventually, a
daily headache develops. Specific causes other
than analgesic overuse may be found. For ex-
ample, some migraineurs develop daily head-
aches after initiating oral contraceptive use or
estrogen replacement therapy.99 Daily head-
aches are more common in patients who smoke
or who ingest excessive caffeine. Chronicity
may also coincide with menopause, a traumatic
event such as the death of a spouse or a par-
ent, major surgery, a severe accident with
trauma to the head or neck, or with an in-
creased amount of stress produced by a change
in employment or retirement, marital difficul-
ties, or systemic illness.99'103'104 A number of
these patients have evidence of cervical dys-
function (e.g., neck stiffness or pain, abnormal
postures, myofascial trigger points) or tem-
poromandibular joint dysfunction.17 Even a
flu-like illness or aseptic meningitis may be a
causal event.
CLUSTER MIGRAINE
There are a few individuals whose attacks fit
the IHS criteria for migraine headaches, but
who experience their attacks in ways similar to
those typically associated with cluster head-
aches.10^ For example, they may develop fre-
quent migraine headaches only during a finite
period of time (several weeks to months) at the
same time every year or two and at no other
time. During otherwise typical migraine at-
tacks, others develop prominent symptoms that
resemble those considered characteristic of
cluster headaches, for example; conjunctival
redness, lacrimation, and rhinorrhea on the
side of the headache. In some patients these
symptoms are severe.
There are also a few patients with otherwise
typical cluster headaches who have symptoms
during their attacks that are typical of migraine,
for example, photophobia and vomiting. Some
patients with cluster headache know of a num-
ber of trigger factors for their attacks, such as
certain foods, chocolate, and strong odors or
fragrances known to precipitate migraine at-
tacks.
Patients with any of these problems have
been diagnosed by some clinicians as suffering
from cluster migraine (or migraine cluster).
The definition is not recognized in the IHS cri-
teria.
STATUS MIGRAINOSUS
Status migrainosus (acute intractable mi-
graine) is the term applied to severe, unre-
lenting migraine attacks that last more than 72
hours, whether treated or not.66 It is an un-
usual condition: persistence of headache for
more than 3 days is reported in less than 1%
of patients.129 The headache is either continu-
 Unusual Forms of Migraine, Variants, and Equivalents
ous throughout the attack, or it is interrupted
by headache-free intervals of less than 4 hours.
Status migrainosus is refractory to the usual
analgesics and is associated with nausea and
protracted vomiting, prostration, and dehydra-
tion. Electrolyte imbalance and hypotension
may occur. Normal sleeping, eating, and activ-
ities of daily living are totally disrupted. Pro-
longed attacks of this type may be precipitated
by severe emotional stresses; misuse of med-
ications such as ergots, analgesics, and nar-
cotics; dietary indiscretions; rebound phenom-
ena following withdrawal of chronically used
analgesic medication; iatrogenic endocrine
causes such as the use of oral contraceptives or
replacement estrogen; presence of systemic ill-
ness; head injury; or alcohol abuse.37'118 Em-
phasis in recent years has been placed on med-
ication overuse as a cause of status migrainosus,
which may be considered a prolonged rebound
headache in many cases. Status migrainosus
may necessitate repeated visits to the emer-
gency department or physician's office for
symptomatic alleviation of pain, or it may re-
quire hospitalization for correction of dehy-
dration and pain relief.37
MIGRAINE EQUIVALENTS AND
PUTATIVE MIGRAINE
EQUIVALENTS
The term migraine equivalents has often been
used with imprecision and ambiguity by dif-
ferent authorities. It has been employed to
specify a large number of inadequately defined
clinical syndromes, among them abdominal mi-
graine and cardiac migraine. Such syndromes
are characterized by episodic, transient organ
system dysfunctions that are believed to be
substitutes for headaches in some individuals
with migraine or with a familial predisposition
to migraine. To make precise definitions more
difficult, the same paroxysmal organ system
dysfunctions are reported to occur simultane-
ously with, or alternating with, typical migraine
headaches.
Migraine-related Vestibulopathy
Chronic, nonspecific symptoms of vestibular
system dysfunction have been related to mi-
graine, although interpretation of older reports
79
is complicated by a lack of standardized defi-
nitions both of migraine and of vertigo. The
manifestations of migraine-related vestibular
symptoms are quite varied, ranging from
episodic true vertigo to lightheadedness, con-
stant or episodic imbalance, non-vertiginous
movementassociated disequilibrium, un-
steadiness, and sensitivity to motion.39'83 The
term migraine-related vestibulopathy has been
applied to the neuro-otological symptoms re-
ported by individuals with migraine. Many mi-
graineurs, especially children with migraine,
have a generalized intolerance to excessive self-
motion (motion sickness) and sensitivity to vi-
sually evoked vertigo.31 In addition, it is clear
that complaints of dizziness and vertigo unas-
sociated with headache are much more fre-
quent in migraineurs than in controls or in pa-
tients with the diagnosis of tension-type
headaches.39-83-114'134 The onset of vestibular
symptoms may occur in childhood or adult-
hood. It appears that many cases of "dizziness"
that are either undiagnosed or diagnosed as
labyrinthitis, vestibular neuronitis, or chronic
nonspecific vestibulopathy are, in fact, mi-
grainous in nature and may respond to anti-
migraine medication. Reports as to the fre-
quency of vestibular testing abnormalities in
migraineurs also vary and consist of a mixture
of normal electronystagmographic (ENG)
studies and abnormal studies with a predomi-
nant peripheral pattern.39'83'114
Benign Paroxysmal Vertigo
of Childhood
A syndrome called benign paroxysmal vertigo
consists of recurrent spontaneous episodes of
vertigo in otherwise healthy children. Many
consider it a migraine equivalent and hypoth-
esize that it is the first manifestation of mi-
graine in younger children.2'87'108 Follow-up
studies of patients with typical benign parox-
ysmal vertigo during childhood show that some
do eventually develop migraine, but the num-
ber who do is disputed.2'87'93 Benign paroxys-
mal vertigo may also occur as an autonomous
event in children who already have migraine
headaches.2
The symptoms usually start in early child-
hood, most often between 1 and 4 years of age.
The attacks of vertigo vary in frequency from
once a month to several times a week, but tend
80 Clinical Aspects of Migraine

Figure 4-2. Symptoms accompanying attacks of paroxysmal vertigo in children. Results of a questionnaire applied to 45
children with at least three attacks of benign paroxysmal vertigo. Abcissa, percent of sample. (Adapted from Russell G
and Abu-Arafeh I: Paroxysmal vertigo in childrenan epidemiological study. Int J Pediatr Otorhinolaryngology 49(Suppl
1):S105-S109, 1999. Copyright 1999 with permission from Elsevier Science.)

to occur very frequently for the first few
months after onset. As a rule, the syndrome
disappears after several months or years. Bouts
of benign paroxysmal vertigo are characterized
by very sudden attacks of vertigo, accompanied
by disequilibrium and ataxia, anxiety, and fre-
quently, nystagmus and vomiting. Pallor and
sweating are frequent (Fig. 4-2). Affected chil-
dren wish to remain absolutely still, and some
describe noise and light intolerance.2 Some
patients may have a less severe form of the ill-
ness, their attacks being characterized by light-
headness, imbalance, and movement-associated
disequilibrium.31 Attacks may last from sec-
onds to hours, but most frequently between 1
and 5 minutes. Pain or headache, aural symp-
toms, tinnitus, and hearing loss are character-
istically absent. Neurological and otorhino-
laryngological examinations are unremarkable,
as are neuroradiological and EEC examina-
tions. There are no signs of permanent vestibu-
lar damage.
Benign Recurrent Vertigo
in Adults
Although controversial because of the various
definitions used to describe the condition,
adults suffer from recurrent, spontaneous
episodes of vertigo that appear similar to those
of the childhood condition. Here, too, migraine
may cause the syndrome that has been termed
benign recurrent vertigo (migrainous vertigo,
migraine-associated dizziness, vestibular mi-
graine).39'44'81'108'112' A family history of mi-
graine is the rule, and a personal present or
past history of migraineparticularly migraine
with aurais found in approximately a third of
cases.83'85 Women are most often affected,
some only as an accompaniment to menstrua-
tion. As with bouts of migraine, attacks of be-
nign recurrent vertigo can be precipitated by
alcohol, lack of sleep, and emotional stress.
Most often, the sensation of vertigo devel-
ops suddenlytypically upon morning awak-
ening. The vertigo may be sufficiently intense
to force the patient back to bed. Nausea, vom-
iting, and hyperhidrosis may be present, but
cochlear symptoms such as tinnitus or focal
neurological symptoms do not occur. Positional
or spontaneous nystagmus may be seen on
ENG examination. The caloric examination
may also be abnormal. An attack can last from
a few minutes to more than 24 hours and usu-
ally subsides gradually. As the vertigo dimin-
ishes, it may be followed by positionally in-
duced vertigo that resolves over hours to days.
Patients who suffer in this way are usually
asymptomatic between vertiginous events, but
 Unusual Forms of Migraine, Variants, and Equivalents
some patients have abnormalities in vestibular
function during the symptom-free interval.83
The frequency of attacks can vary from once
daily to twice a year.
Benign Paroxysmal Torticollis
in Infancy
Benign paroxysmal torticollis in infancy is an
uncommon, self-limiting condition character-
ized by recurrent episodes of head tilt.22'34 The
onset usually occurs within the first month of
life. The majority of infants with the problem
appear pale, vomit, and are irritable or agitated
during the episodes. The head tilt is usually the
only neurological sign, but a bent trunk pos-
ture may also be present. Children past infancy
can show signs of disequilibrium and unsteady
gait and may complain of headache.43 The con-
dition usually resolves by the age of 2 or 3 years.
The nature of the neurologic dysfunction un-
derlying paroxysmal torticollis is unknown, but
the syndrome may be a variant of benign parox-
ysmal vertigo of childhood. Some children with
paroxysmal torticollis later develop paroxysmal
vertigo and others develop migraine.43
Cyclic Vomiting
Because of the high prevalence of migraine in
children with the cyclic vomiting syndrome
(bilious attacks, bilious headache} and in mem-
bers of their families, the shared list of provoca-
tive triggers such as excitement and stress, and
the favorable clinical response to medications
effective in migraine prophylaxis, this syn-
drome is regarded by some as a migraine equiv-
alent.1'92 Others have attributed the syndrome
to psychogenic causes, epilepsy, or a mito-
chondria! disorder. The syndrome consists
of recurrent, stereotyped, intense, discrete
episodes of vomiting in children with normal
health in between episodes.4 The duration of
the vomiting varies from hours to days. The fre-
quency of episodes averages 12 per year. Pa-
tients may also complain of headache, photo-
phobia, phonophobia, and abdominal pain.
They appear pale and may develop pallor,
fever, diarrhea, and dehydration. The episodes
resolve spontaneously if untreated. The same
syndrome may occur in adolescents and young
adults.
81
Abdominal Migraine
Much controversy surrounds the concept of
abdominal migraine.9'18'73'154 Some authori-
ties doubt its existence; others consider the
syndrome an epileptic phenomenon, or sim-
ply psychogenic. There is little controlled,
prospectively collected information about re-
current abdominal pain without demonstrable
pathology. Nonetheless, a high childhood inci-
dence of pain (abdominal pain, bilious attacks)
has been reported.4 Perhaps 1 in 10 children
of school age suffers from recurrent abdomi-
nal pain. The diagnosis of abdominal migraine
is made in a number of these patients. There
are children whose attacks are precipitated by
trigger factors similar to those of children with
migraine.3 Many have a strong family history
of migraine. Some respond to specific prophy-
lactic anti-migraine drugs. Some already suffer
from concurrent migraine or ultimately de-
velop it. Contradictory reports, however, show
a low incidence of migraine in later life.7'122
The results of long-term follow-up studies of
children with recurrent abdominal pain sug-
gest a benign prognosis in the majority. Symp-
toms of abdominal migraine may start at any
age from the first year of life, but the mean age
of onset is around 7 years.
Abdominal pain is rarely mentioned as an ac-
companiment of typical migraine attacks in
adults, but some adults without identifiable
intra-abdominal pathology suffer from recur-
rent attacks of abdominal pain without con-
current headache.18 These individuals may
have a personal or strong family history of
typical migraine headaches.9'95'97'132 Their
episodes of abdominal pain usually start in
childhood but may begin in early adult life. Al-
though episodic abdominal pain in adults is
rarely diagnosed as migraine in adults, it should
be, because some cases respond to prophylac-
tic antimigraine medication.
The central characteristic of abdominal mi-
graine in both children and adults is prolonged,
paroxysmal attacks of upper abdominal, peri-
umbilical, or epigastric pain, accompanied by
a variety of autonomic symptoms such as pal-
lor or flushing (Table 4-3).97-155 The pain,
which may have been preceded by a migrain-
ous-like prodrome of listlessness, yawning, and
drowsiness, can be crampy or steady, mild or
extremely severe, but it is usually intense
enough to prevent the individual from contin-
82 Clinical Aspects of Migraine
Table 4-3. Abdominal Migraine
(in Adults)
Frequent family history of migraine
Frequent history of classic or common migraine
in the patient
Attacks of abdominal pain beginning before age
40
Recurrent, identical attacks of abdominal pain
No abdominal symptoms between attacks
Duration of attacks from 1 to several hours
Pain usually localized in upper abdomen
Data from Lundberg (1975).97
uing with normal activities. It can last from a
few minutes to many hours. Most sufferers
choose to lie down in a dark room and try to
sleep. Attacks may be infrequent or recur sev-
eral times a week. The patients usually suffer
from nausea and sometimes vomiting as well,
and some also complain of bloating and diar-
rhea. Fever may be present, and the patient
may be lethargic. The diagnosis of abdominal
migraine should not be made until appropriate
investigations have eliminated the presence of
all other possible pathological abdominal pro-
cesses. Various episodic abdominal conditions
such as biliary disease, partial bowel obstruc-
tion, and the irritable bowel syndrome need to
be excluded.95
Transient Global Amnesia
Transient global amnesia is a syndrome char-
acterized by an abrupt, profound, but tempo-
rary loss of short-term memory associated with
severe retrograde amnesia for events during
the attack. During an episode, patients remain
conscious but may be bewildered, anxious, and
distressed, and usually they are cognizant of
their memory difficulties. The registration and
recall of current events are impaired. Other
neurological signs and symptoms are usually
absent. Most attacks last less than 12 hours; the
average duration of attacks is 6 to 8 hours. Pa-
tients have no remaining abnormalities other
than permanent amnesia for events during the
attack and, as a rule, for a few hours preced-
ing it. Most patients suffer a single attack, al-
though the risk of annual recurrence ranges at
between 3.4% and 4%.71'109 The syndrome oc-
curs most often in middle-aged people.
The amnesia that occurs transiently in this
syndrome resembles the permanent amnestic
syndrome that follows bilateral damage to me-
dial temporal structures. As a result, transient
global amnesia has been conventionally attrib-
uted to transient ischemia in the mesial tem-
poral lobes and hippocampus caused by throm-
boembolic cerebrovascular diseasethat is, a
TIA involving the vertebrobasilar system.
However, there is evidence against the TIA
theory: attacks are more extended than con-
ventional TIAs and strokes within the appro-
priate vascular territory causing permanent
memory loss are rare. >74 Nor is transient
global amnesia associated with the conven-
tional risk factors for cerebrovascular disease.74
Moreover, although studies of cerebral blood
flow changes in patients with transient global
amnesia have not yielded uniform results,
changes are not confined to the territory of a
single cerebral artery, such as the posterior
cerebral artery. Substantial unilateral or bilat-
eral hypoperfusion, especially in a medial tem-
poral locus, is typical during attacks.136
Several authorities have advocated a mi-
grainous cause for this syndrome.38'74 Their ra-
tionale for viewing transient global amnesia as
a "migrainous equivalent" includes a frequent
history of migraine; prevalence of such a his-
tory in transient global amnesia patients is
about 25%.38'74 Case-control studies have
shown that the prevalence of migraine in pa-
tients with the syndrome is significantly greater
than in matched groups of normal controls and
patients with conventional TIAs.74'107'135'180
Some episodes of transient global amnesia oc-
cur during typical migraine attacks. In 20% to
40% of patients, headache and nausea are said
to accompany or immediately follow the am-
nesia.71'74^ At present we can say no more than
that migraine may play a causal role in a pro-
portion of cases of transient global amnesia, but
the association is still unproven and its nature
is unknown. The cause of the symptoms in a
small subgroup of patients with recurrent
episodes of transient global amnesia is evi-
dently epileptic.74
Cardiac Migraine
Migraine can be one of the symptoms that ac-
companies angina pectoris, particularly in those
patients with variant angina (Prinzmetal's
angina) caused by coronary artery spasm.90 The
 Unusual Forms of Migraine, Variants, and Equivalents
condition has been called cardiac migraine
(thoracic migraine, precordial migraine). These
patients are reported to experience typical angi-
nal-type chest pain in association with migraine
headaches. Their chest pain, however, is gen-
erally not related to exertion. Electrocardio-
grams usually show nonspecific T-wave abnor-
malities and occasionally ST-segment depression
or elevation. The chest pain is relieved by sub-
lingual nitroglycerin.
Several reports have been published on
the association between migraine and angina
pectoris caused by coronary artery
spasm.54'86'90'156'169 Among these patients,
however, not all experience angina together
with migraine. For some, variant angina occurs
spontaneously during a migraine attack; alter-
natively, variant angina and migraine coexist in
the same patient, but symptoms referable to
the two conditions do not occur at the same
time. It may be that there is a tendency for va-
sospasm to occur in different vascular beds at
different times in the same patient with mi-
graine, but available studies are too limited to
ascertain or rule out a specific comorbid rela-
tionship between variant angina and migraine.
OPHTHALMOPLEGIC MIGRAINE
Ophthalmoplegic migraine is a very rare con-
dition consisting of attacks of headache associ-
ated with partial or complete unilateral oculo-
motor palsy in the absence of a demonstrated
intracranial or orbital lesion.162 The unusual
presentation and the results of recent MRI in-
vestigations have added to the perception that
ophthalmoplegic migraine is not a migrainous
disorder.
The typical patient with what is now called
"ophthalmoplegic migraine" is a child or ado-
lescent of either sex, with a strong male pre-
ponderance.64 Most patients suffer their first
attack before the age of 12, but there are case
reports of infants and of adults reaching their
fourth or fifth decades before having an initial
episode.13'55'177 Reports differ about a family
history of migraine in these patients.55'64
The initial feature of an attack is pain that is
always located on the same side as the subse-
quent ophthalmoplegia, although isolated cases
of bilateral involvement have been reported.78
The discomfort characteristically develops be-
hind or above the eye, but as the attack pro-
gresses, it may radiate to adjacent structures
83
such as the cheek, temple, or forehead.13 The
pain is moderate to severe, continuous and
non-throbbing, and is usually described as
"boring" in nature. It increases in intensity over
a 48-hour period and may persist for 1 to 4
days. In half the cases, nausea and photopho-
bia accompany the head pain.64 As the head-
ache reaches its peak, or as it begins to sub-
side, the symptoms (diplopia) and signs (ptosis,
extraocular muscle paresis, dilatation of the
pupil) of ophthalmoplegia emerge on the af-
fected side, progressively worsening. The first
sign is usually ptosis. Paresis of the ocular mus-
cles develops next. In many cases, the condi-
tion progresses to total unilateral oculomotor
nerve palsy. It may be partial, involving only
the superior or inferior branch of the third
nerve. 4>82 The abducens and trochlear nerves
are much less often affected than is the oculo-
motor nerve.55 On rare occasions, the oph-
thalmic division of the trigeminal nerve may be
involved.55 The reaction of the pupil to light is
partially or totally lost, and the pupil is dilated
in most, but not all, patients.55-167 Reports in
young patients of transient, otherwise unex-
plained, pupillary dilatation, with or without
headache, have been also tentatively ascribed
to ophthalmoplegic migraine.176 In such cases,
the pupil is large and reacts very little, if at all,
to light.89'176
The oculomotor paresis usually disappears
over a period ranging from a week to a month
or two. Attacks can recur after a patient has
been symptom-free for a period of several
months to years, and when the attacks recur,
the symptoms and signs may alternate sides. In
children, ophthalmoplegic attacks usually be-
come less frequent with time. Some patients
suffer multiple attacks without any residual
deficit. But repeated ophthalmoplegic attacks
may cause permanent damage to the oculo-
motor nerve, leaving a slight degree of ptosis,
a sluggish pupil, or, occasionally, a residual,
mild oculomotor paresis.64'82
Recent MR studies after gadolinium admin-
istration in several patients with ophthalmo-
plegic migraine have demonstrated enhance-
ment or significant enlargement of the
oculomotor nerve in the interpeduncular
space.115'175 No enhancement of the cavernous
sinus or adjacent dura is seen. The enhance-
ment and thickening of the oculomotor nerve
are generally transient and almost completely
resolved in 7 to 9 weeks.100 On the basis of
these recent MR results, it may well be that
84 Clinical Aspects of Migraine
ophthalmoplegic migraine represents recur-
rent episodes of demyelinating or inflamma-
tory oculomotor nerve neuropathy.
Because in some cases the Tolosa-Hunt syn-
dromea painful, granulomatous inflamma-
tory process that involves the cavernous sinus,
the superior orbital fissure, or orbit and the en-
closed cranial nervesmay mimic ophthalmo-
plegic migraine, several publications have sug-
gested that either a retro-orbital inflammatory
process could be involved in the pathogenesis
of ophthalmoplegic migraine or ophthalmo-
plegic migraine is a variant of Tolosa-Hunt
syndrome.64'144 Palsies of the oculomotor,
trochlear, and abducens nerves, in any combi-
nation, are possible in patients with Tolosa-
Hunt syndrome. Frequent, but not invariable,
dysfunction of the optic and oculosympathetic
nerves and of the first two divisions of the
trigeminal nerve also occur. However, the clin-
ical picture differs in that the headache and
ophthalmoplegia occur simultaneously in pa-
tients with the Tolosa-Hunt syndrome and the
duration of symptoms is more prolonged than
in ophthalmoplegic migraine. The Tolosa-
Hunt syndrome is most common in the fourth
through the sixth decades of life, while oph-
thalmoplegic migraine typically occurs in
younger individuals. The course of the two ill-
nesses is also different. The Tolosa-Hunt syn-
drome occurs either as a monophasic illness
lasting 8 weeks or more in untreated cases, or
as an entity recurring at intervals of months or
years.63 Finally, the dramatic improvement in
symptoms in patients with Tolosa-Hunt fol-
lowing administration of corticosteroids is be-
lieved by some to be so typical as to constitute
a necessary diagnostic criterion.
As indicated above, attacks of ophthalmo-
plegic migraine have a notably constant pattern
both in the same patient and among different
patients. The diagnosis of ophthalmoplegic mi-
graine should not offer problems if there is a
history of previous attacks, especially if pre-
ceding occurrences involved the opposite side.
If the pattern is not followed, other causes for
the symptoms must be sought. Noninvasive
imaging studies such as MRI and magnetic res-
onance angiography (MRA) should be per-
formed in all patients to exclude the presence
of an aneurysm. In particular, one should sus-
pect an aneurysm of the internal carotid artery
on the main trunk or at the junction of the pos-
terior communicating artery. The differential
diagnosis also includes sphenoidal mucoceles
or tumors, pituitary apoplexy, periarteritis with
inflammation of the carotid siphon, and dia-
betic ophthalmoplegia. Considering the severe,
unilateral headache associated with pupillary
dilation, episodes of unilateral glaucoma with
pupillary block must also be excluded.
ALTERNATING HEMIPLEGIA
OF CHILDHOOD
Alternating hemiplegia of childhood (paroxys-
mal hemiparesis of childhood) is a very rare
condition that has traditionally been consid-
ered a variant of hemiplegic migraine. The af-
fliction is characterized by repeated attacks of
hemiparesis or hemiplegia that last from a few
minutes to a few days and involve alternate
sides of the body.20'141 The bouts of hemiple-
gia are associated with dystonic posturing
(tonic fits), choreoathetoid movements, nys-
tagmus and other ocular abnormalities, and
autonomic disturbances such as tachycardia,
mydriasis, and sweating.45'84 Episodes of quad-
riplegia can occur either when the hemiplegia
shifts from one side to another or as an isolated
manifestation. The tonic fits can also occur in-
dependently of the hemiplegic episodes, and
can be unilateral or bilateral. The attacks are
accompanied by screaming, irritability, and
sometimes brief loss of consciousness. Sleep
relieves both the weakness and the associated
paroxysmal phenomena.20 After the onset of
the problemusually before 18 months of
agethe child, who has been developing nor-
mally, shows evidence of mental retardation
and neurological deficits that become increas-
ingly noticeable with the passing of time.
Alternating hemiplegia has been proposed as
a form of complicated migraine caused by a
paroxysmal vascular disturbance that affects
structures supplied by the vertebrobasilar sys-
tem.57 Evidence supporting this proposal is
modest, resting mainly on a higher than ex-
pected prevalence of migraine in the families
of affected children. The relation of alternat-
ing hemiplegia to migraine, if any, is uncer-
tain.42 Alternatively, alternating hemiplegia has
been considered a channelopathy, cerebral
vasculopathy, or an epileptic problem, al-
though paroxysmal EEC abnormalities have
not been described. In sum, the pathogenesis
 Unusual Forms of Migraine, Variants, and Equivalents
remains uncertain, and it is likely that the syn-
drome has more than one etiology.
POSTICTAL HEADACHES
Headache following generalized tonic-clonic
seizures is a well-described feature of major
motor seizures.137 Similar headaches can de-
velop after minor motor seizures, although less
frequently. A postictal headache develops reg-
ularly in at least half of all epileptics. It is gen-
eralized, moderately intense, and throbbing in
nature. It can have the characteristics of a mi-
graine headache, and some migraineurs con-
sider their postictal headaches to be identical
to their independently occurring migrainous
headaches.10'*37'158
SUMMARY
At times, the diagnosis of migraine can be a
complex affair. When headache is absent, the
diagnosis becomes still more difficult. But
headache-free attacks of migraine certainly do
occur, and not infrequently. The number of
clinical phenomena that have been associated
with migraine attacks is exceptionally broad,
probably too broad. There is controversy over
the clinical states designated as migraine equiv-
alents and complicated migraine, and even if
everyone agreed they were migraine, these
conditions would be challenging to define. In
addition, it is dubious whether ophthalmo-
plegic migraine is caused by processes similar
or identical to those responsible for migraine.
Nor is it clear whether the group of clinical
conditions that includes transient global am-
nesia, abdominal migraine, cardiac migraine,
and alternating hemiplegia of childhood is mi-
grainous in nature. As investigators, we can
continue to probe the mechanisms, and as clin-
icians, we must continue to be careful ob-
servers, especially of subtle symptoms and
findings.
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Chapter 5

Initiators, Precipitators, and Triggers

INITIATION OF MIGRAINE Visual Stimuli

PRECIPITATION OF INDIVIDUAL Auditory Stimuli
ATTACKS Motion and Motion Sickness
PSYCHOSOCIAL STRESS Olfactory Stimuli
Types of Stressors Smoking
Weekend Headaches and Let-down Ice Cream Headache
Migraine HYPERSENSITIVITY TO
DIETARY FACTORS ENVIRONMENTAL FACTORS
Vasoactive Amines PRESCRIPTION DRUGS
Tyramine ILLICIT DRUGS
Chocolate TRAUMA-TRIGGERED MIGRAINE
Caffeine DISORDERS OF THE NECK
Citrus Fruits Myofascial Trigger Points
Alcohol Extension-flexion (Whiplash) Injury
Monosodium Glutamate MEDICAL CONDITIONS
Nitrites Chronic Fatigue Syndrome/Fibromyalgia
Artificial Sweeteners Acquired Immunodeficiency Syndrome
ALLERGY Dialysis
HUNGER AND HYPOGLYCEMIA Platelet Disorders
SLEEP Eyestrain
EXERTION SUMMARY
Sexual Activity
PHYSICAL AND ENVIRONMENTAL
FACTORS
Seasonal Factors and Changes in Weather

INITIATION OF MIGRAINE proportion of these initial migraine headaches

An intrinsic biological substrate, presumably
genetic, predisposes certain people to develop
migraine headaches. Among those who have
apparently never experienced migraine, an
event may occur that triggers a headache per-
ceived to be their "first" attack. Blau has found
that many individuals with migraine are con-
vinced they can identify a specific occurrence
that preceded their first attack.14 And a large
90
occur during an interval of intense emotional
stress.47'106 Such initiating experiences are
generally dramatic (although not necessarily
bad)emotional pain such as a death in the
family or a divorce, or a joyful life event such
as a pregnancy or the birth of a baby can set
off recurrent migraine headaches. Hormonal
changes, of course, are factors in migraine dur-
ing pregnancy and birth, but emotional stress
is extremely important too. Physical trauma, es-
 Initiators, Precipitators, and Triggers 91

pecially head injury, and iatrogenic causes gen-
erally involving contraceptive pills or nitrate-
containing anti-anginal drugs are also frequent
initiators of a first migraine attack. Once the
first migraine attack has occurred, the individ-
ual has the potential to develop further attacks.
PRECIPITATION OF
INDIVIDUAL ATTACKS
Biological factors alone may be sufficient to
precipitate or trigger recurrent attacks in some
migraineurs. The timing of attacks follows an
endogenous rhythm with no overt external ini-
tiators (trigger factors, precipitating events).
Approximately 15% of migraineurs say that
trigger factors play no role in their headaches.86
But for most migrainous patients, specific ex-
ogenous factors as well as endogenous ones
trigger their attacks.171'188-194'233 Psychosocial
conditions, various foods, physical stimuli,
changes in hormonal levels, or administration
of medications are common factors (Table
5-1). The most prominent ones in adults in-
clude anxiety, frustration, or anger; fatigue or
sleep disturbances; menstruation; consump-
tion of alcohol or certain foods; skipped meals
and hunger; and a variety of sensory stimuli (ex-
posure to certain smells and odors, bright sun-
light, etc.).175'189'193'205'233 Fatigue and sleep
deprivation appear to be common triggers of
headache in children, as are stress and fight-
ing, excitement, fear, illnesses or fever, over-
exposure to sunlight, physical exercise, and
missed meals.5'27
Trigger factors do not cause migraine, rather
they are responsible for inducing a particular
attack. It is tempting to speculate that mi-
graineurs in general have a lowered threshold
to commonplace stimuli that usually do not
provoke headaches in non-migrainous individ-
uals. However, the catalog of factors reported
to provoke migraine attacks is so extensive that
we must infer either that subgroups of mi-
graineurs have different biologic abnormalities
or that a common, unique mechanism operates
in all migraineurs, but is activated in different
individuals by a broad range of phenomena. In
any event, each person appears to have a dis-
tinctive and possibly unique inventory of trig-
gers that either act singly or together to pre-
cipitate a bout of migraine.
Many migraine precipitants also provoke
headaches in non-migraineurs (Fig. 5-
1) 15,30,201 jror example, hunger headaches,

Table 5-1. Major Precipitants of Migraine Attacks

Stress
Food stuffs Cheese, chocolate, citrus
Food additives Monosodium glutamate, nitrites, aspartame
Alcohol Red wines especially
Hunger Skipping meals, delayed meals, inadequate amounts of
food
Weather changes Alterations in barometric pressure, heat, cold
Visual stimuli Bright lights, flashing lights, glare, stripes, fluorescent
lights
Auditory stimuli Loud and blaring noise or music
Olfactory stimuli Perfumes, colognes, aftershave lotions, cigarette and
cigar smoke, diesel and gasoline fumes, paint, tar
Sleep Too much or too little
Physical exertion Excessive exercise, overexertion, fatigue
Medications Nitroglycerin, reserpine
Head trauma
Local pains Eyes, teeth, jaw, sinuses, neck
Hormonal changes Menstruation, ovulation, pregnancy, oral contraceptives,
hormonal replacement therapy
Data from Blau and Thavapalan (1988);19 Linet and Stewart (1987);130 Scharff et al. (1995);201
Selby and Lance (I960);205 and Van den Bergh et al. (1987).233
92 Clinical Aspects of Migraine

Figure 5-1. Headache intensity in migraineurs and non-migraineurs according to precipitating factors. The headache in-
tensity was measured on a visual analogue scale. The patients were selected from a random national pool of households
in France. A significantly different intensity between the two groups is indicated by an asterisk. (Adapted from Chabriat
H, Danchot J, Michel P, Joire JE, and Henry P: Precipitating factors of headache. A prospective study in a national con-
trol-matched survey in migraineurs and non-migraineurs. Headache 39:335-338, 1999, with permission.)

premenstrual headaches, so-called stress head- sider such self-reports to be inadequate.37'150

aches, and alcohol hangovers are provoked by
stimuli known to trigger some migraine head-
aches. Emotional, dietary, physical, and envi-
ronmental factors are also reported to precip-
itate tension-type headaches. 01 Nitroglycerin
prescribed for angina, and nitrates in preserved
meats and fish can produce throbbing head-
aches both in migraineurs and in some indi-
viduals without a history of migraine headaches
(see Chapter 11).
Knowledge about most triggers, although re-
peatedly ascertained in patient histories, is
anecdotal. Precise figures as to the relative im-
portance of specific trigger factors in the gen-
eral population of adult migraineurs are diffi-
cult to obtain because much of the data has
been collected from patients attending spe-
cialized clinics. Many studies leave the meth-
ods used to obtain the data unspecified or in-
completely described. Very few randomized
controlled trials have been published, even for
dietary factors, and the relatively few published
trials often differ in their conclusions. And al-
though many individuals report that certain
factors trigger headaches, some studies con-
Nonetheless, clinical experience reveals how
critical it can be to identify trigger factors, be-
cause when the right combination of specific
influences are removed, many patients experi-
ence a significant decrease in the frequency
of attacks.19 In other words, it may be life-
changing for a particular migraineur to abstain
from alcohol, eliminate chocolate, discontinue
contraceptive pills, obtain adequate sleep, and
eat three regular meals a day.
Sensitivity to a particular stimulus may take
many years, or even decades, to evolve. Mi-
graineurs may be able to drink alcohol with im-
punity in their youth, but cannot tolerate even
a small quantity after 20 years of suffering from
migraine. What triggers attacks at one stage of
life may no longer induce them at a later stage.
In general, however, the number of trigger fac-
tors increases with age and with duration of dis-
ease. 233
Identification of trigger factors can be diffi-
cult. A patient exposed to a putative trigger
does not always develop an attack of migraine.
Perhaps a certain threshold dose, concentra-
tion, or intensity is necessary before an attack

can occur; or perhaps the precipitant is a nec-
essary but not a sufficient factor to initiate an
attack. Induction of attacks may be multifacto-
rial, requiring simultaneous or serial exposure
to several factors. The latter possibility fits ob-
servations that during premenstrual and men-
strual days, some women are sensitive to alco-
hol and certain footstuffs that they can tolerate
at other times in their cycle.19'42 A potentiat-
ing effect of alcohol on headache vulnerability
following consumption of monosodium gluta-
mate has also been reported.200
How most triggers precipitate migraine at-
tacks is generally unclear. There are theories
about how a few stimuli affect susceptible peo-
ple. Some chemical triggers such as alcohol and
nifedipine are hypothesized to produce va-
sodilatation. However, if vasodilatation is re-
sponsible for the pain, why do many potent
cerebral vasodilators such as COa and pa-
pavarine rarely cause headache? Moreover,
many of the substances purported to produce
headaches have only modest effects on blood
vessels. The direct effects of alcohol on cere-
bral blood vessels, for example, are insignifi-
cant, and alcohol produces only minor changes
in cerebral blood flow.146 Yet alcohol clearly
can trigger bouts of migraine. In sum, a va-
sodilatatory action is unlikely to be the sole
mechanism in the process.
PSYCHOSOCIAL STRESS
Psychological factors play a crucial role in mi-
graineurs' experience with headaches. There is
a complex interconnection of factors that trig-
ger individual attacks, mechanisms used to
cope with stress and recurrent head pain, ef-
fects of chronic head pain on the personality,
and the persistence of chronic headaches. In
other words, psychological makeup interacts
with biologic substrata to trigger, exacerbate,
and/or maintain a headache state. Some au-
thorities feel that migraine may be best re-
garded as a biopsychosocial illness. If so, acute
psychological events that evoke emotional
changes may be the most common precipitants
of migraine attacks.106-175'188'205'233 Data do in-
dicate that prolonged stress also contributes to
the frequency of migraine attacks.106 The re-
lationship between stress and headaches, how-
ever, is extremely complex, with rates for stress
as a headache precipitant reported from as low
as 17% to as high as 61%.3'8-59'129'm>188>193
Initiators, Precipitators, and Triggers 93
Types of Stressors
Differentiation should be made between two
types of stressors: major life events and minor
daily hassles. The term major life events refers
to sporadic occurrences that require substan-
tial adjustment. Examples of major life events
are loss and bereavement, serious physical ill-
ness, marital separation or divorce, retirement,
change in residence, and legal difficulties.
Most evidence indicates that migraine suffer-
ers are not exposed to greater or more nu-
merous major stresses or major life events than
are individuals without headaches.46'143'163
Minor daily hassles, a term used to refer to
repeated irritants, minor stresses, or problems
that characterize daily life, are significant in
triggering and maintaining migraine. These in-
clude environmental stimuli such as changes in
weather and noise levels, daily frictions such as
traffic jams and long lines, as well as ongoing
responsibilities for family, household upkeep,
employment, financial obligations, and social
commitments. Minor stresses may affect gen-
eral health more than major life events.185 Al-
though there is conflicting data about whether
individuals with headaches experience more
hassles than those without headaches, there is
agreement that the number of a migraineur's
daily hassles is a better predictor of headache
frequency and intensity than are major life
events.46'73'74 This is true for both men and
women and for patients with either migraine
headaches or tension-type headaches (Fig.
5-2). Interpersonal stress and hassles may be
more important for women, whereas occupa-
tional stress may play a greater role for men/84
Children frequently state that anxiety over
schoolwork (especially tests) makes their heads
hurt.11 Adolescents complain that attending
classes, doing homework, and preparing for ex-
ams are frequent causes of headache.2 Many
attacks in adults occur in anticipation of some
socially demanding duty such as attending a
large party or going on a family vacation; an at-
tack of migraine frequently results in cancella-
tion or delay of the anxiety-provoking event.
Some situations considered pleasurable or re-
warding by most individuals may also trigger
headaches. Winning a contest or receiving a
raise in salary or a promotion can fall into that
category. An individual patient's reaction to
each situation is idiosyncratic, determined by
complex and not necessarily conscious assess-
ments of a specific event.63 It becomes stress-
94 Clinical Aspects of Migraine

Figure 5-2. Daily hassles as a function of headache and gender type. (A) The same number and severity of daily hassles
are experienced by patients with migraine and with tension-type headaches. (B) Women and men experience the same
number of daily hassles, but women rate their hassles as more severe. (Adapted from Fernandez E and Sheffield J: Psy-
chosocial stressors predicting headache occurrence: the major role of minor hassles. Headache Q 6:215220. 1995, with
permission.)

ful solely by virtue of the person's reaction
and so one student's exhilarating challenge to
write an exam essay becomes another's pain,
nausea, and vomiting. A reasonable hypothesis
is that migraineurs are predisposed by intrin-
sic biological factors to experience a given
amount of stress more intensely than control
subjects do.178 There is also little doubt that
acute stress can augment the intensity and du-
ration of an ongoing migraine headache.
Hassles are significantly associated with the
onset of headache.46 On the day of a headache,
or in the days immediately preceding one, the
migraineur is reported to experience a greater
than usual number of hassles.47'129'21^220'221
Attacks typically occur on the day when stress
levels are high, or 1 day later.120 These hassles
seem particularly stressful, increasing the pa-
tient's cognitive-emotional reaction to their
negative impact on the quality of life, but the
issue is complex, for it may be that prodromal
mood changes (including irritability and tense-
ness), episodes of fatigue, and a decrease in the
quality of sleep that often precede headaches
by a day or more contribute to the perception
that the hassles are especially stressful.10*'218
Migraine activity and stress appear to have
a reciprocal, self-perpetuating relationship:
migraine activity results in subsequent stress,
and vice versa. 10 Pain may, in fact, also be
identified by migraineurs as the most stressful
aspect of their lives. However, although the re-
lationship between hassles and headaches is
undoubted, statistical analysis of the data indi-
cates that hassles account for only a small pro-
portion of the variance in headache frequency
and intensity.74 The remaining variance must
be attributable to other factors. Even so, re-
sponse to stress constitutes an important set of
variables that one must consider when evalu-
ating the generation of migraine attacks. Head-
ache sufferers appear to appraise stressful
events more negatively than do controls, and
to employ less effective coping strategies and
skills in their efforts to manage stressful events,
acting in a more passive or avoidant manner
than do patients without headaches.63'213 Mi-
graineurs tend to place great reliance on med-
ication. Stress is also believed to engender
more self-blame and repression in headache
patients than in controls.
Avoidance is a prominent strategy among
migraine sufferers in attempting to cope with
trigger factors. Some migrane sufferers make
extraordinary efforts to avoid physical precipi-
tants and exacerbators of their migraine at-
tacks, such as bright lights, loud noise, and cer-
tain smells and odors, especially perfumes and
cigarette smoke. Behavior changes in others re-
sult less from severe and continued head pain
than from an attempt to avoid headaches by
curtailing exposure to hassles and psychologi-

cal stresses. These changes in behavior may oc-
cur even when patients are free of pain because
of the fear of developing headaches. In con-
trast, many men and women with frequent, re-
curring migraine headaches learn to perform
reasonably; many continue to work produc-
tively and seek medical services only sporadi-
cally.
Weekend Headaches and
Let-down Migraine
Data conflict over increased weekend fre-
quency of migraine attacks. Although some ob-
servers note a weekly periodicity, with an in-
creased frequency of headaches on weekends,
others have found no statistical association
of headache with specific days of the
week 39,61,107,159,166 It is cieaii however, that
there are individual patients whose attacks pre-
dominate during weekends, and it is reported
that weekend headaches occur more often in
patients with migraine without aura and in
men.45'229 Weekend headaches may be related
to increased consumption of alcohol, over-
sleeping, caffeine withdrawal, and/or relaxation
after the work-week period of stress.39'107'159
The notion of "let-down migraine" is an inter-
esting one. There are stories, perhaps apoc-
ryphal, about a famous neurosurgeon who was
consistently headache-free in the operating
room, but was always hit with severe migraine
when the surgery was complete. Clinical ob-
servations support the idea that patients with
migraine have a penchant to develop head-
aches after the culmination of a stressful situ-
ation, during the let-down period of relaxation
and repose. Many migraineurs, for example,
develop headaches at the end of the school
year, following the submission of a major re-
port or paper, or when starting a holiday.
DIETARY FACTORS
There is a subgroup of migraineurs who suffer
from dietary migraine. Its incidence varies
from study to study: some indicate that per-
haps as many as 50% of migraine patients be-
lieve that a percentage or all of their attacks
are induced by foods; other studies indicate
that the incidence may be as low as
10% 176,177,188,193,194,205,233' According to some
surveys, about one-fifth of patients attending a
Initiators, Precipitators, and Triggers 95
headache clinic report sensitivity to cheese,
chocolate, or citrus fruit, and usually to all
three.176'177 Others have not been able to find
tyramine-containing foods, or foods like choco-
late that contain high concentrations of other
amines, to be a major influence.154'196
Controlled data that might prove a relation-
ship between diet and migraine attacks are
meager. The subject is complicated by not only
dearth of sound scientific study but also a
plethora of misconceptions about diet in the
popular press and on television. Many patients
have either placed themselves, or have been
placed by physicians, on a restricted diet that
has deprived them of chocolate, cheese, wine,
and other foods all at one time without any at-
tempt to determine that even one of the re-
stricted items plays a role in the pathogenesis
of their headache problem. The psychological
stress of "cheating" on that diet, together with
the fear that the food will cause a migraine,
may be enough to trigger a migraine indepen-
dent of the food's chemical contribution, if any.
The headache would then, of course, confirm
the food as an offending trigger. A coincidence
between ingestion of a particular food and an
attack of migraine as much as a decade earlier
has many other patients convinced that the
food triggers attacks. They may have avoided
that item of food ever since. Determining
which foods trigger headaches in the subgroup
of migraine sufferers who do have dietary mi-
graine is complicated by findings that particu-
lar foods may not provoke attacks on every oc-
casion that they are ingested, nor are all
migraine patients sensitive to every potentially
offending substance.
Investigations of how diet influences the fre-
quency and severity of migraine attacks are
challenging to perform. Not only is the placebo
effect potent in such studies, but inconve-
niences associated with a precisely altered diet
make patient compliance difficult to control.
Most investigators apply a 24-hour time re-
striction as an outside limit for reactions to
foods, even though there are reports of delayed
reactions.42'101'249 Double-blind administra-
tion of the putative offending food in gelatin
capsules has frequently resulted in negative re-
sults, perhaps because food-induced attacks of
migraine are often dose related. Gelatin cap-
sules may not deliver an adequate dose of the
offending food. Moreover, dietary substances
may interact with other susceptibility factors,
including the degree of emotional or physical
96 Clinical Aspects of Migraine
stress or the time in the menstrual cycle. And
it may even be that dietary components act as
triggers for attacks only when additional fac-
tors are active. In sum, definitive data about
dietary migraine are in some ways elusive.
The mechanisms of diet-provoked headache
are obscure. Some of the foods frequently cited
as triggering migraine attacks contain vasoac-
tive amines. It is felt by many authorities that
small amounts of these chemicals can precipi-
tate an attack in susceptible individuals. Other
foods reported to act as migraine precipitants
do not contain amines. Some authorities hy-
pothesize that food triggers migraine attacks
via an allergic reaction, but, as reviewed below,
a definite relationship between migraine and
food allergy remains unproven. It is also pos-
sible that the occurrence of a migraine attack
after the consumption of a specific food may
depend upon a conditioned reflex to that food.
In fact, sociological and cultural factors almost
certainly play a role in determining food sen-
sitivity. For example, French migraineurs fre-
quently incriminate white wine, eggs, and
chocolate, but practically never dairy products
and citrus fruits.182 In England and other parts
of Europe, dairy products and red wine are fre-
quently cited as precipitants.177'233
Vasoactive Amines
A variety of monoamines, such as tyramine, /3-
phenylethylamine, and octopamine, are desig-
nated vasoactive amines because they influ-
ence blood pressure. All have been thought to
be migraine triggering factorsoften on the
basis of insufficient evidence. In normal indi-
viduals, oxidative deamination by monoamine
oxidases (MAOs) and sulfate conjugation of the
aromatic hydroxyl group by phenolsulfotrans-
ferases (PSTs) found in the bowel are believed
to decrease the absorption of vasoactive amines
in foods. Once absorbed, however, vasoactive
amines are enzymatically broken down in the
body by two major mechanisms. The first is ox-
idative deamination of the side chain by MAOs
in the liver, the second involves PSTs.
Two forms of MAO are found intracellularly
in the mitochondria throughout the body, but
primarily in the brain, the liver, and the lining
of the gastrointestinal tract. MAO-A acts on
norepinephrine and serotonin; MAO-B acts on
phenylethylamine. Dopamine and tyramine
are metabolized by both isoenzymes. Mi-
graineurs have been postulated to have a defi-
ciency of MAO activity. If so, a monoamine ox-
idizing deficiency would allow increased
absorption of vasoactive substances and would
also interfere with their breakdown. The only
source of MAO-containing tissue that is read-
ily available for clinical investigation is the
platelet, which contains only the B form of
MAO. During headache-free periods, some
migraine patients do have lower MAO levels in
their platelets than normal controls, but in-
creases or no change at all also occurs.161
Moreover, the correlation between MAO
platelet levels and a predisposition to dietary
migraine is weak, and activity values overlap
greatly between patients and control groups.
The idea that MAO deficiency is a causative
factor in the production of dietary migraine is
outdated. Finally, low platelet MAO activity is
not confined to migraineurs; low levels of ac-
tivity are found in patients with cluster head-
ache, schizophrenia, and alcoholism.
The PST enzymes are present in platelets in
two forms, referred to as the monoamine (M)-
and the phenol (P)-sulfating forms. The names
refer to the preferred substrates for the two
isoenzymes: M-PST specifically catalyzes the
sulfation of monoamines such as serotonin, do-
pamine, epinephrine, and norepinephrine; P-
PST sulfates neutral amines. Platelet levels of
P-PST are relatively low in "dietary mi-
graineurs" (migraineurs who are certain that
dietary factors trigger their headaches) as com-
pared to in "non-dietary" migraineurs or con-
trols.1'85'134'216 M-PST is also diminished in the
platelets of patients with dietary migraine, but
less significantly so. If platelet PST activities
reflect those elsewhere in the bodyand the
levels of platelet P-PST activity are significantly
correlated with the levels of PST in other tis-
sues such as brain, liver, and gastrointestinal
tractthe delayed detoxification of amines by
PSTs may trigger dietary migraine.239 The
marked overlap of values between the platelet
enzyme levels of those suffering from dietary
migraine and those of controls substantially
limits the appeal of this idea.
Tyramine
Tyramine (p-tyramine) is a sympathomimetic
amine postulated to trigger headaches in mi-

graineurs indirectly by causing release of nor-
epinephrine and other catecholamines from
nerve endings and the adrenal medulla. The
release of catecholamines is responsible for the
hypertensive reactions following intravenous
administration of tyramine both in normal in-
dividuals and in patients taking MAO inhibi-
tors. The transient increase in blood pressure
occurs within 1 to 3 minutes; some migrainous
individuals also experience migraine attacks 1
to 36 hours after such an infusion.83 The dif-
ference in the latencies between the hyper-
tensive and migrainogenic effects suggests that
the amine's role in the pathogenesis of mi-
graine does not depend upon its ability to re-
lease catecholamines.
Tyramine is formed when the enzyme tyro-
sine decarboxylase decarboxylates the amino
acid tyrosine. Tyrosine is a common amino
acid. Small amounts of tyramine are found in
many foods. In contrast, large quantities of
tyramine are formed only in aged, fermented,
or spoiled food products. Microorganisms con-
taining tyrosine decarboxylase, for example,
ripen certain cheeses, cure some sausages, and
ferment sauerkraut.
Much of the literature about high concen-
trations of tyramine in specific foods comes
from isolated and often unproven case reports
of hypertensive crises that occurred after pa-
tients on MAO inhibitors ate certain foods.
Largely on the basis of these case reports, a
number of authorities have recommended that
various foods (aged cheese, yogurt, sour cream,
chicken livers, sausages, bananas, avocados,
canned figs, raisins, peanuts, soy sauce, pick-
led fish, fresh-baked breads, nuts, pork, vine-
gars, beans, and broad bean pods) be elimi-
nated from the diet of all migraineurs because
of their supposedly high tyramine content. As
a result, a large number of patients painstak-
ingly restrict their diets to avoid tyramine.
Many physicians automatically place mi-
graineurs on tyramine-free diets at the initial
consultation, despite the present consensus
that tyramine is probably not an effective mi-
graine trigger in more than a small percentage
of migraineurs.
Very rare, but definite hypertensive reac-
tions have occurred in patients on MAO in-
hibitors following ingestion of some of these
foods, but in most cases the fact that the food
was at room temperature for a long period of
time or was spoiled is thought to be have been
Initiators, Precipitators, and Triggers 97
responsible. In other reports about MAO in-
hibitors, the hypertensive reactions were
caused by constituents of the food other than
tyramine. For example, broad bean pods (not
the actual beans) contain L-DOPA; banana
pulp contains modest amounts of serotonin and
dopamine, and small amounts of L-DOPA and
norepinephrine.72 These compounds may or
may not trigger migraine attacks when admin-
istered orally, but they can certainly induce hy-
pertensive reactions in patients taking MAO in-
hibitors. As a result, much conflicting and
overcautious advice regarding tyramine en-
dures and is frequently perpetuated in the mi-
graine literature.
Some foods, particularly some cheeses, do
contain high concentrations of tyramine (Table
5-2). Matured and ripened cheeses such as
Camembert, Brie, cheddar, Emmenthaler,
Parmesan, Roquefort, Bleu, and Stilton con-
tain large amounts of tyramine (up to 2000
//.g/g), especially when not fresh and not prop-
erly stored and refrigerated.149'161 However,
the tyramine content of different cheeses
varies enormously, depending upon the man-
ufacturing process and the length of ripening.
Long-matured cheeses (e.g., fully matured
cheddar) and blue-veined cheeses (e.g., Dan-
ish Bleu, blue Stilton) have the highest
concentrations of tyramine.66 In contrast,
processed cheeses like American or Velveeta
contain low concentrations, and cream cheese,
cottage cheeses, yogurt, and sour cream have
barely detectable levels unless they have been
allowed to ferment for extended periods at
room temperature. A recent report indicates
that pizzas from large-chain commercial out-
lets contain only small amounts of tyramine.208
For those sensitive to tyramine, caution must
Table 5-2. Foods Containing
Substantial Quantities of Tyramine
Some matured and ripened cheeses
Dried salted herring
Some sausages
Sauerkraut
Yeast extracts
Badly stored protein-containing foods
Some beers, ales, and chiantis
Data from Evans et al. (1988);66 McCabe (1986);149 Rice
et al. (1976);191 and Sens (1969).206
98 Clinical Aspects of Migraine
be exercised when ordering pizzas from
smaller outlets or gourmet pizzas known to
contain aged cheeses.
Dried salted herring (and possibly other
dried fish) contains large amounts of tyramine,
as do some sausages (some bolognas and
salamis, pepperoni, and summer sausage).
Vacuum-packed jars of pickled herring contain
low levels of tyramine, but when opened and
left unrefrigerated for even 2 hours, substan-
tial levels of tyramine develop. Banana skins,
but not the pulp, contain tyramine; most peo-
ple do not eat the skins. Fresh raspberries and
very ripe avocados contain low to moderate
amounts.231 Sauerkraut, yeast extracts (Brewer's
yeast), beers and ales on tap, and chiantis con-
tain variable amounts of tyramine.206'225 Ver-
mouth has a high tyramine content. Soy sauce
contains a trace. It is important to know, how-
ever, that foods normally containing low con-
centrations of tyramine may increase their
amine content if spoilage occurs. For example,
protein-containing foods that are not fresh or
have been inadequately refrigerated or stored
do contain high levels of tyramine. Badly stored
chicken livers and beef livers are notorious
offenders.
Although as many as 38% of patients believe
that cheese is a definite factor in producing
their headaches, controversy surrounds the
tyramine's ability to induce migraine at-
tacks.119'214 Some studies have demonstrated
that tyramine administration can reliably pro-
duce migrainous symptoms in food-sensitive
migraineurs, while other investigations have
failed to show an infallible effect.78'101'154'196'215
Apparent conflicts in the findings appear to be
caused, at least in part, by differences in pro-
cedures and in patient selection. On balance,
some clinical data support a role for,tyramine
sensitivity in a subgroup of migraine patients,
but the data are not very conclusive.
Chocolate
Chocolate is the most frequent food cited by
patients as a trigger and is listed by many au-
thors as a major precipitant of migraine at-
tacks.42'101'154'175'205 The headache is stated to
take as long as 24 hours to develop.84 Choco-
late is often cited as a more potent trigger in
children than in adults.11'138 In fact, chocolate
is often the only food or beverage identified as
a headache antecedent in children. Although
three double-blind trials have differed as to
chocolate's ability to produce headaches,
chocolate does appear to be a genuine head-
ache trigger in a definite, but small, minority
of migraineurs.84'139'154
Blau has hypothesized that some patients
with putative chocolate-induced headaches
may eat chocolate as a result of a craving ex-
perienced during a prodrome unrecognized as
the actual beginning of an attack. When the
headache develops, these individuals indicate
that the bout was triggered by the chocolate,
when in actuality, the eating of chocolate was
not the cause, but a manifestation of an ongo-
ing migraine attack.15
The biochemical explanation for the putative
effects of chocolate is obscure. One hypothe-
sis is that the potent vasoactive amine (3-
phenylethylamine, which is also found in some
cheeses and in red wine, is responsible for pro-
voking headaches.203 The concentration of /3-
phenylethylamine and other amines in choco-
late is low, however, suggesting that either
chocolate-induced migraine attacks are not re-
lated to /3-phenylethylamine or chocolate-
sensitive migraineurs are susceptible to ex-
ceedingly small amounts of /8-phenylethy-
lamine. Reports conflict about oral /8-
phenylethylamine triggering headaches in
patients who describe chocolate-provoked mi-
graine attacks.155'197 Chocolate does contain a
complex mixture of other compounds that are
potentially capable of affecting migraineurs, in-
cluding a large number of phenolic compounds
such as tyramine, octopamine, and serotonin,
and phenolic flavenoids that are also present in
red wine.113 And although chocolate and other
products derived from the cocoa tree also con-
tain the methylxanthine derivative theo-
bromine in uniquely high amounts, the ability
of this substance to produce headaches has not
been evaluated.
Caffeine
Caffeine, a methykanthine, is naturally pres-
ent in coffee seeds (beans) and tea leaves and
is therefore present in foods and drinks made
from derived products such as coffee and tea.
Cocoa products also contain caffeine (and
theobromine). Tea contains theophylline.
There is appreciable variability in the caffeine
 Initiators, Precipitators, and Triggers 99

Table 5-3. Caffeine Content of take levels (100 mg/day).94 The headaches oc-
Common Beverages and Medications cur because even modest amounts of caffeine
can produce physical dependence, and symp-
Caffeine (mg) toms of withdrawal appear when the usual in-
take is discontinued210. Caffeine withdrawal
Coffee (6 oz, percolated) 85-135 headaches usually occur 8 to 16 hours after the
Coffee (6 oz, drip) 105-175 last "dose," but may start sooner. They usually
Coffee (6 oz, instant) 45-70 peak at 24 to 48 hours, although some may last
Tea (6 oz, brewed) 20-60 for several days to a week. The most frequently
Cola (12 oz) 35-65 reported withdrawal symptom is headache,
Ginger ale (12 oz) 0 but drowsiness, fatigue, anxiety, irritability,
Root beer (12 oz) 0 restlessness, difficulty concentrating, clouded
Mountain Dew (12 oz) 52 thinking, and nausea may also occur.95 Char-
Pepsi Cola (12 oz) 37 acteristically, there is prompt relief if more caf-
Tab (12 oz) 44
feine is consumed.
Caffeine withdrawal headache should be
Anacin 32
considered a diagnosis for the following indi-
Excedrin 65 viduals:
Esgic 40 1. Those with weekend headaches. Persons
Fioricet 40 who ingest significant amounts of caffeine
Fiorinal 40 during the work week may develop with-
Cafergot 100 drawal headaches on weekends when
their caffeine intake is reduced;39
2. Those with early morning headaches that
may be caused by caffeine deprivation
overnight.
content of tea and coffee, depending upon the 3. Those who develop headaches during the
alkaloid content of the coffee beans or tea fasting before surgical procedures or
leaves and upon the method of brewing (Table postoperatively.10
5-3). A 6-oz cup of coffee can contain between It was thought that most, if not all, of caf-
45 and 175 mg of caffeine; a cup of tea be- feine's pharmacologic actions could be ex-
tween 20 and 60 mg of caffeine, and 1 mg of plained by its ability to inhibit phosphodi-
theophylline. Drip-brewed and percolated cof- esterases. Caffeine, however, is a relatively
fee contains more caffeine than instant coffee. weak phosphodiesterase inhibitor that requires
A cup of cocoa has about 250 mg of theo- concentrations above those usually encoun-
bromine and about 5 mg of caffeine. Caffeine tered in vivo with normal intakes of the alka-
is added to cola drinks, numerous non-cola loid. Antagonism of adenosine at cell surface
soft drinks, many prescription and over-the- receptors is currently believed to underlie most
counter analgesics, and even some bottled wa- of caffeine's pharmacologic effects. Concen-
ters. In the United States the daily per capita trations of caffeine that correspond to plasma
caffeine consumption is estimated at about 240 concentration when consumption of normal
mg, but is much higher in England and Swe- amounts of caffeine are consumed antagonize
den (over 400 mg/day).95 adenosine AI and AA receptors.
Approximately 10% of patients indicate that
their migraine headaches are produced by the
consumption of coffee or a caffeine-containing Citrus Fruits
product.201 However, throbbing headaches
similar to migraine develop in migraineurs who Citrus is one of the most frequently reported
consume moderate or even modest amounts of precipitants of migraine headache. '91>101 Cit-
caffeine-containing products if their daily in- rus fruits contain at least two monoamines
take of caffeine is reduced suddenly. High in- octopamine (p -hydroxyphenylethanolamine)
take of caffeine intake is not a prerequisite, as and synephrine.223'224 Octopamine is a vasoac-
symptoms can occur in individuals ingesting tive amine capable of producing headaches in
low to moderate (235 mg/day) or even low in- susceptible individuals.82
100 Clinical Aspects of Migraine
Figure 5-3. Venn diagram of the overlap between food and alcohol sensitivity in migraineurs. Data from patients at-
tending a migraine clinic. There was a significant statistical relationship between sensitivity to cheese/chocolate and to red
wine and also to beer. (Adapted from Peatfield RC: Relationships between food, wine, and beer-precipitated migrainous
headaches. Headache 35:355-357, 1995, with permission.)
Alcohol
Between 20% and 50% of migraineurs believe
that alcohol consumption is a definite precipi-
tant 175,176,188,201,205^33 jt h&s been proposed;
however, that wine does not induce migraine
attacks when consumed in small quantities dur-
ing meals under stress-free conditions.164 Most
food-sensitive migraineurs are also sensitive to
alcohol, and there is considerable overlap in
the pattern of reactions to foods, beer, red
wine, and other alcoholic beverages (Fig.
53).176 In particular, the association between
food sensitivity and beer appears clear-cut. Cu-
riously, many migraineurs in the United States
and the United Kingdom believe that red wine
provokes migraine more easily than white wine
does, while on the European continent, white
wine is viewed as the major culprit. The alco-
hol content of red and white wine is similar.133
Red wines, but not white wines, produce en-
dothelium-dependent arterial vasodilatation, a
presumed result of released nitric oxide (NO)
(see Chapter 10).75
Most migraine attacks provoked by alcoholic
beverages are presumably not caused by the
ethanol itself, but by cogeners chemicals that
help to give beverages their characteristic fla-
vors. White wines, vodka, light scotches, and
light whiskeys have low cogener content and
can be tolerated in small amounts by some, but
not all, migraineurs.133 Patients reporting sen-
sitivity to red wine developed more migraine
from red wine than from vodka flavored to
mimic the taste of red wine.133 The important
causative agent in red wine has been postulated
to be tyramine, even though chianti and other
red wines do not have significantly higher tyra-
mine content than that of white wine.102 Com-
plex phenol compounds (flavenoid phenols)
have been suggested as alternative candidates.
They are present in very much higher concen-
trations in red than in white wine, but there is
no direct evidence for their involvement in
1 30
1 VI
migraine. *
Monosodium Glutamate
Monosodium glutamate (MSG) is extensively
employed as a flavor enhancer. In addition to
widespread use by Chinese chefs, a large pro-
portion of canned, frozen, diet, snack, and pre-
pared foods contain it (Table 54). Soy sauce

Table 5-4. Foodstuffs that Frequently
Contain Monosodium Glutamate (MSG)
Fast-food hamburgers and fried chicken
Frozen foods (especially dinner entrees)
Canned, powdered, and dehydrated soups and
bouillons
Potato chips, corn chips, dry roasted nuts, and
prepared snacks
Canned and processed meats
Diet foods and weight loss products
Cured and luncheon meats and sausages
Poultry (frozen turkey) injected with "natural
juices"
Prepared sauces, salad dressings, mayonnaise,
soy sauce, stuffings, dips, mustards, and gravies
Gourmet salts and seasonings and salt
substitutes
Data from Mauskop and Brill (1997)148 and Scopp
(1991).204
also contains substantial amounts of MSG. It is
frequently difficult to identify MSG in pre-
pared foods because manufacturers use a vari-
ety of terms for it including, "hydrolyzed veg-
etable protein" (8% to 20% MSG), "calcium
casemate" (4% to 20% MSG), "hydrolyzed
plant protein," "protein hydrolysate," "natural
flavor," "natural flavorings," "glutavene," and
"kombu extract."204 According to current Fed-
eral Drug Administration (FDA) regulations,
only when MSG itself is added to a food must
it be identified as monosodium glutamate in
the label's ingredient list.
When ingested in sufficient quantities (3
to 5 g), MSG induces adverse reactions in
about one-third of normal individuals (Chinese
restaurant syndrome, Kwok's syndrome).190
Ninety percent will react to 10 g of MSG. An
average bowl of egg drop soup has 3 g, but a
typical serving of MSG-containing food con-
tains less than 0.5 g. A reaction is most likely
if the MSG is eaten in a large quantity on an
empty stomach or in a liquid such as a rapidly
absorbed clear soup. The most common symp-
toms of the Chinese restaurant syndrome are
band-like headaches and sudden feelings of
tightness in the facial and jaw musculature that
develop within 60 minutes of ingestion of
MSG. There are reports of dizziness, diarrhea,
nausea, abdominal cramps, paresthesias of the
Initiators, Precipitators, and Triggers 101
mucous membranes of the mouth and palate,
flushing and sweating of the face, burning or
pressure pain in the neck, shoulders, and chest,
palpitations, and weakness.246
A large number of migraineurs develop in-
tense, throbbing, unilateral or bilateral head-
aches 15 to 30 minutes after eating even small
amounts of MSG. Many individuals cannot dis-
tinguish these attacks from their usual migraine
attacks. The small amounts of MSG that pro-
duce headaches in susceptible migraineurs are
generally insufficient to produce the complete
Chinese restaurant syndrome. Often it is the
postprandial migraine that makes them suspect
that MSG was in their food.
Nitrites
Sodium nitrite is employed as a preservative
and to prevent color changes in processed and
cured meats and fish, including frankfurters,
bacon, ham, bologna, salami, pepperoni,
sausages, corned beef, pastrami, and lox. Some
individuals develop headaches minutes to
hours after ingesting nitrite-containing prod-
ucts (hot dog headaches).105 These headaches
are typically bitemporal or bifrontal and usu-
ally throbbing in nature, and occasionally ac-
companied by facial flushing. Although nitrite
headaches share some features with migraine,
it is uncertain whether nitrite-provoked head-
aches represent migrainous events rather than
nonspecific vascular headaches.
Artificial Sweeteners
Aspartame (NutraSweet, L-aspartyl-L-pheny-
lalanine methyl ester, and Equal, which also
contains phenylalanine) is used extensively as
a synthetic sweetener in diet sodas, prepared
foods, sugarless chewing gum, and desserts and
as a tabletop sugar substitute. Not only is head-
ache the most frequent consumer complaint
related to aspartame, but 8% of migraineurs
cite it as a precipitating factor.132 Three clini-
cal trials, however, came to disparate conclu-
sions about aspartame as a dietary trigger of
headache.118'2"2'234 The one that was a rigidly
controlled, double-blind inpatient study, pre-
sumably excluding a number of exogenous fac-
tors that may act synergistically with aspartame
to trigger headaches, found that aspartame did
not cause headaches.202 Until further data are
102 Clinical Aspects of Migraine
reported, we can only assume that some peo-
ple are particularly susceptible to headaches
caused by aspartame and should regard it as a
potential migraine trigger in selected patients.
ALLERGY
Allergy is thought by many to cause migraine
headaches. Allergy is by definition a hypersen-
sitivity to an antigen accompanied by a specific
immune response that results in the produc-
tion of IgE antibodies. There is no doubt that
IgE-mediated reactions in patients who suffer
from both migraine and allergic disease can in-
deed produce migraine headaches, but only if
the offending allergen causes a systemic reac-
tion with some manifestations of anaphy-
laxis.115 In contrast, allergic migraine is said to
occur when ingestion of a particular food or ex-
posure to a specific air-borne allergen induces
only migraine attacks. Whether allergic mi-
graine is a common (or even a real) phenom-
enon is moot.91'137'157'183 Much of the confu-
sion has resulted from inadequate controls
when therapeutic measures were investigated;
nor has the therapeutic potential of placebo
been adequately considered.
A large body of literature indicates that al-
lergy to certain foods provokes migraine at-
tacks. The list of foods is not only extensive but
also includes many common foods: wheat, or-
anges, eggs, milk and other dairy products,
beef, pork, corn, yeast, soybeans, shellfish,
onions, and peanuts.91'112'156 Elimination diets
have been reported to relieve migraine head-
aches completely, or almost completely, in a
very high proportion of migraineurs, particu-
larly in children, reflecting the feeling that food
allergy is more frequent among them. >91>136.157
Presumptive IgE-mediated headaches have
been produced in some patients with double-
blind placebo-controlled challenges of specific
foods. But because the effect of a putative al-
lergen is probably dose related, for many pa-
tients, insufficient allergen may have been de-
livered in gelatin capsules and the test results
may be very misleading.62'136 As with the di-
etary factors discussed above, conclusions
about specific foods for the most part have
been based on anecdotal evidence, patient his-
tories, uncontrolled studies, and on challenge
tests that were performed without appropriate
placebo controls. Food has a complex compo-
sition in which the nutritional elements are
amalgamated with a number of chemical con-
stituents that occur naturally, are induced by
the methods of food handling (fermentation,
canning, cooking), or are artificially added as
food additives. This obviously complicates at-
tempts to determine what exactly a patient is
allergic to.
It has proved difficult to identify offending
foods either by skin tests or by measurements
of the serum levels of total IgE or antigen-
specific IgE. Nor are serum levels useful to
predict the effect of foods in migraine patients
or even to demonstrate a correlation between
specific IgE and provocative foods. Antihista-
minics do not effectively prevent, or even
ameliorate, migraine in most individuals. An
unequivocal immunologic component for mi-
graine has been challenging to demonstrate
and to correlate with the clinical picture.181
And unfortunately, the subject of allergy-
triggered migraine has been further compli-
cated and obscured by polarization of allergists
into "orthodox" (scientific) schools and "un-
orthodox" (clinical ecology) schools.
Immune-allergic alterations mediated by
non-IgE-mediated mechanisms such as levels
of IgG or IgA immunocomplexes, lymphokines
or other cytokines, or serum complement have
been postulated to play a role in migraine. But
documenting them has also caused contro-
versy.181 As one example, both alterations in
serum complement levels and normal levels
have been reported. Accordingly, evidence is
insufficient at present to support an im-
munopathological basis for migraine. It is even
possible that immunological deficits develop as
a consequence of migrainous episodes. This is
a subject that needs further exploration.
HUNGER AND HYPOGLYCEMIA
While hunger that results from missing meals,
eating inadequate meals, dieting, or fasting is
widely thought to be a major precipitating fac-
tor for migraine, the issue is complex and prob-
lematic.42'108'175'193'201 In a large survey of
women with migraine, deprivation of food for
5 hours during the day or 13 hours during the
night was reported to precede many bouts of
migraine, but only a minority of patients actu-
ally ascribed the attacks to fasting.42 In another
investigation, only 50% of patients with mi-
graine developed attacks after fasting for 19
hours.16 Approximately 25% of children report

that they develop headaches after skipping a
meal.128 Hunger-induced headaches are com-
mon in Jews who fast on Yom Kippur when
food and drink are not permitted for 25 hours
and in Muslims during the month of Ramadan
when food and drink are not permitted during
daylight hours.87'160 Many migraineurs and
some non-migraineurs, however, develop a
type of headache in this situation that more
closely resembles tension-type headache than
migraine. Development of headache following
fasting is more common among a group of
chronic headache sufferers than among those
with non-chronic headaches.160
It has been posited that the major reason for
the migraine headaches induced by fasting is
hypoglycemia, but a number of reports weaken
this presumption:
1. Headaches may be present in fasting in-
dividuals without hypoglycemia.42
2. Excessively low blood sugar is not a nor-
mal consequence of fasting, and blood
glucose levels are not necessarily low pre-
ceding headaches associated with fast-
ing.16^08
3. Migraineurs can endure a substantial de-
gree of insulin-induced hypoglycemia
without developing headache. 7^In con-
trast, typical hypoglycemic episodes in
insulin-dependent diabetics caused mi-
graine attacks in more than half of those
with a history of migraine.144
4. Administration of carbohydrates to pa-
tients with migraine headaches suppos-
edly induced by hypoglycemia has been
reported to have both beneficial and ad-
verse effects.16-92-142
Hypoglycemia per se may therefore not be
the only factor responsible for migraine in-
duced by fasting.17^'186 Nonetheless, in some
migraineurs, an evolving attack as a result of
delay in eating may be ameliorated by eating a
meal. The mechanism is unknown, but missing
a meal may be only one incident in a time of
excessive activity or stress which in itself would
be likely to bring about a migraine attack.
Moreover, although the level of blood sugar is
primarily determined by insulin secretion, the
rates of glucose production and utilization are
also affected by glucagon, epinephrine, corti-
sol, and growth hormone levels. These factors
may be influenced by stress in a number of
ways. Fasting for prolonged periods may also
produce caffeine-withdrawal headaches. None-
theless, anecdotal clinical experiences support
Initiators, Precipitators, and Triggers 103
the notion that reductions in blood sugar, es-
pecially if prolonged, will produce migraine.
Although quantitative data are lacking, many
patients with migraine are said to have idio-
pathic postprandial reactive hypoglycemia, a
drop in blood sugar in response to feeding. Pre-
sumably, idiopathic postprandial reactive hy-
poglycemia represents an exaggeration of ordi-
nary physiological reactions. The blood glucose
level ordinarily rises soon after the ingestion of
food and then returns to normal. Hypo-
glycemia, with blood glucose levels of less than
50 mg/dL without accompanying symptoms,
occurs in many normal individuals in response
to the stimulus of a glucose load or a high-
carbohydrate meal. In fact, low blood glucose
values occur during the postprandial state in
25% of normal, asymptomatic individuals.28
The diagnosis was previously made on the
basis of abnormal 5-hour glucose tolerance
tests.52 But there are problems with regard to
interpretation of the results of 5-hour oral glu-
cose tolerance test:
1. The results of such tests are variable even
in patients with proven hyperinsulinism.
2. Normal individuals can have low blood
sugar levels at the third hour.
3. The presence and severity of hypo-
glycemic symptoms is difficult to corre-
late with blood sugar responses.
The test is now largely discredited as a diag-
nostic tool.207 A normal plasma glucose level
reliably obtained during the occurrence of
spontaneous symptoms eliminates the possibil-
ity of a hypoglycemic disorder; no further eval-
uation is required. A blood glucose level lower
than 50 mg/dL is necessary for diagnosis.
The diagnosis of idiopathic postprandial re-
active hypoglycemia has come under a great
deal of criticism, and its occurrence is now con-
sidered low. It appears to occur primarily in in-
dividuals who consume a peculiar diet that has
a high composition of refined carbohydrate
calories, but may also develop in individuals on
a self-imposed weight loss program who peri-
odically break the dieting by the ingestion of
refined carbohydrates ("junk food"). Perhaps,
however, migraineurs are more sensitive to the
effects of a high-carbohydrate meal than non-
migraineurs. Ingestion of large quantities of
foods containing simple sugars has been said
to cause attacks in some migraineurs. It is also
possible that migraineurs are more sensitive to
a modest reduction in blood sugar than other
people are. Some patients have indicated that
104 Clinical Aspects of Migraine
their migraine substantially improved when
they were placed on a frequent-feeding, high-
protein, low-carbohydrate diet, but data on this
are limited.52
SLEEP
Although the great majority of migraineurs find
that a brief period of sleep has therapeutic
value in aborting attacks, for some individuals
too little sleep, or excessive sleep, can actually
precipitate attacks.13'169'193'201'233 Many mi-
graine sufferers wake up with headaches on
weekends and holidays when they sleep later
than they ordinarily do. For this reason, mi-
graineurs should be strongly urged to arise at
a uniform time each day.
Some migraine patients are awakened from
nocturnal sleep, or from a daytime nap, with a
severe, throbbing headache. Nocturnal mi-
graine attacks are most common in the early
morning hours. A clear tendency for such head-
aches to begin either during rapid eye move-
ment (REM) sleep or immediately following
REM sleep has been reported, even though
this sleep phase occupies only about 15% to
20% of total sleep time.53'54 Preliminary data
also indicate that more deep sleep occurs dur-
ing nights followed by migraine attacks than
during non-migraine nights.51'54 Polysomno-
graphic recordings have also shown that dur-
ing daytime napping only the deeper stages of
sleep (III, IV, and REM) induce migraine.51
Migraine patients appear to have essentially
normal sleep patterns during all-night poly-
somnographic recording sessions.58
Sleep disorders are claimed to be more
common in children with migraine than in chil-
dren without it. For example, somnambulism,
head banging, night terrors, and sleep breath-
ing disorders may be more frequent in children
with severe migraine.10'11'25 This subject, how-
ever, has received only modest attention and
requires further documentation.
The relationship between migraine head-
aches and obstructive sleep apnea and snoring
is uncertain. Headache may be the presenting
symptom of sleep apnea. Most reviews of the
subject list morning or early awakening head-
ache as a common symptom, with an incidence
of up to 36%.96'16^'232 However, reports are
vague about the types of headaches that pa-
tients with obstructive sleep apnea and snoring
suffer from. It is not known whether these con-
ditions are causal in the genesis of migraine
attacks.
EXERTION
Fatigue, whether it comes from exertion or
from lack of adequate rest, can give rise to mi-
graine headaches.233 In addition, any form of
exercise may precipitate headaches (benign ex-
ertional headache, effort migraine) in the ab-
sence of cranial or intracranial pathology. Ex-
ertional headache occurs both in poorly
conditioned persons who exercise infrequently
and in trained athletes. Almost all of the pa-
tients either have migraine or have a family his-
tory of migraine. These headaches are throb-
bing, bilateral or unilateral with typical
migrainous features such as nausea, vomiting,
and photophobia.170 Generally the headache
occurs at the peak of exercise and usually sub-
sides as activity ceases. Prolonged attacks of
headaches lasting 24 hours can also occur.
The effort that precipitates benign exertional
headache is generally protracted, uncharacter-
istically strenuous, excessively violent, physi-
cally stressful, and associated with exhaus-
tion.145 But effort migraine can also occur
during less intense, but more prolonged activ-
ity. Running, rowing, tennis, football, squash,
bowling, weight-lifting, and dancing have all
been implicated.56'145^ Several recent papers
from Japan have placed emphasis on exertional
headaches evoked by swimming.114'153 Other
factors include lack of a proper warm-up be-
fore exercise, dehydration, and exercising at
high altitudes, in heat, or under conditions of
changing barometric conditions.41 Caffeine,
poor nutrition, and alcohol usage are thought
to be contributing factors. In children the prob-
lem is more prevalent among boys, usually in
relation to competitive sports and endurance
contests.11
Although patients with exercise-induced
headaches usually have no demonstrable in-
tracranial pathology, they should be assessed
for arteriovenous malformations (AVMs),
aneurysms, pheochromocytomas, and for the
presence of lesions in the posterior fossa.173
Sexual Activity
A distressing type of headache that is usually
considered a form of exertional headache is

headache associated with sexual activity (coital
cephalgia, benign sex headache, benign orgas-
mic cephalgia).'180 Some of these headaches
appear migrainous in nature. Benign head-
aches associated with sexual activity can be di-
vided into three types.126'172
The first, most common type usually occurs
during or slightly before orgasm with the
abrupt onset of extremely severe, usually bi-
lateral, throbbing pain located in the occipital
region, behind the eyesor the pain may be
generalized.167 The bout may be accompanied
by nausea, vomiting, and photophobia, lasting
from minutes to several hours.
Men are affected more often than women,
the gender distribution being due perhaps to
the intensity of physical exertion in the sexual
act. However, because the same type of head-
ache can come on when the individual is mas-
turbating or playing a completely passive sex-
ual role, the symptoms should be attributed
more to sexual excitement than to physical
strain or exertion. Headaches are more fre-
quent when several orgasms occur during one
sexual encounter. Headaches associated with
sexual activity appear to have an unpredictable
clinical pattern. They may appear suddenly,
continue for a length of time and stop abruptly,
or occur regularly for many years.16'
Because many patients have a personal or
family history of migraine, this type of coital
headache is considered by some authorities to
be a variant of migraine.172'180'209
The second type of headache associated with
sexual activity is a dull, tight, cramping head-
ache, usually bilateral, and occipital and cervi-
cal in location. It can occur during sexual ac-
tivity. It usually intensifies as sexual excitement
increases and is generally preorgasmic. The
headache is similar in quality to tension-type
headaches. It may be related to excessive con-
traction of head and neck musculature and is
believed to arise in association with the spasm
of craniofacial and cervical musculature prior
to orgasm.
The third type of headache is from low cere-
brospinal fluid pressure, perhaps as the result
of a dural tear that occurred during the phys-
iologic stress of coitus. The relationship of pos-
ture to pain in these patients is identical to that
seen in patients with headache following lum-
bar puncture.
Most coital headaches are benign, but some
are malignant. Thus subarachnoid hemorrhage
may occur at the time of intercourse. The oc-
Initiators, Precipitators, and Triggers 105
currence of a disturbance of consciousness,
stiff neck, and residual pain the day after the
incident characterizes the headache caused by
subarachnoid hemorrhage and distinguishes it
from benign orgasmic cephalgia.
PHYSICAL AND
ENVIRONMENTAL FACTORS
A variety of physical or environmental factors
may trigger migraine attacks. Changes in
weather, glare, noise, rhythmic movement, and
strong smells are potent migrainogenic stimuli
for many migraineurs.
Seasonal Factors and Changes
in Weather
A number of patients report that their attacks
have a seasonal periodicity. In other words,
they have attacks mainly, if not exclusively, at
certain times of the year.23'90'124 Investigations
have ascribed high attack rates to a variety of
months and seasons, so it is difficult to attribute
seasonal changes in migraine frequency to al-
lergic factors such as changes in the levels of
pollens or molds.
Although up to 78% of patients indicate that
variations in weather patterns trigger bouts of
migraine or aggravate acute episodes of pain,
there is little agreement in the literature about
the specific weather triggers.90'158'188'193'226
For example, many patients state that thun-
derstorms consistently precipitate attacks. For
other migraineurs, cold weather; warm or hot
weather; dry winds (such as the Chinook, the
Mistral, the Sirocco, the Chamsin, or the Santa
Ana); the onset of humid, hot weather; or
rapidly falling atmospheric pressure are re-
ported to be significant factors.179 Bouts of mi-
graine with aura are often noticed by mi-
graineurs when they have been decompressed
from a hyperbaric environment or exposed to
diminished barometric pressure during high-
altitude flight or sojourns in the mountains.2'4
The reductions in barometric pressure during
such procedures are much larger than those
that occur as a result of changes in weather.
Furthermore, migraine frequency has also
been reported to increase when the atmo-
spheric pressure rises.90 There are studies in
which no change has been found in the num-
106 Clinical Aspects of Migraine
ber of attacks at different levels of atmospheric
pressure, air temperature, rain, sunshine, or
humidity or during adverse weather condi-
tions.49'^7'124'166 It is safe to say that whatever
part weather assumes in precipitating migraine
attacks, its effects vary widely among individu-
als and among situations.
Visual Stimuli
Prolonged exposure to the glare of intense light
is a potent trigger for headaches in between
30% and 45% of migraine patients.205'235 Ex-
posure to sun is especially effective, although
reliable data regarding the length of exposure,
the intensity of the sunlight, and the ambient
temperature are not available. However, head-
aches appear more prevalent on sunny days, es-
pecially when there is snow on the ground.90
Many patients wear sunglasses much of the
time, and many have learned to restrict expo-
sure to strong light, especially that reflected
from water or snow. As a result, they forgo
summer beaches and ski vacations. Other pa-
tients report that exposure to flickering or
flashing lights constitutes a specific provocative
situation.242'243 They avoid flickering light in a
cinema or from a television screen, lighting
from fluorescent bulbs, repetitive flashes of
photographic strobe lights, and night driving
(because of oncoming automobile headlights)
A proportion of migraineurs are bothered by
viewing striped or strongly contrasting pat-
terns.140'244 The visual discomfort experienced
by migraineurs in viewing such patterns may
be determined by the color of the light used
for illumination.35 Although headaches are fre-
quently reported by persons working for ex-
tended periods of time at computer display
screens, the headaches are mainly generalized
tension-type headaches resulting from postural
abnormalities affecting the neck and pericra-
nial muscles rather than migraine headaches.
Auditory Stimuli
Some migraineurs find that exposure to un-
pleasant, blaring noise will give them a mi-
graine. They frequently emphasize the inten-
sity, duration, and insistent beating quality of
noise produced by such varied stimuli as traf-
fic, pneumatic drills, machines, and rock mu-
sic bands.81 Even sounds that are generally
considered benignfor example, conversation
in a large party or a crowded shopping mall
may induce headaches.
Motion and Motion Sickness
Motion is known to precipitate migraine, es-
pecially in children. Between 9% and 15% of
children with severe migraine report that trav-
eling sets off their migraine headaches.11'36 A
number of authorities have indicated that both
children and adults with migraine, and in par-
ticular migraine with aura, have an increased
vulnerability to develop motion sickness. The
prevalence of motion sickness in children with
migraine is estimated to vary between 26% and
60%.10'11'32'117 However, some experts do not
find a significant excess of motion sickness in
children with migraine.50'162 Nevertheless, it is
widely believed that children with motion sick-
ness often go on to develop migraine in later
life.32'117'125 Perhaps as many as 60% of adult
migraineurs attencfing clinics have a history of
severe motion sickness in childhood.205
Olfactory Stimuli
Many migraineurs are very sensitive to partic-
ular odors.18'193'201 The smells may be those of-
ten considered unpleasant, such as cigarette
and cigar smoke; paint, diesel, and gasoline
fumes; tar and asphalt; newsprint; some deter-
gents; furniture polishes; and ammonia, chlo-
rine, and various industrial chemicals. Aromas
that most people find pleasant, such as per-
fumes, colognes, aftershave lotions, and fra-
grances added to hair sprays, shampoos, and
other toiletries, may also be offenders. Many
migraineurs are literally tortured by the in-
ability of spouses and children to understand
this type of problem. Bouts of migraine are un-
controllable when family members refuse to
stop using offending fragrances and toiletries
or to stop smoking in the bedroom and car.
Other patients have difficulty in close-packed
elevators or commuter trains, especially in the
early morning when perfumes, colognes, and
aftershave lotions have recently been applied.
Department stores, where perfume samples
are liberally dispensed on passing customers,
are offenders. Some migraineurs who are seri-
 Initiators, Precipitators, and Triggers 107

ously affected by fragrances have found it nec- Table 5-5. Environmental Factors
essary to avoid any gatherings where people are Identified by Patients with Multiple
likely to be heavily scented. Chemical Sensitivities as
Causing Symptoms
Smoking
Adhesives/glues Laser printers
Data about the frequency of smoking by mi- Aftershave Medicines
graineurs are inconsistent; in comparison to Air freshner Mothballs
the general population, both a higher and a Auto and diesel Nail polish
lower incidence of smoking has been re- emissions Newspaper print
ported.31'71'135'141'165'174'236 Although possible Carpeting Paint and varnish
association between smoking and migraine has Contaminated water Particle board
not been studied with thoroughness, several Copy machines Permanent press
groups of investigators consider smoking to be clothing
Correction fluid
a risk factor for migraine.31'141'222 About one-
Detergents Pesticides
third of patients contend that smoking (as op-
posed to smelling the smoke of others) initiates Disinfectants Plastics
or exacerbates their headache symptoms.236 Dry cleaning Polluted urban air
The daily smoking rate and the cigarette's nico- Fabric softener Smokestack emissions
tine level appear to affect headache activity.174 Felt tip markers Synthetic fabrics
Fiberglass Tobacco smoke
Ice Cream Headache Food additives, Veneered wood
colorings, and dyes Vinyl products
Ice cream headache (cold-stimulus headache) Formaldehyde Woodsmoke
is transient head pain produced by eating ice
cream or other frozen food, or drinking iced
beverages.12'187 Application of a cold substance mous range of culprits found in air, water, food,
to either the palate or the posterior pharyngeal drugs, and habitat (Table 5-5). The variety of
wall causes the pain, which develops within a physical and psychological symptoms attrib-
minute of exposure, is usually bilateral, and is uted to prolonged, low level exposure to com-
usually located in the frontal or anterior tem- mon substances is designated chemical sensi-
poral regions. The orbit and palate may be in- tivity syndromes (multiple chemical sensitivity
volved. The pain lasts for less than 5 minutes syndrome, sick building syndrome, environ-
after the cold stimulus is removed. About 30% mental illness). Symptoms are myriad and in-
to 40% of non-migraineurs experience ice clude headache, confusion, memory deficits,
cream headaches, but opinion is divided as to cognitive difficulties, affective disorders, in-
whether they are more frequent in patients somnia, anorexia, myalgia, clumsiness, pares-
with migraine.12'59'187 The incidence of ice thesias, eye and throat irritation, and fatigue.
cream headaches in migraineurs is said to vary Some patients also complain of excessive sen-
from 27% to 93%.59'18 There is also dispute sitivity to light, sound, and touch. Objective
regarding correlation of the site of ice physical signs are absent. Patients with such
cream-induced pain and the usual site of head- problems are believed by clinical ecologists to
ache pain.12'60 In rare patients, an ice cream suffer from the toxicological effects of envi-
headache may trigger a bout of migraine.12 ronmental chemicals or from dysregulation of
the immune system, and are treated with ex-
treme dietary and environmental restrictions
HYPERSENSITIVITY TO and provocation-neutralization techniques.
ENVIRONMENTAL FACTORS Many, if not all, the substances postulated as
factors in ecological illness are also reported to
Many patients, and some physicians (clinical trigger migraine headaches. A number of stud-
ecologists), believe that individuals can become, ies have indicated an association between
hypersensitive (or allergic) to common envi- headaches and workplace exposure to air con-
ronmental factors. Patients identify an enor- ditioning, office machines, mixed solvents, arid
108 Clinical Aspects of Migraine
the like.104'116'151 Moreover, some migraineurs
with frequent attacks do have symptoms rem
iniscent of chemical sensitivity syndromes.
Some are even able to indicate with extreme
precision their sensitivity to specific sub-
stances. But it is difficult, if not impossible, to
attribute the cause of migraine to environ-
mental chemical exposure.
Most physicians believe that some chemi-
cals, pollutants, and other environmental fac-
tors can influence general health. There are
those, however, who hypothesize that chemi-
cal sensitivity causes diseases and disorders,
including migraine. The hypothesis posits a
two-step process that occurs in vulnerable
individuals:
1. An inaugural salient exposure (e.g., a one-
time, intermittent, or continuous exposure to
pesticides, solvents, or air contaminants in a
sick building) results in decreased tolerance for
common, low-level chemical inhalants (e.g., car
exhausts, fragrances, cleaning agents, foods,
drugs, caffeine, and alcohol). In other words,
multiple chemical sensitivity is acquired in re-
lation to some documentable environmental
exposure that may initially have produced a
demonstrable toxic effect.
2. Thereafter, ubiquitous, formerly well-
tolerated substances generate symptoms and
cause illness. Symptoms involve more than one
organ system, recurring and abating with a pre-
dictable response to particular environmental
stimuli. Symptoms can be provoked by expo-
sures to concentrations of chemicals that are
demonstrable, but very low. The clinical man-
ifestations are subjective, and there is no ob-
jective evidence of organ system damage or
dysfunction. No widely available test of organ
system function can account for the symptoms.
Little has been published about the rela-
tionship^) between issues of clinical ecology
and the development of allergy, or about treat-
ment with extremely restricted environmental
situations or provocation-neutralization tech-
niques.29'70 In particular, objective diagnostic
criteria for the syndrome are missing, and there
is no body of sound investigations that would
allow critical analysis of the hypothesis. Con-
sequently, a working definition of chemical
sensitivity syndrome currently relies on reports
of subjective symptoms of distress and on their
attribution to environmental exposures rather
than on currently measurable, objective evi-
dence of disease. Moreover, the phenomena
described appear to conflict with accepted tox-
icological principles. For example, dose-
response relationships are accorded no role in
the formulation of explanations, diagnoses, or
therapeutic maneuvers. More "hard evidence"
is needed; and until it is available, the results
of most clinical ecological treatment will con-
tinue to be viewed as the consequence of ei-
ther placebo effects or the removal of offend-
ing physical stimuli from the environment.
Most clinicians and biomedical scientists re-
main dubious about the validity of chemical
sensitivity syndrome, a point of view reflected
in the American Medical Association's position
paper on the subject.38
PRESCRIPTION DRUGS
In susceptible individuals, a number of pre-
scribed medications have the potential to in-
duce throbbing headaches, typical migraine at-
tacks with all associated features, or dull,
constant headaches that may exacerbate pre-
existing migraine headaches. Frequently re-
ported drugs are listed in Table 5-6. Informa-
tion about the relative incidence of headache
Table 5-6. Prescription Medications
Reported to Exacerbate or Induce
Headache
Vasodilators
Nitroglycerine, isorbide dinitrate
Antihypertensives
Reserpine, captopril, atenolol, metoprolol,
prazosin, minoxidil
Non-steroidal Anti-inflammatory Drugs
Indomethacin, diclofenac, piroxicam
Hz-receptor Antagonists
Cimetidine, ranitidine
Calcium Channel Blockers
Nifedipine, verapamil
Hormonal Preparations
Contraceptives, danazol, estrogens, clomiphene
Antibiotics
Griseofulvin, trimethoprimsulfamethoxazole
Data from Solomon (1991).217

related to different drugs is sparse.6 Nitroglyc-
erin, used for the treatment of angina pectoris,
can provoke intense, pulsating, bifrontal or
bitemporal headaches that occur consistently
and are dose dependent (see Chapter 11). Par-
enteral administration of reserpine induces
headache in most migraineurs, but only infre-
quently in normal control subjects/6 Such
headaches are often unilateral, throbbing, and
frequently associated with nausea and even
vomiting. And although the headache may du-
plicate many of the usual migraine symptoms,
reserpine does not reproduce auras in mi-
graineurs who usually have them. After with-
drawal of indomethacin, or within 24 hours af-
ter a single administration of the drug, a severe
symmetrical, pulsating headache can result.
The same is true for certain other non-steroidal
anti-inflammatory drugs (NSAIDs).
ILLICIT DRUGS
Headaches are common among cocaine,
heroin, and marijuana users.65 Little is known
about headache and other illicit drugs, al-
though we do know that using specific sub-
stances is not correlated with a specific head-
ache type.65 Marijuana has been used for the
symptomatic relief of migraine headaches, but
some patients have been noted to develop
bouts of migraine without aura after abruptly
stopping long-term marijuana use.64-195
A wide variety of neurological symptoms
(e.g., seizures, focal symptoms or signs, vertigo,
stupor, coma, tremor) cause cocaine users to
seek medical attention. Headache is one of
these symptoms.131 As many as 75% of cocaine
users describe intense headaches which they
regard as related to the drug.33'238 Such head-
aches must be viewed with seriousness, be-
cause cocaine abusers sometimes develop in-
tracranial hemorrhages and ischemic strokes.
Cocaine headaches can develop acutely, dur-
ing a cocaine binge, or upon withdrawal. The
description of the headaches varies from case
to case, but migraine-like headache has been
described in users who otherwise do not get
headaches and have no family history of mi-
graine.55'199 Patients with a history of migraine
may be at increased risk for a migraine attack
after cocaine use.127 In contrast, cocaine has
also been reported to relieve migraine head-
aches in some chronic headache sufferers.24
Self-medication with cocaine has even been
Initiators, Precipitators, and Triggers 109
demonstrated as a factor in cocaine addiction
9/1
among migraineurs. *
Heroin addicts have a significantly higher in-
cidence of headache than do non-addicts.48 A
number of disparate headache syndromes have
been described. Some heroin addicts complain
of a severe throbbing headache associated with
heroin intake, but others complain of fron-
totemporal, pulsating, long-lasting migraine-
like headache during drug withdrawal.
TRAUMA-TRIGGERED
MIGRAINE
Minor or trivial head trauma can, on occasion,
provoke an attack of migraine.99 Similar
episodes have been reported after exten-
sionflexion neck (whiplash) injuries. Within
minutes after "heading" the ball, soccer play-
ers may experience blurring of vision followed
by a headache (footballer's migraine).147 Most
patients with trauma-triggered migraine have
a personal or family history of migraine and
most are children or adolescents. Whatever the
cause, the attack usually begins within a few
minutes of the trauma, but the symptoms can
last from hours to days. The head pain has the
characteristics of a migraine and is usually ac-
companied by nausea and vomiting. It may be
preceded by, or associated with, visual,
hemisensory disturbances, or hemiparesis.
These latter attacks are said to be indistin-
guishable from attacks of migraine with aura or
from complicated migraine. Trauma-induced
attacks of migraine without aura are either less
commonly seen or less commonly reported. An
unusual syndrome of transient blindness with
headache following head injury in children has
been described.93 Sometimes the headaches
coexist with symptoms of confusion, agitation,
incoherence, and somnolence that resemble at-
tacks of acute confusional migraine.
DISORDERS OF THE NECK
Many patients' headaches are associated with
pathological problems in the cervical spine and
spinal cord. Cervical spondylosis, for example,
can result in pain in the orbit and frontal re-
gions, but whether the cervical spine is the ac-
tual source of head pain is a matter of dispute.
On the basis of generally vague evidence, a
110 Clinical Aspects of Migraine
number of cervical structuresintervertebral
and facet joints, ligaments, nerve roots, mus-
cleshave been implicated as the origins of
head pain.9 However, head pain arising from
conditions located in myofascial and articular
tissues of the neck have long been recog-
nized.22'40'230 Pain from trigger points in mus-
cles receiving their sensory innervation from
GI to Ca (e.g., the small cervico-occipital mus-
cles, the semispinalis capitis, the splenius ca-
pitus, the splenius cervicis, the trapezius, and
the sternocleidomastoid muscles) and from the
median and lateral atlanto-axial, the atlanto-
occipital, and particularly the C^C^ and C^C^
cervical zygapophysial joints can be referred to
various regions of the head.20'211 Controversy
notwithstanding, pain in the cervical region can
initiate migraine in individuals susceptible to
the affliction, or induce migraine attacks in pa-
tients with preexisting migraine.44 For these
patients, appropriate treatment of the cervical
abnormality can diminish the frequency of
attacks.
Myofascial Trigger Points
When a myofascial trigger point involves the
musculature of the head, neck, or shoulders, it
often refers pain to an area of the head or neck
where that pain can act as a stimulus for mi-
graine attacks. In other words, the pain result-
ing from activation of specific myofascial trig-
ger points may precipitate attacks of migraine.
A great number of migraine episodes are initi-
ated in such a manner, yet a surprising num-
ber of clinicians overlook this common phe-
nomenon.44 Involvement of trigger points in
migraine is indicated by the following findings:
1. A large number of migraineurs experi-
ence neck pain, stiffness, and limitation
of the range of motion during and be-
tween 1bouts 01r migraine. K7'7Q
2. Clinical examination of migraineurs often
reveals active trigger points in the head,
neck, and shoulder musculature, which,
when palpated, can precipitate bouts of
headache that are identical to the pa-
tient's spontaneous bouts of migraine.17'198
3. Pressure on trigger points during mi-
graine attacks can increase pain consid-
11 927
erably.
4. Patients themselves often observe that
neck pain can trigger their headaches.17
5. Physical therapy, or manipulation of the
neck, can trigger an attack of migraine
within minutes to a few hours.79
6. Blockade of trigger points by injection is
often effective therapy for migraine head-
aches.227
A patient with a myofascial pain syndrome
characteristically complains of a zone of per-
sistent, dull, deep, aching pain localized in a
specific muscle; in addition, a well-delineated,
extremely sensitive trigger pointof which the
patient may or may not be awarecan be dem-
onstrated (Table 5-7).211 The pain may have
begun abruptly or gradually, and ranges in in-
tensity from a low-grade discomfort to extreme
incapacitation. Pain may be present at rest or
appear only after movements that stretch the
muscle containing the trigger point. Trigger
points themselves are small, highly localized,
extremely tender areas located in muscle
and/or fascia. Each trigger point refers pain
and tenderness in a predictable pattern. As
seen in Figure 5-4, each muscle has its own
referred pain pattern specific for the trigger
points in that muscle. Moreover, pain of this
kind has a regional distribution that does not
follow the pattern seen with radicular or pe-
ripheral nerve problems.
The major characteristic of a trigger point is
that moderate, sustained pressure on the point
reproduces or intensifies the spontaneous pain,
causing a behavioral or verbal response from
the patient. Characteristically, the patient is
startled or jumps when pressure is applied to
Table 5-7. Clinical Characteristics of
Myofascial Pain
Persistent, dull, deep, aching pain localized in a
specific pattern in affected muscles
Well-delineated, extremely sensitive trigger
points
Application of pressure to trigger point causes
patient to be startled or to jump
Referral of pain in a predictable pattern when a
trigger point is pressed
Reproduction of spontaneous pain complaint
when a trigger point is pressed
Tense cord or rope of muscle fibers palpable in
affected muscle
Alleviation of pain by stretching or injection of
trigger point

Figure 5-4. Representative myofascial pain syndromes of the head. Examples of locations of trigger points in selected
muscles of the neck and shoulders are shown together with referred pain patterns. X, trigger points; dots, referred pain
patterns. (A) Upper trapezius muscle; (B) sternocleidomastoid muscle; (C) suboccipital muscles. (Adapted from Simons
et al., 1999,211 with permission.)
the trigger point (jump-sign). Duplication of
the patient's pain when pressure is exerted is
the most compelling confirmation of an active
trigger point. Trigger points are typically lo-
cated in areas of muscle that are palpably
firmer than the rest of the muscle. The trigger
point itself may feel like a tense cord or rope
of muscle fibers when the tip of the finger is
rubbed perpendicular to the direction of the
fibers.
The onset of a myofascial pain syndrome can
sometimes be traced to an acute muscle over-
load, a twisting or straining movement, an overt
injury or traumatic event such as an automo-
bile accident or a fall. Other times, a sports ac-
tivity in which a muscle or a group of muscles
is used excessively, or chronic mechanical over-
loading of a muscle, such as occurs in neck and
shoulder muscles in patients with scoliosis, can
account for th|e gradual development of this
sort of pain. Frequently, however, there is no
obvious precipitating event, and the patient is
uncertain about the precise date of onset. The
diagnosis of myofascial pain syndrome, espe-
cially when the onset is gradual, is challenging
because there are few objective signs and no
diagnostic laboratory tests. Routine laboratory
tests demonstrate no abnormalities; nor is elec-
tromyographic examination of the involved
muscles abnormal. Nevertheless, it is worth-
while to check manually for trigger points in
patients whose history warrants it, for such in-
Initiators, Precipitators, and Triggers 111
dividuals can often be helped by physical ther-
apy and other therapeutic modalities.
Extension-flexion
(Whiplash) Injury
Whiplash (extension-flexion injury to the neck)
is a poorly understood phenomenon that often
gives rise to recurrent migraine headaches or
exacerbates existing migraine.77'98 Whiplash
results from sudden acceleration-deceleration
forces to the neck and head. Rear-end collision
is the most typical mechanism, but whiplash
can also occur from rotational and lateral flex-
ion injuries. Transient occipital and/or cervical
pain and stiffness lasting several hours to days
are common and are generally ascribed to
stretching of the cervical muscles and liga-
ments, with or without contusion.9 The
whiplash syndrome excludes patients with trau-
matic disc protrusions and damage to the cord
or nerve roots.
The chronic aspects of the syndrome are
controversial. Many patients have intense and
prolonged complaints after what appear to be
minor injuries to the soft tissues of the neck.
Headache is common, although the mecha-
nism that causes it is poorly understood. In in-
dividuals predisposed to develop migraine, the
headaches sometimes represent the onset, or
exacerbation, of migraine.240 Other patients
112 Clinical Aspects of Migraine
develop daily, dull, aching headaches, and
some of them also experience superimposed,
periodic episodes of throbbing pain that seem
typical of migraine. Severe cervical pain, mus-
cular tenderness, and limitation of movement
of the neck may also result even when the
whiplash seemed minor. Many patients de-
velop myofascial trigger points in the cervical
and shoulder musculature. Patients also com-
plain of symptoms characteristic of the post-
traumatic syndrome or postconcussive syn-
drome, such as dizziness, tinnitus, depression,
anxiety, and irritability, and cognitive alter-
ations involving memory and attention span.67
Apparently, the mechanical forces producing
extension-flexion injuries can be transmitted to
the skull to affect brain stem and cerebral
structures.
MEDICAL CONDITIONS
Chronic Fatigue
Syndrome/Fibromyalgia
The Chronic fatigue syndrome (CFS) (chronic
fatigue immunodysfunction syndrome) is not a
new or "fashionable" diagnosis, as some may
claim. Over the past 50 years a number of re-
ports have detailed sporadic or epidemic syn-
dromes of fatigue associated with a flu-like ill-
ness. The reports have variously designated the
problem as Iceland disease, benign myalgic en-
cephalomyelitis, epidemic neuromyasthenia,
and Royal Free Hospital disease. The disorder
attracted recent attention because of a major
outbreak in the United States coupled with the
strong realization that CFS is a widespread,
largely underrecognized and underdiagnosed
illness. On the basis of recent data, epidemiol-
ogists estimate the prevalence to be between
76 and 233 per 100,000 people.97 Although
CFS is probably a heterogeneous disorder,
much is now known of the epidemiology, clin-
ical features, and prognosis of the condi-
tion.68'241 The syndrome, which may be chronic
or recurrent, is characterized by persistent, ex-
cessive fatigue that reduces previous activity by
at least 50%, and some combination of weak-
ness, sore throat, myalgia, migratory arthralgia,
sleep disturbance (hypersomnia or insomnia),
neuropsychological complaints (memory loss,
excessive irritability, confusion, inability to con-
centrate, difficulty thinking, and depression),
and headache.80'121 Some patients are com-
pletely disabled by the fatigue, muscular weak-
ness, and pain. To make the diagnosis, other
clinical conditions that may produce similar
symptoms have to be excluded (e.g., preexist-
ing malignancy, autoimmune disease, hypothy-
roidism, sleep apnea, and psychiatric diseases).
Although the cause of CFS is unknown and
the pathogenisis is poorly understood, a num-
ber of studies have implicated humoral and cell-
mediated immunologic abnormalities (e.g., re-
duced number of natural killer cells, partial hy-
pogammaglobulinemias), suggesting that CFS
is associated with disordered regulation of the
immune system with persistent viral infection
or reactivation of a preceding viral illness (e.g.,
high human herpesvirus 6 titers; high cy-
tomegalovirus titers). The syndrome is consid-
ered by many to be the expression of an ab-
normal antiviral response that has produced a
dysregulation in the production of cytokines.
Genetic predisposition may be necessary for
development of the syndrome.
Fibromylagia is a chronic musculoskeletal
disorder characterized by widespread pain, ex-
treme tenderness to digital palpation at specific
anatomic sites ("tender points"), morning stiff-
ness, diffuse arthralgias, and other clinical
manifestations including fatigue, sleep difficul-
ties, depression, irritable bowel and bladder,
Raynaud's phenomenon, and headache.245'247
The pathogenesis of fibromylagia is not well
understood. Limited data suggest a genetic
predisposition that influences peripheral and/
or central pain mechanisms and neuroen-
docrine dysfunction. It is often difficult to dif-
ferentiate patients with fibromylagia from
those with CFS. Over 70% of patients with de-
bilitating fatigue develop persistent, diffuse
muscle pain.88 Between 50% and 85% of fi-
bromyalgia patients complain of general fa-
tigue.248 Similarly, tender points, the hallmark
of fibromyalgia, are also common in CFS.87>122
It has been estimated that 20% to 70% of pa-
tients with fibromyalgia meet the criteria for
CFS and that 35% to 75% of patients with CFS
also have fibromyalgia.26'111
Although significant psychological factors
(especially depression) may be present in sub-
groups of patients with CFS and fibromylagia,
they do not play a primary causative role, but
rather are considered one of the constellation
of symptoms. Depression may also arise from

living with chronic illness. Whatever the cause,
psychological factors act to exacerbate symp-
toms, including headache, which is prominent
in both syndromes (perhaps 50% of patients).
The headache is frequently persistent and
daily, one of a type, severity, or pattern differ-
ent from headaches that the patient may have
had in premorbid state. It may have the qual-
ities of chronic tension-type headaches or of
transformed migraine. Migraineurs with CFS/
fibromyalgia tend to develop much more fre-
quent and severe attacks.
Acquired Immunodeficiency
Syndrome
The human immunodeficiency virus (HIV)
virus easily invades the CNS. A significant pro-
portion of patients with the acquired immuno-
deficiency disease (AIDS) complain of head-
ache.89'13'2 Headache in AIDS patients may
indicate life-threatening illnesses such as op-
portunistic infections or neoplasms, but with
better anti-viral treatment and therapy for op-
portunistic infections, benign, primary head-
aches are appearing as an important and fre-
quent cause of head pain in HIV-infected
patients.109'152'212 In some patients, these
headaches have characteristics associated with
migraine including aura.192 Migraine itself may
appear at any time during the course of the ill-
ness. It may be distinguished from migraine in
non-infected individuals by its later age of on-
set and the frequent absence of family or past
history of headaches. The headaches may start
for the first time in patients with substantial
immunosuppression and may not respond to
conventional antimigraine therapy. One study,
in contrast, indicates that migraine may show
amelioration during HIV infection.69
Dialysis
During a renal dialytic session, about 70% of
patients develop headaches.237 In patients with
a past history of migraine, the symptoms fre-
quently resemble their previous attacks. Dialy-
sis headaches begin between the second and
third hours of dialysis, and usually last the whole
day, their severity determined by the length of
the interval between periods of dialysis.
Initiators, Precipitators, and Triggers 113
Platelet Disorders
Attacks of migraine have been reported in pa-
tients with blood dyscrasias involving platelets.21
Patients with thrombocytopenic purpura have
migraine attacks at times when platelet de-
struction causes a sudden decline in platelet
count.43 In contrast, patients with essential
thrombocythemia have brief attacks of sudden
cerebral or visual dysfunction accompanied by
headache when platelet levels rise.123 Visual
symptoms include transient monocular blind-
ness and scintillating scotomas. These attacks
may resemble attacks of migraine with aura.
They are abolished by low-dose aspirin or re-
duction of platelet counts to normal.
Eyestrain
Eyestrain (asthenopia) arises from uncorrected
refractive errors or from disturbances of ocu-
lar alignment (heterophoria). Many patients
believe that either of these two conditions can
be the basis for recurrent head pain including
migraine. Eyestrain, however, is an infrequent
cause of headache.34 It is possible for eyestrain
to produce a feeling of heaviness or a mild, dull,
aching pain around or behind the eyes that may
radiate to the forehead and temples.228 But de-
spite pain around the eyes or in the temples,
eyestrain does not cause symptoms character-
istic of migrainethrobbing pain, photopho-
bia, nausea or vomiting.
SUMMARY
Many older physicians were educated at a time
when migraine was believed to befall those
with "migraine personalities." Chocolate, red
wine, ripe cheese, and menstrual cycles could
initiate or exacerbate headaches, but emotional
makeup was the primary factor that separated
migraineurs from the blissfully headache-free.
This chapter has provided a sense of how
complicated an interaction there is between
genetic substrate, external irritants, lifestyle
practices, and medical conditions. The genes
that render some individuals susceptible to
developing migraine have not even been
identified. Altering them will not occur soon.
But some external irritants can be avoided;
114 Clinical Aspects of Migraine
exposure to others can be reduced; daily
choices about meals, exercise, and sleep can be
made; and certain physical problems can be
addressed.
This is certainly not to say that all migraine
headaches can be eliminated in all patients. But
in most cases, the physician and the patient
need to work together as detectives to ferret
out the particular combinations of initiators,
precipitators, and triggers that give rise to that
person's migraine. Even the ideal dose of the
ideal medication will be less than effective if
the migraineur continues to live under the in-
fluence of factors that exacerbate his or her
headaches.
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Chapter 6
Hormones
MENARCHE
MENSTRUATION
Premenstrual Syndromes and Menstrual
Difficulties
Menstrual Migraine
Menstrual Cycle Modulation of Pain
Endocrinology of the Menstrual Cycle
Effects of Ovarian Hormones and
Neurosteroids on the Brain and
Vasculature
Because migraine is an affliction so common in
women, it would not be unreasonable to expect
to find it linked with hormonal cycles such as
menstruation, ovulation, pregnancy, the early
postpartum period, lactation, and menopause.
And indeed, the physiologic changes intrinsic to
these cycles profoundly affect the patterns and
severity of migraine in a large proportion of fe-
male patients. Substantial evidence indicates
significant connections between changes in es-
trogen and progesterone levels and migraine.
Less evidence links prolactin to migraine.
MENARCHE
The long-held view that women's migraine
headaches often begin around the time of the
menarche was largely based upon adult recall
ability. Recent epidemiologic studies of young
women confirm that the incidence of new cases
of migraine peaks near, or shortly after, the age
at which menarche is reported to occur in de-
veloped countries.94 Between 14% and 18% of
women have their first attack during the year
of menarche or the year after; this is especially
120
ORAL CONTRACEPTIVES
PREGNANCY
DELIVERY
LACTATION
Endocrinology of Lactation
Migraine and Lactation
MENOPAUSE AND POSTMENOPAUSE
SUMMARY
true for migraine without aura. Menarche
varies between the ages of 9 and 16, with a
mean of 12.5 years in developed countries. A
trend in the last century toward earlier onset
in affluent societies has been attributed to im-
proved nutrition and general health of younger
women, but may in large measure be secondary
to reaching a salient percentage of body fat.
MENSTRUATION
Most textbooks put the interval between men-
strual periods at 28 days during the active re-
productive years, but the majority of women
neither consistently experience 28-day cycles
nor ovulate on day 14. Cycles vary between 26
and 34 days.35 The interval is frequently longer
(and irregular) during adolescence and the peri-
menopausal period (Fig. 6-1 ).115 These longer
menstrual cycles are associated with frequent
anovulatory cycles.52 A number of factors in-
fluence cycle length, including ethnic differ-
ences, absolute weight and changes in weight,
physical activity, and psychological stresses-
pecially major life events.35

Figure 6-1. Median menstrual-cycle lengths during the reproductive life of women from menarche (year 0) to meno-
pause (year 40) (middle line). Ninety percent of all cycles fall within the upper and lower lines. (Adapted from Treloar
et al., 1967,11S with permission.)
Premenstrual Syndromes and
Menstrual Difficulties
Migraine that precedes menstruation may oc-
cur alone or as part of either the premenstrual
syndrome (PMS) or the premenstrual dys-
phoric disorder (formerly late luteal phase
dysphoric disorder).79'110 Both problems are
legitimate illnesses that consist of cyclic recur-
rence of physical, mental, and behavioral symp-
toms that occur at any time after ovulation, but
particularly in the late luteal phase of the men-
strual cycle, and disappear during the full flow
of menses. Some women experience a brief
episode of symptoms at ovulation, followed by
a symptom-free period with a recurrence of
premenstrual symptoms late in the luteal
phase. The most severely affected women have
symptoms that commence at ovulation, in-
crease during the luteal phase, and only disap-
pear after menses terminate. (Some women
have severe, non-migrainous headaches in the
late luteal phase that peak in intensity the day
prior to menstruation or on the first day of
menstruation.42'121 This is a particular problem
among those who suffer from PMS.42)
It has been estimated that over 90% of
women with migraine suffer from premen-
Hormones 121
strual symptoms of one type or another.63 In
20% to 30% of migraineurs the symptoms are
significant. The precise etiology remains un-
certain: no consistent alterations of hormones,
prostaglandins, vitamins, trace elements, or
electrolytes are found in women with these dif-
ficulties.44 The symptoms, however, depend
upon ovulation and parallel changes in proges-
terone and estrogen production. This has been
demonstrated by investigations showing sup-
pression of premenstrual symptoms when the
ovaries are removed or ovarian function is med-
ically inhibited by analogs of gonadotrophin-
releasing hormone (GnRH) or danazol (an eth-
yltestosterone derivative that suppresses the
enzymatic synthesis of sex steroids and binds
competitively to both androgen and progestin
receptors). Symptoms of PMS return in
women with bilateral oophorectomy when es-
trogen and progestogens are prescribed to
mimic the ovarian cycle.34'81
Premenstrual syndrome consists of some
combination of fatigue, depression, irritability,
anxiety, minor mood changes, breast engorge-
ment and tenderness, back ache, abdominal
distension, and weight gain (Table 61). Pre-
menstrual dysphoric disorder is less common
than PMS, affecting 3% to 8% of women.110 It
122 Clinical Aspects of Migraine
Table 6-1. Clinical Features of Premenstrual Disorders
Physical Symptoms
Fatigue
Weight gain and edema
Breast pain/tenderness
Joint pains
Headache
Emotional Symptoms
Emotional lability
Hopelessness/depression
Social withdrawal
Insomnia
Behavioral Changes
Binge eating
Crying episodes
Cognitive Changes
Forgetfulness
Inability to concentrate
Data from Keye (1998).4
is much more unpleasant than PMS and exerts
a much greater psychological penalty. Women
with premenstrual dysphoric disorder describe
premenstrual symptoms of irritability, anger,
anxiety, dysphoria, amnesia, and lability of
mood that seriously impede their lifestyle, sig-
nificantly impair their ability to function, and
disturb their relationships. Violent behavior
has been described.
Women with migraine report significantly
higher rates of menstrual difficulties, including
excessive bleeding with menstrual periods, ex-
cessively painful menses, and irregular periods,
than women without migraine.7 During men-
struation, migraine is often associated with
crampy menstrual pain (dysmenorrhea).65
Menstrual Migraine
The term menstrual migraine refers to mi-
graine attacks that occur perimenstrually. Be-
cause of major differences in the definition
of what constitutes menstrual (catamenial)
migraine, reports of its frequency vary
widely.20'62 A number of authorities indicate
that as many as 60% of women migraineurs re-
port headaches occurring with menstruation,
Backache/cramps
Sensitivity to light, noise, or touch
Abdominal bloating
Food cravings, especially for sweets
Clumsiness and incoordination
Anxiety/tension
Hostility/irritability
Feelings of inadequacy/rejection
Loss of patience
Avoidance of social activities
Physical/emotional abuse of family/friends
Confusion
Inability to problem solve
or note that many of their attacks develop with
a constant temporal relationship to menstrua-
tion.30'40'65'67 Most women, however, have at-
tacks throughout the cycle with an increased
number in the perimenstrual period (Fig.
6-2). These women are said to have menstru-
ally-related migraine (menstrually triggered
migraine}. Only 7% to 14% of women have
their headaches exclusively at the time of men-
struation.30'65'67 These women are said to have
true menstrual migraine.
Women with menstrual migraine (the term
includes both menstrually related and true
menstrual migraine) are more inclined to have
had the onset of migraine at menarche, to have
fluid retention and weight gain associated with
menses, and to improve during pregnancy.21
Menstrual precipitation appears to be more
firmly associated with migraine without aura
than migraine with aura.5'-1-6'62'92 The majority
of menstrual migraine headaches occur just
prior to, or during, menstruation. Most studies
of menstrual migraine include any bouts of mi-
graine occurring during the perimenstrual pe-
riod. This period is variably defined and ranges
from day 2 or day 3 before the onset of
menses to the second to fifth day of the cy-
cle.40'62'112 More rarely, migraine will occur
 Hormones 123

Figure 6-2. Proportion of person-days on which headache was reported for each day of the menstrual cycle. Data from
74 diary study participants. Solid line shows proportion of person-days with any type of headache. Dotted line indicates
the overall proportion of headaches. (Adapted from Johannes CB, Linet MS, Stewart WF, et al.: Relationship of head-
ache to phase of the menstrual cycle among young women: a daily diary study. Neurology 45:1076-1082, 1995, with per-
mission.)

immediately after the menstrual flow ends.
Some women relate their migraine attacks to
ovulation. These patients characteristically
have bouts of migraine at midcycle. Migraine
attacks that occur only during ovulation are
rare, and epidemiologic studies have not found
an association between ovulation and migraine
attacks.65'94
Menstrual migraine generally occurs dur-
ing, or just after, the simultaneous fall of cir-
culating progesterone and estradiol levels
during the cycle, but the fall in estrogen lev-
els appears to be the significant trigger. The
natural decline in the secretion of estrogens
by the corpus luteum in the premenstrual
phase, rather than the absolute level of the
hormone, has been hypothesized as the
causative migrainogenic factor.103 This hy-
pothesis rests largely on findings from inves-
tigation of a small number of patients. Ex-
perimental injection of estrogen preparations
to maintain a high plasma level of the hor-
mone during the premenstrual and menstrual
period did not postpone menstruation, but it
did delay the expected headaches until the es-
trogen level fell (Fig. 6-3).105>106 MacGregor
has tabulated other evidence supporting the
hypothesis that estrogen withdrawal after high
levels is a major factor in producing migraine
attacks:63
1. When the estrogen level decreases after
21 days of elevated levels in women tak-
ing combined oral contraceptives, many
experience bouts of migraine.
2. Migraine is often ameliorated during
pregnancy when estrogen levels rise and
stay elevated.
3. Migraine frequently recurs shortly after
delivery when estrogen levels fall precip-
itously.108
4. Migraine typically occurs during the week
free from postmenopausal estrogen re-
placement therapy in the old treatment
regimen of 21 days on and 7 days off.46
5. The results of a placebo-controlled,
double-blind crossover study of the ef-
fects of estradiol (with or without a
progestogen) in oophorectomized women
showed that there was increased fre-
quency of headache when an estrogen
preparation was followed by a non-estro-
gen preparation. 1Q
124 Clinical Aspects of Migraine

Figure 6-3. Effect of estradiol on menstrual migraine. Patient had at least one severe migraine attack clearly related to
menstruation for at least six cycles. One untreated menstrual period and one period when estradiol valerate (10 mg) was
administered 4 days before the onset of menstruation are illustrated. (Adapted from Somerville BW: The role of estra-
diol withdrawal in the etiology of menstrual migraine. Neurology 22:355-365, 1972, with permission.)

6. Migraine frequency decreases in some that testosterone, follicle-stimulating hormone

menopausal women. Menopause is a time
when estrogen levels are low and do not
fluctuate.85
Clinical endeavors to prevent migraine oc-
curring at menstruation by elevating estrogen
levels have produced contradictory re-
sults.18'68'105'106 Nor have comparisons of es-
trogen levels among groups of women with
menstrual attacks, with non-menstrual mi-
graine, and without migraine yielded results
that are simple to interpret.3'18'80'82 As for pro-
gesterone, experimental manipulation of levels
during the menstrual cycle delays uterine
bleeding but does not prevent the appearance
of migraine at the expected time in the cycle.102
While some older clinical studies reported that
administration of progesterone preparations
prevented menstrual attacks, today the drop in
progesterone that precedes menstruation is not
believed to be consequential in the timing of
menstrual migraine.1''32 Studies have shown
(FSH), and luteinizing hormone (LH) levels
are normal during attacks of migraine occur-
ring at menstruation.21
Menstrual Cycle Modulation
of Pain
The cyclic fluctuations in gonadal hormone lev-
els in normally menstruating women are re-
lated to variations in pain sensitivity and re-
sponsiveness to pain. In most but not all
studies, higher thresholds to experimentally in-
duced pain are obtained in the follicular (pre-
ovulatory) phase, and lower thresholds in the
luteal (postovulatory) phase of the cycle.25'28'87
These hormonally correlated fluctuations in
pain perception are presumably reflected in in-
vestigations of how the menstrual cycle affects
the severity of headaches.
 Hormones 125

Endocrinology of the
Menstrual Cycle

By convention, the menstrual (ovarian) cycle is

usually stated to last 28 days, to begin on the
first day of the menses and to end on the last
day before the next menses. The follicular
phase of the menstrual cycle starts on day 1 of
the cycle, the first day of menses. Ovulation is
said to occur on day 14. The second half of the
cycle is called the luted phase. Normal opera-
tion of the menstrual cycle, as well as the at-
tendant changes in estrogen and progesterone
levels, depends upon the coordinated activity
of neurons and cells in several different struc-
tures including the hypothalamus, pituitary,
and ovary (Fig. 6-4). These different neurons
and cells in the hypothalamic-pituitary-
ovarian axis include (1) hypothalamic neurons
that secrete GnRH, (2) gonadotrophs in the an-
terior pituitary that synthesize and secrete LH
and FSH, and (3) estrogen- and progestin-
secreting ovarian cells.
The GnRH-secreting neurons in the hypo-
thalamus are not organized into separate nu-
clei but occur as loose networks of cells pri- Figure 6-4. Hypothalamic-pituitaiy-ovarian axis: sche-
marily distributed in the arcuate nucleus of the matic representation of peptide and steroidal factors that
medial basal hypothalamus and the preoptic regulate gonadotrophin biosynthesis and release. FSH, fol-
area of the anterior hypothalamus (Fig. 6-5). licle stimulating hormone; GnRH, gonadotrophin-releas-
ing hormone; LH, luteinizing hormone; +, facilitation; ,
The GnRH neuronal system displays rhythmic inhibition. (Adapted from Holt JA: Reproductive hor-
behavior, with volleys of neuronal firing oc- mones and their mechanisms of action. In Lobo RA,
curring every 60 to 90 minutes.45 Pulsatifity is Mishell DR, Paulson RJ, and Shoupe D (eds): Mishell's
necessary for stimulation of the pituitary; con- Textbook of Infertility, Contraception, and Reproductive
tinuous GnRH secretion produces inhibition of Endocrinology, 4th ed. Blackwell Science, Maiden, MA,
1997, pp 26-45.)
pituitary function. The rhythmic behavior of
these neurons appears to be an intrinsic mem-
brane property, but the rate and amplitude,
which vary with the phase of the menstrual cy- stimulatory or inhibitory effects depending
cle, are modulated by a variety of neurotrans- upon the physiologic state of GnRH neurons.
mitters and hormones. As an example, norepi- The levels of ovarian hormones are also im-
nephrine released from axon terminals of portant, as explained below.
neurons originating in the locus coeruleus and As expected, the rhythmic firing of hypo-
in medullary noradrenergic systems, acting at thalamic neurons is reflected in pulsatile re-
ai-adrenergic receptors, stimulates GnRH re- lease of GnRH, which occurs from presynap-
lease. The stimulation occurs by a process of tic terminals of GnRH neuron axons that
disinhibition: the norepinephrine inhibits in- project down the tuberoinfundibular tract to
terneurons that tonically secrete the inhibitory the median eminence (Fig. 6-6).123 These ax-
transmitter gamma-aminobutyric acid (GABA) ons terminate in an extensive plexus of boutons
on GnRH neurons.50 Endogenous opioid pep- on the capillaries of the hypophyseal portal sys-
tides reduce GnRH release both by inhibiting tem that delivers GnRH to its target cellsthe
the presynaptic release of norepinephrine and pituitary gonadotrophs in the anterior pitu-
by inhibiting GnRH neurons directly. Dopa- itary. The pulsatile nature of hypothalamic
mine acting at DI receptors can produce either GnRH release determines the episodic secre-
126 Clinical Aspects of Migraine

Figure 6-^5. Neuroanatomic relationships among aminergic, dopaminergic, opioidergic, and gonadotropin-releasing hor-
mone (GnRH) neurons within the hypothalamus. Note GnRH neurons terminating on the portal capillaries. 1, preoptic
anterior hypothalamic area; 2, median eminence; 3, locus coeruleus; MB, mammillary body; OC, optic chiasm. (Adapted
from Yen SSC: The human menstrual cycle: neuroendocrine regulation. In Yen SSC, Jaffe RB, and Barbieri RL (eds):
Reproductive Endocrinology. Physiology, Pathophysiology, and Clinical Management, 4th ed. WB Saunders, Philadelphia,
1999, pp 191-217, with permission.)

tion of pituitary gonadotrophins.45 Prolonged,
continuous administration of GnRH down-
regulates the number of receptors on go-
nadotrophs. Slower or higher frequency of
pulsatile GnRH neuronal firing changes the
sensitivity of GnRH receptors on pituitary go-
nadotrophs and subsequently alters ovulation
and menstruation.
Variations in pulse frequency of GnRH neu-
rons are sensitive to ovarian steroid hormonal
feedback (i.e., the levels of estrogen and pro-
gesterone). As an example, progesterone se-
creted by the corpus luteum during the luteal
phase of the cycle progressively slows the pul-
satility of GnRH release. Although receptors
for estrogen and progesterone have been iden-
tified in multiple neuronal cell types including
those that release dopamine and the opioid /3-
endorphin, they have not been detected on
GnRH-secreting neurons. These findings indi-
cate that ovarian steroids alter hypothalamic
GnRH release indirectly through effects on
neuronal systems known to synapse on GnRH
neurons. Whether estradiol exerts negative or
positive feedback on GnRH neurons depends
on timing, concentration in the circulation, as
well as interaction with progesterone.
The second group of cells in the hypothalamic-
pituitary-ovarian axis consists of gonadotrophs
in the anterior pituitary that synthesize and se-
crete LH and FSH. As expected, pituitary syn-
thesis and secretion of the gonadotropins LH
and FSH is largely dependent upon the pulse
frequency of GnRH-secreting neurons and the
resulting pulsatile release of GnRH. The
plasma levels of FSH and LH, and the ratio of
LH to FSH release, vary during the menstrual
cyclevariations that reflect long-term
changes dominated by the mid-menstrual cy-
cle peak of LH release with superimposed
 Hormones 127

taining thecal cells. When, preparatory to ovu-

lation, an immature follicle begins to develop
into a Graafian follicle, the surrounding gran-
ulosa cells proliferate to form multiple layers.
Follicular fluid accumulates in the interstitial
spaces between these cells. The fluid spaces
eventually fuse and enlarge to form a Graafian
follicle with a primary oocyte lying against the

Figure 6-6. Characteristic volleys of neuronal activity

(MUA, multiunit electrical activity, bottom trace) recorded
from the medial hypothalamus in relationship to concen-
tration of luteinizing hormone (LH, upper trace) in the pe-
ripheral circulation. Recording made in an ovariectomized
rhesus monkey. The pulsatile nature of the LH levels re-
flects changes in gonadotropin-releasing hormone (GnRH)
levels. (Adapted from Knobil E: The electrophysiology of
the GnRH pulse generator. J Steroid Biochem 33:669-671,
1989, with permission from Elsevier Science.)

short-term elevations (Fig. 6-7). The plasma

levels are also influenced by direct feedback on
the pituitary from circulating estrogens and
progestins secreted by the ovary. Depending
upon the stage of the menstrual cycle and the
frequency of GnRH neuronal pulses, estrogens
can either suppress or increase the secretion of
FSH and LH by altering the sensitivity of the
anterior pituitary gonadotrophs to GnRH.
Plasma LH rises slightly in the late follicu-
lar phase of the menstrual cycle, followed by a
prominent preovulatory surge (LH surge) and
a decrease during the luteal phase. In contrast,
plasma FSH displays a rise during the late
luteal and early follicular phases, followed by a
decline that is interrupted at midcycle by a
modest elevation coinciding with the preovu- Figure 6-7. Daily changes in plasma concentrations of
latory LH peak. ovarian and pituitary hormones in women during normal
The final group of cells that helps regulate menstrual cycles. Values are the mean and standard errors
of the mean of results obtained from daily serum samples
the menstrual cycle are in the ovary and se- of nine normal women. Day 0 is the day of the mid-cycle
crete estrogens and progestins. The relation- luteinizing hormone (LH) peak. Ovulation occurs on day
ship between gonadotropins and the menstrual +14 of the cycle. Eg, estradiol; FSH, follicle stimulating
cycle depends upon ovarian follicular growth hormone; Prog, progesterone; 17aOH Prog, 17-hydroxy-
and development, much of which is an intrin- progesterone. (Adapted from Thorneycroft IH, Mishell
DR Jr, Stone SC, Kharma KM, and Nakamura RM: The
sic ovarian function (Fig. 6-8). A follicle is relationship of serum 17-hydroxyprogesterone and estra-
composed of an oocyte and surrounding gran- diol-17/3 levels during the human menstrual cycle. Am J
ulosa cells embedded in ovarian tissue con- Obstet Gynecol 111:947-951, 1971, with permission.)
128 Clinical Aspects of Migraine
Figure 6-8. The life cycle of the human ovary. (Adapted from Porterfield SP: Endocrine Physiology, 2nd ed., Mosby, St
Louis, 2001, with permission.)
wall. The LH surge brings about rapid follicu-
lar enlargement, culminating in follicular rup-
ture and ovulation. The LH surge normally
lasts 48 to 50 hours, with ovulation occurring
approximately 10 to 12 hours after peak levels
of the gonadotropin are attained. The ovum is
discharged from the follicle about 13 to 15 days
prior to menstruation (using a standard 28-day
cycle), thus completing the follicular stage of
the cycle.
During the second, postovulatory half (luteal
phase, secretory phase) of the menstrual cycle,
a corpus luteum is formed from the ruptured
follicle. Capillaries and fibroblasts from the
surrounding stroma proliferate. The mural
granulosa cells, together with the surrounding
theca and the invading vasculature, intermin-
gle to give rise to a corpus luteum that func-
tions as an endocrine gland. The functional
lifespan of the corpus luteum is normally 14
days, after which it spontaneously regresses
and atrophies. Corpus luteum function is un-
der the control of LH secretion. The luteal
phase is characterized by secretion of increas-

Table 6-2. Plasma Concentrations of Estradiol and Progesterone
Steroid Hormone Stage of Life
Estradiol Premenopausal
Pregnancy (term)
Postmenopausal
Progesterone Premenopausal
Pregnancy (term)
107
Data from Stanczyk (1997).
ing amounts of progesterone under the influ-
ence of LH. Progesterone secretion com-
mences near the beginning of the midcycle LH
surge, reaching a peak of approximately 25 mg
per day at the midluteal phase. The secretion
progressively declines as luteinolysis occurs
and heralds the next cycle. The increase in pro-
gesterone concentration as the cycle progresses
reflects the process of luteinization of the gran-
ulosa cells after acquisition of LH receptors
and the subsequent ability of LH to initiate
progesterone biosynthesis.
Circulating levels of estrogens (mainly estra-
diol) remain low during menses and for ap-
proximately a week after menstruation (Table
6-2). Then estradiol begins an exponential in-
crease as the maturation of the dominant fol-
licle progresses. The increase usually reaches
its maximum in the periovulatory period, the
day before the LH surge. A maximum of
300-400 /u,g per day is secreted during the late
follicular phase resulting in levels of about 600
pg/mL at the time of ovulation. The increasing
amounts of estradiol secreted by the follicle are
responsible for triggering the preovulatory LH
surge.
After the LH surge, around the time of ovu-
lation, plasma estradiol levels fall rapidly for
several days as a result of an abrupt and tran-
sient fall in ovarian production of estradiol.
This fall in circulating estradiol may be at-
tended by brief, occult intermenstrual bleed-
ing. A resurgence of ovarian steroidogenic ac-
tivity in the luteal phase results in a sustained,
secondary increase in plasma estradiol levels.
Hormones 129
CONCENTRATION
(ng/mL)
Phase of Cycle Mean Range
Follicular 50 20-100
Preovulatory 250 150-600
Luteal 125 75-300
16,000
15
Follicular 0.2 0.06-0.37
Luteal 8.9 4.3-19.4
150 125-190
This increase reaches its summit in the mid-
point of the luteal phase of the cycle and then
declines in the immediate premenstrual phase.
Luteinizing hormone and FSH act on the
two types of ovarian follicular cells capable of
secreting steroid hormones: granulosa cells and
thecal cells (Fig. 6-9). Follicle-stimulating hor-
mone is the main promotor of follicular matu-
ration, and FSH is important for early granu-
losa cell proliferation during the follicular
phase of the menstrual cycle. It is also respon-
sible for promoting the development of LH re-
ceptors. Luteinizing hormone acting on thecal
cells promotes progesterone and androgen
production from cholesterol that is delivered
from the blood where it is bound to low-
density lipoprotein (LDL). Aromatase activity
induced by FSH in the granulosa cells enzy-
matically converts thecally derived androgens
to estradiol and estrone in granulosa cells.
Thus, both gonadotropins stimulate the syn-
thesis of estradiol and estrone: FSH by ensur-
ing an adequate aromatase activity and LH by
stimulating the theca cells to produce abundant
amounts of androgen precursor. In addition,
LH is responsible for the increases in estrogen
levels during the last half of the cycle.
Another feedback system exists. Two poly-
peptide factorsinhibin and activinhave
been isolated from ovarian follicular fluid.75
These polypeptides have potent effects on go-
nadotroph function and, in particular, on the
feedback regulation of gonadotropin gene ex-
pression that in turn regulates gonadotropin
primarily FSHbiosynthesis and secretion.
130 Clinical Aspects of Migraine

Figure 6-9. The two cell/two gohadotrophin synthesis of follicular estrogen. ATP, adenosine triphosphate; cAMP, cyclic
adenosine monophosphate. (Adapted from Yeh J and Adashi EY: The ovarian life cycle. In Yen SSC, Jaffe RB, and Bar-
bieri RL (eds): Reproductive Endocrinology. Physiology, Pathophysiology, and Clinical Management, 4th ed. WB Saun-
ders, Philadelphia, 1999, pp 153-190, with permission.)

Follicle-stimulating hormone stimulates both peptides, and prostaglandins. Progesterone

granulosa and luteal cells to produce inhibin,
but, in turn, inhibin suppresses pituitary syn-
thesis and secretion of FSH. In contrast, ac-
tivin made in granulosa cells stimulates FSH
secretion.
The uterus responds to both estrogens and
progestins. Estrogen stimulates growth of the
epithelial and stromal cells of the endome-
trium. Progesterone secreted by the corpus lu-
teum promotes the morphological and secre-
tory changes necessary for pregnancy and
causes the uterus to secrete mucus, specific
withdrawal leads to arterial spasm, sloughing of
the superficial layer of the endometrium, and
menses.
Effects of Ovarian Hormones and
Neurosteroids on the Brain
and Vasculature
In addition to their influence on reproductive
organs, ovarian hormones and their metabo-
 Hormones 131

Figure 6-10. Putative synthetic pathway for local transmitter synthesis in the central nervous system. Steroids in the
brain are derived from peripheral endocrine glands and by their local synthesis from cholesterol in glial cells. (Adapted
from Lambert JJ, Belelli D, Hill-Yenning C, and Peters JA: Neurosteroids and GABAA receptor function. Trends Phar-
macol Sci 16:295-303, 1995, with permission from Elsevier Science.)

lites exert a variety of genomic and non-
genomic pharmacological effects on blood ves-
sels and on neurons in the brain.1'77'125 Analy-
sis of steroidal hormone actions on the brain is
complicated: not only do secretory products of
steroidogenic endocrine glands, borne by the
blood stream, affect brain tissue, but the brain,
independent of the ovaries, can also synthesize
certain steroids de novo in glial cells (Fig.
6-10).48 The term neurosteroids is used to des-
ignate steroids synthesized by the brain. Their
function together with steroids imported into
the central nervous system (CNS) is challeng-
ing to assess.
132 Clinical Aspects of Migraine
Gene expression, transcription, and transla-
tion are altered by hormonal receptor activa-
tion of target genes. Steroids also modify
neurotransmitter receptor function, act on
neurotransmitter synthesis, release, and activa-
tion, affect ion channels, and cause nitric ox-
ide (NO) release. The mechanisms of all these
effects are discussed below.
1. Effects mediated by hormone receptor ac-
tivation of target genes result in alterations in
gene expression, transcription, and translation.
Intracellular (genomic) receptors are the site
where ovarian steroid hormones exert their
classical mechanism of action on target neu-
rons. Because of the time required for activa-
tion of the transcriptional and translational ma-
chinery of cells and for protein biosynthesis,
such effects usually take hours to result in phys-
iologic consequences. Their lipid nature allows
steroid hormones to cross the bilipid cell mem-
brane easily by simple diffusion and then bind
to intranuclear receptors. At target sites, cir-
culating estrogens combine with high-affinity
intracellular nuclear receptors. Estrogen re-
ceptors are transcription factors that undergo
conformational changes after estrogen binds to
them. The estrogen-estrogen receptor com-
plexes form dimers that bind to specific sites
in the control regions of their target genes. In
association with other transcriptional factors,
the dimers enhance or suppress gene expres-
sion.8'22 The classic effects of estrogen (devel-
opment of female sexual characteristics, deter-
mination of metabolic rate, establishment of fat
distribution) and progesterone (regulation of
uterine and mammary cell growth, mainte-
nance of pregnancy, inhibition of sexual be-
havior) are thought to occur through such ge-
nomic mechanisms.
2. Modification of neurotransmitter recep-
tor function. Some steroid hormone metabo-
lites rapidly alter neuronal excitability, modify-
ing the receptor activities of both GAB A, the
most abundant and most prominent inhibitory
transmitter in the CNS, and glutamate, the ma-
jor excitatory transmitter in the brain and
spinal cord. GABAA and N-methyl-D-aspartate
(NMDA) glutamate receptors have been es-
tablished as prime targets for such steroid ac-
tions.49'69
GABAA receptors are coupled to Cl~ ion
channels such that activation of the receptor by
GABA allows an influx of Cl~ ions into the neu-
ron. The resultant increases in membrane po-
tential and conductance effectively shunt the
influence of excitatory transmitters. In mam-
malian brain, the progesterone metabolites
allopregnanolone (3a -hydroxy-5a -pregnan-20-
on3), pregnanolone (3a-hydroxy-5/3-pregnan-
20-one), and pregnanediol (5/3-pregnane-3,20-
dione) are detected in mammalian brain in
concentrations high enough to act at the
GABAA receptor. These metabolites have at
least three different actions on GABAA recep-
tors: they increase the mean channel open-time
of GABA-activated Cl~ channels; they aug-
ment the frequency of single channel openings
after exposure to a given amount of GABA;
and, in high concentrations, they directly acti-
vate the GABAA receptor in the absence of
GABA (i.e., they are GABAmimetic). All these
effects cause an augmentation of GABA-medi-
ated inhibition. As a result of these actions, ste-
roid hormones have anesthetic, hypnotic, anx-
iolytic, and analgesic effects.27>47>^
In contrast to the actions of allopreg-
nanolone, pregnanolone, and pregnanediol,
pregnenolone sulfate (5a-pregnane-3/3-ol-20-
one sulfate), another progesterone derivative,
acts as an antagonist at GABAA receptors. And
at concentrations greater than those producing
antagonism at GABAA receptors, the com-
pound also enhances glutamate's actions.128
Glutamate directly gates (opens) ionotropic
glutamate receptor (iGluR) channels. The
iGluRs are classified into three types accord-
ing to how efficaciously selective glutamate ag-
onists affect them: (a) NMDA, (b) AMPA (a-
amino-3-hydroxy-5-methylisoxazole-4-proprio
nate), and (c) kainate. When an agonist binds
to an iGluR site, cationic channels open, caus-
ing a substantial influx of Na + and an efflux
of K + ; the result is a depolarization of the
membrane. Pregnenolone sulfate potentiates
NMDA-mediated actions by increasing the
frequency of NMDA channel opening and
the mean open-time of the NMDA cation
channel.6
3. Actions on neurotransmitter synthesis
and release. Estrogen increases the activity
of choline acetyltransferase, resulting in in-
creased acetylcholine synthesis.61 Estrogen
also activates endothelial and brain nitric oxide
synthase through signal pathways that involve
either tyrosine kinase or mitogen-activated
protein kinase.14
4. Actions on ion channels. Estrogen rapidly
activates Ca2+-dependent K + channels that
hyperpolarize smooth muscle cells, resulting in
muscle relaxation and vasodilatation.118 The

activation of K + channels occurs by means
of a pathway involving NO and production
of its second messenger, cyclic guanosine
monophosphate (cGMP).122
The progesterone metabolites pregnenolone
and pregnenolone sulfate acting at neuronal
membrane receptor sites are also potent in-
hibitors of Ca2+ currents. The Ca2+ currents
are inhibited via a G protein-coupled mecha-
nism associated with the activation of protein
kinase C.24 Because influx of Ca2+ is pivotal to
transmitter release, these actions may regulate
presynaptic synaptic processes.
5. Release of NO from endothelial cells. 17)3-
Estradiol binds to specific estrogen receptors
on human endothelial cells. The result is rapid
release of NO from, and activation of, guany-
late cyclase.93 Nitric oxide plays a pivotal role
in regulating cytosolic Ca2+ levels in smooth
muscle and as a result is a potent vasodilator
(see Chapter 10).
As seen from the variety of potent actions,
ovarian steroid hormones and neurosteroids
have the potential to influence migraine. How-
ever, which of their innumerable actions is ei-
ther necessary or sufficient to initiate migraine
attacks is difficult to determine.72'101
ORAL CONTRACEPTIVES
Considerable attention has been paid to the ef-
fects of oral contraceptive agents on migraine.
Ever since the early 1960s, when oral contra-
ceptives were first extensively prescribed, they
were reported to initiate and to worsen mi-
graine headaches in a substantial proportion of
patients.
Two types of oral contraceptives are in cur-
rent use: those composed of synthetic estrogen
and progestin and the so-called progestin
minipills.
Combined oral contraceptives consisting of
synthetic estrogen and progestin are generally
prescribed for 21 days of a 28-day cycle. A
month's supply of some combination pills con-
tain two or three dosage combinations of es-
trogen and progestin. Each dosage combina-
tion is given for an interval varying from 5 to
11 days during the 21-day medication period.
Combined oral contraceptives disrupt fertility
by inhibiting ovulation. They interfere with the
secretion of GnRH from the hypothalamus and
suppress pituitary release of FSH and LH.
These preparations consistently inhibit the
Hormonest 133
133
midcycle gonatropin surge. They also induce
changes in cervical mucus and in the endome-
trium that make sperm transport and implan-
tation of the embryo unlikely. Withdrawal
menstruation occurs during the pill-free
interval.
Progestin oral contraceptives (minipills) con-
sist of a synthetic progesterone derivative
(without added estrogen) given continuously in
a low dose. Although they cause variable sup-
pression of FSH and LH secretion and of ovu-
lation, their principal mode of their action may
lie in making cervical mucus inimical to sperm
transport. Minipills also produce biochemical
and physiological changes in the endometrium
that reduce the possibility of implantation.
Normal ovulation occurs in most women, al-
though ovarian cycles and duration of bleeding
may be irregular. Minipills are less effective
than combined oral contraceptives and their
use is often restricted to older women whose
fertility is already reduced and to women for
whom combination oral contraceptives are
contraindicated.
There are only scanty data concerning the
effect of progestin-containing oral contracep-
tives, but they appear to be associated with a
low incidence of headache.39 Nor do progestin-
containing pills appear to pose an increased
risk for stroke.54 Norplant, a system of sub-
dermal implants that releases a steady dose of
the progestin levonorgestril for 5 years, is re-
ported to cause headaches in between 5% and
20% of women.60-99 The effects on the fre-
quency of headache of a long-acting parenteral
progestin (medroxyprogesterone acetate, Depo-
Provera) on the frequency of headache are not
known.
For the most part, current views of the un-
desirable side effects of combined oral contra-
ceptives in migraineurs have been extrapolated
from studies of women taking preparations that
contained higher concentrations of estrogens
and progestins than are currently in use. The
first-generation oral contraceptive agents con-
tained 150 /Ag of estrogen. Studies in the late
1960s and early 1970s were based on formula-
tions that typically contained 80 or 100 /u,g of
estrogen (second-generation oral contracep-
tives). The third-generation oral contraceptives
now in widespread use in the United States
contain 30 or 35 /Ltg of estrogen. These low-
estrogen preparations have a significantly lower
incidence of serious side effects than the older
products. Ethinyl estradiol has remained the
134 Clinical Aspects of Migraine
estrogen in almost all combined oral contra-
ceptives. The newest pills contain various pro-
gestin formulationseither norethindrone-
type progestins (norethindrone, norethindrone
acetate, ethynodiol acetate, or norethynodrel)
or norgestrel-type progestins (norgestrel or lev-
onorgestrel).
Although much of the data conflict, use of
combined oral contraceptives clearly produces
several different clinical patterns in mi-
graineurs; one of these, stroke, is clearly seri-
ous.2'4'97 These patterns are discussed below.
First, there may be no change in the pattern
of migraine. For most migrainous women, the
inception of low-estrogen preparations does
not change the pattern of existing migraine at-
tacks.89
Second, there may be an improvement of
migraine. This is seen in a substantial minority
of women. Cessation of migraine has even
been observed in almost 4% of female mi-
graineurs.29'51'95
A third pattern is that new-onset migraine
occurs. Between 10% and 30% of women pre-
disposed to migraine developed headaches for
the first time after starting the older, first-
generation, high estrogen-containing oral con-
traceptives.46'^1 The headaches usually ap-
peared during the first few menstrual cycles,
but sometimes developed after prolonged oral
contraceptive use. In general, migraine attacks
occurred on the pill-free days of a cycle when
the serum level of hormones dropped.29'46'51
Discontinuation of the medication resulted in
a marked improvement in a large number of
patients, although the improvement was slow
and could take months.19'46 Contraceptive
medications apparently provoked headaches
more frequently in women with a family his-
tory of migraine.4'46'51 Quantitative data con-
cerning the risk of developing migraine while
taking third-generation, low estrogen-contain-
ing contraceptives are unavailable.
A fourth clinical pattern developing from use
of combined oral contraceptives is exacerba-
tion of preexisting migraine. Both the severity
and frequency of migraine headaches were re-
ported to increase in up to half the women with
previously established migraine who were tak-
ing high-estrogen contraceptives.4'19'46 The at-
tacks generally occurred during the contracep-
tive-free interval of the monthly cycle. This
worsening of headaches was more likely to oc-
cur in patients who showed one or more of
the following characteristics: they were multi-
parous, more than 30 years old, had unusually
long or short menstrual cycles, had menstrual
migraine before starting the pill, and
smoked.31'51 Most women who experienced
this intensification did so within the first sev-
eral months of starting birth control medica-
tion.95 Discontinuation of the medication re-
sulted in improvement in some individuals over
a period of 6 to 12 months.19'46 More recent
data indicate that only between 3% and 5%
women using third-generation oral contracep-
tion experience exacerbation of their mi-
graine.89 It may well be that low-estrogen con-
traceptives are only minor exacerbators of
migraine.
A variation in the pattern of preexisting mi-
graine may also occur. Patients with migraine
without aura may develop auras while on com-
bined oral contraceptives.95 Older studies in-
dicated that women whose pattern of attacks
changed from migraine without aura to mi-
graine with aura after starting contraceptive
therapy appeared to be at particularly high risk
for the development of permanent neurologic
deficits as a result of migrainous infarction.
Finally, cerebral infarction may result from
use of combined oral contraceptives. Setting
consideration of migraine aside, a 2- to 10-fold
increased frequency of ischemic strokes was re-
ported among women taking first-generation,
high-estrogen oral contraceptives as compared
to women of the same age not taking
them.88'100 This increased risk was most
marked in women over 35 years of age and
those with vascular risk factors such as hyper-
tension and cigarette smoking. The relation-
ship between hemorrhagic stroke and use of
oral contraceptives was less clear-cut, although
most studies indicated an increase in risk on
the order of <50%. Data about the current as-
sociation between low-estrogen combined oral
contraceptives and ischemic stroke in non-
migrainous women vary markedly among dif-
ferent studies.36'53'54'98'114'127 Some investiga-
tors have reported increased risks; others have
failed to find an increase. The prevailing opin-
ion is that there is a small relative risk of oc-
clusive stroke for women of reproductive age
who use third-generation oral contraceptives.
However, the attributable risk is small, in part
because the incidence of stroke in this age
range is very low. Some studies report one to
three strokes per 100,000 women that are at-
tributable to oral contraceptive use.37'113 Data
that differ slightly but provide essentially the
 Hormones 135

Table 6-3. Risk of Thrombotic Stroke: Migraine and Oral Contraceptives

At age 20 At age 40
per 100,000 per 100,000
women women

Women without migraine not taking COCs Background risk 2.0 20

Women without migraine taking COCs Absolute risk 3.6 36
Women with migraine not taking COCs Absolute risk 5.6 56
Women with migraine taking COCs Absoluterisk 10.0 100
COG, combined low estrogen-containing oral contraceptives. Background risk: the rate of occurrence of stroke in
women without risk factors for stroke; absolute risk: the difference in rates of occurrence of stroke in women with a risk
factor (e.g., COCs, migraine, migraine + COCs) and women without a risk factor.
Adapted from MacGregor and Guillibaud (1998).66 Data from Lidegaard (1993, 1994, 1995).54~56

same conclusions have been summarized by
McGregor and Guillebaud (Table 6-3).66 It
must be noted, however, that the risk of both
ischemic and hemorrhagic strokes in non-
migraineurs who take oral contraceptives is
clearly increased in patients who smoke, are
over 35, and/or who have a history of hyper-
tension.126'127 Smoking is the most substantial
risk factor that, when combined with oral con-
traceptives, dramatically increases the risk of
stroke.126'127 To put the matter in context, the
risk of stroke in young non-migrainous women
without risk factors who use modern low-dose
oral contraceptives is considerably lower than
the risks of pregnancy.
As for migrainous patients, the results of
most studies from two decades ago indicated a
further increased risk of stroke in those taking
high-estrogen oral contraceptives, but the data
differed as to how much migraine increased the
risk.15'26'74 Several recent investigations of low
estrogen-containing oral contraceptives have
also shown that the risk of stroke in migraineurs
is increased.9'12'38'54'55'116 Data from several
pertinent studies are summarized in Table 6-4.
The risk of stroke among migraineurs taking

Table 6-4. Odds Ratio for Thrombotic Stroke

Migraine +
Ethinylestradiol COC Use* Migraine Alone COC Use
Study (Mg) (OR) (OR) (OR)
Collaborative Group (1973)15 >50 4.9 2.0* 5.9
Tzourio et al. (1995)116 50 4.8
30-40 2.7 3.0 13.9
(without aura)*0 (with and
without aura)
6.2 (with aura)**
Lidegaard (1995)55 50 2.9
30-40 1.8 2.8 5.0
(with or
without aura)t
Carolei et al. (1996)9 >50 1.8 3.7 No data
(with or
without aura) j
WHO Study (1996)127 >50 1.53 No data No data
Chang et al. (1999)12 <50 1.2 2.97 (without aura) 16.9
3.8 (with aura)
COC, combined oral contraceptives; OR, odds ratio. "Data not differentiated for ethinylestradiol dose. "Diagnosis
based on two or more of the following symptoms: unilateral headache, throbbing pain, visual scintillation, vomiting, and
other symptoms. fDiagnosis made using IHS criteria. $ Self-reported diagnosis; attack frequency >1 per month.
Adapted from MacGregor and Guillibaud (1998).66
136 Clinical Aspects of Migraine

oral contraceptives is significantly higher if Although migraine is not thought to pose a

their headaches include auras.9 In addition, it hazard for the pregnancy, the fetus, or the de-
is now clear that the risk of migrainous infarc- livery, it is unclear whether or not there is
tion is greater when women on contraceptive an association between migraine and pre-
medication have other risk factors for stroke eclamptic or eclamptic toxemia.71'78'120 The in-
such as hypertension or a lipid disorder. This cidence of abortion, stillbirth, and congenital
is also the case for women who smoke, for mul- malformations in the pregnancies of women
tiparous women, and for women older than 30. with a history of migraine headaches is not
Because risk of stroke depends upon the es- higher than among non-migraineurs.120
trogen concentration, as the dose decreased
during the past 15 years, the relative risk of
stroke in non-migraineurs taking oral contra-
DELIVERY
ceptives has fallen. In large part this reflects a
lower steroid concentration, but there are
During the week following delivery, 30% to
other factors: these products are being used by
40% of all women develop headaches.108'109
younger women and adolescents who lack
Rapidly falling levels of estrogenic hormones
other risk factors for cardiovascular disease,
are thought responsible.108'109 Such headaches
and potential users are being more systemati-
usually last for more than a day, and not infre-
cally screened, particularly with respect to
quently for 2 or 3 days.109 Some women have
blood pressure. Whether this same decline in
increased headaches for a month after deliv-
the rate of stroke is occurring in women with
ery.96 While the majority of postpartum head-
migraine has not been examined separately.
aches are believed to be mild episodes of mi-
But it is clear that although low-estrogen
graine without aura, there are instances of
preparations may have diminished the vascular
women who experience several bouts of mi-
risks of oral contraception, they have not erad-
graine with aura soon after delivery. Most who
icated them.
suffer from postpartum headaches had mi-
graine before their pregnancies or have a
strong family history of migraine. Postpartum
PREGNANCY
migraine appears to be more common in mul-
tiparous women.96 The headaches can occur in
Pregnancy can alter the pattern of established
women who have been free from migraine dur-
migraine. The traditional view, now supported
ing the latter part of pregnancy. Unfortunately,
by careful epidemiologic studies, is that for half
when a pregnancy ends, preexisting migraine
to three-quarters of patients, migraine im-
is often intensified.
proves during pregnancy and may even cease,
especially during the second and third
trimester.13'30'90'1^* Attributed to sustained
high estrogen levels, the improvement is more LACTATION
common among women with migraine without
aura.11'13'117 Migraine with aura is usually not Surprisingly little is known about the effects of
ameliorated. The remission rate is higher in lactation on migraine. This is unexpected be-
women who are pregnant for the first time. In cause lactation causes important changes in the
addition, the improvement is more likely to oc- pituitary-ovarian axis and in the secretion of
cur when a women's headaches previously cor- hormones that have the potential to influence
related with hormonal events such as menar- migraine. In particular, some data imply that
che, menstrual periods, or oral contraceptive prolactinquite apart from lactationmay be
use. In contrast, some migraineurs worsen dur- involved in the genesis of migraine attacks.
ing pregnancy, and migraine is said to develop
during the first trimester in between 10% and
25% of women without a history of prior mi- Endocrinology of Lactation
graine.11'70'96'104 If bouts of migraine evolve for
the first time during pregnancy, they fre- Lactotrophs, the anterior pituitary cells that
quently have auras or may even consist of at- synthesize and secrete prolactin, constitute
tacks of complicated migraine.11'16 20% to 50% of the total pituitary cell popula-

tion depending upon the gender and physio-
logical status of the person.58 Unlike other pi-
tuitary cells, lactotrophs release their hormone
at a high rate in the absence of hypothalamic
control. The synthesis and release of pituitary
prolactin are, however, influenced by a com-
plex, dual hypothalamic regulatory system
comprised of inhibitory and stimulatory pro-
lactm-releasing factors. Dopamine is presumed
to be the major prolactin inhibitory factor
activation of D2 dopamine receptors on lac-
totrophs potently inhibit prolactin release. Do-
pamine is secreted into the portal vessels by
the tuberoinfundibular dopamine system with
cell bodies located in the arcuate and periven-
tricular nuclei of the medial-basal hypothala-
mus. A feedback mechanism is involved in the
dopamineprolactin system: prolactin induces
dopamine release, thereby inhibiting further
prolactin secretion.33 In contrast, thyrotropin-
releasing hormone (TRH) has a pronounced
stimulatory effect on prolactin secretion. Va-
soactive intestinal peptide (VIP) and an-
giotensin II also stimulate prolactin release.
Superimposed on a continuous baseline pro-
lactin secretion, additional prolactin is secreted
in pulses of varying amplitude. Prolactin
plasma levels in the adult human average 10
jag/L, and the normal limit is about 20 /tg/L.
(Values in men and prepubertal children are
lower than in adult women.) The concentration
of prolactin begins to increase in the first
trimester of pregnancy and rises to levels dur-
ing the last trimester that are 10 to 20 times
the concentration in nonpregnant women with
normal menstrual cycles. This rise presumably
results from the high level of estrogen, a hor-
mone that substantially promotes both the syn-
thesis and secretion of prolactin. The prolactin
level remains elevated for up to 3 weeks post-
partum even in the absence of suckling. Pro-
lactin is the key hormone controlling milk pro-
duction. The process of lactogenesis, however,
involves estrogen as well. Initial growth of the
breasts' ductal system is controlled by estrogen.
Development of the lobuloaveolar system re-
quires both estrogen and prolactin. Synthesis
of milk protein and fat is regulated principally
by prolactin.
High prolactin levels are maintained by
suckling, which stimulates the nipple mechan-
ically and initiates the lactation process. Pro-
lactin levels are a function of the frequency and
duration of feeding. Sensory signals originating
Hormones 137
in the nipple are conveyed to the hypothala-
mus where they induce an acute release of pro-
lactin and oxytocin. Part of this process also
reduces the release of dopamine, with a con-
sequent reduction in the concentration of por-
tal blood dopamine. Oxytocin causes contrac-
tion of the myoepithelial cells of the mammary
alveoli and ducts, resulting in the ejection of
milk (milk letdown). Only 20% to 30% of the
normal volume of milk is released in the ab-
sence of oxytocin release.
Breast-feeding profoundly inhibits repro-
ductive function. Suppression of the pituitary-
gonadal axis is related to the strength of the
sucking stimulus. The link between the activa-
tion of nerve terminals in the nipple and dis-
ruption of the pattern of GnRH release from
hypothalamic neurons is, however, unknown.
The interference with GnRH release reduces
LH (and to a lesser extent FSH) release from
the pituitary. In non-breast-feeding women,
ovarian follicle development resumes within 2
to 3 weeks postpartum and the first ovulation
can occur as early as 6 weeks postpartum. Dur-
ing lactation, ovarian activity is suppressed in
most, but not all, women and ovarian steroid
secretion is minimal. When suckling is re-
duced, the normal pattern of gonadotrophic re-
lease starts to develop with appropriate secre-
tion of ovarian steroids.
Migraine and Lactation
Although women with migraine have normal
prolactin levels during all phases of the men-
strual cycle, increased prolactin levels do occur
in some conditions associated with migraine at-
tacksstress, hypoglycemia, exercise, and oral
contraceptive use. >23>83 In addition, among
women attending an infertility clinic, head-
aches were found to be twice as common
among women who had hyperprolactinemia as
among those who did not.43 Several studies
have shown that prolactin release in women
with migraine is enhanced more by dopamine
antagonists and inhibited less by L-DOPA than
in controls, an indication that an altered
dopaminergic control of prolactin secretion
may be present in migraineurs.80'84'119 Finally,
the stimulatory effects of TRH on prolactin
secretion are enhanced during bouts of
migraine.80-86
138 Clinical Aspects of Migraine
MENOPAUSE AND
POSTMENOPAUSE
Natural menopause, resulting in the cessation
of menses, is caused by a depletion of ovarian
follicles responsive to gonadotrophins and the
consequent diminution of estrogen and pro-
gesterone secretion. Menopause occurs at a
mean age of 50 years in the United States and,
with rare exceptions, all women living beyond
55 years of age will experience menopause. Be-
cause life expectancy isisv increasing, m
women in developed coun tries will spend ap
proximately 30 years in the postmenopausa
state. By convention, the diagnosis of meno-
pause is made in retrospe ct after 12 months of
amenorrhea. The perimenopa use (climacteri
includes the period prior to menopause when
endocrinologic changes associated with the
menopause are occurring, as w ell as the fir
year following the menopause. The post-
menopause is defined as the years after the
menopause.
The clinical perimenopause lasts about 4
years in Caucasian women. About 10 years
prior to menopause, fertility wanes, and about
2 years later, hormonal levels begin to
change.76 During this time, the median length
of the menstrual cycle generally increases, re-
sulting primarily from changes in the duration
of the follicular phase of the cycle. In addition,
anovulatory cycles become more prevalent.
A number of the signs and symptoms of
menopause are listed in Table 6-5. Many of
these are thought to result from diminished
Table 6-5. Features of Menopause
Physical Changes
Vasomotor instability
Vaginal atrophy and dryness
Loss of skin elasticity
Decline in HDL
Cardiovascular disease
Hot flashes
Osteoporosis
Decreased size of the uterus/breasts
Increases in LDL/total cholesterol
Fatigue
Hdl, high-density lipoprotein; LDL, low-density lipoprotein.
levels of circulating estrogens because they re-
spond to, or are reversed by, hormonal re-
placement therapy. The characteristic hot
flasha sudden, transient flushing of the skin
accompanied by sensations ranging from
warmth to intense heat and profuse sweating
is a consequence of vasomotor instability. In-
terestingly, the majority of women note that
the initial symptom of a hot flash is a sensation
of pressure in the head, akin to a headache.41
The postmenopausal ovary is atrophic with
a thin cortex usually devoid of follicles. And be-
cause the postmenopausal ovary no longer con-
tains follicles, it is also devoid of granulosa cells
that convert androgens to estradiol. The stroma
of the menopausal ovary is, however, still ca-
pable of secreting moderate amounts of an-
drostendione and testosterone. The adrenals
also continue to synthesize androgens in sig-
nificant quantities. In fact, the level of circu-
lating testosterone is only slightly lower than
that observed in premenopausal women. Ovar-
ian atrophy occurs despite exposure to high cir-
culating levels of gonadotrophins. Serum go-
nadotrophin levels increase severalfold after
the menopause, and by 1 year postmenopause,
serum FSH levels are 10 to 15 times and LH
levels about 3 times higher than in young
women.10 Serum gonadotrophin concentra-
tions subsequently decline slowly with advanc-
ing age.
Estrogen production in postmenopausal
women results almost exclusively from extra-
ovarian metabolism. More than 50% of post-
menopausal women are capable of synthesiz-
ing some estradiol outside the ovaries and do
Emotional Symptoms
Depression
Insomnia
Anxiety
Irritability
Behavioral and Cognitive Changes
Decreased cognitive functioning
Alterations in libido
Decreased memory
Difficulty concentrating
 Hormones 139

not encounter all the consequences of estradiol

deprivation. Extraovarian estradiol synthesis is
seen in adipose tissue and may occur in brain,
bones, and arterial walls. The most prevalent
estrogen prior to menopause is estradiol; after
menopause the primary estrogen is estrone.
The average estrogen production in the post-
menopause is estimated to be 40 /Ag per day of
estrone and 6 ^tg per day of estraoUol. In con-
trast, in premenopausal women, 8 to 500 /ug
per day of estradiol and 80 to 300 /x,g per day
of estrone are produced.59 Because of de-
creased estrogen production, after menopause
the serum estradiol level concentrations fall to
values similar to, or lower than, those in men
of similar age (5-20 pg/ml).
A number of alternative migraine headache
patterns can emerge as women mature, age,
and undergo menopause, although, as Marcus
and colleagues have cogently pointed out, in-
terpretation of available data is difficult be-
cause various investigations have major short-
comings.73 As a result of these shortcomings,
quantitative data vary over wide ranges and
their value is limited, at best. The alterations
in migraine include the following:
1. No change in pattern of migraine. Many
female migraineurs (between 20% and 43%)
do not notice a change in the frequency or
severity of their migraine headaches.16'30'^5
2. Improvement or cessation of migraine.
There are widespread, anecdotal reports of im-
pressive declines in the prevalence of migraine
during or after menopause. Substantial data do
indeed show the prevalence of migraine de-
clining with advancing age.57'111 Many subjects
become headache-free with advancing age
(Fig. 6-11).91'129
What proportion of migraineurs improve or
have a remission of symptoms because of
menopause is uncertain. Estimates about im-
provement or loss of migraine put the figure at
between 14% and 67% (Fig. 6-12).16'30'64'85 A
number of factors doubtless play a role, espe-
cially decreased stress as a result of maturing,
divorce, the end of childbearing or fear of
unwanted pregnancy, retirement, and/or shift
of occupation. How much the reduction of
migraine headaches some postmenopausal
women experience is essentially a function of
changed hormonal status or merely a reflection
of psychosocial maturity may never be deter-
mined. Data gathered from migraineurs who
undergo premature menopause induced by
Figure 6-11. Age at which migraine disappeared in 52
patients. The data were obtained from 46 women and 6
men, 20 patients with migraine with aura and 32 with mi-
graine without aura, followed in a migraine clinic. (From
Blau JN: Loss of migraine: when, why and how. J R Coll
Physicians 21:140-142, 1987. Published by Royal CoUege
of Physicians, with permission.)
surgical oophorectomy are unenlightening in
this regard. The procedure is reported to ex-
acerbate migraine in about two-thirds of cases
and to improve migraine in only about one-
third of women (Fig. 6-12).85
3. Change in the quality of their attacks.
Some patients note an alteration in the char-
acter of their attacks. Loss or reduction of
vomiting and loss of the aura are the most com-
mon changes.124 Anecdotal information indi-
cates that in only a minority of women does mi-
graine increase in frequency or severity, but
published estimates vary widely from 18% to
46% 16,30,64,85
4. Transformation of migraine. There is a
subgroup of perimenopausal, menopausal, and
postmenopausal migraine patients for whom
migraine loses its typical pattern of clear-cut,
episodic, recurrent attacks separated by peri-
ods of complete freedom from headaches.
More and more tension-type headaches de-
velop in the intervals between bouts of mi-
graine. Other patients also develop frequent or
daily tension-type headaches, but gradually lose
their migraine. These latter women have de-
veloped transformed migraine (see Chapter 4).
140 Clinical Aspects of Migraine

flow of headaches. And indeed, modern data

presented here confirm long-held conceptions
that migraine frequently appears around the
time of menarche, is often subject to cyclical
hormonal changes, and is affected by preg-
nancy and delivery, as well as by exogenous es-
trogens (oral contraceptives). latrogenic prob-
lems caused by the prescription of oral
contraceptives and the dangers of stroke must
be paramount in all physicians who treat mi-
graine. How the prolactin of lactation interacts
with the migraine process is less clear. Inter-
preting the data about the final decades of a
woman's lifewhen anecdotal evidence tells
us that menopause is responsible for significant
migraine reductionis more problematic.
Some migraine improves, some worsens, some
changes in quality. What the percentages are,
and how they correlate with hormonal events,
is by no means certain.

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Chapter 7
Examination and Investigation
of the Migraineur
THE MIGRAINE HISTORY
CLINICAL EXAMINATION OF THE
PATIENT WITH MIGRAINE
Interictal Examination
Ictal Examination
IMAGING PROCEDURES
Computed Tomographic Scans
Magnetic Resonance Imaging
ELECTROPHYSIOLOGICAL STUDIES
Electroencephalograms
Visual Evoked Potentials
The EEC and Visual Evoked Potentials in
the Evaluation of Patients with Migraine
The history of a patient with migraine is con-
siderably more important than the physical ex-
amination because the diagnosis of migraine
relies largely, if not entirely, upon the patient's
description of symptoms. Abnormal neurolog-
ical signs are unusual in cases of uncomplicated
migraine. A comprehensive and detailed his-
tory does much to reassure the physician that
the diagnosis of migraine is the correct one.
But just as important, a comprehensive and de-
tailed history does much to reassure the patient
that the physician is interested and concerned.
Because an effective physicianpatient rela-
tionship is the key to successful management
of migraineurs, the initial history-taking visit is
the single most important chance to construct
such rapport. Many migraineurs have received
unsatisfactory care in the past and are defen-
sive about their problems. More than a few
come to the initial consultation with the nega-
tive expectation that the examining physician
Somatosensory and Auditory Evoked
Potentials
Event-related Potentials
Habituation of Evoked and Event-related
Potentials
OTHER DIAGNOSTIC TESTS
Thermography
Angiography
Lumbar Puncture
Neuropsychologic Testing
SUMMARY
will be as unsympathetic and as unhelpful as
previous physicians were. Extraordinary care
may be necessary both to obtain a complete
history and to establish an atmosphere of trust
and optimism.
A number of factors have the potential to
complicate the relationship between physicians
and patients with migraine, especially if the
physician does not suffer from headaches. The
first is that physicians can easily lose patience
with otherwise healthy individuals who have
the misfortune to be afflicted with migraine.
Most physicians have had little or no specific
training in the treatment of headaches, and
have had little experience with the particular
problems associated with migraine. Despite
this, many physicians believe that patients with
migraine can be approached in ways similar to
those used for patients with other medical and
neurological complaints. This is generally not
the case. Examination and subsequent man-
145
146 Clinical Aspects of Migraine
agement of the patient with migraine takes a
great deal of time, perseverance, and compas-
sion, whichas a result of the pressures of
modern medicine and difficulties with man-
aged careare commodities frequently in
short supply. Furthermore, patients may have
already seen one or more ophthalmologists,
otolaryngologists, allergists, neurologists, den-
tists, radiologists, psychiatrists, psychologists,
physical therapists, chiropractors, and acu-
puncturists. Each of these practitioners has
probably considered the headache to result
from conditions he or she was most knowl-
edgeable about, and treated the patient ac-
cordingly. A single migraineur may have had
extensive radiological procedures (including
computed tomography and magnetic reso-
nance imaging) electroencephalograms, pre-
scribed glasses, biofeedback, psychotherapy,
acupuncture, allergy injections, manipulation
of the neck, intradural steroid injections, and
sinuses drainedall without efficacy.
Another factor that can complicate the
physician-patient relationship is that migraine
is not the type of easily remedied medical or
surgical problem that most doctors prefer.
Running counter to a physician's inclination to
search for somatic illnesses that can be objec-
tively confirmed, no laboratory results are suf-
ficiently precise to serve as markers for this ill-
ness. Migraine is a "low-tech" condition. But
because modern medical training largely fo-
cuses on "high-tech" diseases that generate
reams of laboratory data, a case of migraine will
frustrate many modern physicians trained to
itemize an extensive list of differential diag-
noses and then to exclude ("rule out") various
possibilities through laboratory tests and spe-
cial investigations. The management of most
patients with migraine requires only a com-
prehensive history and a careful physical and
neurological examination; the vast majority of
migraineurs can be evaluated appropriately
and accurately without resorting to any labora-
tory and radiographic procedures. And as soci-
ety becomes increasingly concerned about es-
calating health-care costs, this point needs
stressing all the moremigraineurs need little
in the way of technology, but much in regard
to the physician listening and asking the ap-
propriate questions.
Also, unless the physician has taken suffi-
cient time during the first visit to construct a
degree of trust and empathy, patients will not
be forthcoming about either significant envi-
ronmental and family problems or difficulties
with excessive drug and medication use. Many
patients disclose that their previous physicians
considered them "weaklings" for "giving in" to
their discomfort and pain and exaggerating the
severity of their symptoms. Too many times
they were told, "the problem is all in your
head"an implication that they were not suf-
fering from real illnesses. "I wish I were in a
wheelchair so that people would believe that I
really am ill" is an often-heard complaint of mi-
graineurs who suffer from frequent, recurrent
attacks. In addition, many patients experienced
unexpected side effects from prescribed med-
ication. If a new patient was never prepared for
potential side effects, the physician may be
faced with an individual who has grave misgiv-
ings about trying new medications. Unless the
physician has the good fortune to be the very
first professional a patient has consulted for
headache, he or she may very well encounter
someone who is suspicious of all physicians. Pa-
tients appreciate physicians who are friendly
and respectful, but many physicians have not
learned to use empathy in their traimng or prac-
tice, and many physicians may feel that they do
not have enough time to develop empathy.
Finally, the fact that the expectations of
physicians and patients are different may com-
plicate their relationship (Table 7-1). Most
physicians assume that headache patients come
primarily for pain relief and medication.88 Al-
though the majority of patients expect pain re-
Table 7-1. Headache Patient Needs
Need %
Explanation of genesis of pain 77
Relief of pain 69
Explanation about medication 32
(side effects and how it works)
Complete neurological examination 31
A doctor willing to follow up the headache 26
Medication 20
Time to ask the doctor questions 20
Treatment other than medication 18
A complete eye examination 11
Skull X-rays 8
Psychiatric examination 3
Data from Packard (1979).88

lief, most want an explanation of what is caus-
ing their pain coupled with the presence of a
thorough, knowledgeable physician who is will-
ing to listen to their complaints patiently and
with understanding. About two-thirds of pa-
tients have fears about organic disease that can
be dispelled during the initial consultation.36
THE MIGRAINE HISTORY
Relief from severity and frequency of migraine
attacks can rarely be achieved unless a thor-
ough history of the nature of that patient's suf-
fering has been taken with tact and sensitivity.
The following information is necessary: a de-
tailed medical, neurological, and family history
together with scrutiny of their occupational, so-
cial, domestic, emotional, dietetic, and envi-
ronmental situation (Table 72). Appropriate
Table 7-2. Significant Elements of
Migraine History
Number and types of headaches
Age and circumstances of onset
Migraine frequency
Duration of attacks
Time and mode of onset of pain
Precipitating or trigger factors
Premonitory or prodromal symptoms
Aura
Location and irradiation of pain
Quality and severity of pain
Aggravating factors
Relieving factors
Associated systemic and neurological symptoms
Postdromal symptoms
Previous treatment and medications and
therapeutic or idiosyncratic responses
Present medication including over-the-counter
remedies
Family history
Previous workups including neuroimaging
procedures
General health and past medical history
Personal history including social and marital
relationships, occupation, habits, intake of
alcohol, coffee, and "recreational" drugs,
sleeping habits, and emotional factors
Review of systems
Examination of the Migraineur 147
emphasis should be placed on the state of the
patient's general health so as to determine
whether the migraine should be considered an
isolated affliction or part of a systemic disease.
Questions about sleeping patterns are neces-
sary. A complete review of systems is necessary
with particular stress on questions about the
function of the eyes, ears, nose, throat, tem-
poromandibular joints, and neck. Inquiry
should be also made as to a family history of
headaches.
Attention must be paid to the patient's past
medication history and to present intake, in-
cluding over-the-counter drugs. A complete
roster should be made of all medications that
have been tried in the past, doses prescribed,
duration of use, and any therapeutic benefits
or untoward side effects. Information about
self-medication is also necessary. A sensitive
but important topic involves pain medication,
sleeping medication, and tranquilizers. It is
also imperative to investigate alcohol, tobacco,
and so-called recreational drug use. Female pa-
tients should be questioned about oral contra-
ceptives and their effect, if any, upon the fre-
quency and severity of attacks.
A competent psychological assessment by
the physician is critical for successful treatment
of patients with migraine, but the scope and
character of the psychological evaluation
should vary with the needs of the patient. The
stresses and events immediately preceding
headaches must be noted. Psychological expe-
riences or reactions that elicit powerful emo-
tions are considered important precipitants for
bouts of migraine. Prolonged stress also con-
tributes to die frequency of migraine attacks;
thus data about social and marital relationships,
family situation, educational qualifications, oc-
cupational responsibilities, and employment
conditions belong in the history. In the case of
child migraineurs, information about parental
and sibling relationships and responses to
stress at school should be sought. It is also im-
portant to determine whether specific psycho-
logical problems precipitate attacks or result
from the burden of contending with chronic,
recurring headaches. If both appear to be the
case, they may well be interconnected; chronic
head pain and associated cognitive difficulties
invariably make social and work situations
more difficult to cope with.
The migraine history is naturally focused on
the nature of migraine attacks, and especially
148 Clinical Aspects of Migraine
upon the pain they cause. All descriptions of
pain are subjective, and many patients unfor-
tunately lack the verbal ability to describe ex-
actly what they have felt. Most patients are sure
that physicians have no idea of the magnitude
of their suffering, and may select inappropri-
ate or confusing hyperbolic language that may
confound the diagnosis-making process. Ac-
cordingly, each physician must develop a ques-
tioning style that will aid patients in articulat-
ing the characteristics of their own attacks. For
example, one might begin with an open-ended
question such as, "What are your headaches
usually like?" If the answer is too vague to be
useful, the physician must be prepared to step
in with more specific questions about location
and type of pain, and how pain changes their
behavior or mood or interferes with their ac-
tivities. In the typical clinical consultation, em-
phasis is usually placed on descriptions of head-
aches in terms of pain severity, duration, and
frequency. But that may well be insufficient.
One must evaluate the overall effect of illness
and its therapy on a patient, and that includes
the psychosocial and occupational effects of re-
current, often disabling head pain.
The migraine history must be taken person-
ally by the treating physician. A questionnaire
filled out by the patient with or without the
help of medical personnel is not adequate;
history-taking not only gives the physician in-
sight into the patient's problems, but the act of
taking a history through sensitive questioning
begins to build the bridge between patient and
doctor. (The topics recommended here for tak-
ing a migraine history are treated only briefly.
See Chapters 3 and 4, where the characteris-
tics of migraine attacks are discussed in greater
depth.) The following points should be covered
during the first meeting.5'63'111
1. The type(s) of headache. Migraine pa-
tients may suffer from more than one type of
headache; some may interpret their varying
symptoms as one type of headache of varying
intensity. Conversely, some patients may be-
lieve they suffer from several different types of
headache when they actually have only one
type that varies in severity. About half of mi-
graineurs experience frequent, or constant,
mild-to-moderate headaches between their
major attacks. Many of them suffer from per-
petual, dull discomfort punctuated by recur-
rent bouts of acute, throbbing "typical" mi-
graine pain. Many patients in whom this
develops use excessive amounts of pain med-
ication that has led to drug-induced headaches
one reason for a thorough medication history.
2. The age of onset. Migraine frequently
commences in childhood or early adulthood.
However, because migraine often has different
symptoms at different ages, a patient may con-
sider as the first attack the first one with se-
vere pain or with a visual aura. That patient,
under careful questioning about typical child-
hood symptoms may disclose a history of mi-
graine that began early in life. Headaches that
have their onset abruptly in later life are more
likely to indicate a pathological condition, while
headaches that have ensued over many years
or decades are most often benign.
3. The circumstances of the first attack. Not
infrequently, the onset of migraine was pre-
ceded by such factors as a head injury, menar-
che, pregnancy, or the initial use of oral con-
traceptives.
4. The temporal pattern of the headache.
Migraine headaches can recur in regular or ir-
regular patterns. Their frequency ranges from
a few times a year to several times a week.
Some patients have several bouts of migraine
followed by long headache-free periods. Other
patients have headaches every week. Some
women note an invariable relationship to their
menses. It is important to determine the aver-
age frequency of attacks for each patient be-
cause changes in the frequency of migraine at-
tacks may indicate the development of an
intracranial lesion in a previously migraineous
patient. In addition, such information will be
needed when judging if particular medications
are efficacious or not.
5. The usual hour of onset of headaches. Al-
though episodes of migraine may develop at
any time of the day or night, most develop early
in the morning.
6. Precipitating or trigger factors known to
bring on bouts. In most patients a variety of
factors, separately or in combination, can set
off migraine attacks. Precipitants include
stressful psychosocial conditions, dietary con-
stituents, missed meals, altered sleep sched-
ules, physical stimuli, certain medications, and
changes in hormonal levels, especially during
the menstrual cycle. Every effort must be made
to identify trigger factors, because the fre-
quency of attacks may be reduced when par-
ticular factors in the environment are altered
or removed, or when behavior is modified.
7. The types of premonitory symptoms.
Many migraineurs notice a number of early sys-

temic, mental, and/or psychological premoni-
tory symptoms that antedate the headache
stage of a migraine attack.
8. The aura preceding the headache. If
auras form part of the pattern of attacks, the
patient must be specifically questioned about
symptoms referable to the visual, sensory, mo-
tor, vestibular, and communication systems.
9. The location of the pain and its radiation.
Migrainous head pain is strictly unilateral in
56% to 68% of adult patients, and in 22% to
31% of childhood migraineurs. It may also be
bilateral or holocephalic. If the pain is unilat-
eral, successive attacks of pain may alternate
sides, or may occur invariably on the same side.
Any region of the head, face, or neck may be
affected. The discomfort may affect unusual lo-
cations such as the vertex, the jaw, or the teeth.
The presence of frontotemporal pain is not
necessary for the diagnosis.
10. The quality of the pain. It is well to bear
in mind that less than half of adult migraineurs
experience a throbbing or pounding compo-
nent to their pain. Often attacks start with a
dull headache, but later develop a throbbing
quality. Many inexperienced physicians erro-
neously believe that a history of throbbing pain
is necessary to make a diagnosis of migraine.
11. The seventy of the pain. The severity of
pain can best be determined by evaluating its
consequences on the patient's daily activities.
The intensity of the pain typically varies among
attacks from an insignificant discomfort to an
incapacitating severity sufficient to require
confinement to bed.
12. The duration of the pain. The duration
of acute migrainous pain can range from a few
hours to several days, but for most patients the
pain lasts a day or less.
13. The factors that exacerbate the pain.
Migrainous pain is characteristically aug-
mented by physical activity or effort, by sud-
den head movement, or by bending over.
14. The maneuvers that ease or relieve the
pain. Migrainous discomfort is typically re-
duced by lying or sitting still. A small number
of patients may experience brief alleviation of
pain by manually compressing the superficial
temporal artery. Some patients find that an ice
pack reduces pain; others favor applying heat
to the head.
15. Symptoms of gastrointestinal or auto-
nomic dysfunction. During an attack, most pa-
tients suffer from photophobia and phonopho-
bia and from nausea, vomiting, or other
Examination of the Migraineur 149
gastrointestinal symptoms such as diarrhea.
Autonomic symptoms such as facial pallor and
cold extremities are frequent.
16. Neurological symptoms during the at-
tack. During attacks of complicated migraine,
focal visual, sensory, motor, or speech distur-
bances may occur. Changes in mental status
and consciousness ranging from minor cogni-
tive changes to a severe organic mental syn-
drome with confusion can develop.
17. The postdromal symptoms. Most mi-
graineurs are notably fatigued, depressed, or
cannot think as well as usual for several hours
to a day following an attack.
CLINICAL EXAMINATION OF
THE PATIENT WITH MIGRAINE
Examination of patients with recurrent head
pain takes place under two distinct circum-
stances. Migraineurs are most often examined
during an interictal period when the clinician's
task is to evaluate chronic or recurrent head-
aches. When a patient is seen during an attack,
however, even when migraine is strongly sus-
pected, emphasis should be placed on ruling
out acute intracranial problems such as menin-
gitis, encephalitis, subarachnoid hemorrhage,
or brain tumor, all of which may require im-
mediate admission to the hospital for diagnos-
tic workup. In both contexts, a full neurologi-
cal exam and a general physical exam are
necessary to detect cases of organic disease that
have presented with migraine-like headache.
Interictal Examination
Because the interictal diagnosis of migraine is
almost always made on the basis of history, the
neurological exam itself is usually an anticli-
max. Between attacks, the neurological exami-
nation of the migrainous patient should be es-
sentially normal. Anisocoria is seen more
frequently in migraineurs than in the general
population.26'27 Examination of the head and
neck may reveal residual tenderness of the
scalp and the pericranial and cervical muscles
for several days after an attack. There may
be well-defined, remarkably sensitive trigger
points and tenderness in the distribution of the
greater occipital nerve or in the shoulders. De-
tection of other objective neurological abnor-
malities between bouts casts suspicion on the
150 Clinical Aspects of Migraine
diagnosis of migraine, and indicates a need for
additional studies.
Ictal Examination
The suffering of patients during a severe mi-
graine attack is obvious. They make every at-
tempt to remain immobile, either lying flat or
sitting propped up. Head movement is espe-
cially avoided. They look ill: their faces are usu-
ally pale or ashen, the skin is usually sweaty
whereas the extremities typically feel cold. Un-
commonly, the forehead may be flushed and
warm. The superficial temporal or the frontal
and supraorbital vessels appear distended and
prominent in some patients, and occasionally
localized edema in the temporal and periorbital
areas may be noted. A small amount of neck
stiffness may be present. The patient may be
moaning or quietly sobbing, irritable or indif-
ferent. A considerable degree of lethargy is not
uncommon. Speech is frequently slow and hes-
itant, and may even be slurred and dysarthric.
There may be evidence of cognitive impair-
ment, or even a significant organic mental syn-
drome may be present. Some patients have dif-
ficulties with word finding.
During an acute attack, it is often difficult to
perform a complete neurological examination
with assessment of the mental status, cranial
nerves, gait, coordination, power, reflexes, and
sensation. Migrainous head pain is exacerbated
by many of the procedures that comprise a rou-
tine neurological examination. For example, in-
spection of the fundi produces extreme photo-
phobic discomfort, but is necessary in a patient
seen for the first time. Gait and muscle
strength testing are difficult because any ma-
neuver that changes the position or causes jar-
ring of the head aggravates the pain.
The examination must also include scrutiny,
auscultation, and palpation of the skull; evalu-
ation and visualization of ears, tympanic mem-
branes, and mastoid areas; examination of the
neck for range of motion and stiffness
(meningeal signs must be tested for if the neck
is stiff); examination of the nose; percussion
and transillumination of the sinuses; evaluation
of the eyes for evidence of increased intraocu-
lar pressure; and auscultation and palpation of
the extracranial vessels.
As the pallor and sweating suggest, exami-
nation usually demonstrates evidence of auto-
nomic nervous system involvement. The pupils
are typically normal, but on occasion, one finds
a Homer's syndrome with ptosis and/or mio-
sis. The pupil is rarely dilated on the side of
the head pain.61 During some attacks, the nose
may show engorged turbinates. The conjuncti-
vae may be injected. Tachycardia and hyper-
tension are often present, but hypotension and
bradycardia are also possible.^'"^Fever occurs
rarelyusually only in children.134 The peri-
cranial and cervical muscles are often tender.85
The sternocleidomastoid, trapezius, tempo-
ralis, and paracervical muscles are most com-
monly involved. Scalp tenderness is frequent
in the forehead, the temples, and the occiput.25
If the patient has complicated migraine, neu-
rological examination may reveal a hemi-
paresis, a hemisensory deficit, a homonymous
hemianopia, aphasia, or decreased vision in
one eye.
IMAGING PROCEDURES
A confident diagnosis of migraine can usually
be made on the basis of a comprehensive his-
tory, followed by a neurological and general ex-
amination. For the vast majority of patients,
laboratory tests, including imaging procedures,
are not necessary because only a small number
(0.3% to 0.4%) of adult or pediatric patients
with uncomplicated migraine and a normal
neurological examination have intracranial
masses or other significant intracranial le-
sions.16'17'51'67-75-87'102 For those under 45, the
rate is even lower. Meta-analysis of studies of
patients with migraine and a normal neurolog-
ical examination performed by the US Head-
ache Consortium revealed a rate of significant
intracranial pathology of 0.18% with computed
tomography (CT) and magnetic resonance
imaging (MRI). These CT and MRI scanning
procedures are not cost-effective as routine
procedures for screening all migraine patients
under age 45 whose physical exams are nor-
mal3,44,f32
Recommendations in the literature as to
whether to use CT scans for headache patients
are, nevertheless, contradictory. Some authors
consider widespread use of CT scans to be
worthwhile;21 others have declared the CT un-
necessary because serious intracranial disease
can be detected by neurological examination.78
A National Institutes of Health (NIH) consen-

sus development conference on the use of CT
scans proposed that CT scans be used for only
a minority of headache patients.81 The NIH
report suggested that the test be considered
solely for patients whose headaches are "se-
vere, constant, unusual, or associated with ab-
normal neurological signs." After reviewing all
published series of cases of migraine, the Qual-
ity Standards Subcommittee of the American
Academy of Neurology concluded that the di-
agnostic assessment of migraineurs with an un-
complicated history of recurrent headaches, no
recent change in the pattern of their disease,
and normal findings on neurological exam need
not include an imaging study. 8 Such studies
may be indicated in "patients with atypical
headache patterns, a history of seizures, or fo-
cal neurologic signs or symptoms." In sum,
most authoritative bodies weigh in against rou-
tine CT scans.
Some situations do warrant imaging proce-
dures for patients believed on clinical grounds
to have migraine. These include:
1. Headache of recent onset
2. Headache with a progressive course
3. Recent, significant worsening of the
"usual" headache, an increase in its fre-
quency without an obvious cause, or
other recent change in pattern of attacks
4. Abnormal neurological examination
5. Existence of associated symptoms such as
seizures, alterations in consciousness,
cognitive changes, or memory loss
6. Hemicrania consistently limited to one
side ("side-locked"), particularly if associ-
ated with contralateral visual or other
symptoms suggesting cerebral dysfunc-
tion
7. Transient neurological events without
subsequent headaches (migraine aura
without headache)
8. First bout of basilar migraine, hemiplegic
migraine, or ophthalmoplegic migraine
9. Presence of an orbital or intracranial
bruit.
The proportion of positive scans depends
upon the clinical setting and the selection of
individuals. The frequency of serious intracra-
nial disease differs greatly in headache patients
who come to see their primary care physician,
in those referred to a specialist, and in those
being evaluated in an emergency room. The
onset of headaches after the age of 50 has been
used as an indication for imaging procedures.
Examination of the Migraineur 151
It appears, however, to be of little value in pa-
tients with late-onset migraine unless the his-
tory is atypical or abnormalities are present
upon neurologic examination.16 Some patients
are convinced that they have serious intracra-
nial lesions, and feel that they require elabo-
rate workups. These patients need reassurance
that their head pain does not result from an
undetected tumor or other lesion. If the con-
fidence of these patients has been gained, most
can be convinced that they do not need un-
necessary tests.
Is CT or MRI the preferred method of ex-
amination when an imaging study is indicated
in a migraine patient? Computed tomography
scanning is a relatively simple, rapid procedure
that can be carried out in most circumstances
without difficulty. It is preferred for the ex-
amination of a patient in an acute situation
where it is necessary to make certain that the
patient does not have intracranial bleeding.
Magnetic resonance scanning is more expen-
sive, requires more exposure time, which can
be a problem in an uncooperative or claustro-
phobic patient, and is contraindicated in the
presence of any intracranial metallic object or
a cardiac pacemaker. Magnetic resonance
imaging is much more sensitive than CT for
the detection of changes in the white matter
and can contrast the gray and white matter.
The MRI has superior ability to visualize struc-
tures in the posterior fossa and in pituitary and
also appears superior for detecting clinically ir-
relevant lesions. Computed tomography scans
are less sensitive in detecting small lesions and
determining the extent of lesions. They are
usually not effective for diagnosing saccular
aneurysms, arterial dissections, and lesions in
the posterior fossa.
Computed Tomographic Scans
Computed tomographic scans show nonspe-
cific abnormalities in a large number of adult
migraine patients, but these lesions are rarely
significant, and accordingly, their presence
should alter neither the diagnosis nor the
course of treatment. Minimal changes, or
changes of no pathological significance, are also
seen in a small number of pediatric or adoles-
cent migraineurs.133 Their frequency ranges
widely from study to study. Most abnormalities
are nonspecific, consisting of mild ventricular
152 Clinical Aspects of Migraine
enlargement sometimes associated with widen-
ing of the cerebral sulci. The frequency of
these findings is disputed; nor is it clear if they
are more common in migraineurs than in con-
trol individuals.17'136 Scattered or focal areas of
cerebral atrophy are sometimes found. The ar-
eas of localized atrophy are most frequently in
the temporal and parietal areas. Although the
presence of CT abnormalities is not correlated
with the duration, severity, or frequency of the
migraine attacks, CT abnormalities are found
more frequently in patients with migraine with
aura than in patients with migraine without
aura.
On occasion, CT scans demonstrate hypo-
dense areas that may or may not be enhanced
by contrast material. In general, these areas of
low density have a limited "mass effect" rela-
tive to their size, are usually surrounded by
meager amounts of edema, and are frequently
transient in nature. Although they may involve
any region of the brain, the occipital lobes are
the most common sites. Hypodense areas are
most often seen in individuals who have resid-
ual neurological deficits after a migraine attack,
but they have also been noted in patients with-
out apparent residual signs of neurological dys-
function. Because these lesions resemble those
produced by ischemic processes, hypodense
areas are thought to represent areas of cere-
bral ischemia.
Magnetic Resonance Imaging
The frequency of parenchymal lesions de-
tected by MRI is clearly higher in migrain-
eurs than expected in the normal popula-
tion_ 15,17,33,51,77,91,136 Earlier studies showed
prevalence rates as high as 46%; more recent
investigations, however, have demonstrated
much lower frequencies.91 White matter ab-
normalities may be more frequent among pa-
tients with basilar migraine and migraine with
aura. The abnormalities consist mainly of sin-
gle, or multiple, bilateral, punctate hyperin-
tensities (white matter foci, unidentified bright
objects, white matter hyperintensities] on both
T2- and proton density-weighted images. Con-
fluent lesions are unusual.33'35 The hyperin-
tensities are especially prominent in the deep
white matter and may be more frequent in the
frontal region and the centrum semiovale (Fig.
7-1 ).17>51 Periventricular white matter lesions
are less frequently seen.91 The presence of the
lesions is not correlated with the frequency of
attacks or the duration of the condition, but as
the figure indicates, the age of the individual
is a major factor.15'51 MRI white matter find-
ings are not a common occurrence in pediatric
migraineurs.77
The presence of multiple, small, hyperin-
tense foci is a nonspecific finding. Similar
small, asymptomatic MRI abnormalities have
been consistently reported in all studies of
healthy control subjects. As an example, they
have been reported in almost 27% of normal
20- to 40-year-olds.50 Such abnormalities also
show up in the scans of patients with multiple
sclerosis, hypertensive small vessel disease, vas-
culitis, and multiple infarcts. In general, how-
ever, the lesions in scans of patients with mi-
graine are smaller than the typical patches of
demyelination of multiple sclerosis. There is an
increased incidence of hyperintense foci in
older individuals with and without migraine.
On rare occasions, larger areas of signal ab-
normality are seen in scans of migraineurs and
are thought to represent areas of infarction.136
The findings consist of focal regions of in-
creased signal intensity on T2-weighted stud-
ies. Such areas may also produce hypointense
signals on Tl-weighted images.
The pathological process responsible for the
white matter hyperintensities is in some dis-
pute. Hyperintensities are generally consid-
ered to reflect a pathologic increase in tissue
water, resulting in prolongation of T2 relax-
ation, but when located in the deep and sub-
cortical white matter, they are usually thought
to reflect ischemic damage and to correspond
to focal rarefaction of myelin, loss of nerve
fibers, and reactive gliosis.33'106 The signifi-
cance of such lesions in the MRI scans of pa-
tients with migraine is simply not known.
In sum, data collected so far from both CT
and MRI scans of "ordinary" migraineurs are
inconclusive. They do not shed light on the
pathophysiological processes involved in this
condition or alter the physician's care of peo-
ple afflicted with this common misery. Far too
many CT and MRI examinations are done sim-
ply because the tests are available, patients ex-
pect them, and physicians believe they are
needed as protection against accusations of
malpractice. In this regard, the NIH Consen-
sus Report and the conclusions of the Ameri-
can Academy of Neurology's Quality Standards
Subcommittee should obviate physician anx-
iety and limit the use of imaging procedures to
 Examination of the Migraineur 153

Figure 7-1. Distribution of white matter hyperintensities in MRI scans. In younger patients (39 years of age or younger),
the lesions are predominantly located in the centrum semiovale and the frontal white matter. With advancing age (40
years or older), the lesions extend to the deeper white matter at the level of the basal ganglia. (Adapted from Igarashi H,
Sakai F, Kan S, Okada J, and Tazaki Y: Magnetic resonance imaging in patients with migraine. Cephalalgia 11:69-74,
1991, with permission.)

non-routine cases. Unless or until imaging pro-
cedures produce more useful information, they
should be restricted to only those cases in
which an abnormal lesion is suspected. All
other patients should be reassured, on the ba-
sis of a careful history and a physical, that they
do not need expensive testing.
ELECTROPHYSIOLOGICAL
STUDIES
Electrophysiological studies are certainly less
expensive than imaging procedures, but their
diagnostic value in patients with migraine is no
more clear. Although many published reports
indicate that electroencephalograms (EEGs)
and visual evoked potentials (VEPs) of mi-
graineurs differ from non-migraineurs, few of
die reported abnormalities are sufficiently spe-
cific to aid in the diagnosis of migraine. It
would be fair to say that, at the present time,
visual evoked potentials are to be considered
experimental, and the major clinical indication
for performing an EEC in a particular mi-
graineur is the need to determine whether a
change of consciousness occurring in associa-
tion with a migrainous headache is syncopal or
epileptic in nature.
Electroencephalograms
Considering the modest value of the EEG
in the diagnosis and management of most
patients with migraine, it has been the focus
of an extraordinary amount of attention. Many
researchers have reported an increased
frequency of EEG abnormalities in mi-
graineurs compared to the population of non-
migraineurs. Although the prevalence of ab-
normal recordings in the interictal period has
been reported to vary between 22% and 72%,
most of these studies have been uncontrolled.
None of the abnormalities reported are exclu-
sively found in patients with migraine. Fur-
thermore, most workers have reported com-
paratively minor findings that have little
specificity. In addition, the criteria for EEG ab-
normality vary from study to study. A number
154 Clinical Aspects of Migraine
of older studies considered records pathologi-
cal that contained findings now considered to
be normal patterns or normal variants, such as
posterior slowing, 14- and 6-Hz positive spikes,
and excessive hyperventilation responses in
young individuals. Some of the older investi-
gations presumably overestimated the propor-
tion of migraineurs with EEC abnormalities:
their samples were biased by patients referred
from headache clinics because of concomitant
neurological deficits or diseases, including
epilepsy. And many studies display a paucity of
age-, gender-, and medication-matched con-
trols or are totally uncontrolled.
INTERICTAL EEC PATTERNS
The interictal EEC patterns most commonly
reported in migraineurs are either disorganized
traces dominated by abnormal fast and slow ac-
tivity, or excessive slow activity that is usually
diffuse but may be focal. Other reported pat-
terns include focal spike or sharp waves, and
rhythmic, high-amplitude slowing during hy-
perventilation. Paroxysmal abnormalities occur
in the records of a few migrainous adults, and
are noted with somewhat higher frequency in
the records of afflicted children.43'131'137 The
degree and the characteristics of the abnor-
malities seen in the EEGs of migraineurs may
vary in serial tracings and, at times, even dis-
appear. As expected, focal EEC abnormalities
occur with the highest frequency in patients
who have focal cerebral hemispheric symptoms
accompanying their attacks.47 An increased in-
cidence of abnormalities is said to be present
in patients with migraine with aura, but this has
not been confirmed.
The incidence or type of EEG abnormalities
cannot be clearly correlated with the type of
migraine, the duration of the affliction, or the
severity, frequency, and length of attacks. At
times, however, the EEGs of patients with
complicated migraine can show a persistent fo-
cus of slow wave changes that is related to the
visual, motor, or sensory defects; this is an ex-
pression of a permanent cerebral lesion.
QUANTITATIVE EEG ANALYSIS
Computer analysis of EEG data has described
some interictal abnormalities, namely differ-
ences in power spectra between control indi-
viduals and patients with migraine.31'32'53'116'117
These power differences correspond to mod-
est changes in background activity and, in gen-
eral, indicate a degree of EEG slowing. Some
studies have shown differences in the symme-
try, modulation, or peak frequencies of the
alpha rhythm in both adults and chil-
dren 18,23,30,41,96,112 Considerable overlap of
findings exists between normal and patient
groups, as well as considerable variability
among studies. The lack of a standardized
method and type of analysis is responsible for
much of the variability. As a result, the value
of EEG spectral analysis in the diagnosis of mi-
graine in individual patients is very limited.
ICTAL EEG PATTERNS
The EEG abnormalities during bouts of mi-
graine without aura have been poorly docu-
mented, but the available data show that ictal
changes in the EEG are infrequent.65 In con-
trast, changes in the EEG occur more fre-
quently during attacks of complicated migraine
or of migraine with aura. Transient, slow wave
disturbances of high or low amplitude have
been recorded from patients who have focal
signs such as scotomas or hemiparesis either
before or during attacks of migraine.8'11'103 The
slow waves may be diffuse, but are usually
asymmetric, with a predominance of slow
waves over the cerebral hemisphere contralat-
eral to the neurological deficit. The EEGs of
some such patients may show insubstantial
changes such as asymmetric alpha activity.68
The abnormalities usually disappear concur-
rent with, or a few days to weeks after, clinical
recovery.
The EEGs of most patients with basilar mi-
graine show transient, posterior, slow wave ac-
tivity during attacks.89'120 Some children and
adolescents with basilar artery migraine have
paroxysmal occipital spike and slow wave ab-
normalities and convulsions.2'39 In such cases,
the epileptiform activity is present only when
the eyes are closed. In contrast, the EEG of
patients with acute confusional migraine dem-
onstrates bilateral slow wave activity.93'128
When spectral analysis and topographic
EEG mapping is used to investigate patients
during attacks with visual aura, a 50% or
greater reduction of alpha power and a smaller
decrement of theta power is recorded.107 In
most cases, the reduction is unilateral, located
on the side of the head pain. It may emerge 12
to 18 hours before a bout of migraine and may
persist for 48 hours after the attack.

PHOTIC DRIVING
The basic EEG rhythm of individuals with mi-
graine appears to be easily influenced by repet-
itive photic stimulation.41'124 Photic driving
(photic following) is a rhythmic response
mainly in traces from the posterior cerebral re-
gions when an individual is subjected to inter-
mittent photic stimulation. The rhythmic re-
sponse occurs either at the same rate as the
flash or at a subharmonic of the flash rate. It
is a normal phenomenon when the rates of
stimulation are in the alpha range. Migraineurs
appear to have augmented photic driving in re-
sponse to high-frequency stimulationa re-
sponse that extends into the range above 20
flashes/second (20 Hz). Power spectral analy-
sis of the EEG during photic stimulation has
demonstrated that the majority of patients with
migraine display increased reactivity of the ba-
sic EEG rhythm to intermittent photic stimu-
lation at rates ranging from 20 to 30 Hz.83'116
Augmented photic driving, however, is not
unique to migraineurs; it is seen in a large pro-
portion of non-migraineurs. The precise im-
port of the extended responses to repetitive
photic stimulation in patients with migraine is
obscure. Nonetheless, reported data about mi-
graineurs are consistent in showing that hy-
perexcitability to light may be a hallmark of the
cerebral cortex in migraineurs between attacks.
Visual Evoked Potentials
Two types of visual stimuli have been used in
visual evoked potential (VEP) studies of mi-
graineurs: flashes of bright light from a gas-
filled strobe light, and repetitive patterns, gen-
erally a checkerboard which alternates from
black-to-white. The VEPs are quantified by
measuring the latencies and amplitudes of se-
lected waveform peaks.
A number of studies show that VEPs evoked
by repetitive flash stimulation are abnormal in
migraineurs in interictal periods.19'40'69'97 The
reported abnormalities, however, vary from
study to study; accordingly, all that can be said
is that in patients with migraine, the amplitude
of some component of the flash VEP was usu-
ally somewhat greater than normal.10'14 A sim-
ple summary is impossible because differences
among the series of subjects (e.g., age, gender,
types of migraine), conditions of testing (e.g.,
wavelength, duration, luminance), and param-
Examination of the Migraineur 155
eters of recording and averaging prevent com-
parison among flash stimulation studies. More-
over, similar changes in VEPs have been re-
ported in patients with tension-type
headaches.19 There are only a few VEP stud-
ies during headaches, but most have demon-
strated reduced amplitudes during bouts of mi-
graine with aura.69'101
The latencies and amplitudes of pattern-
reversal VEPs are also said to be altered in
some patients who have migraine attacks, par-
ticularly if they have migraine with visual auras.
The frequency and type of abnormalities again
vary markedly among different series. In addi-
tion, a number of investigators have not found
any significant differences between either
adult or pediatric migraine patients and con-
trols.71-95'100'113 The reason for the variability
in results has not been investigated in detail,
but may be caused by methodological differ-
ences with regard to stimulated field, contrast,
and the spatial and temporal frequency of the
patterns used. The check size, a determinant
of the spatial frequency, may be particularly
important.84 It has been suggested that there
is an imbalance between the luminance and
contour-processing visual systems in mi-
grainean imbalance that can manifest itself
in abnormalities in VEPs if attention is paid to
parameters of stimulation.84
The EEG and Visual Evoked
Potentials in the Evaluation of
Patients with Migraine
If the data from either EEGs or VEPs consis-
tently demonstrated a marked difference be-
tween migraineurs and non-migraineurs, we
would have an extremely useful tool for deter-
mining biological abnormality. Unfortunately,
despite the reams of data, and the actuality that
many neurologists routinely order EEGs for
new patients with migraine, electrophysiologi-
cal analysis of the EEG or VEPs is of little use
in the diagnosis and treatment of individual
cases of ordinary migraine. It also is clear that
VEPs have relatively low sensitivity, specificity,
and predictive value in the diagnosis of mi-
graine.62
On the basis of the results of published stud-
ies, the Quality Standards Subcommittee of the
American Academy of Neurology has reason-
ably concluded that the EEG is not useful in
the routine evaluation of patients with head-
156 Clinical Aspects of Migraine
ache." It may be used for patients with asso-
ciated symptoms that indicate a possible sei-
zure disorder or episodic loss of consciousness.
Somatosensory and Auditory
Evoked Potentials
Although possible changes in somatosensory
and auditory evoked potentials have been re-
ported in patients with migraine, the changes
have been neither consistent nor convincing.
Suggestions that a permanent impairment of
brain stem function occurs in migraineurs have
been made on the basis of findings that audi-
tory evoked potentials were either abnormal
or asymmetric.24'94'105 Some investigations
have demonstrated a strong intensity depen-
dence of auditory evoked potentials.130 Differ-
ing changes in somatosensory evoked poten-
tials have also been found.13'20'72
Event-related Potentials
The contingent negative variation (CNV) is a
slow cortical potential recorded over the scalp
during a simple reaction-time task. The task
(usually pushing a button) is triggered by an
imperative stimulus preceded by a warning
stimulus. The CNV is recorded over the scalp
as a negative shift of EEC and can be detected
by averaging. The amplitude of the GNV is
thought to be associated with expectation, at-
tention, preparation, motivation, and readiness
to perform a task.
Most, but not all, investigations show that
the mean CNV amplitude is increased in adults
and children with migraine without aura com-
pared to normal controls or patients with tension-
type headaches (Fig. 7-2).4'7'57-70'79'104'108 It is
unchanged in patients with migraine with aura.
The increased CNV amplitude appears limited
to intervals between attacks of migraine: daily
recordings show a slow rise in negativity of the
CNV. The highest CNV amplitudes are
recorded just before an attack.5^"60 Although
the reasons for changes in the CNV are still un-
clear, it does appear to have promise as a di-
agnostic tool.
P300 (or P3) is an event-related cortical po-
tential evoked either by visual or auditory stim-
uli. It is thought to reflect cerebral activity dur-
ing sensory information processing and
analysis. Several reports about P300 in mi-
graineurs have appeared but the results are
largely contradictory.24'38'76
Habituation of Evoked and
Event-related Potentials
Deficient habituation of several evoked- and
event-related potentials has been reported in
migraineurs. For example, non-migraineurs
demonstrate habituation of the amplitude of
the VEP during sustained pattern-reversal
stimulation; migraineurs characteristically ex-
hibit a lack of habituationor even potentia-
tion.1'109 The absence of a decrement over time
might partly account for the increased ampli-
tudes reported in some VEP investiga-
tions.22'40'114 The higher mean average of th
CNV amplitude and other event-related po-
tentials in migraineurs between attacks is also
attributable to a decreased rate of habituation
over trials compared to controls.58'129 Defi-
cient habituation has also been described in the
latency of an event-related potential produced
by repetitive visual stimuli.29 Loss of habitua-
tion may be specific to migraine, as it is not
seen in patients with tension-type headaches.
Habituation is thought to protect the cere-
bral cortex against overstimulation from repet-
itive, meaningless stimuli. The cellular and psy-
chological processes intrinsic to habituation are
probably diverse and intricate, involving, as
they do, the ability of the brain to process sen-
sory information, and presumably, the activity
of different neurotransmitter systems. The pre-
cise mechanisms involved in habituation are,
however, not known. Whether a lack of habit-
uation represents a specific alteration in corti-
cal information processing in migraineurs re-
quires further investigation.
OTHER DIAGNOSTIC TESTS
Thermography
The facial thermogram of most normal, healthy
individuals is symmetrical in pattern.123 The
warmest areas are near the inner canthi and
the deep skin folds. The forehead is less warm
and the ears and nose are cooler than the rest
of the facial structures. In contrast, the fore-
 Examination of the Migraineur 157

Figure 7-2. Contingent negative variation (CNV) recording in a 24-year-old patient suffering from migraine without aura.
Both records were taken between attacks. The left-hand trace showing an increased CNV amplitude was recorded before
therapy and the right-hand trace was recorded after a 3-month course of propranolol. The tracings represent the aver-
ages of 32 trials. Note the decreased CNV amplitude after successful prophylactic therapy. (Adapted from Schoenen J
and Timsit-Berthier M: Contingent negative variation: methods and potential interest in headache. Cephalalgia 13:28-32,
1993, with permission of Blackwell Science Ltd.)

head temperature of approximately 65% to
85% of migraineurs has one of two distinctive
patterns. Either a distinct cold patcha dis-
crete region of the forehead more than 0.5C
cooler than nearby areasor a more wide-
spread area of diminished temperature located
on one side in the supraorbital region of the
forehead.37'74'121'123 Some, but not all, investi-
gators have reported that these patterns occur
in patients with tension-type headaches and
also in control subjects, but much less fre-
quently.37'123 Paradoxically, the distinctive
thermographic findings have been reported to
disappear in many patients following success-
ful treatment, and to remain unchanged de-
spite effective treatment.122'125'126
Conflicting data also exist with regard to
whether the face and scalp become cooler or
warmer during migraine headaches. A lower
facial temperature in the ipsilateral frontotem-
poral region was originally reported during uni-
lateral bouts of migraine.64'74 More extensive
observations during migraine attacks have in-
dicated that the ipsilateral frontotemporal re-
gion becomes approximately 1C warmer than
to the contralateral side. >42 The increased
temperature is significantly greater in that sub-
group of migraine patients whose head pain is
relieved by manual compression of the ipsilat-
eral superficial temporal artery.
Most, if not all, severe attacks of migraine
affect the autonomic nervous system in some
way. We see pallor, cold extremities, and the
like. But despite some provocative findings, e-
pecially with regard to the possibility of inter-
ictal asymmetric patterns, the merits of ther-
mography in the diagnosis or management of
patients with migraine remain to be demon-
strated.
Angiography
Angiography very rarely, if ever, provides in-
formation about cases of migraine useful
enough to justify the risk. When a migraineur
has a normal neurological exam and a normal
CT or MR! scan, there is little or no justifica-
tion to perform angiography. In the occasional
case when angiography is necessary, it is pru-
dent to refrain from performing the test dur-
ing an acute attack of migraine because of the
difficulty in decidingshould a neurological
deficit ensuewhether it resulted from the
procedure or was caused by the migraine at-
tack itself.
Angiograms obtained to determine the cause
of prolonged neurological defects in mi-
graineurs are generally normal, although in a
few patients, arterial branch occlusions or nar-
rowings were assumed, but not proven, to be
caused by vasospasm have been demonstrated.
A negative study, however, does not exclude
occlusion in small cerebral branch vessels not
visualized by angiography. Although different
patients have lesions in different vessels, le-
158 Clinical Aspects of Migraine
sions have been seen in all major cerebral ar-
terial trunks.12'34 Angiographic data obtained
during an attack of migraine are limited, but
are also usually reported as normal.6'45'82'92 A
few cases of carotid angiography have shown
filling of the posterior cerebral artery or upper
part of the basilar artery.118'119
Quite apart from consideration of angiogra-
phy as a diagnostic tool for migraine, an in-
creased risk from angiography has been re-
ported among migraineurs.54'90 Deterioration
of the neurological status has been seen in
some patients with complicated migraine.48
Cortical blindness that resolved over several
days has occurred following vertebral angiog-
raphy, but is also reported to occur in non-
migrainous individuals.46 Many of the compli-
cations reported in the past resulted from di-
rect carotid or vertebral arterial punctures and
the use of older and more toxic radiographic
contrast materials. Direct carotid and vertebral
arterial punctures are no longer used; accord-
ingly, the risks of angiography in migraineurs
are not believed to be higher than for patients
in the general population.115 Less serious, but
nevertheless unpleasant for the patient, is the
development of a migraine attack or aura fol-
lowing arteriographic procedures. This has
been documented, particularly after direct
puncture or catheterization of the carotid
artery.52'86 Acute attacks are also seen follow-
ing injections delivered via a catheter from the
femoral artery passed up to the internal carotid
or vertebral artery. The attack may develop
preceding the injection of X-ray contrast ma-
terial or after it. There may be a delay of about
30 to 60 minutes between carotid arterial punc-
ture and the onset of aura symptoms.
Lumbar Puncture
The cerebrospinal fluid (CSF) pressureand
the CSF itselfare almost always normal dur-
ing attacks of uncomplicated migraine.127 And
even though transiently elevated protein levels
(up to 150 mg/dl) and white blood cells
(WBCs) in the CSF have been reported in pa-
tients with complicated migraine and migrain-
ous infarction, lumbar puncture is rarely re-
quired to evaluate patients with migraine
headaches.8'56 It should be reserved for those
cases where subarachnoid hemorrhage, menin-
gitis, or encephalitis is suspected.
Neuropsychologic Testing
Some migraineurs may show evidence of cog-
nitive impairment in periods between attacks
of migraine. Such abnormalities may consist of
mild limitation of memory, difficulty with at-
tention, slower reaction times, and decreased
ability to abstract.49'55'66'80-110'135 As a result,
patients with migraine may show impairment
on batteries of standard neuropsychological
tests when compared to control individuals
without headache.49 It is undocumented if
such cognitive impairments have practical im-
plications with regard to the individual's profi-
ciency to maintain normal intellectual and oc-
cupational undertakings.
SUMMARY
The material in this chapter has been arranged
in order of importance. It cannot be stressed
too often or too emphatically that the migraine
history is the cornerstone of the entire process
of diagnosing and treating migraine patients.
Migraine is diagnosed not only through talking
about the symptoms but also through the act
of taking a detailed history, which, if done with
sensitivity and patience, begins to build an ed-
ifice of trust between patient and doctor.
Treating migraine is an interactive process. Oc-
casionally, the first medication prescribed will
eliminate a patient's symptoms, but this is not
the usual scenario. More typically the patient
will have to experiment with various life-style
changes, while the physician will have to try
different approaches. The migraineur must
have confidence in the physician, or the patient
will give up too soon, convinced that yet an-
other doctor has failed to help. The kind of
doctor-patient relationship needed to manage
a difficult case of migraine cannot begin with
a questionnaire followed by a perfunctory
exam, the ordering of a great many expensive
laboratory tests, and a hurriedly written pre-
scription. Examining a patient with migraine
takes time, patience, and understanding.
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Chapter 8
Differential Diagnosis
TENSION-TYPE HEADACHE
CLUSTER HEADACHE
Paroxysmal Hemicrania
Hemicrania Continua
HEADACHES OF CERVICAL ORIGIN
Occipital Neuralgia and Related Problems
TEMPOROMANDIBULAR JOINT
DYSFUNCTION
UNRUPTURED ARTERIOVENOUS
MALFORMATIONS AND
MIGRAINOUS AURAS
EXPANDING INTRACRANIAL LESIONS
GIANT CELL ARTERITIS
TRIGEMINAL NEURALGIA
IDIOPATHIC INTRACRANIAL
HYPERTENSION
LOW CEREBROSPINAL FLUID PRESSURE
HEADACHE WITH CEREBROSPINAL
FLUID PLEOCYTOSIS
When a patient suffers from recurrent mi-
graine attacks that consist of prodrome, aura,
headache, and postdrome, the diagnosis is
readily apparent. The diagnosis becomes still
easier if the headache is unilateral and throb-
bing, exacerbated by activity, and accompa-
nied by nausea, vomiting, and photophobia.
If close relatives have similar headaches, and
if the patient volunteers information that
headaches can be precipitated by certain di-
etary indiscretions, hormonal changes, or ex-
posure to specific environmental stimuli such
as cigarette smoke, flashing lights, or fra-
grances, clinicians can feel even more confi-
dent about making a diagnosis of migraine.
But unfortunately, migraine is a disorder with
diverse manifestations and not all attacks are
OPHTHALMOLOGICAL HEADACHES
SINUSITIS
HYPERTENSION
PHEOCHROMOCYTOMA
HEADACHES AS EMERGENCIES
Headaches Associated with Aneurysms
and Arteriovenous Malformations
Thunderclap Headaches and Crash
Migraine
Headaches Associated with Ischemic and
Hemorrhagic Vascular Disease
Carotid and Vertebral Artery Dissection
Toxic Vascular Headaches
Headaches Secondary to Meningeal
Infection
SUMMARY
textbook cases. Some patients describe an in-
complete picture that can challenge a diag-
nostician. Accordingly, for every headache
that is not a textbook case, the differential di-
agnosis must consider all conditions that
might cause symptoms comparable to those
of migraine. Quite a large number of head-
ache-producing conditions are easy to rule
out. But on occasion the clinician may find it
considerably more difficult to distinguish ten-
sion-type headache and cluster headache
from migraine, because these common con-
ditions often share characteristics with mi-
graine headaches.
An extremely important factor in making a
differential diagnosis is the duration of the
symptoms. Those who suffer from migraine,
163
164 Cinical Aspects of Migraine
tension-type, or cluster headaches have had re-
current head pain for many years. Special con-
sideration is needed for any patient who is suf-
fering from an initial headache, headaches of
relatively brief duration (i.e., a few days, weeks,
or months), a headache described as the worst
of one's life superimposed on a history of pre-
vious headaches, or a significant change in the
pattern of long-standing headaches. In any of
these situations, it is obviously of prime im-
portance to distinguish commonplace, "be-
nign" headaches from head pain that signals
danger.
The circumstances of the examination are
also germane to making a differential diagno-
sis. When a patient is initially seen during an
acute attack, the diagnoses to consider are not
the same as when the first examination occurs
during an interictal period. The former re-
quires rapid evaluation and response. A num-
ber of serious conditions such as subarachnoid
hemorrhage, meningitis, ischemic vascular
events, and arterial dissections must be differ-
entiated from an acute bout of migraine. Other
conditions such as acute sinusitis and acute
glaucoma must also be considered. One must
move quickly to rule out all serious causes for
acute symptoms. If the patient is found to be
experiencing a severe attack of migraine, ac-
tion can then be taken to relieve suffering. In
contrast, an interictal examination can be per-
formed at a more leisurely pace and appropri-
ate emphasis can be placed on a meticulous
history which, if taken carefully and thought-
fully, usually reveals those patients who are
migraineurs.
The differential diagnosis of migraine is
made by considering every cause of recurrent
head pain, together with a large number of con-
ditions that can produce repeated focal neuro-
logical symptoms or signs. One must include
headaches that mimic migraine but are actu-
ally the initial symptom of systemic or local in-
tra- and extracranial disorders. As can be seen
by the roster of conditions considered in this
chapter, the inventory can be considerable.
The focus here is on those types of headaches
relevant to the differential diagnosis of the ma-
jor subtypes of migrainemigraine with aura
and migraine without aura. For the differential
diagnosis of relatively unusual types of mi-
graine such as hemiplegic migraine, basilar mi-
graine, retinal migraine, and migrainous in-
farction, consult Chapter 4.
TENSION-TYPE HEADACHE
Migraine and tension-type headaches (muscle
contraction headaches, tension headaches, psy-
cho genie headaches, stress headaches] have
customarily been judged independent clinical
entities.97 The International Headache Society
(IHS) has formalized the distinction.48 But
many clinicians are dubious about differentiat-
ing them completely (see Chapter 1). Several
groups of researchers feel that migraine and
tension headaches may not be discrete head-
ache entities at all. It is often difficult to make
a clinical distinction, and for that reason, it may
well come to pass that future "official" classifi-
cation schemes will in some way link migraine
and so-called tension-type headaches.
A number of factors account for the diffi-
culty in distinguishing between migraine and
tension-type headaches:
1. For many patients, tension-type head-
aches appear to precede or accompany their
migraine attacks. Their bouts of head pain have
features of both tension-type and migraine
headaches (mixed headache syndrome}.
2. Many patients complain of a continuous,
diffuse, dull discomfort on which is superim-
posed periodic episodes of throbbing pain
more typical of migraine (chronic daily head-
ache syndrome; transformed migraine).74'14
3. Large numbers of migraineurs experi-
ence two distinct types of headache at separate
times: one that easily conforms to the criteria
for migraine, and one that fulfills the criteria
for tension-type headache.95
4. Patients diagnosed as having tension-type
headaches frequently have symptoms (albeit
usually of mild degree) commonly ascribed to
migrainenamely, a throbbing component of
the head pain, anorexia, nausea, phonophobia,
and photophobia.4'61'93 Frequently, however,
the nausea results from the large quantity of
analgesic medications so commonly consumed
by patients with this condition. Dizziness, light-
headedness, and fatigue are also common ac-
companiments of both migraine and tension-
type headache. Furthermore, the pain of a
tension-type headache can, at times, be aggra-
vated by routine physical activity.93
5. Medications and other therapies that
help migraineurs may also benefit some pa-
tients with tension-type headaches.
In other words, the symptoms of a surpris-
ing number of patients give rise to ambiguous

classifications.75 These caveats to viewing ten-
sion-type headache as uniquely separate from
migraine should cause diagnosticians to be
skeptical about formal descriptions of tension-
type headaches and open-minded when exam-
ining patients presumed to suffer from them.
In routine practice, the diagnosis of tension-
type headache is to some extent a diagnosis of
exclusion, based to a large extent on the lack
of symptoms that characterize other idiopathic
or symptomatic headaches.
The IHS, nevertheless, promulgates what
appear to be clear-cut criteria for tension-type
headache (Table 8-1 ).48 And to be fair, many
patients who complain about a type of head-
ache appear to meet all of these criteria. In sur-
veys of the general population in North Amer-
ica and Western Europe, the 1-year prevalence
of episodic tension-type headache varies from
approximately 30% to 80%.96 The prevalence
of chronic tension-type headaches in the gen-
eral population is 2% to 3%.98'106
Individuals with symptoms of so-called
tension-type headache regularly describe their
pain as a dull, aching sensation that feels as if
a band were constricting their head. They of-
ten explain that their scalp is too tight, and that
their head seems to be squeezed in a vise or
forced into a tight hat or headband. Pain is typ-
ically reported as bilateral; more than half the
patients claim that it involves the frontal, tem-
poral, or frontotemporal regions.37 But the
pain may extend to the occipital region, and
25% of patients provide accounts of occipital
or occipitonuchal locations as the only site of
Table 8--1. Diagnostic Criteria for
Episodic Tension-type Headache
Headache has at least two of the following
characteristics:
Pressing/tightening quality
Mild to moderate intensity
Bilateral location
No aggravation by routine physical activity
Both of the following occur during headache:
No nausea or vomiting
Either photophobia or phonophobia may occur
Normal neurological exam and no evidence of
organic disease that could cause headaches
From the Headache Classification Committee of the In-
ternational Headache Society.48
Differential Diagnosis 165
pain.63 At times, however, the pain can, like
many migraine attacks, be unilateral. Unilateral
tension-type headaches occur in between
12.5% and 20% of patients and may even be
side-locked.19'124 Tension-type headaches may
even involve a localized area of the head. In
other words, although a majority of patients
have bilateral pain in the frontal and/or tem-
poral area, location of the pain does not by it-
self identify this type of headache. Moreover,
there may be multiple sites of pain that vary
from headache to headache.124 Some individ-
uals with this type of headache complain of
stiffness and tightness in the muscles of their
necks, a common complaint in migraine as
well. Neck discomfort often extends to the
shoulders, involving the trapezius and even the
upper back muscles. Scalp tenderness is fre-
quently noted when combing or brushing hair.
In addition, a sensation of tightness and aching
in the face is a common complaint.
The pain characteristically waxes and wanes
throughout the entire day and varies from day
to day. According to IHS criteria, the pain is
mild to moderate in severity, although more
than 40% of patients report interference with
their normal activities. 3 Between 10% and
15% experience severe pain.38'94'106 It is not as
intense as the pain associated with the usual
case of migraine that brings a patient to a physi-
cian, and it is rarely severe enough to awaken
a person from sleep. Patients generally de-
scribe tension-type headache pain as a steady
ache or cramp, even though a throbbing com-
ponent occurs in approximately one-quarter of
patients.61 But unlike the pain that character-
izes migraine headaches, routine physical ac-
tivity exacerbates the discomfort in only ap-
proximately one-third of patients.63'70'93
Examination during a headache episode may
not reveal any abnormalities. Tenderness of
pericrania! muscles, however, is a common
finding, and appears similar to that seen dur-
ing a migraine attack.14'62 Passive and active
movements of the neck may be somewhat lim-
ited as a result of cervical muscle contraction.
Tension-type headaches can be episodic
(acute) or chronic. Episodic tension-type head-
aches are extremely common, consisting of re-
current bouts of headache that can last from
minutes to days. These headaches are custom-
arily mild and are typically relieved by over-
the-counter analgesics. Most patients do not
seek medical attention, nor do they lie down in
166 Cinical Aspects of Migraine

Figure 8-1. Distribution of subjects with chronic daily headache according to their reported age at onset of chronic ten-
sion-type headache (CTTH) and transformed migraine (TM). The age of onset of transformed migraine was significantly
lower than that of chronic tension-type headache. The data were obtained from subjects in an unselected population.
(Adapted from Castillo J, Munoz P, Guitera V, and Pascual J: Epidemiology of chronic daily headache in the general pop-
ulation. Headache 39:190-196, 1999, with permission.)

quiet, dark rooms. As is the case with mi-
graineurs, patients with episodic tension-type
headaches ordinarily begin to suffer from them
in adolescence or early adulthood. Episodic
tension-type headaches characteristically occur
once or twice monthly.41'106
In contrast to episodic bouts, chronic
tension-type headache is unremitting. The pain
has the clistinction of being continuous for ex-
tended periodsfor weeks, months, years, or
even decades. It is noteworthy that many of the
patients who develop chronic tension-type
headaches begin as sufferers from intermittent
attacks of migraine. The age of onset of trans-
formed migraine is significantly lower than that
of chronic tension-type headache (Fig. 8-1 ).15
After a period of years of intermittent, but re-
current headache, they develop continuous
pain with the characteristics of a tension-type
headache. Again, as with migraine, women are
afflicted with the problem more than men.
The symptom that brings patients who pre-
sumably suffer from tension-type headaches to
the doctor is probably the frequency or un-
remitting nature of the pain rather than its
severity. In contrast, migraineurs with infre-
quent attacks often seek treatment if those in-
frequent attacks are very intense, whereas mi-
graineurs with very frequent attacks may never
see a physician if their attacks are less severe
and respond reasonably well to over-the-
counter analgesics. The plethora of advertise-
ments that focus on pounding headaches that
upset one's stomach may lead many mi-
graineurs to believe that such headaches are a
normal part of life. Unless the bouts signifi-
cantly interfere with functioning, this latter
group may never mention them to a doctor or
may dismiss them during routine physicals. In
other words, physicians in most clinical situa-
tions may be basing their distinctions between
migraine and tension-type headaches on a
skewed population: migraineurs who have se-
vere attacks versus sufferers from tension-type
headaches who have far less severe, but very
frequent attacks. If there were some way to fac-
tor in migraineurs who experience mild to
moderate pain, we might find it far more dif-
ficult to distinguish these two afflictions.
In sum, the most striking difference between
patients with chronic tension-type headache
and most migraineurs is that the former have
daily headachesa pattern of suffering that
distinguishes them from migraineurs who en-
dure clear-cut, severe, but discrete recurrent
attacks of migraine. Some cases of episodic
tension-type headache, however, can be ex-
ceedingly challenging to differentiate from mi-

graine without aura, perhaps because they ap-
pear as different points on a single spectrum
rather than different types of headache. After
all, both groups of headaches may be recur-
rent, of long duration, non-throbbing, bilateral,
and of mild-to-moderate intensity. To compli-
cate matters, either type can have throbbing
pain. Both types can have associated nausea,
photophobia, and phonophobia. Both can be
associated with stiffness and tenderness of neck
and shoulder musculature and with pericrania!
tenderness. At the extremes of the spectrum,
migraine is easy to differentiate from tension-
type headache. When the symptoms are more
similar or overlap, the clinician may be pre-
sented with a challenge.
CLUSTER HEADACHE
Cluster headache (migrainous neuralgia, Nor-
ton's headache, histaminic cephalgia, spheno-
palatine neuralgia, Vidian neuralgia, Sluder's
neuralgia} derives its name from the unique
pattern of headaches: frequent attacks are clus-
tered together for weeks or months at a time,
but are separated by remission periods that
usually last months or even years. The clusters
of headaches vary in duration, usually for a
month or two, although some continue for 3
months or even longer.58'111 Most patients
have one cluster of attacks per year. About 10%
of patients suffer from chronic symptoms with-
out any periods of remissionfor them, "clus-
ter headache" is a cruelly inaccurate designa-
tion.
During a cluster period, one or more attacks
can occur daily.71 In most cases, the frequency
ranges to as many as three per day, although a
patient may be symptom-free for 2 or 3 days
in a row. Some more unfortunate patients may
have seven or eight bouts of head pain in a 24-
hour period. Attacks can occur at any time of
the day or night; nocturnal events are fre-
quent.101 A typical attack lasts from 15 minutes
to 3 hours. There is a predilection among
women for the longer attacks to occur.58 In
contrast to migraine, only exceptionally does a
bout of cluster last longer than 3 hours. How-
ever, documentation does reveal a range from
between 5 minutes and 2 days.45'116
The description of a cluster headache differs
markedly from that of a migraine headache
(Table 8-2). The pain is customarily of a non-
Differential Diagnosis 167
Table 8-2. Diagnostic Criteria for
Cluster Headache
At least 5 attacks
Severe, unilateral orbital, supraorbital, and/or
temple pain that lasts for 15 to 180 minutes
Headache is associated with at least one of the
following signs:
Conjunctival injection
Lacrimation
Nasal congestion
Rhinorrhea
Forehead and facial sweating
Miosis
Ptosis
Eyelid edema
Frequency of attacks from one every other day
to eight per day
Normal neurological exam and no evidence of
another organic disease that could cause
headaches
From the Headache Classification Committee of the In-
ternational Headache Society.48
pulsating type and reaches its maximum sever-
ity in 5 to 10 minutes. It is typically specified
as "deep": but patients use terms such as "bor-
ing," "squeezing," "pressing," "lancinating,"
"searing," "burning," "stabbing," "tearing," or
"piercing." The intensity of pain is excruciat-
ing, usually said to be unbearable. It is consid-
ered much more severe than the pain of a typ-
ical migraine attack.
Cluster headache pain is unilateral in loca-
tion. For a small number of patients, the side
may change from one cluster period to another
and, exceptionally, there are shifts from one
side to the other during a single cluster pe-
riod.58 The pain most often affects an area in
and around the orbit or the temple, although
it may begin in the face.71 The pain may spread
to neighboring cranial and cervical regions
such as the frontal area, cheek, mandibular an-
gle, upper jaw, roof of the mouth, teeth, back
of the neck, suboccipital area, and the front of
the neck along the course of the carotid
artery.58 Occasional patients find that the pain
affects the ear and the ipsilateral shoulder and
arm. Patients have been described in whom
pain was confined to cervico-occipital re-
gions.102 Patients may note some residual sore-
168 Cinical Aspects of Migraine
ness that can persist in the area affected by the
pain for some time after an attack.
The pain is characteristically accompanied
by supplemental symptoms and signs that in-
dicate involvement of the autonomic nervous
system on the side of the head.24 These phe-
nomena include conjunctival injection, lacri-
mation, nasal congestion, rhinorrhea, forehead
and facial sweating, miosis, ptosis, and eyelid
edema. Some patients also develop symptoms
commonly seen in migraineurs. Thus, photo-
phobia can accompany attacks of cluster, al-
though there is considerable disagreement
about its frequency, reportedly between 5%
and 72%.58 Nausea can also occur, but again,
there is no accord about the frequency (5.5%
to 54%).58>71 Vomiting is rare. The only focal
neurologic manifestation of cluster headache is
Homer's syndrome. This is generally transient,
but after repeated attacks it may become per-
manent.80 The neurological examination is oth-
erwise normal.
The behavior of most patients during a clus-
ter headache is very different from that of pa-
tients with migraine. Migraineurs typically wish
to lie still in a quiet, dark room. Patients in the
throes of a cluster headache are typically rest-
less. They usually cannot bear to lie or sit still;
instead they pace or walk about. Some patients
are frankly agitated and may moan, cry, or even
scream.71 They have even been known to bang
their heads against walls.
Cluster headaches may develop at any age,
but the onset is generally in the second or third
decades of life.58 They are seen in children and
an onset after age 65 is not uncommon.57 In
contrast to migraine, between 70% and 93% of
patients are men, but the incidence in women
appears to be increasing.111 Cluster headache
and migraine may coexist in the same pa-
tient.1'1^114 In general, migraine typically
emerged before cluster headache did, but it
may or may not remain after the onset of clus-
ter headache.
Many men afflicted with cluster headaches
have distinctive facial features.46 Hazel eye
color is common. The skin on their faces is
characteristically thick, coarse, and markedly
wrinkled, especially on the forehead. Often the
facial skin in the malar regions has a pitted peau
d'orange (orange peel) appearance or is telang-
iectatic. A plethoric appearance may be pres-
ent. The men frequently have broad chins and
skulls. These facial characteristics have been
designated "leonine".46 In addition, the pa-
tients are often tall, well built, and athletic in
appearance.
In the vast majority of cases, cluster head-
ache is easy to differentiate from migraine, pro-
vided one takes an adequate history. Although,
like migraine, nausea and photophobia can ac-
company cluster headaches, most clinicians re-
port these as infrequent occurrences. Other
characteristics provide a clear contrast between
the two. The unique temporal pattern of at-
tacks, the severity of the pain, the behavior of
patients during attacks, the obvious involve-
ment of the autonomic nervous system, and of-
ten the patient's appearance, should readily al-
low one to make the diagnosis of cluster
headache. But all to often appropriate ques-
tions about these phenomena are not asked,
and the patient goes misdiagnosed.
Paroxysmal Hemicrania
Paroxysmal hemicrania is a rare disorder. At-
tacks have pain characteristics and associated
autonomic symptoms and signs that are simi-
lar to those of cluster headache.110 Paroxysmal
hemicrania differs from cluster headache, how-
ever, in the shorter duration and greater fre-
quency of the attacks. Bouts of paroxysmal
hemicrania generally last between 5 and 30
minutes, and occur with a frequency greater
than five a day. They may return as a often as
30 times in a day.2 In contrast to cluster head-
aches, women are more frequently affected
than men. Most cases are chronic (chronic
paroxysmal hemicrania), although some pa-
tients have episodic hemicrania.8 Indometh-
acin produces a dramatic response in all cases,
and is therefore used as therapeutic confirma-
tion of the diagnosis.
Hemicrania Continua
Hemicrania continua is characterized by a con-
tinuous headache of moderate intensity.79 In
almost all patients, the pain is unilateral and
usually does not shift sides. Superimposed on
the continuous baseline pain, described as a
steady ache or a throbbing sensation, are re-
curring attacks of ipsilateral severe, pounding
head pain that can last from less than an hour
to several days. These headaches are often ac-

companied by nausea, vomiting, and photo-
sensitivity. The exacerbations may be triggered
by exertion or by alcohol. Nocturnal attacks are
common. In addition, some patients experi-
ence daily recurring idiopathic stabbing head-
aches ipsilateral to the hemicranial dull ache,
often only during exacerbations. Autonomic
phenomena such as lacrimation, conjunctiva!
injection, nasal congestion, rhinorrhea, ptosis,
or eyelid edema are usually present, but are
less prominent than those seen in patients with
cluster headache. A rapid response to in-
domethacin is considered necessary to make a
diagnosis.
Hemicrania continua could be mistaken for
migraine. Migraine is frequently unilateral and
does not alternate sides in about one-fifth of
patients.19'66 Both hemicrania continua and
migraine are more common in women and
have a comparable age of onset. The distribu-
tion of pain is similar in both conditions, with
a predominance in the forehead and temple.
Nausea and photophobia are common in both
and they share trigger factors that include al-
cohol, exertion, stress, odors, and chocolate.12
However, the history of unilateral pain with su-
perimposed episodes of more severe pain ac-
companied by autonomic phenomena as well
as the rapid response to indomethacin should
make the diagnosis of hemicrania continua
apparent.
HEADACHES OF
CERVICAL ORIGIN
Chapter 5 includes a discussion of how pain in
the cervical region could precipitate bouts of
migraine in persons already vulnerable to the
disorder. Migraine can be triggered by cervi-
cal spine disease, myofascial syndromes that
involve the musculature of the neck and shoul-
ders, or whiplash injury. In addition to trig-
gering migraine attacks in susceptible individ-
uals, any person affected with degenerative or
traumatic disease of the upper cervical spine
or with a myofascial syndrome may develop as-
sociated, but non-migrainous, head pain.3"
Which of the various structures in the neck
is the source of the pain remains a matter of
dispute. Many individuals with extensive de-
generative alterations in the cervical spine do
not suffer from head pain, while others af-
Differential Diagnosis 169
flicted with unrelenting, severe pain in the
head have only minor changes observed on
imaging studies. Accordingly, it is sometimes
difficult to assert that a headache does, in fact,
emanate from the neck. Nonetheless, head-
aches associated with disorders of the neck
have a number of properties that point to a
source in the cervical spine or in surrounding
soft tissues.5 Among these symptoms are:
1. Protracted neck and suboccipital or oc-
cipital pain
2. Localized neck tenderness
3. Trigger points in the neck muscles
4. A relationship between the headache and
neck movement, specific cervical maneu-
vers, or sustained neck posture
5. Resistance to, or restriction of, cervical
movements
6. Abnormal postures of the head and neck
7. Intensification of the pain by deep, sub-
occipital pressure
8. Evidence from physical or radiological
examination of degeneration, or of injury
to the cervical vertebrae or soft tissues.
Patients with cervical spondylosis or disc dis-
ease in the upper cervical spine often experi-
ence pain in their necks, shoulders, and heads,
as do patients with anomalies or humors of the
craniovertebral junction, cervical canal steno-
sis, and cervical spine neoplasms. Those who
suffer with pain from one of this group of dis-
orders typically have abnormal findings on neu-
rological examination.
How frequently benign, recurrent head-
aches occur with cervical disorders is contro-
versial.26-81 Two types of headache are of
cervical origin: cervicogenic headaches and
non-specific headaches of cervical origin.
Cervicogenic headaches have been de-
scribed and analyzed in detail by Sjaastad and
by others.89 These authors consider cervico-
genic headaches a clear-cut entity character-
ized by strictly unilateral, frontotemporal head-
aches.35'112'113 According to their explicit
criteria, all episodes in an individual are con-
fined to the same side of the head.35'113 The
pain is persistent, but superimposed bouts of
increased pain lasting hours to days vary its
severity. The autonomic nervous system may
be involved with lacrimation, conjunctiva! in-
jection, and rhinorrhea on the side of the head-
ache. During severe attacks, phenomena usu-
ally associated with migraine such as nausea,
vomiting, phonophobia, and photophobia can
170 Cinical Aspects of Migraine
Table 8-3. Symptomatic
Characteristics of Cervicogenic
Headache: The Consensus from
the Literature
Mandatory Features
Unilateral headache or unilateral headache with
spread to the other side
Side consistency; does not change sides within or
between headaches
Associated suboccipital, neck, or neck-shoulder
pain
Pain initiated in the neck with spread to the head
Headache episodes of varying duration; no
consistent temporal pattern
Mild-to-moderate intensity of headache; non-
excruciating; usually non-throbbing
Additional Features
Headaches have a mechanical precipitant (e.g.,
prolonged or awkward head or neck postures or
neck movements)
History of neck injury (e.g., whiplash or
accumulation of minor trauma as in prolonged
static working conditions)
Data from JuU (1998).55
develop. Signs and symptoms of cervical in-
volvement such as neck stiffness, pain, and re-
stricted range of motion are customary. Ipsi-
lateral shoulder, arm, or hand pain can also be
present. Attacks of head pain can be elicited
by particular movements of the head or neck
or by palpation of specific tender areas in the
neck and occipital region.35 A history of head
or neck trauma is common. These symptomatic
characteristics of cervicogenic headache have
recently been summarized by Jull (Table
83).55 The diagnosis is confirmed by local
anesthetic blockade of the cervical zygap-
ophysial joints or the C2/C3 nerve roots.
Nonspecific headaches of cervical origin
have no exclusive features to differentiate them
from headaches such as migraine without aura,
head pain caused by intracranial pathology, or
chronic tension-type headaches with pericra-
riial tenderness.27'53'54 Because of a connection
with symptoms that include neck discomfort,
stiffness, or pain, a cervical source is presumed.
A history of cervical trauma is often elicited.
These headaches are generally bilateral, but
can be asymmetric or even unilateral. The pain
is often felt in the occiput and subocciput, or
as frontal or retro-orbital pain that originates
in the occiput, subocciput, or neck.54 It can also
be referred to the forehead, orbits, or temples.
The headaches are either daily and uninter-
rupted with fluctuations in severity, or episodic
at frequent intervals. Most often, patients ex-
perience dull, aching discomfort, which is eas-
ily confused with tension-type headaches.
Some few patients have throbbing headaches
that may be misconstrued by the unwary as mi-
graine. The presence of cervical symptoms,
however, should clarify the diagnosis.27'53'54
The structures in the neck responsible for
headaches have not been identified with cer-
tainty, but head pain has been acknowledged
to originate from conditions located in myo-
fascial and articular tissues of the neck.11 Two
principal postulates have been proposed for
headaches generated from cervical structures:
1. Headaches of cervical origin are caused
by pain referred from active trigger points in
cervical muscles that receive their sensory in-
nervation from Cl to C3.21'44>5 Trigger points
in the small cervico-occipital muscles, the
semispinalis capitis, the splenius capitus, the
splenius cervicis, the trapezius, and the sterno-
cleidomastoid muscles refer pain to various re-
gions of the head.36'109'123 Both between and
during bouts of headache, active trigger points
can often be found in the neck and shoulder
musculature of patients whose putative diag-
nosis is headache caused by cervical pathol-
ogy.32'35'50 Pressure on these trigger points can
duplicate or initiate headache, and inactivation
of trigger points can often eliminate such head-
aches.32-8*113
2. Headaches of cervical origin are caused
by joint dysfunction involving the upper cervi-
cal synovial joints. Neck and head pain is as-
sumed to arise from arthropathy of the median
and lateral atlanto-axial, the atlanto-occipital,
and particularly the C2/C3 and C3/C4 cervical
zygapophysial joints.10 The articular pathology
is unspecified. In support of this postulate is
the fact that local anesthetic blockade of the
cervical zygapophysial joints or the C2/C3
nerve roots diminishes headaches and neck
pain in many, but not all, patients.89
Because the distribution of head and neck
pain produced by both trigger points in cervi-
cal and shoulder muscles and cervical joint
problems is similar, the above two proposals
for the origin of headaches are not mutually ex-

elusive. The muscles and the joints implicated
in the process share the same segmental nerve
supply.
Occipital Neuralgia and
Related Problems
In the pathogenesis of headache, the role of
the greater occipital nerve (or its parent dorsal
rami) is problematic. A number of syndromes
implicating the occipital nerve have been re-
ported, but occipital nerve involvement as a
primary cause of headache is uncommon. Oc-
cipital neuralgia is characterized either by
paroxysmal or continuous, unilateral, burning
or stabbing occipital pain that often radiates to
the frontal region.9'39^ The episodes of pain are
sometimes accompanied by a dull, persistent
ache. Patients can have hypoalgesia, hyperal-
gesia, or dysesthesias in the distribution of the
greater occipital nerve and circumscribed ten-
derness over the nerve as it crosses the supe-
rior nuchal line. Infiltration of the nerve with
local anesthetic relieves the pain. Myofascial
trigger points in suboccipital muscles, however,
can also cause occipital pain and may produce
a clinical picture that closely mimics the symp-
toms of occipital neuralgia.39'43 Occipital neu-
ralgia is thought to be caused by trauma, in-
jury, inflammation, or compression of the
occipital nerve somewhere along its course
from the C2 dorsal root to the periphery.
TEMPOROMANDIBULAR JOINT
DYSFUNCTION
Disorders of the temporomandibular joint
(TMJ) and the associated muscles of mastica-
tion are recognized as major sources of orofa-
cial pain and headache.42 Temporomandibular
joint pain and dysfunction result from two dis-
tinct entities: oromandibular dysfunction and
TMJ disease. Oromandibular dysfunction (myo-
fascial pain-dysfunction syndrome, temporo-
mandibular joint pain-dysfunction syndrome,
Costen's syndrome, craniomandibular dys-
function) is primarily associated with pain of
myofascial origin. One or more trigger points
are present in the muscles of mastication. A
number of etiologic components have been im-
plicated in the production of trigger points in
Differential Diagnosis 171
these muscles. Among them are psychophysi-
ologic factors such as stress and depression,
malocclusion, misalignment of the jaws, habit-
ual parafunction of the jaws (clenching and
grinding of teeth, bruxism, fingernail biting,
jaw posturing, frequent gum chewing, cheek
biting), and abnormal head and neck posture.
The other TMJ disorder is temporomandibu-
lar joint disease, caused by organic, intra-
articular pathology such as internal derange-
ments of the articular disk, degenerative joint
disease, traumatic or congenital lesions, in-
flammation, or other organic diseases that
cause ankylosis and chronic dislocation. In
addition, prolonged pathophysiologic distur-
bances of the muscles of mastication with per-
sistent muscle spasm or continuous jaw func-
tion with the condyle in an abnormal position
may cause degenerative, structural changes in
the TMJ.
The following signs and symptoms may be
present in either form of TMJ dysfunction:
1. Recurrent pain in the region of the TMJ.
The pain may be localized in the preauricular
area, the mandible, or in the muscles of mas-
tication. The latter muscles may feel tight af-
ter prolonged chewing. Patients often com-
plain of deep ear pain, or of pain spreading
throughout the maxilla and mandible. Some in-
dividuals also experience neck pain and stiff-
ness. The pain is frequently bilateral, but can
occur on only one side of the face or in only
one temple. Wherever the pain is located, how-
ever, it is usually of moderate intensity, de-
scribed as a persistent, dull ache that often has
a boring or gnawing quality. The pain seems to
develop spontaneously, but is usually aug-
mented by chewing, talking, or yawning. Its
time of day variessome individuals endure
their most intense pain in the morning, others
in the afternoon, and still others have no fixed
pattern.
2. Muscle tenderness upon palpation. In
particular, the masseter, temporalis, lateral
pterygoid, sternocleidomastoid, and other neck
muscles are involved.
3. Tenderness in the TMJ.
4. Limited interincisal opening as a result of
muscle spasm and fatigue, or as a result of a
displaced joint meniscus. The inability to open
the jaws can vary from a limitation of only a
few millimeters to an almost complete inca-
pacity to separate the teeth. An opening of less
than 40 mm is judged abnormal.
172 Cinical Aspects of Migraine
5. Lateral deviation of the jaw from the mid-
line during opening and closing. The shift of
the mandible from the midline as the jaw opens
and closes can range from a barely detectable
deviation to several millimeters.
6. Clicking of the joint during movement.
Because 35% to 40% of normal adults have
clicking sounds in the TMJ, this finding can
only be used as a secondary diagnostic crite-
rion. If no other symptoms are present, indi-
viduals with joint sounds require no treatment.
7. Locking of the jaw.
Other symptoms include tinnitus or other
vague ear symptoms, and a sensation that one's
bite is different. In addition, somatic and emo-
tional changes are often associated with TMJ
dysfunction. Patients frequently complain of
altered sleep patterns, fatigue, anxiety, and de-
pression. In sum, the typical location and char-
acter of the pain and the findings on examina-
tion of the jaw, together with the absence of
nausea, vomiting, photophobia, and other usual
symptoms, should be sufficient to differentiate
temporomandibular joint dysfunction from mi-
graine.
UNRUPTURED
ARTERIOVENOUS
MALFORMATIONS AND
MIGRAINOUS AURAS
The prevalence of migraine among patients
with arteriovenous malformations (AVMs) is
controversial. Although it is not often that one
finds vascular headache accompanied by auras
of the migrainous type as the sole manifesta-
tions of an AVM, some investigators consider
migrainous auras to be frequent symptoms of
occipital AVMs; others consider the relation-
ship between migraine and AVMs nothing
more than coincidental.13'47'76'83'119 When vi-
sual phenomena do occur in a patient with an
AVM, they do not usually conform to the pat-
tern, timing, appearance, and development ex-
pected of typical migrainous scintillations.59'119
The auras may follow the onset of headache,
may be either fleeting or excessively prolonged,
and/or they may be restricted to a particular
part of the visual field rather than spreading
progressively across the visual field as they do
before a migraine headache.87 In other words,
although migraine and AVMs may coincide,
more often they can be distinguished if a care-
ful history is taken and a careful examination
performed. Interestingly, convincing bouts of
migraine with aura have been reported to cease
after excision or radiosurgical treatment of oc-
cipital AVMs, leading one to speculate that in-
deed there are unusual AVMs that cause auras
that satisfy IHS criteria.60'118
EXPANDING INTRACRANIAL
LESIONS
Expanding intracranial lesionstumors, ab-
scesses, or hematomascommonly produce
headaches. Individuals with primary brain tu-
mors report headaches as their primary symp-
tom about 25% to 35% of the time, and the
overall incidence of headache in patients with
primary and meta-static tumors has been re-
ported to be as high as 70%.117'126 The fre-
quency of headache in patients with brain tu-
mors is increased when there is a prior history
of headache.34 Many of these patients consider
their brain tumor headaches identical to their
preexisting headaches. Most brain tumors,
however, call attention to themselves by other
symptoms whose prominence may mask the ac-
companying headache. If emphasis is placed on
those patients whose intracranial lesions cause
head pain, one usually finds it to be both mod-
est and transitory or episodic in nature. Some
patients do experience persistent pain, but it is
relieved by over-the-counter medications in
about one-half the cases. Once the medication
wears off, the head pain typically recurs. Other
patients do have more substantial discomfort,
although rarely is it as intense as the head pain
associated with a severe bout of migraine.100
Headaches associated with intracranial masses
typically increase in frequency and severity in
parallel with the focal or generalized neuro-
logical symptoms produced by the enlarging
mass. If obstructive hydrocephalus with in-
creased intracranial pressure develops, the
headache may become very severe and resis-
tant to ordinary analgesics.
The headache associated with intracranial
lesions usually has a deep, aching, steady, dull
character. The classical tumor headache is de-
scribed in textbooks as intensified by bending,
coughing, or straining, and is sometimes more
severe in an erect than in a recumbent posi-

tion. The textbook definition also has the head-
ache occurring in the early morning. And al-
though the pain may be worse in the early
morning for some patients, even awakening
them from sleep, most patients experience
their headaches at any time during the day or
night.34'49'100 Pain may be localized anywhere
about the head. Supratentorial masses tend to
produce frontal or temporal head pain,
whereas lesions in the posterior fossa charac-
teristically cause occipitonuchal pain. When
the headache is occipital or suboccipital, it is
occasionally associated with stiff or aching neck
muscles, and tilting of the head toward the side
of the tumor. Unless the pain is severe, nausea
is usually slight. Because of the posterior loca-
tion of many childhood tumors which displace
or compress the medulla, vomiting is not in-
frequent.49
A mass that produces abrupt increases in in-
traventricular pressure can result in episodic
headaches that can be confused with migraine
without aura. Colloid cysts, intraventricular
meningiomas, choroid plexus papillomas, and
other intraventricular tumors can all generate
this clinical picture. These lesions can produce
sudden, intense, bilateral headaches of great
severity accompanied by nausea and vomiting,
weakness of the legs, and possibly loss of con-
sciousness. In a minority of cases, the pain is
said to be both precipitated by, and relieved
by, changes in posture.68'82 Vision may be
blurred owing to the acute rise in intracranial
pressure. Gait disturbances and papilledema
sometimes occur. When these latter group of
symptoms is present, there is no reason to con-
sider migraine in the differential diagnosis.
Except for the masses mentioned in the
previous paragraphthose that produce
abrupt increases in intraventricular pressure
intracranial lesions do not usually cause
episodic headaches that could be confused
with migraine with or without aura. Despite
this general pattern, case reports have ap-
peared that describe brain tumors and other
forms of intracranial lesions mimicking mi-
graine.69'84-86'99'105 The articles report mi-
grainous auras in patients with occipital lobe
tumors, pituitary tumors, tumors of tile lateral
and third ventricle, and parasagittal tumors.
Such cases are exceedingly rare. Clinical de-
scriptions of their visual phenomena are so lim-
ited that it is difficult to determine whether the
symptoms actually do resemble migraine
Differential Diagnosis 173
auras.16'23'104 While some descriptions fulfill
the IHS criteria for migraine, head pain caused
by intracranial masses is invariably of recent
onset.85'120 Differential diagnosis of this latter
group, then, seems to depend upon the mi-
graineur's usually long-standing history of
headache.
GIANT CELL ARTHRITIS
Giant cell arteritis (temporal arteritis) is an
inflammatory disease of the cranial arteries
whose most common symptom is headache. In
contrast to migraine, which most frequently
develops before the age of 40, this condition
almost always occurs in individuals older than
50 years. Like migraine, it affects women more
frequently than men. About three-quarters of
patients have scalp arteries (usually the super-
ficial temporal artery) that are exquisitely ten-
der to pressure, and that are swollen and cord-
like to palpation. Impressive redness and
swelling may overlay the branches of the su-
perficial temporal artery. In addition, pulsation
may be absent in distal branches, although it is
usually possible to feel a pulse in the main
trunk of the temporal artery.
The pain of giant cell arteritis is frequently
felt in tile scalp, especially over inflamed ves-
sels. It usually involves one or both temporal
regions, although it can occur in any region of
the head.115 No specific quality characterizes
the pain of this disease: it may be aching, throb-
bing, burning, boring, or sharp, and may be
mild or severe. Patients also report ice-pick
pains. Throbbing may be present at first, but
this symptom typically attenuates, or even
ceases, after the early phase of the disease.
Some patients describe a burning sensation
a feature most unlike other headaches that in-
volve blood vessels. The headache of giant cell
arteritis may be persistent or intermittent, but
whatever form it takes, without treatment the
headache tends to progress steadily over a pro-
longed course of months.
Visual loss can be an initial symptom of tem-
poral arteritis. Most often, however, visual
symptoms appear later in the course of the ill-
ness. When they do develop, it is with rapid-
ityover a period of minutes to hours. Their
usual cause is ischemic damage to the optic
nerve and retina on one or both sides. Older
studies reported that visual loss in untreated
174 Cinical Aspects of Migraine
Table 8-4. Diagnostic Criteria for
Giant Cell Arteritis
One or more of the following:
Swollen and tender scalp artery
Elevated erythrocyte sedimentation rate (ESR)
Disappearance of headache within 48 hours of
steroid therapy
Temporal artery biopsy showing giant cell
arteritis
From the Headache Classification Committee of the In-
ternational Headache Society.48
patients had a frequency up to 50%. More re-
cent investigations usually report the incidence
to be much lowerbetween 7% and 21%. The
reduction in frequency is presumably a func-
tion both of earlier diagnosis and of effective
treatment.
Polymyalgia rheumatica is frequently associ-
ated with, or antedates, giant cell arteritis.31
About half the patients with giant cell arteritis
have polymyalgia rheumatica, and about 15%
to 20% of cases of polymyalgia rheumatica
have or develop giant cell arteritis. Systemic
signs and symptoms such as low-grade fever,
malaise, anorexia, fatigue, night sweats, and
weight loss may be part of the clinical picture.
Patients with polymyalgia rheumatica also
complain of aching and morning stiffness that
can affect the shoulders and upper arms, neck
and torso, and hips and thighs. Their muscles
may be tender, and sometimes slightly weak.
Atrophy, however, is unusual. These systemic
symptoms may precede the headache of giant
cell arteritis by several months.
Another muscular problem that has been
linked to temporal arteritis is jaw claudication.
It consists of ischemic pain felt in the mastica-
tory muscles when the patient chews; the pain
is relieved by rest. A history of jaw claudication
is unusual among the general population, but
is almost pathognomonic of giant cell arteritis.
Typically, the erythrocyte sedimentation
rate (ESR) is strikingly elevated during the ac-
tive phase of temporal arteritis. The mean el-
evation is 100 mm/hour. But 30% of cases have
an ESR below 40 mm/hour. Well-documented
cases of giant cell arteritis with normal ESRs
have also been seen.125
In sum, giant cell arteritis can be clinically
differentiated from migraine by several factors:
advanced age of onset, the constant and usu-
ally progressive nature of the head pain, find-
ings of inflammation of the temporal artery,
frequent history of systemic symptoms, and,
frequently, elevated ESR. Confirmation is ob-
tained by histopathological examination of bi-
opsy material from the temporal artery. When
treated with steroids, the headache of giant
cell arteritis usually recedes within 48 hours
(Table 8-4).
TRIGEMINAL NEURALGIA
Trigeminal neuralgia (tic douloureux) is char-
acterized by brief episodes of severe, jabbing
pains that radiate through the mandibular or
maxillary divisions of the trigeminal nerve.
Trigger zones are typically located around the
nares and the mouth, prompting an attack
when excited by even trivial stimuli. The char-
acteristic temporal pattern of attacks makes
them easily distinguishable from migraine.
IDIOPATHIC INTRACRANIAL
HYPERTENSION
Headaches that are occasionally difficult to dif-
ferentiate from migraine can be caused by id-
iopathic intracranial hypertension (pseudotu-
mor cerebri, benign intracranial hypertension,
otitic hydrocephalus, serous meningitis, menin-
geal hydrops], which is characterized by in-
creased intracranial pressure in the absence of
focal lesions, hydrocephalus, intracranial infec-
tion, or hemorrhage. l
Almost all patients with idiopathic intracra-
nial hypertension complain of headache. Al-
though the headache is usually generalized,
some patients suffer from bitemporal, occipi-
tal, or even unilateral headaches. Frequently
it is retroocular in location. The character of
the head pain also varies. In general, the pain
is constant and relatively mild, but many pa-
tients complain of throbbing head pain. But
whichever kind of pain a patient suffers from,
it is intensified by activities that raise intracra-
nial pressure, such as exertion, coughing, or
straining. In addition, the pain is frequently ac-
companied by nausea and vomiting. Patients
often complain of intense headaches upon
awakening. In view of this range of symptoms,
patients who give a history of throbbing head-

ache with nausea and vomiting may appear to
be migraineurs, when, in fact, idiopathic in-
tracranial hypertension is the cause of the
symptoms. The question, then, is how does the
clinician differentiate the former from the lat-
ter?
Most patients with idiopathic intracranial hy-
pertension have an additional symptom that
distinguishes their condition from migraine,
namely, gradually diminishing vision. This re-
sults from compression of optic structures, so
that restricted peripheral visual fields, enlarged
blind spots, visual blurring, and transient visual
obscurations are produced. Papilledema is
usually, but not always, present on funduscopic
examination. One even sees hemorrhages and
exudates in untreated cases. Except for pa-
pilledema and transient abducens palsy that
may be bilateral, the neurologic exam is oth-
erwise normal (Table 8-5).
The cerebrospinal fluid (CSF) pressure is el-
evatedusually in the range of 250 to 450 mm
of water. Although rare cases have normal rest-
ing CSF pressures, continuous monitoring
demonstrates transitory elevations of CSF
pressure, even when there is no activity or
straining. The CSF does not have any chemi-
cal or cellular abnormalities. For a diagnosis of
idiopathic intracranial hypertension to be
made, neuroimaging studies should reveal no
evidence of a mass lesion, of ventricular en-
largement, or of venous sinus thrombosis.
Sometimes, however, the differential diag-
nosis may be difficult. Preexisting migraine
Table 8-5. Diagnostic Criteria for
Benign Intracranial Hypertension
Fulfills the following criteria:
Increased intracranial pressure (>200 mm of
water)
Normal neurological exam except for
papilledema and VI nerve palsy
No mass lesion; no ventricular enlargement on
neuroimaging
Normal or low CSF protein concentration and
normal cell count
No evidence of venous sinus thrombosis
Headache intensity related to variations of
intracranial pressure
From the Headache Classification Committee of the In-
ternational Headache Society.48
Differential Diagnosis 175
may worsen if idiopathic intracranial hyper-
tension develops.17 In addition, some patients
with features of transformed migraine and a
chronic daily headache who are refractory to
treatment have been reported to have in-
creased intracranial pressure, but without pa-
pilledema.73
Idiopathic intracranial hypertension fre-
quently occurs in overweight adolescent girls
and in young women of childbearing age.
While the condition may mimic migraine in
some few patients, most of them have pa-
pilledema. Only those very few without pa-
pilledema cause real diagnostic difficulties. In
such cases, the relative constancy of these
headaches should alert the physician to look
beyond migraine, as should a history lacking
photophobia, phonophobia, and all of those
symptoms that drive the typical migraineur to
seek a quiet, dark room. Ultimately, however,
diagnosis depends upon CSF pressure exami-
nations.
LOW CEREBROSPINAL
FLUID PRESSURE
In contrast to the previous condition, headache
can also be caused by low CSF pressure. The
most common cause of low CSF pressure is
leakage following a spinal puncture (lumbar
puncture headache). Low CSF pressure may
also occur from a dural tear during an epidural
block. In those situations, the diagnosis is
clearcut. But an identical clinical picture can
arise spontaneously (primary intracranial hy-
potension, spontaneous intracranial hypoten-
sion).64 The CSF can leak through the cribri-
form plate, the petrous bone, a basal skull
defect, or a spontaneous tear in the spinal
theca. When a leak develops through the crib-
riform plate or the petrous bone, the resultant
CSF rhinorrhea or otorrhea may not be ap-
parent to the patient. And when spinal thecal
tear occurs, there may be no symptoms at all
that a patient would be expected to notice. Ac-
cordingly, the etiology of the headache may be
obscure, and from this point of view, diagnosis
is made difficult.
Diagnosis of a low-CSF pressure headache
is first made clinically. In most cases the head-
ache is dull, pulsating, and generalized, al-
though it may be accentuated in the frontal or
occipital regions. Neck stiffness, nausea, vom-
176 Cinical Aspects of Migraine
iting, diplopia, tinnitus, photophobia, and ver-
tigo may occur.92 The headache subsides after
reclining or lying flat, but it is characteristically
Augmented by an erect position. This is the
most telling symptom: headaches associated
with low CSF pressure have such a character-
istic relationship to position that the differen-
tiation from migraine should cause few diffi-
culties.
1
'8
78
In terms of test findings, the CSF pressure
is usually lowtypically atmospheric or very
low. A few patients have CSF opening pres-
sures that are consistently within normal lim-
its.77 The CSF may also show variable increases
in protein concentration and lymphocyte
count. In addition, there is often diffuse
meningeal enhancement on gadolinium-
enhanced MR images of the brain. Downward
displacement of the cerebrum and cerebellar
tonsils, flattening of the pons and optic chiasm,
and small or obliterated prepontine and
perichiasmatic cisterns may also occur. The
presence and location of a CSF leak may be
demonstrated by radionuclide cisternography
or myelography.
HEADACHE WITH
CEREBROSPINAL FLUID
PLEOCYTOSIS
Several reports describe adults and children
who develop a self-limited illness characterized
by throbbing, migraine-like headaches with re-
peated, changing, but self-limited sensory, mo-
tor, speech, and visual disturbances.6'7'40 Males
seem to be more frequently affected than fe-
males. Patients typically are in their third or
fourth decade. The patients do not necessarily
have a history of migraine, although some do.
The syndrome consists of headaches that are
recurrent, moderate to severe, and bilateral or
unilateral, with a variable duration from an
hour to a week. More than half the patients
have nausea and vomiting. The syndrome could
easily be mistaken for migraine at onset.
The most common neurological deficits are
cheiro-oral numbness and hemiparesis accom-
panied by a motor aphasia. The duration of the
neurological deficits is much longer than that
of the usual aura in either typical or compli-
cated migraine attacks. The prognosis is usu-
ally good; the neurological episodes and head-
aches generally resolve within 2 months.
The diagnosis depends upon a CSF exami-
nation. Cerebrospinal fluid pleocytosis, gener-
ally lymphocytic and ranging from 12 to 350
per mm*, is found. The CSF protein may also
be high. Except for transient, focal, decreased
radionuclide uptake in brain single photon
emission computerized tomography (SPECT),
neuroradiological studies are usually normal.40
Transitory, focal, non-epileptiform electroen-
cephalographic changes may be seen.6'40
OPHTHALMOLOGICAL L
HEADACHES
The eyes are often indicted as sources for head-
ache. Quite apart from actual pathology, many
people are convinced that headaches are
caused by reading in poor light, by reading in
the wrong position, or even by reading too
much. As far as medical facts are concerned,
the frequency of headaches produced by pri-
mary disorders of the eye is certainly overesti-
mated. But when a headache is actually attrib-
utable to demonstrable ocular or orbital
pathology, the patient's history and physical ex-
amination are almost always incompatible with
migraine. It is true that bouts of migraine with
aura are often preceded by visual phenomena,
and that migrainous pain is often located in or
around the eye. Nevertheless, migraine head-
aches are quite different from ophthalmologi-
cal headaches or head pain. Unlike migraine,
the pain caused by an ophthalmological prob-
lem is almost always correlated with use of the
eyes or with apparent physical signs of ocular
disease. Serious ocular causes of eye pain are
usually associated with inflammation such as
iritis or conjunctivitis, or with a cloudy
cornea.20
Chronic glaucoma may cause severe, recur-
rent periorbital pain or a persistent, low-grade
diffuse headache. Intermittent blurring of vi-
sion is common, but is dissimilar to visual ab-
normalities that often precede attacks of mi-
graine with aura. The impaired vision of
chronic glaucoma lasts longer than the blurred
or foggy vision that may be part of a migrain-
ous aura. When the affected eye of a patient
with chronic glaucoma is examined, there may
be no overt findings. In long-standing glau-

coma the optic nerve head may be pale and
show cupping. A diagnosis of chronic glaucoma
is established by tonometry.
In contrast to chronic glaucoma, acute
narrow-angle glaucoma (angle-closure glau-
coma) may be accompanied by acute pain and
severe, generalized headache owing to a sud-
den rise in intraocular pressure. The condition
occurs in middle-aged or elderly individuals
who are anatomically predisposed to crowding
of the anterior segment of the eye. Acute glau-
coma can cause excruciating, prostrating eye
and orbital pain often accompanied by nausea,
vomiting, and photophobia. The pain may in-
volve the forehead and temple on the side of
the affected eye. Vision can blur and fade, and
a complaint of colored halos around lights is
frequent. The nausea, vomiting, photophobia,
and disturbances of vision may mimic a mi-
graine attack, but careful physical examination
should enable differentiation of the two condi-
tions. Thus, in patients with acute narrow-an-
gle glaucoma, the cornea may appear cloudy or
gray because of edema, the pupil is often fixed
to light and mid-dilated, and the conjunctiva
appears red and inflamed. Minimal ocular
compression demonstrates a hard rigid globe
and intensifies the ocular and periocular pain.
Inflammatory disorders of the iris, ciliary
body, and choroid, such as anterior uveitis-
iritis and posterior uveitis-choroiditis, can
cause head pain centered around the eye. The
inflammation causes a dull, frequently severe,
occasionally throbbing pain in and around the
eye. The pain is usually persistent, although it
typically fluctuates in intensity. Patients also
experience sensitivity to light, blurring of vi-
sion, burning, and tearing. Physical examina-
tion reveals findings quite unlike those seen in
patients with migraine. The pupil is constricted
because of spasm of the iris sphincter. The eye
is red and tender to palpation.
Optic neuritis is another condition that may
cause eye or orbital pain. Its symptoms are also
easily differentiated from migraine, both by
history-taking and examination, although in a
substantial proportion of cases, diagnosis is dif-
ficult at first because the pain precedes the vi-
sual symptoms by several days. Optic neuritis
causes blurring or loss of vision in addition to
pain. The pain is usually located in, behind, or
around the eye. Customarily the patient re-
ports that the pain is increased by extreme
Differential Diagnosis 177
movement of the globe. The eye and perior-
bital regions may be tender to mild pressure.
SINUSITIS
An extraordinary number of patients complain
of "sinus trouble," strongly convinced that their
recurrent headaches are caused by chronic si-
nusitis. Despite the strength of their convic-
tions, most of these patients have inaccurate
perceptionspartly die result of advertising
media that oversell so-called "sinus medica-
tions." Daily exposure to misleading advertis-
ing reinforces the belief many patients already
have that all pains located in the frontal or pe-
riorbital regions are "sinus headaches." In re-
ality, many actually suffer either from migraine
associated with nasal congestion caused by
turbinate swelling, or from chronic tension-
type headaches. But because many of these pa-
tients respond to "sinus medications" (which
usually incorporate analgesics and deconges-
tants), all too often they cannot be dissuaded
from their convictions that they have sinus
headaches.
Chronic sinusitis is not a frequent cause of
headache or face pain. When it does cause
headache, the pain is characterized by a dull
ache or a feeling of pressure either over the af-
fected sinus or over the midface. The pain in-
creases with head movement, coughing, sneez-
ing, stooping, or bending. These symptoms are
accompanied by intermittent nasal congestion
and obstruction. Thick postnasal secretions are
nearly always present. A common symptom of
chronic sinusitis is day and night coughing. Be-
cause the pain is rarely throbbing, and because
photophobia, nausea, and vomiting are un-
usual, differentiation of chronic sinusitis from
migraine should cause little difficulty.
Acute sinusitis can cause intense frontal or
cheek pain. Sphenoid sinusitis pain may be felt
behind the eyes or in the occipital region. If
the ethmoid sinuses are involved, pain around
the area of the eyes and above the bridge of
the nose may be experienced. If the frontal si-
nus is involved, the pain is generally in the
forehead. Pain resulting from maxillary sinusi-
tis is primarily felt in the malar eminence. The
pain may radiate to other areas in head, face,
or neckfor example, around or behind the
eyes, in the maxillary teeth, and in the vertex,
178 Cinical Aspects of Migraine
temporal, or parietal areas of the cranium. The
pain is usually constant, dull, and aching, al-
though occasionally it is throbbing or sharp.
Characteristically, the pain associated with
acute sinusitis is augmented by bending for-
ward, jarring the head, and straining. Fever,
nasal obstruction, purulent nasal or postnasal
discharge, productive cough, and pharyngitis
are typical accompaniments. Percussion, or
digital pressure over the involved sinuses will
produce discomfort or intensify the pain.
Pathological findings on a CT scan confirm the
diagnosis. This condition most often develops
when the patient has an acute viral or bacte-
rial upper respiratory infection. Acute sinusi-
tis, however, has been documented in associa-
tion with allergy, swimming, flying, dental
repair, or trauma. Given its characteristics,
there is little likelihood that acute sinusitis will
be misdiagnosed as migraine.
HYPERTENSION
Chronic, uncomplicated hypertension of a mild
to moderate degree does not commonly result
in headache. In contrast, marked hyperten-
sionwhen the diastolic blood pressure rises
to more than 120 or 130 mm Hgcan cause
headaches. Such levels of hypertension are
usually seen in malignant (accelerated) hyper-
tension that produces severe retinopathy. In
these latter cases, the resulting headache is
temporally related to any rise in blood pres-
sure, and disappears within a few days after the
blood pressure is lowered.
A hypertensive headache has no specific di-
agnostic features. Ordinarily it has a dull,
throbbing quality, with generalized discomfort,
although the occipital area may be a prominent
site of head pain. This type of headache often
develops or is most pronounced in the early
morning, sometimes awakening the patient
from sleep. Vomiting may occur. The intensity
lessens after 2 or 3 hours as the patient rises
and starts to moves about. Any undertaking
such as bending, stooping, coughing, or strain-
ing, which increases either the blood pressure
or the intracranial pressure, may augment the
headache. In sum, even though excessive hy-
pertension has the capacity to cause head-
achessome of which are accompanied by
vomiting, and worsen when the patient
bendsthere should be no problem in making
a diagnosis. The height of the blood pressure
and the lack of a typical migraineur's history
clearly differentiate these two conditions.
PHEOCHROMOCYTOMA
Pheochromocytomas produce excessive amounts
of pressor amines, whose abnormally high lev-
els cause abrupt rises in blood pressure, ac-
companied by headache and other dramatic
symptoms. For many patients with these tu-
mors, the precipitous rises in blood pressure
produce short-lasting, generalized, throbbing
or pounding headaches that are alleviated as
the hypertensive peak diminishes. During an
attack, the patient may appear acutely ill
drenched in sweat, with cold extremities and
dilated pupils. Especially severe episodes of
headache may be attended by nausea, vomit-
ing, tachycardia, palpitations, tremulousness,
anxiety, and pallor.
The attacks of elevated blood pressure vary
considerably in frequency, severity, and dura-
tion from patient to patient. At least half the
headaches last less than 15 minutes, the ma-
jority end within an hour. Headaches may oc-
cur without warning or may be precipitated by
stimuli such as postural changes, physical ex-
ertion, or even emotional upsets. Headache as-
sociated with hypertension, palpitations, and
diaphoresis strongly suggests the diagnosis of
pheochromocytoma, and should be sufficient
to differentiate such headaches from migraine.
HEADACHES AS EMERGENCIES
Physicians often encounter patients with acute
headaches. Many of these are acute attacks of
migraine. But up to 16% of patients who come
to emergency departments with a primary
complaint of headache have headaches that are
associated with serious neurological conditions,
including subarachnoid hemorrhage, mass le-
sion, meningitis, and intracerebral hemor-
rhage.107 When there is reason to suspect an
emergency, appropriate diagnostic tests must
be performed expeditiously, and a diagnosis
made as quickly as possible. Delay can have
disastrous consequences.
A thorough assessment is imperative under
three circumstances: when the patient com-
plains (1) that the headache is the first one of

its kind; (2) that it is the most severe headache
that he or she has ever had; or (3) that it rep-
resents a distinct change in the pattern of his
or her usual recurrent headaches. Notice must
be taken if a migraineur complains of new neu-
rological symptoms or is found to have focal
neurological signs. Particular attention is also
necessary when any patient has signs of
meningeal irritation, alterations in either men-
tal status or alertness, changes in the eye
grounds, unexplained vomiting, or fever. A his-
tory of previous head trauma, HIV infection, a
systemic malignancy, or bleeding disorder
should suggest the possibility of serious in-
tracranial pathology. These latter patients need
an extensive neurological evaluation, including
CT or MRI scan and lumbar puncture. Head-
aches beginning after the age of 50 or 55 are
much more likely to be caused by a serious
problem.
Headaches Associated with
Aneurysms and Arteriovenous
Malformations
As a rule, unruptured, intracranial aneurysms
and AVMs are not connected to long histories
of frequent headaches. Evidence that unrup-
tured vascular malformations and aneurysms
cause chronic, recurrent headaches is, for the
most part, anecdotal and retrospective. There
are, however, trustworthy reports that when
one of these lesions expands, it can produce
pain, frequently associated with neurological
symptoms. And acute or subacute headaches
are grave indeed. The pain associated with an
unruptured aneurysm has been ascribed to ex-
pansion of an aneurysm, to leaks that warn of
impending hemorrhage, or to bleeding con-
fined to the arterial wall. Among patients
whose aneurysms ultimately rupture, between
30% and 60% experience the sudden onset of
excruciating, generalized, or hemicranial head-
aches (sentinel headaches) 1 or 2 days prior to
aneurysmal rupture. The headaches can ante-
date the rupture of an aneurysm and the sub-
sequent subarachnoid hemorrhage by several
days, or even weeks.25'65 Such headaches may
be unassociated with the usual symptoms and
signs of subarachnoid hemorrhage. Neck stiff-
ness may be absent and the headache may sub-
side over a period of hours. These headaches
may be accompanied by nausea and vomiting,
Differential Diagnosis 179
particularly if the lesion is located in the pos-
terior fossa. Both acute and subacute pain, in
the absence of rupture, may be challenging to
differentiate from migraine, but the unremit-
ting nature of the headache is a major cue.
Rupture of either an AVM or an aneurysm
produces an extremely intense headache that
is most likely to develop abruptly, although it
may occasionally evolve incrementally over a
period of several hours. The pain is reported
as extreme or cataclysmic. It is usually oliffuse,
but may become lateralized. A decreased level
of consciousness, vomiting, convulsions, and
focal neurological signs are common, their de-
velopment depending upon the locus of the
rupture and upon the rupture being accompa-
nied by development of an intracerebral hem-
orrhage or hematoma. Examination of the pa-
tient may additionally show nuchal rigidity and
retinal or preretinal hemorrhages.
The seriousness of an acute rupture is obvi-
ous. Nor is the condition difficult to recognize.
Small, non-catastrophic, subarachnoid hemor-
rhages from aneurysms or AVMs can present
greater diagnostic challenge. The symptoms
may mimic migraine, producing a localized
headache accompanied by nausea and vomit-
ing. The absence of a history of migraine
should cause the physician to look further. A
CT scan that shows subarachnoid blood and
lumbar puncture that yields bloody spinal fluid
will lead to the proper diagnosis. If, however,
a long-time migraineur develops a non-
catastrophic, subarachnoid hemorrhage with
migraine-like symptoms, diagnosis is more
problematic. In this case, the extraordinary
severity of the head pain should provide the
necessary clue for the physician to initiate the
relevant diagnostic measures.
Thunderclap Headaches and
Crash Migraine
The term thunderclap headache was originally
used to designate the very rapid onset of a se-
vere and unusual headache. Many patients re-
fer to the pain as the "worst pain ever." The
sudden onset and the severity of the headache
make it appear to be caused by a subarachnoid
hemorrhage, even though, in most cases, the
patient's CSF is clear and the CT scan shows
no subarachnoid blood.22'72 Angiography in pa-
tients with this type of headache generally does
180 Cinical Aspects of Migraine
not show an aneurysm.72'122 These cases can
be designated benign thunderclap headaches.
Seventeen percent of these patients experience
recurrent thunderclap headaches. 22 The
cause of benign thunderclap headaches is ob-
scure, but they are so unlike migraine that they
should present no problem in the differential
diagnosis. However, because patients with
aneurysmal subarachnoid bleeding can fre-
quently present with headaches of either al-
most instantaneous or rapid onset, often with
no other symptoms, the characteristics of a
thunderclap headache necessitates an emer-
gency worlcup even though the data ultimately
reveal that there was no emergency. There are
few, if any, characteristics to distinguish benign
from symptomatic thunderclap headaches. In
addition, a small minority of patients with
sudden-onset, severe headaches and neither
loss of consciousness nor focal deficits may
have perimesencephalic hemorrhage, a benign,
non-aneurysmal variety of subarachnoid hem-
orrhage.
A sudden-onset migraine attack (crash mi-
graine, blitz migraine) is rare, but can occur.
Again, subarachnoid hemorrhage must be
ruled out before the diagnosis is made.
Headaches Associated with
Ischemic and Hemorrhagic
Vascular Disease
Headache is a relatively common accompani-
ment of acute ischemic or hemorrhagic
cerebrovascular disease, including ischemic
stroke, cerebral embolism, transient ischemic
attacks (TIAs), and intracerebral hemor-
rhages.3'29'33'41'90'121 A number of studies indi-
cate that between 11% and 34% of patients
with large cerebral infarctions, between 3%
and 23% of patients with lacunar infarction,
and between 33% and 65% of patients with in-
tracerebral hematomas suffer from head-
ache.51
The IHS criteria for headache associated
with stroke require the headache to have a
close temporal relationship with the onset of
the vascular problem: 48 hours for ischemic,
and 24 hours for hemorrhagic stroke. In actu-
ality, episodic headaches may precede an isch-
emic ictus by days or even weeks. In such cases,
diagnosis is subject to uncertainty, especially
when the patient has no previous history of an
ischemic cerebral event.28'41 The headaches as-
sociated with stroke are equally inclined to be
rapid or gradual in onset. They frequently last
minutes to hours, although, on occasion, they
can last for days.3 The duration is generally
longer in patients with hemorrhagic stroke than
with ischemic stroke. The quality of the pain
differs widely among patients. In most patients
it is not throbbing and ranges in severity from
trivial to severe.41^6'90 It is more intense in pos-
terior lesions than in those localized to the an-
terior circulation.
Cerebrovascular disease headaches typically
indicate involvement of large rather than small
vessels, but do not necessarily correlate with
the size of the infarct.41'52 Stroke in the basi-
lar distribution area, especially the posterior
cerebral circulation, is more often associated
with headache than stroke in the carotid terri-
tory.52'56'121 Occipital headache is primarily en-
countered in patients with cerebellar or occip-
ital lobe lesions (Fig. 8-2). Headaches are
bilateral in approximately one-half of patients.
But the one-half of patients whose headaches
are lateralized have pain that is ipsilateral to
the side of the involved bloodvessels.52'121 Dif-
fuse or poorly localized headaches are fre-
quent. In a manner similar to migraine, the in-
tensity of cerebrovascular disease headaches is
increased by bending, straining, and/or jarring
the head.28 Vomiting is infrequent.
As far as the differential diagnosis is con-
cerned, the neurologic symptoms of TIAs must
be distinguished from the aura of migraine. A
build-up or march of motor and sensory symp-
toms is usually much more rapid (seconds to a
minute) in TIAs than in migraine. Migrainous
auras usually consist of a slow march of symp-
toms taking minutes to move from one region
of the body to another. The progression from
visual to sensorimotor symptoms is common in
migraine and rare during TIAs. In migraine, vi-
sual auras such as scintillating scotomas are
common; TIAs do not produce scintillating sco-
tomas and even homonymous hemianopias are
unusual. Although not invariable, TIAs are usu-
ally shorter than auras.
Many headaches associated with ischemic
cerebrovascular disease are enough unlike mi-
graine that they present no confusion. How-
ever, some older patients, either with no prior
history of migraine or with a newly changed
pattern of headaches, may describe episodic,
throbbing headaches. These headaches may
suggest migraine. The physician must be cau-
 Differential Diagnosis 181

Figure 8-2. Schematic localization of stroke related to localization of resulting headache. The location of each vascular
lesion is marked with an X. The X's in the center indicate brain stem lesions. (Adapted from Vestergaard K, Andersen G,
Nielsen MI, and Jensen TS: Headache in stroke. Stroke 24:1621-1624, 1993, with permission.)

tious when evaluating older patients with new,
or recently altered headaches. Although mi-
graine may emerge at any age, the first diag-
nosis that comes to mind in an elderly individ-
ual without antecedent attacks should not be
migraine. Ischemic cerebrovascular disease
should be ruled out first.
Carotid and Vertebral
Artery Dissection
Head pain together with focal ischemic neuro-
logical deficits are common in patients with
carotid or vertebral artery dissection.67'108 In
fact, the headache present in up to three-
fourths of all patients is frequently the earliest
symptom of both carotid artery and vertebral
artery dissections. Neck and face pain also oc-
cur. In most cases, a similar pain has not been
experienced previously. The headache associ-
ated with dissection is usually slowly progres-
sive, either steady or throbbing, and can be
quite severe. The duration of the pain is vari-
able: from 1 hour to 30 days, but less than a
week is common. At times, patients may have
several attacks of short-lasting, incapacitating
head pain.
Dissection can occur either spontaneously or
as a result of trauma, often trivial, to the head
182 Cinical Aspects of Migraine
or neck. The cause of the spontaneous dissec-
tions is unknown, although fibromuscular dys-
plasia, elastic tissue disease, hypertension, and
migraine are primarily implicated. Sudden
stretching of the artery from any number of
causesjolts that produce extension-flexion
injury during a motor vehicle accident, chiro-
practic manipulation of the neck, sports activ-
itiesare traumas reported to cause dissec-
tions.
Most often, dissections involve the extracra-
nial portion of the internal carotid artery. The
head pain in such cases characteristically pre-
cedes neurological deficits by a week or two,
or even longer. It is typically hemicranial on
the side of a carotid dissection, but can be bi-
lateral and diffuse even when the dissection is
unilateral. The headache may come on rapidly
or gradually. It has a predilection for orbital,
periorbital, and frontal regions. Sharp pains lo-
cated in the neck, jaw, pharynx, or face are de-
scribed. The pain in vertebral artery dissections
is usually distributed over the posterior head
regions or occiput and accompanied by neck
pain. However, the location of the pain is vari-
able and can involve, in isolation or in combi-
nation, any part of the head.
Imaging of either a narrowed artery or in-
tramural hematoma is needed to establish a di-
agnosis. Magnetic resonance imaging can visu-
alize the mural hematoma, the degree of
arterial wall expansion, and the relationship
with surrounding tissues. Ultrasonography has
also been shown to be a sensitive and reliable
diagnostic tool for dissections of the internal
carotid artery. Angiographic methods are still
considered to be the most accurate means of
establishing a diagnosis.
Toxic Vascular Headaches
The phrase toxic vascular headache is applied
to a headache caused by intense cerebral va-
sodilatation resulting from a high fever of any
cause. Most such headaches appear as part of
a systemic viral or bacterial infection such as
influenza or typhoid. The pain of toxic vascu-
lar headache is not distinctive. Patients de-
scribe it as dull, deep, and aching in quality. At
times it may have a throbbing component. The
pain is almost always bilateral, possibly local-
ized to the frontotemporal regions of the head,
the back of the head, or the occipito-cervical
region. Ocular or retro-orbital pain worsened
by eye movement is a characteristic accompa-
niment. Patients with toxic vascular headaches
do not have classical signs of meningeal irrita-
tion, but they may have cervical myalgia or
neck stiffness (meningismus) that limits neck
movement. If the symptoms are severe enough
to suspect bacterial meningitis, such patients
must receive immediate investigation and ur-
gent treatment.
Acute viral infections are commonly accom-
panied by headache. Headaches lasting for the
duration of an illness are typical accompani-
ments of systemic infectious disorders such as
influenza, infectious mononucleosis, measles,
and mumps. The headache may resemble mi-
graine, but more often is persistent rather than
episodic, and aching rather than throbbing.
Headaches Secondary to
Meningeal Infection
Infection of the meninges is a source of acute,
intense headache. Nuchal rigidity together
with severe headache and fever are character-
istic of meningitis. Most of the time the head-
ache is generalized, but sometimes it predom-
inates in frontal or occipital areas. The pain
may extend into the neck, and frequently also
extends down the back. A change in the level
of consciousness, photophobia, nausea, and
vomiting are also typical of this condition.
Viruses, bacteria, fungi, and the tubercle bacil-
lus may be causative agents. Firm diagnosis
rests upon clinical evaluation and lumbar
puncture.
SUMMARY
As the material reviewed in this chapter indi-
cates, a number of clinical conditions produce
symptoms that can be confused with those con-
sidered to be diagnostic of migraine. Some of
these conditions, especially tension-type head-
aches, are intimately related to migraine. Oth-
ers result from particular systemic or localized
disease processes. Although the clinician mak-
ing a diagnosis of migraine must be wary of a
number of these conditions, a diagnosis of mi-
graine can generally be made based almost en-
tirely on a comprehensive and detailed history.

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115. Solomon S and Cappa G: The headache of temporal
arteritis. J Am Geriatr Soc 35:163-165, 1987.
116. Sutherland JM and Eadie MJ: Cluster headache. Res
Clin Stud Headache 3:92-125, 1972.
117. Suwanwela N, Phanthumchinda K, and Kaoropthum
S: Headache in brain tumor: a cross-sectional study.
Headache 34:435-438, 1994.
118. Troost BT, Mark LE, and Maroon JC: Resolution of
classic migraine after removal of an occipital lobe
AVM. Ann Neurol 5:199-201, 1979.
119. Troost BT and Newton TH: Occipital lobe arteri-
ovenous malformations. Clinical and radiologic fea-
tures in 26 cases with comments on differentiation
from migraine. Arch Ophthalmol 93:250-256, 1975.
120. Verma A, Rosenfeld V, Forteza A, and Sharma KR:
Occipital lobe tumor presenting as migraine with typ-
ical aura. Headache 36:49-52, 1996.
121. Vestergaard K, Andersen G, Nielsen MI, and Jensen
TS: Headache in stroke. Stroke 24:1621-1624, 1993.
122. Wijdicks EFM, Kerkhoff H, and Van Gijn J: Long
term follow-up of 71 patients with thunderclap head-
ache mimicking subarachnoid hemorrhage. Lancet
ii:68-70, 1988.
123. Williams HL and Elkins EC: Myalgia of the head.
Arch Phys Ther 23:14-22, 1942.
124. Wober-Bingol C, Wober C, Karwautz A, et al.:
Tension-type headache in different age groups at two
headache centers. Pain 67:53-58, 1996.
125. Wong RL and Korn JH: Temporal arteritis without
an elevated erythrocyte sedimentation rate. Am J
Med 80:959-964, 1986.
126. Yung WK, Sawaya R, Curran WJ, and Fuller GN:
Intracranial metastatic central nervous system tu-
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258.
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PART II

PATHOPHYSIOLOGY
This page intentionally left blank
Chapter 9
The Prodrome and the Aura
PRODROMES
THE WOLFF HYPOTHESIS AND THE
PRIMARY NEURONAL HYPOTHESIS
CEREBRAL BLOOD FLOW
XENON (133XE) METHODS
INTERICTAL CEREBRAL BLOOD FLOW
MEASUREMENTS
CHANGES IN CEREBRAL BLOOD FLOW
DURING THE AURA
SERIAL REGIONAL CEREBRAL BLOOD
FLOW MEASUREMENTS
SPREADING DEPRESSION
Cerebral Blood Flow and Spreading
Depression
Mechanism of Spreading Depression
Many migraineurs experience prodromes that
precede their headaches by several hours or
even days (see Chapter 3). Prodromal symp-
toms consist of variations in mood and behav-
ior, fatigue, and/or symptoms attributable to
the cervical musculature and the gastrointesti-
nal tract. Only some of these indicate nervous
system involvement. Auras are distinctly dif-
ferent from prodromes. They generally last for
minutes, and the symptoms imply significant
neurological abnormalities of visual, somato-
sensory, motor, speech, or brain stem function.
Auras have been studied extensively. The vari-
ety of approaches and techniques used to study
aura have led to interesting hypotheses about
the pathophysiology of migraine. In contrast,
limited study has been devoted to prodromes,
and consequently we know little about the their
underlying mechanisms.
MAGNETOENCEPHALOGRAPHY
POSITRON EMISSION TOMOGRAPHY
FUNCTIONAL MAGNETIC RESONANCE
IMAGING
THE SPREADING DEPRESSION
HYPOTHESIS AND MIGRAINE
CLINICAL OBSERVATIONS: AURAS AND
CEREBRAL ISCHEMIA
SUMMARY
PRODROMES
Three major possibilities have been proposed
for the genesis of prodromal symptoms:
1. Hypothalamic dysfunction. During the
pre-headache phase, some migraineurs experi-
ence irritability, hunger, craving for food, dif-
ficulties with temperature control, and somno-
lence. Intriguing parallels have been described
between the pre-headache phase of these pa-
tients and a similar catalog of symptoms pro-
duced by lesions of the ventromedial nucleus
of the hypothalamus in experimental animals.34
2. A dopaminergic mechanism. When dopa-
minergic agents are administered to migrain-
eurs, the compounds not only cause headaches,
but also produce symptoms often considered
part the prodrome: drowsiness, nausea, and
yawning. Such observations have led some re-
189
190 Pathophysiology
searchers to suggest that a dopaminergic mech-
anism gives rise to prodromal symptoms and
may be involved in the initiation of migraine
attacks.63'83 (The dopaminergic hypothesis of
migraine is discussed in detail in Chapter 12.)
3. A serotonergic mechanism. Involvement
of serotonin (5-hydroxytryptamine, 5-HT) in
the production of prodromal symptoms is
based on circumstantial evidence. In particu-
lar, via their wide distribution over the neu-
raxis, 5-HT-contaim'ng neurons in the midbrain
raphe system are hypothesized to play a key
role in a number of behaviors such as mood,
sleep, appetite, and cognitive function.68 Al-
teration in these behaviors are often seen dur-
ing prodromes. (The role of 5-HT in migraine
is also discussed in more detail in Chapter 12.)
The complex changes in mood and behav-
ior, and the neurological and autonomic symp-
toms manifested during the prodrome, may
conceivably involve complex interactions of all
three: hypothalamic dysfunction combined
with dopaminergic and/or serotonergic mech-
anisms.
THE WOLFF HYPOTHESIS AND
THE PRIMARY NEURONAL
HYPOTHESIS
The pioneering experimental efforts of Harold
G. Wolff and his associates yielded the first
comprehensive set of assumptions about the
cause of migrainous symptoms. Their specula-
tions, well summarized in Wolffs 1963 mono-
graph, led to the hypothesis that vasoconstric-
tion of intracranial vessels reduces blood flow,
resulting in cerebral hypoxia.108 This cerebral
hypoxia was thought responsible for the neu-
rological deficits that characterize migrainous
auras. Wolff also assumed that a sterile in-
flammatory reaction around blood vessels and
vasodilatation of the extra- and intracranial cir-
culation follow the vasoconstriction so that
nerve endings in inflamed vascular walls are
stretched, giving rise to the head pain of a mi-
graine attack.30'*05 Wolff considered distension
of the scalp vessels to be the major cause of
migrainous head pain. The intracranial vasodi-
latation was conceived of as a reactive hyper-
emia generated by the preceding cerebral hy-
poxia. In sum, Wolff considered migraine to be
a primary vascular problem.
Wolffs arguments in support of the vascular
origin of migraine symptoms could only be
based on indirect evidence because research
techniques to study cerebral blood flow (CBF)
directly had not yet been developed. He made
the following observations:
1. Visual auras transiently regressed when
cerebral vasodilatation was induced by amyl ni-
trate administration or by inhalation of 10%
CO2 and 90% O2.62
2. During the headache, the amplitude of
the superficial temporal artery pulse increased,
and concomitantly, the throbbing or pounding
quality of the pain migraine correlated with
these increases in pulse amplitude.
3. Ergotamine, which reduced the pulsa-
tions of the superficial temporal artery, re-
lieved the migraine pain.30
Not all of these observations stand up under
scrutiny. For example, in some of Wolffs
recordings, the superficial temporal arterial
pulsations are of equivalent amplitude both be-
fore and during a severe headache.5 Nor have
other investigators been able to verify a signif-
icant correlation between the magnitude of the
temporal artery pulse and the intensity of head
pain.9 The vascular theory of migraine also fails
to explain the genesis of prodromal events,
many of which likely stem from central nervous
system (CNS) processes. In addition, some of
the drugs used successfully to treat migraine
attacks have little or no direct effect on blood
vessels.
Even so, Wolffs ideas dominated scientific
analysis of the cause of migraine symptoms for
many decades. Most investigators have chosen
to adopt an alternative viewthe so-called
primary neuronal hypothesis for the genesis of
migraine and its symptoms. This hypothesis
posits that migraine is primarily a process orig-
inating in the brain parenchyma and that any
involvement of cephalic blood vessels is a sec-
ondary phenomenon. In the past decade or so,
the primary neuronal hypothesis has risen in
prominence, until it has come to dominate
much present-day thinking about causation of
migraine symptoms. Ironically, the primary
neuronal hypothesis owes its present popular-
ity to modern technology that has allowed the
investigation of the role of vascular factors in
migraine and, in particular, the development
of techniques that measure CBF serially dur-
ing attacks of migraine.

As we think about the primary vascular hy-
pothesis versus the primary neuronal hypothe-
sis, we must remain aware that these two
propositions are not necessarily competitors.
Neither provides a full explanation for the aura
or for the headache, nor are they mutually ex-
clusive. Indeed, there are indications that both
vascular and neurogenic phenomena must be
invoked to explain the large body of clinical and
experimental observations about migraine
attacks.
CEREBRAL BLOOD FLOW
Cerebral blood flow (CBF) is usually expressed
as a quotient whose numerator is cerebral per-
fusion pressure and whose denominator is
cerebrovascular resistance. Cerebral perfusion
pressure is taken as the difference between the
systemic arterial pressure and the cerebral ve-
nous pressure. The latter is normally very low
when compared to the systemic arterial pres-
sure and, for practical purposes, the cerebral
perfusion pressure can be considered a func-
tion of the mean systemic arterial pressure. De-
termining cerebrovascular resistance is some-
what more complicated. In most circulations,
the arterioles provide most of the resistance to
blood flow. But because large cerebral arterial
branches are long, whereas cerebral arterioles
have comparatively much shorter lengths, large
arteries may actually account for a substantial
portion of the vascular resistance in the brain.
In the resting state, the large extracranial and
surface vessels of the brain are estimated to
constitute between 39% and 51% of the total
cerebrovascular resistance. Under normal con-
ditions, small arteries and arterioles less than
400 fJLm in diameter account for the remaining
resistance to flow.
Controversy exists about the relative contri-
butions of small and large arteries to resistance
changes under various physiological and patho-
logical conditions.33 In addition, the cerebral
circulation appears to lack the precapillary
sphincters that are responsible for substantial
resistance to blood flow in other circulations.
Finally, although the meningeal circulation ap-
pears to have an abundance of arteriovenous
shunts, there is uncertainty over whether such
shunts are important for regulating CBF in the
human carotid circulation.38'42'89
The Prodrome and the Aura 191
XENON (133XE) METHODS
The vast majority of hemodynamic studies dur-
ing or between attacks of migraine have been
performed with 133Xe. This inert gas can be in-
haled or administered by an intravenous or in-
tracarotid bolus of radioisotope-containing
saline. When the 133Xe arrives at the brain, it
diffuses freely across capillary walls and dis-
solves rapidly in the brain tissue. Subsequently,
unlabeled arterial blood washes out (clears) the
radioisotope from the tissue. The rate of clear-
ance is a function of the rate of cerebral per-
fusion (i.e., the CBF). External measurements
of radioactivity are made over the brain by one
or more stationary scintillation detectors. An
individual detector views a distinct region of
the brain through a lead collimator.
During decay, 133Xe emits photons of two
energies (80 and 30 KeV). Low-energy photons
produced deep within the brain are absorbed
by overlying brain tissue to a considerable de-
gree, and as a result, may lack adequate energy
to reach the scintillation detectors. Conversely,
superficial structures may supply a dispropor-
tionately large number of both high- and low-
energy photons to the scintillation detector. It
may be that most scintillation detection mea-
surements of CBF indicate changes in only the
superficial layers of the brain.
Inhalation or intravenous injection of 133Xe
have the advantage of being relatively non-
invasive, but both suffer from technical short-
comings that derive from extracerebral con-
tamination caused by the presence of radioiso-
tope in the cranial air passages when inhalation
is used and by the labeling of soft tissues out-
side the cranial cavity. Another shortcoming is
that intracerebral contamination is produced
by scattered counts of radioactivity from the
contralateral cerebral hemisphere. All of these
factors limit the accuracy of the measurements.
The injection of 133Xe via the internal carotid
artery reduces the problem of extracerebral
and intracerebral contamination, but the tech-
nique necessitates preparation. The method is
invasive, requiring the insertion of an in-
dwelling catheter into the internal carotid
artery. Moreover, carotid catheterization itself
may alter CBF.78 Puncture of the carotid artery
appears to provoke migraine attacks in many
migraineurs, particularly those who are prone
to bouts of migraine with aura. But because
192 Pathophysiology
such an induced attack does not develop im-
mediately, this method has made it feasible to
investigate CBF before the onset of induced
attacks, during the aura, and during the head-
ache phase of an attack in a single patient. Such
serial data are, of course, limited to one hemi-
sphere labeled during a study.
The tomographic features of the single-
photon emission computed tomography
(SPECT) technique permit visualization of re-
gional CBF (rCBF) in gray and white matter
at several transverse levels. Early studies mea
sured rCBF after inhalation or intravenous in-
jection of 133Xe. More recently, other SPECT
tracers have been used, one of the most pop-
ular being 99mTc-D,L-hexamethyl-propylene-
amine-oxime (99mTc-HMPAO). This compound
has reasonable radiation characteristics for
SPECT imaging, but because it is firmly re-
tained in the brain for several hours, serial
studies are hard to perform. Complications re-
sulting from radioactivity that emanates from
extracerebral structures and from superimpo-
sition of different tissue layers are eliminated
by SPECT techniques, but the spatial resolu-
tion is limited.
INTERICTAL CEREBRAL BLOOD
FLOW MEASUREMENTS
Although migraineurs have usually been con-
sidered to have normal cerebral perfusion be-
tween attacks, a number of conflicting reports
have shown both increased (hyperperfusiori)
and decreased interictal blood flow (hypoper-
fusion) in various brain regiOns.18'43'44'47'60'94
The alterations of CBF are usually minor, and
typically are less prominent in patients without
aura than in those with aura. One estimate is
that one-quarter of all patients show persistent
changes in the posterior parts of the hemi-
sphere usually involved during attacks of mi-
graine with aura.23 It is unclear if the rCBF
changes observed during interictal periods are
the result of permanent neurological dysfunc-
tion caused by repeated, transient episodes of
reduced CBF or if they reflect abnormal vas
cular regulation between attacks. As expected,
a high proportion of patients with complicated
migraine have reduced CBF in damaged re-
gions of the brain thought responsible for the
neurological symptoms.
CHANGES IN CEREBRAL
BLOOD FLOW DURING
THE AURA
If changes in rCBF are the basis for the neu-
rological deficits that characterize auras, then
such changes should correlate with the symp-
toms of the migraine attack. Early investiga-
tions of cerebral perfusion during spontaneous
migraine attacks did indeed demonstrate sig-
nificant decreases in rCBF early in at-
tacks.39'55'56'76'91'98 Because of differences in
methodology and technical difficulties inher-
ent in studying acute migraine attacks, how
ever, reports have varied as to both the fre-
quency and the regularity of the changes in
rCBF. Widespread reductions, bilateral reduc-
tions, and focal reductions of CBF have all
been reported. But even though the data are
not as clear-cut as desired, the results from a
number of investigations imply an association
between focal neurological symptoms and
changes in rCBF.
SERIAL REGIONAL CEREBRAL
BLOOD FLOW MEASUREMENTS
Improved techniques for measuring rCBF with
133
Xe, especially when using multiple scintilla-
tion detectors, make feasible detailed accounts
of the sequence and spatial qualities of vascu-
lar events in the brain during bouts of migraine.
The largest series of rCBF studies using 133Xe
during attacks of migraine are those of Olesen
and colleagues in Copenhagen. Their investi-
gations involved the catheterization of a carotid
arterya procedure that triggered attacks of
migraine with aura in all patientsand mea-
surement of rCBF in 254 areas of one cerebral
hemisphere.
Changes in CBF were documented at least
5 to 15 minutes before patients noted the first
symptoms of the migrainous aura (Fig. 9-
1).557,75,76 These changes consisted of rCBF
reductions (hypoperfusion), which Olesen's
group designated by the term oligemia. Oli-
gemic changes appeared to be restricted to the
neocortex. Recordings showed them to start
posteriorly, but because the intracarotid injec-
tion method studies are confined to the vascu-
lar territory of the internal carotid artery, there
was no way to determine whether the CBF re-
 The Prodrome and the Aura 193

Figure 9-1. Schematic illustration demonstrating the sequence of eventshypoperfusion, aura, headache, and hyper-
perfusionthat occur during evoked attacks of migraine with aura. Angiography was performed at time 1 hour and ini-
tiated a migraine attack. The time axis was arbitrarily chosen to illustrate a typical result. Cerebral blood flow (CBF) was
measured with 133Xe. (Adapted with permission from Olesen J, Friberg L, Skyh0j Olsen T, et al.: Timing and topography
of cerebral blood flow, aura, and headache during migraine attacks. Ann Neural 28:791-798, 1990.)

ductions were initiated in the occipital lobes.
As the area of hypoperfusion expanded during
a study, aura symptoms ensued. Aura symp-
toms regularly disappeared by the time the
CBF was maximally reduced. In addition, the
hypoperfused state often prevailed, even
though the patients had no residual neurolog-
ical deficits.56'100 In fact, not only did the
oligemia outlive the aura, but CBF reductions
typically persisted for the first several hours of
the attack.
Oligemia encompassed the parietal, tempo-
ral, central, and posterior frontal regions of the
cortex. The territory of the anterior cerebral
artery was not typically involved. The decrease
in rCBF began posteriorly and appeared to
spread anteriorly; Olesen's group used the
term spreading oligemia (spreading hypoper-
fusion) to describe this phenomenon (Fig.
9-2). The reduced CBF was estimated to move
with a velocity of 2 to 3 mm/minute and ap-
peared to transgress the vascular boundaries of
the major cerebral arteries. This latter point
was used by Olesen to buttress his idea that the
reduced flow results from constriction of arte-
rioles rather than from a process involving large
cerebral arterial vessels. The data also seemed
to show that major cytoarchitectonic bound-
aries, or major foldings of the brain (such as
the lateral and central sulci), constrain pro-
gression of the hypoperfusion. On occasion, a
short-lasting, focal hyperperfusion (hyperemia)
was seen in the initial stages of the attack be-
fore the oligemia was noted.25'76 The hyper-
emia appeared to arise posteriorly and to
spread forward.
Olesen and colleagues have stressed the
point that the CBF reduction is modestit
drops on average to 40 ml/100 g/minuteand
well above the threshold for ischemia, which
has been determined in animal experiments to
be approximately 20 ml/100 g/minute. They
consider the magnitude of the reduction in-
sufficient to explain the development of focal
neurological symptoms. Nevertheless, Olesen
suggested that both the severity and duration
of aura symptoms are related to the degree and
duration of CBF alterations.74 With short-
lasting, mild aura symptoms, rCBF changes are
not marked and may only last for 30 minutes.
When the aura is substantial, rCBF changes are
more marked and may last for many hours.
Vascular reactivity to various stimuli during
migraine attacks has been studied by a num-
ber of investigators, including the Copenhagen
group. The cerebral vasodilator response to
changes in pCO% is impaired during the aura.92
Such an impairment appears limited to hy-
194 Pathophysiology

Figure 9-2. Diagram illustrating the Copenhagen group's

hypothesis of progression of migraine with aura. The hy-
pothesis illustrated by the diagrams presupposes that spread-
ing depression occurs in humans and that it is responsible
both for the changes in cerebral blood flow (CBF) and for
the focal neurological symptoms and signs seen during the
aura. Schematic illustrations are of lateral views of the hu-
man brain at approximately 30-minute intervals following the
onset of an attack. The lighter dotted area represents the re-
gion of hypoperfusion, the darker dotted area is the region
of disturbed neuronal function accompanying the hypothe-
sized spreading depression, and the arrows indicate the di-
rection in which the depression spreads. Spreading depres-
sion (I) is thought to be evoked at the occipital pole of the
brain during the onset of the attack and to progress anteri-
orly. At the region of the spreading depression, temporary
changes in ionic concentrations and neuronal firing are pos-
tulated to occur and to be responsible for the development
of focal symptoms. Areas previously affected by the hypoth-
esized spreading depression (2), have depressed CBF for 2
to 6 hours. The CBF in regions uninvaded by the hypothe-
sized spreading depression (3) continues to be normal. The
area of oligemia (4) progressively extends as the hypothe-
sized spreading depression (5) shifts more anteriorly. The
spreading depression is hypothesized to stop at the central
sulcus. Still later, the hypothesized spreading depression has
stopped, but a persistent reduction of CBF remains (6). At
this point, the patient no longer has focal neurological symp-
toms, but suffers from headache. (Adapted from Lauritzen
M: Cerebral blood flow in migraine and cortical spreading
depression. Acta Neural Scand 76 (Suppl 113):1-40, 1987,
with permission of Munksgaard International Publishers
Ltd., Copenhagen, Denmark.)

poperfused areas of the brain.57 Some investi-
gators found a reduced response of cerebral
vessels to changes in systemic blood pressure
(impaired cerebral autoregulation), whereas in
other studies, rCBF remained constant in re-
sponse to an elevation of blood pressure.57'91'92
Physiological activation by stimuli such as mov-
ing a hand or speaking did not increase CBF
in hypoperfused cerebral regions affected by
the migrainous process.57
The decreases in rCBF during an induced
attack of migraine with aura are accompanied
by significant increases in global 62 extraction
fraction, but cerebral metabolic rate remains
essentially unchanged.24 These results have
been interpreted to mean that the focal CBF
reductions during the aura phase of a migraine
attack are not secondary to reduced cerebral
metabolism.
The observations made by Olesen and co-
workers using intracarotid 133Xe provide con-
siderable food for thought. Their data, how-
ever, might be open to criticism on the grounds
that the attacks they studied were all triggered
by the procedure. Carotid puncture has un-
certain effects on CBF, and may well have af-
fected the results. One could question whether
the changes in rCBF recorded with the 133Xe
technique develop during spontaneous bouts
of migraine. This same group of investigators,
however, complemented their work with
SPECT studies of patients with spontaneous
attacks of migraine with aura, and the SPECT
studies complement the 133Xe studies exceed-
ingly well. These studies have yielded essen-
tially the same findingsnamely, that focal re-
gions of hypoperfusion of the cerebral cortex
were found contralateral to the side of the fo-
 The Prodrome and the Aura 195

cal neurological symptoms.1'55 Similar changes
have been found in juvenile patients with mi-
graine with aura.102 In contrast, SPECT stud-
ies of patients during attacks of migraine with-
out aura showed no changes in rCBF.21'55'74'77
In sum, the seminal investigations of Olesen
and co-workers appear to show the following:
1. The blood flow in hypoperfused brain re-
gions does not achieve ischemic values. The de-
creases in CBF during the aura phase are mod-
estestimated to be 25% to 30% with the
intracarotid 133Xe technique and 20% with
SPECT studies. Accordingly, ischemia is not
thought by Olesen and colleagues to be the
cause of the neurological symptoms that com-
prise the aura; the hypothesis that the aura is
produced by primary vascular causes is un-
likely.
2. The area of oligemia expands in size and
spreads anteriorly as the attack progresses.
3. The anterior spread of reduced CBF is
independent of the boundaries of the major
cerebral artery territories. This finding has
been interpreted to mean that it is doubtful
that vasospasm of a major cerebral artery sup-
plying a discrete area of the cerebral cortex is
the cause of the blood flow reduction.
4. There is a poor correlation between the
prolonged time course of the reduced rCBF
and the considerably shorter duration of the fo-
cal neurological symptoms comprising the
aura.
The aggregate of these findings persuaded
Olesen and colleagues that a primary vascular
cause of migraine with aura is unlikely. They
believe that the aura is neurogenically deter-
mined. In other words, both the oligemia and
the aura are responses to some type of primary
neuronal dysfunction or to a neuronal process
that is the generative event for migraine attacks
(at least of attacks of migraine with aura). They
see reduced rCBF as an epiphenomenon, a
process correlated with, or a consequence of,
the depression of neuronal activity, but not re-
sponsible for the symptoms. They posit a neu-
ronal phenomenon called cortical spreading
depression as the process causing the aura
symptoms, the spreading oligemia, and, after a
delay, the headache.50'51'73
Olesen's conclusion had in fact been reached
earlier, albeit on the basis of different evi-
dence.26'48'59'69 The psychophysiologist K.S.
Lashley, for example, used his knowledge of
the retinotopic organization of the visual sys-
tem to estimate that the process responsible for
his own scintillating scotomas traveled in a
wave across the occipital cortex at a rate of 2
to 3 mm/min (Fig. 9-3).48 Lashley's calcula-

Figure 9-3. Successive observations of an expanding scintillating scotoma. The progressive involvement of the visual field
was plotted at intervals indicated in minutes. The fixation point is marked by an X. The short, straight lines oscillate. The
area within the dotted lines is the scotoma. (Adapted from Lashley KS: Patterns of cerebral integration indicated by the
scotomas of migraine. Arch Neurol Psychiatry 46:331-339, 1941. Copyrighted 1941, American Medical Association.)
196 Pathophysiology

tions have been confirmed, and the patterns trochemical gradient of cortical neuronal mem-
have been related to the functional organiza- branes is abolished during spreading depres-
tion of the striate cortex.87 Similar calculations sion. The process is transient.
have been made for somatosensory aura symp-
toms developing along the postcentral gyms. l
A few years after Lashley made his observa- Cerebral Blood Flow and
tions, Leao described a neurological process in
Spreading Depression
experimental animals which he designated
spreading depression. He found that when the
Spreading depression in the cortex of experi-
cerebral cortex of experimental animals was
mental animals is accompanied by prominent
stimulated in various ways, a wave of depressed
changes in blood flow (Fig. 9-5). Increased
neuronal activity accompanied by changes in
glucose metabolism, intense arteriolar dilata-
CBF extended across the exposed cortex at ap-
tion, and a substantial increase of CBF is seen
proximately the same rate that Lashley had es-
initially.29'45'50'107 The hyperemia is not coin-
timated.58 Leao proposed a possible relation-
cident with the onset of the DC potential shift,
ship between spreading depression and spread
but occurs immediately after the wave has
of the migrainous aura.59 Thus, a number of
passed at a time when the firing of cortical neu-
E ieces of data had already circumstantially re-
ited spreading depression and spreading
oligemia. Olesen's findings that presumably
rons and synaptic transmission are still entirely
blocked. This hyperemic phase is caused by the
increased local 63 demand resulting from the
show spreading oligemia are now being used
high metabolic activity and increased substrate
as the basis for modern concepts of spreading
demand required to reconstitute membrane
depression as the cause of migraine aura.
ionic gradients by active ionic transport across
neuronal and glial membranes. The spreading
depression-associated hyperemia appears to
SPREADING DEPRESSION
be mediated at least in part by a depolarization
of trigeminal sensory and parasympathetic
The spreading depression that Leao found in
fibers that results in a release of vasoactive
the exposed cerebral cortices of experimental
trigeminal and parasympathetic neurotrans-
animals such as rats and rabbits is a response
mitters (see Chapter 10).86 After the short-
of the cerebral cortex to various kinds of stim-
lasting hyperemic phase, cortical blood flow
uli including local electrical or mechanical
begins to drop and is reduced by about 20% to
stimulation or local application of either the ex-
30% below baseline, presumably because arte-
citatory amino acid neurotransmitter glutamate
rioles constrict.49'54'85 The reduction persists
or high concentrations of KCl. Any of these
for about 60 to 90 minutes, long after neuronal
stimuli sets up a transient wave front that sup-
function has returned to normal. Blood pres-
presses both evoked and spontaneous neuronal
sure autoregulation remains normal, but corti-
activity. The depression spreads in all direc-
cal vessels do not respond in a ordinary man-
tions from its site of origin. It propagates slowly
ner to changes in pCO2- The decreased blood
at a rate of 2 to 3 mm/minute across the sur-
flow seen after spreading depression in exper-
face of the cortex. Neurons are markedly de-
imental animals has been hypothesized as
polarized during the process. Simultaneously,
analogous to the spreading oligemia reported
a large, predominantly negative, DC potential
during attacks of migraine by Olesen and
develops in the extracellular space. The DC po-
colleagues.
tential shift and the neuronal depression are
accompanied by large ion fluxes in and out of
cells (Fig. 9-4). In particular, the extracellular
K + concentration increases from a resting level Mechanism of Spreading
of 3 mM to as high as 50 mM. In contrast, the Depression
concentration of extracellular Ca2+ decreases
from 1.3 mM to 0.07 mM, and Na + declines The mechanism of spreading depression is im-
from 154 to 59 mM. These impressive changes perfectly understood, but appears to involve
in ionic concentrations suggest that the elec- K + ions and the neurotransmitter glutamate.
 The Prodrome and the Aura 197

Figure 9-4. Changes in extracellular ionic concentrations, DC potential, and neuronal firing during spreading depres-
sion elicited in rat cortex. The process was initiated by a needle stab in the frontal cortex. The concentration of extracel-
lular K + markedly increases; the levels of Na + , Ca2+, and H + diminish. Recording of the discharges of a single cortical
neuron (unit act., unit activity) indicates that cessation of firing accompanies the changes in ionic levels. The neuron is
totally silent for more than 1 minute. Ve is the DC potential that is predominantly negative in the extracellular space. Slow
recovery occurs over a period of more than a minute. (Adapted from Lauritzen M: Cortical spreading depression as a pu-
tative migraine mechanism. Trends Neurosci 10:8-12, 1987, with permission of Elsevier Science.)

Enhanced neuronal excitation, coupled with spreading depression.53 Release of endogenous

firing in a localized region of the cortex, is
known to result in the local build-up of K + in
the extracellular space. The increased extra-
cellular K + is thought to depolarize adjacent,
inactive neurons, causing the process to spread.
In other words, spreading depression is hy-
pothesized to result from release of excessive
amounts of K + that can no longer be contained
by reuptake, diffusion, or transport away from
the active site by the glial K+-buffering sys-
tem.71 But in addition, glutamate is released by
the depolarization and concomitant increase in
intracellular neuronal Ca2+ that occur during
glutamate activates neuronal receptorsa pro-
cess that can also initiate movements of Na + ,
K + , and Ca2+ ions. Some or all of this ionic
movement may play an important role in the
genesis and expansion of spreading depression.
Pharmacologic antagonism of the actions of
glutamate at N-methyl-D-aspartate (NMDA)
receptors inhibits both the initiation and prop-
agation of spreading depression.53-70 At this
point, no one knows whether the actions of K +
or glutamate alone give rise to spreading de-
pression, or whether their interactions cause
the phenomenon.72
198 Pathophysiology

Figure 9-5. Cortical blood flow changes recorded by laser Doppler flowmetry (A) during and after the peak of spread-
ing depression. Spreading depression was initiated by pinprick 10 mm from the site of Doppler probe. The change in
DC potential (B) was recorded from an electrode placed under the probe. Note the initial hyperemia following the peak
of the change in DC potential followed by depression of blood flow. (Adapted from Piper RD, Lambert GA, and Duck-
worth JW: Cortical blood flow changes during spreading depression in cats. Am J Physiol 26LH96-H102, 1991, with
permission.)

MAGNETOENCEPHALOGRAPHY bral metabolism non-invasively during mi-

Postsynaptic currents generated in the cerebral
cortex cause weak external magnetic fields
that can be detected outside the head by su-
perconducting quantum interference device
(SQUID) sensors. Because experimental spread-
ing depression in animals produces such dra-
matic changes in the electrical activity of the
brain, a strong magnetic field develops. If
spreading depression occurs in humans, it
should produce changes in cranial magnetoen-
cephalographic (MEG) recordings. Indeed,
slow, long-duration magnetic field changes
have been recorded in migraine patients with
and without aura both between and during at-
tacks. These changes have not been noted in
patients suffering from other forms of head-
ache or in normal controls.3 Although the shifts
are very similar to those observed in MEG
studies in experimental animals with spreading
depression, the specificity of the signals in hu-
mans is unknown. It is still too early to state that
occurrence of spreading depression has been
demonstrated by MEG during the aura. Fur-
ther observations and replication are required.
POSITRON EMISSION
TOMOGRAPHY
Positron emission tomography (PET) is a pow-
erful technique for measuring rCBF and cere-
graine attacks. In PET, the physical properties
of positrons are employed, which are small par-
ticles emitted from radionuclides. Positrons are
equal in mass, but opposite in charge, to elec-
trons. After traveling several millimeters
through tissue, positrons interact with elec-
trons, leading to mutual destruction of the par-
ticles. Two gamma photons are formed by each
interaction and travel in opposite directions
from the site of annihilation. A pair of external
detectors attached to a coincident circuit po-
sitioned on opposite sides of the positron-
emitting source record the coincident photons
as they arrive. Repeated measurements can be
performed because the isotopes used in PET
studies have short half-lives.
The technology is cumbersome, making
PET difficult for the study of unpredictable,
spontaneous bouts of migraine. As a result,
PET has been used in a relatively small num-
ber of patients. In one exceptional investiga-
tion, however, PET measurements of CBF us-
ing 15O2-labeled water were obtained from a
patient who developed a spontaneous and un-
expected bout of migraine without aura while
she was already lying in the PET apparatus for
another purpose.110 A decrease in rCBF spread
across the cortical surface of the occipital lobes
toward the parietal and occipitotemporal areas
at a relatively constant rate. Subcortical gray
structures such as the basal ganglia and the
thalamus were unaffected. The territory of the

posterior and middle cerebral arteries was
spanned by the changes in CBF. The decreases
in CBF were substantial and were of the order
of 40%, which is larger than the decreases re-
ported with 133Xe and SPECT studies.
Much comment has been generated by this
case report because it unequivocally demon-
strated spreading hypoperfusion during a spon-
taneous attack of migraine. Compton-scattered
radiation is not a factor: it only minimally af-
fects data obtained with the PET technique.
These observations have been used to buttress
the idea that spreading oligemia is putatively
caused by spreading depression, thereby indi-
cating that spreading depression in animals is
comparable to that in humans.
The results of this one-of-a-kind study are at
odds, however, with the conceptions of mi-
graine that emerge from 133Xe blood flow and
SPECT studies. In particular, the major rCBF
changes measured by PET occurred in a pa-
tient whose minor visual blurring did not oc-
cur until well into the attack, and who accord-
ingly had an attack of migraine without aura.
If spreading depression is the postulated basis
for the migrainous aura, then the process in
this patient should have produced an aura. In
addition, the reductions in CBF were bilateral
and symmetrical. If the process responsible for
reducing CBF affects both cerebral hemi-
spheres, it is difficult to explain unilateral
auras. Previous studies using SPECT have
stressed the idea that alterations in rCBF are
not seen in bouts of migraine without
aura.49'74'77 Moreover, the degree of reduced
CBF, of the order of 40%, is substantial and
approaches ischemic levels. In sum, the data
from this one patient are undoubtedly signifi-
cant but raise questions as to the relationship
between spreading oligemia/spreading depres-
sion and the genesis of auras.
Other PET studies do not support the hy-
pothesis that spreading depression is the basis
of the migrainous aura. One PET study, for ex-
ample, investigated 11 cases of migraine with
and without aura during aura and headache
phases of attacks that, for the purposes of the
study, were precipitated by consumption of red
wine.2 When the data were analyzed on a group
basis, no significant changes in blood flow were
found during the aura, although a number of
individual subjects developed areas of de-
creased perfusion. During the headache phase,
The Prodrome and the Aura 199
areas of hypoperfusion were seen in the pri-
mary visual cortex. The results are not com-
patible with the idea that ischemia is involved
in the genesis of migraine symptoms; nor do
they promote the concept that spreading de-
pression causes the migrainous aura. Another
PET study showed slight global CBF de-
creases, but no focal rCBF changes.4
In contrast, a PET study performed on a
subject late in a spontaneous attack of migraine
with aura showed a focal reduction in CBF and
an increase in oxygen extraction, while the
cerebral oxygen consumption was normal.35 A
second patient with the same condition exhib-
ited normal oxygen extraction and oxygen me-
tabolism. The PET studies performed during
the early stages of reserpine-induced attacks of
migraine with and without aura have shown a
global decrease in the cerebral metabolism of
glucose.90 In patients with aura, the changes
were not confined to the hemisphere pre-
sumed to be site of the process responsible for
the aura. These latter findings neither support
nor negate the presence of ischemia, but they
provide little support for the hypothesis that
spreading depression localized to one hemi-
sphere is responsible for the aura of a migraine
attack.
FUNCTIONAL MAGNETIC
RESONANCE IMAGING
Magnetic resonance imaging (MRI) is based on
the detection of electromagnetic signals that
emanate from spinning hydrogen protons
when they are excited by a radio frequency
(RF) pulse applied in the presence of an ex-
ternally generated static magnetic field. The
RF pulse excites the spinning protons and
causes their spins to become synchronized
(phase locked), thereby allowing their sum-
mated contributions to produce a measurable
signal. Techniques of MRI have been adapted
in recent years so that brain images sensitive
to local changes in blood flow are possible.
Some MRI techniques allow evaluation of isch-
emia, and unlike conventional MRI, which is
used mainly to demonstrate morphologic ab-
normalities, functional magnetic resonance
imaging (fMRI) allows one to study changes in
CBF that occur as a result of neuronal activity.
Although it is not yet possible to determine ab-
200 Pathophysiology
solute blood flow, fMRI can enable collection
of repeated, multiple, high-resolution images
that are a visual record of the evolution of
events during a migraine aura. This technology
is being used to analyze both spontaneous and
evoked attacks of migraine with aura. The re-
sults, however, differ among studies.
During spontaneous visual auras, relative de-
creases in CBF (approximately 16% to 53%)
limited to the gray matter of the occipital cor-
tex contralateral to the involved visual hemi-
field have been described.15'93 Unlike the
133
Xe studies, brain regions other than the oc-
cipital cortex did not show gross changes in
blood flow. The changes in rCBF were ac-
companied by modest decreases in cerebral
blood volume (6% to 33%). Possible "spread-
ing" of the perfusion defect was seen in one
subject. Hyperemia was not seen at any point
during the patients' auras or headaches. The
CBF changes during auras remained well
above the threshold for ischemia. In addition,
there were no observable changes in the ap-
parent diffusion coefficient (a measure of the
mobility of water molecules in the brain) either
while the patients were symptomatic or after
resolution of the visual symptoms. Because
changes in the mobility of water are often a
consequence of cerebral ischemia, one could
infer that the reduced CBF during the aura had
not been substantial enough to produce cere-
bral ischemia. No significant changes in CBF
were noted in patients with migraine without
aura.
The blood oxygenation level-dependent
fMRI technique (fMRI-BOLD) takes advan-
tage of MRFs signal intensity being propor-
tional to the amount of oxyhemoglobin and
deoxyhemoglobin in erthrocytes. In this tech-
nique, deoxyhemoglobin (which is paramag-
netic) is used as an endogenous contrast
agent. When neuronal activity increases, lo-
cal metabolism is also augmented and leads
to local vasodilatation and increased blood
volume and blood flow. As a result, an excess
of oxygenated hemoglobin is delivered to the
activated brain region, the local concentra-
tion of deoxyhemoglobin decreases, and the
MR signal in those regions increases in in-
tensity. In other words, increases in BOLD
signal are typically detected when CBF in-
creases more than the cerebral metabolic rate
in activated cortical regions (e.g., as a result
of visual stimulation).
The BOLD technique was used to deter-
mine altered blood flow in a study that used vi-
sual activation with a checkerboard stimulus to
trigger migraine headaches in patients with and
without aura.11 Some, but not all, visually trig-
gered headaches (with and without auras) were
preceded and accompanied by suppression of
BOLD response to the on-off visual stimulus.
The suppression propagated into contiguous
occipital cortical areas at a rate that ranged
from 3 to 6 mrn/min; it was accompanied by a
bilateral increase in T2*-weighted signal in-
tensity, a finding presumably indicating va-
sodilatation, increased perfusion, and tissue hy-
peroxygenation. As noted above, the increased
perfusion with intense arteriolar dilatation and
an increase of CBF immediately succeeded the
band of spreading depression in experimental
animals. Two of the patients who developed vi-
sual auras developed suppression and increases
in rCBF. Their auras, however, were atypical
compared to their usual spontaneous auras.
Correlations between the increases of blood
flow and headache showed that bilateral in-
creases in CBF were seen in patients with both
unilateral and bilateral headaches, changes in
CBF were not seen in all patients who devel-
oped headaches, and in one patient only uni-
lateral CBF changes were seen, although the
patient experienced bilateral pain. In another
report by the same group, hyperoxygenation of
the occipital cortex bilaterally was seen in a pa-
tient with a spontaneous visual aura consisting
of a homonymous quadrantanopsia.106 The au-
thors postulated that initial activation of a mi-
graine attack, independent of whether there
are aura symptoms, is associated with a spread-
ing suppression of cortical responses to visual
stimuli. Their inference is that spreading sup-
pression is a manifestation of spreading de-
pression. But if that is so, their conclusions ex-
pand spreading depression to migraine both
with and without aura.
Another investigation that used similar tech-
niques showed BOLD signal changes during
typical spontaneous visual auras in three sub-
jects.3011 Initially, a focal increase in the BOLD
signal (possibly an manifestation of vasodilata-
tion) occurred within the contralateral extra-
striate occipital cortex. This BOLD alteration
advanced contiguously at a rate averaging 3.5
mm/minute over the occipital cortex in a
retinotopic fashion. This advance was compat-
ible with the outward spread of the visual aura

from central to peripheral visual fields. The
BOLD signal (and the BOLD response to vi-
sual activation) then diminished (possibly an
indication of vasoconstriction). The first af-
fected areas were the first to recover.
THE SPREADING DEPRESSION
HYPOTHESIS AND MIGRAINE
Because there is no better explanation cur-
rently available, many investigators now con-
sider spreading depression to be a plausible
explanation for the migraine aura. The evi-
dence is all circumstantial, but substantial
nonetheless. The hypothesis is supported by
similarities between changes in blood flow/
oxygenation in humans and certain phenomena
associated with spreading depression in animal
models.52 For example, spreading depression
is followed by cortical hyperemia and a short-
lasting hyperemia has been reported in the ini-
tial stages of visual auras.1i.2530a,76,i06 More_
over, the hyperemia has been reported to to
expand progressively in size just as spreading
depression does in laboratory animals.30a The
initial hyperemia in cortical spreading depres-
sion is followed by hypoperfusion. The modest
CBF reductions reported by the Copenhagen
group in most patients are approximately the
same as the level found in experimental ani-
mals after spreading depression, and they too
appear to expand at a constant rate.55 As noted
above, the cerebrovascular response to changes
in pCO2 is impaired during migraine with aura
and a similar pattern occurs in experimentally
induced spreading depression. Finally, the
oligemia associated with spreading depression
continues for 1 to 2 hours in experimental an-
imals, and the oligemia in migraine patients
persists for 1 to several hours in humans.
Despite all of this circumstantial evidence,
whether spreading depression in animal ex-
periments is identical to the phenomena ob-
served in humans during the aura is far from
certain. While spreading depression can be
easily provoked by cortical stimuli in lower an-
imals such as rats and rabbits with smooth
(lissencephalic) cerebral cortices, it is more dif-
ficult to elicit in animals such as cats and mon-
keys with convoluted (gyrencephalic) cortical
surfaces. Similarly, propagation of spreading
depression also appears to be limited in ani-
The Prodrome and the Aura 201
mals such as primates with complex cortical ar-
chitecture. Spontaneous, unprovoked spread-
ing depression is not observed in experimental
animals. Furthermore, spreading depression
has never been convincingly demonstrated in
the undamaged human neocortex.28
Some inhalant anesthetic agents block
spreading depressionperhaps this accounts
for the inability to record the phenomenon of
spreading depression in many neurosurgical
patients. Even so, stimuli that reliably evoke
the process in experimental animals fail to do
so in cerebral cortices of non-anesthetized pa-
tients undergoing cortical resections.66'84'85 A
possible example of the phenomenon appear-
ing intraoperatively in the human hippocam-
pus and caudate nucleus has been reported, al-
though the DC potential changes produced by
injection of KC1 in that study were not associ-
ated with the suppression of neuronal activ-
ity.103 Repetitive cycles of spreading depres-
sion have been recorded from the cortex of one
deeply comatose patient with severe head in-
jury.65
Because spreading depression is a reversible
phenomenon, it cannot explain either the fre-
quent persistence of neurological deficits after
attacks of migraine with aura, the long-lasting
focal abnormalities demonstrated in some pa-
tients by the use of electroencephalographic
(EEC) and computed tomographic (CT) scans,
or the rare vascular occlusions seen after auras.
In rare instances, the aura, particularly if it is
visual, may reach its peak of intensity abruptly.
It would be difficult to explain such phenom-
ena by a spreading depression-like process. In
addition, aura symptoms do not always con-
form to the pattern of scotomas and teichop-
sias advancing across the visual field. Spread-
ing depression affects a larger area of cortex
than the isolated parts associated with aura
symptoms. Comparison of the pharmacology of
spreading depression in animals and the aura
in humans has revealed other discrepancies. As
one example, various drugs used in the pro-
phylaxis and in the acute treatment of migraine
affect neither the development nor the propa-
gation of experimental spreading depres-
sion.31'40'41 Transient recovery from visual aura
symptoms has been observed after administra-
tion of vasodilator substances, whereas such
compounds have no effect on the elicitation or
propagation of experimental spreading depres-
sion.32^41'46'96
202 Pathophysiology
The spreading oligemia/spreading depres-
sion hypothesis depends heavily upon distinc-
tions between cerebral oligemia and ischemia,
yet the 133Xe methods used to quantify cere-
bral perfusion suffer from technical shortcom-
ings that make it difficult to discriminate
oligemic values (approximately 40 ml/100 g/
minute) from ischemic values (approximately
20 ml/100 g/minute). As a result, the Copen-
hagen group's conclusions about rCBF may be
open to alternative interpretations. The phe-
nomenon known as scattered radiation (Comp-
ton scatter) raises questions about what their
data may mean.99'100 In addition, as noted be-
low, MR and PET studies that do not have the
drawbacks of 133Xe methods also show flow re-
ductions that approach ischemic levels in some
investigations.
CLINICAL OBSERVATIONS:
AURAS AND CEREBRAL
ISCHEMIA
Bits and pieces of clinical data from a variety
of sources point toward and away from a vas-
cular process as the cause of the migraine aura.
Many clinicians would ascribe a vascular pro-
cess that produces ischemia to various aura
phenomenaamong them, those neurological
deficits that persist well beyond the end of a
migraine headache and that may even remain
permanently. Also on the list are protracted,
focal EEG abnormalities and hypodense areas
on CT scans. Of particular importance in as-
cribing these phenomena to an ischemic pro-
cess is the observation that focal hypodensities
on CT scans taken after attacks of migraine
with aura are identical in general contour and
topography to those of patients with non-
migrainous stroke.10'36'37 Magnetic resonance
imaging has also documented similar cerebral
parenchymal lesions in patients who have had
attacks of migraine with aura.19-79'88
Traditionally, the cerebral ischemia puta-
tively responsible for long-lasting or permanent
migrainous symptoms has been thought by
clinicians to be caused by vasospasm. This
proposition, which is based more on intuition
than on experimental evidence, remains con-
troversial.8'^2 Angiographic examples of arte-
rial narrowing often ascribed to vasospasm
have been seen associated with attacks of mi-
graine with aura.12'17'27'64'88'95'97'101 A mag-
netic resonance angiogram (MRA) in a young
woman that was performed 6 hours after the
onset of a visual/motor/sensory aura showed a
narrow-caliber posterior cerebral artery with
occlusion of distal branches.67 A follow-up
MRI and MRA 16 days after the attack showed
complete resolution of the arterial changes. In
some cases in which arterial narrowing has
been observed, however, the site does not cor-
relate with the clinical features as to location
or temporal course of symptoms.101 A small
number of angiograms performed in patients
with presumed migrainous infarction have
shown occlusion of an appropriate intracranial
artery.13'16'20 In contrast, some angiographic
investigations performed after attacks charac-
terized by long-lasting or permanent neuro-
logical changes have not demonstrated
changes in arterial diameter or arterial occlu-
sion.7'14'22'81'82'88 Absent the ability to predict
which headache will result in permanent
deficits so that angiography can be performed
during that attack, ascribing the migrainous in-
farction to ischemia (caused by spasm of an in-
tracranial artery) is difficult to prove. But
within the context of having to choose the pri-
mary neuronal and primary vascular hypothe-
ses, one would not expect spreading depression
to produce persisting neurological deficits be-
cause the electrophysiological changes that
characterize it are completed within 15 min-
utes and the process is considered a totally re-
versible one that does not injure neurons.
If changes in carotid blood flow occurred
during attacks of migraine, the vessels of the
optic fundus or of the conjunctiva might be ex-
pected to show alterations in diameter. Retinal
vessels are branches of the ophthalmic artery,
which, in turn, is derived from the internal
carotid artery. Each conjunctival circulation
consists of an anastomosis of branches from
both the internal and external carotid circula-
tions. These vessels are relatively easy to ac-
cess, but unfortunately studies have not pro-
duced a coherent picture of vascular changes
during migraine. During migraine attacks, the
vessels of the optic fundus show either no sig-
nificant changes or only minor variations.108
And although the caliber of conjunctival ves-
sels is reported to vary during bouts of mi-
graine, there is no agreement as its signifi-
cance. Most observers have noted dilatation of
conjunctival blood vessels accompanied by re-
duced blood flow and aggregation of red

cells.6'80'104'109 These latter investigations are
compatible with known reductions in migraine-
induced capillary flow in the carotid system.
SUMMARY
Studies from a number of laboratories have
documented CBF changes in the brains of pa-
tients who suffer from migraine with aura. Al-
though reductions of CBF during the aura have
been repeatedly noted, data from these stud-
ies vary as to the nature and degree of the re-
duction. And despite enormous amounts of ef-
fort, we can still do no more than theorize as
to whether these changes in CBF represent
primary or secondary events in migraine. The
idea that spreading depression is the basis for
both the aura and changes in CBF has perme-
ated thinking about the pathophysiology of mi-
graine with aura. What many do not realize is
that spreading depression is a working hypoth-
esisnot an accepted factand that data in-
compatible with the postulate are available.
The next chapters will explore what is known
and what is speculated about other aspects of
the pathophysiology of migraine headaches.
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Chapter 1 0
Control of the Cerebral Circulation
SYMPATHETIC INNERVATION
PARASYMPATHETIC INNERVATION
Cholinergic Parasympathetic Nerves
Nitric Oxidean Atypical Modulator/
Transmitterand Parasympathetic Nerves
Vasoactive Intestinal Polypeptide
TRIGEMINOVASCULAR FIBERS AND
CEREBRAL BLOOD FLOW
REGULATION
BRAIN STEM EFFECTS ON THE CRANIAL
CIRCULATION
Locus Coeruleus
Raphe Nuclei
Serotonin Receptors
Serotonin and Intracranial Blood Vessels
Brain Stem Activity and Migraine
Changes in cerebral blood flow (CBF), as the
previous chapter attests, are implicated in the
onset and development of migraine attacks.
Perhaps alterations in CBF play a role in other
phases of migraine as well. But control of the
cerebral circulation is a very complex process,
or set of processes, and there is much that we
do not yet understand about it quite apart from
how it affects (and is affected by) migraine. We
do know that neural influences exerted by the
release of various types of transmitters from
perivascular nerves are among the factors im-
portant in regulating CBF, as are endothelial
control of cerebrovascular tone and the level
of local metabolites and chemical stimuli pro-
duced by cerebral tissue metabolism (meta-
bolic coupling).
Cerebral arteries and arterioles are inner-
vated by a dense network of perivascular nerve
fibers that come from several sources both ex-
BASAL NUCLEUS
ENDOTHELIAL CONTROL OF CEREBRAL
VESSELS
Nitric Oxide
Arachidonic Acid Metabolites
Endothelins
NITRIC OXIDE AND NEURONS
Nitric Oxide and Spreading Depression
OTHER FACTORS REGULATING
CEREBRAL BLOOD FLOW
Protons and Carbon Dioxide
Bradykinin
Histamine
Adenosine
SUMMARY
trinsic and intrinsic to the brain. These sources
include an extensive sympathetic innervation
from the superior cervical ganglia, a modest
parasympathetic nerve supply arising predom-
inantly from the facial nerve with cell bodies
in the sphenopalatine and otic ganglia and in
the internal carotid microganglia, a supply from
the trigeminovascular system, an innervation
from brain stem nuclei including the locus
coeruleus and possibly the raphe nuclei, and
fibers originating in the basal forebrain. These
nerve fibers secrete a remarkable number of
neurotransmitters and neuromodulators that
alter blood vessel diameter. Among such com-
pounds are norepinephrine, acetylcholine,
neuropeptide Y, vasoactive intestinal peptide,
nitric oxide, serotonin, substance P, neurokinin
A, and calcitom'n gene-related peptide.
Recent findings that endothelial cells syn-
thesize and release substances that produce va-
207
208 Pathophysiology

sodilatation and vasoconstriction have led re- SYMPATHETIC INNERVATION

searchers to realize that the endothelium plays
a major, and hitherto unrecognized, part in the
regulation of vascular tone. Evidence has ac-
cumulated that nitric oxide, released by endo-
thelial cells, may be of special importance as a
regulator of the cerebral microcirculation dur-
ing neuronal activity. As for regional cerebral
blood flow (rCBF), cerebral tissue metabolism
raises the the levels of local metabolites and
various chemical stimuli increase rCBF by
means of several different molecular regula-
tors. A number of chemicals, such as arachi-
donic acid metabolites, bradykinin, and hista-
mine, are released by tissue cells, platelets, and
mast cells. These substances have also been
proposed as local regulators of CBF.
Denervation experiments have shown that the
majority of intracranial sympathetic fibers orig-
inate in the superior cervical ganglia (Fig.
10-1 ).71 A comparatively sparse contribution,
mainly to the more caudal arteries of the cir-
cle of Willis that supply the vertebrobasilar ter-
ritory, is derived from the stellate ganglion. All
these ganglia give rise to fibers that follow
the internal and external carotid arteries and
their branches to form a well-developed plexus
in the adventitia of cerebral arteries and
arterioles.
Norepinephrine has been considered the
primary transmitter in perivascular sympa-
thetic nerves. An abundant supply of nor-

Figure 10-1. Schematic illustration of the autonomic innervation of the cerebral vasculature. The source of the sympa-
thetic innervation is the spinal cord. The cervical sympathetic preganglionic nerve innervates the superior cervical gan-
glion which then supplies the major blood vessels. Both norepinephrine (NE) and neuropeptide Y (NPY) are colocalized
in the postganglionic adrenergic nerves. The preganglionic parasympathetic nerves originate in the superior and inferior
salivatory nuclei and project as the greater and lesser superficial petrosal nerves to the sphenopalatine and otic ganglia.
Both acetylcholine (ACh) and vasoactive intestinal polypeptide (VIP) are colocalized in some parasympathetic postgan-
glionic cholinergic nerves. Many, if not all, postsynaptic cholinergic nerves also release nitric oxide (NO). (Adapted from
Hara H, Hamill GS, and Jacobowitz DM: Origin of cholinergic nerves to the rat major cerebral arteries: coexistence with
vasoactive intestinal polypeptide. Brain Res Bull 14:179-188, 1985, with permission.)

adrenergic sympathetic fibers surrounds cere-
bral arteries, ranging from large pial arteries to
small parenchymal arterioles. 38 In contrast,
veins have a less dense sympathetic innerva-
tion. Arterioles are not all innervated to the
same degree, however, and the density of no-
radrenergic sympathetic innervation varies
markedly among different regions of the brain.
As an example, 60% of the arterioles in the
parietal cortex have a noradrenergic sympa-
thetic innervation, but only 10% to 30% of the
arterioles in the medulla, occipital cortex, and
cerebellum have such an innervation.42 This
suggests that the sympathetic nervous system
has preferential effects on certain regions of
the brain.123 Noradrenergic fibers from the lo-
cus coeruleus also contribute to the innerva-
tion of the cranial vasculature.
Perivascular application of norepinephrine,
or stimulation of the superior cervical trunk,
generally results in constriction of primate
cerebral vessels.40'147 But although they all
constrict to some degree, cerebral arteries are
less sensitive to exogenous norepinephrine and
sympathetic stimulation than are peripheral ar-
teries. Norepinephrine-induced contractions
of human cerebral vasculature are blocked by
a-adrenoceptor antagonists.136 Cerebral arter-
ies in vitro can also undergo /3-adrenoceptor-
mediated vasodilatation in response to appli-
cation of exogenous norepinephrine. But al-
though /3i- and /32-adrenoceptors have been
demonstrated on human pial arteries, the role
of/3-adrenoceptors is obscure.33
Recent evidence also shows that norepi-
nephrine is not the only transmitter substance
released from sympathetic nerve terminals.
Most sympathetic postganglionic perivascular
nerves also contain neuropeptide Y (NPY),
colocalized with norepinephrine.33 NPY-
immunoreactive nerve fibers appear to be the
most abundant of all the peptide-containing
nerve populations in the cerebrovascular bed
of both experimental animals and humans. A
dense network of NPY-containing nerve fibers
in the superficial layers of the brain lies close
to small arterioles. Numerous NPY-containin
fibers are also seen in the wall of the major ar-
teries of the circle of Willis and around pial ar-
teries. Via actions at YI receptors, NPY not only
serves as a direct and potent constrictor of
cerebral and pial arteries and arterioles, but it
also has complex interactions with norepi-
Control of the Cerebral Circulation 209
nephrine.2 NPY's postjunctional actions en-
hance blood vessel contractions produced by
exogenous norepinephrine or stimulation of
the sympathetic innervation. The peptide also
has prejunctional effects that limit the release
of norepinephrine from nerve terminals. The
postjunctional potentiating actions usually pre-
vail over the prejunctional effects.
Despite decades of study, the role of the ex-
trinsic sympathetic system in regulating CBF
remains uncertain.'5 Resting sympathetic
tone, which is present in other vascular beds,
appears minimal in the cerebral circulation
under normal conditions, as witnessed by find-
ings that sectioning of the cerebrovascular
sympathetic supply has little effect on resting
CBF. Moreover, in contrast to potent actions
in other vascular beds, sympathetic stimula-
tion produces only modest changes in CBF.16
Sympathetic stimulation does constrict large
cerebral arteries, although small resistance
vessels downstream are either unaffected or
dilate so slightly that blood flow is essentially
unaltered. It does appear that the role of the
sympathetic innervation becomes more signif-
icant, however, when steady-state conditions
are altered. The sympathetic system may func-
tion as a vasoconstrictor system to limit cere-
brovascular dilatation and to modulate in-
creases in flow evoked by hypertension,
intense metabolic stimuli, or hypoxia. How mi-
graine might fit into the workings of this sys-
tem is unknown.
PARASYMPATHETIC
INNERVATION
Just as our present knowledge of how the sym-
pathetic innervation of the cerebral circulation
may function to regulate CBF is limited, the
case for the parasympathetic nerve supply is
also confusing. It is known that parasympa-
thetic nerves which innervate cerebral vessels
secrete or release at least three substances:
acetylcholine, nitric oxide (NO), and vasoactiv
intestinal polypeptide (VIP). Cerebral neuro-
genic vasodilatation, the major effect produced
by activation of the parasympathetic system,
appears to be largely the result of the actions
of NO. How acetylcholine and VIP function is
not entirely understood.
210 Pathophysiology
Cholinergic Parasympathetic
Nerves
Immunohistochemical mapping studies have
elucidated the origins and pathways of cranial
cholinergic parasympathetic nerves. Pregan-
glionic parasympathetic neurons are present
in the superior and inferior salivatory nuclei
situated rostral to the dorsal motor vagus nu-
cleus (Fig. 10-1). Postganglionic cholinergic
parasympathetic fibers that innervate supra-
tentorial vessels arise from cell bodies in the
superior salivatory nucleus, exit from the brain
stem in the seventh (facial) cranial nerve, pass
through the geniculate ganglion without
synapsing, and traverse the greater superficial
petrosal nerve to synapse in the sphenopalatine
and otic ganglia and internal carotid mini-
ganglia.70''1'14" Cholinergic fibers from the
sphenopalatine ganglia are then distributed to
major cerebral and dural vessels by means of
the ethmoid nerves as they traverse the eth-
moid foramina. Postganglionic parasympa-
thetic innervation of the basilar artery comes
mainly from cell bodies in the vagal ganglia, al-
though there is some contribution from the
sphenopalatine ganglia. Perivascular choliner-
gic nerves are more dense in the rostral areas
of the brain. Innervation is heaviest in arteries
and larger arterioles, and somewhat sparse in
intraparenchymal vessels. Although stimula-
tion of the parasympathetic system at each of
these points can increase blood flow, it is now
clear that much, if not all, parasympathetic va-
sodilating actions result from the actions of
NO. In the context of the pathogenesis of mi-
graine pain, it should be noted that stimulation
of the parasympathetic system can produce va-
sodilatation of dural and meningeal vessels.
Nitric Oxidean Atypical
Modulator/Transmitterand
Parasympathetic Nerves
Nitric oxide synthase (NO synthase, the en-
zyme responsible for the synthesis of NO) is
localized in cerebral and meningeal perivascu-
lar nerve fibers, and in cholinergic neurons in
the sphenopalatine ganglion.10'"4-84 Choliner-
gic nerve fibers that contain NO synthase are
also distributed to major arteries constituting
the circle of Willis and its branches.139 Inhibi-
tion of NO synthase reduces the cholinergic va-
sodilator response. Because of this, it appears
that a substantial portion of the cerebral neu-
rogenic vasodilator response involves NO.138
Two processes may be involved: activation of
muscarinic receptors on endothelium with sub-
sequent synthesis and endothelial release of
NO, and the release of NO from the same
parasympathetic fibers that release acetyl-
choline.
The search for the identity of the potent va-
sodilator known as endothelium-derived relax-
ingfactor (EDRF) led to the discovery that NO
is not only a transmitter/modulator released by
parasympathetic perivascular nerves but is also
present in, and released from, vascular endo-
thelium, including the endothelium of cerebral
arteries, and neurons (Fig 10-2).50>78 Its
synthesizing enzyme, NO synthase, requires
nicotinamide-adenosine dinucleotide phos-
phate (NADPH) and oxygen to convert the
guanidino nitrogen of the semi-essential amino
acid L-arginine into NO and citrulline. Neural
and endothelial isoforms of the enzymes are
constitutively expressed, and when the intra-
cellular Ca2+ concentration is elevated as a re-
sult of receptor-dependent agonist stimulation,
association with the Ca2+/calmodulin complex
occurs with high affinity, resulting in enzyme
activation.
Figure 10-2. Schematic representation of the sources of
nitric oxide (NO) in the CNS. Nitric oxide is produced by
endothelium, neurons, and astrocytes. Activation of gluta-
mate (Glu) receptors stimulates NO synthase, causing lo-
cal production of NO, which can diffuse extracellularly to
affect local arterioles. Parasympathetic nerve fibers are
present in the walls of arterioles. Astrocytes can also re-
lease NO extracellularly. (Adapted from Faraci FM and
Brian JE: Nitric oxide and the cerebral circulation. Stroke
25:692-703, 1994, with permission.)

Nitric oxide is an unstable, free-radical,
lipophilic molecule with a half-life of <5 sec-
onds and a diffusion distance of 50 to 100 fj,m
in biological tissues. The compound appears
unique among modulators in that it does not
act on conventional cell surface receptors. In-
stead, NO released from perivascular nerves,
neurons, and endothelium by diffusion, rather
than by exocytosis, diffuses across the cell
membrane of vascular smooth cells where it di-
rectly activates the soluble isoform of guany-
late cyclase within the cells. The result is the
synthesis and accumulation of intracellular
cyclic guanosine monophosphate (cGMP). In
turn, cGMP, acting as a second messenger, de-
creases vascular tone. The exact mechanism of
this process is unknown, but it would appear
that activation of cGMP-dependent protein ki-
nases plays an important role in NO-induced
vasodilatation. In addition, NO plays a pivotal
role in regulating cytosolic Ca2+ levels by pro-
moting Ca2+ storage into intracellular com-
partments, increases in Ca2+ efflux, and de-
creases of Ca2+ influx through the smooth
muscle cell membrane. These effects lead to a
reduction in the cytosolic Ca2+ concentration
and to myosin dephosphorylation, and pre-
sumably are important in vascular smooth mus-
cle relaxation.
Vasoactive Intestinal Polypeptide
Nerve fibers containing VIP form a prominent
plexus in the walls of both cerebral and ex-
tracerebral blood vessels.35'55 Many VlP-con-
taining fibers emanate from the sphenopalatine
ganglion with contributions from the otic gan-
glion and from microganglia around the inter-
nal carotid artery.69'132'14" The VIP-containing
fibers are also found on all the vessels of the
circle of Willis but are most prominent on the
anterior vessels.26'154 Despite an overlap in the
pattern of distribution of acetylcholine- and
VIP-containing cerebrovascular nerves, it is
unclear if the two transmitters are colocalized
in the same neurons.25'152
With regard to function, VIP causes relax-
ation of isolated cerebral arteries, arterioles,
and veins by activating specific VIP receptors
on smooth muscle cells. This VIP-induced
vasodilatation is most prominent in small ar-
teries and arterioles. It does not depend upon
an intact endothelium and presumably does
Control of the Cerebral Circulation 211
not involve NO. However, as as the case with
acetylcholine, NO appears to be is co-released
with VIP. As expected from these observations,
intracarotid infusion of VIP causes modest in-
creases of CBF in primates.36
TRIGEMINOVASCULAR FIBERS
AND CEREBRAL BLOOD
FLOW REGULATION
In addition to sympathetic and parasympa-
thetic innervation of cerebral vasculature,
neural influences from the trigeminovascular
system are exerted on the cerebral and
meningeal circulations. Not only do trigemi-
novascular fibers constitute an afferent sensory
system but they also have vasomotor functions.
Afferent nociceptive trigeminal fibers that in-
nervate dural and pial vessels both store and
secrete neuropeptides. These neuropeptides,
especially substance P, neurokinin A, and cal-
citonin gene-related peptide (CGRP), function
as neurotransmitters.68'99'151 Trigeminovascu-
lar fibers release neurotransmitter peptides on
secondary neurons in the brain stem and spinal
cord. But, as will be discussed in detail in the
next chapter with regard to the genesis of mi-
graine pain, it has now become apparent that
such fibers also release neuropeptides periph-
erally from their free endings on blood vessels
in brain and meninges.31
Ample immunocytochemical evidence has
established that the human cerebral and men-
ingeal circulations are supplied by popula-
tions of nerve fibers containing substance P,
neurokinin A, and CGRP. There is also direct
physiological evidence provided by stimulation
experiments that neuropeptides have cerebral
vasodilatory properties. In fact, CGRP is the
most potent vasodilator transmitter found in
the cerebral vascular system.80 When the
nasociliary nerve is stimulated, an increase in
ipsilateral cortical blood flow results.41 This va-
sodilatation is caused mainly by CGRP re-
leased from trigeminovascular fibers. Similarly,
electrical stimulation of the dura mater causes
dural vasodilatation that is mostly produced by
CGRP.87'101 The vasodilating properties of
CGRP depend upon activation of adenylyl cy-
clase and the production of cAMP in cerebral
vascular smooth muscle.80 In contrast, the va-
sodilatation produced by substance P and neu-
212 Pathophysiology
rokinin A requires an intact endothelium and
is largely mediated by the release of NO (see
below)/12
Other factors involving the trigeminal con-
trol of CBF are also important. When the
trigeminal ganglion itself is stimulated, in-
creased CBF results in large part from reflex
neurovascular events. The pathway is believed
to involve a reflex arc whose afferent limb con-
sists of trigeminal primary afferent fibers
synapsing in the brain stem and connecting the
spinal trigeminal nucleus with the superior and
inferior salivatory nuclei.60 The efferent limb
of the reflex involves the seventh cranial nerve
(which is the main parasympathetic outflow for
cerebral and extracerebral arteries) and the
sphenopalatine and otic ganglia. Although sec-
tioning the seventh cranial nerve does not
alter resting CBF, sectioning it (or administer-
ing the ganglion blocking agent hexametho-
nium) reduces the increased in arterial blood
flow ordinarily evoked by trigeminal ganglion
stimulation.61 The reflex vasodilatation em-
ploys the transmitter VIP, exerting indirect
effects on carotid arterial blood flow.61'63 A
similar neurovascular reflex also operates in
the intracranial circulation, but with less
effect.56'115
Because trigeminal nerve sectioning does
not alter resting CBF, it is thought that
trigeminovascular neurons have no tonic effect
on resting CBF and, accordingly, play only a
modest role in the moment-to-moment control
of the cerebral circulation." But, as discussed
above, trigeminal ganglion stimulation in-
creases rCBF, specifically in the frontal and
parietal cortices of both experimental animals
and humans.39-56 Extracerebral blood flow is
also increased by such stimulation.44'59 Perhaps
the trigeminovascular system functions to
reestablish normal vascular diameter and suf-
ficient cerebral perfusion when there is intense
cerebral vasoconstriction.39 Here, again, we
must await further data.
BRAIN STEM EFFECTS ON THE
CRANIAL CIRCULATION
Locus Coeruleus
Central, as opposed to sympathetic, noradren-
ergic innervation of the brain arises from sev-
eral discrete collections of cells that are dis-
tributed from the rostral pons to the caudal
medulla. The most significant body of central
noradrenergic neurons is located within the lo-
cus coeruleus, a. prominent, pigmented nucleus
in the caudal pons. Although the locus
coeruleus is small, highly collateralized branches
arising from its neurons innervate the entire
neuraxis, including the forebrain, brain stem,
cerebellum, and spinal cord. In addition to
synaptic contacts on neurons, some noradren-
ergic fibers from the locus coeruleus lie in close
apposition to small intraparenchymal mi-
crovessels, capillaries, and venules, especially
those in the brainstem.133 This neuronal and
vascular intraparenchymal innervation is pre-
dominantly ipsilateral. Doubt exists as to
whether fibers from the locus coeruleus in-
nervate large cerebrovascular vessels. They do
not appear to innervate dural blood vessels.96
The locus coeruleus is considered by some
investigators to be a central counterpart of the
sympathetic ganglia, innervating the cere-
brovascular system in much the same way that
sympathetic nerves supply peripheral vascular
beds. Although investigations of the influence
the locus coeruleus has upon CBF in experi-
mental animals have not always been in agree-
ment, a number of studies have shown that
electrical stimulation of the locus coeruleus
produces a rapid, but modest, decrease in ip-
silateral CBF as a result of vasoconstriction, as
well as increased vascular resistance in the in-
ternal carotid circulation.57'58'91'114 In experi-
mental animals, CBF is reduced by approxi-
mately 35%, especially in the ipsilateral
occipital cortex.57 Such results imply that the
vascular input from the locus coeruleus has a
constrictor action on cerebral blood vessels.
The vasoconstriction is mediated by a-adreno-
ceptors in a manner analogous to the sympa-
thetic innervation of cranial blood vessels.
Raphe Nuclei
Serotonin (S-HT)-containing CNS neurons are
confined to the raphe nuclei, a collection of
cells in the median and paramedian zones of
the brain stem. From the raphe nuclei, highly
branched, ascending and descending axons
project to, and innervate neurons in, virtually
the entire CNS. There is thus little doubt that
5-HT acts as a central neurotransmitter and has
potent vasoactive properties. But whether
serotonergic nerve fibers of central origin
 Control of the Cerebral Circulation 213

i.e., nerve fibers that both synthesize and
release 5-HTinnervate large or small pial
vessels is a matter of controversy. Although bio-
chemical studies and fluorescence histochem-
ical investigations have demonstrated a system
of perivascular nerves that contain 5-HT, it is
uncertain whether these fibers are of periph-
eral or central origin, and whether the pres-
ence of the indolamine in them results from
uptake or synthesis.20'125
Perivascular sympathetic nerve terminals
are clearly able to take up 5-HT from extra-
cellular fluid in vitro, store it, and release it
when depolarized. In experiments with blood
vessels fixed by immersion after dissection
(and therefore exposed to 5-HT), 5-HT-con-
taining nerve fibers emanating from the supe-
rior cervical ganglia appear to innervate the
major cerebral arteries and small pial vessels.
In experiments where vessels are fixed before
dissection, 5-HT-containing fibers are sparse
or absent. This finding has led to the hypoth-
esis that, in the cerebral circulation, 5-HT is
taken up and stored in cerebrovascular sym-
pathetic nerves. It has also led to the conclu-
sion that there are no authentic serotonergic
nerve fibers innervating cerebral arteries. In
other words, 5-HT may be a "false neuro-
transmitter" of blood vessels. Along this line,
nerve fibers containing 5-HT, but not trypto-
phan-5-hydroxylase (the rate-limiting enzyme
in the biosynthesis of 5-HT), have also been
demonstrated in the dura mater of experi-
mental animals.131 An additional 5-HT com
ponent presumably arises from the raphe nu-
clei (Fig. 10-3), although fibers originating
there do not appear to innervate the
dura 94>96.97.104

Figure 10-3. Schematic representation of the serotonergic innervations of extracerebral and intraparenchymal blood ves-
sels. Extracerebral blood vessels are innervated by serotonergic fibers that putatively arise from the superior cervical gan-
glion with a possible contribution from serotonergic fibers originating in the brain stem raphe nuclei. As these vessels bi-
furcate and perforate the cortical mantle, they are initially surrounded by the Virchow-Robin spaces. When these spaces
disappear, the intraparenchymal microvessels composed of small arterioles, small veins, and capillaries develop. These in-
traparenchymal vessels appear to be innervated by serotonergic fibers from the raphe nuclei. Aq, aqueduct of Sylvius;
Scp, superior cerebellar peduncle. (Adapted from Cohen Z, Bonveto G, Lacombe P, and Hamel E: Serotonin in the reg-
ulation of brain microcirculation. Prog Neurobiol 50:335-362, 1996, with permission of Elsevier Science.)
214 Pathophysiology

Serotonin Receptors of the subclasses (e.g., 5-HT4 and S-HTy) use

It has been established that 5-HT produces
both contraction and relaxation of cerebral and
meningeal blood vessels. The dichotomy of ef-
fects depends upon the blood vessel that re-
ceives a 5-HT input and especially upon the
5-HT receptors that are present on that ves-
sel. Although our knowledge about 5-HT re-
ceptors is incomplete, substantial molecular,
biochemical, and pharmacological evidence
indicates that there are seven distinct 5-HT re-
ceptor classes (Table 10-1). Molecular cloning
has further identified receptor subtypes,
bringing the total number of different 5-HT
receptors to 14. Three fundamental properties
of a receptorits operational (pharmacologi-
cal), transductional (receptor coupling to G
proteins and second messengers, or direct cou-
pling to ion channels), and structural (primary
amino acid sequence) attributeshave been
used as the basis for the most recent classifi-
cation proposed by the Receptor Nomencla-
ture Committee of the International Union
of Pharmacology. Using this classification
scheme, most 5-HT receptor subclasses ex-
hibit a distinct pharmacology, although some
the same transduction pathways. (Note the re-
vised nomeclature: the receptor previously
designated 5-HTpp is now called 5-HTjg; the
former 5-HT1Da receptor is now referred to as
5-HT ID; 5-HTs is now 5-HTip, and the former
5-HTic receptor is now 5-HT2C-)
Among the seven receptor types in the new
classification, the anti-migraine drug sumatrip-
tan is an agonist at sites in the 5-HTi class. Not
surprisingly, researchers in the field of mi-
graine have focused attention on them (see
Chapter 17). Currently, six 5-HTi receptor
subtypes, 5-HT1A to 5-HTiF, are clearly de-
fined, all of which inhibit adenylate cyclase ac-
tivity. 5-HTiB and 5-HTio receptors are dis-
tinct gene products with approximately 70%
sequence homology, but are very similar from
a pharmacological point of view. The 5-HTiB
receptor appears located exclusively on vascu-
lar smooth muscle cells, whereas the 5-HTiD
receptor is present on trigeminal nerve termi-
nals that innervate blood vessels.67'117
The 5-HT2 receptor class comprises three
subtypes: 5-HT2A, 5-HT2B, and 5-HT2C. They
all stimulate the hydrolysis of phosphatidylino-
sitol and mobilize intracellular Ca . Of note

Table 10-1. Internation Union of Pharmacology Classification and

Nomenclature for 5-HT Receptors

Receptor Previous Transduction

Type Subtype Name Mechanism Location
5-HTi 5-HT1A IcAMP Neuronal, mainly CNS
5-HT1B 5-HT1D/3 IcAMP CNS blood vessels
5-HT1G
5-HT1D 5-HT1Dtt IcAMP CNS neurons, trigeminovascular neurons
5-HT1E IcAMP CNS neurons
5-HT1F 5-HT6 IcAMP
5-HT2 5-HT2A 5-HT2 |PI CNS neurons, blood vessels, platelets
5-HTB 5-HT2p tPI CNS blood vessels
5-HT2C 5-HTlc tPI Choroid plexus
5-HT3 Directly coupled CNS + peripheral neurons
to cation channel
5-HT4 fcAMP CNS neurons + blood vessels
5-HT5
5-HT6 |cAMP
5-HT7 5-HTx tcAMP CNS neurons + blood vessels
CNS, central nervous system; | cAMP, negatively coupled to adenylyl cyclase with decreased production of cAMP;
f cAMP, positively coupled to adenylyl cyclase with consequent increased production of 3',5'-cyclic adenosine monophos-
phate; f PI, increased phosphoinositide turnover.

are findings that mRNA coding 5-HT2B re-
ceptors is strongly expressed in human arach-
noid tissue, internal carotid and middle
meningeal arteries, and dura mater, while
there is little or no expression of 5-HT2C re-
ceptor mRNA in these tissues.126 The reverse
is true of brain. The 5-HT2B receptor has been
identified as the 5-HT receptor mediating
endothelium-dependent relaxation of cerebral
arteries.
5-HT4, 5-HTe, and S-HTy receptors en-
hance adenylate cyclase activity. The 5-HTi, 5-
HT, 5-HT4, and 5-HTy families of 5-HT re-
ceptors are linked to G proteins, which play an
intermediary role in transmembrane signaling
and are responsible for coupling 5-HT recep-
tors to appropriate cellular effector systems
that generate second messengers. In contrast,
5-HTs receptors consist of directly linked
cation channels which, when activated, pro-
duce changes in membrane cationic perme-
ability without the involvement of second mes-
sengers.
The term S-HT^like was used in the past to
identify a heterogeneous group of 5-HT re-
ceptors located mainly on blood vessels. Acti-
vation of 5-HTi-like sites was believed to cause
constriction of cerebral bloodvessels. The term
is now outdated and 5-HTi-like receptors are
thought to correspond to 5-HTiB, 5-HTiD, 5-
HTiF, and/or 5-HTy receptors. Finally, al-
though a gene product has been identified for
5-HTs and 5-HTe receptors, a recognized
physiological correlate for these receptor pro-
teins has yet to be defined.
Serotonin and Intracranial
Blood Vessels
mRNAs for various 5-HT receptors are located
both on endothelium and smooth muscle of
cerebral arteries and veins.141 Activation of en-
dothelial 5-HT2B receptors results in increased
activity of NO synthase, release of NO, and re-
laxation of vascular smooth muscle. S-HTj re-
ceptors are also located on endothelium. These
receptors induce smooth muscle contraction,
although it is not known how. Depending upon
vessel size, activation of 5-HTiB and 5-HTaA
receptors on smooth muscle causes either vaso-
constriction or vasodilatation.95 In contrast, 5-
HTy smooth muscle receptors are involved in
vasodilatation. In other words, 5-HT regulates
Control of the Cerebral Circulation 215
both vasoconstriction and vasorelaxation, act-
ing in complex ways that involve 5-HT recep-
tor subtypes whose functional effects are often
in opposition.
The cranial vessel response to applied
perivascular 5-HT depends, at least in part,
upon its regional location in the cerebrovascu-
lar tree and its preexisting vascular tone. To
complicate matters, different anatomical seg-
ments of the same artery may have varying re-
sponses to 5-HT.137 5-HT produces a pre-
dominantly contractile response in isolated,
large pre- and post-circle of Willis arteries and
large veins, although it is uncertain which re-
ceptor is involved/27'110 Arterioles are dilated
presumably via activation of 5-HT/ receptors.
Systemically administered 5-HT is in general a
potent constrictor of the extracranial arteries,
although it has minimal effects on the in-
tracranial circulation. Nor does intravascular 5-
HT significantly change blood flow in humans
or other primates, provided the blood-brain
barrier is intact.90'13"
How the 5-HT-containing neurons of the
raphe nuclei are involved in the functional con-
trol of CBF remains a matter of controversy.
Whether stimulation of the raphe increases or
decreases CBF depends on the type and level
of anesthesia used in the experiments and on
the precise site of stimulation within the raphe
nuclei.13'23'142 Most studies have shown that
the major effect of raphe stimulation is va-
sodilatation of the extracerebral (the major
cerebral arteries at the base and over the con-
vexities of the brain together with their rami-
fications as small pial vessels that run in the
subarachnoid space) and of the intracerebral
circulations accompanied by an increase in
CBF.22'62
Brain Stem Activity and Migraine
Alterations in the activity of the brain stem
monoamine systems have been causally impli-
cated in the vascular processes that occur dur-
>89
ing migraine attacks. As indicated above,
stimulation of the locus coeruleus or the raphe
can change CBF. In particular, the locus
coeruleus is hypothesized to cause constriction
of the ipsilateral cranial blood vessels when
norepinephrine, released by axons from the nu-
cleus, binds to a-adrenoceptors. It is conceiv-
able that decreased blood flow in the occipital
216 Pathophysiology
cortex that results from neural activity in the
locus coeruleus causes the aura. In addition,
positron emission tomographic (PET) studies
have shown activation of an area of increased
blood flow in midline brain stem structures in-
cluding the locus coeruleus and the raphe nu-
clei during the headache phase of spontaneous
attacks of migraine (see Chapter II).28'148
BASAL NUCLEUS
Although the anatomical connections between
the cholinergic fibers derived from the basal
forebrain (basal nucleus of Meynert) and the
cerebral vessels are still unsatisfactorily de-
fined, there is no doubt that stimulation of the
basal nucleus substantially increases cortical
blood flow in the ipsilateral cerebral hemi-
sphere.12'88 That this is partly a result of acti-
vating both muscarinic and nicotinic receptors
is verified by the attenuation of the increase in
CBF after administration of either muscarinic
or nicotinic cholinergic receptor antago-
nists.12'25 But a heavy innervation of NO syn-
thase-containing neurons also projects from
the basal forebrain to microvessels. The pos-
sibility has been raised that that not only
cholinergic but also nitergic basal forebrain
neurons are involved in the flow response ob-
served following stimulation of the basal fore-
brain. It also may be that the cholinergic
parasympathetic nervous system exerts a va-
sodilatory action on major cerebral arteries and
pial vessels, whereas the intrinsic cholinergic
and nitergic input may effect increases in CBF
at the level of the intraparenchymal microvas-
culature.124'140 The role of the basal nucleus in
the pathophysiology of migraine is unknown.
ENDOTHELIAL CONTROL OF
CEREBRAL VESSELS
The vascular endothelium can affect the tone
of adjacent smooth muscle by producing and
releasing potent, short-lasting, vasorelaxant
and vasoconstricting factors. Three endothe-
lial-dependent vasodilators are currently rec-
ognized (Fig. 10-4): endothelial-derived hy-
perpolarizing factor (EDHF), NO, and
vasodilator prostanoids. Endothelial-derived
hyperpolarizing factor hyperpolarizes smooth
muscle by opening K + channels. Its chemical
nature and that of its precursors are unknown,
but a consensus is building that EDHF is an
arachidonic acid metabolite or a closely related
molecule. The prostanoids, such as prostacy-
clin (PGl), stimulate adenylate cyclase and
produce vasodilatation by increasing cAMP.
The final common denominator among the en-
dothelial-derived vasodilators appears to be
that they reduce the concentration of intracel-
lular Ca2+ and, as a consequence, smooth mus-
cle relaxes. In addition to relaxing factors, vas-
cular endothelium also produces at least two
potent vasoconstrictors: endothelin-1 (ET-1)
and thromboxane A (TXAs), a result of the
arachidonic acid cascade. These two com-
pounds work by increasing intracellular smooth
muscle Ca2+. Under physiologic conditions, a
delicate balance exists between endothelial-
derived relaxing and endothelial-derived con-
stricting factors.
Nitric Oxide
Endothelial NO is believed to play an espe-
cially important role in regulating the cerebral
vasculature. The synthesis of NO, and its sub-
sequent diffusion from endothelial cells, is in-
creased by a number of vasodilatory neuro-
transmitters or neuromodulators acting at
specific endothelial receptors. Activation of
muscarinic MI or MS receptors by acetyl-
choline, NK1 receptors by substance P, 63 re-
ceptors by bradykinin, HI receptors by hista-
mine, and ETfi receptors by endothelin,
together with physical (shear) forces, mobilizes
Ca2+ and raises its intracellular concentration,
and increased NO synthesis takes place (Fig.
10-5).
NITRIC OXIDE AND
CEREBROVASCULAR REGULATION
Blockade of NO synthase has no effect on cere-
bral glucose utilization and oxygen consump-
tion. But such blockade has been shown to de-
crease basal levels of arterial cGMP, produce
cerebral vasoconstriction, and decrease resting
CBF.78 Obviously, these effects cannot be at-
tributed to depressed cerebral energy metab-
olism. Rather, they imply that NO must be con-
tinuously released under resting conditionsa
continuous supply of NO is required to regu-
late resting vascular tone and basal blood
flow.47'134 Available evidence indicates that
both neuronal and endothelial NO participate,
 Control of the Cerebral Circulation 217

Figure 10-4. Relaxation of vascular smooth muscle cells by diffusible vasodilator substances from endothelial cells. Prosta-
cyclin (PGl^) activates adenylyl cyclase, leading to increased production of cyclic AMP (cAMP). Nitric oxide (NO) acti-
vates guanylate cyclase, yielding increased levels of cyclic GMP (cGMP). Endothelium-derived hyperpolarizing factor
(EDHF) causes Ca2+-dependent K + channels in vascular smooth muscle to open, leading to hyperpolarization. All of
these actions lead to a decrease in the intracellular Ca2+ concentration and smooth muscle relaxation. AA, arachidonic
acid; ATP, adenosine triphosphate; GTP, guanosine triphosphate; L-Arg, L-arginine; NOS, NO synthase; R, membrane
receptor; X, unknown precursor. (Adapted from Vanhoutte PM: Old-timer makes a comeback. Nature 396:213-215, 1998,
with permission.)

although it has been suggested that endothe-
lium is the primary source of the NO that in-
fluences basal cerebral blood vessel tone.78
Arachidonic Acid Metabolites
Arachidonic acid metabolites are important
controllers of arterial diameter and blood flow.
Because arachidonic acid functions as an in-
tracellular second messenger, and because the
compound is metabolized to so many vasoac-
tive metabolites, it is difficult to establish its
precise physiologic role in the control of cere-
bral and meningeal circulations.
Cells contain arachidonic acid esterified in
the sn-2 position of membrane glycerophos-
pholipids. The arachidonic acid cascade results
in the biosynthesis of a group of unsaturated
fatty acids (prostaglandins, leukotrienes, and
related compounds) called eicosanoids. The
process begins after various stimuliincluding
218 Pathophysiology

Figure 10-5. The synthesis and release of nitric oxide (NO) from endothelial cells is increased by a number of vasodilatory
neurotransmitters or neuromodulators acting at specific endothelial receptors. The NO diffuses to smooth muscle cells
where it activates the enzyme guanylate cyclase, resulting in the conversion of guanosine triphosphate (GTP) to cyclic
GMP (cGMP). cGMP presumably activates specific protein kinases, which causes a decrease in the concentration of in-
tracellular Ca2+. (Adapted from Thomsen LL: Investigations into the role of nitric oxide and the large intracranial arter-
ies in migraine headache. Cephalalgia 17:873-895, 1997, with permission.)

stretch of blood vessels, the response to a num-
ber of agonists (including bradykinin and his-
tamine), injury, and inflammationinitiates an
influx of Ca2+ ions. The increased Ca2+ con-
centration causes a phospholipase enzyme, cy-
tosolic phospholipase A2, to translocate to the
cell membrane where the enzyme catalyzes the
hydrolysis of the esterified arachidonic acid.
Arachidonic acid, having just been liberated
from cell membranes by the action of phos-
pholipase, is rapidly metabolized into eico-
sanoids by three principal pathways: the cyclo-
oxygenase pathway, the lipoxygenase pathway,
and the cytochrome P-450 epoxygenase path-
way (Fig. 106). Eicosanoids are synthesized
not only by brain tissue but also in die walls of
cerebral blood vessels and in platelets.
Little, if anything, is known about products
of the cytochrome P-450 epoxygenase pathway
as they might relate to migraine. We know a
bit more about leukotrienes formed by the
lipoxygenase pathway. The sufidopeptide (cys-
teinyl) leukotrienes (LTC4, LTD4, and LTE^)
produce contraction of vascular smooth mus
cle in a variety of locations.76 They produce a
substantial constriction of pial vessels.121
Leukotriene concentrations are increased after
cerebral ischemia. Transient elevations of spe-
cific leukotrienes (LTB4 and LTC4) have been
measured during attacks of migraine with
aura.54 There are far more data about the
cyclo-oxygenase limb of the arachidonic acid
cascade. This limb produces prostanoids, par-
ticularly prostaglandins (PGEi, PGE2, etc.),
 Control of the Cerebral Circulation 219

Figure 10-6. Current concepts of arachidonic acid metabolism. Three multienzyme pathways are required for synthesis
of eicosanoidscyclo-oxygenase, lipoxygenase, and cytochrome P-540. 5-HPETE, 5-S-eicosatrienic acid; 12(15)-HPETE,
12(15)-S-hydroxyeicosatetraenoic acid; LTB4, leukotriene B4; LTC4, leukotriene C4; LTD4, leukotriene D4; LTE4,
leukotriene E4.

prostacyclin (PGI2), and thromboxane A% latation of extracranial blood vessels.107 In

(TXA), some of whose actions do indeed seem
relevant to the study of migraine. Different cell
types have widely varying capacities to synthe-
size prostanoids. Arachidonic acid, for exam-
ple, is converted mainly to PGI2 by endothe-
lial cells in blood vessel walls, but to TXA2 in
platelets.
Prostanoids also affect the cranial blood ves-
sels in complex ways, the various prostanoids
differing in how they affect different vascular
beds.143-150 PGE2 reduces CBF but increases
extracranial blood flow.113 PGEi is considered
a potent vasodilator of most vascular beds; in
humans, intracarotid infusion of PGEi causes
both a slight increase in CBF and a marked di-
physiologically relevant concentrations, PGIa
has been demonstrated to be a potent cerebral
vasodilator, whereas TXA2 is a potent vaso-
constrictor of cerebral arteries.10'In addition,
endothelial cell-synthesized PGI2 prevents
platelet adhesion to the endothelium, while
platelet-derived TXA2 augments platelet ag-
gregation and adhesion to the capillary wall.
Because of this wide variety of conflicting ac-
tions, it is difficult to predict how a particular
blood vessel might respond when the arachi-
donic acid cascade is activated.
Prostaglandins and PGl have been impli-
cated in the development of migraine ever
since it was reported that prolonged infusion
220 Pathophysiology

of them cause headaches. When individuals
who do not ordinarily suffer from migraine re-
ceive infusions of some prostaglandins (such as
PGEi), they develop severe and frequently
throbbing headaches. These bouts are usually
bifrontal, and like many attacks of migraine, are
accompanied by nausea, vomiting, and such au-
tonomic symptoms as flushing and sweat-
ing.17'109'111 Abdominal cramps also accom-
pany the headaches. In some cases, the
headaches are preceded by visual phenomena,
such as flashing lights, that are similar to mi-
grainous auras. When infused, PGIgp causes
less dramatic phenomenanamely nonspe-
cific, dull, throbbing headaches. However sug-
gestive these observations may be, their value
may be questioned because of the high doses
employed.
The overproduction of prostanoids by cra-
nial artery endothelium has been proposed to
be an intrinsic abnormality in migraineurs.102
Some investigators have reported prostaglandin-
like biological activity in the cerebrospinal fluid
(CSF) of migraine patients during severe at-
tacks; others have been unable to detect it.1'5'9
Data as to whether prostanoid blood levels
change during migraine attacks are also in con-
flict.^5-53'83'105 But although experimental data
are not clear-cut, prophylactic employment of
drugs that inhibit prostaglandin synthesis, such
as aspirin and non-steroidal anti-inflammato-
ries, do often suppress the symptoms of mi-
graine. Attempts have been made to formulate
a prostaglandin hypothesis of migraine, but the
full range of symptoms from which migraineurs
suffer cannot be explained by variations in
prostaglandin levels alone.17
Endothelins
Although three endothelin isoforms with po-
tent vasoactive properties have been charac-
terized, only one form, endothelin-1 (ET-1), is
normally expressed in endothelial tissue (Fig.
10-7). mRNA for ET-1 is detectable in cere-
bral endothelium.79 Endothelin-1 is a potent
activator in vitro and in vivo of human cranial
arteries.3'106 Endothelins cause a short-lived
vasodilatation and potent and sustained vaso-
constriction of large cerebral arteries and
parenchymal arterioles.122 These opposite re-
sponses depend upon the specific cerebral ves-
sel receptors activated. Vasoconstriction occurs
via activation of endothelin-A (ETA) and
endothelin-B (ETg) receptors located on era-

Figure 10-7. Schematic diagram illustrating the synthesis and release of endothelin-1 (ET-1) and its actions on recep-
tors in endothelium. ET-1 gene transcription results in the formation of preproET-1 mRNA (ET gene expression). Pre-
proET is converted to bigET by an endopeptidase. BigET is cleaved to ET-1 by endothelin-converting enzyme (ECE).
ET-1 can activate TA and ETs receptors and cause smooth muscle contraction, and ETfi receptors on endothelium cause
activation of nitric oxide synthase (NOS), production of NO, and smooth muscle relaxation. (Adapted from Faraci FM
and Heistad DD: Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev 78:53-97,
1998, with permission.)

nial vascular smooth muscle. Vasodilatation,
mediated by NO, is produced by activation of
endothelial ETB receptors.85'10" Because the
relaxant action of endothelin is of short dura-
tion, whereas the vasoconstriction is long-last-
ing, the ultimate response of human cerebral
arteries is primarily constriction.106
Endothelial cells produce endothelins at a
slow rate, and circulating levels are extremely
low.43 The rate of production is regulated by a
variety of hormones and other vasoactive sub-
stances, including angiotensin II, catechol-
amines, atrial natiuretic hormone, PGE, and
PGIg. Various organs, particularly the lungs, re-
move endothelins from plasma by rapid up-
take. But despite a very short half-life, the bi-
ological effects of endothelins are long-lasting.
This presumably reflects their effectiveness in
occupying receptors.
A possible role for endothelins in migraine
has been suggested.32'51'52 Plasma levels of ET-
1 are elevated during migraine attacks, but not
during episodic or chronic tension-type head-
aches. i'*2'73-82 Levels are especially high at
the beginning of migraine attacks, but the
ETA/ETe receptor blocker bosentan is inef-
fective in aborting acute migraine attacks.82'98
The significance of these findings is not known.
NITRIC OXIDE AND NEURONS
In addition to perivascular parasympathetic
nerves and endothelium discussed above, there
is NO synthase activity in parenchymal neu-
rons.103 Approximately 1% to 2% of parenchy-
mal neurons in the brain express NO syn-
thase.14 Ultrastructural studies have shown
that NO synthase-containing neurons have
dendritic processes and axon terminals closely
associated with intracerebral arterioles and
capillaries.45'118 Because NO is highly dif-
fusible, the presence of NO synthase in
parenchymal neurons that lie near blood ves-
sels suggests that NO produced by these neu-
rons could influence local cerebral vascular
tone. In particular, it is believed that when glu-
tamate receptors on NO synthase-containing
neurons are activated, NO-mediated dilatation
of cerebral arterioles occurs.49'100 In support of
this, NO synthase inhibitors block arteriolar di-
latation induced by glutamate's excitation of
neurons.48
Control of the Cerebral Circulation 221
A close correlation exists between brain ac-
tivity and rCBF. Increments in neuronal firing,
especially when produced as a result of synap-
tic activity, lead to increases in metabolism and
to subsequent augmentation in blood flow. The
alterations in CBF resulting from focal brain
activation are spatially restricted to the sites
where cellular activation occurs. Nitric oxide
has been implicated as a major mediator for
coupling of CBF to brain activity and metabo-
lism,77 Nitric oxide has the requisite features
required of a mediator of the vasodilatation
that results from neural activity: it is synthe-
sized by active neurons, it is diffusible and
short-lived, and it is highly potent.
Nitric Oxide and
Spreading Depression
Although the blood flow changes that accom-
pany and follow spreading depression may have
components that are sensitive to NO released
from neurons or from blood vessel endothe-
lium, inhibition of NO synthase has not yielded
clarifying data. Inhibition of NO synthase has
been shown in different studies to abolish
completely, to attenuate, to have no substan-
tial effect, or to potentiate the degree of
cerebrovascular dilatation that immediately
follows spreading depression.21'30'46'144'153 Af-
ter spreading depression, however, cortical NO
concentrations show a peak of release, followed
by a decrease.116 The putative role of NO in
the genesis of spreading depression is intrigu-
ing, but uncertain.
OTHER FACTORS REGULATING
CEREBRAL BLOOD FLOW
A number of chemical substances such as pro-
tons (H + ions), CO2, bradykinin, histamine,
and adenosine have potent effects on the cere-
bral circulation. Each has been proposed as a
regulator of the cerebral circulation during
neuronal activity. Accordingly, discussion of
their vascular actions belongs in this chapter.
Some of these chemicals, however, are thought
to be involved not only in the regulation of
CBF but also in the genesis of head pain, by
virtue of their effects on trigeminal nociceptive
terminals. (Consideration of how some of these
222 Pathophysiology
compounds interact with the trigeminal noci-
ceptive system is discussed in Chapter 11,
which focuses on the pathophysiology of mi-
grainous head pain.)
Protons and Carbon Dioxide
A rise in interstitial H + concentration follows
the increase in rCBF during increased neu-
ronal activity. So although protons are potent
vasodilators, it is doubtful that they initiate the
changes in CBF. It may be that protons help
to maintain the vasodilatation. Because CO af-
fects the cerebral vasculature by modulating
the actions of perivascular pH, the same argu-
ment applies to CC>2.
Bradykinin
Bradykinin is a potent dilator when applied to
the perivascular side of pial arteries. It relaxes
cerebral arteries and arterioles through an NO-
mediated process. The peptide's relaxing ef-
fects have also been recorded in isolated extra-
and intraparenchymal cerebral arteries.24'149
In addition to its action on endothelium,
bradykinin is an initiator of the arachidonic acid
cascade, stimulating cyclo-oxygenase and lead-
ing endothelial cells to produce PGI2. Corre-
spondingly, inhibitors of cyclo-oxygenase blunt
the response of a number of arteries to
bradykinin. This suggests that the release of
vasodilator prostanoids such as prostacyclin
contributes to bradykinin's endothelium-
dependent relaxations.19
Bradykinin exerts its effects via two types of
kininergic receptors, but most of its actions are
mediated through activation of 62 receptors.
B2 receptors are located on the membrane of
endothelial cells; their activation produces re-
laxation of cerebral vessels.145 In addition, 62
receptors are linked to the release of NO.119
In contrast, BI receptors for bradykinin are not
expressed to any significant extent in normal
tissues. Their physiological role is unclear. BI
receptors may be of greater significance in
pathophysiological conditions, particularly dur-
ing inflammation, when they are synthesized in
large numbers.120 Although bradykinin is
known to be formed during ischemia, injury,
and inflammation, no data about blood brady-
kinin levels during bouts of migraine are avail-
able. Raised CSF bradykinin levels have been
reported in a minority of patients during mi-
graine attacks.18
Histamine
The role of histamine in the pathogenesis of
migraine is another subject of debate.92 Ex-
perimental headaches can be produced by in-
travenous administration of histamine, and de-
layed migraine headaches can follow hours
later (see Chapter 11). Acute histamine-
induced headaches are pharmacologically dif-
ferent from migraine; they can be terminated
by the administration of HI receptor antago-
nists, whereas migraine headaches are unaf-
fected by such drugs.86 Histamine headaches
are immune to doses of ergotamine, which can
abort migraine attacks. Clearly, acute hista-
mine-induced headaches are not identical to
migraine.
Histamine is found both in histaminergic
nerves and in the granules of mast cells. Be-
cause of their perivascular locations around ar-
terioles in the meninges and in the brain, the
mast cells are regarded as the main source of
the histamine that acts on blood vessels.29 His-
tamine is a vasodilator in the human cerebral
circulation. This effect is partially mediated by
an endothelial HI receptor coupled to the
production of NO, and partially via a H2 re-
ceptor associated with smooth muscle cells in
extracranial, meningeal, and cerebral arter-
ies.81'108 Intracarotid infusions of histamine do
not alter rCBF.86
Studies of histamine metabolism in con-
nection with migraine have been largely in-
conclusive. Blood histamine levels have been
reported as normal and as high during sponta-
neous migraine attacks. Both normal and in-
creased urinary secretion of histamine and his-
tamine metabolites have been observed during
attacks.6'93'128 Between attacks, histamine lev-
els are said to be higher in migraineurs than in
control subjects, although the significance of
this finding is not known.7'66'74 Interestingly,
skin biopsies taken from the involved side of
the head of migraineurs during attacks have de-
granulated mast cells. Increased numbers of
basophils and degranulated basophils are
found in the blood taken from the temple, an
indication that mast cells are activated during

a migraine attack.127'135 Combined HI and H
receptor blockade provides poor prophylaxis
for migraine headaches.8 All in all, although the
amine may represent one element in the patho-
genetic process, little exists to support the idea
that histamine alone is responsible for the
pathophysiological events known to occur dur-
ing attacks of migraine.
Adenosine
Adenosine is yet another dilator of cerebral and
meningeal vessels. The effect is mediated
mainly by AI and A subtypes of PI purinergic
receptors. Purinergic receptors occur in large
numbers on the nerve endings of cerebral and
meningeal vessels and also on platelet mem-
branes.37'72 Levels of adenosine and other re-
lated purine compounds (AMP and cAMP) rise
rapidly during hypoxia, or even during mild
oligemia such as that which may occur during
the migrainous aura.11 Under these conditions,
it is believed that purines are released mainly
by endothelial cells, although there may be
contributions from aggregating platelets and
from perivascular nerves. Whether these phe-
nomena are pertinent to the migrainous pro-
cess is yet to be determined. Infusion of aden-
osine has been shown to produce intense
migrainous headaches, and we do know that
during attacks, circulating levels of adenosine
increase in patients with migraine without
aura 15,65,129
SUMMARY
It is obvious that the control of the cerebral cir-
culation is extremely complex and that it dif-
fers from the peripheral circulation. Although
technological developments have allowed dis-
covery of various factors involved in regulating
CBF, many new concepts have yet to be di-
gested. Among them are the precise function
of cerebrovascular endothelium and the seem-
ingly ubiquitous role of NO, the part played by
the neuropeptides of the trigeminovascular
system, and the functions of histamine, en-
dothelins, and adenosine. In addition, enough
data conflict to make us aware that there is
much to be learned about the vascular changes
occurring during a migraine attack.
Control of the Cerebral Circulation 223
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Chapter 1 1

Head Pain and Associated Symptoms

LOCUS OF MIGRAINE PAIN ACTIVATION OF NOCICEPTORS

INTRACRANIAL SOURCES OF Histamines
MIGRAINE PAIN Arachidonic Acid and Metabolites
AFFERENT TRIGEMINAL AND CERVICAL Bradykinin
SYSTEMS (THE TRIGEMINOCERVICAL Serotonin
SYSTEM) Protons
CENTRAL TERMINATIONS OF AFFERENT Nerve Growth Factor
FIBERS Endothelins
THALAMIC, SUBCORTICAL, AND NEURAL MECHANISMS OF
CORTICAL PROJECTIONS MAINTAINED PAIN: PERIPHERAL
REFERRED PAIN SENSITIZATION
AFFERENT TRANSMITTERS NEURAL MECHANISMS OF
THREE THEORIES OF THE SOURCE OF MAINTAINED PAIN: CENTRAL
MIGRAINOUS HEAD PAIN SENSITIZATION
DILATATION OF PROXIMAL PARTS OF ENDOGENOUS PAIN-MODULATING
LARGE CEREBRAL VESSELS SYSTEMS
CEREBRAL BLOOD FLOW DURING Periaqueductal Gray
MIGRAINOUS HEAD PAIN On- and Off-cells
NEUROGENIC INFLAMMATION AND Monoamines and Nociception
VASCULAR PAIN Opioid Peptides
Neuropeptide Actions During Neurogenic Endorphins and Migraine
Inflammation CENTRAL ACTIVATION OF PAIN-
Neurogenic Inflammation and Migraine MODULATING SYSTEMS
ACTIVATION OF THE NAUSEA AND VOMITING
TRIGEMINOVASCULAR SYSTEM AND PHOTOPHOBIA
MIGRAINE ATTACKS SUMMARY

When lay people hear the word "migraine,"
they think of a pounding headache with nau-
sea and vomiting. Recent decades have seen a
growth of understanding of the pathophysiol-
ogy of that head pain. Less is known about the
nausea, vomiting, and photophobia that ac-
company it. Against a background of older, tra-
ditional views of head pain, this chapter will
consider the much more complex and fasci-
228
nating theories of how head pain (and other
symptoms) develop.
Because the extracranial circulation was ac-
cessible to study, Harold G. Wolff and his col-
leagues focused on the role vasodilatation of
the superficial temporal artery and other
branches of the external carotid artery played
in the genesis of head pain. Until recently, most
neurologists accepted Wolffs ideas, including

the concept that migraine pain is a condition
caused primarily by distension of branches of
the external and possibly the internal carotid
artery. Wolff himself hypothesized that other
factors were necessary for the production of
pain such as the accumulation of certain neu-
ropeptides within, and in, the vicinity of the
vessel walls.49 Nevertheless, most neurologists
have continued to assume that vasodilatation is
sufficient to excite pain-sensitive nerve endings
(nociceptive nerve endings, nociceptors] in the
arterial walls. As this chapter will demonstrate,
experimental proof is available for alternative
explanations.
LOCUS OF MIGRAINE PAIN
A number of clinical observations undermine
the claim that vasodilatation accompanied by
increased pulsations of arteries, especially ex-
tracranial arteries, is the sole cause of migraine
pain.34 First, pulsating or throbbing pain is not
pathognomonic of a primary vascular origin.
Pulsating pain is felt after injury or inflamma-
tion in a number of structures, and represents
a vascular response to inflammation in either
vessels or in their surrounding structures. Sec-
ond, only slightly more than half of migraine
patients experience pulsating pain.221 Studies
performed subsequent to Wolffs have shown
that either there is no consistent difference be-
tween the pulsations on the headache and the
headache-free sides of the head or the pulse
amplitude of the frontal branch of the superfi-
cial temporal artery is larger on the side of a
unilateral headache in only a minority of mi-
graineurs who experience pulsating pain.81 In
addition, if extracranial vasodilatation is the
cause of pain, patients might be expected to be
flushed during bouts of migraine, but mi-
graineurs are most often pale or even ashen;
flushing during attacks is unusual.34 Nor is
there convincing evidence that changes occur
in extracranial blood flow to skin and muscle
during bouts of migraine.87'138 And finally, if
vasodilatation of the superficial temporal artery
is the major factor in pain production, one
would expect that manual compression of the
superficial temporal artery would eliminate
pain in all migraine sufferers. In fact, com-
pression of the artery temporarily reduces the
pain for only a minority.3 ;81 Similarly, occlu-
sion of extracranial vessels by means of a blood
Head Pain and Associated Symptoms 229
pressure cuff placed around the head with the
cuff pressure elevated above the systemic
blood pressure does not alleviate the headache
in most patients.34
Some of these findings can be explained by
the observation that those patients whose
throbbing headache can be attenuated by ap-
plication of pressure over the superficial arter-
ies appear to form a separate subgroup with
larger pulsations of the frontal branch of the
superficial temporal artery and thermographic
evidence of increased facial blood flow on the
side of the headache.81 Except for this sub-
group, the data lead one to conclude that di-
latation of the superficial temporal artery and
its branches is not a major cause of migraine
headache pain in most patients. Clinical evi-
dence that the pain has an intracranial compo-
nent is derived from the observations that al-
most all patients suffer intensely from head
movement, particularly when the head is
rapidly rotated or jolted.34
INTRACRANIAL SOURCES OF
MIGRAINE PAIN
It has been known for many years that electri-
cal stimulation or distension of the main trunks
of the dural arteries, of the dural sinuses and
their tributary veins, and/or of the proximal
segments of the large pial arteries comprising
the circle of Willis can evoke headache-
like pain in neurosurgical patients (Fig.
ll-l).92'93'230'238 The arteries become less sen-
sitive over the hemispheric convexities. More
recently, mechanical dilatation of the internal
carotid and middle cerebral arteries during bal-
loon angioplasty carried out under local anes-
thesia has been noted to give rise to periorbital
and frontotemporal pain (Fig. ll-2).^16 In con-
trast, the pial arteries and veins located over
the convexity of the cerebral hemispheres are
not very sensitive to stimulation. The dura, es-
pecially the supratentorial dura covering the
cerebral convexities, is relatively insensitive to
painful stimuli, except along the margins of the
dural sinuses, the sites where cerebral veins en-
ter these sinuses, and along the course of the
meningeal arteries.230'238'29' Pain is not pro-
duced by stimulating the skull, the choroid
plexus, the ventricular ependyma, the brain pa-
renchyma, or the cerebral veins.
230 Pathophysiology

Figure 11-1. Referral of pain elicited by stimulation of intracranial vessels. The fields of referral are based on observa-
tions of Wolff. 1C, internal carotid artery, MC, middle cerebral artery, PC, posterior cerebral artery, MMA, middle
meningeal artery, SSS, superior sagittal sinus. (Adapted from Lance JW: Mechanism and Management of Headache, 5th
ed. Butterworth Heinemann, Oxford, 1993, with permission of Butterworth Heinemann Publishers, a division of Reed
Educational & Professional Publishing, Ltd.).

When intracranial arteries are stimulated,

Figure 11-2. Sites of referred pain (shaded areas) pro-
duced by balloon inflation in selected portions of the mid-
dle cerebral artery (MCA) stem. (Adapted from Nichols
FT, Mawad M, Mohr JP, Stein B, Hilal S, and Michelsen
WJ: Focal headache during balloon inflation in the inter-
nal carotid and middle cerebral arteries. Stroke 21:555-
559, 1990, with permission.)
pain reported to be throbbing, aching, or bor-
ing in nature is referred to specific loci such as
the ipsilateral temple, forehead, retro-orbital,
periorbital, and frontal regions. Moreover, the
pain is referred in specific patterns. Stimula-
tion of the circle of Willis, the proximal ante-
rior cerebral artery, and die middle cerebral
artery produces pain in, behind, or around the
ipsilateral eye. Disturbance of the posterior
cerebral artery elicits pain in retro-orbital or
parietal regions. Stimulation of the intracranial
part of the internal carotid artery leads to pain
within, behind, or above the eye. Parietotem-
poral, orbital, or auricular pain is produced by
stimulating the middle meningeal artery; or-
bital pain is produced by stimulating the ante-
rior meningeal artery. All these data indicate
that nociceptive transmission from supratento-
rial structures is carried by perivascular pial
and dural afferents and referred to the somatic
receptive fields of the trigeminal nerve. In con-
trast, stimulation of the vertebral and basilar
arteries induces pain in the back of the head

and in the neck. These latter results show, at
least in part, that nociceptive impulses from
certain posterior structures refer pain to areas
also innervated by cervical roots.
Clinical observations suggest that for some
patients, dural venous sinuses located close to
the midline (or possibly their tributary veins)
are also loci for whatever process causes mi-
graine headache. More than a third of mi-
graineurs experience bilateral pain. For 40%,
the pain is steady and aching rather than pul-
sating, and many find it is augmented by ma-
neuvers such as bending over, coughing, sneez-
ing, breath holding, or strainingall of which
increase intracranial venous pressure. Such
characteristics are compatible with involve-
ment of dural venous sinuses. Accordingly, it
is not unexpected that stimuli applied to large
veins at the base of the brain and to the sagit-
tal and transverse sinuses or their tributary
veins produce orbital and frontal pain.
AFFERENT TRIGEMINAL AND
CERVICAL SYSTEMS (THE
TRIGEMINOCERVICAL SYSTEM)
The periadventitial tissue and the superficial
adventitia of pial and dural blood vessels con-
tain abundant plexuses of small-diameter
myelinated and unmyelinated nerve fibers as
well as of some larger myelinated fibers.62'230
Many of the fibers are sensory in origin in that
they are axons of ipsilateral, small and medium-
sized primary afferent neurons located in the
trigeminal ganglia and in the upper cervical
dorsal root ganglia.192'219 The dura itself also
has a substantial trigeminal sensory innervation
that is most dense along the border of the su-
perior sagittal sinus.8 Much of the dural in-
nervation consists of unmyelinated C-fibers
and slowly conducting A6 fibers.66'148'276
Nociceptive afferent fibers from arteries and
venous sinuses above the tentorium arrive in
the brain stem chiefly via the trigeminal (fifth)
cranial nerve, whereas the fibers from vessels
below the tentorium are carried primarily
through the upper cervical nerves. Although all
three divisions of the trigeminal nerve are in-
volved in transmitting nociceptive information
from intracranial vessels, branches of the oph-
thalmic (Vi) division are the major source of
pain-sensitive afferents.230'269 Results from
Head Pain and Associated Symptoms 231
surgical procedures verify the importance of
the ophthalmic division in generating migrain-
ous pain. For example, surgical treatment of
migraine headache has shown that the head
pain can be attenuated by trigeminal rhizot-
omy, trigeminal ganglion alcohol injection, or
bulbar tractotomy, particularly when the skin
supplied by the first trigeminal division is ren-
dered anesthetic.92'225
The trigeminal ganglion (gasserian ganglion,
semilunar ganglion), the location of the
pseudounipolar primary afferent cell bodies of
the trigeminal nerve, is located on the petrous
bone near its apex in the middle cerebral fossa.
As expected, the ophthalmic division of the
trigeminal ganglion is the source of most of the
cell bodies whose afferent axons innervate
dural and pial vessels. Dural, and probably pial,
arteries, however, are also innervated in part
by the maxillary (2) and mandibular (V3) di-
visions of the ganglion.8'192'219'267
The exact pathway connecting the trigemi-
nal ganglia and the cerebral vessels is a matter
of some dispute. Innervation of the cerebral
vessels appears to involve at least six different
nerves or groups of nerve fibers.151'152
1. The nervus tentorii (tentorial nerve of
Arnold) innervates the superior surface of the
tentorium cerebelli, the posterior portion of
the falx cerebri, the walls of the sagittal, trans-
verse, and straight sinuses, and the torcular
Herophili (Fig. 11-3). Older descriptions of
the nerve indicated that it arose from the oph-
thalmic branch of the trigeminal nerve proxi-
mal to the superior orbital fissure.93'230 And in-
deed, in the schematic drawing of Figure 11-3,
the dotted line of the nervus tentorii does ap-
pear to branch off the first division of the
trigeminal nerve. The tentorial nerve may,
however, be a branch of the cavernous plexus
of nerves rather than a direct branch of the
ophthalmic nerve.267 The cavernous plexus
consists of an intermingling of trigeminal and
autonomic fibers lying in the connective tissue
surrounding the ophthalmic and abducens
nerves in the lateral wall of the cavernous si-
nus. Afferents from the plexus are dispensed
directly to the internal carotid artery and are
distributed along its intracranial branches to
reach dural and venous structures.
2. The anterior meningeal nerves (anterior
and posterior ethmoidal nerves) are branches
of the intraorbital portion of the ophthalmic
branch of the trigeminal nerve. They enter the
232 Pathophysiology

Figure 11-3. Schematic diagram of the three divisions of the trigeminal nerve, the gasserian ganglion, and the upper
cervical nerve roots. The interrupted lines indicate the route taken by the descending spinal tract of the trigeminal nerve,
the path taken by crossed second-order nerves ascending to rostral structures such as the thalamus, and the position taken
by the nervus tentorii (tentorial nerve of Arnold). (Adapted from Lance JW: Mechanism and Management of Headache,
2nd ed. Butterworths, London, 1973, with permission.)

cranium as nasociliary nerves through the crib-
iform plate. This small bundle of fibers carries
painful impulses from the anterior cranial fossa
and the anterior aspect of the falx cerebri to
the trigeminal ganglion.
3. The nervus spinosus of Luschka is a re-
current branch of the extracranial part of the
mandibular nerve. As expected from its name,
the nervus spinosus enters the cranial cavity via
the foramen spinosum.230 It joins the middle
meningeal artery, supplying both the dura of
the anterior and middle cranial fossae and the
dura overlying the lateral convexity of the cere-
brum.
4. The middle meningeal nerves (nervus
meningeus medius) emerge from the intracra-
nial portion of the maxillary nerve to accom-
pany the frontal branch of the middle
meningeal artery. These nerves innervate the
dura of the anterior middle fossa and the sphe-
noid ridge.
5. A major innervation of the rostral pial
vessels comes from the ophthalmic division of
the trigeminal nerve. 192>252>267 Two or three
short, fine branches of the intracavernous part
of the ophthalmic nerve appear to join the cav-
ernous plexus. In addition, the maxillary nerve
appears to contribute fibers to pial vessels via
an orbitociliary branch. These latter fibers are
thought to pass caudally through the infraor-
bital fissure to join the fibers from the oph-
thalmic division in the cavernous plexus and to
innervate the internal carotid artery and its
branches.118
6. Several satellite miniganglia are located
on the internal carotid artery at sites in the
carotid canal and in the cavernous sinus. Mini-
ganglia are of various sizes: some contain less
than 20 neurons, others contain several hun-
dred neurons. These structures may contribute
to intracranial vessel innervation. Composed of
neurons that resemble those of the trigeminal
ganglion, the miniganglia are believed to con-
tain cell bodies of some trigeminal afferent
fibers.252'277
Not only is there dispute about how cerebral
vessels are innervated, there is also some con-
fusion about where certain other afferent nerve
fibers originate. Under question are the noci-
ceptors responsible for supplying painful sen-
sation to the dura mater that lines the poste-
rior cranial fossa, the dural blood vessels of the

posterior fossa, and the basilar and vertebral
arteries. At various times, researchers have be-
lieved that alone or in various combinations,
the facial, glossopharyngeal, vagal, spinal ac-
cessory, sympathetic, or upper three cervical
nerves supplied these structures. Now, how-
ever, a consensus has been reached with re-
gard to the posterior fossanamely that it re-
ceives afferent innervation from fibers arising
chiefly from cell bodies in the upper three cer-
vical dorsal root ganglia, but with variable con-
tributions from the trigeminal nerve.13'151'152'256
The branches of the cervical nerves, however,
frequently travel to the posterior fossa with the
tenth and twelfth cranial nerves. The tenth
cranial nerve may also supply a small number
of afferents to the basilar artery.147
Some midline vascular structures are inner-
vated by bilaterally projecting sensory fibers.
The superior sagittal sinus, for example, re-
ceives bilateral trigeminal ganglion innerva-
tion.192 The anterior cerebral arteries and the
rostral basilar artery also receive projections
from both trigeminal ganglia.256
CENTRAL TERMINATIONS OF
AFFERENT FIBERS
Primary afferent trigeminal nociceptive axons
exit from the trigeminal ganglion in the trigem-
inal sensory root (portio major). The root
passes through the posterior cranial fossa to en-
ter the anterolateral portion of the pons.
Anatomical data indicate that the nociceptive
axons, or branches of these axons, descend cau-
dally to join the bundle of fibers designated the
spinal tract of the trigeminal nerve. At the cau-
dal end of the medulla oblongata, the spinal
tract merges into the tract of Lissauer in the
spinal cord. Terminal and collateral branches
of the spinal tract end in the nucleus of the de-
scending tract of the trigeminal nerve. Recent
investigations have shown that afferent fibers
from pain-sensitive intracranial structures also
terminate in the upper spinal segments. In
other words, a moderate number of trigeminal
fibers extend as far down as the second or third
cervical segment, and histological data show
that these fibers terminate in the dorsal horn
of the upper cervical spinal cord.13 That con-
siderable overlap exists between the trigeminal
and cervical distributions is demonstrated by
findings that the same areas of the cervical dor-
Head Pain and Associated Symptoms 233
sal horn gray matter that receive trigeminal af-
ferents also receive ramifications from the first
three cervical dorsal roots.
From the dorsal horn of the spinal cord, the
nucleus of the descending trigeminal tract ex-
tends rostrally to the principal trigeminal sen-
sory nucleus in the pons. This descending nu-
cleus is divided in a rostral-to-caudal direction
into three subnuclei: the nucleus oralis, the nu-
cleus interpolaris, and the nucleus caudalis
(Fig. 11-4). The last of these, the nucleus cau-
dalis, is located at the obex of the fourth ven-
tricle, extending to the cervical cord at the sec-
ond or third segment. The nucleus caudalis has
traditionally been perceived as the fundamen-
tal locus from which pain information is relayed
to more rostral levels of the central nervous sys-
tem (CNS).
The perception that the nucleus caudalis is
involved in transmitting painful sensations is
based in large part on data collected from pa-
tients after lesions were made in their spinal
trigeminal tracts for the purpose of treating
trigeminal neuralgia. These patients lost their
Figure 11-4. Diagram illustrating the subdivisions of the
trigeminal sensory nucleus. The subnucleus caudalis is
continuous with the dorsal horn. (Modified from Olszewski
J: On the anatomical and functional organization of the
spinal trigeminal nucleus. J Comp Neurol 92:401-413,
1950, reprinted with permission of Wiley-Lass, Inc., a sub-
sidiary of John Wiley & Sons, Inc.)
234 Pathophysiology

ability to perceive pain in areas of the face in-
nervated by the trigeminal nerve. Because the
nucleus caudalis is a rostral continuation of the
dorsal horn and because it also has morpho-
logical similarities to the dorsal horn, the view
of the nucleus caudalis as being important in
the funneling of pain makes sense. In addition,
neurons in the nucleus caudalis usually func-
tion in ways comparable to those of dorsal
horn nociceptive neurons. Most unmyelinated
trigeminal afferent fibersthose fibers puta-
tively involved in nociceptive mechanisms
terminate in the nucleus caudalis. All of these
factors support the traditional view that pain
pathways connect to the nucleus caudalis.
Recent data, however, suggest that the anat-
omy of these pain pathways differs somewhat
from that of the traditional view. Large num-
bers of unmyelinated fibers have been found
to project from pial arteries to the nucleus in-
terpolaris. The nucleus interpolaris, and possi-
bly the nucleus oralis, also functions to process
nociceptive information from intracranial
structures.13'66 These data, as well as investi-
gations of individual brain stem and spinal neu-
ron activation, demonstrate that we must mod-
ify traditional views of where trigeminal fibers
make their synaptic terminations.
Activation of pain-sensitive intracranial
structures such as the superior sagittal sinus
and the middle meningeal artery causes neu-
ronal discharges, or signs of neuronal activa-
tion (as determined by immunocytochemical
labeling for c-fos), in three main locations:

Figure 11-5. Coronal reconstruction of the somadendritic tree and initial axonal trajectory of a neuron located in the
deep gray matter (lamina V) of the subnucleus caudalis of the cat. The neuron was excited by electrical stimulation of the
dura. The axon is marked by triangles. The Roman numerals I to V (placed in the dorsal horn) indicate Rexed's laminae.
(From Strassman AM, Potrebic S, and Maciewicz RJ: Anatomical properties of brainstem trigeminal neurons that respond
to electrical stimulation of dural blood vessels. J Comp Neurol 346:349-365, 1994, reprinted with permission of Wiley-
Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

1. The traditionally recognized brain stem
areas, including the nucleus caudalis and,
to a lesser extent, the nucleus interpo-
laris.39-65'85'127'260 Within the nucleus
caudalis, neurons responsive to intracra-
nial vascular stimulation are located in
both superficial and deep layers (Fig.
11-5) 66:108,127,260
2. The dorsal horns of the of the first two
segments of cervical spinal cord, pre-
dominantly in Rexed's laminae I and
y!27,166,273,274
3. A newly described spinal area located in
the region of the lateral cervical nucleus,
i.e., lateral to the dorsal horn in the sec-
ond cervical segment.13'162'166 Activation
of neurons in this region following
stimulation of intracranial pain-sensitive
structures has been confirmed by autora-
diographic studies.110
The input to all three locations involves the
trigeminal system, but the spinal areas derive
additional contributions from cervical dorsal
roots. Many neurons receive a convergent in-
put from facial cutaneous receptive fields,
tooth pulp, and cranial vessels.9'166 Findings
that compounds effective in treating acute
bouts of migraine (including acetylsalicylic
acid, dihydroergotamine, and triptans able
to cross the blood-brain barrier) inhibit neu-
rons in these locations demonstrates their
importance in the transmission of migraine
pain 58,107,126,145
Second-order nociceptive neurons activated
by spinal and trigeminal afferents have been
divided into two types: wide dynamic range
(WDR) neurons and nociceptive-specific neu-
rons with one input. The latter respond exclu-
sively to noxious stimuli, whereas WDR neu-
rons are driven by both noxious and innocuous
stimuli, albeit more powerfully by noxious
stimuli. Both types are present in the nucleus
caudalis and in the cervical dorsal horn.66'260
In the nucleus caudalis, each WDR neuron re-
ceives synaptic inputs from several afferent
fibers, including nociceptive inputs (arriving
via AS and C-fibers) and non-nociceptive in-
puts that are activated by mechanical stimuli of
weak intensity delivered to the skin of the face
or the globe of the eye. In the spinal cord, the
size of the receptive field of a WDR neuron
responding to cutaneous stimuli varies; it de-
pends upon presynaptic and postsynaptic in-
hibitory mechanisms activated by impulses in
Head Pain and Associated Symptoms 235
afferent fibers (other than those directly
synapsing on the neuron) and in descending
fibers. Data are insufficient to determine if
WDR neurons activated by dural afferents are
controlled in a similar manner.
THALAMIC, SUBCORTICAL,
AND CORTICAL PROJECTIONS
Nociceptive information reaches rostral struc-
tures through several parallel neuronal path-
ways. In particular, two major pathways must
be consideredthe trigeminothalamic path-
way and the trigemino-parabrachial pathway.
Axons from deeper-lying cells in the nucleus
caudalis and in the cervical spinal cord project
via the trigeminothalamic tract (quintothala-
mic tract] to the contralateral thalamus. Elec-
trophysiological and anatomical studies have
shown that a major site for the termination of
axons in this tract is the classical somatosen-
sory-receiving nucleus of the thalamusthe
so-called ventrobasal complex, which consists
of the ventroposterolateral (VPL) and ventro-
posteromedial (VPM) nuclei and regions just
ventral to the ventrobasal complex. Neurons
activated by stimulation of intracranial struc-
tures activate neurons in VPM and its ventral
periphery.10'110 Units in VPM that are excited
by intracranial vascular stimulation also have
facial receptive fields located particularly in ar-
eas of the face and supplied by the ophthalmic
division of the trigeminal nerve or are activated
by stimulation of afferents from tooth pulp.10
Neurons in VPM project to the ipsilateral pri-
mary somatosensory cortex in the postcentral
gyms. This pathway from spinal cord and nu-
cleus caudalis to postcentral gyms is the clas-
sic neospinothalamic pathway that presumably
mediates the sensory-discriminative aspects of
pain.
Trigeminothalamic axons also project to
other areas of the thalamus. Electrophysiolog-
ical studies show that the medial part of the
posterior complex (a nucleus in the caudal thal-
amus at the meso-diencephalic junction) and
the intralaminar nuclei (consisting of several
small cell groups in the internal medullary lam-
ina) contain neurons responsive to intracranial
vascular stimulation.66'110 The intralaminar nu-
clei have diffuse cortical projections, particu-
larly to the frontal lobe and the limbic system
including the insula. Anatomical and physio-
236 Pathophysiology

Figure 11-6. Central pathways for pain and associated dysphoria. Pain transmission neurons from the nucleus caudalis
and the dorsal horn project to the somatosensory cortex via the ventroposteromedial nucleus (VPM) of the thalamus, to
the cingulate and insular cortex via the posterior part of the ventromedial nucleus (VMpo) and intralaminar nuclei (ILN)
of the thalamus, and to the amygdala via the parabrachial nucleus. The nucleus caudalis/dorsal horn-VPM-somatosen-
sory cortex pathway is thought to mediate the sensory-discriminative aspects of pain. The limbic structures are presum-
ably involved in the unpleasant or dysphoric aspects of pain. (Modified from Fields HL: Pain modulation and headache.
In Goadsby PJ and Silberstein SD (eds): Headache. Butterworth Heinemann, Boston, 1997, pp 39-57, with permission.)

logical investigations have demonstrated that a
dense input from spinothalamic (and presum-
ably trigeminothalamic) neurons is also sent to
the posterior part of the ventral medial nucleus
(VMpo) and to the dorsomedial nucleus.55 And
because almost all neurons in the nucleus are
selectively activated by noxious stimuli, VMpo
appears to be a specific nucleus for pain sen-
sation in primates. VMpo projects to the mid-
dle layers of the insular cortex.
Noxious stimuli also activate limbic struc-
tures through a midbrain relay that bypasses
the thalamus. Spinal and trigeminal nocicep-
tive neurons project in large numbers to the
midbrain to terminate in the parabrachial nu-
cleus? The spinal-parabrachial pathway orig-
inates in superficial neurons of the dorsal horn
that receive substantial input from substance
P-releasing C-fibers and high-threshold AS
fibers. In turn, the parabrachial nucleus sends
fibers to the amygdala and hypothalamus. Neu-
rons within the parabrachial area respond to
most types of noxious (but not non-noxious)
stimulation and appear to signal the intensity
of noxious stimulation. This pathway appears
to provide the main nociceptive input to the
parts of the brain that are concerned with the
emotional-affective dimensions of pain (Fig.
11-6).
REFERRED PAIN
Mechanical and electrical stimulation of pial
and dural arteries and of venous sinuses pro-
duces pain in temporal, retro- and periorbital,
frontal, occipital, and cervical regions. These
locations support a concept that pain arising
 Head Pain and Associated Symptoms 237

Figure 11-7. Theories of referred pain. (A) Branched primary afferent hypothesis. A single primary trigeminal afferent
branches to supply both an intracranial artery and the skin. The artery is the source of pain, but the pain is perceived in
the skin. The existence of such branched fibers in the trigeminal system has not been documented. (B) Convergence-pro-
jection hypothesis. Primary afferents from skin and from intracranial vessels converge on the same medullary pain-pro-
jection neurons in the subnucleus caudalis. The brain mistakenly "projects" the sensation arising in the afferent from the
intracranial artery to the skin. Such convergence of afferents from peripheral and intracranial structures have been dem-
onstrated in the trigeminal system. (Modified from Fields HL: Pain. McGraw-Hill, New York, 1987, with permission of
McGraw-Hill.)

from intracranial vascular structures is referred
to somatic receptive fields of the trigeminal
nerve.92>93'230'23^ In other words, the source of
the pain is in a location different from the place
where the pain is actually perceived. Two ma-
jor mechanisms have been proposed to explain
the referral of such pain.
The first is the branched primary afferent
hypothesis of Sinclair,268 who postulated that
some primary afferent fibers bifurcated, fur-
nishing branches to both somatic and visceral
structures (Fig. 11-7A). As a result of this bi-
furcation, Sinclair suggested, sensory messages
from a somatic structure (such as the skin of
the temple) and a visceral structure (such as an
intracranial blood vessel) were carried by the
same afferent, so that the message from the vis-
ceral branch could be misinterpreted by the
brain and localized as pain in the temple. But
does Sinclair's theory actually account for the
phenomenon of referred pain? Branching of
primary afferents does indeed occur. Some
trigeminal ganglion cells send axon collaterals
to innervate more than one intracranial ves-
sel.208'219 For example, trigeminal ganglion
neurons innervating the middle meningeal
artery may also send projections to innervate
the middle cerebral artery. Axonal branches of
single afferent trigeminal neurons, however, do
not innervate both intra- and extracranial struc-
tures. Accordingly, the lack of appropriate
neural connections negates the theory.193'219
The second proposed mechanism of re-
ferred pain is the convergence-projection hy-
pothesis of Rucfo,249 who presumed that re-
ferred sensation was caused by the synaptic
connections of both visceral and somatic affer-
ents onto the same relay neurons. If the trigem-
inal vascular afferents project onto nociceptive
relay neurons that also receive somatic inputs
from skin and muscle, impulses from either in-
put could be capable of initiating activity in the
same trigeminal relay cells (Fig. 11-7B). The
relay cells could, in turn, project to rostral sen-
sory areas in the brain.
The convergence-projection theory is gen-
erally thought to supply the best explanation
of referred headache pain because electro-
physiological studies have demonstrated that
both vascular and somatic trigeminal affer-
ents do synapse on single neurons within the
nucleus caudalis.260 There is a population of
neurons in the brain stem trigeminal complex
and upper cervical spinal cord that can be ac^
tivated both by stimulation of major dural
blood vessels, such as the superior sagittal si-
nus and middle meningeal artery, and by
noxious mechanical stimulation within a fa-
cial receptive field that typically includes
the cornea and periorbital skin (Fig. 11-
8) 66,88,164,166,276 The fadal receptive fields
largely overlap the distribution of dural pain
in humans. Thus activation of intracranial af-
ferents could excite sensory pathways also ex-
cited by somatic afferents. This process is
thought to elicit a sensory experience at the
somatic input, and not at the vascular origin
of the noxious stimulus.
238 Pathophysiology
Figure 11-8. Convergent input onto a rat medullary dor-
sal horn neuron. Extracellular recordings made from a neu-
ron in the medullary dorsal horn. The histogram is a plot
of the neuron's firing rate (impulses/second) by brush
(brush) stimuli applied to the infraorbital (IO) nerve area;
by noxious mechanical stimuli (pinch) applied to the supra-
orbital (SO), infraorbital, and mental (M) nerve areas; and
by von Frey filament (v. Frey, 1.0 g) applied to the dura.
(Adapted from Ellrich J, Andersen OK, Messlinger K, and
Arendt-Nielsen L: Convergence of meningeal and facial
afferents onto trigeminal brainstem neurons: an electro-
physiological study in rat and man. Pain 82:229-237,1999,
with permission.)
AFFERENT TRANSMITTERS
As noted in the previous chapter, many, but
not all, small-diameter, nociceptive, trigeminal
and upper cervical, sensory primary afferent
fibers that innervate the cranial vasculature
contain and secrete neuropeptides. These neu-
ropeptides include the tachykinins (substance
P and neurokinin A) and calcitonin gene-
related peptide (CGRP). Much recent data in-
dicate that in the trigeminal system, and in
other afferent systems, these peptides act as
nociceptive neurotransmitters in a large num-
ber of unmyelinated C-fibers and in a propor-
tion of thinly myelinated A5 fibers. Immuno-
histochemical techniques have demonstrated
that in pial arteries and veins and in the dura,
there is a delicate, but dense, network of sub-
stance P-, neurokinin A-, and CGRP-contain-
ing fibers and varicose terminals.287 The den-
sity of peptide-containing nerve fibers and
terminals is higher in the proximal parts of the
circle of Willis and in the vertebrobasilar sys-
tem than in more distal arterial structures.277
Trigeminal afferent nerve fibers that innervate
the cerebrovascular bed almost always contain
more than one peptide. For example, all
trigeminal afferents that contain substance P
or neurokinin A also contain CGRP. Other
peptides, including cholecystokinin and
galanin, have been identified within trigeminal
fibers projecting to intracranial vessels. Their
role, however, has not been determined.
Cell bodies of substance P- and CGRP-
containing afferent fibers are located in several
locations, among them trigeminal ganglion, the
C2 dorsal root ganglion, and the internal
carotid microganglia.68'277'287 Unilateral trigem-
inal ganglionectomy, however, substantially re-
duces the levels of all peptides in the rostral
intracranial vessels, an indication that the
trigeminal ganglion is the major source of the
afferent peptidecontaining fibers.302 As in af-
ferent fibers, two or more peptides coexist
in many of the same nerve cells, although a
subset of trigeminal ganglion cells and nerve
fibers contain only CGRP and not substance
p _ 175,220,277 Cerebrovascular substance P-
containing nerve fibers appear to originate
from cell bodies mainly in the ophthalmic di-
vision of the trigeminal ganglion.192'254 It has
been estimated that substance P is present in
15% to 20% of the neurons in the trigeminal
ganglion.184'302 Putative nociceptive substance
P- and CGRP-containing fibers end in all three
subnuclei of the nucleus of the descending
tract of the trigeminal nerve.281 The densest
projections are to the nucleus caudalis and the
caudal part of nucleus interpolaris.
Unmyelinated and thinly myelinated pri-
mary spinal and trigeminal afferent fibers that
contain neuropeptides and mediate nocicep-
tion also secrete the excitatory neurotransmit-
ter glutamate.196'272 Because blockers of glu-
tamate receptors reliably reduce pain behavior,
it is assumed that "pain" messages are medi-
ated, at least in part, by glutamate's actions on
dorsal horn neurons.130
Glutamate is an example of a "fast" trans-
mitter which, when bound to ionotropic gluta-
mate receptors (iGluRs), opens voltage-
insensitive ionic channels in postsynaptic mem-
branes within a rapid and brief millisecond
time frame. As such, glutamate is ideally suited
to signal the onset, duration, and intensity of a
noxious stimulus. There are data indicating that
glutamate serves such functions when it is re-
leased from nociceptive fibers onto relay neu-
rons in the dorsal horn and nucleus caudalis.
Presynaptic glutamate-containing terminals
and neurons with N-methyl-D-aspartate
(NMDA) and non-NMDA iGluRs and have

been identified in the superficial laminae of the
trigeminal nucleus caudalis and in the spinal
dorsal horn where C-fiber nociceptive affer-
ents mainly terminate.123'132'279 Glutamate has
also been shown to excite neurons in the nu-
cleus caudalis.257 Furthermore, stimulation of
the superior sagittal sinus excites units in the
nucleus caudalis by activating both NMDA and
non-NMDA iGluRs.272 Finally, both NMDA
and non-NMDA iGluR antagonists block the
activation of neurons in the nucleus caudalis
caused by trigeminal ganglion, superior sagit-
tal sinus, or meningeal stimulation of trigemi-
novascular nociceptive afferents.51'203'204'272
In contrast to the actions of glutamate at
iGluRs, there is a superimposed, extra tier of
intracellular chemical control mechanisms me-
diated by "slow" transmitters such as the
tachykinins and CGRP. The evidence is exten-
sive that the tachykinins substance P and neu-
rokinin A play important roles in sensory pro-
cessing in the dorsal horn of the spinal cord
and, presumably, in the nucleus caudalis.
There are at least three different types of
tachyldnin (NK) receptors: NK1, NK2, and
NK3, preferentially activated by the peptides
substance P, neurokinin A, and neurokinin B,
respectively. A role for NK1 and NK2, but not
the NK3, receptors in nociceptive processing
has been demonstrated. As expected from this
finding, neurokinin B has not been implicated
in nociceptive transmission. Both substance P
and neuroldnin A are contained in fine dorsal
root afferent fibers and in synaptic endings in
the dorsal horn. Noxious, but not innocuous,
peripheral stimuli cause the release of sub-
stance P in the substantia gelatinosa.82 In ad-
dition, application of exogeneous substance P
excites those spinal dorsal horn neurons that
are responsive to noxious stimuli; minimal ef-
fects are seen on neurons not responsive to
such stimuli.258 NK1 receptors and mRNA
coding for NK1 receptors have been demon-
strated on neurons in the superficial and deep
dorsal horn laminae of the spinal cord.3"3
Knockout mice with disruption of the NK1 re-
ceptor gene do not have normal responses
to noxious visceral stimuli that evoke neuro-
genic inflammation.161 Finally, NK1 antago-
nists block the response of dorsal horn neurons
both to noxious stimuli and to microapplication
of substance P.234
As expected, activation of nucleus caudalis
neurons by trigeminal ganglion stimulation or
Head Pain and Associated Symptoms 239
meningeal stimulation of trigeminovascular no-
ciceptive afferents is reduced by NK1 antago-
nists.51'199 Therefore, it seems curious that they
have no effect on neuron firing in the nucleus
caudalis when the superior sagittal sinus is
stimulated.109 The discrepancy may result from
findings that substance P comes into play as an
afferent transmitter only under certain condi-
tions. Compared to glutamate, for example,
higher frequencies of primary afferent stimu-
lation are required to evoke the spinal release
of substance P.83 Studies have shown that nox-
ious stimulus-induced internalization of NK1
receptors, a marker of substance P release, oc-
curs in dorsal horn neurons only when stimu-
lus intensities are well above the threshold for
pain.1 Data suggest that tachykinins in spinal
primary afferent fibers are required when in-
tense pain is experienced and that substance P
is involved only in situations involving sub-
stantial or prolonged stimulation of nocicep-
tors. As a result, when the preprotachykinin A
gene, which encodes substance P and neu-
rokinin A, is genetically disrupted, the behav-
ioral response to a mildly painful response re-
mains intact, but the response to moderate or
intense pain is significantly reduced.44
The neuropeptides and glutamate have a
complex reciprocal interaction at several levels
in the dorsal horn and, presumably, in the nu-
cleus caudalis. These interactions enhance
synaptic efficacy. Glutamate appears to pro-
mote substance P release by activating presy-
naptic NMDA receptors on the terminals of
primary afferent fibers.183 In turn, substance P
can potentiate the action of glutamate on post-
synaptic NMDA receptors.236 Calcitonin gene-
related peptide also excites some nociceptive
dorsal horn neurons, but it also has reciprocal
interactions with substance P.200 Concentra-
tions of CGRP that alone have little or an in-
consistent effect, markedly potentiate the ex-
citatory action of substance P or noxious
stimulation on dorsal horn neurons.33
THREE THEORIES OF THE
SOURCE OF MIGRAINOUS
HEAD PAIN
Several processes may be implicated as the
source of migraine pain: (1) the vasodilatation
may involve the proximal parts of the large ba-
240 Pathophysiology

sal cerebral conductance arteries; (2) changes DILATATION OF PROXIMAL

in regional cerebral blood flow (rCBF) largely
determined by intracerebral resistive arterioles
may be related to head pain; or (3) the trigemi-
novascular system may be implicated in a pro-
cess of neurogenic inflammation responsible
for sensitizing nociceptive nerve fibers that in-
nervate dural and meningeal vessels. Each of
these three possibilities, which are not mutu-
ally exclusive, must be considered in light of
recent research.
PARTS OF LARGE
CEREBRAL VESSELS
Referred head pain can be produced by dis-
tension of the proximal parts of the large cere-
bral arteries that comprise the circle of Willis.
Inferences about possible changes in the di-
ameter of large intracranial vessels during at-
tacks of migraine have been made using trans-

Figure 11-9. Blood flow velocities in middle cerebral arteries during attacks of migraine with aura. Twenty-five patients
with unilateral pain were examined. The mean velocity was significantly lower on the side of the headache than on the
non-headache side. The decreased mean velocity was interpreted as showing vasodilatation of the middle cerebral artery
during attacks of migraine with aura. Note the variability of responses as well as the seven patients who had higher or un-
changed velocities on the affected side. The mean values are illustrated with a bold line (standard error of the mean
marked with vertical lines). (Adapted from Thomsen LL, Iversen HK, and Olesen J: Cerebral blood flow velocities are
reduced during attacks of unilateral migraine without aura. Cephalalgia 15:109-116, 1995, with permission.)

cranial Doppler ultrasonography (TCD), which
is a non-invasive technique that permits mea-
surement of blood velocity in the circle of
Willis and the large intracranial vessels using
low-frequency ultrasound that adequately pen-
etrates die acoustic barriers of the skull. These
arteries can be insonated through the skull.
Commercially available transcranial Doppler
devices employ a probe that emits an ultra-
sound signal that is reflected from the red
blood cells traveling through the arteries at the
base of the brain. The same probe receives the
reflected signal and transmits it to a computer
that uses the Doppler shift principle to provide
information about peak flow velocity. Although
the relationship between blood flow velocity
and the diameter of blood vessels is not always
consistent, in general, a decreased blood flow
velocity is considered to reflect dilatation of
the large arteries, provided the rCBF remains
constant.
During bouts of migraine, reductions in
CBF velocity on the side of the headache have
been reported and interpreted as an indication
that the large intracranial arteries have di-
lated.74'100'28^ But even in these studies, some
subjects have clearly higher velocities on the
side of the head pain (Fig. 11-9). Friberg and
colleagues measured reductions in blood flow
velocity in the middle cerebral artery during
spontaneous attacks of migraine with and with-
out aura when 133Xe single-photon emission
computerized tomography (SPECT) measure-
ments of rCBF were unchanged.100 The lower
velocity in the feeding artery, at a time when
rCBF is normal in the territory of brain sup-
plied by that artery, can best be explained by
dilatation. The velocity changes in the middle
cerebral artery were reported to return to nor-
mal values after treatment with sumatriptan.100
Friberg's study, however, was limited to only
seven patients: four had migraine with aura,
three had migraine without aura. And because
the 133Xe inhalation technique for measuring
blood flow has been shown to alter blood flow
velocities, these results must be replicated us-
ing other techniques.253
In contrast, a number of other TCD studies
during migraine headaches have variously
found a lack of significant changes, but with
no significant differences between pain and
headache-free sides, decreased velocities, or
enhanced velocities.43'99'179'214'229'248'285-305'308
Head Pain and Associated Symptoms 241
These findings are not surprising. It is known
that substantial variability of blood flow veloc-
ities occurs among healthy people, and that the
recordings are influenced by a number of bio-
logical factors (including age, hematocrit, fi-
brinogen concentration, arterial pCOa, and
cardiac output). In sum, we presently lack sub-
stantial and convincing evidence allowing a
firm conclusion that distension of the large
cerebral arteries is necessary to induce the pain
of a migraine attack. Flow changes may not be
relevant to migraine pathogenesis at all.
CEREBRAL BLOOD FLOW
DURING MIGRA1NOUS
HEAD PAIN
If a change in the caliber of small intracerebral
vessels were to play an important role in pro-
ducing migrainous pain, variations in CBF
might be expected to correlate with the head
pain. And indeed, a number of authorities, us-
ing traditional methods to measure CBF, have
described both focal and global hyperemia dur-
ing the headache phase of attacks of migraine
with and without aura.104-155'198'218 Other in-
vestigators, however, have found hyperemia to
occur only in some patients.114'270 Moreover,
it is important to note that although a number
of studies demonstrated changes in blood flow
during headaches, often the changes were bi-
lateral and symmetrical even when the patients
experienced unilateral headaches.155'197
The concept of hyperemia during the head-
ache phase has been challenged by the Copen-
hagen group. These investigators have docu-
mented that the onset of hyperemic changes in
CBF measured by 133Xe techniques bears a
poor temporal relationship to the development
of head pain in patients suffering from mi-
graine with aura.172'223 In contrast to assertions
attributing pain to hyperemia, the Copenhagen
group found that the head pain in patients with
migraine with aura develops at a time when
rCBF is reduced. Moreover, although pain typ-
ically emerges when the aura recedes, hyper-
emia characteristically takes many hours to de-
velop and may persist for many hours or even
daysi.e., long after migrainous head pain has
disappeared.5'113'197 As for attacks of common
migraine, the Copenhagen group has shown
242 Pathophysiology
that such headaches, although clearly painful,
are commonly unaccompanied by any signifi-
cant focal changes in CBF.171'172
A different pattern of blood flow changes
during the headache phase has been demon-
strated by positron emission tomographic
(PET) studies. Investigations during sponta-
neous and red wine-induced attacks of mi-
graine with and without aura have consistently
demonstrated a long-lasting decrease in global
CBF 7,27,124,298 Because PET is a more sensi-
tive technique for measuring CBF than the
133
Xe and SPECT methods, PET data may ac-
count in part for the discrepant results. More
information is obviously needed. In addition,
we need to learn the extent to which these dif-
ferences may be a consequence of method-
ological differences, of studying CBF at dif-
ferent times after the onset of an attack, and
of including migraine patients both with and
without aura. On balance, however, it appears
questionable that changes in the diameter of
the small cerebral vessels causing changes in
CBF are responsible for the head pain of a mi-
graine attack.
NEUROGENIC INFLAMMATION
AND VASCULAR PAIN
The elegant investigations of Moskowitz and
colleagues have shed an intriguing light on the
mechanisms that cause head pain during mi-
graine attacks. Moskowitz has proposed that
perivascular neurogenic inflammation involv-
ing meningeal vessels plays a preeminent role
in the production of migrainous pain.206 The
inflammatory hypothesis rests on findings that,
under experimental conditions, mechanical or
chemical stimulation of craniovascular noci-
ceptive nerve endings or antidromic electrical
stimulation of the trigeminovascular system
produces neurogenic inflammation involving
the vessels of the dura.119'185'207 Vasodilatation,
plasma extravasation with enhanced transcyto-
sis and subsequent perivascular edema forma-
tion, endotheHal acfhesion and aggregation of
platelets, and degranulation of mast cells all fol-
low activation of the trigeminovascular system.
Overall, the histological appearance suggests
an evolving sterile inflammatory response.
Neurogenic inflammation presumably also oc-
curs in the walls of larger dural vessels and
dural sinuses equipped with vasa vasorum
structures in which inflammation may develop
at the microvascular level, producing protein
extravasation with subsequent edema forma-
tion and activation of nociceptive terminals in
the large vessels.
When nociceptive afferents are excited and
fire, neuropeptides are released centrally onto
second-order neurons in the nucleus caudalis
of the brain stem and also in the dorsal horn
of the spinal cord. The neuropeptides cause
these second-order neurons to transmit noci-
ceptive signals to the CNS. Discharging noci-
ceptive afferents, however, also have the
unique ability to release neuropeptides from
their peripheral perivascular terminalsthe
so-called efferent function of afferent termi-
nals. In other words, upon activation of these
nerves, impulses proceed both anti- and ortho-
dromically. Furthermore, the process spreads
from one nerve terminal to another by means
of axon reflexes. When nerve impulses travel-
ing orthodromically in an afferent nerve fiber
reach a branch point, they are thought to fire
antidromically in collateral branches. In turn,
when the action potential reaches the periph-
eral terminals of the collateral branch, it causes
the release of neuropeptides. The process may
also spread from one intracranial vessel to an-
other, because trigeminal fibers send branches
to innervate more than one intracranial vessel.
The idea that neurogenic inflammation de-
velops following antidromic release of neu-
ropeptides from intracranial trigeminovascular
nociceptive nerve terminals is supported by a
number of findings in experimental animals:
1. Despite its usual depiction as a thick and
dense avascular membrane, the dura has a
complex vascular network.149 The dura mater
is innervated by a plexus of peptidergic affer-
ent nerve fibers containing substance P, neu-
rokinm A, and CGRP.148'287 These peptidergic
sensory fibers terminate both around blood
vessels and in the dural connective tissue near
vessels.
2. Neurogenic inflammation, manifested by
vasodilatation, leakage of plasma proteins from
dural blood vessels, aggregation and endothe-
Hal adhesion of platelets, and activation of mast
cells, is observed following trigeminal ganglion
stimulation.75'185'261
3. Electrical stimulation of the trigeminal
ganglion causes antidromic release of sub-
stance P and CGRP, results in elevated levels
 Head Pain and Associated Symptoms 243

of these peptides in blood draining from the
sagittal sinus, and depletes CGRP from the nu-
cleus caudalis.41'154'*07
4. Substance P, neurokinin A, and CGRP
augment meningeal blood flow and provoke in-
creases in dural vessel diameter, increases that
are blocked by neurokinin and CGRP antago-
nists.159'295
5. A number of NK1 receptor antagonists
(that block the actions of substance P) inhibit
neurogenic plasma protein extravasation (a
good measure of neurogenic inflammation)
produced by trigeminal ganglion stimula-
tion.227'262
6. Activation of nociceptive craniovascular
afferents by electrical stimulation of the supe-
rior sagittal sinus results in elevated levels of
CGRP in external jugular vein blood.105'304
7. Capsaicin (8-methyl N-vanillyl-6-none-
amide), the active ingredient of hot peppers of
the Capsicum family, is known to depolarize
unmyelinated (C) and a minority of thinly
myelinated (A6) nociceptive afferent nerves.
Capsaicin also causes the release of neuropep-
tides from nerve endings and produces neuro-
genic inflammation in the dura.125
8. Intracranial neurogenic inflammation is
not observed in experimental animals lacking
unmyelinated C-fibers.185
it dilates meningeal arteries.159'226 Stimulation
of trigeminal afferents innervating the dura re-
leases CGRP from peptidergic afferent termi-
nals causing vasodilatation and increasing
meningeal blood flow, an important element of
neurogenic inflammation.159 In contrast, sub-
stance P released from dural nerve fibers does
not play an important role in regulating dural
arterial flow.45
Neurogenic Inflammation
and Migraine
There is circumstantial evidence that the hu-
man trigeminovascular system is activated dur-
ing migraine attacks. In particular, raised lev-
els of CGRP are found in external jugular
venous blood (Fig. 11-10); these levels nor-
malize after administration of sumatriptan pro-
duces relief of migraine symptoms. 4a>10 El-

Neuropeptide Actions During

Neurogenic Inflammation
The actions of substance P, neurokinin A, and
CGRP differ. Whereas substance P and neu-
rokinin A seem for the most part to mediate
plasma extravasation from postcapillary venules
in the dura mater, CGRP contributes little to
this response.185'226 Substance P and neu-
rokinin A cause protein leakage through vas-
cular walls presumably by acting directly on
NK1 receptors located on postcapillary venule
endothelium.226 Following trigeminal stimula-
tion, both vacuolation and an increased num-
ber of cytoplasmic vesicles thought responsible Figure 11-10. Changes in levels of calcitonin gene-
for transporting plasma proteins across the ves- related peptide (CGRP) during attacks of migraine with
and without aura. Open bars represent control measure-
sel wall are seen in the endothelium of post- ments of CGRP levels taken from external jugular vein.
capillary venules.76 Some venules also show Filled bars represent measurements during migraine at-
subintimal edema. (Arterioles do not often tacks. Asterisks indicate significant difference from control
show such alterations.) Although CGRP does values. Values represent mean SEM; N 10-22.
CGRP-LI, CGRP-like immunoreactivity. (Adapted from
not cause such plasma extravasation by itself, Edvinsson L and Goadsby PJ: Neuropeptides in migraine
it does potentiate the extravasation produced and cluster headache. Cephalalgia 14:320-327, 1994, with
by both substance P and by neurokinin A, and permission.)
244 Pathophysiology
evated levels of CGRP (and substance P) in the
jugular vein are also seen when the trigeminal
ganglion is stimulated by thermocoagulation
during surgery for trigeminal neuralgia.105
Moreover, antimigraine medications, in con-
centrations similar to those used therapeuti-
cally, inhibit neurogenic inflammation of the
dura.41'42'186'255 For example, ergots and trip-
tans, which act at 5-HTiB/io receptors located
on blood vessels and trigeminal nerve termi-
nals (to cause meningeal arterial vasoconstric-
tion and reduce the release of peptides) and
acetylsalicylic acid, which diminishes the for-
mation of prostanoids (essential compounds in
the production of inflammatory responses), are
effective in the treatment of acute migraine
pain.
Some data, however, indicate that neuro-
genic inflammation may not be the only factor
producing migraine pain. Certain potent in-
hibitors of neurogenic extravasation in experi-
mental animals are ineffective for treating
acute attacks. Substance P antagonists block
plasma protein extravasation, but various sub-
stance P receptor antagonists are not effective
against acute migraine attacks.111 Studies of
bosentan, a competitive, selective, non-peptide
receptor antagonist of endothelin, have shown
that plasma extravasation, produced by stimu-
lation of the trigeminal ganglion or by admin-
istration of capsaicin, is prevented in experi-
mental animals by the compound. Bosentan,
however, is not effective in aborting attacks of
migraine.38'189 In addition, CP-122,228, a spe-
cific 5-HT agonist that is 1000-fold more ef-
fective than sumatriptan in inhibiting neuro-
genic inflammation, is ineffective in human
migraine attacks.174'247 It may well be that neu-
ronally active compounds that are devoid of
vasoconstrictor action, such as substance P an-
tagonists, bosentan, and CP122,288, are inef-
fective in migraine because effective anti-
migraine therapy must consist of both anti-
inflammatory and vasoconstrictive effects, and
these compounds do not cause vasoconstriction
(see Chapter 17). One conclusion is that both
dural vasodilatation and inflammation are nec-
essary for the production of migraine pain.
Other data indicate that plasma extravasa-
tion occurs in the retina and the dura when the
trigeminal ganglion is experimentally stimu-
lated. During acute attacks of migraine, how-
ever, retinal plasma extravasation is not seen
with fluorescein or indocyanine angiography in
humans.191 It may be that branches of the
trigeminal nerve innervating the eye are not in-
volved in migraine or, alternatively, that plasma
extravasation does not occur in the dura dur-
ing migraine attacks.
In sum, definitive proof that the pain of mi-
graine is caused solely by an inflammatory pro-
cess that involves the activation of the trigemi-
novascular system is lacking. The neurogenic
inflammatory model of migraine pain may have
shortcomings that will have to be addressed in
the future, but it remains a reasonable work-
ing hypothesis to explain many of the phe-
nomena associated with migraine pain.
ACTIVATION OF THE
TRIGEMINOVASCULAR SYSTEM
AND MIGRAINE ATTACKS
The trigeminovascular system appears to be
the final common pathway for the generation
of migraine pain. But how the activation of
trigeminovascular neurons is initiated and what
excites the perivascular trigeminovascular no-
ciceptors are not known. In theory, trigemino-
vascular neurons could become activated at
various points along their length from their
axon terminals in blood vessel walls to central
terminations within the brain stem. Several hy-
potheses that might account for activation of
trigeminovascular neurons are worth consider-
ing.
1. Substantial local meningeal vasodilata-
tion leads to increased transmural pressure that
activates trigeminal terminals, thereby initiat-
ing the process of neurogenic inflammation.
Excessive dilatation of meningeal blood vessels
can elicit firing of trigeminovascular C-fibers
and A5 fibers to activate and sensitize central
trigeminal neurons.59 The firing of trigemino-
vascular fibers presumably causes the release
of neuropeptides from their peripheral end-
ings, thereby initiating the inflammatory pro-
cess underlying migraine pain and perpetuat-
ing the vasodilatation.
It may be that activation of the parasympa-
thetic fibers innervating dural blood vessels
produces the initial vasodilatation or that mon-
aminergic nuclei (raphe and locus coeruleus lo-
cated in the area of the "migraine generator")
become activated at the onset of an attack (Fig.
ll-ll).72'292
 Head Pain and Associated Symptoms 245

Figure 11-11. Schematic diagram of the trigeminal and parasympathetic innervation of dural blood vessels. The oph-
thalmic (first) division of the trigeminal nerve with cell bodies in the trigeminal ganglion (Vg) innervates dural blood ves-
sels. These bipolar neurons project to second-order neurons in the trigemmocervical complex (trigeminal nucleus cau-
dalis and dorsal horns of Cl and C2). Pain signals from the trigeminospinal complex ascend through the trigeminothalamic
tract to rostral brain structures such as the thalamus. Preganglionic parasympathetic autonomic neurons project from the
superior salivatory nucleus (SSN) to synapse in the sphenopalatine, otic, and carotid microganglia on neurons that proj-
ect to dural blood vessels. (Modified from May A and Goadsby PJ: The trigeminovascular system in humans: pathophys-
iologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood
Flow Metab 19:115-127, 1999, with permission.)

2. The parasympathetic nervous system ac-
tivates meningeal C-fibers directly, producing
neurogenic inflammation. This hypothesis is
supported by data that shows electrical stimu-
lation of the sphenopalatine ganglion, the ma-
jor source of the intracranial parasympathetic
innervation, induces plasma protein extravasa-
tion from the dura mater in experimental ani-
mals.67 Several actions may be involved.
Acetylcholine release by parasympathetic neu-
rons activating muscarinic receptors (presum-
ably producing release of NO) has been shown
to stimulate C-fibers directly, leading to
plasma extravasation.54'235 Second, activation
of cholinergic receptors induces mast cell de-
granulation in the meningeal vascular territory,
where the histamine released from mast cells
has inflammatory actions.244 Finally, NO re-
leased from parasympathetic nerves may cause
dural vasodilatation.
3. Nitric oxide is responsible for initiating
the process underlying migraine pain. Evi-
dence that NO may mediate nociceptive trans-
mission in the CNS and may release CGRP
from trigeminovascular nerve endings, coupled
with knowledge that significant headaches can
result from ingestion of nitrite-containing food,
from nitroglycerin medications, or from expo-
sure to nitroglycerin in explosives factories, has
led to the proposal that NO plays a significant
role in the pathogenesis of migraine.222 In fact,
Olesen and coworkers have proposed that NO
is a candidate for the causative molecule in mi-
graine.224 This claim is based on three sets of
findings: (a) nitroglycerin (glyceryl trinitrate)
and histamine can produce experimental head-
aches in both normal volunteers and mi-
graineurs;135'136 (b) transcranial Doppler and
SPECT studies have shown that nitroglycerin
induces intracranial arterial dilatation;61'135
and (c) preliminary studies have shown that ad-
ministration of a NO synthase inhibitor reduces
the severity of migraine pain and accompany-
ing symptoms.169
246 Pathophysiology

Figure 11-12. Nitroglycerin (glyceryl trinitrate)-induced headaches. Comparison of mean headache scores (0-10 scale)
in response to intravenous administration of nitroglycerin (0.5 /ag/kg/min for 20 minutes) in migraineurs (open circles)
and controls (non-migraineurs, closed circles). Note the substantially stronger headaches in migraineurs, as well as the
development of delayed headaches. (Adapted from Olesen J, Thomsen LL, and Iversen H. Nitric oxide is a key molecule
in migraine and other vascular headaches. Trends Pharmacol Sci 15:149153, 1994, with permission.)

Nitroglycerin and histamine may produce
headaches by mechanisms that involve NO. In
human cerebral blood vessels, histamine acti-
vates endothelial HI receptors that stimulate
NO synthase, the formation of NO, and pre-
sumably the release of increased amounts of
NO.284
Nitroglycerin appears to cause NO release
by means of an enzymatic process that is
not entirely understood.120 Not all non-
migraineurs develop headaches after nitro-
glycerin administration. In those who do, the
headaches vary in intensity from mild to mod-
erate, are short-lived, pulsating and increased
by physical activity, but lack the typical mi-
graine features such as nausea, photophobia,
and phonophobia.135'136'222'283 In contrast,
migraineurs are significantly more sensitive to
nitroglycerin, developing intense headaches
that may not be at all brief and are stronger
in intensity than the headaches produced in
controls. Then, unlike controls whose head-
aches recede within 2 hours, 80% of mi-
graineurs go on to develop full-blown mi-
graine headaches within 24 hours of the
nitroglycerin infusions. In other words, char-
acteristic, but delayed, migraine attacks can
develop several hours after administration of
nitroglycerin (Fig. 11-12).
Experimental headaches produced by intra-
venous or intracarotid administration of hista-
mine are bifrontal and bioccipital in location
and throbbing in nature. Migraine patients are
more sensitive to histamine than are control
subjects, reacting to smaller doses. In addition,
histamine infusions will frequently cause mi-
graineurs first to develop pain on the side of
the head that is customarily affected during
their migraine attacks, and in this regard,
histamine-headaches correspond to migraine
attacks. The experimental headaches, however,
are accompanied by facial flushing and are not
associated with nausea or other symptoms
characteristic of migraine such as photo- and
phonophobia. As with nitroglycerin, when his-
tamine is administered to migraineurs, they
frequently develop delayed migraine several
hours after the infusion. 70
Histamine (unlike nitroglycerin) does not
cross the blood-brain barrier and therefore

when administered systemically, presumably
works on endothelial receptors. As noted
above, TCD and SPECT studies have shown
that nitroglycerin induces intracranial arterial
dilatation. 1>135 But convincing evidence cou-
pling dilatation of large cerebral arteries and
the pain of migraine is limited. The mechanism
of the process by which NO putatively triggers
migraine attacks is unknown. Nor is it known
whether the NO is released from perivascular
nerves, endothelium, or parenchyma! neurons.
Intrarterial nitroglycerin activates afferent
trigeminovascular pathways at a site at, or pe-
ripheral to, second-order neurons in the
trigeminal nucleus.163 But its half-life is very
short, and because bouts of migraine occur up
to several hours after the infusion of nitroglyc-
erin or histamine, it is unlikely that NO itself
is directly responsible for the pain of the de-
layed migraine attacks.
4. A wave of spreading depolarization, such
as that seen in spreading depression, activates
nociceptive fibers by directly sensitizing adja-
cent pial and dural trigeminal afferents.117'20Q
Some investigators have reported that cortical
spreading depression is associated with signs of
activation of trigeminal nucleus caudalis neu-
rons, a finding interpreted to indicate firing of
trigeminal nociceptive fibers.209 Others have
failed to find trigeminovascular neuron activa-
tion or activation of neurons in the trigeminal
nucleus caudalis, and it may well be that the
reported activation of trigeminal nociceptive
fibers actually results from injection of
KCl used to induce spreading depres-
sion.86'133'134'165 Moreover, if spreading de-
pression were to activate trigeminal afferents,
it would be expected to cause an increase in
CGRP in the jugular blood similar to the in-
crease seen following electrical stimulation of
the trigeminal ganglion or trigeminal fibers in
the wall of the superior sagittal sinus. Such data
about the release of CGRP in jugular veins of
experimental animals are no better than equiv-
ocal 53,86,232,243,291 jn addition, spreading de-
pression does not evoke plasma protein ex-
travasation in the meninges.86
5. Primary afferent depolarization excites
trigeminovascular nociceptive fibers. Labora-
tory experiments show that volleys from vari-
ous types of afferent trigeminal and dorsal root
fibers and impulses in pathways descending
from a number of supraspinal structures in the
brain stem and cerebrum have the capacity
to depolarize the central terminals of affer-
Head Pain and Associated Symptoms 247
ent trigeminal and dorsal root nociceptive
fibers.18'116 This depolarization, termed pri-
mary afferent depolarization (PAD), results
from the release of the amino acid neuro-
transmitter GABA by interneurons located in
the nucleus caudalis and in the dorsal horn.
These interneurons, which make synaptic con-
tacts (so-called axoaxonic synapses) in the nu-
cleus caudalis and dorsal horn on the central
terminals of trigeminal and dorsal root afferent
fibers, release GABA when they are excited by
afferent or descending inputs. If the amplitude
of PAD is sufficient, antidromic primary affer-
ent trigeminal root and dorsal root fiber dis-
charges (trigeminal root and dorsal root re-
flexes) are produced. Antidromic discharge of
fine afferents (AS as well as C-fibers) releases
peptides, and initiates and maintains neuro-
genic inflammation.296 In other words, there
may be a major positive feedback mechanism
involved in neurogenic inflammation.
Admittedly, we do not yet know the precise
mechanisms activating trigminovascular neu-
rons and leading to the dural inflammatory
process and vasodilatation implicated in mi-
grainous pain. There is, however, additional ev-
idence to link the trigeminal nerve to a mi-
graineur's suffering. Two pieces of clinical
evidence suggest that hyperexcitability of the
trigeminal system or its reflex connections is
present between migraine attacks. First of all,
a substantial number of migraineurs sponta-
neously develop discrete, jabbing, sharp pains,
designated ice pick-like pains, at the site of
their customary headaches. These pains are
postulated to result from spontaneous dis-
charges of trigeminal afferent fibers. In addi-
tion, ice cream headaches, the transient head
pain that develops when a cold stimulus con-
tacts either the palate or the posterior pharyn-
geal wall, are frequent in patients with mi-
graine. For some migraineurs, the pain of ice
cream headache is located in the same region
of the head where their migraine attacks usu-
ally occur. This pain is considered to involve a
reflex mechanism that includes the trigeminal
nerve.
ACTIVATION OF NOCICEPTORS
Consideration of factors that alter nociceptors
in other parts of the body may shed light on
those processes that give rise to the painful, in-
tracranial vascular processes involved in mi-
248 Pathophysiology

Figure 11-13. Some of the putative events involved in the activation and sensitization of intracranial nociceptor termi-
nals. Following activation of a nociceptive terminal, impulses generated in the terminal propagate orthodromically. Axon
reflexes are produced when the impulse reaches a branch point and propagates antidromically into another terminal
branch. This results in the release of neuropeptides including substance P (SP), neurokimn A (NKA), and calcitonin gene-
related peptide (CGRP). The peptides act on the blood vessels to induce vasodilatation and plasma extravasation. The in-
terstitial levels of bradykimn, synthesized from plasma proteins, rise. Substance P also causes the release of histamine and
other substances from mast cells including leukotrienes (LTs), prostaglandins (PGs) and serotonin (5-HT) from platelets.

grainous head pain. In skin, muscle, joints, and
viscera, neurogenic inflammation affects the
properties of nociceptive terminals. An attrac-
tive proposal is that nociceptor terminals are
chemosensitive. Indeed, in different tissues,
excitation of nociceptive primary afferents by
inflammatory mediators is well established.
Throughout the body, nociceptors are acti-
vated and sensitized by a number of pain-pro-
ducing substances (algesic or algogenic chemi-
cals, inflammatory mediators] released as a
result of the inflammatory process. Perivascu-
lar nerve endings, mast cells, plasma, platelets,
blood vessels, and tissue cells produce or se-
crete the various inflammatory mediators such
as histamine, arachidonic acid metabolites,
bradykinin, 5-HT, protons, and nerve growth
factor. All are known to affect the properties
of chemosensitive nociceptive nerve terminals
directly or indirectly and to contribute to the
inflammatory response in peripheral tissues.
Inflammatory mediators can lower the thresh-
old or initiate neuronal discharge. Further-
more, the pain these substances produce is ca-
pable of outlasting the stimulus. Moskowitz has
proposed that the same processes that occur in
peripheral and deep tissues, such as skin, mus-
cle, joints, and viscera, also take place in the
trigeminovascular system, giving rise to pro-
longed activation and sensitization of cranial
vascular nociceptors and to the perception of
pain (Fig. 11-13). Indeed, experimental data
show that primary trigeminal afferents inner-
vating the dura mater respond to inflammatory
mediators in a manner similar to that of noci-
ceptors from other tissues.37'66'260'276 In addi-
tion, there is evidence that vasodilatation of the
meningeal vessels, presumably generated by
the inflammatory process, may be necessary to
generate the afferent nociceptive message.
Histamine
Although histamine is unable to excite periph-
eral nociceptive sensory endings directly, the
compound is clearly involved in neurogenic in-
flammation, causing plasma extravasation by an
action on postcapillary venules.167 Released by
mast cells, histamine produces dilatation of ar-
terioles and capillaries. HI receptors are un-
doubtedly important in this latter response,
whereas the role of Ha receptors in this pro-
cess is uncertain.
When trigeminovascular fibers are activated,
a component of the resultant inflammatory ef-
fects appears, caused by the action of released
peptides on mast cells (Fig. 11-14). This is a
reasonable presumption because antidromic
activation of trigeminal afferents degranulates
 Head Pain and Associated Symptoms 249

Figure 11-14. Model for the possible interrelationships between sensory neuropeptides and mast cell activation. CGRP,
calcitonin gene-related peptide; SP, substance P. (Adapted from Ottosson A and Edvinsson L: Release of histamine from
dural mast cells by CGRP, Cephalalgia 17:166-174, 1997, with permission.)

dural mast cells, an indication that they have
released their contents.14'75'76 CGRP and sub-
stance P release histamine from dural mast
cells.228 This appears to set a feedback mech-
anism in motion: after mast cells are activated,
histamine causes the release of substance P and
CGRP from trigeminal nerve fibers by a pro-
cess involving HI receptormediated influx of
Ca2+ ions.28" To complicate the picture, the
major source of histaminethe mast cells
synthesizes and secretes numerous other pow-
erful inflammatory mediators, such as NO,
prostaglandins and leukotrienes, and proteo-
lytic enzymes and phospholipases, that can lead
to the production of other vasoactive and pain-
producing molecules.
Arachidonic Acid
and Metabolites
In tissues exhibiting inflammation, the levels of
prostanoids (prostaglandins, prostacyclin, and
thromboxanf? AS) formed from arachidonic
acid are elevated. The predominant prostanoid
is PGE2, which is released from the dura mater
during antidromic electrical stimulation of the
trigeminal ganglion; and this suggests a possi-
ble relationship of prostanoids to migraine
pain.84 Prostanoids do not cause pain when ap-
plied to nociceptive nerve endings in modest
concentrationsamounts probably present in
vivo at sites of inflammation. Rather, the pri-
mary role of PGE, PGl, and possibly other
prostanoids such as PGFa, is to lower the
threshold of the nociceptive endings of un-
myelinated trigeminal fibers (Fig. 11-15).35
PGE2 has additional effects as well. The com-
pound sensitizes nociceptive terminals to
bradykinin and 5-HT, it enhances neuropep-
tide release that leads to vasodilatation, and it
activates platelets that release 5-HT.245>289
PGE2-induced actions on nociceptors are pre-
sumably produced by augmentation of a
tetrodotoxin-resistant, voltage-gated Na + cur-
rent that is implicated in the activation of no-
ciceptors and is the target of several algogenic
substances.137 Recent functional evidence sug-
gests that tetrodotoxin-resistant Na + currents
Figure 11-15. Diagram showing the coupling of prostanoid receptors to intracellular second messenger systems and the
resulting modulation of ion channels in sensory nerve endings. In response to mechanical or chemical stimulation,
prostanoids, particularly prostaglandin E2 (PGE2) and prostacyclin (prostaglandin 12, PGI2) are produced by metabolism
of arachidonic acid. PGE2 and PGI2 act on prostanoid receptors on nearby sensory nerve endings. Prostanoid receptor
activation stimulates phospholipase C (PLC) and adenylate cyclase, resulting in (1) increased phosphoinositide turnover
with production of inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG), and (2) increased production of cyclic AMP
(cAMP), respectively. The activity of phosphokinase C (PKC) and phosphokinase A (PKA) is increased by these second
messengers, resulting in modulation of ion channels, an increase in antidromically propagating action potentials, an in-
crease in cytosolic Ca2+, and local peptide release. ATP, adenosine triphosphate; 5-HT, serotonin. (Adapted from Bley
KR, Hunter JC, Eglen RM, and Smith JAM: The role of IP prostanoid receptors in inflammatory pain. Trends Pharma-
col Sci 19:141-147, 1998, with permission from Elsevier Science.)

250

are important for transduction at nociceptive
nerve endings in the intracranial dura.275
The leukotriene prostanoids (especially the
sufidopeptide leukotrienes) have direct and
potent actions on the endothelial lining of post-
capillary venules, where they promote vascular
permeability and cause plasma leakage.63 Leu-
kotrienes have also been implicated in sensiti-
zation of nociceptors and in the enhancement
of nociceptor responsiveness to other algogenic
agents.17'-233 Both mechanisms cooperate in
promoting inflammation and pain.
Bradykinin
The peptide bradykinin is thought to be one of
the main initiators of early inflammation in pe-
ripheral tissues. It produces dilatation of arte-
rioles, increased vascular permeability with for-
mation of edema, and activation of nociceptors.
In addition to its vasodilator and algogenic
properties, bradykinin triggers a positive in-
flammatory feedback cycle, stimulating the re-
lease of prostaglandins which in turn amplify
the responsiveness of neurons to kinins.
Bradykinin is derived when serine protease
kallikreins act upon inactive precursorsthe
the bloodborne ag-globulins called kininogens.
Although their high molecular weight confines
kininogens to the blood stream, bradykinin can
reach the site of inflammation.
Bradykinin is among the more potent en-
dogenous algogenic mediators and causes pain
in humans when administered intradermally or
intra-arterially.52 The pain occurs presumably
because bradykinin excites and sensitizes noci-
ceptive afferent terminals in peripheral so-
matic tissues and in viscera. 62 receptors on
nociceptors appear to be involved in the pro-
cessa conclusion inferred from observations
that B receptors are localized to sensory nerve
terminals and from data showing that the pain
caused by endogenous kinin release during in-
flammation is blocked by selective B2 receptor
antagonists.271 Bradykinin's effects are specific
to nociceptive fibers in that it depolarizes af-
ferent terminals of C-fibers and AS fibers, but
not terminals of large-diameter myelinated
fibers.168 The bradykinin-induced depolariza-
tion depends mainly upon enhancing a
tetrodotoxin-resistant, voltage-gated Na + cur-
rent. Such depolarization also induces an influx
of Ca2+ ions, causing both the release of the
Head Pain and Associated Symptoms 251
neuropeptides substance P and CGRP and the
stimulation of arachidonic acid production. In
experimental animals, bradykinin excites in-
tracranial trigeminovascular nociceptive end-
ings.65
Bradykinin has indirect actions on nocicep-
tors as well. In this regard, prostaglandins ap-
pear implicated in bradykinin-induced excita-
tion of nociceptors: cyclo-oxygenase inhibitors
(which block the synthesis of prostaglandins)
suppress bradykinin-induced responses, and
PGE2 and PGI2 enhance the sensitizing effects
of bradykinin on nociceptors.47 In turn,
bradykinin activates phospholipase A2> which
stimulates the synthesis and subsequent re-
lease of prostaglandins from cells.176 The pep-
tide also amplifies the weak action of histamine
on nociceptors.157 Thus, not only does brady-
kinin excite nerve endings directly but it also
has complex interactions with other inflamma-
tory mediators.
Serotonin
Many inflammatory mediatorsbradykinin,
histamine, prostaglandins, leukotrienes, etc.
are formed at the site of inflammation or are
released from cells participating in the inflam-
matory process. These inflammatory mediators
are potent platelet receptor agonists, responsi-
ble for the activation of platelets during an
acute inflammatory response. The platelets
themselves play an important role in acute in-
flammation: they aggregate at inflammatory
sites where they liberate 5-HT, a potent algesic
substance, which, when applied to nerve end-
ings in skin, muscle, joints, and viscera, excites
nociceptive C-fibers.195 The direct excitatory
action of 5-HT on nociceptors is mediated by
5-HTs receptors.246 In addition, 5-HT poten-
tiates the nociceptive actions of other algesic
agents such as bradykinin.
Protons
Protons (H + ions) frequently accumulate in in-
flamed tissues where low pH is an important
component of inflammatory pain. Acidic solu-
tions selectively stimulate nociceptive neurons
and potentiate the action of a number of in-
flammatory mediators. Decreases in pH evoke
nerve discharges in about 40% of fibers that
252 Pathophysiology

Figure 11-16. Schematic representation of nociceptive sensory nerve terminal activation by protons (H + ions). The pro-
tons act at a receptor to open a cation channel. The resulting flux of cations depolarizes the terminal and produces an ac-
tion potential. The depolarization and the increase in intraterminal Ca2+ results in the release of neuropeptides. CGRP,
calcitonin gene-related peptide; NKA, neurokinin A; SP, substance P.

transmit nociceptive impulses.240 Small sen-
sory neurons respond to protons by opening
H+-gated non-selective cation channels. The
resulting flux of cations depolarizes the termi-
nals, raises the concentration of free, intracel-
lular Ca2+ ions, and causes the release of neu-
ropeptides from nociceptive nerve terminals
(Fig. 11-16).31'102 Small-diameter trigeminal
neurons putatively involved in nociception are
activated by a decrease in pH.158
Nerve Growth Factor
The neurotrophin nerve growth factor (NGF)
produced by blood vessels activates high-
affinity tyrosine kinase receptors (TrkA) that
are present on about 45% of those small-di-
ameter spinal dorsal root and trigeminal gan-
glion neurons that give rise to unmyelinated ax-
ons.15 Almost all small-diameter neurons that
express TrkA also contain CGRP and substance
P. There is now good evidence that NGF is a
key regulator of nocieptive thresholds: (1) ap-
plication of exogenous NGF activates and sen-
sitizes nociceptors;299 (2) the concentration of
NGF increases at sites of inflammation;3
(3) sensitization of cutaneous primary afferent
nociceptors produced by inflammation is
blocked by pharmacological or immunological
manipulations that antagonize the actions of
NGF;156'299 and (4) NGF stimulates up-regu-
lation of peptide levels in nociceptive affer-
ents.299 However, NGF, has a slow onset of
action, mediated by phosphorylation of tran-
scription factors in the nucleus that bind di-
rectly or indirectly to specific DNA sequences
of target genes. Little is known about the pre-
cise links of the process, but NGF does appear
to regulate the expression of ion channels sen-
sitive to protons. The role of NGF, if any, in
acute headache may be limited by its slow on-
set of action, but it may be a factor in sustain-
ing head pain.

Endothelins
A role for endothelin-1 in the mediation of
dural neurogenic inflammation has been pro-
posed.38 As mentioned above, plasma extrava-
sation in the dura mater produced either by
stimulation of the trigeminal ganglion or by ad-
ministration of capsaicin is prevented by ad-
ministration of bosentan, a competitive, selec-
tive, non-peptide antagonist of endothelin
receptors. The effect of endothelins is
thought to be mediated by activation of presy-
naptic ETe receptors located on the terminals
of trigeminovascular fibers. Activation of TB
receptors is believed to stimulate the release of
neuropeptides involved in neurogenic inflam-
mation. ETfi receptors are hypothesized to be
activated by endothelin-3 released by primary
sensory afferent trigeminal fibers.38
NEURAL MECHANISMS OF
MAINTAINED PAIN:
PERIPHERAL SENSITIZATION
Several different processes may be involved in
the development of the severe pain that most
migraineurs experience. Sensitization of pe-
ripheral dural nociceptors is one of these. Pe-
ripheral sensitization of nociceptive terminals
may result in (1) a decreased threshold to nox-
ious stimuli; (2) such an increase in terminal
responsiveness to physical and chemical stim-
uli that normally non-noxious stimuli activate
the sensitized receptor; and (3) continuous,
spontaneous, afferent fiber firing. All three
processes demonstrably occur in primary
trigeminal afferent neurons that innervate the
dural venous sinuses.276 After exposure to
products of inflammation, the terminals of such
neurons are strongly activated by mechanical
stimuli that initially evoked little or no firing.
It has been postulated that sensitization of
meningeal afferents contributes to the charac-
teristic mechanical hypersensitivity of migraine
headaches (manifested by worsening of pain by
Valsalva maneuvers or sudden head move-
ment).276
Peripheral sensitization is a process em-
bodying modification of the ionic and chemical
properties of the nerve endings. It is produced
by chemical stimulation of dural receptive
fields with algogenic inflammatory substances
Head Pain and Associated Symptoms 253
that activate G protein-coupled receptors
which then activate second messengers. Pro-
tein kinase A (PKA), activated by cAMP, and
protein kinase C (PKC), activated by diacyl-
glycerol (produced by the hydrolysis of mem-
brane phosphoinositides), are implicated in the
intracellular signaling processes that sensitize
nociceptors. Protein kinase A and C phospho-
rylate ion channels and change their proper-
ties. In particular, phosphorylation by protein
kinase A has been to shown to modify tetrodo-
toxin-resistant, voltage-sensitive Na + currents
specific to nociceptors, increasing the magni-
tude of the Na + currents to depolarization.
NEURAL MECHANISMS OF
MAINTAINED PAIN: CENTRAL
SENSITIZATION
Another process hypothesized to play a part
in maintaining head pain is sensitization of
second-order neurons in the trigeminocervical
system. A great deal of data show that periph-
eral inflammation, such as that proposed as the
basis for migraine pain, results in increased ex-
citability of spinal and trigeminal neurons.78'131
This increased excitability is characterized by
a lowered response threshold, the inauguration
of spontaneous activity, enhanced responses in
the suprathreshold range, the recruitment of
novel inputs, and enlarged receptive fields.
Such changes in central sensory processing and
excitability of relay neurons occur following no-
ciceptor C-fiber inputs that last only tens of
seconds to minutes. 2 The process is called cen-
tral sensitization. The perceptual correlates of
sensitized central nociceptive pathways are a
lowered pain threshold, increased painfulness
of suprathreshold stimuli (hyperalgesia), and
generation of pain by activation of low-
threshold A/3 mechanoreceptors (allodynia). If,
as most data strongly suggest, neurogenic in-
flammation is a major cause of migraine pain,
then alterations in central pain-processing re-
sulting from excessive nociceptive input from
intracranial blood vessels increase that pain. In
experimental animals, application of inflam-
matory agents to the dura not only activates
brain stem trigeminal neurons but also sensi-
tizes them for up to 10 hours.39 Hyperex-
citability of central pain pathways develops in
migraineurs as shown by the development of
254 Pathophysiology
cutaneous allodynia outside of pain-referred
areas in 79% of migraineurs during attacks.40
Although a number of hypotheses have been
proposed to explain the process, it is now
generally accepted that the development of
central sensitization depends greatly upon on-
going afferent activity from the site of inflam-
mation. Substance P and glutamate released
from sensory terminals and acting at NK1 and
NMD A receptors, respectively, are intimately
involved in the process.77'286'288 I it it is also
evident that other factors, especially the intra-
cellular signal transduction pathways initiated
by activation of NK1 and NMD A receptors, are
operative. In other words, inflammatory pain
and intense afferent nociceptive input alter the
dorsal horn and trigeminal nucleus circuitry by
a number of processes, some of which are in-
terrelated. These include the following:
1. Development of "windup" in wide dy-
namic relay (WDR) neurons. When nocicep-
tive second-order dorsal horn and nucleus cau-
dalis neurons receive a low-frequency C-fiber
input, an acute, constant response is produced.
This baseline response to noxious stimuli is
abolished by selective AMPA antagonists,
demonstrating that the reponse is mediated by
AMPA receptors. The baseline is not altered
by NMDA antagonists. If, however, the stim-
ulus is given at a higher frequency, the re-
sponses of second-order neurons are trans-
formed to a much higher level of activity, and
the firing rate increases with each subsequent
stimulation. As a result, the response to later
stimuli is substantially greater than the original
response and is often followed by a significant
after-discharge. Windup is the term for the
dramatic increases in both the duration and
magnitude of the neuronal responses that oc-
cur in response to high-frequency C-fiber in-
put. The term relates to the changes that oc-
cur during an initiating stimulus. Sensitization,
a persistent increase in excitability, is inaugu-
rated by windup that may only last for a mat-
ter of seconds. Selective NMDA antagonists
substantially reduce the windup of central neu-
rons.70 There is also a small, but significant,
contribution from NK1 receptors.22
2. Release of Mg2+ block of NMDA recep-
tors on relay neurons. Under resting condi-
tions, the contribution of NMDA receptors to
dorsal horn and nucleus caudalis relay neuron
firing is limited by a voltage-dependent Mg2+
block of the NMDA receptor ion channel.
When nociceptive afferents fire, release of
neuropeptides activate NK1 receptors. This in-
creases the cytosolic Ca2+ concentration in
postsynaptic neurons by means of Ca2+ influx
and the release of Ca2+ from intracellular
stores. Protein kinase is activated and phos-
phorylates serine and threonine residues on
NMDA receptors.121 This changes the kinetics
of Mg2+ binding to the NMDA receptor in nu-
cleus caudalis neurons.50 The consequence is
a partial removal of the Mg2+-dependent
blockade, thereby increasing the sensitivity of
spinal and trigeminal neurons to glutamate and
allowing activation of NMDA receptors at rest-
ing membrane potentials.50 The increased in
glutamate sensitivity explains some of the elec-
trophysiological changes that occur during cen-
tral sensitization: previously subthreshold in-
puts now begin to generate action potentials
that alter receptive field properties and make
the entire system hypersensitive.
3. NMDA-induced enhancement of cytoso-
lic Ca2+ concentration and activation of NO
synthase. Production of NO is also intimately
linked to NMDA receptor activation that pro-
duces an influx of Ca2+. Nitric oxide synthase
is activated by Ca2+ ions acting on a calmod-
ulin site. Increased production of NO, as well
as subsequent activation of the enzyme guany-
late cyclase, which enhances synthesis of
cGMP in the spinal cord (and presumably in
nucleus caudalis), has been identified as an im-
portant component of central sensitization. In
particular, NO synthase inhibitors, application
of extracellular hemoglobin, which blocks in-
ter-cellular NO transport by binding NO, and
inhibitors of guanylate cyclase have been
shown to prevent components of sensitization
dependent upon activation of NMDA recep-
tors.153'194 In addition, elevation of NO levels
in the spinal dorsal horn by application of an
NO donor or activation of the cGMP pathway
enhances the responses of spinothalamic neu-
rons to both innocuous and noxious stimuli.180
4. Expansion of receptive fields and changes
in the excitability of relay neurons receiving
convergence of intracranial vascular and ex-
tracranial somatic afferents. Brief exposure of
dural afferents to inflammatory substances re-
sults in changes in the electrophysiological
properties of central trigeminal neurons that
receive convergent input from the dura and
from extracranial afferents.39 These newly sen-
sitized trigeminal neurons show a lowered

threshold and an increased excitability in re-
sponse to brushing or heating the periorbital
skinstimuli to which they had shown only
minimal or no response prior to chemical stim-
ulation of the dura. The extracranial tenderness
that accompanies migraine may be explained
by the sensitization of central trigeminal neu-
rons that receive convergent input from both
the dura and the skin.
Again, NMDA-mediated synaptic events are
thought to play a role in the increased ex-
citability of central trigeminal neurons that re-
sults from in-flammatory pain. Substantial ev-
idence indicates that NMDA antagonists are
effective in blocking the effects of peripheral
inflammatory pain on dorsal horn neurons; pre-
sumably the same mechanism is present in the
central trigeminal neurons.115
5. A decrease of inhibitory processes.181'265
The effectiveness of inhibitory transmission by
GABAA and glycine receptors acting at both
pre- and postsynaptic sites is reduced by pro-
longed nociceptive inputs. As a result, the level
of excitability of dorsal horn neurons is in-
creased and this affects the magnitude of cen-
tral sensitization.
6. Changes in the phenotype of low-
threshold afferents. Continued firing of C-
fibers can alter the phenotype of low-thresh-
old, myelinated A/3 afferents. The process in-
volves the gene for preprotachykinin I (the
precursor of substance P), which, when in-
duced, allows the low-threshold, mechanosen-
sitive Aj8 fibers to secrete substance P as C-
fibers do and to evoke prolonged excitatory
potentials in dorsal horn and nucleus caudalis
neurons.215'217 In effect, by switching pheno-
type, these low-threshold sensory neurons have
acquired some of the characteristics and func-
tion of nociceptive fibers. The mechanism of
the phenotypic switch is unknown.
7. Unmasking, or activating, previously
(silent) ineffective synapses to form temporary,
or novel, synaptic contacts between low-thresh-
old afferents and dorsal horn or nucleus cau-
dalis neurons normally activated by high-
threshold afferents. Some glutamergic synapses
between primary afferent fibers and dorsal
horn or nucleus caudalis neurons are ineffi-
cient or silent. It may be that ineffective sen-
sory transmission results from postsynaptic
currents too small to depolarize second-order
neurons to threshold for action potentials, or
from second-order neurons that develop nor-
Head Pain and Associated Symptoms 255
mal postsynaptic currents but have increased
thresholds for action potentials. The mecha-
nism of activation of silent synapses is unclear,
but their recruitment is known to increase the
excitability of WDR neurons that amplify all
sensory inputsthose from low-threshold af-
ferents that normally convey information about
innocuous stimuli and those from nociceptive
specific neurons that respond only to noxious
stimuli.
8. Alteration in gene expression in trigemi-
nal and spinal neurons. Noxious stimulation
up-regulates gene expression in spinal cord and
central trigeminal neurons. For example, acti-
vation of intracranial nociceptive pathways can
rapidly induce immediate early genes, such as
c- fos and c-jun, in those trigeminocervical
neurons that participate in pain transmis-
sion.60'108'204 Immediate early genes, in turn,
affect both the transcription of target genes and
the future synthesis of cellular peptides and
proteins. Target gene expression modifies the
phenotype of the neurons. Such changes may
alter the function and excitability of second-
order spinal cord neurons responsible for the
forwarding of nociceptive information.
In sum, central sensitization is a complex
process. It is certain that arrival of impulses in
unmyelinated afferents triggers prolonged ex-
citability of neurons in the spinal cord and
trigeminal nucleus. There is also evidence that
NK1 and NMDA receptors, the actions of glu-
tamate, glycine, GABA, substance P, and NO
are involved, as are alterations in gene expres-
sion and neuronal phenotypes. Central sensiti-
zation must be considered to play a key part in
intensifying and prolonging the pain of a mi-
graine attack.
ENDOGENOUS
PAIN-MODULATING SYSTEMS
Also among the hypotheses of what might
cause migraine pain is a proposal, first offered
in preliminary form by Sicuteri and recently
resurrected and extended in modified form by
Fields, that migraine is a disorder of the en-
dogenous pain modulating systems.95'264 The
hypothesis grew out of investigative work
demonstrating that certain supraspinal struc-
tures exert potent effects on spinal cord and
brain stem sensory function. In other words,
transmission involving nociceptive trigeminal
256 Pathophysiology
and spinal neurons is controlled by a number
of central nervous circuits responsible for
the inhibition and facilitation of pain path-
ways.95'97'139'259 Several networks that partici-
pate in the control of pain have components in
the mesencephalic periaqueductal gray matter
(PAG) and pontine and medullary structures.
When activated by electrical stimulation, these
structures can modify pain sensation and in-
hibit behavioral reactions evoked by noxious
stimuli. The abnormality underlying migraine
pain is hypothesized to result in an alteration
of function of these systemseither activation
of descending systems that facilitate process-
ing of pain signals by trigeminal and spinal neu-
rons or a suppression of descending pathways
that inhibit such processing of pain signals in
brain stem and spinal cord. The result is a cen-
tral hyperalgesia and an augmentation of the
central perception of pain.
When pain-modulating networks in the
brain are activated by nociceptive stimuli, var-
ious anatomic systems in the brain stem par-
ticipate. The spinothalamic and trigeminothal-
amic tracts distribute collateral branches at
various points in the brain stem as they ascend
toward their destinations in the thalamus. Di-
rect connections also exist between dorsal horn
neurons excited by noxious stimuli and brain
stem structures. Neurons in the PAG, as well
as related pontine and medullary structures, re-
ceive substantial input from both trigeminal
and spinal neurons that convey nociceptive in-
formation. Physiological studies have demon-
strated that a substantial number of neurons in
the PAG (and other areas in the brain stem)
are responsive to noxious stimuli.28'294 Inter-
pretation of these data has led to development
of a hypothesis that entails the presence of en-
dogenous analgesic systems to explain the func-
tional significance of the descending brain
stem systems. The PAG, its connections, and
their spinal projections are thought to consti-
tute a negative feedback loop activated by stim-
uli that cause pain. The negative feedback cir-
cuit produces an inhibition of the trigeminal
and spinal transmission of nociceptive mes-
sages, and hence, and analgesia. The contrary
also seems to occur, increasing evidence indi-
cates that these systems can enhance, as well
as depress, the processing of nociceptive in-
formation. These brain stem systems are pre-
sumably activated during attacks of migraine
pain.
Periaqueductal Gray
The PAG is a major site capable of producing
analgesia when appropriately stimulated. Acti-
vation of the PAG by electrical stimulation has
several consequences for descending pain
modulation: it diminishes spinal and trigeminal
reflex responses, it inhibits the firing of noci-
ceptive neurons in the trigeminal nuclei and
dorsal horn produced by C-and AS fiber stim-
ulation, and it produces behavioral analgesia in
animals and pain relief in humans.128'3"6
Significant inputs to the PAG come directly
from the dorsal horn of the spinal cord and
from the trigeminal nuclear complex, or as col-
laterals of spinothalamic and trigeminothala-
mic axons.36 Neurons in the PAG are activated
by stimulation of the superior sagittal sinus.146
The PAG also participates in an ascending pain
system. There are projections from the PAG to
the ipsilateral thalamus including the so-
matosensory ventrobasal region.241
Direct and indirect descending projections
from the PAG to superficial trigeminal and
dorsal horn neurons have been described. They
appear to play critical roles in controlling
transmission of nociceptive information.178
The direct projections of the PAG to the spinal
cord and to the trigeminal nuclear complex
are, however, sparse. Descending influences
from the PAG are, for the most part, relayed
through synapses in two brain stem sites: the
rostral ventromedial medulla (RVM) and the
dorsolateral pontine tegmentum (DLPT) (Fig.
11-17).
Sites within the RVM that project to the
spinal cord and trigeminal nuclei include the
midline nucleus raphe magnus and several nu-
clei in the adjacent ventral reticular forma-
tion.97 In turn, these nuclei project directly and
massively to laminae I, II, and V of the trigem-
inal caudalis and, via bulbospinal fibers de-
scending in the spinal dorsolateral funiculus, to
nociceptive neurons in laminae I, II, V, VI, and
VII of the dorsal horn of the spinal cord.29'187
These laminae are known to contain the ter-
minals of small-diameter nociceptive primary
afferents, as well as neurons that respond to
noxious stimuli and project to the thalamus.
Therefore, it is not unexpected that electrical
stimulation of sites in the RVM, especially in
the nucleus raphe magnus, produces effects
similar to those seen following stimulation of
the PAGnamely, elevated threshold for no-
 Head Pain and Associated Symptoms 257

Figure 11-17. Descending projections from the brain stem. The periaqueductal gray (PAG), rostroventral medulla (RVM),
and dorsolateral pontine tegmentum (DLPT) are reciprocally interconnected. The RVM is thought to exert both excita-
tory (+) and inhibitory ( ) control over pain-transmission neurons that ascend to the thalamus with projections to PAG.
The descending pathway from DLPT is thought to be mainly inhibitory. 5-HT, 5-hydroxytryptamine (serotonin); NE, nor-
epinephrine. (Modified from Fields HL: Pain modulation and headache. In Goadsby PJ and Silberstein SD (eds): Head-
ache. Butterworth Heinemann, Boston, 1997, pp 39-57, with permission.)

ciceptive responses and reflexes and reduced On- and Off-cells

firing of neurons excited by nociceptive inputs
in the nucleus caudalis and dorsal horn.4'242
In addition, lesions of the nucleus raphe mag-
nus prevent the inhibition of behavioral and
dorsal horn responses produced by stimulation
of the PAG.103
The DLPT is linked to both the PAG and
the RVM. The DLPT projects directly to the
spinal cord dorsal horn. Electrical stimulation
of areas in the DLPT produces effects similar
to those seen when stimulating the RVM, such
as a decrease of reflex withdrawal responses to
noxious stimuli.
Although research emphasis has been placed
on the mechanisms that underlie inhibition of
nociception and production of analgesia, re-
cent data indicate that descending brain stem
pathways can enhance as well as depress pain
processing. These opposing inhibitory and fa-
cilitatory actions on nociceptive transmission
are mediated by two physiologically distinct
classes of neurons in the RVM, the on-cell and
the off-cell (Fig. 11-18).97 The firing pattern of
these neurons varies with the onset of with-
drawal reflexes evoked by noxious stimuli and
258 Pathophysiology

Figure 11-18. Schematic diagram of effect of on-cells and off-cells on pain transmission neurons in dorsal horn (and
presumably in nucleus caudalis). Both cell types are located in the rostral ventromedial medulla (RVM). On-cells are in-
hibited by opioids ( ) and are believed to excite (+) pain transmission neurons. Off-cells are excited by opioids ( + ) and
putatively inhibit () pain transmission neurons. (Modified from Fields HL: Pain modulation and headache. In Goadsby
PJ and Silberstein SD (eds): Headache. Butterworth Heinemann, Boston, 1997, pp 39-57, with permission.)

in their responses to opiates. On-cells show
bursts of activity that begins just prior to with-
drawal from a noxious stimulus. Because of this
firing pattern, and because opiates inhibit their
firing directly, on-cells are thought to have a
facilitatory effect on nociceptive transmis-
sion.96 In contrast, off-cells appear to be in-
hibited by noxious stimuli, their firing ceasing
abruptly just before a withdrawal reflex begins.
Off-cells are inhibited by on-cells and are
therefore activated indirectly by opioids. Off-
cells are thought to inhibit spinal cord noci-
ceptive neurons tonically.122 Neurons of a third
class, called neutral cells, demonstrate no al-
teration in firing associated with withdrawal re-
flexes or opioid analgesic administration. Their
role in pain transmission, if any, is obscure.
It would be expected that activation of PAG
circuits that produce analgesia would excite the
off-cells and inhibit the on-cells. And indeed,
injection of morphine into the PAG (a proce-
dure known to produce analgesia) increases the
baseline firing of off-cells and inhibits on-
cells.23
Monoamines and Nociception
That central monoaminergic pathways are in-
volved in pain-modulating circuits is un-
doubted. Three major pieces of data support
this conclusion. First, a large number of 5-HT-,
norepinephrine-, and dopamine-containing
fibers project from the brain stem to the
trigeminal nuclei and to the dorsal horn of the
spinal cord. Second, a number of studies have
established that activity in bulbospinal mono-
aminergic pathways is associated with de-
pressed nociceptive transmission.26 Finally,
when monoaminergic neurons are destroyed,
or when CNS monoamines are depleted phar-
macologically, there is a substantial reduction
in analgesia produced by stimulation of the
PAG and other brain stem sites.2

A major component of the endogenous an-
tinociceptive system consists of 5-HT-contain-
ing axons that originate in the RVM and de-
scend to the nucleus caudalis and to the spinal
dorsal horn, linking them to the PAG.25>5^The
role of 5-HT in descending inhibition has been
demonstrated in several ways. Electrical stim-
ulation of the nucleus raphe magnus and other
areas in the RVM releases 5-HT from bul-
bospinal terminals in the dorsal horn. Mi-
croapplication of 5-HT inhibits spontaneous
and synaptically induced firing of spinothala-
mic and nucleus caudalis neurons. Intrathe-
cally administered 5-HT produces analgesia
that can be suppressed by 5-HT antagonists.300
Several different 5-HT receptor subtypes, in-
cluding 5-HTiA, 5-HTiB, and 5-HT3 types,
may participate in the process that modulates
central nociceptive responses.89'231 The RVM,
however, does not have a homogeneous popu-
lation of neurons. A growing body of experi-
mental data suggests that multiple neurotrans-
mitter systems are involved when raphe-spinal
neurons are activated. In several raphe nuclei,
for example, cells containing 5-HT and pep-
tides such as substance P or enkephalin and
cells containing GABA and glycine have been
observed.142-143
Norepinephrine-containing neurons from
the locus coeruleus, the subjacent nucleus sub-
coeruleus, and other pontine groups of norepi-
nephrine-containing cells in the DLPT also
project to the trigeminal nuclear complex and
spinal cord.160'2*53 Stimulation of the locus
coeruleus has a predominantly inhibitory effect
on the discharge of spinal nociceptive cells and
on spinal nociceptive reflexes.144-205 Intrathe-
cal administration of selective adrenergic 0.%-
agonists causes long-lasting analgesia and a
high concentration of a2-binding sites is pres-
ent in the superficial layers of the dorsal
horn.239 These data suggest that the analgesic
effects of the locus coeruleus are mediated by
norepinephrine acting on 2-adrenoceptors.
Investigations of brain stem control of noci-
ception have emphasized descending 5-HT
and norepinephrine pathways, but descending
dopaminergic pathways may also be involved.
The nucleus caudalis and spinal cord receive
projections from dopamine-containing cell
bodies located within the caudal dien-
cephalon.182 Although the exact site of action
where dopamine acts in the trigeminal nucleus
and in the spinal cord is unknown, there is ev-
Head Pain and Associated Symptoms 259
idence of its role: activity in the spinal
dopaminergic system produces a decrement of
nociceptive neuron firing and an increase of
the reflex nociceptive threshold.140'141 In ad-
dition, alterations in dopaminergic transmis-
sion attenuate the analgesic effects of both
electrical stimulation of the PAG and systemic
morphine administration.2
Opioid Peptides
Endogenous opioid peptides that share actions
with the active stereoisomers of opiate alka-
loids and that are antagonized by pure opiate
antagonists have been linked to many of the
modulatory effects that brain stem structures
have on nociceptive transmission. Midbrain
and other brain stem nuclei connected with
pathways descending to the spinal dorsal horn
and to the nucleus caudalis are rich in certain
opioid peptides and receive opioid peptide-
containing fibers from other structures, in-
cluding the basal hypothalamus. When injected
into the PAG, morphine produces analgesia.301
Furthermore, microinjection of opioid antago-
nists into the PAG blocks the analgesic effect
of systemically administered opioid analgesics.
Opiate-sensitive regions have also been found
in the nucleus raphe magnus and surrounding
regions in the medulla. The actions of opiates
injected into these sites are either fully or par-
tially blocked by opiate antagonists, an indica-
tion that the compounds activate specific opi-
ate receptors.71'30 In sum, brain stem areas are
important for the clinical effects of opiates.
Such a conclusion is reinforced by observations
that lesions of the PAG or of the RVM reduce
the analgesia produced by systemic morphine
administration.
Although multiple endogenous peptide opi-
oid ligands have been described, all appear to
derive from one of three precursors: prepro-
opiomelanocortin, preproenkephalin, and pre-
prodynorphin. Preproopiomelanocortin gives
rise to the endorphin group that includes (3-
endorphin. This precursor is present in ex-
tremely high quantities in the intermediate
lobe of the pituitary and in the corticotroph
cells of the adenohypophysis. j3-endorphin-
containing cell bodies are concentrated in the
basal hypothalamus, which distributes axons to
parts of the limbic system, to the PAG, and to
the locus coeruleus. Thus, the j8-endorphin
260 Pathophysiology
system conforms to loci believed to produce
analgesia by means of electrical stimulation. It
is not surprising that intraventricular adminis-
tration of /3-endorphin produces potent anal-
gesia, or that increases in cerebrospinal fluid
(CSF) /3-endorphin levels are seen after brain
stimulation in humans. Current knowledge is
also compatible with observations that bilateral
destruction of /3-endorphin-containing cell
bodies in the hypothalamus diminishes the
content of /3-endorphin in the brain and lessens
the analgesic actions of PAG stimulation.
Preproenkephalin gives rise to the enkeph-
alins, including both leu-enkephalin and met-
enkephalin. Enkephalin-containing cells and
fibers are widely distributed. Enkephalins are
present in the neural lobe of the pituitary in
fibers derived from the paraventricular
and supraoptic nuclei of the hypothalamus.
They are also found in the PAG, the raphe nu-
clei, the nucleus caudalis, and the dorsal
horn.57 Several lines of evidence suggest that
enkephalin-containing interneurons in the
nucleus caudalis and dorsal horn play a role in
the control of nociceptive information, espe-
cially because the cell bodies and proximal den-
drites of spinothalamic cells receive synapses
from enkephalin-containing interneurons. '25
Moreover, applied in the vicinity of nucleus
caudalis and spinal dorsal horn nociceptive
neurons, enkephalins suppress their responses
to noxious stimuli.6'307
Preprodynorphin is the precursor of the
dynorphin family. Dynorphin is present in
large quantities in the adenohypophysis, the
PAG, and those layers of the nucleus caudalis
and dorsal horn concerned with the processing
of nociceptive information.150 The compound,
however, is not a potent analgesic substance
and its role in nociceptive functioning is a mat-
ter of dispute.
Endorphins and Migraine
A number of investigators have assayed the
levels of various endogenous opioids in both
plasma and CSF of migraineurs. Their data
for enkephalins both during and between at-
tacks are inconsistent: elevated, reduced, and
normal enkephalin levels have been re-
ported.11'94'98'210'211'266 The data for endor-
phins is somewhat different. As with enke-
phalins, plasma /3-endorphin levels yield
mixed results: depending upon the group of
researchers, there are reports of higher, un-
changed, and lower plasma levels of /3-
endorphin during attacks.11'12'16'17 Plasma /3-
endorphin levels, however, are reported as
being normal between attacks of mi-
graine.16'17'91'212'278 As for CSF /3-endorphin
levels, they are significantly reduced during
migraine headaches. This, however, is not
unique to migraineurs. Reduced levels of /3-
endorphin are found in patients with chronic
pain, whatever its cause or origin. And it
should be noted that patients with chronic
daily headaches have consistently reduced
levels. That so much of this data is inconsis-
tent makes it difficult to draw inferences
about the function of the endogenous endor-
phin system in migraine headaches.90
CENTRAL ACTIVATION OF
PAIN-MODULATING SYSTEMS
Central pain pathways appear to be involved in
the production of migraine pain.95 Positron
emission tomographic (PET) measurements of
rCBF demonstrate increased blood flow in
midline brain stem structures during the head-
ache phase of spontaneous attacks of migraine
without aura.72-292 Although PET scans lack
the resolution to pinpoint the precise brain
stem nuclei activated, the increased blood flow
appears to be in the dorsal midbrain in the re-
gion of the PAG, slightly contralateral to the
side of the headache. The locus coeruleus and
raphe nuclei may also be included. Activation
persists even when sumatriptan has relieved all
symptoms, including headache, nausea, and
photophobia. Moreover, when experimental,
non-migrainous head pain is produced, activa-
tion is not observed in the brain stem, but
rather in the cingulate cortex, frontal cortex,
and insular cortex, where it would be expected
for generalized pain.190 Nor is brain stem acti-
vation seen in PET scans of patients during at-
tacks of cluster headache. 8 Because brain
stem activation fails to develop during other
types of head pain, it is unlikely to have re-
sulted from pain perception alone. It would
seem that brain stem activation is specific for
migraine attacks and that, as has been sug-
gested, the activated area represents a "mi-
M
graine generator in the brain stem.71
1 1
What then might be the precise role of the
PAG? Until recently, our thinking has been
dominated by ideas about the PAG being used
 Head Pain and Associated Symptoms 261

Figure 11-19. Pathways that mediate psychological influences on pain transmission. Limbic areas of cortex (cingulate
and insular) project both directly and via the amygdala to the peraqueductal gray (PAG), which controls pain transmis-
sion neurons, the dorsal horn, and nucleus caudalis via the rostral ventromedial medulla (RVM). (Modified from Fields
HL: Pain modulation and headache. In Goadsby PJ and Silberstein SD (eds): Headache. Butterworth Heinemann, Boston,
1997, pp 39-57, with permission.)

to inhibit nociception. The PAG actually has a
previously unsuspected degree of complexity.
There is growing recognition that the PAG is
pivotal in coordinating behavioral responses to
stressful situations.20'21 It plays a major role in
the brain circuitry that integrates behavioral
responses to threatening stimuli, and it is a cen-
tral site for processing the symptoms of fear
and anxiety. As an example, stimulation of cer-
tain sites in the human PAG produces un-
pleasant-to-intolerable sensations, such as feel-
ings of intense fear and dread.213 In conscious
experimental animals, stimulation of specific
loci in the PAG generates threat displays with
vocalization and strong flight responses.19'69
As expected from a structure that is involved
in multiple processesanalgesia, integration
of different behavioral states, and the coordi-
nation of reactions to stressthe connections
of the PAG are widespread and complex. Ma-
jor afferent inputs originate from forebrain lim-
bic areas including the anterior cingulate and
anterior and posterior insular and perirhinal
cortical fields that extend from the frontal pole
almost to the caudal pole of the hemi-
sphere.21'263 There are also robust projections
from the hypothalamus, thalamus (particularly
the intralaminar nuclei), and the amygdala.4'21
It is noteworthy that most of the areas pro-
jecting to the PAG have been implicated in
functions also associated with the PAG, in-
cluding emotion and nociception (Fig. 11-19).
On the basis of observations that strong emo-
tions potently affect the perception of painful
stimuli, Fields proposed that limbic forebrain
structures can mobilize the pain-modulating
circuits.95 A reasonable question is: when the
limbic forebrain activates the PAG, the area of
262 Pathophysiology
the brain proposed to be the "migraine cen-
ter," can such structures produce migraine
head pain? Through their afferent connections
to the PAG, limbic forebrain structures acti-
vated by trigger factors or by stimuli that cause
emotional stress are well positioned to modu-
late neuronal circuits that exert bidirectional
control over pain transmission. Observations
that some patients develop headaches imme-
diately after electrodes are implanted in the
PAG provide evidence for this idea.237'290 The
post-implantation headaches can occur in pa-
tients not previously troubled by headaches; for
some individuals, they persist for months to
years. The headaches resemble migraine.
Some patients reportedly develop both a pat-
tern of intermittent, recurrent, pounding head-
aches and a syndrome that includes visual
disturbances, nausea, and vomiting. Adminis-
tration of 5-HT precursors exaggerated the
pain in one patient; in others, the pain was al-
leviated by reserpine and ergotamine. Pertur-
bation of the PAG, it would seem, may pro-
duce head pain with many characteristics of
migraine.
NAUSEA AND VOMITING
Nausea and vomiting are common during mi-
graine attacks. Emesis is a complex event that
must integrate excitation and inhibition of both
visceral and somatic musculature.24'46 It ne-
cessitates the synchronized activity of a con-
siderable number of motor nuclei, including
those that innervate the abdominal muscula-
ture, the diaphragm, the intercostal muscles,
and the muscles of the larynx, pharynx, and
tongue. The motor act of vomiting is primarily
produced by changes in intra-abdominal and
intrathoracic pressures generated by the respi-
ratory muscles.112 The process also involves the
neurons and the intrinsic nerve cells that in-
fluence tone and peristalsis of the esophagus,
stomach, and small intestine and contraction of
the sphincteric muscles. Changes in gastroin-
testinal activity include a retrograde giant con-
traction that propagates from the mid-small in-
testine to the antrum. In addition, this reflex
interacts with autonomic functions responsible
for pallor, salivation, cold sweats, pupillary di-
latation, tachycardia, and hypotension.
Older studies indicated that vomiting in ex-
perimental animals could be induced by elec-
trically stimulating the lateral medullary retic-
ular formation of the brain stem. Lesions in this
site rendered animals refractory to emetic
agents. A standard textbook concept of the
"vomiting center" evolved from these studies
whereby a variety of emetic stimuli converged
on the vomiting center, which coordinated all
of the necessary somatic and autonomic activ-
ity. Recently, however, the concept of a dis-
crete vomiting center has been revisited.202 At-
tempts to replicate older experiments have
failed. Accordingly, the idea of a single anatom-
ical center, responsible for all of the activity
that occurs during vomiting, is in flux.
Two alternative hypotheses have been pro-
posed to explain how vomiting occurs. Ac-
cording to one theory, a "central pattern gen-
erator" for emesis coordinates the process.4>101
The central pattern generator consists of an in-
terneuronal network that sequentially activates
the various motor and autonomic nuclei. The
postulated central pattern generator's identity
is a matter of dispute, but one candidate is the
nucleus of the solitary tract. This area receives
inputs from trigeminal primary afferents that
innervate intracranial arterial and venous struc-
tures (Fig. 11-20).13'108 It is also the major in-
tegrative nucleus for visceral afferent informa-
tion, and it receives inputs from baroreceptor,
respiratory, gustatory, and gastrointestinal sys-
tems and from the area postrema.251 The nu-
cleus of the solitary tract is known to be in-
Figure 11-20. Diagram delineating the c-fos expression
that occurs in the caudal medulla of the monkey after elec-
trical stimulation of the superior sagittal sinus. Each dot
represents afos-positive cell, all of which are concentrated
in the trigeminal nucleus caudalis (TNC) and in the com-
missural nucleus of the tractus solitarius (cNTS). (Adapted
from Goadsby PJ and Hoskin KL: The distribution of
trigeminovascular afferents in the nonhuman primate
brain Macaco nemestrina: a c-fos immunocytochemical
study. J Anat 190:367-375, 1997, reprinted with the per-
mission of Cambridge University Press.)
 Head Pain and Associated Symptoms 263

volved in the integration of autonomic afferent

inputs from many peripheral organs, and it also
integrates a number of complex motor acts,
such as swallowing, breathing, and chewing,
that involve brain stem neurons. In addition,
stimulation of the nucleus of the solitary tract
evokes retching and emesis in experimental an-
imals. In sum, the nucleus of the solitary tract
is not only susceptible to trigeminovascular ac-
tivation but also has many of the attributes ex-
pected of a central pattern generator.
Another theory offered to explain the pro-
cess of vomiting focuses on discharges in local
reflex circuits in the brain stem. Such reflex cir-
cuits activate each effector motor and auto-
nomic nucleus involved in emesis.64'201 The act
of emesis, then, is a consequence of these nu-
clei acting in sequence as a coordinated con-
trol system. Such a hypothesis clarifies obser-
vations, that rather than inducing the entire act
of emesis, electrical stimulation of particular
areas of the medulla evokes particular compo- Figure 11-21. Light-induced pain in migraineurs and in
nents of it, such as salivation or retching. control subjects before, during, and after painful mechan-
ical-pressure stimulation of the face. Light-induced pain is
Nausea and vomiting also involve the significantly increased in migraine sufferers, but not con-
chemoreceptor trigger zone located in the area trol subjects. (Adapted from Drummond PD: Photopho-
postrema, a circumventricular structure lo- bia and autonomic responses to facial pain in migraine.
cated at the caudal aspect of the fourth ventri- Brain 120:1857-1864, 1997, with permission of Oxford
University Press.)
cle in the region of the obex. The area postrema
lacks blood-brain and CSF-brain barriers and,
as a result, its neural structures are easily
reached by chemical compounds and drugs cir- not in control subjects (Fig. 11-21).80 Accord-
culating in the blood and CSF. The chemore- ingly, it is believed that the pain associated with
ceptor trigger zone is stimulated by dopamine photophobia is carried through the ophthalmic
agonists, including L-DOPA and apomorphine, division of the trigeminal nerve. The process
and by opioids and ergots. Excitation of ap- appears to involve neurogenic inflammation of
propriate receptors in the chemoreceptor trig- the eye.173 In contrast, the disagreeable sense
ger zone results in vomiting. of excessive brightness may be caused by im-
paired central regulation of visual input. 9

PHOTOPHOBIA
During a headache almost all migraineurs de-
velop an enhanced, and generally disagreeable,
sensitivity to light. Not only does light cause
pain, but patients experience an uncomfort-
able, exaggerated sense of brightness. After ex-
tirpation of the trigeminal ganglion, painful
photophobia does not involve the eye on the
side of the surgery, an observation indicating
that the trigeminal nerve is necessary for the
development of photophobia.173 In addition,
painful stimulation of areas of the face inner-
vated by the trigeminal nerve increases light-
induced pain in migraineurs during attacks, but
SUMMARY
The major locus of migraine pain appears to
consist of dural blood vessels. Nociceptive af-
ferent fibers from arteries and venous sinuses
are carried in the trigeminal nerve (trigemino-
vascular system) and in the upper cervical
nerve roots. Although the classical theory of
migraine pain proposes that the pain results
only from vasodilatation that stretches noci-
ceptors located within the walls of blood ves-
sels, documentation to establish intracranial va-
sodilatation as the sole or primary cause of
migrainous head pain is lacking. Recent data
264 Pathophysiology
indicate that dural neurogenic inflammation
with dural vascular dilatation, edema formation
in vessel walls, and a number of chemical and
physiological processes that excite and sensi-
tize vascular afferent nociceptive terminals are
more likely to produce the pain associated with
migraine headaches. Several processes, includ-
ing sensitization of central sensory processing
pathways and descending modulation of pain
transmission neurons, are available to modify
the rostral transmission of nociceptive infor-
mation. Central pain pathways may also be in-
volved in the production of migraine pain. In
particular, the periaqueductal gray matter, a
region of the brain with wide connections to
limbic structures and major indirect descend-
ing pathways, may be specifically activated dur-
ing migraine attacks.
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 Chapter 1 2
The Serotonin Hypothesis and
Other Theories
CEREBRAL HYPEREXCITABILITY
SEROTONIN AND THE INITIATION OF
MIGRAINE ATTACKS
Location of Serotonin
Normal Platelet Function
Platelet Activation, Serotonin Metabolism,
and Migraine
Serotonin and Migraine
A unifying hypothesis of migraine must explain
the complete, elaborate chain of events that
lead up to and are manifest during an attack.
The migraine diathesis includes much more
than aura and head pain. There is a whole
range of premonitory symptoms, autonomic
changes, cognitive and psychologic phenom-
ena, and postdromic symptoms. An overarch-
ing theory must deal with the cause of mi-
graine, not just the mechanisms that give rise
to putative changes in blood flow and to head
pain. But despite a great deal of study and spec-
ulation, researchers are far from developing an
adequate, unified hypothesis. There is even
controversy about the mechanisms we under-
stand bestnamely, those that underlie the
aura and pain of the migraine attack. Two ma-
jor hypotheses about those mechanismsthat
(1) spreading depression is the cause of the
aura and (2) inflammatory trigeminovascular
processes cause head painhave already been
discussed. This chapter will offer several other
theories about the causation of migraine.
CEREBRAL HYPEREXCITABILITY
Migraine patients have been postulated to have
an interictal cortical hyperexcitability that is re-
274
DOPAMINE HYPOTHESIS
MAGNESIUM
DECREASED MITOCHONDRIA!. ENERGY
RESERVE
THE SYMPATHETIC DYSFUNCTION
THEORY
SUMMARY
sponsible for the triggering of migraine attacks.
A number of studies have indicated that the oc-
cipital cortex, in particular, may be hyperex-
citable and that, as a result, visual function in
migraineurs differs from that of normal indi-
viduals. Visual symptoms are prominent fea-
tures of migraine attacks. There are patients
whose attacks are triggered by visual stimuli
such as glare, flickering or flashing lights, and
strongly contrasting patterns. When compared
to control individuals, migraineurs have a low-
ered threshold for discomfort caused by light
between attacks.89'137'147 They have aug-
mented photic driving in response to high-
frequency stimulation. The amplitude of some
components of visual evoked potentials is
greater in migraineurs than in controls.45'115
Migraineurs report more intense illusions and
more discomfort with grating patterns of cer-
tain spatial frequencies than controls.146 Fi-
nally, patients with migraine with aura react
faster in tasks reflecting low-level visual pro-
cessing than do subjects without migraine.148
Most of the abnormalities reflect dysfunction
at the cortical level, but precortical visual pro-
cessing may also be impaired.
Percutaneous transcranial magnetic stimula-
tion has been used to assess the excitability of
the visual cortex directly. An intriguing inves-
 The Serotonin Hypothesis and Other Theories 275

Figure 12-1. Comparison of the threshold levels for observing phosphenes in patients with migraine with aura and in
control subjects when the occipital lobes were activated by transcranial magnetic stimulation. Abscissa: percentage of
maximal stimulation output of the apparatus; ordinate: probability that subjects would see phosphenes (bright scintilla-
tions in the visual field). (Adapted from Aurora SK, Ahmad BK, Welch KMA, Bhardhwaj P, and Ramadan NM: Tran-
scranial magnetic stimulation confirms hyperexcitability of occipital cortex in migraine. Neurology 50:1111-1114, 1998,
with permission.)

tigation has shown that when the stimulator is
placed over the occipital lobes, all patients with
migraine with aura see phosphenes (bright
scintillations in the visual field), but only a small
percentage of control individuals do.9 In addi-
tion, the threshold for observing phosphenes is
lower in migraine patients than in those con-
trols who do observe phosphenes (Fig. 12-1).
The results have been used to support the hy-
pothesis that migraineurs display interictal oc-
cipital cortical hyperexcitability.142 Conflicting
data have also been reported, but they have
been conditionally explained on the basis of
methodological differences.1'10 In contrast,
when transcranial magnetic stimulation has
been used to study the motor cortex of patients
with migraine, the results have been conflict-
ing with regard to threshold, and conclusions
regarding persistent, generalized cortical hy-
perexcitability cannot be made.1'17'88'138'139'145
The exact cellular and molecular mecha-
nisms for the proposed occipital cortex hyper-
excitability is unknown. A number of factors
have been proposed that include low intracel-
lular Mg2+, defective mitochondria! oxidative
phosphorylation, or inherited dysfunction of
Ca2+ channels (see Chapter 2). Data support-
ing these factors as the cause of changes in cor-
tical excitability are equivocal or lacking. Al-
ternatively, the cortical hyperexcitability may
be a consequence of, rather than the cause of,
migraine attacks. Visual cortical inhibitory neu-
rons are important in maintaining the stability
of the cortex. It has been proposed that isch-
emic or near-ischemic events during the mi-
graine aura may selectively damage these neu-
rons.32 Again, there is no direct evidence that
hyperexcitability is acquired.
SEROTONIN AND
THE INITIATION OF
MIGRAINE ATTACKS
For more than three decades serotonin (5-HT)
has figured prominently in speculation about
migraine. A sizable collection of biochemical,
276 Pathophysiology
pharmacological, and anatomical evidence sug-
gests several roles for 5-HT in the genesis of
migraine.64'92'128 One theory proposes that 5-
HT, released from platelets, sets off migraine
attacks. Another school of thought claims that
release of 5-HT from perivascular terminals of
central serotonergic nerve fibers begins the at-
tack. Systemic metabolic changes in 5-HT me-
tabolism are also suggested as the initiator of
migraine headaches. It has been postulated
that migraine is a chronic, low-serotonin syn-
drome with attacks triggered, among other
things, by a sudden increase in 5-HT re-
lease.71'83 Central 5-HT hypersensitivity re-
sulting from 5-HT neuronal depletion has also
been advanced as the basis for migraine.106
These various proposals have given rise to what
is called the serotonin hypothesis of migraine.
Some aspects of serotonergic activity have
been reviewed in previous chaptersnamely
innervation of cerebral arteries by serotonergic
fibers, inhibitory effects of raphe stimulation
on the transmission of nociceptive information,
and actions of 5-HT on both cranial blood ves-
sels and nociceptive nerve endings. The ensu-
ing sections will consider other aspects of sero-
Figure 12-2. Biosynthesis of serotonin.
toninergic activity that appear pertinent to the
pathophysiology of migraine.
Location of Serotonin
The human body contains about 10 mg of 5-
HT. Ninety percent resides in enterochromaf-
fin cells in the mucosa of the gastrointestinal
tract. Some of the remainder is present in the
central nervous system (CNS), in a few pe-
ripheral nerves, and in mast cells, but most of
the remaining 10% is found in platelets. Sero-
tonin is synthesized from dietary tryptophan in
both enterochromaffin cells and neurons. This
is not the case in platelets. Accordingly, for all
5-HT-containing cells except platelets, hydrox-
ylation of tryptophan, catalyzed by the rate-
limiting enzyme tryptophan hydroxylase, re-
sults in the formation of 5-hydroxvtryptophan,
which is then transformed into 5-HT by the ac-
tions of the nonspecific enzyme L-aromatic
amino acid decarboxylase (Fig 12-2). A portion
of the 5-HT released by enterochromaffin cells
overflows into the portal circulation. Most of it
is removed from the blood as a result of enzy-
 The Serotonin Hypothesis and Other Theories
Figure 12-3. Metabolism of serotonin.
matic degradation by monoamine oxidase
(MAO) in the liver. Of the remaining fraction,
little escapes uptake by pulmonary endothe-
lium that inactivates it by means of MAO (Fig.
12-3). The product of this reaction, 5-hydrox-
yindoleacetaldehyde, can be further oxidized to
5-hydroxyindoleacetic acid (5-HIAA) or re-
duced to 5-hyroxytryptophol.
In contrast to cells that synthesize 5-HT,
platelets procure their supply of 5-HT by avid
Na+-dependent uptake from the small fraction
remaining in plasma. They store the 5-HT in
dense granules. As a result, human blood con-
tains about 0.1 to 0.3 /Ltg/mL of 5-HTalmost
all of it stored in platelets.
Normal Platelet Function
The behavior of platelets during and between
migraine attacks has received considerable at-
tention, especially from Hanington, who pro-
posed that migraine is a disease of platelets.67
According to her hypothesis, migraineurs'
platelets are abnormal and their behavior
changes during migraine attacks, giving rise to
bouts of migraine that occur because of
changes in platelet function. This hypothesis
277
aroused considerable controversy in the past.
Today, we are not at all clear what role they
play, although there is evidence that platelets
may be involved in the pathogenesis of mi-
graine.
Blood contains between 150,000 and 400,000
platelets per cubic milliliter. They are small,
anuclear, discoid cells with diameters of 1.5 to
3 (Jim (Fig. 12-4). Platelets have smooth sur-
faces with indentations into which the canalic-
ular system opens. This system constitutes a
network of channels leading from the interior
of the platelet to the surface so that the extra-
cellular space communicates with much of the
interior. The cytoplasm of platelets accommo-
dates two types of secretory granules. Dense
bodies contain calcium, 5-HT, epinephrine,
norepinephrine, dopamine, met-enkephalin
(metmonine-enkephaiin), and nucleotides,
such as adenosine triphosphate (ATP), adeno-
sine diphosphate (ADP), guanosine triphos-
phate (GTP), and guanosine diphosphate
(GDP). The other type consists of a-gmnules,
which contain platelet factor 4 (PF4) and )8-
thromboglobulin. When activated, platelets are
believed to empty the substances stored in their
secretory granules into the canalicular system
that leads to the surrounding environment. In
278 Pathophysiology

(Fig. 12-6).127 Although this observation has

been confirmed, not all investigators have been
able to find consistently increased urinary 5-
HT-metabolite excretion, and others have
failed to detect a significant increase at
^19,38,39,43,50,76 The role of 5_HT in trigger-
ing, or sustaining, migraine attacks has in-
trigued many researchers, and their interest re-
mains peaked despite the finding that urinary
5-HIAA excretion greatly surpasses the in-
creases anticipated if the exclusive origin of the
metabolite were the 5-HT released from
platelets. That platelets are a source of the ca-
Figure 12-4. Diagram of an inactive platelet in the plane tabolized 5-HT followed reports that platelet
of the longest diameter. (Adapted from Winther K and 5-HT concentration can fall substantially
Hedman C: Platelet function and migraine. In Olesen J (about 30% to 45%) during migraine attacks
and Edvinsson L (eds): Basic Mechanisms of Headache. (Fig. 12-7).7'16'38'41'103'130 In addition, the drop
Elsevier, Amsterdam, 1988, pp 301-312, with permission.)
in platelet 5-HT occurs far more frequently in
patients suffering from migraine without aura
(Fig. 12-8).52 However, as Figure 12-7 shows,
the fall in platelet 5-HT is preceded by such a
addition, activated platelets produce vasoactive preheadache rise that the subsequent drop ul-
prostanoids such as thromboxane Ag, prosta-
glandin GH, and prostaglandin PGGg.
A wide variety of physiological substances
stimulate and activate platelets by acting at re-
ceptors located on the platelet surface. These
include a- and /3-adrenoceptors, and receptors
for thrombin, histamine, 5-HT, ADP, and the
prostanoids prostacyclin and thromboxane A.
When platelets are activated, their first re-
sponses are platelet adhesion and shape
change. In the presence of fibrin, platelets stick
together, establishing an irreversible aggre-
gate. Next, normally discoid platelets are trans-
formed into spheres, pseudopodia are ex-
truded, and finally substances are released
from granules through the surface-connected
canalicular system (Fig. 12-5). In vitro studies
show that when 5-HT is the sole agonist, it in-
duces nothing more than an insubstantial and
reversible aggregation of platelets. In contrast,
even low concentrations of 5-HT strikingly en-
hance the platelet responses evoked by subop-
timal concentrations of other agonists.125

Platelet Activation, Serotonin

Metabolism, and Migraine
Interest in 5-HT began with the observation
that during bouts of migraine some patients
have increased urinary levels of 5-HIAA, the
main catabolic product of 5-HT metabolism
Figure 12-5. Diagram of an activated platelet. Different
products are released through the canalicular system con-
nected to the surface. ADP, adenosine diphosphate; ATP,
adenosine triphosphate. (Adapted from Winther K and
Hedman C: Platelet function and migraine. In Olesen J
and Edvinsson L (eds): Basic Mechanisms of Headache.
Elsevier, Amsterdam, 1988, pp 301-312, with permission.)
 The Serotonin Hypothesis and Other Theories 279

Figure 12-6. Schematic representation of changes in total plasma 5-HT (reflecting platelet 5-HT), urinary excretion of
5-hydroxyindoleacetic acid (5-HIAA), and urine volume in migraine patients. Each column indicates a 12-hour period,
first during a time of freedom from headache, then before, during, and after headache. (Adapted from Curran DA, Hin-
terberger H, and Lance JW: Methysergide. Res Clin Stud Headache 1:74-122, 1967, with permission.)

timately leads to increased amounts of urinary-
free 5-HT during attacks in individuals so af-
fected.5 The change in 5-HT levels is a sys-
temic one, not confined to the cerebral
circulation. Reduced levels are found in blood
drawn from both the antecubital vein and the
external jugular vein. And although these al-
terations clearly occur, it is not known whether
the alterations in platelet 5-HT levels are spe-
cific for, and causally associated with, the pro-
duction of migraine attacks.
The reported declines of 5-HT during a mi-
graine attack have been postulated to be
caused by the liberation of 5-HT from activated
platelets and its subsequent catabolism.55
Other biochemical evidence for platelet acti-
vation and release of granule contents exists.
For example, significantly elevated plasma lev-
280 Pathophysiology

change in platelet function.27'67'73'84 Both nor-

mal and increased sensitivity to platelet-
activating factor have been demonstrated.66'75
During the headache-free phase of migraine,
when platelets are stimulated, the secretory
function of dense bodies and a-granules is al-
tered. The significance of this finding is not
known. A number of reports indicate increased
in vitro platelet aggregatability in blood taken
during and between attacks; these results

Figure 12-7. Mean values for plasma 5-HT before, dur-

ing, and after migraine headache in a group of patients.
The plasma levels reflect the 5-HT content of platelet-en-
riched plasma. (Modified from Anthony M, Hinterberger
H, and Lance JW: The possible relationship of 5-HT to
the migraine syndrome. Res Clin Stud Headache 2:29-59,
1969, with permission.)

els of the platelet-specific products /3-throm-

boglobulin and PF4 are associated with the fall
of platelet 5-HT in as many as 50% of migraine
attacks.41'91
What causes the changes in platelet 5-HT
activity in migraineurs? Under consideration
are two possibilities: (1) some type of defect
within the platelets themselves, and (2) the
presence of a 5-HT-releasing factor circulating
in plasma.
For the first possibility, a defect within the
platelets, researchers have yet to establish Figure 12-8. Serotonin content of individual platelets
whether or not abnormal function in platelets during migraine-free periods and during attacks; data
is caused by defects. A number of studies have taken from patients with aura and without aura. Arrows in-
dicate group means, amol = 10~18 mol. (Adapted from
claimed abnormal function in platelets, but the Ferrari MD, (Delink J, Tapparelli C, et al..: Serotonin me-
results are inconsistent. As an example, ADP tabolism in migraine. Neurology 39:1239-1242,1989, with
reportedly increases, decreases, or causes no permission.)
 The Serotonin Hypothesis and Other Theories
were not replicated in other investiga-
tions.36'66'80'81'84-133 Between migraine attacks,
the proportion of circulating platelet microag-
gregates is greater than normal, and is elevated
still further during the prodromal period of an
attack.25'63 Unfortunately for our understand-
ing of how platelet aggregation affects mi-
graine, the reported hyperaggretability of
platelets is unrelated to the severity of the mi-
graine. In addition, serial investigation during
acute bouts of migraine has failed to show a
correlation between platelet aggregation and
migraine-related neurologic symptoms.36 Many
of these discrepancies may be related in part
to methodological and technical differences,
but their overall effect makes suspect any re-
lationship between platelet aggregation in vitro
and migraine pathogenesis.
The second possible cause of changes in 5-
HT activity concerns a plasma-borne, 5-HT-
releasing factor. During bouts of migraine, the
plasma of some migraineurs has been reported
to contain a soluble factor capable of releasing
5-HT from platelets. This as-yet unidentified
factor releases 5-HT from platelets in blood
taken either from migraine patients between
attacks or from normal subjects.46'103'104 Met-
enkephalin, which is co-stored with 5-HT in
platelet granules, is also released from platelets
by plasma drawn during migraine attacks.51
The evidence for the presence of a releasing
factor is still uncertain, however, and some in-
vestigators deny its presence.
Active transport of 5-HT into platelets (sero-
tonin uptake) regulates in large measure the
amount of 5-HT contained in platelets. Just as
in other studies that consider some aspect of
the relationship between 5-HT and mi-
graineurs' platelets, data about 5-HT uptake
are equivocal. Thus, although normal 5-HT up-
take into the platelets of migraineurs has been
reported, there is also documentation for de-
creases and increases of uptake.28'68'70'90'141
During and between migraine attacks, the max-
imal rate of uptake (Vmax) has been reported
to be the same as control values, increased, and
reduced40-81'86-90'103'113 Data also contradict
with regard to the concentration of platelet 5-
HT during headache-free intervals. Most stud-
ies show that the 5-HT content of platelets is
normal; nevertheless, some reports show either
increased or decreased 5-HT levels.40'41'99'141
The amounts of 5-HT potentially available
for release from platelets during migraine at-
281
tacks may be trivial from a pharmacological
point of view, for several reasons. First, the
quantity is exceedingly small. In addition, 5-
HT released from platelets is cleared from
plasma very rapidly. Ninety-five percent of it
is removed by one passage through the lungs.
Perhaps most important, migraine attacks are
not induced by intravenous administration of
5-HT.78 It seems unlikely that platelet-released
5-HT could be responsible by itself for the
changes in regional cerebral blood flow (rCBF)
seen during migraine attacks. But platelet-de-
rived 5-HT may have additional actions that
may not be trivial from a pharmacological point
of view. Serotonergic mechanisms that amplify
platelet activation presumably continue to
function during bouts of migraine. This ren-
ders the compound capable of inducing and fa-
cilitating platelet activation such that local re-
lease of 5-HT may lead to the enhanced
release, or biosynthesis, of platelet prostanoids.
In addition, synergism is manifest between 5-
HT and prostanoids such as thromboxane A,
both released from activated platelets. The sig-
nificance of this 5-HT amplification in mi-
graine has yet to thoroughly evaluated.
In sum, although abnormalities in platelet
function have been reported in migraine suf-
ferers, a consistent abnormality of platelet
function has not been demonstrated.74 Even if
one were proved, what role such abnormalities
might play in the genesis of migraine is indef-
inite at best. To accept the platelet disorder hy-
pothesis, it would be necessary to show that ac-
tivation of platelets specifically precipitates
attacks of migraine by itself; data in this regard
are unavailable. The preceding point is
strengthened by the poor correlation between
changes in platelet function and the intensity
of migraine in individual patients. Accordingly,
it remains ambiguous whether abnormal
platelet activation and other derangements in
platelet function are in any way causative or are
only epiphenomena.
Serotonin and Migraine
In addition to data about possible relationships
between platelet and urinary 5-HT levels, 5-
HT metabolites, and migraine, quite a few
other pieces of evidence (some of which have
been treated elsewhere) have been used to
support the 5-HT hypothesis:
282 Pathophysiology
1. Activation of a diversity of 5-HT recep-
tors on the extra- and intracerebral vasculature
can cause both vasoconstriction and vasodila-
tion upon exposure to 5-HT. Whether 5-HT-
containing nerve fibers that innervate blood
vessels have a peripheral or a central source,
and whether the presence of the indolamine in
these nerves results from uptake or synthesis
are unclear (see Chapter 10).
2. Serotonin appears to play an important
role in the endogenous pain control pathways
(see Chapter 11). Although complete under-
standing of the ways in which 5-HT affects the
rostral transmission of nociceptive information
in the CNS is not yet available, we are already
certain that manipulation of serotonergic neu-
rons has potent effects on both behavioral re-
sponses to pain and the responses to noxious
stimuli by neurons in the spinal cord and the
trigeminal nuclear complex. It has been hy-
pothesized, but not proven, that the endoge-
nous pain control system is involved in the gen-
esis of migraine attacks and in the control of
head pain caused by a bout of migraine.
3. Serotonin excites peripheral nociceptive
nerve endings by activating specific 5-HT re-
ceptors located on them (see Chapter 11). It
also potentiates the algesic actions of other
compounds such as bradykinin and prosta-
noids. Presumably such actions also take place
on trigeminovascular nociceptors.
4. Intravenous administration of 5-HT can
alleviate the symptoms of migraine.6'78 This ef-
fect is thought to result from effects exerted by
the amine on specific 5-HT receptors located
on the central and peripheral terminals of
trigeminovascular nociceptive afferents and on
dural blood vessels. Similar effects are pro-
duced by administration of triptans, but no data
indicates that the receptors in question are in-
volved in the production of migraine attacks.
5. The 5-HT system in the brain has been
implicated in the regulation of mood, appetite,
and sleep, all of which are disrupted when pa-
tients develop an attack of migraine. However,
we lack evidence to implicate 5-HT in the al-
teration of these phenomena before and dur-
ing migraine attacks.
6. Increased synthesis of 5-HT in the brain
between attacks has been reported in mi-
graineurs.33 The significance of this finding is
not known.
7. Several drugs that affect 5-HT release
and uptake cause headaches. For example,
whereas reserpine produces headaches only
infrequently in control subjects, the drug's de-
pletion of neural and platelet 5-HT in mi-
graineurs provokes headaches that can dupli-
cate the patients' usual bouts of migraine.54
The headaches are associated with not only a
fall in platelet 5-HT but also a rise in urinary
5-HIAA.29 Headaches can also be induced in
migraineurs by fenfluramine (m-trifluoromethyl-
N-ethyl-amphetamine), a halogenated deriva-
tive of amphetamine.112 Like reserpine, it pro-
duces a rapid release of 5-HT, increases extra-
cellular levels of 5-HT in brain, and then
depletes brain 5-HT. Fenfluramine also selec-
tively inhibits 5-HT reuptake.57 As with reser-
pine, fenfluramine-induced headaches have
the characteristics of spontaneous migraine at-
tacks in migraineurs. During the early stages
of treatment with the selective 5-HT-reuptake
blockers zimelidine and femoxetine, the drugs
cause an increase in the frequency and sever-
ity of migraine attacks.132
These data provide evidence that an acute
increase in serotonergic function, whether ac-
complished by release or blockade of reuptake,
can lead to the development of migraine in sus-
ceptible individuals. Most drugs that have been
used in these investigations are not selective
with respect to their cellular targets of action,
the substances released, or the compounds
whose uptake is blocked. They all have con-
comitant effects on aminergic systems other
than the 5-HT system. In other words, the mi-
grainogenic effects seen after administration of
these drugs are compatible with a role for 5-
HT in the genesis of migraine attacks, but it is
equally possible that when such drugs induce
migraine attacks, the neural or vascular systems
that use multiple amines are involved as well.
8. Activation of specific 5-HT receptors
may initiate migraine attacks. This idea is based
on the effects of pharmacological agents that
are touted to act at specific 5-HT receptors.
Most efforts have involved study of the actions
of w-chlorophenylpiperazine (mCPP), the ma-
jor metabolite of the antidepressant trazadone.
This compound can induce severe headaches
that either resemble migraine without aura or
fulfill International Headache Society (IHS)
criteria.24'85 The headaches are frequently uni-
lateral and throbbing, accompanied by nausea
and photophobia. mCPP-induced migraine-
like headaches are more common in individu-
als with a personal history of migraine than in
 The Serotonin Hypothesis and Other Theories
controls, but they can appear in individuals
without such a history.24'61 Migraineurs have
noted that mCPP provokes headaches that are
indistinguishable from their naturally occur-
ring headaches.
It has been proposed that mCPP is a 5-HT
agonist that activates both 5-HT2B and 5-HTc
binding sites. How activation of 5-HT2B/2C re-
ceptors might initiate migraine is unknown.
One recent hypothesis is that activation of en-
dothelial 5-HT2B receptors in cranial blood
vessels induces the synthesis and release of
NO, which then diffuses to adjacent smooth
muscle to cause potent vasodilatation.56 Con-
currently, NO would stimulate the perivascu-
lar trigeminovascular sensory afferents that
transmit nociceptive impulses. In support of
this idea, mRNA transcripts for the 5-HT2B
receptor have been detected in human menin-
geal blood vessels.121 Unfortunately, raCPP's
usefulness as a 5-HT receptor probe is limited
because the compound is a relatively nonse-
lective 5-HT agonist displaying affinity for 5-
HT1A, 5-HTiB, 5-HTiD, 5-HT2B/2C, and 5-HT3
sites in the brain of experimental ani-
mals.65'77'122 It does, however, have the high-
est affinity for 5-HT2B/2C sites. Moreover, it has
recently been demonstrated that raCPP is a
partial agonist at cloned human 5-HT2C re-
ceptors. Curiously for the proposal being dis-
cussed, wCPP is an antagonist at the cloned
human 5-HT2B receptor.154 mCPP also shows
a greater functional selectivity (> 10-fold) for
the human 5-HT2B than for the human 5-HT2C
receptor.23'134
mCPP may have presynaptic actions that en-
hance synaptic and extracellular levels of 5-HT
in the brain.14'110 The compound also displays
considerable affinity for 5-HT transporter sites
in human brain.13 A mCPP-induced reversal of
the presynaptic 5-HT transporter results in a
substantial increase in the extracellular con-
centrations of the amine.14'47 The data indicate
that mCPP's agonist effects in brain may be in-
direct. That mCPP produces severe headaches
in migraineurs is undoubted, but a consider-
able time lag exists between the peak plasma
levels after administration of raCPP (more than
3 hours) and the development of headaches (4
to 12 hours).60 This renders wCPP's use as a
challenge agent to assess the role of specific
postsynaptic 5-HT receptor function in mi-
graine problematic. What is happening during
this period of time is unknown.
283
9. Some drugs used in migraine prophylaxis,
including methysergide, propranolol, and tri-
cyclic antidepressants, act at specific 5-HT re-
ceptors or affect 5-HT uptake (see Chapters
20, 21, and 23). Some act as agonists, some be-
have as antagonists, and others have mixed
agonist-antagonist actions.
In sum, the involvement of 5-HT in migraine
is supported by a large amount, and great va-
riety of, circumstantial evidence. Investigations
have so far failed to specify either a definitive
locus, or a definitive mechanism of action that
implicates 5-HT in the genesis of migraine
headaches. Data that might support its role in
migraine are not sufficient to distinguish be-
tween a vascular or a neurogenic site. In other
words, the changes in serotonergic mecha-
nisms reported to accompany migraine head-
aches may result from altered excitability of
neurons in the raphe nuclei; anomalies in
platelet activation; altered mechanisms for 5-
HT-uptake, storage, and release in neurons
and/or platelets; or activation of nitric oxide
(NO) synthase. Does 5-HT affect cerebral or
brain stem neurons or cranial blood vessels, or
does it work at both sites? Is there a hyper- or
hypofunction of the central serotonergic sys-
tem? There are no unambiguous data for any
these points. It is even unclear whether an in-
crease or a decrease of serotonergic function
(i.e., a lack of 5-HT or an augmented avail-
ability), or even a hypersensitivity to 5-HT, is
responsible when a bout of migraine develops.
To date, then, sound, unambiguous proof that
5-HT is the agent responsible for the genesis
of migraine attacks is lacking.
DOPAMINE HYPOTHESIS
As an alternative to the serotonergic hypothe-
sis, a substantial body of suggestive data impli-
cates dopamine in the pathogenesis of mi-
graine.
1. We have known for many years that sev-
eral functions involved in migraine attacks,
such as pain perception, nausea and vomiting,
and changes in affect are partially controlled
by dopaminergic systems. >126 Peroutka has
pointed out that a clinical overlap exists be-
tween stimulation of dopamine receptors and
some symptoms of migraine (Fig. 12-9).108
2. Migraineurs may be more sensitive to the
effects of dopamine agonists than individuals
284 Pathophysiology
Figure 12-9. The clinical overlap between the symptoms produced by stimulation of dopamine receptors and migraine.
(Adapted from Peroutka SJ: Dopamine and migraine. Neurology 49:650-656, 1997, with permission.)
without the affliction. For example, low doses
of dopaminergic agonists induce arterial hy-
potension more frequently in patients with
migraine than in healthy controls.22'126 Head-
aches indistinguishable from spontaneous
migraine attacks are produced in some mi-
graineurs when small oral doses of apomor-
phine or intravenous dopamine are given.44'117
In others, low doses of apomorphine or
bromocriptine cause signs and symptoms (e.g.,
anorexia, nausea, vomiting, pallor, sweating,
and yawning) that are considered part of mi-
graine attacks.3'20'31'44 Unfortunately, however
suggestive, most of these studies involved small
numbers of individuals and lacked control sub-
jects. These studies need to be replicated.
3. For some migraineurs, the entire mi-
graine attack can be prevented if the peripheral
dopamine D2 receptor antagonist domperi-
done is administered during the prodrome.140
4. A number of medications that are potent
antagonists of dopamine D2 receptors (e.g.,
prochlorperazine, chlorpromazine, and halo-
peridol) can be used efficaciously to treat acute
migraine attacks.15'26'34'53
5. Recent reports indicate that patients suf-
fering from migraine with aura have an in-
creased frequency of certain alleles of the do-
pamine D2 receptor gene (DRD2) (see
Chapter 2).109
All these findings suggest that activation of
dopamine receptors may play a role before
and/or during bouts of migraine. Whether
changes in dopamine metabolism accompany
migraine attacks is unclear; most of the data
collected so far are incomplete and contradic-
tory 30,42,79,105,114
MAGNESfUM
Recent clinical and experimental reports have
implicated Mg2+ in the pathophysiology of mi-
graine, although no one has offered a coherent
explanation that relates changes in Mg2+ lev-
els in various bodily compartments to migraine.
Hypomagnesemia, low red blood cell Mg2+,
and low cerebrospinal Mg2+ levels have been
reported in some, but not all, migraine patients
either interictally or during migraine at-
tacks 2,58,59,95,96,^0,124,131,135 LQW semm i(m_
ized Mg2+ has also been reported, but only
during attacks and only in a minority of pa-
tients.93 It is difficult to determine a consistent
pattern of magnesium deficiency from the data,
as the results are variable and the differences
between migraineurs and controls are small.129
Platelet levels of ionized Mg2+ are normal in
patients with and without aura.98 Studies using
31
P nuclear magnetic resonance (31i:>-NMR)
spectroscopy have demonstrated a low ictal
concentration of free cytosolic Mg2+ in the
brain, but reports about possible interictal
changes differ.87'116 Although a role for Mg2+
in the pathogenesis of migraine has been pos-
tulated, the significance of these changes in the
cation levels is unknown.144 It should be noted,
 The Serotonin Hypothesis and Other Theories
however, that some, but not all, studies have
shown Mg2+ administration to have a thera-
peutic effect in migraine.48'94'107'111
Because at resting membrane potentials the
N-methyl-D-aspartate (NMDA) receptor
cation channel is blocked by Mg2+ ions, at-
tempts have been made to relate the putative
low levels of Mg2+ in migraine to the actions
of the excitatory neurotransmitter glutamate. A
decrease in Mg2+ ions has been suggested to
play a role in the genesis of migraine attacks
by reducing the Mg2+ block of NMDA recep-
tors, thereby increasing the excitability of cere-
bral cortical neurons. Mg2+ ions block NMDA
channels in a voltage-dependent manner by en-
tering the pore from either the extracellular or
the cytoplasmic side of the membrane. Block-
ade of the NMDA response by intracellular
Mg2+ is unlikely to be significant at physiolog-
ical Mg2+ concentrations. In contrast, physio-
logical concentrations of extracellular Mg2+
play an important role. The NMDA receptor
is, however, fully saturated at Mg2+ concen-
trations of approximately 100 /xMseveral or-
ders of magnitude below physiological con-
centrations of extracellular Mg2+ (about 1.0
mM) or ionized Mg2+ (0.6 mM).93 The rela-
tively small decrements in Mg2+ concentration
that occur during migraine attacks would
therefore have no effect on NMDA receptor
function.
DECREASED MITOCHONDRIAL
ENERGY RESERVE
While still an experimental tool, magnetic res-
onance spectroscopy (MRS) employs comput-
erized spin-labeling methods to monitor meta-
bolic activity in living tissues.100 It allows
non-invasive, in vivo measurements of the
spectra of phosphorylated compounds, includ-
ing ATP, phosphocreatine, inorganic phospho-
rus, and the low-energy products of hydrolysis
of ATP and phosphocreatine. Although limited
by a number of technical problems, these mea-
surements can potentially provide important
information about the energy status of human
brain.
A number of observations using in vivo 31P-
MRS have shown that an impairment of mito-
chondria! respiration is characteristic of some
migraine subtypes.100'101 Bioenergetic changes
have been reported in brain, muscle, and plate-
285
lets of adult and pediatric migraineurs during
interictal and ictal periods.11"2'87'101-118'119-1^
Such changes in brain energy consist mainly of
a decrease in the ratio of phosphocreatine (i.e.,
the high phosphate reservoir of the cell) to the
lower energy inorganic phosphate. This altered
ratio may reflect disordered mitochondria!
function that could enhance the susceptibility
for headache development when brain energy
demand is increased or when the supply of ox-
idizable substrates and C>2 is decreased.
THE SYMPATHETIC
DYSFUNCTION THEORY
A number of the signs and symptoms associ-
ated with migraine headaches indicate periph-
eral autonomic nervous system dysfunction. No
one questions the correlation between attacks
of migraine and autonomic nervous system dys-
function manifested by cutaneous vasocon-
striction, gastrointestinal complaints, sweating,
nasal congestion, pupillary changes, and car-
diac irregularities. At issue, however, is causa-
tion. Some authorities feel that dysfunction of
the autonomic nervous system does not result
from the migraine attack, but rather plays a
central part in initiating it.18'72 Abnormal ac-
tivity in the sympathetic limb of the autonomic
nervous system is purported to change the tone
of the cranial vasculature, thereby inaugurat-
ing a chain of events that produces both the
aura and the pain of migraine attacks. Accord-
ing to this formulation, transient release of nor-
epinephrine from sympathetic nerve endings
produces vasoconstriction of cerebral blood
vessels, a process that gives rise to the aura of
classical migraine. The headache phase is as-
sociated with vasodilatation produced by a re-
flex hyperemia.
Evidence used to support claims that sym-
pathetic dysfunction is a major causative factor
in migraine attacks includes the following:
1. Intra- and extracranial arteries are well
supplied with sympathetic nerve fibers. How-
ever, the role of the sympathetic system in reg-
ulating CBF is unclear, and activation of the
sympathetic system has little effect on CBF
(see Chapter 10).
2. Conditions that activate the sympathetic
nervous system, such as emotional stress, ex-
ercise, orgasm, rapid eye movement (REM)
286 Pathophysiology
sleep, and hypoglycemia, can also trigger bouts
of migraine.
3. Propranolol and some other /3-adreno-
ceptor antagonists provide effective prophy-
laxis for many migraineurs. But although fii-
and /32-adrenoceptors have been demonstrated
in human pial arteries, the more significant
norepinephrine-induced contractions of the
cerebral vasculature appear to involve a-
adrenoceptors.
In sum, the evidence that the sympathetic
system is causative in attacks of migraine is
meager. Migraineurs have been extensively
studied with regard to how the peripheral sym-
pathetic limb of their autonomic nervous sys-
tems functions.35'123'136 Although evidence has
been repeatedly demonstrated of impaired pe-
ripheral vasomotor reactivity, increased fluctu-
ations in heart rate, defective cardiovascular re-
flexes, altered pupillary responses, increased
levels of neuropeptide Y, and abnormal sweat-
ing function, there is no unanimity of opinion
as to whether migraineurs have hypo- or
hyperactive sympathetic nervous systems and/
or concomitant parasympathetic dysfunc-
tion^21,35,49,62,69,97,^02,136 Moreover,
ical investigations of peripheral sympathetic
nervous system activity have yielded contra-
dictory results.4'123 Thus, experimental support
for the idea that dysfunction of the peripheral
autonomic nervous system is responsible for
initiating sieges of migraine is limited at best.
SUMMARY
Sixty years ago, a number of opinions existed
about the etiology of migraine.3' Most of these
ideasthat migraine was caused by eyestrain,
hypophyseal strangulation by ossification about
the sella turcica, periodic obstruction of the
foramen of Monro, toxemia from some disor-
der of intestinal digestion, hepatobiliary upsets,
allergy, or psychosomatic causesdo not fit in
with our modern approaches to medicine.
Most have been rightly discarded. To replace
them, new hypotheses have been offered that
might explain the symptoms of migraine head-
ache.
Much effort has been expended to implicate
5-HT as the agent responsible for the genesis
of migraine attacks. But no one has found a lo-
cus for the changes in 5-HT activity that could
initiate the process. Where, in blood vessels or
neurons, does 5-HT act if it is, indeed, re-
sponsible for migraine attacks? More recently,
the idea that dopamine is involved in the patho-
genesis migraine symptoms has received at-
tention, and some intriguing evidence has ac-
cumulated. Finally, the roles played by the
sympathetic nervous system and Mg++ remain
interesting but puzzling. Data indicating that
the occipital cortex is hyperexcitable in mi-
graine are stimulating, but more information
must be gathered and the findings replicated.
As we can see from the discussion in this
chapter and in the three previous ones, the
pathophysiology of migraine remains both
enigmatic and imperfectly understood. No sin-
gle hypothesis explains the process success-
fully, and the causes of migraine headache
symptoms are still controversial. This is so in
part because a unifying explanation of migraine
must account for the complete sequence of
events in a typical attack of migraine: pro-
drome, aura, headache pain, and postdrome.
The systemic, neurologic, cognitive, affective,
gastrointestinal, and autonomic dysfunctions
that are usually associated with bouts of mi-
graine indicate a bewildering array of altered
function in the cerebrum, brain stem, hypo-
thalamus, eye, intra- and extracranial vascula-
ture, and autonomic nervous system. A theory
must account for dysfunction in all of these
structures. A comprehensive and acceptable
account of these altered mechanisms must also
encompass the modifications of cerebral blood
flow, the role of platelets, the effectiveness of
pharmacological intervention, and the mecha-
nism of action of migraine triggers. Such a
comprehensive account is still beyond our ken.
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PART III

MANAGEMENT OF
ACUTE ATTACKS
This page intentionally left blank
Chapter 1 3
Trigger Factors and
Non-pharmacological Approaches
COMPLIANCE
THE PLACEBO RESPONSE
EVIDENCE-BASED MEDICINE
THE ROLE OF THE INTERNET, THE
MEDIA, AND NATIONAL
ORGANIZATIONS
MANAGEMENT OF MIGRAINEURS
AVOIDANCE OF TRIGGER FACTORS
Headache Diary
Dietary Changes
Sleep and Eating Patterns
Discontinuation of Smoking
Medications and Hormones
Physical and Environmental Factors
BEHAVIORAL TREATMENTS
Biofeedback
Relaxation Therapy
At its mildest, migraine is an unpleasant disor-
der, but for many individuals migraine is a grim
obstacle to normal life. Attacks can cause ma-
jor disruptions in behavior, severely reducing
one's ability to engage in work, in family, or so-
cial activities. Patients with migraine must
therefore be taken seriously and treated with
compassion and understanding. In fact, a sat-
isfactory physician-patient relationship is cru-
cial to effective control of migraine headaches.
The physician who spends adequate amounts
of time with each patient and who combines
this with judicious use of pharmacologic and
non-pharmacologic approaches can restore
most patients to worthwhile, reasonably pain-
free lives.
Ideally, treatment begins when an empa-
thetic physician takes a careful history and per-
Cognitive-behavioral Training
Psychotherapy
OTHER NON-PHARMACOLOGICAL
STRATEGIES
Exercise
Physical Therapy and Modalities
Ophthalmological Factors
Occlusal Adjustment
Alternative/Unconventional Migraine
Therapies
Hypnosis
Acupuncture
Transcutaneous Electrical Stimulation
Chiropractic
HERBAL REMEDIES
SUMMARY
forms a physical examination in such a way that
the patient is truly convinced of the diagnosis
of migraine. Migraineurs frequently fear that
they have a serious, organic disease, even
though they often do not admit to such fears.
It is the physician's duty to reassure them that
potentially malignant causes of headache are
not present. Other patients are apprehensive
that the clinician will consider their problem
psychogenic. Once these anxieties are allevi-
ated, for many the chief concern is to under-
stand the cause of the head pain and the vari-
ous accompanying symptoms.
Patients also need to be told what can be
reasonably expected from working closely with
their physicians. The possible treatment alter-
nativestheir benefits and limitationsshould
be discussed. Some patients expect complete
293
294 Management of Acute Attacks
pain relief or even a complete "cure." They
must be made to understand that only a mi-
nority of patients become absolutely headache-
free, even under optimal conditions, and that
migraine differs from simple bacterial infec-
tions or surgically remediable conditions like
appendicitis. Migraineurs must also be made
to understand that they suffer from a chronic,
probably inherited, affliction that may require
attention for the rest of their lives. Often arti-
cles in the popular press, on the Internet, or in
"self-help" books have led them to believe that
treatment will not require much personal ef-
fort or responsibility, that their condition can
be ameliorated, for example, by simple mea-
sures such as changes in diet. All such patients
must be made to realize that while simple mea-
sures are useful and do constitute a valuable
component of treatment, they are rarely suffi-
cient for complete control of recurrent head-
aches. They must understand that they will
have to work diligently by exercising, practic-
ing interventional behavioral techniques, keep-
ing headache diaries, and avoiding triggers; the
effectiveness of migraine management ulti-
mately depends on what they do or fail to do,
specifically on how they respond to their symp-
toms, and how well they adhere to drug, diet,
and exercise regimens. The physician will in-
variably encounter misconceptions about med-
ications. Some migraineurs expect preventative
medication to magically ameliorate their head-
aches. Many members of this group are un-
aware that anti-migraine medications do not
work in every individual, and that many of the
medications used for the therapy of migraine
headaches have untoward side effects. Their
preconceived ideas must be gently, but firmly,
adjusted. Still other patients expect that nar-
cotics and other analgesics, sedatives, and tran-
quilizers will be made readily available on de-
mand. Again, these patients must be made
aware of the dangers of these medications and
taught that these drugs will frequently worsen
their chronic problem.
It is not sufficient for physicians to estimate
how severe headache pain is. Physicians who
care for patients with migraine must ascertain
how much disability headache pain causes, par-
ticularly, how much day-to-day functions are
disrupted. Does migraine affect the patient's
abilities to perform at work or school? Does it
interfere with normal family functioning and
family dynamics? Does it disrupt leisure and
recreational activities and curtail social activi-
ties? If the patient's normal activities are in dis-
array because of migraine, a consultation
longer than the standard office visit coupled
with aggressive treatment may be needed.
Developments in the way medical care is de-
livered have placed increasing restrictions on
the physician's ability to provide the time and
effort necessary to care adequately for patients
with significant migraine. Efforts to delegate
education, supervision, and history-taking to
ancillary personnel, including nurses, nurse
practitioners, and psychologists, may be suc-
cessful, but only if the "team" is integrated and
there is time for communication. This type of
approach is expensive and may be unsuited for
the average physician's office. Time and reim-
bursement constraints are increasingly limiting
appropriate management of migraineurs.
Most migraineurs are cared for by primary-
care physicians or family practitioners, and few
ever see neurologists (Table 13-1). It is there-
fore extremely important for physicians who
provide primary care to be well-versed in the
evaluation and treatment of migraine. Trained
for the generalises role, primary-care physi-
cians or family practitioners should be specially
qualified to undertake the extensive evaluation
of migraineurs and to address quality-of-life is-
sues with the ultimate goal of enhancing over-
all care. They presumably already have a long-
standing relationship with the patient and the
patient's family. Their records already include
the past medical history and the medications
patients are taking. A focus on the present
problems should be rapidly achieved.
Table 13-1. Consultations for
Headache
PATIENTS (%)
Provider Male Female
Family practitioner 44.5 46.3
Internist/pediatrician 12.0 9.3
Ophthalmologist 11.0 14.3
Neurologist 5.3 5.0
Otolaiyngologist 3.5 3.9
Obstetrician/gynecologist 1.3
Chiropractor 3.7 1.7
Data from Headache Prevalence Study, Washington
County, Maryland.713
 Trigger Factors and Non-pharmacological Approaches
The majority of primary-care physicians,
however, find migraine a difficult condition to
manage. This may result from unfamiliarity
with contemporary research on migraine and
the latest treatment protocols, or from a lack
of time to take an adequate history, perform
neurological and general physical examina-
tions, and advise patients. Primary-care physi-
cians, who are gatekeepers for consultation
with appropriate specialists, may not consider
migraine serious enough to warrant appropri-
ate referrals, even in difficult or complicated
cases.72 Many patients get inappropriately re-
ferred to specialists, including ophthalmolo-
gists, otolaryngologists, allergists, dentists, and
psychiatrists who are rarely well-versed in mi-
graine management. And even if an appropri-
ate consultation is obtained, neurologists un-
fortunately vary considerably in their ability to
manage patients with migraine. Many neurol-
ogists are not especially interested in headache
treatment, and/or their practices are not
equipped to deliver essential, sophisticated
support, referrals to non-physician therapists,
and appropriate follow-up care. If primary-care
physicians and neurologists are unable to con-
trol a patient's migraine after appropriate time
and effort have been expended, referral to a
comprehensive headache clinic is in order. A
comprehensive headache treatment center is
usually staffed by a variety of health profes-
sionals (including physicians, nurses, psychol-
ogists, and physical therapists) who work to-
gether to provide multimodal headache
management.
COMPLIANCE
Clarifying a patient's mistaken preconcep-
tions or expectations about their treatment is
not the only problematic issue physicians face.
Patients frequently deviate from the recom-
mendations given to them about medication
regimes, diet, exercise, and changes in lifestyle.
Patient compliance includes the patient's mo-
tivation (or ability) to complete indicated diag-
nostic evaluations, attend scheduled physician
or clinic appointments, effect recommended
lifestyle changes, and take prescribed medica-
tions properly. The percentage of general med-
ical patients who make errors in taking pre-
scribed drugs ranges between 29% and 59%.116
For headache patients, more than half are non-
295
compliant.92 Even more troubling is the fact
that patients may mishandle medication in
ways that could pose serious threats to their
health. The percentage response to advice
about diet and exercise is presumably similar.
Although physicians tend to blame the per-
sonality characteristics of the patient for non-
compliance, a number of interconnected fac-
tors are usually at play. Compliance, for
example, is affected by patients' perceptions of
physicians' empathy and listening skills, by how
acceptable patients find the treatment, and by
what beliefs individuals have regarding health
matters in general. Patients who have some in-
sight into the nature of their illness, who dis-
cern some benefits from their treatment, and
who perceive an association between the two
are more inclined to take medication properly
than those who lack this insight.42 Depressed
patients are less likely to be compliant than
non-depressed patients.29 In addition, data in-
dicate that noncompliant patients are more
likely to be younger and of lower socioeco-
nomic status and educational attainment than
patients who do comply.25 Participation of
spouses and other family members in treat-
ment appears to enhance adherence to in-
structions.
But the major determinant in compliance
with therapy is the relationship between the
physician and patient (Table 13-2). It improves
with regular contact and continuity of care. Ef-
fective communication between doctor and pa-
tient is crucial. The quality of interpersonal
care is always important to patients, but it is
especially necessary when a patient is battling
a chronic condition such as migraine. Com-
prehension of the patient's needs and satisfac-
tion of their (reasonable) expectations will in-
Table 13-2. Important Characteristics
of Physicians Desired by Patients
Physician Quality Patients (%)
Willingingness to answer questions 86
Educates about causes 77
Explains how to treat attacks 72
Teaches how to avoid attacks 69
Medical expertise 67
Empathy 61
Data from Upton and Stewart (1999) 72
296 Management of Acute Attacks
crease the probability of compliance. The
amount of time spent in education of patients
is also a major factor. Studies have shown that
increasing patient involvement in care by
means of negotiation and consensus-seeking
improves patient satisfaction, compliance, and
outcomes.' 64 Patients who understand their
diagnosis and attain some knowledge about the
pathophysiology of migraine and the goals of
migraine treatment respond more favorably.
Because much of what the doctor tells the
patient is forgotten, compliance can be im-
proved if the patient is provided with written
information about treatment regimens and ex-
act instructions regarding medications.71 Pa-
tients are often confused and distressed when
they find out from their pharmacist that they
are taking medications commonly used for de-
pression, heart disease, or epilepsy. Patients
must understand the nature of the medications
that they are taking. It is helpful to explain how
the drug works in migraine, to clarify any de-
lays in the onset of action, and to discuss the
potential for side effects and the likely dura-
tion of treatment.92 Enlisting the aid of family
members is also valuable. Patients should be
encouraged to regard themselves as active part-
ners in the course of their treatment, sharing
responsibility with their physicians for handling
their condition.98 And perhaps most important
of all, better compliance occurs when the
physician is enthusiastic about treatment and
optimistic about its outcome.
THE PLACEBO RESPONSE
Despite longstanding feelings in the medical
community that symptoms responding to
placebo are "imaginary" and that patients re-
sponding to placebos are neurotic, it is now
clear that placebos have powerful effects on
pain and other symptoms from functional and
organic causes. A substantial placebo response
can occur when either pharmacologic or non-
pharmacologic treatments are provided for mi-
graineurs. Sometimes the placebo response
can be dramatic (Fig. 13-1). Placebo responses
make biomedical objectivity difficult, and study
of placebos uncovers the inconsistencies and
uncertainties about which factors are active in
treatment. Moreover, even though the placebo
response is controlled for when data from drug
studies is analyzed, because of its variable
Figure 13-1. Representation of the time course of the re-
sponse to placebo in a trial of an acute migraine medica-
tion in which, by accident, all patients received placebo. A
response to placebo (moderate to severe pain decreased
to mild or no pain) was noted at 30 minutes and increased
thereafter. Use of a headache (HA)-free endpoint shows
that a placebo response is noted at 1 hour. (Adapted from
Goadsby PJ: The scientific basis of medication choice in
symptomatic migraine treatment. Can J Neurol Sci
26(Suppl 3):S20-S26, 1999, with permission.) Data from
Jhee et al. (1998).62
forms, the placebo response still emerges as
tangible, substantial, and authentic. Placebos
can not only have powerful therapeutic actions
but can also produce substantial side effects,
the most common of which are drowsiness,
headache, nervousness, insomnia, and nausea.
The responses to placebos are usually de-
rived from treatment studies that include a
placebo control group. In these studies, the
placebo response is usually considered a source
of error that might confound interpretation of
results. Placebo responses vary greatly, ranging
from 21% to 62% in different investigations.10"
Considerable evidence indicates that the mag-
nitude of the placebo response depends upon
the situations and settings in which the placebo
is administered. For example, the percentage
of responses attributable to placebos is lowest
in double-blind studies, higher in single-blind
studies, and highest in uncontrolled clinical re-
ports. The latter situation, which closely ap-
proximates clinic or office treatment, maxi-
mizes placebo responses. The placebo response
is greater in clinical trials of narcotic analgesics,
such as morphine, than in trials of weak anal-
 Trigger Factors and Non-pharmacological Approaches
gesics, such as aspirin. Higher placebo per-
centages are particularly common in illnesses
such as migraine where symptoms wax, wane,
fluctuate, and undergo spontaneous remis-
sions. Effectiveness also depends upon the
severity of pain: effectiveness is directly pro-
portional to the severity of the patient's pain.70
As would be expected, the expectations of
patients and physicians, the character of the
physician-patient interaction, the information
given to the patient, and the patient's subjec-
tive experience of the setting in which the
treatment takes place are of considerable im-
portance in determining the placebo response.
The response is more powerful when both doc-
tors and patients anticipate a beneficial out-
come. Patients' beliefs are also important.
There is evidence that larger placebo pills work
better than small ones, that capsules are more
effective than pills, that two pills decrease
symptoms more than one, and that injected
placebos are more efficacious than oral place-
bos. The color of capsules is another important
variable.14 Such data indicate that the percep-
tual characteristics of the preparation are im-
portant in defining placebo responses. In ad-
dition, placebos with side effects (such as
atropine) are more effective than inactive
placebos (such as lactose).118
Studies to delineate the personality charac-
teristics of placebo responders have inconsis-
tent findings. It appears that most individuals
are capable of responding to placebos. Nor are
placebo responses invariable: an individual may
respond to placebo on one occasion, but not
on others. Adequately controlled research
must be cognizant of, and responsive to, such
variations. Most double-blind, placebo-
controlled migraine drug studies merely sub-
tract placebo responses from drug responses.
Unfortunately, the placebo group incorporates
numerous nonspecific variables that may inde-
pendently influence responses. The placebo
must be appreciated as a distinctive agent with
complex consequences.
EVIDENCE-BASED MEDICINE
Using "evidence" to determine medical prac-
tice is not new. Our definition of evidence,
however, has evolved, and now includes new
standards and methods of gathering data and
new probalistic procedures for analyzing it.
297
The idea of a randomized, double-blind,
placebo-controlled trial represents a shift away
from the traditional methods of acquiring
knowledge through clinical experience. The
traditional method of reporting clinical infor-
mation as a detailed case report or as a series
of cases without the use of formal research
methodology is no longer considered reliable
because it is subject to the reporter's bias.38 In
such observational studies, each patient's treat-
ment was deliberately chosen rather than ran-
domly assigned, so there is an unavoidable risk
of selection bias and of systematic differences
in outcomes that necessarily result from the
treatment itself. Randomization is the key pro-
cess by which bias and confounding are mini-
mized.
It is currently mandatory to evaluate new
treatments and new drugs by randomized, con-
trolled trials performed on restricted, selected
populations in which the outcomes of the new
treatment are contrasted and compared with
the effect of a placebo or of an established
treatment. Practicing physicians increasingly
base their decisions on evidence gathered dur-
ing controlled trials, rather than on the au-
thority of an expert.23 As a result, analysis of
results and dissemination of information in the
clinical literature increasingly deemphasizes
intuition and nonsystemic clinical experience
as insufficient for clinical decision-making.38 In
other words, there has been a paradigm shift
from opinion-based medicine to evidence-
based decision-making based on randomiza-
tion.
Extrapolation of data from controlled trials
of headache medication and treatments to pa-
tients in the office or clinic is, however, often
difficult. Although enormous efforts have been
made in recent years to determine the effects
of anti-migraine medications, migraine is par-
ticularly problematic for an evidence-based ap-
proach. Even when strictly defined by Inter-
national Headache Society (IHS) criteria,
migraine may represent several different con-
ditions with substantial variation in genetic
substrate and response to environmental influ-
ences. Moreover, it is often difficult to assign
a single IHS diagnosis in the usual office set-
tings because many patients have headaches
that have migrainous features, but that may or
may not be migraine. In particular, it is fre-
quently challenging to apply the results of con-
trolled investigations to individual patients.21
298 Management of Acute Attacks
Most trial patients, but few office patients,
suffer from nothing but migraine. Many "rou-
tine" office patients have coexisting tension-
type headaches and/or concomitant medical
problems. Patients recruited in clinical trials
have the advantage of additional clinic visits
and laboratory tests, as well as increased con-
tact with physicians and research staff. The ex-
pectation of a novel intervention provides an
environment that influences clinical out-
come.17 Because different clinical trials are
carried out with diverse samples of migraineurs
in dissimilar environments and with varying
criteria for diagnosis, response rates, and con-
ditions of testing (e.g., dose, dosing regimens),
the performances of the same or different
drugs in different trials are often difficult to
compare, or are not comparable at all.20
Nor are the results of clinical trials described
in the same manner for each drug. Different
placebo rates are common, and make quanti-
tative assessments of responses to medications
difficult to compare. Physicians must carefully
consider to what extent their own migraine pa-
tients resemble those in a trial and to which
patients the results of the investigation can be
applied. Trials are usually carried out in mul-
tiple centers and deemphasize the relationship
between clinician and patient. Such a relation-
ship is of crucial importance both in decision-
making and often in determining the outcome
of migraine treatment. In addition, in conven-
tional clinical practice, there is a great deal of
patient choice about when, or whether, to take
a medication, in contrast to controlled trials
where every effort is made to make sure that
treatment is taken as designed. Reports of clin-
ical trials usually lack data about clinical vari-
ables (such as responses to previous therapy,
difficulties with compliance and reasons for
noncompliance, psychological status, patient
expectations) that are critically necessary in de-
ciding how to care for particular migraineurs.
In sum, the conditions in the office or clinic
setting often fail to replicate many controlled
studies.
The problems encountered when managing
patients with migraine are complicated further
because a number of medications and thera-
pies routinely used to treat migraine have never
been subjected to the scrutiny of well-designed
clinical trials. Economic constraints make it im-
possible to perform large randomized trials
without commercial support from pharmaceu-
tical companies. It is therefore unlikely that
some medications no longer under patent but
commonly used for the treatment of migraine
will ever be tested. Sometimes, only a very few
state-of-the-art studies about a particular drug
may be available. Further bias may be intro-
duced because journal editors are more in-
clined to publish positive than negative re-
sults.31 Recently, there has been a
disconcerting trend to only publish abstracts of
clinical trials rather than supply complete data
in a published article. Too few details are pre-
sented in abstracts to allow full assessment of
the trial. In addition, we must realize that few
data are available regarding the long-term con-
sistency of therapy response or the relative
merit of various treatments.
Dahlof has demonstrated that individual
headache patients express distinct preferences
for different medications, even though such
preferences do not inevitably correlate with
treatment efficacy.20 Factors such as rapidity
of onset of action, duration of action, and rate
of production of adverse events are important
in determining patient preference. Moreover,
the difficulties with using placebo-treated pa-
tients as controls alluded to in the previous dis-
cussion complicate analysis of controlled stud-
ies. Most trials match an active drug with a
placebo and the results do not aid in deciding
which of several active agents should be the
choice for use. Finally, it is obvious that exter-
nal evidence may be inapplicable or inappro-
priate for individual patients. Ideally, clinical
expertise and intuition must be combined with
external evidence from controlled trials. But
because of the fallacies and bias of uncon-
trolled experience, and despite the caveats just
enumerated, for the foreseeable future, data
from controlled studies must comprise the ba-
sis for much therapeutic decision-making
about treating headache patients.
THE ROLE OF THE INTERNET,
THE MEDIA, AND NATIONAL
ORGANIZATIONS
It is an understatement to say that the infor-
mation age has the potential to alter doctor-
patient relationships profoundly both for bet-
ter or for worse.46 Knowledgeable patients may
take a much more active role in management
 Trigger Factors and Non-pharmacological Approaches
of their medical problems. The new accessi-
bility may also provide patients with informa-
tion necessary to deal with physicians who have
not paid appropriate attention to their head-
ache problems. But less sophisticated patients
may make demands, based on articles in the
press, television reports, hearsay, or browsing
the Internet, for treatments or tests for which
there is no justification. Patients can consult
Internet sites that contain significant amounts
of information about their condition. Some pa-
tients come to consultations with reams of
downloaded material. Some of it is irrelevant,
some misleading or downright erroneous, but
some may be excellent. The information on the
Internet is extensive, but poorly organized, and
not edited or filtered. Its uneven quality is a
major disturbing factor. Patients can develop
preconceived ideas about their symptoms, the
mechanisms of migraine, the diagnostic exam-
inations they require, and the types of treat-
ment they should be offered. Superficial pre-
sentations on television programs, articles in
local newspapers written by reporters without
specific knowledge or appropriate scientific
background, and the numerous self-help books
about alternative medicine practices that are
untried and untested by time, let alone scien-
tific trials, can cause serious misconceptions.
Inaccurate coverage of published scientific pa-
pers, overstatement of adverse effects or risks,
incomplete, and often misleading, information
about benefits, and evidence of sensationalism
are not uncommon in the media.85 The poorly
digested and/or inaccurate reports that patients
bring to their office visits represent another po-
tential barrier to physician-patient trust, but
also represent additional opportunities to es-
tablish trust and educate the patient.
Two national agenciesthe National Head-
ache Foundation (NHF) and the American
Council for Headache Education (ACHE)
provide a wide range of services to individual
migraineurs. For a modest fee, membership
provides patients with information about cur-
rent research findings, brochures about dietary
and lifestyle management, and answers to spe-
cific headache-related questions. Both agen-
cies maintain informative Web sites (NHF:
http://www.headaches.org; ACHE: http://www.
achenet.org/). Web links of value are also pro-
vided by the Journal of the American Med-
ical Association (JAMA), JAMA Migraine In-
formation Center (http://www.ama.org/special/
299
migraine/migraine.htm) and the Canadian Med-
ical Association Journal (http://www.cma.ca/
CMAJ).
MANAGEMENT OF
MIGRAINEURS
A suitable course of treatment must be for-
mulated by the physician in partnership with
the patient. Migraine varies widely in its man-
ifestations; its management must therefore be
individualized to address the characteristics,
frequency, severity, and duration of each pa-
tient's migraine headaches; the intensity of as-
sociated symptoms; and the nature of the head-
ache's interference with work, family, and
leisure activities. Patients whose headaches are
mild and sporadic need very different man-
agement from that for patients whose head-
aches are frequent and disabling. The physi-
cian must keep firmly in mind that the goal of
migraine treatment is not merely to relieve
pain but to reestablish the patient's ability to
function normally. Concurrent medical and
psychological problems, such as hypertension,
heart disease, depression, and insomnia; preg-
nancy (or unprotected sex); and concomitant
use of other medications must not be ignored.
Consideration must be given to health mainte-
nance organizations (HMOs) and other health
insurance restrictions on the number of visits
and the use of certain medicationsfactors
that may substantially limit treatment choices.
Management of migraineurs generally con-
sists of several major components:
1. Patient education about the diagnosis,
pathophysiology, and migraine triggers
11 how
especially i i iby re-
to prevent attacks
moving or avoiding precipitants. Patients
must be made aware of the major role
they play in managing their headaches
by initiating and maintaining lifestyle
changes. Appropriate emphasis must be
placed on the importance of general
health measures such as diet, exercise,
and sleep. Patients must fully understand
the underlying mechanisms of headache
and the steps that they can take to man-
age their disorder.
2. Establishment of realistic expectations
about what can and cannot be done to al-
leviate migraine.
300 Management of Acute Attacks
3. Use of a variety of non-pharmacologic
treatments, including biofeedback and
relaxation procedures. Patients must be
made aware that they can develop be-
havioral and cognitive skills that change
ingrained physiological responses and at-
titudinal behaviors to acute and chronic
pain.
4. Use of abortive or symptomatic medica-
tion to diminish or eliminate both pain
and the accompanying symptoms of acute
attacks.
5. If indicated, long-term prophylactic treat-
ment to reduce and minimize the fre-
quency, severity, and duration of recur-
ring bouts of migraine.
This chapter will concentrate on the first three
measures, especially the non-pharmacologic
treatment of migraine headaches.
AVOIDANCE OF
TRIGGER FACTORS
A myriad of factors can provoke bouts of mi-
graine (see Chapter 5). Each individual has a
unique catalog of precipitants that act alone or
together to trigger an attack. An estimated 85%
of migraineurs recognize one or more definite
trigger factors.122 But although most patients
identify some precipitants, only a limited num-
ber are cognizant of all of them. Accordingly,
once a diagnosis of migraine has been firmly
established, the physician should systematically
go through a list of potential triggers with each
patient. When a migraineur becomes aware of
how wide the range of possible triggers is and
how significant a role they may play, that indi-
vidual will begin to see the need to keep a head-
ache diary to identify his or her own triggers.
It is essential that the individual migraineur
identify those triggering mechanisms that may
be operative in the production of his or her
own headaches. Then each patient must be
made to realize that he or she has optionsto
abstain from the provocative circumstance or
to chance a migraine attack.
Because removal of individual precipitants
may reduce the frequency of attacks by up to
50%, for many patients, they must truly accept
the concept that identification of trigger fac-
tors is essential for successful headache man-
agement.12 Patients must realize that identifi-
cation and modification (or even removal) of
these factors may be crucial components in
their treatment. For example, many headaches
may be prevented if a migraineur sensitive to
wine or chocolate avoids them. Similarly, if
headaches seem worsened by contraceptive
pills, headache frequency or severity may be
substantially reduced if a migraineur stops us-
ing them. Other patients improve when they
receive appropriate amounts of sleep, do not
oversleep on weekends, and eat meals on a reg-
ular schedule each day. In other words, elimi-
nation of triggers must be tailored to each pa-
tient. The roots of noncompliance often sprout
from unexplained and unappealing lifestyle
changes that yield no fruitful results.
Headache Diary
Patients often feel frustrated when they are
asked to furnish accurate reports on the nature,
severity, and frequency of their headaches. In
part, the wide variability of migraine attacks in
an individual is responsible for their inability
to provide quantitative information. Systematic
daily recording, however, is necessary for the
identification of trigger factors, and serves to
monitor medication and to evaluate other kinds
of treatment. The systematic daily recording is
commonly known as a headache diary. 103 A
number of variables can be recorded, but the
most important aspects of the attack include
the time of onset, the duration, the severity,
the impact on functioning, any medication
taken for the headache and its associated symp-
toms, the time to relief, and any identifiable
precipitating factors or environmental factors.
An excellent headache diary is supplied by
ACHE (Fig. 13-2). Alternatively, a 3 X 5 inch
spiral-bound notebook is adequate for the task
and can be routinely kept at hand. Such diaries
generate important data, allowing careful ad-
justment of medication. They should be
brought to every office visit.
Dietary Changes
Although as many as 45% of migraineurs con-
tend that some or all bouts are linked to in-
gestion of specific foods, manipulation of a pa-
tient's diet alone will rarely produce dramatic
results.48'96'122 Nonetheless, many physicians
automatically place patients on an extremely
 Trigger Factors and Non-pharmacological Approaches
Figure 13-2. Headache diary published by American Council for Headache Education (ACHE). (With permission from
ACHE.)
restricted diet without taking the effort to de-
termine beforehand if particular foods are typ-
ically followed by migraine attacks in these pa-
tients. Such diets eliminate or reduce intake of
foods and drinks believed to be rich in vasoac-
tive amines as well as alcohol, caffeine,
monosodium glutamate (MSG), and nitrites.
The value of this approach is debated, and most
studies suffer from lack of adequate controls.
Except for the compulsive few who avoid the
entire list for years, patient compliance with re-
stricted, unappealing diets is notoriously poor.
Furthermore, the stress of trying to stay on the
diet, or of cheating, may itself induce migraine.
Patients dislike being deprived of favorite foods
for extended periods of time unless they are
really convinced that these foods are triggers.
And if the patient does not fully comply with
the dietary restriction, who is to say which
foodstuffs, if any, in combination with new, di-
etary stresses, might trigger an attack of mi-
graine in a particular patient? There is no
301
choice but to spend time helping individual pa-
tients to distinguish their particular food sen-
sitivities and then remove only those foods that
the patients come to recognize as agents.
Occasionally the association between food
and the onset of head pain is unmistakable;
more often it is not. Most patients have diffi-
culty recognizing dietary factors, especially
since some foods do not trigger headaches un-
less other precipitants are also present. In ad-
dition, a food's capacity to trigger a migraine
attack is often dose related. Maintenance of a
food log is a simple procedure to establish
which foods are related to headaches. The pa-
tient can either jot down all foods and drinks
ingested every day or retrospectively remem-
ber and list the foods eaten the day before and
the day of a headache. Using these aids, an
intelligent person can determine which, if
any, components of his or her diet are con-
sistently or frequently correlated with bouts
of migraine.
302 Management of Acute Attacks
Although relatively few patients state that
their headaches are related to consumption of
coffee or other caffeine-containing beverages,
caffeine-withdrawal headaches may be respon-
sible for weekend headaches and for headaches
experienced upon awakening. The daily con-
sumption of caffeine should be limited to two
cups of coffee (or its equivalent).
Sleep and Eating Patterns
A majority of migraineurs suffer less if they fol-
low a consistent routine from day to day, in-
cluding weekends and holidays. This can be a
significant circumventer of headaches. Changes
in sleep patterns, for example, are known to
trigger migraines in a proportion of patients.
Accordingly, migraineurs should refrain from
oversleeping, undersleeping, or napping (un-
less napping is part of their regular schedule).
Although delayed awakening on weekends,
holidays, and vacations (with resultant head-
aches) spoil many migraineurs' leisure time or
vacations, they are often reluctant to give up
the luxury of sleeping in. A potential solution
is to suggest that they set their alarms for the
usual time, eat a small breakfast, and then go
back to sleep.
The relationship between low blood sugar
and migraine is complex (see Chapter 5). But
there is little doubt that many migraineurs are
sensitive to fasting and to hunger. Because pa-
tients may find themselves stricken when they
have missed a meal, emphasis must be placed
on eating breakfast, not skipping lunch, or de-
laying dinner. Some patients need to carry a
substantial snack with them just in case they
find themselves faced with a significant delay
in food intake times. It is not surprising that
some patients report improvement of their
symptoms when placed on a frequent-feeding,
low-carbohydrate, high-protein diet.26
Discontinuation of Smoking
Smoking has been considered a risk factor for
migraine by several groups of investiga-
tors.16'76'114 In addition, the number of ciga-
rettes smoked and their nicotine content ap-
pear to affect headache activity.95 Although
hard-and-fast data are unavailable, discontinu-
ation of smoking is a potentially helpful mea-
sure. Many patients also report secondhand
smoke to be a powerful migraine trigger.
Medications and Hormones
Some medications can increase the frequency
and severity of migraine attacks. This group
includes some H blockers, some calcium
channel blockers, some non-steroidal anti-
inflammatory drugs (NSAIDS), a number of
antihypertensive drugs, nitroglycerine, and
some hormonal preparations (see Table 5-6).
Substitutions of comparable medications by
the patient's primary-care physician can some-
times alleviate the situation.
Whether oral contraceptives should be dis-
continued depends in part on social factors.
But even if these preparations do not appear
to affect frequency or severity of attacks, every
patient must be fully informed of her increased
risk factors so that she can make a rational de-
cision about their use (see Chapter 6). On the
other hand, contraceptive pills must be dis-
continued if focal neurological symptoms are
present.
Physical and Environmental
Factors
Many migraineurs are troubled by certain con-
ditions of light, noise, smells, and temperature.
Some environmental factors are unavoidable,
but others can be modified if they precipitate
bouts of migraine. In particular, patients
should pay attention to lighting conditions at
home and at work. Fluorescent lighting should
be eliminated if it is a factor in the provocation
of attacks. For some patients, tinted glasses
may be of value both indoors and outdoors. Mi-
graineurs need to become aware that some
trigger factors are beyond their control, in-
cluding hormonal variations in the menstrual
cycle, barometric fluctuations, and other peo-
ple's choice of perfume or smoke. Being con-
scious of what may set off an attack may help
each individual make decisions about how to
deal with potential triggers. They may change
seats in a restaurant, go home, leave a stress-
ful task for another day, and so forth. From a
 Trigger Factors and Non-pharmacological Approaches
psychological point of view, patients benefit
from becoming aware of the extent to which
they can intervene in preventing or mitigating
an attack. There is comfort in knowing that one
is not simply a hapless victim of a painful, dis-
ruptive condition.
BEHAVIORAL TREATMENTS
Clinicians have long realized that psychologi-
cal phenomena play a pivotal role in the gen-
esis and maintenance of migraine headaches.
In particular, a migraineur's psychological
makeup may influence the triggering of some
attacks. Psychological factors also determine
how a patient copes with repeated episodes of
head pain and what consequences chronic
head pain has on personality, behavior, and
lifestyle. To address such factors, a number of
self-regulatory, non-invasive behavioral tech-
niques such as biofeedback (both thermal and
electromyographic), simple relaxation ther-
apy/autogenic training, and cognitive stress-
coping or management skills programs have
been used effectively. All have the potential to
reduce the frequency, and sometimes the in-
tensity, of migraine headaches, but no one pro-
gram has been proven substantially more ef-
fective than any other. Although some data are
in disagreement, meta-analyses and narrative
reviews have concluded that behavioral thera-
pies may produce outcomes similar to, or bet-
ter than, commonly used prophylactic phar-
macotherapies, but most studies of behavioral
management involve patients from specialized
centers, and the results may not be generalized
to the general population.1'5'58'105 Some follow-
up studies have found that treatment gains are
maintained for periods of 1 to 5 years.8'73'112
Nevertheless, there are several reviews critical
of the efficacy of behavioral therapy to treat
migraine.57'12"'121
As noted by the U.S. Headache Consor-
tium,108 behavioral therapies appear to be es-
pecially appropriate for migraine patients who
have the following traits:
1. A preference for nonpharmacologic man-
agement
2. Difficulties tolerating specific medica-
tions
3. Medical contraindications to specific
medications
303
4. An inadequate response to medications
5. A history of excessive use of medications
for the acute treatment of headaches
6. Substantial stress, particularly when cou-
pled with insufficient abilities to manage
stress; or are
7. Are pregnant, plan to become pregnant,
or are nursing.
Biofeedback and other behavioral therapies
for patients with migraine headaches are
widely accepted treatments, even though it has
not been ascertained to what extent nonspe-
cific factors and placebo effects account for
improvement. Some of the studies can be crit-
icized for their small sample sizes, absence of
adequate control groups, intermingling of sev-
eral different behavioral treatments in the
same patient, or lack of satisfactory criteria to
assess outcome.57 In addition, there are no
strict criteria to determine which behavioral
method is most appropriate for which groups
of patients. Most choices are based on acces-
sibility of competent practitioners in the clin-
ician's locale. When therapists of all sorts are
available, many patients are taught biofeed-
back techniques and relaxation exercises as
components of a comprehensive behavioral
approach that includes cognitive restructuring,
stress management techniques, and patient
education.
Although the factors that determine re-
sponsiveness to behavioral treatments have
not been systematically investigated, the pro-
cess seems to work better in younger than in
older adults.7'27 Elderly patients typically take
longer to learn the technique, but with proto-
col adjustments, elderly migraineurs can reach
the same level of outcome as younger
adults.63'90 In contrast, children and adoles-
cents seem to do particularly well with
biofeedback.55'68'91'105 Patients who are nei-
ther habituated to drugs nor abusing medica-
tions do better than patients ingesting large
quantities of analgesics.15'81 Patients with so-
matic complaints do not respond well. Data
conflict as to gender differences in re-
sponses.27'101 A considerable obstacle to wide-
spread use of behavioral therapies is their
availability, cost, and uncertain insurance cov-
erage. They typically require substantial clini-
cian contact and numerous clinic visits, fre-
quently necessitating from 10 to 20 hours of
professional contact.
304 Management of Acute Attacks
Biofeedback
Thermal and electromyographic biofeedback
are widely used non-pharmacologic procedures
for treating migraine. The technique enables
individuals to control either skin temperature
or muscle tensionfunctions of their nervous
systems that used to be regarded as beyond vo-
litional or conscious control. In general, the
biofeedback training paradigm follows an op-
erant conditioning framework, teaching pa-
tients to raise their skin temperature and/or re-
duce their muscle tension in response to visual
or auditory cues from biophysiological instru-
ments that measure these functions.
Thermal biofeedback gained popularity
many years ago when it was believed that an
increase in peripheral blood flow would de-
crease cranial vascular activity. Although this is
no longer thought to account for its efficacy,
thermal biofeedback is still used for patients
with migraine headaches. Patients are taught
to increase hand or finger temperature by
means of electronic feedback, coupled with in-
struction by a trained therapist. A lightweight
thermistor or a thermocouple is attached to a
finger, whereupon information about skin tem-
perature is immediately displayed either on a
meter or a numerical display, or else it is con-
verted to a tone. Subjects are instructed to try
to make their hands grow warm; they are given
simple instructions such as "warm your hands,"
or "warm your hands and make the needle on
the meter move." There may also be sugges-
tions on the use of warmth-related imagery, or
the repetitive use of autogenic phrases such as
"my hands are warm," or "I can feel the blood
rushing into my fingers." By trial and error,
each individual discerns the subjective state
and subtle internal cues related to the changes
in skin temperature. The intended effect of
biofeedback is to enable patients to demon-
strate voluntary control over their skin tem-
perature both in and outside the biofeedback
laboratory.
Electromyographic (EMG) biofeedback at-
tempts to enhance voluntary control over the
striated muscles of the head, face, and neck.
For this purpose, surface electrodes are placed
on the skin over selected muscle sites. The
frontalis muscle, the trapezius, and the mas-
seter muscles are typically selected. As with
thermal biofeedback, the electrodes are con-
nected to a visual or auditory display, and the
patients are counseled to use imagery, auto-
genic phrases ("my muscles are relaxed"), or
whatever works to decrease electrical activity
in the muscles.
The available data hold no exclusive status
for thermal biofeedback in the management
of migraineurs. Electromyographic biofeed-
back is more commonly used in the treatment
of tension-type headaches and less often in
the treatment of migraine, even though ther-
mal and EMG biofeedback are statistically
equivalent with regard to their ability to re-
duce migraine activity.18 Moreover, clinical
evidence suggests the usefulness of combin-
ing finger temperature feedback with EMG
biofeedback.27
Biofeedback is frequently integrated with a
number of other behavioral techniques such as
relaxation training (see below). This mixture of
treatments is believed to produce a better re-
sult than either treatment element by itself, but
the conclusion remains untested.6 Biofeedback
and relaxation therapies may not be inter-
changeable. Individual patients who fail to re-
spond to one form of therapy may respond to
another. Counseling and psychotherapy have
also been combined with biofeedback, but,
again, the value of their concomitant use has
not been determined.
POSSIBLE MECHANISMS
At present, the mechanisms by which biofeed-
back produces improvement in migraine are
obscure. There are, however, three major hy-
potheses about how biofeedback works.
1. Biofeedback improves migraine because
patients are able to reduce excessive sympa-
thetic outflow. Some investigators feel that dys-
function of the autonomic nervous system plays
an important role in causing bouts of migraine
(see Chapter 12). One corollary would be that
control of sympathetic activity should improve
a patient's condition. We know that the pe-
ripheral vasculature in the fingers is primarily
mediated by activity of the sympathetic ner-
vous system and that there is no significant
parasympathetic innervation of the digital ar-
terial bed. Accordingly, decreased sympathetic
nervous system activity is believed necessary
for peripheral vasodilatation and ensuing hand-
warming to occur. Peripheral vasodilatation, in
other words, is postulated to result exclusively
 Trigger Factors and Non-pharmacological Approaches
from reduced sympathetic (a-adrenergic) ac-
tivity.
However, doubt must be cast upon the idea
that the conscious ability to reduce sympathetic
nervous system activity is by itself the impor-
tant factor in determining the therapeutic out-
come of biofeedback. Individuals who are
taught to cool their hands by biofeedback train-
ing respond as well as patients who are taught
to warm their hands.45"69 Furthermore, being
able to change sympathetic nervous system
function (that is, to control digital or hand tem-
perature) is not firmly correlated with reports
of successful headache reduction.15 The con-
verse is also true: headaches have been suc-
cessfully treated with thermal biofeedback in
subjects who could not maintain the thermal
responses. Most studies find no statistical rela-
tionship between headache improvement and
the degree of control over hand-warming.65'68
Moreover, similar clinical results can be ob-
tained with EMG biofeedback, which does not
involve a learned autonomic change.15
Learned alterations in sympathetic activity
may, in fact, be relatively unimportant in de-
termining the therapeutic outcome of biofeed-
back. As noted below, relaxation training does
not provide the patient with physiologic feed-
back information, yet it is as effective as some
biofeedback procedures in the treatment of mi-
graine headache.11-109 Perhaps before a subject
is able to achieve an adequate response to
biofeedback, that subject must first relax. In
other words, relaxation may be unknowingly
combined with biofeedback.
2. Biofeedback is a method by which indi-
viduals can modify important cognitive, emo-
tional, and behavioral responses.15 Biofeed-
back may derive its therapeutic potential by
demonstrating to individuals that they can con-
trol bodily functions. The increase in aware-
ness and perceived control of physiological
events is thought to be a critical component of
the biofeedback process.
3. Biofeedback-induced improvement in
headache activity is caused by nonspecific ther-
apeutic effects. Controversy exists about the ex-
tent to which the treatment effects of biofeed-
back are caused by placebo effects produced
by expectations of improvement, association
with professionals concerned with migraine,
and detailed record-keeping.18'65 Some stud-
ies, however, report that biofeedback results in
greater headache reduction than a placebo
305
control.19 In contrast, other investigations find
that similar reductions in headache intensity
occur regardless of whether patients are given
true or false temperature feedback.87
Relaxation Therapy
The rationale for relaxation therapy is based
on the probably outdated idea that physical
tension contributes to head pain. Although
conclusions differ about how much relaxation
techniques can diminish the frequency of mi-
graine attacks, they do appear to be effective
for many patients.'104'112^ Relaxation training
is less complicated treatment than biofeed-
back. No equipment is needed and little ex-
pertise is required. Three of the best known
techniques are progressive relaxation, auto-
genie training, and breathing exercises.
1. Progressive relaxation. A widely used re-
laxation methodthe Jacobson technique
has the patient concentrate on various major
muscle groups in order to consciously relax
them. Subjects sequentially tense and hold,
and then relax, muscles throughout the body,
usually starting with the feet and working up
to the head. Focus is placed on the sensations
associated with muscular contraction and its
absence. Patients practice often, until they can
relax their bodies easily without needing overt
instructions.
2. Autogenic training. Autogenic training
stresses the silent repetition of, and concen-
tration on, a series of brief phrases. Such
phrases include suggestions that the extremi-
ties are heavy and warm, that respiration is
even, and that the forehead is cool. Subjects
may be asked to visualize themselves lying on
a warm beach or in another calm, soothing set-
ting. Emphasis is placed on verbal methods
rather than on directions regarding the con-
scious production of a physiological change.
Regular practice over a period of many months
is necessary. Repetition of the phrases is said
to induce calmness, relaxation, and specific
bodily and mental changes.
3. Relaxation by means of breathing exer-
cises. Relaxation induced by breathing is based
on eastern meditative practices. Slow, deep
breaths are used to induce muscle relaxation.
Typically, all forms of relaxation training in-
volve office-based instruction followed by
home practice that frequently makes use of au-
306 Management of Acute Attacks
diotapes. Each technique educates the indi-
vidual to be aware of muscle tightness and
tenseness followed by relaxation. An overall re-
laxed state can be developed. Other techniques
that may produce the same types of effects in-
clude yoga and transcendental meditation. The
mechanisms through which relaxation reduces
pain are still under debate.
Cognitive-behavioral Training
Cognitive-behavioral training (stress-coping
training, cognitive therapy, cognitive-stress-
coping training, cognitive-behavioral therapy)
is based on the hypothesis that an individual's
affect and behavior (including responses to
headache triggers and head pain) are largely
determined by a process of cognitive appraisal
whereby the individual comprehends events in
terms of their perceived significance.77 Work-
ing from the premise that patients must be ac-
tively involved in learning to manage their
problems, cognitive interventions seek to fur-
nish a battery of problem-solving or coping
skills that can be used to handle circumstances
and stressors that often give rise to a bout of
migraine.9'10'102 Once a patient is able to rec-
ognize, evaluate, and modify maladaptive
thinking patterns and dysfunctional beliefs, the
patient can be trained to control headaches by
changed "cognitions"that is, the way he or
she analyzes, assesses, and conceives of events.
Although research in this field is difficult to
assess, cognitive-behavioral training appears
to have moderate effectiveness in mi-
graineurs.102'112'113 The sensitivity and skills
of the therapist are more critical than those
needed to teach biofeedback or relaxation.
Similarly, the relationship between patient
and therapist must be good. Although a num-
ber of studies on this technique are available,
most involve small numbers of subjects. Few
have investigated their subjects in a controlled
manner, and even then, the investigatory
techniques have varied widely among re-
searchers.67'84 A recent meta-analysis of stud-
ies that meet strict criteria for research design
and data-reporting concludes that stress-
coping training produces outcomes in mi-
graineurs that are comparable to those re-
ported for relaxation and thermal biofeedback
techniques.79
Psychotherapy
Psychodynamic psychotherapy and psycho-
analysis presuppose that headache pain is de-
rived from strong and unresolved difficulties in
the patient's unconscious. As noted previously,
anger, anxiety, depression, and maladaptive re-
actions to stress may indeed be important fac-
tors in the development of headaches and may
be substantial determinants of how each mi-
graineur responds to his or her affliction. But
while formal psychotherapy and psychoanaly-
sis for patients with migraine enjoyed a vogue
in the past, no controlled studies have shown
the efficacy of psychotherapy as a headache
treatment. Most clinicians have concluded that
the results with regard to head pain are disap-
pointing.
Patients with migraine may, however, have
concurrent psychiatric disorders. Depression is
often seen in patients with headaches. In ad-
dition, many individuals with a history of
migraine and major depression also have an
anxiety disorder. These disorders frequently
warrant psychiatric consultation and may re-
quire individual psychotherapy.
OTHER NON-PHARMACO-
LOGICAL STRATEGIES
Exercise
Excessively strenuous or physically stressful ex-
ercise may actually precipitate an attack of mi-
graine. In the prodromal period or during an
attack, most patients automatically restrict
their activity level because movement usually
exacerbates an ongoing migraine. But for some
migraineurs, exercise can abort attacks.22
Moreover, aerobic exercise has been reported
to be a valuable component of migraine man-
agement.41'53'110 This may be important, be-
cause patients suffering from headache disor-
ders are often found to have reduced aerobic
endurance.89 A program of regular aerobic ex-
ercise reportedly decreases the frequency, in-
tensity, and duration of migraine head-
aches.22'52'74'123 However, the connection
between the management of migraine and ex-
ercise still needs research.
 Trigger Factors and Non-pharmacological Approaches
Physical Therapy and Modalities
Pain or injury in the cervical or cranial region
often has negative consequences for mi-
graineurs (see Chapter 5). For example, pain
resulting from a myofascial trigger point lo-
cated in cranial, neck, or shoulder musculature
may precipitate bouts of migraine.24 Whiplash
and similar trauma to the cervical spine often
exacerbate existing migraine. Appropriate anti-
migraine pharmacological therapy may be in-
sufficient to provide relief, if not combined
with treatment of the underlying myofascial
and cervical problems.
Management of myofascial pain includes
eliminating perpetuating structural factors and
taking specific measures to treat trigger
points.40-44'47'50 Concentrating on pain abate-
ment, and not on correcting causative and per-
petuating components, often leads to recurrent
pain. No specific drug therapy alleviates myo-
fascial problems. Muscle relaxants are typically
of little value because spasm is not the basis of
the pain. Tricyclic antidepressants, which are
beneficial in the management of chronic pain
and headache, may be ineffectual unless ther-
apy is also aimed at eliminating whatever pro-
duces trigger points. Approaches to myofascial
pain include the following:
1. Local trigger point therapy. Local anes-
thetic injections are a temporizing measure
that effectively inactivates trigger points and
diminishes, or eradicates, referred pain even
for months.59'99'100 How long the relief persists
depends upon the chronicity and intensity of
the myofascial problem and how satisfactorily
perpetuating factors are addressed in the in-
terim.47'60 Trigger point injections should be
regarded as ancillary in nature, provided in
conjunction with a therapy program directed
toward restoration of normal muscle function.
2. Physical therapy. Physical therapy mo-
dalities (e.g., hot packs, ultrasound, therapeu-
tic massage) are valuable for diminishing pain.
Such modalities are believed to mechanically
disrupt and inactivate trigger points. They
should be used to prepare the muscles for ther-
apeutic stretching and strengthening and for
reestablishing function in weak and tight mus-
cles.82 Physical therapy may also be combined
with relaxation training and/or biofeedback.75
3. Control of perpetuating factors. Posture
training is typically necessary. It is important
307
that the patient comprehend what good pos-
ture entails and what the consequences of poor
posture are. Weak muscles should be strength-
ened by suitable exercises. Tight and shortened
muscles should be stretched actively and pas-
sively. Postural training should begin during
physical therapy, but maintaining good posture
must become part of a a conscious lifestyle. In
addition, ergonomic management is often ef-
fective, providing patients with desks and
chairs that promote good sitting postures.66
Ophthalmological Factors
The relationship between eyestrain caused by
uncorrected refractive errors or disturbances
of ocular alignment and migraine is a matter of
controversy. There are no firm data to indicate
either that eyestrain is responsible for migraine
headaches or that correction of ocular prob-
lems eliminates migraine headaches.
Occlusal Adjustment
Occlusal adjustment involves dental proce-
dures to improve a patient's bite, thereby re-
ducing tension in the jaw muscles that might
induce or exacerbate migraine pain. Limited
data are available, but it appears that occlusal
problems do not have a major etiological role
in migraine and that occlusal adjustment is in-
effective in preventing migraine.43'115
Alternati ve/U nconventional
Migraine Therapies
The estimated number of annual visits to
providers of alternative medicine (complemen-
tary medicine, integrative medicine, uncon-
ventional medicine) exceeds the number of vis-
its to all U.S. primary-care physicians. Little is
known about the safety, efficacy, mechanism of
action, and cost-effectiveness of individual al-
ternative therapies.33'35'36 The theoretical ba-
sis of many therapies (e.g., homeopathy) are
speculative and empirically ill-founded. Some
are known to have dangers and can cause ad-
verse events. Most have not been analyzed by
established rules of evidence: there is a paucity
308 Management of Acute Attacks
of supporting evidence for the value of most
alternative procedures and a low standard of
much of the evaluation. Many studies are
methodologically flawed with poor design, in-
adequate outcome measures and statistical
analysis, and lack of follow-up data. Despite
these drawbacks, the majority of physicians
now endorse some form of alternative therapy
for their patients.13 Many physicians believe
that various of these therapies are useful or ef-
ficacious, much of this belief being rooted in
regional practice or cultural norms.2'3 Although
"holism" is, at best, an enigmatic concept, many
advocates of alternative practices promote
their treatments by asserting that their theories
are "holistic" and take into account both the
bodily and spiritual aspects of humanity's na-
ture, whereas orthodox medicine strives to ex-
plain and treat disease in physicochemical
terms. The placebo effect of these therapies is
usually not discussed.
Interestingly 24% of patients who use alter-
native therapies do so for the management of
headaches.2'3 Because there are sparse con-
trolled data and largely inconclusive evidence
as to how effective alternative treatments for
migraine are, it is unclear how to counsel pa-
tients who request, or already use, alternative
therapies.32 The difficulty is increased by the
enormous number of therapies now available.
Most physicians have no knowledge of modal-
ities such as traditional Chinese medicine, be-
havioral optometry, detoxification therapy
(colon therapy, chelation therapy, herbal bowel
cleaners), homeopathy, magnetic field therapy,
naturopathic medicine, enzyme therapy, and
hyperbaric oxygen administration. None can be
recommended at this point.36 Less obscure al-
ternative therapies include hypnosis, acupunc-
ture, chiropractic, and some herbal remedies.
Hypnosis
Hypnosis is used to produce relaxation and to
diminish a patient's perceptions of pain. It of-
fers a less comprehensive approach than cog-
nitive therapy, but shares many elements with
it, including an emphasis on the role of men-
tal events in pain production and the use of
suggestion and imagery. There are few con-
trolled studies of efficacy. Hypnosis may have
a limited role in the management of migraine.
Acupuncture
Several uncontrolled, or partially controlled,
studies and anecdotal reports discuss the value
of acupuncture for treating migraine.4'30'56'124
Most of the evidence indicates some thera-
peutic gain, but research standards have been
inadequate and there is debate about whether
acupuncture has any specific effects over and
above placebo.78'80 Data that compare acu-
puncture to other headache therapies are con-
tradictory. Moreover, any efficacy seems to de-
crease rapidly after the end of treatment.97 The
treatment is painful for some patients and re-
quires repeated visits. It is not without risks
that include hepatitis and HIV infections from
improper handling of needles, inadvertent
puncture of arteries and nerves, pneumotho-
rax, and cardiac tamponade.34'37
Transcutaneous Electrical
Stimulation
Transcutaneous electrical nerve stimulation
(TENS) has been used to diminish many types
of pain syndromes, but only a few publications
consider its effects on headaches.39'54'107'111
No compelling evidence has been published
showing that TENS has major effectiveness in
the treatment of migraine.
Chiropractic
Spinal manipulation (the use of high-velocity
thrusts directed to one or more of the joints
of the cervical spine) and mobilization (any
manual therapy that does not involve a high-
velocity thrust) are chiropractic techniques to
treat an array of conditions, including migraine.
Three randomized investigations indicate that
chiropractic manipulation can reduce migraine
frequency and severity.93'94'119 Two uncon-
trolled case series have reached the same con-
clusion.117'126 In another study, spinal manip-
ulation appeared as effective in treating
migraine as amitriptyline.88 The quality of the
data, however, prevents reaching firm conclu-
sions. Moreover, complications, such as verte-
brobasilar artery accidents (presumably dissec-
tions resulting from the proximity of the
 Trigger Factors and Non-pharmacological Approaches
vertebral artery to the lateral cervical articula-
tions), are well documented following both
cervical manipulation and mobilization, and
should give one pause before recommending
chiropractic therapy for patients with mi-
graine.28'49'61
HERBAL REMEDIES
Sales of herbal remedies in the United States
exceed $1.5 billion per year and are increasing
at a rate of 25% a year.86 One frequent con-
sideration for trying such products appears to
be headache. Many patients are attracted to
herbal drugs because they are "natural." They
fail to realize that drugs are drugs, whatever
their source, and that there may be more risk
in taking remedies with an unknown content
of a variety of substances than taking a precise
amount of a well-defined drug. Adverse effects
from such therapies are not necessarily trivial.
Except for feverfew (Tanacetum parthe-
nium), a member of the chrysanthemum fam-
ily, there is little published information about
the effects of herbal remedies on migraine.
Feverfew is used in England as a migraine
preventative. There is anecdotal evidence of
its clinical effectiveness and some controlled
evaluation, but efficacy has not been estab-
lished beyond reasonable doubt.125 Nor have
long-term toxicity studies been performed.
Feverfew in whole leaf form or capsules can
cause mouth ulcers and gastric distress. It may
inhibit blood clotting and should not be used
by patients taking anticoagulant medication.
No controlled data support anecdotal reports,
and natural-remedy, self-help books indicate
that ginko (Ginko biloba], garlic (Allium
sativum), ginger (Zingiber officinale), ginseng
(Panax quinquefolius in American ginseng;
Panax ginseng in Oriental ginseng), and dong
quai (Angelica sylvestris) could be helpful in
treating migraine. There is no standardization
of the strength of herbs, and most are not la-
beled to show their concentrations. Side ef-
fects have been reported, as well as interac-
tions with commonly used medications, and
some are contraindicated in certain medical
conditions.83 Ginseng, for example, should
not be used in patients with asthma, high
blood pressure, cardiac arrhythmias, or clot-
ting problems.
309
SUMMARY
The management of patients who are afflicted
with migraine is a complex affair. It always
starts with the initial interview which must be
structured to provide the patient with an idea
of what can and cannot be achieved from ap-
propriate treatment. The crux of effective man-
agement is to individualize therapy as much as
possible to the patient's needs. As we shall see
in the next several chapters, the mainstay of
management is the prudent employment of
one or more of the many medications that are
comparatively specific for migraine. But med-
ications alone, without support, counseling,
and advice about behavior and lifestyle, are in-
adequate. In large measure, management of
patients with migraine consists of an educa-
tional process that enables the affected indi-
vidual to make intelligent decisions about re-
moving or altering precipitating elements and
about making changes of lifestyle. Behavioral
techniques, such as biofeedback and simple re-
laxation therapy, at times, but not always, lead
to an impressive decrease in the frequency and
intensity of the headaches. Wide clinical ac-
ceptance of behavioral techniques as treatment
modalities for migraine has been gained, and
one should not hesitate to use these procedures
in appropriately selected patients.
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Chapter 1 4

Anti-emetics, Analgesics,
Barbiturates, and Opiates

ANCILLARY INTERVENTIONS BUTALBITAL-CONTAINING ANALGESIC

HEADACHE RECURRENCE DRUGS
CHOICE OF ANTI-MIGRAINE Side Effects and Contraindications
MEDICATION ISOMETHEPTENE MUCATE
Side Effects Side Effects and Contraindications
RESCUE THERAPY OPIOIDS/NARCOTICS
COST CONSIDERATIONS Side Effects
MEDICATION OVERUSE CORTICOSTEROIDS
ANTI-EMETICS/PROKINETIC MAGNESIUM
MEDICATIONS MECHANISMS OF ACTION OF
ASPIRIN AND ACETAMINOPHEN MEDICATIONS FOR ACUTE
Side Effects and Contraindications MIGRAINE ATTACKS
CAFFEINE Anti-emetics
OTHER NON-STEROIDAL ANTI- Aspirin, Non-steroidal Anti-inflammatory
INFLAMMATORY AGENTS Drugs, and Acetaminophen
Side Effects Butalbital
Contraindications Opioids
SUMMARY

Even though the majority of migraine head-
aches are described as severe, they are treated
with simple over-the-counter (OTC) analgesics
(Fig. 14-1). Migraineurs will usually confer
with a physician only if their attacks are very
intense, prolonged, and/or resistant to simple
medications. They seek medical care especially
when the frequency or severity of their head-
aches interferes with daily living. For a great
many migraineurs, non-pharmacologic ap-
proaches, education, elimination of trigger fac-
tors, and changes in lifestyle undoubtedly di-
minish the frequency of migraine attacks. Only
rarely will such treatment prevent all attacks,
and most migraineurs who seek treatment will
314
also require abortive and/or symptomatic ther-
apy for their acute episodes.
The objective when treating an acute attack
is to ameliorate the symptoms while not in-
ducing substantial side effects (Table 14-1). A
major aim is to return the patient to full func-
tion, although for some patients the symptoms
can only be reduced and made more bearable.
Among innumerable available remedies and
techniques, some have proven to be very ef-
fective, while others, although of little proven
value, are still used by convention. Different
authorities describe remarkably varied treat-
ment strategies. And because of the large
placebo effect, determining how an acute bout
 Anti-emetics, Analgesics, Barbiturates, and Opiates 315

Figure 14-1. Medication use by migraineurs and by individuals with severe headaches of other types. The pie charts
show the proportion of patients who use over-the-counter medications (open areas), prescriptions (striped areas), and
no medication (solid areas) by gender. (Adapted from Celentano DD, Stewart WF, Lipton RB, and Reed ML: Med-
ication use and disability among migraineurs: a national probability sample survey. Headache 32:223-228, 1992, with
permission.)

of migraine will respond to various medications
is sometimes difficult to assess in the clinic.
Medications for abortive or symptomatic
treatment of migraine work more effectively if
taken at the first sign of headache; when ad-
ministered late in an attack, oral medications
may be poorly absorbed or ineffective. Unfor-
tunately, many migraineurs are hesitant to take
medications prior to the onset of severe pain.
The significance of early treatment must be
emphasized during the patient's initial consul-
tation. Equally important, an adequate dose of
medication is necessaryrepeated inadequate
quantities of an agent can actually protract a
headache that might have been successfully
treated early on. Ironically, many medications
that may effectively treat acute migraine head-
aches if given early enough in sufficiently high
doses also have great potential to induce head-
ache. Overuse of simple analgesics, non-
steroidal anti-inflammatory drugs (NSAIDs),
butalbital-containing analgesics, opiates, er-
gots, and triptans can cause chronic headaches;
some can also produce addiction. Accordingly,
their use must be carefully monitored and con-
trolled. The OTC medications that television
commercials have led the general population
to view as "benign" capsules or tablets to be
taken at will can covert mild-to-moderate
headaches to more disabling ones.
The situation is rather complicated. Physi-
cians often find themselves facing patients with
Table 1 4-1 . Aims of Abortive/
Symptomatic Treatment
Reduce or eliminate severity of pain
Lessen or vanquish associated symptoms (nausea,
vomiting, photophobia)
Diminish the duration of the attack
Return the patient to normal function
Not induce side effects
316 Management of Acute Attacks
preconceived notions; these patients may not
wish to take potent medications because this
would be a sign of "weakness," and are inclined
to wait to see how bad the headache is going
to get before they succumb to taking pills. In
trying to tough it out, they may allow headaches
amenable to early intervention to develop into
ones that are far less effectively treated. Iron-
ically, the same patients who are reluctant to
take prescription drugs may not hesitate at all
before taking frequent, even daily, OTC anal-
gesics, bringing on themselves rebound head-
aches and a chronic daily headache syndrome
(see Chapters 4 and 25). Accordingly, the im-
portance of doctor-patient discussion of med-
ication can never be stressed too much.
ANCILLARY INTERVENTIONS
Medications alone are frequently insufficient
to treat an ongoing migraine attack. Many pa-
tients find it necessary to lie down in a dark-
ened room, apply cold packs to their heads or
necks, and attempt to sleep. Placing an ice pack
on the scalp or neck lessens the pain intensity
substantially in about a third to a half of mi-
graineurs, especially if the headache is mild to
moderate.25'^0'86
Some patients find the pain eliminated by
even a short period of sleep; others require
deep sleep lasting several hours.5'6 Patients
able to sleep recover more fully than those who
only rest or doze. A short-acting sedative such
as diazepam (5 to 10 mg) may be very helpful.
In some countries, walk-in clinics provide the
migraineur with a simple analgesic, an anti-
emetic, a sedative or tranquilizer, and a place
to sleep for a few hours.78'115 Such clinics are
remarkably successful. But solitude and sleep
are unrealistic for some patients, especially if
attacks develop at work, away from home, or
at a time and place that requires the migraineur
to continue to act responsibly. In that situation,
treatment that does not cause somnolence is
necessary.
HEADACHE RECURRENCE
Headache recurrence has been described as
reappearance, after successful treatment, of
migraine and its associated symptoms of nau-
sea and photophobia within 4 to 72 hours of a
migraine attack. This phenomenon is charac-
teristic of all medications used against acute
migraine. The phenomenon varies with med-
ication. An individual may have recurrences
with one medication, but not another. Not sur-
prisingly, the longer a particular patient's at-
tack lasts, the higher the risk for headache re-
currence; the severity of a bout does not seem
to be a factor. The risk for headache recurrence
is patient-dependenti.e., some patients ex-
perience frequent headache recurrences, or
they rarely do.108 There are remarkably few
clinical differences between patients who have
recurrent attacks and those who don't, but
headache recurrence is more common in
women than men.97'108 Interestingly, headache
recurrence also occurs following administra-
tion of placebos that eliminate the acute symp-
toms.
CHOICE OF ANTI-MIGRAINE
MEDICATION
There is no consensus about medication pref-
erences, dosages, routes of administration, for-
mulations, and combinations. The lack of ap-
propriate, controlled clinical data and varying
prescribing practices in different parts of the
world are factors. But the most significant fac-
tor in the lack of consensus is that no one drug
is suitable for all patients with severe acute mi-
graine. Flexibility is necessary to customize
therapy.
There are two major strategies for selecting
treatments each reflecting different philosoph-
ical approaches to headache management. The
first strategy is the classical, step-wise (stepped
care, step-care] approach that has been in
vogue for decades. Treatment is initiated with
the simplest and most inexpensive, nonspecific
medications, and, if unsuccessful, is advanced
to more potent and expensive agents until a re-
sponse is obtained (step-care across attacks}.
Simple analgesics are usually tried first; if these
are without efficacy, isometheptane or NSAIDs
are prescribed, then butalbital-containing medi-
cations; then narcotics; and finally ergots (see
Chapter 15) and triptans (see Chapter 16) (Fig.
14-2). The patient can begin at the level of
treatment warranted by prior history of re-
sponse to particular medications. This ap-
proach is frequently favored in managed-care
treatment guidelines. Stepped-care may easily
 Anti-emetics, Analgesics, Barbiturates, and Opiates 317

STEPED WITHIN STRATIFIED CARE

STEP-CARE
ATTACK CARE First-Line Therapy
Attack 1; ASA, Stage 1; Combined Start with therapy
Non-Rx NSAID OTC analgesic suited for attack
profile, associated
Attack 2; Combined OTC Stage 2: NSAID symptoms, and level
analgesics of disability

Attack 3; RxNSAIDs Stage 3; Ergot, DHE, or

Triptan

Attack 4: Mixed butalbital, Stage 4; Rescue Therapy -

Isometheptene, etc. Opiate/Opioid,
Steroid
Attack 5: Opiates/opioids
Move to Stepped
Within-attack Care
Attack* Ergotamme For Rescue Therapy

Attack 7: DHE-45

Attack 8: Triptans
Figure 14-2. Typical approaches when using step-care, step-care-within-attack, and stratified-care strategies in mi-
graineurs. ASA, aspirin; DHE, dihydroergotamine; NSAID, non-steroidal anti-inflammatory drug; OTC, over the counter;
Rx, prescription. (From Sheftell FD and Fox AW: Acute migraine treatment outcome measures: a clinician's view.
Cephalalgia 20(Suppl 2):14-24, 2000, with permission.)

provide suitable therapy for patients with mild-
to-moderate headaches that respond to simple
analgesics. It is a judicious scheme for mini-
mizing the improper use of triptans and con-
trolling health-care costs. But it is inappropri-
ate for patients with incapacitating pain
associated with vomiting and prostration. For
such unfortunate persons, not only will pro-
longed morbidity, treatment failures, and nu-
merous office visits likely punctuate the road
to successful treatment but they will also un-
dermine trust in physicians. Moreover, both
patients and physicians often become discour-
aged. Patient lapses from treatment may result.
The step-care approach is also be used for
individual attacks (step-care within attacks). At
the beginning of an acute attack, patients in-
augurate therapy with a simple analgesic, a
NSAID, or a combination-analgesic. If an in-
effective result is obtained at a specific time af-
ter initiating therapy, a stronger medication
such as a triptan is taken. This approach is gen-
erally considered an inferior way to treat an at-
tack of migraine because precious time is
wasted early in the attack when so-called
stronger medications are likely to be more ef-
fective.68
The second approach is based on the
premise that substantial differences in head
pain, associated-symptom severity, and disbil-
ity require initial therapy based on the patient's
account of those symptoms (stratified care,
customized care).65 This is the best approach
to patients who suffer from severe, prolonged,
incapacitating headaches unresponsive to sim-
ple analgesics.68 The step-care series of inef-
fective (albeit usually inexpensive) medications
can be avoided, especially since, with the ad-
vent of the triptans, most physicians realize that
current anti-migraine drugs are better than any
318 Management of Acute Attacks
Figure 14-3. Headache responses at 1, 2, and 3 hours in
(1) stratified-care patients (striped bars) with moderate at-
tacks (aspirin, 800 to 1000 mg, plus metoclopramide, 10
mg) or severe attacks (zolmitriptan, 2.5 mg); (2) step-care-
across-attacks patients (solid bars) in whom initial treat-
ment in two attacks was 800 to 1000 mg aspirin, plus 10
mg metoclopramide and switched to 2.5 mg zolmitriptan
for three attacks; and (3) step-care-within-attacks in pa-
tients (open bars) whom initial treatment for all attacks was
800 to 1000 mg aspirin, plus 20 mg metoclopramide. Pa-
tients not responding to treatment after 2 hours received
escalated treatment to 2.5 mg zolmitriptan. More attacks
in the stratified-treatment group had a statistically signifi-
cant headache reponse compared to that in the step-care-
across-attacks treatment group. Statistically significantly
more attacks in the stratified-care treatment group showed
a 1- and 2-hour headache response than in step-care-
within-attacks group. P < 0.001 for those with stratified
care vs. step-care across attacks ( e ) and for those with strat-
ified care vs. step-care within attacks ( eo ). (Adapted from
Lipton RB, Stewart WF, Stone AM, Lainez MJA, and
Sawyer JPC: Stratified care vs step care strategies for mi-
graine. The Disability in Strategies of Care (DISC) Study:
a randomized trial. JAMA 284:2599-2605, 2000. Copy-
righted 2000, American Medical Association.)
previously available. This has caused the step-
wise approach to be modified or abandoned for
patients with severe migraine (Fig. 14-3). In
fact, if patients have not previously responded
to self-medication with simple analgesics or
NSAIDs, many physicians now prescribe trip-
tans immediately. Patients with incapacitating
headaches should not be subjected to initial
therapy trials with less potent compounds un-
less triptans are contraindicated.
Choice of medications and route of admin-
istration depend upon several factors:
1. Speed of headache onset. Headaches that
reach their peak rapidly or develop nocturnally,
awaking the patient from sleep with a full-
blown attack, require medications that are
rapidly absorbed. Parenteral, nasal, or rectal
routes of administration are usually necessary.
2. Seventy. Mild-to-moderate attacks usu-
ally respond to simple analgesics, NSAIDs, or
butalbital-containing medications. If ineffec-
tive or if attacks are moderate to severe, dihy-
droergotamine or triptans are prescribed. Nar-
cotics have a limited, but definite, role in
managing patients whose severe attacks are not
alleviated by other medications or for whom
triptans and ergots are ineffective, not well tol-
erated, or contraindicated (Table 142).
3. Frequency of attacks. Because of the dan-
gers of rebound and of developing chronic
daily headaches, symptomatic headache med-
ications should not be used more than twice a
week. Patients who use symptomatic headache
medications more frequently require prophy-
lactic medications even if their headaches are
only mild to moderate in severity. Prophylaxis
is mandatory if patients have frequent, severe
bouts of migraine.
4. Pattern and seventy of associated symp-
toms. Nausea and vomiting are the most trou-
bling symptoms for some patients and can be
debilitating. In addition, some medications
used to treat acute attacks may cause nausea
and vomiting. If nausea is a prominent symp-
tom, an anti-emetic should be administered
early and/or parenteral, nasal, or rectal med-
ications prescribed.
5. Presence ofcomorbid medical conditions
or psychiatric problems. Ischemic cardiovas-
cular disease, history of peptic ulcer, gastritis,
or depression, and other medical problems
substantially limit the medications that can be
administered. For example, triptans and ergots
should not administered to patients with car-
diac or vascular disease. NSAIDs should not be
prescribed for individuals with upper gastroin-
testinal problems (see Table 14-3 for more ex-
amples).
6. Medications presently being taken for mi-
graine or other illnesses. Medication interac-
tions must be avoided. For example, triptans
should not be administered to patients who
have taken ergots within the last 24 hours or
to those on monoamine oxide (MAO) inhibi-
tors.
7. Patient's past medication history and ef-
fectiveness of previous treatments. It is crucial
to determine if previously used medications
were administered in optimal doses and what,
if any, side effects were produced. It is very
 Anti-emetics, Analgesics, Barbiturates, and Opiates 319

Table 14-2. Abortive/Prophylactic Therapy

Migraine Migraine Abortive
Severity Frequency* Medicationt Prophylaxis
Mild to moderate Infrequent OTCs, NSAIDs, combinations No
Mild to moderate Frequent OTCs, NSAIDs, combinations Think prophylaxis
Severe Infrequent Triptans, DHE, ergotamine, narcotics Think prophylaxis
Severe Frequent Triptans, DHE, ergotamine, narcotics Prophylaxis mandatory
"Infrequent: <3 to 4 migraine attacks per month; frequent: >3 to 4 migraine attacks per month.
tCombinations, butalbital-containing analgesic medications; DHE, dihydroergotamine; OTCs, over-the-counter med-
ications; NSAIDs, non-steroidal anti-inflammatory medications.

possible that previously prescribed drugs were
discontinued too soon, never given in adequate
doses, or administered by an improper route.
8. Patient preferences. For some patients,
relief from pain is their most important prior-
ity; for others the head pain may be bearable
if nausea and vomiting are controlled. Rectal
administration is unacceptable in certain cul-
tures and to certain individuals, even though it
is the most effective route for medications such
as ergotamine tartrate and certain anti-emetics.
Also, if the suppository needs refrigeration, it
will be useless in many situations. Other pa-
tients will refuse injectable medications. It is
necessary to discuss options sensitively.
9. Patient's vulnerability to addictive prob-
lems. A patient's propensity to overuse either
OTC or prescription medications must be
taken in account. A history (or perhaps even a
family history) of alcoholism or drug abuse
should raise red flags in this regard.
10. Patient's reproductive status. Many
medications for acute migraine attacks cannot
be used if a patient is either pregnant, at-
tempting to conceive, or lactating. Such pa-
tients may be limited to acetaminophen and
narcotics (see Chapter 24).
Side Effects
Only about one-quarter of physicians take time
to discuss potential side effects and complica-
tions of medication with their patients.1 Time
constraints are a major factor. But some physi-
cians simply do not feel that it is necessary to

Table 14-3. Abortive/Symptomatic Therapy: Contraindications

Medication Contraindications
Aspirin Peptic ulcer, gastritis, impaired renal function, age <12
years, pregnancy
Acetaminophen Liver disease
Butalbital History of medication overuse, addiction, or alcoholism;
concurrent use of alcohol or sedative/hypnotic/tranquilizer
drugs
NSAIDs Peptic ulcer, gastritis, impaired renal function, pregnancy,
lactation
Narcotics History of medication overuse, addiction, or alcoholism;
concurrent use of alcohol or sedatives/hypnotics/
tranquilizers; lactation
Ergots Coronary artery/peripheral vascular disease, thrombophlebitis,
pregnancy, lactation
Triptans Coronary artery disease, complicated migraine, uncontrolled
hypertension, monoamine oxidase therapy, pregnancy,
lactation
320 Management of Acute Attacks
advise patients even though informed consent
is implicit in any patient consultation. Many
others are reluctant to discuss potential adverse
events because they believe the power of sug-
gestion may lead to an increased incidence of
side effects. Controlled studies, however, show
that explicitly informed patients do not have an
increased incidence of side effects.47'59 These
studies should make it clear that one of the
tenets of informed consentbeing made
aware that there are potential adverse events
and complicationsdoes not compromise
pharmacological intervention. It is valuable to
provide patients with written drug information.
If this is not done, many sophisticated patients
will read the Physicians' Desk Reference (PDR)
in their local libraries or look for pertinent in-
formation on the Internet. In either case, they
may decide not to take the medication because
they become frightened or upset by a list of
side effects that is unaccompanied by a physi-
cian's comments.
RESCUE THERAPY
Effective rescue medication should be pro-
vided to patients with certain symptoms, in-
cluding unusually severe, disabling headaches;
unusual, full-blown, severe, nocturnal head-
aches; pronounced vomiting that precludes
taking usually effective oral medications; an in-
consistent response to medications; and a pat-
tern of headache recurrence (Table 14-^).
These patients should be provided with a
rapidly absorbed formulation such as injectable
or intranasal ergot, injectable triptan, narcotic
nasal spray, or injectable neuroleptics. These
Table 14-4. Rescue Medication for
Acute Migraine Attacks
Rescue medication should be provided for patients
with the following:
Unsually severe, disabling attacks
Severe nocturnal headaches
Severe headaches upon awakening
Pronounced vomiting preventing use of oral
medications
Inconsistent response to abortive/symptomatic
medications
A pattern of recurrent headaches
medications may save patients from consider-
able suffering as well as costly visits to emer-
gency departments.
COST CONSIDERATIONS
Before the advent of health maintenance or-
ganizations (HMOs), expense was not usually
considered.112 Medications were selected al-
most solely for their effectiveness, side-effect
profile, and ease of administration. But new
migraine medications such as the triptans are
much more costly than older medications like
ergotamine. A 1995 estimate concluded that to
treat half the ideal candidates with sumatrip-
tan would increase pharmacologic costs at least
$3 billion per year.42 The cost is doubtless
higher today. It has thus become necessary
to factor direct costs of medication into the
decision-making process. This unfortunate ne-
cessity benefits medical insurers, but does not
make economic sense to society. Migraine it-
self has enormous costs: for example, it is esti-
mated to cost American employers about 13
billion dollars a year because of missed work-
days and impaired work function (see Chapter
I).48 Added to these direct costs are the im-
pressive effects migraine has on the functional
capacity of sufferers at school and at home. As
cogently pointed out by Von Seggern and Adel-
man, even though a medication is inexpensive,
it is not cost-effective if it is an inadequate ther-
apeutic agent (Table 14-5).112
MEDICATION OVERUSE
All analgesic drugs, taken in excessive amounts
for prolonged periods of time, can both induce
and maintain headache. The triptans and er-
gots can also produce increased frequency of
attacks with consequent dependence and mis-
use (see Chapters 15 and 16). Frequently, the
result is transformation of episodic migraine at-
tacks into a chronic daily headache. Mi-
graineurs frequently practice self-medication
without medical control or supervision and
take excessive amounts of both prescribed and
OTC medications. Some patients make a dis-
tinction between prescription and OTC med-
ications. Because they perceive OTC medica-
tions as harmless, many patients overuse them
while believing that they are following doctor's
 Anti-emetics, Analgesics, Barbiturates, and Opiates 321

Table 14-5. Cost of Acute Migraine Therapy

Medication Brand Name Price Average Wholesale ($)
Acetaminophen/butalbital/caffeine Fioricet (1 tablet) 0.65
Acetaminophen/codeine Tylenol #4 (1 tablet) 0.68
Aspirin/butalbital/caffeine Fiorinal (1 tablet) 0.82
Diclofenac Cataflam (50 mg; 1 tablet) 1.81
Hydrocodone/acetaminophen Vicodin (1 tablet) 0.50
Ibuprofen Motrin (800 mg; 1 tablet) 0.45
Isometheptene mucate Midrin (2 capsules) 0.49
Ketorolac Toradol (60 mg; 1 IM injection) 7.44
Metoclopramide Reglan (10 mg; 1 tablet) 0.77
Naproxen Naprosyn (500 mg; 1 tablet) 1.14
Naproxen sodium Anaprox (550 nig; 1 tablet) 1.31
Oxycodone/acetaminophen Percocet (1 tablet) 0.56
Oxycodone/aspirin Percodan (1 tablet) 1.01
Prochlorperazine Compazine (10 mg; 1 tablet) 0.97
Prochlorperazine Compazine (25 mg; 1 suppository) 3.38
Promethazine Phenergan (25 mg; 1 tablet) 0.45
Propoxyphene/acetaminophen Darvocet-N 100 (1 tablet) 0.64
Butorphanol Stadol nasal spray (10 mg/ml; 2.5 ml) 86.86
Trimethobenzamide Tigan (250 mg; 1 capsule) 0.69
IM, intramuscular.
Data from 2000 Red Book, Medical Economics Data, Inc. (non-generic prices).

orders. In addition, most patients are utterly
unaware of the relationship between daily, or
frequent, use of analgesics and chronic daily
headaches. They do not understand that excess
self-medication may exacerbate or perpetuate
headaches.
Despite extensive efforts at education, many
physicians remain unaware of the dangers of
exacerbating their patient's migraine through
the overuse of analgesics, narcotics, and ergots.
Often the anti-migraine drugs were prescribed
with the best of intentions. Most headache suf-
ferersand unfortunately many of their physi-
cianstacitly assumed that substantial daily
use of analgesics, narcotics, and ergots resulted
from severe, unremitting daily head pain. Their
physicians did not know to educate their pa-
tients or set limits on their use. Their patients
then used the drugs in progressively larger
quantities and, ultimately, in unmistakable ex-
cess. It is now widely conceded that the
excessive use of simple analgesics (including
aspirin and acetaminophen), NSAIDs, butal-
bital-preparations, narcotics, ergots, and trip-
tans worsens and maintains head pain over
time. In other words, such medications play a
substantial role in transforming episodic head-
ache into daily headache. Such headaches are
now believed to be drug-induced or rebound
headaches. They are ameliorated, often in a
dramatic fashion, after drug intake is stopped,
an actuality that endorses the argument that
excessive drug-taking produced them.
Anti-migraine medication should not be
regularly used more than 2 days a week, and,
in an optimal situation, less frequently. It may
be used more frequently, but for a limited time,
for menstrual migraine or for acute intractable
head pain when prophylactic medications are
ineffective or contraindicated.
ANTI-EMETICS/PROKINETIC
MEDICATIONS
Because most acute bouts of migraine are as-
sociated with nausea and/or vomiting, the need
for anti-emetic medication is often very great.
Although most patients are not completely
overcome by vomiting, there are cases in which
322 Management of Acute Attacks

severe, repetitive emesis, if left uncontrolled,

leads to dehydration that requires hospitaliza-
tion. Nausea may begin in the prodromal phase
or very early in the headache phase. Anti-
emetic medications should be given as soon as
possible. Early treatment is important not just
to allay troublesome symptoms but also be-
cause some of the remedies administered for
acute attacks of migraine can themselves cause
nausea and anti-emetic premedication is help-
ful. In addition, delayed gastric emptying, even
in migraineurs who do not complain of nausea,
impairs absorption from reduced motility of
the gastrointestinal tract during migraine.8'110
It may be accompanied either by gastric di-
latation and stasis or by prolonged gastric con-
traction. Because drug absorption occurs
mainly in the proximal small intestine, delay in
gastric emptying impairs absorption of orally
administered anti-migraine medications.110
Gastric emptying and peristalsis during
bouts of migraine can be promoted by the use
of the proldnetic drug metoclopramide
(Reglan). If adequate blood levels are attained,
metoclopramide enhances motility of smooth
muscle from the esophagus through the prox-
imal small bowel. As an example, aspirin
reaches its time to reach the peak plasma con-
centration (tmax) much faster during headache-
free intervals than during headaches.109 Meto-
clopramide has been shown to increase the
rate of aspirin absorption significantly (Fig.
14_4).88,89>Jlio The compound is thought to be
effective in this way only when it has been
given before the analgesic, but this has not
been studied in depth.110 Although metoclo-
pramide's ability to enhance analgesic efficacy
during acute bouts of migraine has been diffi-
cult to demonstrate in controlled trials, 10 mg
of oral metoclopramide is widely recom-
mended during the therapy of acute migraine
as an adjunct to simple analgesics (and other
medications such as NSAIDs and er-
gots) 89>95>103,106
Metoclopramide is also an effective anti-
emetic (Table 14-6). Intramuscular or intra-
venous injections are very efficacious adminis-
tration routes, with more than 85% of patients
reporting a significant reduction in nausea and
vomiting.49'102 Because bioavailability of the
drug after oral administration has been re-
ported to vary widely in healthy volunteers,
some skepticism has been voiced about how ef-
ficacious metoclopramide is when adminis-
Figure 14-4. Effect of metoclopramide (MCP) on ab-
sorption of aspirin (ASA) during migraine attacks. Solid
line, ASA + MCP during migraine attack; broken line,
ASA between attacks; dotted line, ASA during migraine at-
tack. (Adapted from MacGregor A: Managing Migraine in
Primary Care. Blackwell Science Ltd., Oxford, UK, 1999,
with permission; based on Volans GN, Br J Clin Pharma-
col 2:57-63, 1975.)
tered orally. It may be that the usual oral adult
dose (10 mg) of metoclopramide will not pro-
duce sufficient blood levels to stimulate every
stomach. Even so, oral metoclopramide re-
mains an invaluable medication for many pa-
tients.
As an anti-emetic, as well as a gastric stim-
ulant, metoclopramide is a relatively innocuous
drug with few substantial side effects. It can,
however, produce some uncomfortable central
nervous system (CNS) effects such as drowsi-
ness, dizziness, and anxiety. As a D receptor
agonist, the compound can cause dystonia,
akathisia, and Parkinson-like symptoms, al-
though this is not particularly common except
when administered in high doses or when given
intravenously. Dystonic reactions are more
common in children and adolescents than in
adults. In rare individuals, tardive dyskinesia
has developed after relatively brief periods of
treatment with repeated low doses.
Other anti-emetics will work effectively
against nausea and vomiting, but none have the
same gastrokinetic actions as metoclopramide.
In fact, some phenothiazine anti-emetics actu-
 Anti-emetics, Analgesics, Barbiturates, and Opiates
Table 14-6. Selected Anti-emetic Drugs Used for Acute Migraine Attacks
Agent Brand Name
Metoclopramide Reglan
Chlorpromazine Thorazine
Promazine Sparine
Promethazine Phenergan
Prochlorperazine Compazine
Trimethobenzamide Tigan
IM, intramuscular administration.
ally delay the absorption of aspirin and other
medications and may, therefore, retard clinical
recovery. Phenothiazines used as anti-emetics
include those in the aliphatic group: chlorpro-
mazine (Thorazine), promazine (Sparine), and
promethazine (Phenergan); and in the piper-
azine group: prochlorperazine (Compazine).
Drowsiness is the most common untoward
consequence of all phenothiazines, the piper-
azines being less likely to cause drowsiness than
the aliphatics. Cholestatic jaundice, granulocy-
topenia, thrombocytopenia, urticaria, dermati-
tis, and gastroenteritis have occurred after phe-
nothiazine administration.
In addition to metoclopramide and the phe-
nothiazines, trimethobenzamide hydrochloride
(Tigan) can be used to control the nausea and
vomiting of an acute migraine attack. With the
usual doses, the incidence of adverse effects is
low; with larger doses, drowsiness, vertigo, di-
arrhea, and cutaneous hypersensitivity reac-
tions may occur.
ASPIRIN AND
ACETAMINOPHEN
In the United States as many as 63% of women
and 75% of men with severe headache use
323
Dosage
Oral: 10 mg every 6-8 hours
IM or IV: 10 mg every 8 hours
Oral: 10-25 mg every 4-6 hours
Suppository: 50-100 mg every 6-8 hours
IM: 25-50 mg every 3-4 hours
Oral: 25-50 mg every 4-6 hours
IM: 50 mg
Oral: 12.5-25 mg every 4-6 hours
Suppository: 12.5-25 mg every 46 hours
IM: 12.5-25 mg every 4-6 hours
Oral: 5-10 mg every 6-8 hours
Suppository: 25 mg every 12 hours
IM: 5-10 mg every 3-4 hours
Oral: 250 mg every 6-8 hours
Suppository: 200 mg every 6-8 hours
IM: 200 mg every 6-8 hours
OTC medications.14 Almost half of those with
disabling headaches use nonprescription med-
ication exclusively.14'58 Many patients are wary
of taking prescription medications, using them
only when the pain is unbearable or severe
enough to interfere with their ability to work.32
Even after a primary-care headache visit, only
a minority of headache patients use headache-
specific abortive treatments such as triptans or
ergotamine.111 The conclusion is that OTC
analgesics such as aspirin, acetaminophen
(Tylenol), ibuprofen (Motrin), and naprosyn
(Alleve) form the mainstay of abortive anti-
migraine treatment. Rapid ingestion of adequate
amounts of one of these simple analgesics may
be all that is required for mild-to-moderate
bouts, although the therapeutic response is fre-
quently incomplete and considerable residual
discomfort remains.79'89'105 With or without
metoclopramide, aspirin (or the highly soluble
aspirin salt, lysine-acetylsalicylic acid [Aspisol],
which is not available in the United States) has
been shown in appropriate, controlled trials to
be superior to placebo.7'15'44'105 Acetamino-
phen is also superior to placebo.66
A number of clinical trials have established
the efficacy of OTC medications in general for
migraine headaches.100 The degree of differ-
ence in efficacy among OTC analgesics is more
324 Management of Acute Attacks
difficult to ascertain. Most early studies did not
recognize the need to establish adequate sen-
sitivity or statistical power to distinguish among
treatments. Moreover, the difference among
oral analgesics is much less than the difference
between a therapeutic dose of any oral anal-
gesic and a placebo.
Patient predilection for certain analgesic
medications is based, at least in part, upon tra-
dition and advertising. In the United States,
brand-name acetaminophen products (espe-
cially Tylenol) are the most widely advertised,
and most widely used, pain killers, while in
some European countries aspirin-containing
products or equivalents (including 1620 mg ly-
sine acetylsalicylate; equivalent to 900 mg of
aspirin) are more typically ingested.
Approximately 35% to 45% of patients con-
sider aspirin alone an effective medication for
acute migraine attacks of mild or moderate in-
tensity.89'105 Combined with metoclopramide
(10 mg), the efficacy rate of aspirin (975 mg,
or lysine-acetylsalicylic acid, 1620 mg) is be-
tween 54% and 58%.15>44'104 Because the ef-
fects of aspirin are dose related, a dose of 975
mg should be administered as soon as possible.
If the headache continues or returns, the same
dosage of aspirin can be repeated in 4 to 6
hours. Some patients consider 1000 mg of ace-
taminophen to be similar in efficacy to 650 mg
of aspirin, but little controlled data are avail-
able to support their opinion. A maximum of
12 aspirin (325 mg) or 8 extra-strength ace-
taminophen (500 mg) tablets can be taken in
1 day. A mixture of aspirin and acetaminophen
is effective, particularly when combined with
caffeine (Excedrin Migraine; acetaminophen,
250 mg; aspirin, 250 mg; caffeine, 65 mg). In
treating all but the most severe cases, this
preparation has been found efficacious in 59%
of patients for reducing head pain, nausea, and
photophobia.39'67
In individuals not having an attack of mi-
graine, salicylates taken by mouth are absorbed
relatively slowly, although substantial plasma
levels occur in less than 30 minutes.63 The rate
of absorption is determined, however, by three
major factors: (1) the gastric emptying time, (2)
the pH, and (3) the rate of disintegration and
dissolution of the aspirin tablets. The gastric
emptying time is important because, although
some absorption does occur in the stomach, the
process of absorption of aspirin (as well as other
anti-migraine medications) takes place largely
in the upper small intestine. As noted above,
gastric stasis is a common feature of migraine
attacks. Nausea and vomiting associated with
the attack itself are also prominent delaying
factors. Drug-induced gastric irritation (which
is frequently caused by aspirin) augments this
effect. Furthermore, patients who vomit must
not only endure the discomfort of it but also
face the confusion of not knowing whether they
have thrown up their medication; and, if so,
what part of the dose. Because salicylate ab-
sorption occurs by passive diffusion across gas-
trointestinal membranes, and because low pH
increases the solubility of salicylate and disso-
lution of aspirin tablets, an increase in stomach
acid (such as that produced by caffeine) en-
hances absorption. The optimum gastric pH for
aspirin absorption is between 2.5 and 4. The
presence of food that buffers pH delays salic-
ylate absorption.
Effervescent or soluble aspirin produces
higher blood levels within a shorter period of
time than do solid tablets, and as a result, ef-
fervescent aspirin preparations are often rec-
ommended by physicians.63'64 Television com-
mercials also urge its use for headaches
accompanied by "upset stomach." One double-
blind placebo-controlled investigation showed,
however, that effervescent aspirin alleviated
headaches in only 37% of patients.105
Side Effects and
Contraindications
Serious adverse reactions are infrequent with
the usual analgesic doses of aspirin, but its con-
tinued use may cause some people to experi-
ence epigastric discomfort or pain, heartburn,
dyspepsia, or nausea. Although occult gas-
trointestinal bleeding occurs in many patients,
the amount of blood lost is usually insignificant.
But if used excessively or for prolonged peri-
ods of time, aspirin can cause gastric ulcera-
tion. In addition, patients who are extremely
susceptible to its effects may develop gastric
ulceration even on modest doses. This is rare;
nevertheless, aspirin should not be used when
there is a recent history of peptic ulcer, gastri-
tis, or gastrointestinal bleeding. Aspirin is also
contraindicated for patients with bleeding dis-
orders. As a result of its antiplatelet and gas-
tric erosive effects, aspirin increases the risk of
bleeding while taking oral anticoagulants. Pa-
 Anti-emetics, Analgesics, Barbiturates, and Opiates
tients taking oral anticoagulants should be cau-
tioned to avoid aspirin and aspirin-containing
products. And for the very small percentage of
patients who are hypersensitive to aspirin, even
small doses may cause a rash or severe ur-
ticarial, or asthmatic-type anaphylactic reac-
tion. The risk of hyper-sensitivity reactions is
significantly higher in patients with a history
of asthma, nasal polyps, or urticaria. Cross-
reactivity with NSAIDs is common. Finally, as-
pirin should not be given to children under age
12 because of the possibility of developing
Reye's syndrome.
Acetaminophen does not have toxic effects
on the gastrointestinal tract. On occasion, stan-
dard doses induce skin rashes or mucosal
lesions. An acute, massive overdose may lead
to liver dysfunction including fatal hepatic
necrosis.
CAFFEINE
Caffeine has long been a constituent of OTC
and prescription analgesics. Caffeine combined
with aspirin and/or acetaminophen (with or
without butalbital) is available. In addition to
commercial products, many migraineurs dis-
cover by themselves that a caffeine-containing
beverage will help abort their migraine attacks.
Concurrent oral administration of caffeine with
aspirin increases the peak plasma concentra-
tion of aspirin by about 20%.116 The reason for
this enhanced availability may lie in caffeine's
ability to increase gastric acidity. Caffeine also
has independent analgesic effects that are
equivalent to acetaminophen in alleviating
nonmigrainous headaches.114 It causes cere-
bral vasoconstriction and may also have anti-
inflammatory properties. In addition, caffeine's
mood-altering properties and the increased
mental alertness, lessened fatigue, and feeling
of well-being that follow ingestion may coun-
terbalance some of the symptoms of migraine.
But because of the clanger of producing
caffeine-withdrawal headaches, restraint must
be practiced to prevent overconsumption of
caffeine-containing drinks and medications.
Some authorities find little evidence to sup-
port the supposition that caffeine is an anal-
gesic adjuvant.118 But the combination of caf-
feine, in a dose greater than 65 mg, and a
simple analgesic appears to be more effective
than a simple analgesic alone for treating pa-
325
tients with a variety of painful states such as
tension-type headaches and dental and epi-
siotomy pain.93 This same conclusion is also as-
sumed to be true of migraine pain, although
insufficient data are available to draw a firm
conclusion.
OTHER NON-STEROIDAL
ANTI-INFLAMMATORY AGENTS
A number of NSAIDs other than aspirin are
capable of reducing the pain of acute migraine
attacks (Table l4-7).26'82>83 Most double-blind
studies have found NSAIDs superior to place-
bos. The NSAIDs diminish both the severity of
attacks and their duration. The need for addi-
tional medication is also reduced.43'85
No oral NSAID has been found to be con-
sistently more effective than another. But al-
though as a group NSAIDs are reportedly sim-
ilar in efficacy, individual patient responses to
one NSAID or another vary markedly. Nor is
there a way to predict which patients might de-
velop side effects to which NSAID. Prescrib-
ing them is often a matter of trial and error. If
a particular NSAID is unsuccessful, an alter-
nate drug in the same class or a drug from an-
other class should be tried. Because it may take
several attempts to find the right match be-
tween patient and medication, NSAIDs should
be prescribed with an optimistic expectation
that they will be helpful. But along with hope-
ful optimism, the patient can be told that if this
medication isn't fully effective, there are oth-
ers that may be more compatible with his or
her makeup.
Large doses (750 to 1000 mg) of naproxen
(Naprosyn), in particular, have proved effec-
tive for acute migraine attacks without
aura.50'75'92'107 There is some question about
its effectiveness against migraine with aura.50
Naproxen sodium (Anaprox) is marketed sep-
arately but has the same pharmacological pro-
file as the parent compound.76 Naproxen so-
dium has the additional advantage of being
more rapidly absorbed than naproxen, and
probably therefore has a faster onset of action.
A dose of naproxen of 825 mg should be used.
When administered to normal fasting individ-
uals, the mean tmax is about 1 hour for
naproxen sodium and about 2 hours for
naproxen. Both naproxen and naproxen so-
dium appear to be more effective for migraine
326 Management of Acute Attacks

Table 14-7. Selected Non-steroidal Anti-inflammatory Agents Used for

Acute Migraine Attacks
Available Size
Agent Brand Name (mg) Dosage
Naproxen Naprosyn 250/375/500 750-100 mg at onset; if needed,
250-500 mg in 1 hour
( maximum 1500 mg per day)
Naproxen sodium Anaprox 275/550 825 mg at onset; if needed,
275-550 mg in 1 hour
(maximum 1375 mg per day)
Ibuprofen Motrin 200/400/600/800 800 mg at onset; if needed,
Advil 400-800 mg in 4 hours
(maximum 3200 mg per day)
Diclofenac-potassium Cataflam 50/75 50-100 mg at onset; if needed,
50 mg in 1 hour
(maximum 200 mg per day)
Ketorolac Toradol 15/30/60 60 mg IM at onset; if needed
60 mg in 4 hours
(maximum 180 mg per day)
IM, intramuscular administration.

when administered after an appropriate dose
of metoclopramide.
Ibuprofen (Motrin, Advil) is also effective in
treating bouts of migraine.43'56'74 In dosages
of 600 to 800 mg, ibuprofen produces a
modest, but significant, reduction in headache
pain and is significantly more effective than
placebo.43'56'91 Ibuprofen is rapidly absorbed
after oral administration in normal individuals.
A peak plasma concentration is seen after 1 to
2 hours.
Oral diclofenac-potassium (Cataflam) and
diclofenac-sodium (Volteran) have also been
found to be significantly more efficacious than
placebo.18'52'69 Diclofenac-potassium is an im-
mediate-release form of the drug, developed
to provide rapid onset of action. Diclofenac-
sodium is formulated as an extended-release
tablet to give a prolonged, slow release of the
active drug and is presumably less effective
than the potassium formulation for acute mi-
graine. One controlled study showed that
diclofenac-potassium (50 and 100 mg) has a
similar degree of analgesic potency and a
quicker onset of action than oral sumatriptan
(100 mg).28
Ketorolac (Toradol) is the only parenteral
NSAID available in the United States. It comes
in a cartridge needle unit for intramuscular
(IM) self-injection. Its advantage over oral
NSAIDs is its rapid onset of action45 min-
utes to peak blood levels. When administered
in a dose of 60 mg intramuscularly, it is re-
ported to be effective against acute mi-
graine.20'98
Indomethacin (Indocin) is available as a
suppository (50 mg) and can be useful for pa-
tients with severe nausea and vomiting. A sig-
nificant percentage of patients, however, have
trouble tolerating its side-effects that primar-
ily affect the gastrointestinal tract. Bleeding,
anorexia, nausea, vomiting, and diarrhea may
all occur. Indomethacin can also cause a sub-
stantial decrease of blood flow in kidneys and
heart, and platelet dysfunction.
Side Effects
Most patients tolerate NSAIDs when taken for
acute bouts of migraine. Gastrointestinal side
effects are the most common adverse reactions,
ranging from mild dyspepsia, epigastric pain,
and heartburn to nausea, vomiting, diarrhea,
and gastric bleeding. Such side effects occur
less frequently than those seen after ingestion
 Anti-emetics, Analgesics, Barbiturates, and Opiates
of aspirin. Gastroduodenal ulcers have devel-
oped in relatively few patients. Most of the se-
rious gastrointestinal side effects occur in pa-
tients who take NSAIDs on a chronic basis.
The NSAID-induced upper gastrointestinal
toxicity is caused by inhibition of mucosal syn-
thesis of prostaglandins, especially PGE and
PGI2- Prostaglandins protect the human gas-
trointestinal system by reducing gastric acid se-
cretion, increasing the production of mucus in
the stomach and bicarbonate in the duodenum,
and increasing submucosal blood flow. The
NSAIDs produce gastrointestinal damage by
inhibiting these defense mechanisms. There-
fore, one should be aware that medications
commonly used for the treatment of peptic ul-
cers, such as antacids and ^-antagonists, are
not effective for the prevention of NSAID-
induced gastric problems.35 A controlled trial
has demonstrated, however, that misoprostal
(Prilosec) significantly reduces the incidence of
gastroduodenal lesions and ulcers in patients
taking NSAIDs."
Chronic use of NSAIDs may interfere with
renal function. They are reported to cause
renal papillary necrosis, acute interstitial
nephritis, and the nephrotic syndrome and to
precipitate acute renal failure. Drowsiness,
headache, dizziness, fatigue, depression, and
ototoxicity have also been reported. Rare in-
stances of jaundice, angioneurotic edema, skin
rashes, thrombocytopenia, and agranulocytosis
have also been seen. A few patients complain
of fluid retention and edema.
Fatty acid cycloxygenase-2 (COX-2) inhibi-
torsrofecoxib (Vioxx) and celecoxib (Cele-
brex)have recently been released as NSAIDs
with a putative lower risk of gastrointestinal
bleeding, but no antiplatelet activity. Data re-
garding their lack of effect on the gastroin-
testinal tract may not be as clear as once
thought, and COX-2 inhibitors are likely to
share some of the renal adverse effects of non-
selective NSAIDs. COX-2 inhibitors have been
prescribed for migraine headaches, but no
published data are available. Rofecoxib is li-
censed for the treatment of acute pain; at pres-
ent, celecoxib is not.
Contraindications
Because inhibition of prostaglandin synthesis
renders the stomach and duodenum more sus-
327
Table 14-8. Contraindications to
the Use of Non-steroidal
Anti-inflammatory Drugs
Active peptic ulcer disease
Gastritis
Coagulation disorders
Impaired renal or hepatic function
Aspirin-sensitive asthma
Pregnancy
Anticoagulation therapy
Congestive heart failure*
Age greater than 65* years
* Relative contraindication.
ceptible to damage, active peptic ulcer disease
and gastritis are absolute contraindications to
the administration of NSAIDs (Table 14-8).
Hypersensitivity to aspirin is also an absolute
contraindication to use of NSAIDs; adminis-
tration of NSAIDs may induce a life-threatening
reaction reminiscent of anaphylactic shock.
The NSAIDs also decrease the synthesis
of thromboxane Aa (TXAg), a potent platelet-
aggregating agent. They should not be given to
patients with bleeding disorders. The NSAIDs
have little effect on renal blood flow in normal
individuals, but diminish it in individuals with
chronic renal or hepatic disease or with con-
gestive heart failure. They should not be pre-
scribed for migraineurs with impaired renal or
hepatic function or a history of renal or hepatic
disease. They should be used with caution in
elderly individuals who are much more sensi-
tive to the adverse effects of NSAIDs than
younger patients. The NSAIDs should not be
used in children because of the danger of de-
veloping Reye's syndrome.
BUTALBITAL-CONTAINING
ANALGESIC DRUGS
A half-dozen or so butalbital-containing prepa-
rations are prescribed widely for migraine at-
tacks (Table 14-9). These commonly used
preparations combine butalbital, a short-act-
ing barbiturate, with either aspirin or acet-
aminophen. Some also contain caffeine; one
includes codeine. It has been assumed that bu-
talbital is capable of reducing anxiety related
328 Management of Acute Attacks

Table 14-9. Butalbital-containing Analgesic Drugs

Agent Brand Name Dosage1"
Aspirin, 325 mg Fiorinal 1 or 2 tablets every 4 hours
Butalbital, 50 mg
Caffeine, 40 mg
Acetaminophen, 325 mg Esgic, Fioricet 1 or 2 tablets every 4 hours
Butalbital, 50 mg
Caffeine, 40 mg
Acetaminophen, 500 mg Esgic Plus 1 tablet every 4 hours
Butalbital, 50 mg
Caffeine, 40 mg
Acetaminophen, 325 mg Phrenilin 1 or 2 tablets every 4 hours
Butalbital, 50 mg
Acetaminophen, 500 mg Phrenilin Forte 1 or 2 tablets every 4 hours
Butalbital, 50 mg
Aspirin, 325 mg Fiorinal with Codeine 1 or 2 capsules every 4 hours
Butalbital, 50 mg
Caffeine, 40 mg
Codeine phosphate, 30 mg
"No more than six butalbital-containing analgesic tablets or capsules should be taken per day.

to bouts of migraine, making pain more bear-
able, but it may have effects on transmission
of nociceptive information that are more per-
tinent to its anti-migraine effects. Because ex-
cessive butalbital use can produce rebound
headaches, butalbital-containing medications
should be limited to the treatment of patients
with infrequent bouts. Although extensive
anecdotal evidence attests to their value in
acute attacks, the medications have not been
evaluated in appropriate controlled trials.33
Moreover, barbiturate-containing preparations
are not approved by the Food and Drug Ad-
ministration (FDA) as a treatment for mi-
graine headaches. Their potential for addic-
tion is high.96 After thorough evaluation of the
risks and benefits, the United Kingdom,
France, Germany, and Australia have with-
drawn barbiturate-containing analgesics from
their markets.
Side Effects and
Contraindications
Fatigue, lightheadedness, a "spaced-out" feel-
ing, and nausea are common side effects of
butalbital-containing analgesics. Euphoria fre-
quently develops.
There are a number of caveats to the use of
butalbital-containing medications (Table 14-
10). Barbiturates frequently cause a feeling of
euphoria. This explains the readiness with
which they are over-usedeven to the point
of full-blown addiction. Frequent or daily bu-
talbital use can produce disastrous effects, ren-
dering patients especially prone to rebound
headaches (drug-induced headaches) (see
Chapter 4). All patients must be specifically
warned of this risk; their physicians must care-
fully monitor the quantities prescribed. These
Table 14-10. Contraindications to
the Use of Butalbital-containing
Medications
History of analgesic overuse
Recovering alcoholics/drug addicts
Depression
Driving/operating machinery within several hours
of use
Elderly or debilitated patients*
'Relative contraindication.
 Anti-emetics, Analgesics, Barbiturates, and Opiates
drugs are not for patients who have a history
of analgesic drug overuse or are recovering al-
coholics or drug addicts. Barbiturate-containing
drugs should not be prescribed for patients
with depression, especially if there is any sus-
picion of suicidal tendencies. Furthermore, be-
cause barbiturates impair mental and physical
functioning, patients must be warned against
taking them if there is any possibility that they
will need to drive or operate machinery in the
next several hours. Finally, butalbital should be
used with extreme caution in elderly or debil-
itated patients, who may respond with obvious
excitement, depression, or confusion.
ISOMETHEPTENE MUCATE
Isometheptene mucate is marketed in combi-
nation with acetaminophen and dichloralphe-
nazone (Midrin). Isometheptene mucate is a
sympathomimetic agent that acts both as an a-
and j8-adrenoceptor agonist and as a vasocon-
strictor; dichloralphenazone is a mild, non-bar-
biturate sedative related to chloral hydrate.
The compound's efficacy possibly results in
part from isometheptene-induced intracranial
and extracranial vasoconstriction. If taken early
in an attack, this combination of medications
is more effective than placebo for mild-to-
moderate bouts of migraine.23'90'117 Isometh-
eptene mucate is not, however, a very potent
medication, and is not very efficacious for the
treatment of severe headaches. Some patients
find it quite satisfactory for mild-to-moderate
bouts when taken early in a migraine attack.
The usual adult dosage is two capsules at the
first sign of a headache and two capsules 45
minutes later if the head pain has not begun to
regress. A total of five capsules can be taken
for a given headaches. The drug should not be
administered more than two or three times a
week to avoid rebound effects.
Side Effects and
Contraindications
Isometheptene mucate is generally well toler-
ated, although drowsiness and nausea are pos-
sible side effects.
Because of its adrenergic properties,
isometheptene mucate should not be pre-
scribed for patients with severe hypertension,
329
Table 1 4-1 1 . Contraindications to
the Use of Isometheptene Mucate
Severe hypertension
Glaucoma
Use of monoamine oxidase inhibitors
Hepatic dysfunction
Renal disease
glaucoma, or for those patients taking
monoamine oxidase inhibitors (MAOIs). It
should not be given to patients with hepatic
dysfunction or renal disease (Table 14-11).
OPIOIDS/NARCOTICS
Treating acute migraine attacks with narcotics
is the subject of intense debate. Some author-
ities have stated that the risk of addiction ren-
ders narcotics ill-advised for any acute bout of
migraine.77 A Danish study estimates that each
year approximately 13 in one million inhabi-
tants become dependent upon narcotics origi-
nally prescribed for migraine.61 But a physi-
cian's abstract fear of the potential for
addiction should not condemn a particular pa-
tient to suffering. Even given a substantial risk
for addiction, infrequent use of small, oral
doses of narcotics, particularly codeine, is still
far better than unnecessary and prolonged dis-
tress for certain patients, including those who
have severe, debilitating pain and who obtain
no relief from other medications; those who
cannot tolerate the side-effects of triptans or
ergots and/or have contraindications to the use
of anti-migraine medications; and those who
are pregnant.119 Narcotics are valuable as res-
cue medication. Prescribing very limited
amounts of the lowest effective dose, together
with specifying the precise number of pills that
may be used between visits, is the key to pre-
venting addiction. In addition, the physician
must know the patient well and maintain reg-
ular follow-up appointments. Call-in requests
for additional medicine should be discouraged.
Parenteral narcotics should not be prescribed
either for self-administration or for adminis-
tration by a family member. In addition, pa-
tients who are recovering alcoholics or recov-
ering drug addicts should receive narcotic
medications only under the most extreme con-
330 Management of Acute Attacks

Table 14-12. Selected Oral Narcotic and Narcotic Combination Drugs

Agent Brand Name Dosage
Acetaminophen, 325 mg Tylenol #3 1 or 2 tablets every 4 hours
Codeine, 30 mg (maximum 6 tablets per day)
Acetaminophen, 325 mg Tylenol #4 1 or 2 tablets every 4 hours
Codeine, 60 mg (maximum 6 tablets per day)
Aspirin, 325 mg Fiorinal #3 1 or 2 capsules every 4 hours
Caffeine, 40 mg (maximum 6 capsules per day)
Butalbital, 50 mg
Codeine, 30 mg
Proproxyphene napsylate, 100 mg Darvocet-N 100 1 tablet every 4 hours
Acetaminophen, 650 mg (maximum 6 tablets per day)
Propoxyphene hydrochloride, 65 mg Darvon Compound 65 1 tablet every 4 hours
Aspirin, 389 mg (maximum 6 tablets per day)
Caffeine, 32.4 mg
Hydrocodone, 5 mg Vicodin 1 to 2 tablets every 4 hours
Acetaminophen, 500 mg (maximum 8 tablets per day)
Hydrocodone, 7.5 mg Vicodin ES 1 tablet every 4 to 6 hours
Acetaminophen, 750 mg (maximum 5 tablets per day)
Oxycodone, 5 mg Percocet 1 tablet every 6 hours
Acetaminophen^ 325 mg Tylox (maximum 4 tablets per day)
Oxycodone, 4.5 mg Percodan 1 tablet every 6 hours
Aspirin, 325 mg (maximum 4 tablets per day)

ditions, even if their sobriety or freedom from
drugs has extended over a period of years. Even
a small amount of narcotic may reestablish
craving for alcohol or narcotics, and result in
return to active addiction.
The combination of a simple analgesic with
codeine (such as the mixture of acetaminophen
or aspirin and codeine), or the combination of
aspirin, caffeine, and butalbital with codeine
may be used if analgesics more potent than as-
pirin or NSAIDs are required (Table 14-12).
The analgesic effects of combining an opioid
with an analgesic appears to be substantially
greater than increasing the dose of either drug
administered by itself.3 Propoxyphene (Dar-
von) has been favored by some clinicians, per-
haps because it was originally thought not to
have the dependence liability of other nar-
cotics. Clinical experience, however, has indi-
cated that propoxyphene has potential for
abuse and addiction, giving it no advantage
over, for example, codeine in this regard. Clin-
ical trials have shown that 90 to 120 mg of pro-
poxyphene orally is equipotent to 60 mg of
codeine. More potent narcotic analgesics such
as oxycodone combined with aspirin (Perco-
dan) or acetaminophen (Percocet, Tylox), or
hydrocodone and acetaminophen (Vicodin)
may be used, but their use should be restricted
to the most severe cases. Finally, because
meperidine (Demerol) is poorly absorbed, it is
not very effective as an oral medication.
Because of a supposed lower potential for
abuse, some clinicians advocate the use of
agonist-antagonist opioid analgesics for acute
migraine attacks. Drugs of this kind include bu-
torphanol (Stadol, Dorphanol), nalbuphine
(Nubain), and pentazocine (Talwin). Mixed
agonist-antagonist opioid analgesics behave as
partial agonists at some opioid receptors, and
 Anti-emetics, Analgesics, Barbiturates, and Opiates
antagonists at others. Analgesics that are par-
tial agonists do bind to opiate receptors but
have only low intrinsic activity (efficacy). As a
result, their dose-response curves exhibit an
analgesic ceiling effect that is lower than the
maximal effect that a full agonist produces.
Moreover, most mixed agonist-antagonist opi-
oid analgesics have been shown to have po-
tential for abuse and addiction. They have no
significant advantages over the established full
agonist analgesics, especially since their antag-
onist activity makes the possibility of supple-
mentation with a pure agonist problematic.
The synthetic, mixed agonist-antagonist bu-
torphanol is available in a nasal spray (Stadol).
It has been reported to be safe and effective
for acute, moderate-to-severe migraine. In
controlled studies, intranasal butorphanol re-
duces migraine pain more than placebo.27'46
Pain is relieved rapidly with an onset of action
within 15 minutes; and the nasal route makes
administration available to patients who are
vomiting. Unfortunately, many patients have
side effects.27 These include dizziness, extreme
drowsiness, nausea, and vomiting. Hallucina-
tions and dysphoria have also been reported.87
The FDA has scheduled butorphanol as a
Schedule IV drug, and unpublished experience
indicates that it has substantial potential for
abuse and addiction, particularly as it is dis-
pensed in a vial that contains approximately 15
doses. It should be prescribed only as rescue
medication, and then only for selected pa-
tients.24 Patients must be warned and educated
about the ability of the drug to induce depen-
dency when misused. They also must be care-
fully monitored throughout their course of
treatment.
Tramadol (Ultram) is frequently prescribed
as a treatment for acute migraine. Tramadol is
a synthetic analogue of codeine that binds with
weak affinity to opiate receptors, but also in-
hibits norepinephrine and 5-HT reuptake. It is
rapidly absorbed after oral doses, with analge-
sia beginning after 1 hour. Common adverse
effects include dizziness, nausea, dry mouth,
and sedation. The abuse potential is thought to
be low, but it has been implicated in the pro-
duction of rebound headaches and in the de-
velopment of daily headache. It is an effective,
if expensive, alternative analgesic that does not
seem to offer any particular advantages over
codeine in the treatment of acute migraine.
331
Side Effects
Some patients develop euphoria at times from
opiates; this sensation may be advantageous
during an acute migraine attack. Some pa-
tients, however, suffer unpleasant dysphoria.
Considerable sedation, drowsiness, confusion,
dizziness, and unsteadiness may also occur.
Pruritis mostly limited to the face, palate, and
torso can occur, and is sometimes very dis-
tressing. This side effect can often be con-
trolled with a low dose of an antihistamine such
as diphenhydramine (Benadryl). Nausea and
vomiting are also frequently seen. And, of
course, constipation is the most common side
effect of all opiates.
CORTICOSTEROIDS
No objective data are available about corticos-
teroids and acute migraine. Theoretically, oral
steroids should not act quickly enough to be of
value, requiring at least 12 to 24 hours to ter-
minate an attack. Most attacks of migraine are
short enough that they ease or cease before
corticosteroids can begin to exert an effect.
Nevertheless, short courses of corticosteroids
such as methylprednisolone, prednisone, or
dexamethasone have been recommended for
symptomatic treatment of migraine, and they
are certainly used widely.3"'55'94 Corticos-
teroids can lead to osteonecrosis even if they
are used for short periods of time, or inter-
mittently, such as for 3 to 4 days per month.
In view of the seriousness of osteonecrosis,
steroids should probably not even be consid-
ered for the usual migraine attack. They should
be used only when alternate therapies cannot
be used or are ineffective. They may have a
role in treating status migrainousus (see Chap-
ter 25).
MAGNESIUM
Administration of magnesium for acute mi-
graine attacks has been studied with varying re-
sults.21'30'37'71'80 When given intravenously, it
appears to benefit some patients and is well tol-
erated, but remains a controversial therapy.
There are data that it is mainly effective in pa-
tients with low serum ionized magnesium lev-
els.70
332 Management of Acute Attacks
MECHANISMS OF ACTION OF
MEDICATIONS FOR ACUTE
MIGRAINE ATTACKS
Anti-emetics
The chemoreceptor trigger zone located in the
area postrema of the fourth ventricle is in-
volved in production of nausea and vomiting
(see Chapter 11). The area postrema is abun-
dantly supplied with receptors for dopamine,
histamine, and acetylcholine, and the chemore-
ceptor trigger zone has an especially high
density of dopamine, histamine, and mus-
carinic cholinergic receptors. This presumably
accounts for findings that dopaminergic, hista-
minergic, and muscarinic antagonists are anti-
emetic to varying degrees. No single anti-
emetic drug binds to all three neurotransmitter
receptors, but all bind to at least one of the
three. A number of drugs with significant
dopaminergic antagonistic properties are espe-
cially beneficial. The anti-nausea effects of
metoclopramide and the phenothiazine deriv-
atives have traditionally been thought to result
from their blocking action at Da-receptors in
the chemoreceptor trigger zone.13'34
In its role as a prokinetic agent, metoclo-
pramide's cellular mechanism of action is not
fully understood, but it is known to be an ag-
onist at 5-HT4 receptors on intrinsic myenteric
neurons. Actions on these receptors is postu-
lated to cause release of acetylcholine. The re-
lease of acetylcholine, and the subsequent ac-
tivation of cholinergic receptors on smooth
muscle, causes constriction of gastric smooth
muscle and facilitates gastric emptying.10
Aspirin, Non-steroidal
Anti-inflammatory Drugs,
and Acetaminophen
Aspirin and other NSAIDs are thought to have
analgesic effects because their inhibitory ac-
tions on the synthesis of prostanoids give them
anti-inflammatory properties. The pharmaco-
logical target of NSAIDs is fatty acid cycloxy-
genase (COX, also known as prostaglandin en-
doperoxide synthase] which catalyzes the
two-step conversion of arachidonic acid to
prostaglandin Ha, the common intermediate in
all prostaglandin biosynthesis. The first step of
this process takes place in the COX active site
when two molecules of oxygen are added to
arachidonate to form the bicyclic intermediate,
prostaglandin Gg. This intermediate diffuses to
the peroxidase active site located on the oppo-
site side of the enzyme, where it is reduced to
prostaglandin H that, in turn, is converted
to physiologically active prostaglandins and
thromboxanes. Aspirin and other NSAIDs in-
hibit only the COX active site. They do not af-
fect peroxidase activity; nor do they inhibit
lipoxygenase pathways or suppress leukotriene
formation.
Two isoforms of COX are known: COX-1,
which is constitutively expressed in blood ves-
sels, platelets, stomach, and kidney; and COX-
2, which is constitutively expressed in the kid-
ney and in neurons of the cerebral cortex and
limbic regions of the brain. It is also constitu-
tive at low activities in most cells, but is in-
ducible (up-regulated) to high activities by cy-
tokines, interleukins, and endotoxins during
inflammatory reactions.45 COX-2 may be the
primary isoform of the enzyme at sites of in-
flammation. In general, the potency of
NSAIDs in inhibiting COX activity parallels
their clinical potency. The NSAIDs act at the
COX active site, and most inhibit both COX-1
and COX-2. But there are differences among
them with regard to their specificity (Table
14-13). For example, low doses of aspirin and
Table 14-13. Cyclooxygenase
Selectivity of Non-steroidal
Anti-inflammatory Drugs
NSAID Ratio"
Aspirin 3.12
Naproxen 1.79
Indomethacin 1.78
Ibuprofen 1.69
Keterolac 1.64
Celicoxib 0.11
Diclofenac 0.05
Roficoxib 0.05
"Expressed as the ratio of the 50% inhibitory concen-
tration of NSAID required to block cyclooxygenase-2
(COX-2) to the 50% inhibitory concentration of NSAID
required to block COX-1 in whole blood. A ratio <1 indi-
cates selectivity for COX-2.
Data from Feldman and McMahon (2000).31
 Anti-emetics, Analgesics, Barbiturates, and Opiates
indomethacin inhibit COX-1 more potently
than COX-2.
Different NSAIDS have different molecular
actions. Aspirin irreversibly inactivates COX-1
and COX-2 by acetylating serine moieties lo-
cated near the active site of the enzyme.22 This
modification interferes with the proper bind-
ing of arachidonic acid.62 Indomethacin causes
a conformational change in the COX protein.
The vast majority of NSAIDs, however, are or-
ganic acids that compete with substrate for the
COX active site. By blocking the COX active
site, NSAIDs reduce the conversion of arachi-
donic acid to prostaglandins, prostacyclin
(PGIg), and thromboxane A (TXA). This
mechanism is thought to prevent the
prostanoid-induced sensitization of nociceptive
nerve terminals in the dura.
The effectiveness of aspirin and other
NSAIDs against migraine pain has buttressed
the idea that an inflammatory reaction in the
cranial vasculature features prominently in
causing that pain. Indeed, the designation of
this class of drugs as anti-inflammatories calls
attention to how they are believed to work. As-
pirin's ability to selectively block neurogenic
inflammation in dural tissue has been demon-
strated. Electrical stimulation of the trigeminal
ganglion induces plasma extravasation in both
intracranial (dura mater) and extracranial (eye-
lid, lip, conjunctiva) cephalic tissues.11 The
leakage in the dura, but not in extracranial tis-
sues, is attenuated by aspirin. But the general
view that the analgesic effects of NSAIDs could
be universally attributed to their inhibitory ef-
fects on the synthesis of peripherally formed
prostaglandins has come under challenge. Not
only is it difficult to demonstrate a significant
correlation between the analgesic efficacy of
various NSAIDs and their inhibitory activity
against prostaglandin synthesis in vitro, but
human and animal studies have presented ev-
idence for additional CNS actions.72
Cerebral potentials evoked by electrical in-
tracutaneous stimulation, tooth pulp stimula-
tion, and painful stimulation of the nasal mu-
cosa are reduced by orally administered
aspirin.9-57 Several investigators have noted
that central pain signals in the thalamus of ex-
perimental animals can be inhibited by sys-
temic administration of NSAIDs.12'41'51 In ad-
dition, spontaneous and mechanically evoked
activity in trigeminal neurons with input from
the dura is inhibited in experimental animals
333
by systemic administration of aspirin in doses
similar to those used in clinical situations.29 Ac-
tivity evoked in the upper cervical spinal cord
by electrical stimulation of the superior sagit-
tal sinus in experimental animals is also blocked
by aspirin.53 The mechanism of aspirin's cen-
tral actions is not known, but autoradiographic
investigations have demonstrated that aspirin
binds with high affinity to central structures,
such as the dorsal horn, involved in the trans-
mission of nociceptive information from
trigeminal afferents. 8
In addition to their anti-inflammatory ac-
tions, there has been speculation that NSAIDs
are helpful in migraine, at least in part, be-
cause they disturb platelet function. The
NSAIDs do indeed prevent the formation by
platelets of TXAa and, as a result, reduce their
ability to aggregate. But because much larger
doses are needed to diminish head pain than
to inhibit platelet aggregation, this phenome-
non may not be of major importance in mi-
graine treatment.
Acetaminophen's mechanism of action is
poorly defined. It has analgesic effects that are
similar to those produced by aspirin, but it has
only weak anti-inflammatory effects. Acet-
aminophen may inhibit prostaglandin synthe-
sis in the CNS, but because it is only a weak
inhibitor of COX-1 and COX-2, the compound
is thought to be effective only in an environ-
ment that is low in peroxides, such as the hy-
pothalamus. In peripheral tissues, acetamino-
phen is unable to inhibit the formation of
prostanoids. By an inhibitory action on nitric
oxide synthesis, it may have the ability to in-
terfere with nociception associated with N-
methyl-D-aspartate (NMDA) and substance P
receptor activation.4 And although some re-
ports suggest an antinociceptive action that in-
volves 5-HT, acetaminophen does not bind to
5-HT receptors.81'84
Butalbital
The GABAA receptor complex possesses spe-
cific binding sites for a variety of neuroactive
substances, including sedative-hypnotic drugs
such as barbiturates. Barbiturates allosterically
modulate the GABAA receptor complex and
can exert at least two actions on GABAA re-
ceptors: barbiturates enhance the activation of
the receptor by GABA, and, at high concen-
334 Management of Acute Attacks
trations in the absence of GABA, they directly
activate the receptor.
Butalbital is a weak barbiturate whose ef-
fects on GABAA receptors have not been
specifically studied. It may, however, exert its
effects on headache pain through binding to
the GABAA receptor. Butalbital reduces neu-
ronal activation produced by excitation of
neuropeptide-containing dural afferents in
the trigeminal nucleus caudalis.17 Its site of
action may be presumed to be in the dorsal
horn and the nucleus caudalis where high
densities of GAB AA receptors have been dem-
onstrated, and at the presynaptic terminals of
putative GABA-containing interneurons in
the nucleus caudalis.2'113 Presumably the ef-
fects of GABA are exerted at both pre- and
postsynaptic sites.
Opioids
The effects of opioid analgesics (narcotics, opi-
ates) are mediated by specific receptors located
on cell membranes of presynaptic terminals,
cell bodies, and dendrites of CNS neurons.
Opiate binding studies have resulted in the
identification of three distinct, well-defined
classes of opioid receptors: JJL, 5, and (K); there
are indications of subtypes within each class.
Each type has unique pharmacological prop-
erties, is differentially distributed in the CNS,
and is implicated in a broad range of behaviors
and functions. Postmortem, autoradiographic
investigations in humans and other primates
Table 14-14. Characteristics of Opioid Receptors
p 8
Transduction G protein-coupled
decrease in
Mechanism cAMP
Distribution PAG
Dorsal horn
Thalamus
Striatum
Locus coeruleus
Raphe nuclei
LRF, lateral reticular formation; PAG, periaqueductal gray.
have demonstrated high concentrations of opi-
oid receptors in structures associated with pro-
cessing nociceptive information: the superficial
layers of the dorsal horn, the medial and in-
tralaminar nuclei of the thalamus, the cortical
projections of the thalamus (namely the cin-
gulate cortex and the prefrontal cortex), and
the periaqueductal gray and its projections
(Table 14-14).
A wide variety of evidence demonstrates that
the standard opioid receptors are coupled to G
proteins which, in turn, modulate intracellular
effectors.16 Depending upon the type of neu-
ron under study, all three receptor classes have
been shown to inhibit adenylate cyclase, de-
crease the conductance of voltage-gated Ca2+
channels, or activate Ca2+-dependent inwardly
rectifying K + channels.54 These effects lead to
an inhibition of neuronal activity and blockade
of transmitter release. But although all three
types of opioid receptor have major effects on
pain, activation of the /^-receptor invariably
produces the most effective analgesia in both
animal models and human clinical settings. /JL-
Receptors, for example, are selectively sensi-
tive to morphine and its alkaloid analogs; their
activation presumably mediates the effects of
opioids in the CNS.120
Because activation of /^-receptors by sys-
temically administered opiates produces anal-
gesia mediated mainly by effects in supraspinal
structures (including the periaqueductal gray,
the nucleus raphe magnus, and the locus
coeruleus), opiates are believed to activate the
descending nociceptive modulating systems
K
G protein-coupled G protein-coupled
decrease in decrease in
cAMP cAMP
Cortex Hypothalamus
Striatum Nucleus accumbens
LRF Substantia nigra
Dorsal horn Raphe nuclei
Dorsal horn
 Anti-emetics, Analgesics, Barbiturates, and Opiates
(see Chapter 11). ju-Opioid agonists also pro-
duce impressive analgesia when administered
intrathecally or injected into the dorsal horn of
the spinal cord. As for the trigeminal system,
/A-receptors are located in the nucleus caudalis.
Morphine administered into the spinal trigem-
inal nucleus caudalis blocks C-fiber inputs that
relay in the superficial layers of the nucleus.19
In particular, /A-receptors on the terminals of
primary afferent fibers mediate presynaptic in-
hibition of peptidergic and glutamatergic pri-
mary afferent input to dorsal horn neurons. (JL-
Receptor activation also appears to be
responsible for many of the other clinical and
side effects caused by opiatese.g., euphoria,
respiratory depression, constipation, pruritis,
nausea and vomiting, and physical depen-
dence.
Activation of (/<)i-receptors produces anal-
gesia at a spinal level; activation of (K)S-
receptors relieves pain by means of supraspinal
mechanisms. (K)-Receptors are also believed
to be responsible for miosis and sedation. 5-
Receptor activation at both spinal and
supraspinal levels produces analgesia; the
spinal level may be more significant. Recently,
systemically administered opiates have also
been found to have peripheral actions.101
These effects, which involve /a-, 5-, and (K)-
receptors, are presumably exerted on the pe-
ripheral terminals of primary afferent fibers.
The result is inhibition of neurogenic inflam-
mation in peripheral tissues. It is not known
yet whether such anti-inflammatory effects oc-
cur intracranially.
A fourth receptor, opioid receptor-like-1
(ORL1), that is 50% identical to the known opi-
oid receptors has recently been identifed. It
does not bind any of the known opioid ligands.
The ORL1 receptors have been detected in
many central regions (e.g., spinal dorsal horn,
periaqueductal gray, raphe nuclei, and the
trigeminal system) involved in migraine.73
A search for ORLl's endogenous ligand has
resulted in the identification of nociceptin/or-
phanin FQ (OFQ/N), a peptide that closely re-
sembles dynorphin. Although early studies in-
dicated that OFQ/N was hyperalgesic when
injected in supraspinal structures, unexplained
contradictory findings make this interpretation
of the data problematic. However, supra-
spinally injected OFQ/N has an antiopioid ac-
tion.40 The role of OFQ/N in nocieption re-
mains enigmatic.
335
SUMMARY
A number of effective analgesic agents are
available that can substantially lessen the
severity and duration of acute migraine at-
tacks, and in some cases even eradicate the
symptoms. But no unanimity exists as to the
best treatment. Many of the medications re-
quire subtlety of use, and many drugs have the
potential to cause unpleasant adverse effects.
Some of the agents used for the treatment of
acute migraine attacks have serious potential
for abuse and, if used in an injudicious man-
ner by the clinician, will only succeed in mak-
ing patients much worse in the long run. But
when a suitable combination of medications is
used carefully, legions of headache sufferers
can be helped. All that is necessary is that the
clinician keep a vigilant watch for possible
difficulties.
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Chapter 1 5
Ergots
ERGOTAMINE
Metabolism
Pharmacokinetics and Clinical Use of
Ergotamine
Ergotamine for Migraine with Aura,
Migraine with Prolonged Aura, and
Complicated Migraine
Adverse Reactions
Until the triptans were introduced in the
1990s, ergotamine tartrate had a 70-year his-
tory of being regarded by many as the drug of
choice for the treatment of acute migraine. Al-
though recent controlled clinical trials show
that ergotamine plus caffeine is efficacious in
less than 50% of patients, many clinicians still
consider the combination a worthwhile med-
ication for acute migraine attacks. Some au-
thorities, however, believe that it is the drug of
choice in only a limited number of patients who
have infrequent or long-duration migraine at-
tacks and are likely to comply with dosing re-
strictions.73 Dihydroergotamine (DHE) was
introduced in the 1940s, and has proven in-
valuable for acute migraine attacks, drug re-
bound headaches, and status migrainosus.
ERGOTAMINE
Ergotamine is not an ideal drug, but it is much
less expensive than the triptans (Table 15-1).
Ergotamine's use, however, is limited by the
necessity for early administration, patient dis-
satisfaction with its side effects, incomplete and
unreliable absorption that results in poor
bioavailability, an erratic pharmacokinetic pro-
Contraindications
Ergotamine Overuse
DIHYDROERGOTAMINE
Pharmacokinetics and Metabolism
Clinical Use of Dihydroergotamine
Adverse Events
Contraindications
SUMMARY
file, and a small margin of safety. Moreover, it
is easy for patients to become physically de-
pendent and overuse ergotamine, which leads
not only to the development of rebound head-
aches but also to toxicity.
Metabolism
The molecular properties of ergotamine have
a bearing on the drug's clinical use. Each er-
gotamine molecule consists of a combination
of peptide and lysergic acid moieties. For ther-
apeutic purposes, two ergotamine molecules
are combined with tartaric acid. Considering
that ergotamine has such a fragile molecular
structure, it is not unexpected that the com-
pound is rapidly metabolized. When adminis-
tered orally, ergotamine is absorbed from the
upper gastrointestinal tract. Because it tra-
verses tiie portal circulation to the liver before
it reaches the systemic circulation, much of this
metabolism occurs in the liver (first-pass ef-
fect). More than 90% of oral ergotamine is sub-
ject to first-pass metabolism. Several of the
metabolites, however, have biologic activity
similar to that of the parent compound. Ergot-
amine and its metabolites are excreted princi-
339
340 Management of Acute Attacks

Table 15-1. Cost of Ergots

Medication Brand Name (Dosage) Average Wholesale Price ($)
Ergotamine/caffeine Cafergot (1 tablet) 0.88
Ergotamine/caffeine Cafergot (1 suppository) 5.32
DHE (1.0 mg/mL) DHE 45 (1 mL) 13.82
DHE nasal spray (0.5 mg/spray) Migranal (2 sprays) 35.41
DHE, dihydroergotamine.
Data from 2000 Red Book, Medical Economics Data, Inc. (non-generic prices)

pally in the feces after biliary elimination.47
Only a small amount is excreted unchanged in
the urine. Rectally absorbed ergotamine avoids
the splanchnic and portal circulation, passing
to a large degree directly into the systemic cir-
culation. The lack of a first-pass effect accounts
for the higher plasma levels of drug after ad-
ministration per rectum compared to the lev-
els reached when the same dose is adminis-
tered per os.
The metabolic breakdown of ergotamine is
reported to proceed in two phases: the a phase
has a plasma half-life of approximately 1.5 to
2.5 hours; the plasma half-life in the (3 phase
is 20 to 30 hours.1-43-46 Even though peak
plasma levels of ergotamine decline, the drug
produces peripheral arterial vasoconstriction
for 24 hours or even longer.71 The dissociation
between the levels of ergotamine in plasma and
the compound's ability to maintain peripheral
vasoconstriction is largely unexplained. Possi-
bly one or more of ergotamine's metabolites
remains active and is responsible for the pro-
longed peripheral vasoconstrictor actions. An
alternative hypothesis is that the drug dissoci-
ates from receptor sites extremely slowly.
Pharmacokinetics and Clinical
Use of Ergotamine
Although for decades clinicians have been
aware that ergotamine can be an effective drug,
the number of appropriately controlled clinical
trials is not extensive. Most, but not all, trials
have shown that ergotamine or ergotamine plus
caffeine are superior to placebo.19'27'36'55'59'77
Two comparative trials have found ergotamine
to be more effective than aspirin.25'26 The
response rate and therapeutic gain for oral
ergotamine are approximately the same as
for oral non-steroidal anti-inflammatory drugs
(NSAIDs) and propoxyphene, and about 15%
less than for triptans.25^7'45'48'59'75
Ergotamine is available in the United States
in oral, sublingual, and rectal suppository for-
mulations (Table 152). In the past, ergota-
mine was prescribed as an inhalant, but this
formulation is no longer sold in the United
States. Nor is parenteral ergotamine available.
Because ergotamine is poorly and erratically
absorbed when administered orallyits bio-
availability is less than 1%plasma levels vary
markedly (Table 15-3).32-58 Although most pa-
tients prefer oral medication, the poor bioavail-
ability limits its clinical usefulness. Following
sublingual administration, ergotamine has
been reported to be undetectable in plasma.72
The bioavailabiliry after rectal administration is
somewhat higher. The compound's bioavail-
ability also varies widely among patients when
it is administered by the same method.2'23 The
unpredictable absorption makes consistent
blood levels difficult to achieve and may ac-
count for the surprisingly wide variations of
clinical response among patients, and even in
the same patient during different attacks.4
To be maximally effective, ergotamine must
be administered in adequate doses. Data indi-
cate that unless a peak plasma concentration of
0.20 ng/mL or higher is achieved within 1 hour,
treatment is usually ineffective.4 Peak concen-
trations measured after oral administration of
2 mg of ergotamine vary widely in different in-
vestigations.2'46-58 The peak is often not
reached quickly enough to be of benefit (Table
153). Oral ergotamine is absorbed so slowly
that plasma levels do not peak before 1 to 3
hours.1'4'58 In contrast, after rectal administra-
tion, peak plasma concentrations are reached
Table 15-2. Ergot Preparations Available in the United States
Brand Dosage Dosage
Agent Name per Attack per Week
Oral
Ergotamine, 1.0 mg Cafergot 1 to 6 tablets (maximum Maximum 10 mg per week
Caffeine, 100 mg Wigraine 6 tablets per day) (2 days per week)

Ergotamine, 0.3 mg Bellergal-S 1 tablet at onset; may repeat

Belladonna, 0.2 mg in 8 hours (maximum
Phenobarbital, 40 ni 2 tablets per day)

Sublingual
Ergotamine, 2.0 mg Ergomar 1 tablet at onset; may repeat Maximum 10 mg per week
in 30 minutes (maximum (2 days per week)
3 tablets per day)

Rectal
Ergotamine, 2.0 mg
Caffeine, 100 mg
Cafergot 1/2 to 1 suppository at onset; Maximum 10 mg per week
suppositories may repeat in 1 hour (2 days per week)
Wigraine (maximum 2 per day)
suppositories

Parenteral
DHE, 1.0 mg D.H.E. 45 1 mg SC, IM, or IV; may 6 mg per week (2 days
per ml repeat in 30-60 minutes per week)* (maximum
(maximum 3 mg per day 2 mg per week IV)
SC or IM)

Intranasal
DHE, 0.5 mg Migranal 1 mg (2 sprays) at onset; 4 mg per week
per spray repeat in 15 minutes (2 days per week)
(maximum 2 mg per day)
DHE, dihydroergotamine; IM, intramuscular administration; IV, intravenous administration; SC, subcutaneous ad-
ministration.
"Larger amounts per week may be given for treatment of acute or chronic intractable headaches (see Chapter 25).

Table 15-3. Ergotamine and Dihydroergotamine: Pharmacokinetics

Drug
F
(%)
'max
(minutes)
tv,
(hours) <Szz> AUC
/tg/L-hour
Oral ergotamine (2 mg) <1 60-180 0.36
Rectal ergotamine (2 mg) 1-3 60 10.5 0.45
IM DHE (1 mg) 24 10-23 2.9-4.4 13.6
IV DHE (1 mg) 100 1-2 13-15 >10
Intranasal DHE (1 mg) 40 45-56 10 1.02 5.1
AUC, area under the plasma concentration-time curve; Cmax, peak plasma concentration; DHE, dihydroergotamine;
F, bioavailability; tmax, time to reach the peak plasma concentration; t\, elimination half-life.
Data from Aellig and Nuesch (1977),1 Ala-Hurula et al. (1979, 1982),2-4 Billow et al. (1986),10 Ekbom et al. (1983),17
Humbert et al. (1996),31 Ibraheem et al. (1983),32 Littele et al. (1982),42 Sanders et al. (1986),58 Schran et al. (1994)62
and Wyss et al. (1991).83

341
342 Management of Acute Attacks
in approximately 1 hour. The plasma levels af-
ter rectal administration are also higher than
after oral administration.32'58
Because its pharmacokinetics and pharma-
codynamics vary greatly, therapeutic doses for
different individuals range considerablyfrom
0.5 to 6.0 mg per attack/9 Attempts should be
made to determine an appropriate, subnause-
ating dose either when the patient is headache-
free or by titrating the dose during several
headaches. This is necessary because ergota-
mine in a dose that causes significant nausea
and vomiting may worsen the intensity of the
head pain.
Most physicians are agree that the maximum
total dose for any one attack should not exceed
6.0 mg orally or 4.0 mg per rectum. An ade-
quate dose must be taken as soon as possible,
but it is frequently stated that increments can
be added in half-hourly or hourly supplements.
If the initial dose is without any effect at all,
however, subsequent doses are frequently dis-
appointing as well. For this reason, many clin-
icians prefer to prescribe a single dose of oral
ergotamineusually 2 to 3 mg (provided that
this is a subnauseating dose for the particular
patient)rather than divided doses. Experi-
ence with divided doses during several attacks
allows an individual to establish the amount re-
quired to produce head pain relief. During
subsequent bouts, the total dose can be taken
at the onset. An occasional patient responds
well to Bellergal-S, a combination of ergota-
mine (0.3 mg), phenobarbital (40 mg), and bel-
ladonna (0.2 mg).
The slow absorption of ergotamine from the
upper gastrointestinal tract and the high inci-
dence of vomiting associated with bouts of mi-
graine substantially limit the efficacy of oral er-
gotamine. The formulation is most appropriate
for patients with slowly evolving migraine with-
out the early onset of nausea. Because of
greater absorption with resulting higher serum
levels, administration of ergotamine by sup-
pository (Cafergot, Wigraine) appears to be the
best method for personal use. Suppositories
contain 2 mg of ergotamine and 100 mg of caf-
feine; some patients find that they can only tol-
erate one-half or one-third of a suppository.
Suppositories, however, must be refrigerated if
the ambient temperature is high enough to
soften them. Most individuals who use ergota-
mine suppositories also require prescription
for an oral ergotamine preparation that can be
used when away from home.
Ergotamine's effect in terminating bouts of
migraine is thought to be improved by the con-
current intake of caffeine, although it is not
known why this is so. Caffeine is said to aug-
ment the rate of absorption of oral ergotamine
even though the combination of caffeine and
ergotamine does not produce higher peak lev-
els.3'60 Administering ergotamine together
with metoclopramide is also superior to the use
of each alone for acute migraine.24 Metoclo-
pramide not only alleviates the nausea of mi-
graine but is also thought to optimize the ab-
sorption of oral ergotamine by increasing the
rate of its passage through the stomach.
Ergotamine for Migraine with
Aura, Migraine with Prolonged
Aura, and Complicated Migraine
Some physicians hesitate to use ergotamine for
patients who have attacks of migraine with
aura, and most are understandably reluctant to
prescribe it for hemiplegic or basilar migraine
in which vasoconstriction is tacitly assumed to
be important in the pathogenesis of the neu-
rological symptoms. The apprehension stems
from a fear of causing increased intracranial
vasoconstriction that could lead to permanent
neurological deficits. Ergotamine, however,
primarily constricts the external carotid artery
and its branches.40 The drug does not signifi-
cantly reduce cerebral blood flow in normal in-
dividuals or in migraineurs during at-
tacks.6'57'74 A few isolated case reports do
attribute the development of neurological
deficits and occlusion or spasm of arteries in
the carotid system to the use of ergotamine. So
it is conceivable that some migraineurs have a
cerebrovascular reactivity to ergot alkaloids
that is different from that of non-migraineurs,
a possibility that has not been studied in depth.
Despite these isolated examples, as a rule, er-
gotamine can be used with relative impunity
for patients with aura who are still in the aura
phase of the attack. In contrast, although there
are no hard data, it might be prudent to avoid
use of ergotamine for patients who have attacks
characterized by prolonged aura or for those
who suffer from complicated migraine.70

Adverse Reactions
Although side effects to ergots do occur with
considerable frequency, ordinarily the unto-
ward effects are not alarming and do not re-
quire discontinuance of the drug. Adverse
events are mostly gastrointestinal. Increased
severity of nausea and vomiting or develop-
ment of these symptoms are considered the
most common side effects. Their frequency ap-
pears to be related to the dose and adminis-
tration route, but all estimates of the incidence
of ergotamine-induced nausea and vomiting
are unreliable because these same symptoms
are so regularly a part of the migraine attack
itself. This underscores the value of determin-
ing a subnauseatmg dose when the patient is
headache-free. Ergotamine is also estimated to
cause one or more of the following symptoms
in 5% to 10% of patients: abdominal cramps,
diarrhea, dizziness, cramps in the thigh and calf
muscles, and paresthesias involving die fingers
and toes. Other side effects such as syncopal
episodes, dyspnea, chest pain, limb claudica-
tion, and tremor are less common.9 Drowsiness
may occur in some patients.
Ergotamine is highly toxic when taken in
large, or frequently repeated, doses. In addi-
tion, a small number of patients have an idio-
syncratically great sensitivity to ergotamine. In
either situation, patients may develop the more
serious picture of clinical ergotism, whose man-
ifestations are caused by either vasoconstric-
tion of peripheral arteries or other vascular
beds or development of an encephalopathy. In-
dividuals with ergotamine hypersensitivity are
particularly susceptible to the drug's vasocon-
strictive effects and can develop toxic symp-
toms after taking recommended doses for only
brief periods of time. Ergotism, however, is
much more frequent among patients who take
the drug daily.
The circulatory changes produced by hyper-
sensitivity or by chronic use of immoderate
amounts of ergot alkaloids can be impressive.
Ergots can produce profound peripheral vaso-
spasm that especially affects the lower extrem-
ities. Vasoconstriction of leg arteries is long-
lasting (24 hours).69 Secondary occlusion and
thrombosis of medium and small arteries may
be superimposed upon the vasospasm. The va-
sospastic segment of the artery typically devel-
ops in the lower one-third of the leg; fortu-
Ergots 343
nately, some collateral circulation is usually
present around it. Intermittent paresthesias of
the distal extremities, coolness of the digits,
and claudication of the legs and arms are fol-
lowed by loss of arterial pulses in the affected
limbs. Although these phenomena are at times
reversible, the end result may be gangrene of
the toes and sometimes the fingers. Several re-
ports indicate that arteriospasm is increased in
patients taking erythromycin, methysergide, or
jS-blockers.20'53'52
More serious is ergotamine's potential to
constrict central vascular beds, including the
coronary, mesenteric, and ophthalmic. Ergot-
amine taken in standard amounts has caused
myocardial ischemia, myocardial infarction, re-
current angina, cardiac arrest, and even sud-
den death. Peroneal nerve palsies have also
occurred, probably caused by constriction of
the vasa nervorum. Ergotamine also constricts
veins, a property that can make varicose veins
painful. Thrombophlebitis has developed and
can occur after only a single administration of
the drug. Ergot-induced vasospasm is treated
by immediate and complete withdrawal of the
drug and by efforts to preserve an effective cir-
culation in the affected parts.
Excessive amounts and/or too frequent use
of ergotamine can also produce an en-
cephalopathy with altered mentation, focal mo-
tor or sensory symptoms, seizures, and even
coma.30'44'64 The cause of such diffuse cerebral
dysfunction is uncertain. Both direct toxic ef-
fects on the brain and severe cerebral vaso-
constriction with ischemia have been postu-
lated as the mechanisms. In several cases,
arteriography has demonstrated occlusion or
spasm of the internal carotid artery, or see-
mental narrowing of intracranial arteries.29'"4
Rare cases of cerebral infarction have been re-
ported.41'52 Cerebral atrophy has also been de-
scribed in chronic users of ergotamine.18
In addition to causing ergotism, overuse of
ergot alkaloids can lead to fibrosis that involves
the pleura, pericardium, and retroperitoneum.
This has been reported in a few patients after
long-term daily use of ergotamine.53'67'68 Rare
individuals develop cardiac murmurs that are
thought to be indicative of aortic or mitral valve
disease or frank valvular disease diagnosed by
echocardiogram.28'51'66 Anorectal ulcers from
the frequent use of suppositories have also
been seen.34
344 Management of Acute Attacks
Contraindications
Because serious vasoconstrictive side effects
are more likely to occur in patients with cer-
tain preexisting conditions, coronary artery or
peripheral vascular diseases such as atheroscle-
rosis, Raynaud's phenomenon, thromboangiitis
obliterans (Buerger's disease), and thrombo-
phlebitis constitute absolute contraindications
to the prescription of ergotamine (Table 15^1).
Most physicians do not prescribe ergotamine
for patients with severe or uncontrolled hy-
pertension for fear that the drug will produce
a substantial elevation of blood pressure. It is
uncertain if hypertensive individuals respond
excessively to ergotamine, but there are docu-
mented increases in systolic and diastolic pres-
sure in normotensive persons of up to 20 mm
of mercury, lasting up to an hour following par-
enteral administration of between 0.25 and 0.5
mg of the compound.71 Ergotamine should be
also used with caution in individuals who are
taking high doses of /3-blockers because of the
concern that /3-blockers might augment the a-
adrenergic vasoconstrictive properties of ergot
alkaloids.8 Because ergotamine is metabolized
Table 15-4. Contraindications to
the Use of Ergots
Coronary artery disease
Prinzmetal's angina
Peripheral vascular disease
Cerebral vascular disease
Thrombophlebitis
Uncontrolled hypertension
Bradycardia
Impaired hepatic or renal function
Hyperthyroidism
Malnutrition
Pregnancy and nursing
Infection and fever
Hemiplegic or basilar migraine or migraine with
prolonged aura
Administration of triptans within prior 24 hours
Coadministration of methysergide0
Coadminstration of erythromycin1*
Age greater than 60 years0
High doses of /3-blockers*
"Relative contraindication.
by the liver and excreted by the kidney, dis-
eases of these organs may facilitate accumula-
tion of ergotamine, producing toxic effects fol-
lowing administration of normal doses of the
substance. A tendency to excessive vasocon-
striction seems to be a consequence of certain
medical conditions such as hyperthyroidism,
malnutrition, pregnancy, and infection, partic-
ularly when associated with sepsis. The con-
current dispensing of erythromycin may also
predispose to the development of peripheral
vasoconstrictive side effects.39 The interaction
between erythromycin, a macrolide antibiotic,
occurs as a result of macrolide complexation
and inactivation of cytochrome P-450 isoen-
zymes that are responsible for the metabolism
of ergot alkaloids. Accordingly, physicians
should make it a habit to remind their patients
of this danger. To be safe, migraineurs must be
told to limit their use of ergotamine when they
are suffering from any infectious process. Er-
gotamine should not be prescribed for preg-
nant women, although, in general, doses much
larger than those required to treat an attack of
migraine are needed to produce uterine con-
tractions and abortion. Ergotamine may pro-
duce symptoms of ergotism in infants exposed
through breast-feeding; accordingly, this is not
a drug that nursing mothers should take.5
Ergotamine Overuse
Most pharmaceutical manufacturers' instruc-
tions for the use of ergotamine recommend a
maximum dosage of 10 mg per week. If taken
every week, however, this dosage is unfortu-
nately well within the range found to cause
chronic ergotism.4'14 Moreover, a substantial
risk of developing chronic headaches exists if
ergotamine is used in the maximal recom-
mended doses, or in lower doses more than
twice a week. It has been suggested that the
amount of ergotamine should be restricted to
no more than 2 mg per week to prevent such
problems, but this is clearly too low a dose to
benefit many patients.61
DIHYDROERGOTAMINE
Dihydroergotamine (DHE) was synthesized by
selectively saturating one of the double bonds

(Cg-Cio) of the parent molecule. Despite its
close chemical similarities to ergotamine,
DHE differs significantly: its peripheral arte-
rial vasoconstrictive properties are much less
substantial, and it is a less potent emetic. This
makes it a considerably safer drug to use.
Moreover, DHE creates little physical depen-
dence, and rebound headaches are also un-
usual.37 In contrast to ergotamine, which is
usually ineffective unless administered early,
DHE has the potential to reduce or eliminate
head pain well into the course of a headache
even at its peak. Thus, despite a dearth of ap-
propriate controlled clinical trials, DHE is con-
sidered a safe and highly effective treatment
for severe bouts of migraine.49'65'78'80'85
Pharmacokinetics and
Metabolism
Dihydroergotamine is currently available for
intranasal and parenteral use. When adminis-
tered intravenously (IV), plasma levels reach
their peak (Cmax) within 1 to 2 minutes (Table
15^3). The drug may also be administered in-
tramuscularly (IM). This route results in more
gradual absorption (tmax of 24 minutes) and
slower onset of action. It can also be given sub-
cutaneously, but plasma levels after subcuta-
neous (SC) administration are 40% lower than
after intramuscular dosing. Intranasal DHE
(Migranal) is more slowly absorbed (tmsK >45
minutes) than parenteral DHE. In addition,
the bioavailability of intranasal DHE is ap-
proximately 40% compared to 100% after IV
use. The terminal half-life (fv2) for all of the for-
mulations is much longer than that of the trip-
tans, approximately 10 hours.
Dihydroergotamine is rapidly metabolized
by the liver. Its major metabolite is 8'-OH-
DHE, which, with DHE's other metabolites,
is excreted in the bile. Only 6% to 7% is ex-
creted unchanged in the urine.
Clinical Use of
Dihydroergotamine
Parenteral DHE is currently available in the
United States in ampules containing 1 mg of
active drug in 1 ml of solvent which can be
administered IV, IM, or SC. The most effec-
tive clinical results are obtained when DHE is
Ergots 345
administered IV. It is a standard treatment for
migraine in some hospital emergency depart-
ments. More that 85% of patients with acute
migraine attacks are reported to respond to IV
DHE.11'49 An IV infusion of normal saline
should be started first. Many physicians rou-
tinely premedicate with an antiemetic such as
metoclopramide (10 mg IM or IV) or prochlor-
promazine (3.5 to 5.0 mg IV).16'50'56 Undiluted
DHE is then given by slow (over a period of 3
to 4 minutes) injection into the IV tubing in a
dose of 0.5 to 1.0 mg. If the headache is unaf-
fected by DHE, or if it is attenuated but re-
turns, another 0.5 to 1.0 mg may be adminis-
tered provided that at least 30 to 60 minutes
have elapsed since the first dose. If repetitive
(every 8 hours) IV administration of DHE is
required, the patient must be hospitalized. The
latter regimen is usually reserved for the treat-
ment of status migrainosus or of drug-induced
headaches (see Chapter 25).
Dihydroergotamine may be administered
IM or SC in doses of 0.5 to 1.0 mg, which can
be repeated at 1 hour intervals to a total of 3.0
mg 21,56 jj. can ke prescribed for home IM or
SC injection and appears to be a safe and ef-
fective intermittent home treatment.7'37 Self-
injection may prevent a visit to the emergency
room or to a physician's office. It is difficult to
determine whether SC DHE is inferior or su-
perior to SC sumatriptan.82 Subcutaneous
DHE has slower onset of action than suma-
triptan but has a longer-lasting effect. The mi-
graine recurrence rates following parenteral
use of DHE are low (8% to 17.7%) A80-82 The
rate of recurrence in patients successfully
treated with SC sumatriptan is estimated to
be approximately two and one-half times that
of patients who respond to subcutaneous
DHE.82 Intramuscular DHE (1 mg plus hy-
droxyzine) and IM (1.5 mg/kg plus hydrox-
yzine) produce comparable results in acute mi-
graine attacks, but DHE has fewer central
nervous system (CNS) side effects, particularly
dizziness.12
Intranasal DHE (Migranal) has been shown
to be consistently superior to placebo in ap-
propriately controlled studies.15'22'38'54-76'^5
The magnitude of the effect varied from small
to moderate. The recommended dosage is 0.5
mg in each nostril, repeated after 15 minutes
for a total dose of 2 mg. Intranasal DHE has a
long duration of action with low recurrence
rates, but its speed of onset is slower than that
346 Management of Acute Attacks
of parenteral DHE or of subcutaneous suma-
triptan. It is less efficacious than subcutaneous
sumatriptan at 2 hours.82
Adverse Events
Adverse events are rare during or after DHE
administration. Nausea is the most distressing
side effect, but this depends in large part on
the route of administration. It is seen most fre-
quently after IV administration; IM, SC, and
intranasal routes require minimal, if any,
antiemetic therapy.80'81 Sedation, anxiety and
restlessness, diarrhea, abdominal discomfort,
muscle pain, fatigue, and body aches have also
been reported.11'49 A very small number of pa-
tients experience worsening of the headache.11
As for intranasal DHE, most side effects relate
to the route of drug administration and involve
the nose and throat (e.g., nasal irritation, rhin-
orrhea, nasal congestion, and altered sense of
taste).85 Nasal symptoms occur in between 6%
and 30% of patients.
Cardiovascular side effects are the most se-
rious potential adverse events. Although cases
of myocardial infarction have been reported af-
ter parenteral administration, they are ex-
tremely rare in practice. Although myocardial
events have been seen in patients without a his-
tory of cardiac disease, most serious adverse
events have occurred in elderly patients al-
ready receiving heparin, erythromycin, or /3-
blockers.13-35'3^49'8"'85 Dihydroergotamine has
the potential to cause peripheral arterial spasm,
but serious problems are infrequent.6'63
Contraindications
Contraindications for DHE are identical to
those for ergotamine. Patients with Prinz-
metal's angina, ischemic heart disease, uncon-
trolled hypertension, or infections should not
receive DHE because of the potential for er-
got hypersensitivity with coronary vasocon-
striction. The drug should not be used in preg-
nant patients (Table 15-4).
SUMMARY
For many years, ergotamine has been used as
a drug of choice to treat acute migraine. But
although inexpensive and often efficacious, er-
gotamine is not an ideal drug. It has been sup-
planted by DHE and the triptans. Ergotamine
has numerous limitations; it must be adminis-
tered very early in an attack if it is to work. It
has many side effects, and only a small margin
of safety. It is an easy drug to overuse, which
results in rebound headaches or in much more
serious toxicity (ergotism). Moreover, its in-
complete and unreliable absorption causes un-
predictable outcomes not only from patient to
patient but from attack to attack in an individ-
ual patient. Accordingly, some authorities con-
tend that it ought to be reserved only for pa-
tients with prolonged attacks or for patients
who cannot tolerate triptans. Most patients will
do better with DHE or triptans than with er-
gotamine. In contrast, DHE has much less tox-
icity than ergotamine and is considered a safe
and highly effective treatment for severe bouts
of migraine. Recurrence of headaches is rare,
and it causes little physical dependence and
few rebound headaches. It is a valuable med-
ication.
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1. Aellig WH and Niiesch E: Comparative pharmacoki-
netic investigations with tritium-labeled ergot alkaloids
after oral and intravenous administration in man. Int
J Clin Pharmacol 15:106-112, 1977.
2. Ala-Hurula V, Myllyla V, Arvela P, Heikkila J, Karki
N, and Hokkanen E: Systemic availability of ergota-
mine tartrate after oral, rectal and intramuscular ad-
ministration. Eur J Clin Pharmacol 15:51-55, 1979.
3. Ala-Hurula V, Myllyla V, Arvela P, Heikkila J, Karki
N, and Hokkanen E: Systemic availability of ergota-
mine tartrate after three successive doses and during
continuous medication. Eur J Clin Pharmacol
16:355-360, 1979.
4. Ala-Hurula V, Myllyla V, and Hokkanen E: Ergota-
mine abuse: results of ergotamine discontinuation,
with special reference to the plasma concentrations.
Cephalalgia 2:189-195, 1982.
5. American Academy of Pediatrics Committee on
Drugs: Transfer of drugs and other chemicals into hu-
man milk. Pediatrics 84:924, 1989.
6. Andersen AR, Tfelt-Hansen P, and Lassen NA: The
effect of ergotamine and dihydroergotamine on cere-
bral blood flow in man. Stroke 18:120-123, 1987.
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Chapter 1 6
Triptans
SUMATRIPTAN
Subcutaneous Sumatriptan
Oral Sumatriptan
Intranasal Sumatriptan
SECOND-GENERATION TRIPTANS:
TRIALS AND COMPARATIVE TRIALS
HEADACHE RECURRENCE
ADVERSE SYMPTOMS
CHEST, NECK, AND THROAT
SYMPTOMS
Serious Adverse Cardiac Events
Actions on Coronary Circulation
There is little doubt that triptans are highly ef-
fective in relieving the head pain of migraine
and the associated debilitating symptoms of
nausea, vomiting, and photophobia. The sub-
cutaneous (SC) formulation of Sumatriptan, in-
troduced in the United States in 1993, truly
revolutionized the management of migraine,
and has substantially expanded the therapeutic
options available to migraineurs. Sumatriptan
is also available in oral and intranasal formula-
tions. In addition, a number of interesting
compounds (second-generation triptans) have
been synthesized (Fig. 16-1). Except for frova-
triptan, which is a carbazole derivative, all sec-
ond-generation triptans are 3.5-substituted
tryptamine derivatives. The Food and Drug
Administration (FDA) and the European Med-
icines Evaluation Agency (EMEA) have re-
leased several of these: zolmitriptan (Zomig),
naratriptan (Amerge), rizatriptan (Maxalt), and
almotriptan (Axert). Eletriptan (Relpax) is be-
ing readied for release. Several more (e.g.,
frovatriptan) are in various stages of develop-
ment and evaluation.
CONTRAINDICATIONS
METABOLISM AND ITS
CONSEQUENCES
COMPARISONS WITH OTHER
TREATMENTS
EFFICACY AND LONG-TERM TRIPTAN
USE
TRIPTAN OVERUSE
CLINICAL USE OF TRIPTANS
SUMMARY
Because sumatriptan has been available
longer than other triptans, most investigations
of their clinical effects have focused on it. Sub-
stantial evidence confirms sumatriptan as a po-
tent, selective medication that can substantially
improve migraineur's quality of life of (Fig.
16-2).25'126'169 Moreover, data indicate that
migraine-induced lost labor costs, a function of
days missed from work and loss of workplace
productivity, are substantially reduced when
sumatriptan therapy is introduced (Figs. 16-3
and l6-4).25>100'12^ In particular, when SC
sumatriptan is self-administered in the work-
place it effectively reduces lost workplace
productivity.161 In addition, treatment with
sumatriptan significantly reduces clinic and
emergency department visits, consultations,
and institutional costs.25'106 A significant draw-
back, however, is the high cost of sumatriptan
and the other triptans (Table 16-1). Nonethe-
less, pharmacoeconomic analysis indicates that
triptans are cost-effective, particularly for pa-
tients with severe migraine attacks and their
employers.5
349
350 Management of Acute Attacks

Triptans are certainly the most studied of all

Figure 16-1. Chemical structures of several triptans.
headache medications. Thousands of patients
have participated in clinical trials, most using
International Headache Society (IHS) criteria
for the definition and diagnosis of migraine.
The trial protocols are generally randomized,
double-blind, placebo-controlled, parallel-
group comparisons, and have tested patients
whose headaches are either moderate (grade
2) or severe (grade 3). Responses to the med-
ication are usually defined as the proportion of
patients who have a mild headache (grade 1)
or no headache (grade 0) at some specified
time point, usually 2 hours, after administra-
tion of the drug.
Because one-point lessening of headache
paini.e., from moderate to mildis consid-
ered a treatment success even though the clin-
ical change may be modest, efficacy is overes-
timated. Two-point or three-point decrements
in pain are undoubtedly more relevant to the
patient, but one-point, two-point, and three-
point decrements are counted equally in eval-
uating efficacy. In addition, most clinical trials
with triptans have stipulated that patients de-
fer use of medication until their headache pain
was moderate to severea procedure that is
counterintuitive to good clinical practice. The

Figure 16-2. Sumatriptan improves the quality of life for migraineurs. Mean scores of the eight dimensions of the Med-
ical Outcomes Study Short-Form-36 Health Survey at baseline, and after 3, 6, and 12 months of sumatriptan therapy. The
patients (n = 148), enrolled in an HMO, had migraine attacks that met IHS criteria. Patients could treat an unlimited
number of mild, moderate, or severe attacks with self-administered subcutaneous sumatriptan (6 mg). The scores were
calculated on a scale from 0 (least favorable) to 100 (most favorable). PF, physical functioning; RP, role-physical (limita-
tions in role functioning as a result of physical health); BP, bodily pain; GH, general health perceptions, VT, vitality, SF,
social functioning; RE, role-emotional (limitations in role functioning as a result of emotional health); MH, general men-
tal health. "P < 0.05 vs. baseline. (Adapted by permission of the publisher from Cohen JA, Beall D, Beck A, et al.: Suma-
triptan treatment for migraine in a health maintenance organization: economic, humanistic, and clinical outcomes. Clin
Ther 21:190-204, 1999, copyright 1999 by Excerpta Medica Inc.)

Figure 16-3. Changes in total disability time, lost pro-
ductivity time, and lost non-workplace activity time after
starting treatment with sumatriptan. The patients (n =
178), enrolled in an HMO, were diagnosed by their physi-
cians to have migraine, but their headaches did not nec-
essarily fulfill IHS criteria. Total disability time = lost
workplace productivity + lost non-workplace activity,
where lost workplace productivity = days missed from
work as a result of migraine + [days worked with migraine
symptoms X (100%-effectiveness while working with mi-
graine symptoms/100%)]; lost non-workplace activity =
days missed from non-workplace activities as a result of
migraine + [days doing non-workplace activities with mi-
graine symptoms X (100%-effectiveness while doing non-
workplace with migraine symptoms/100%)]. "P < 0.049
from baseline; *SP < 0.049 from 3 months from baseline.
(Adapted from Lofland JH, Johnson NE, Batenhorst AS,
and Nash DB: Changes in resource use and outcomes for
patients with migraine treated with sumatriptan. Arch In-
tern Med 159:857-863, 1999. Copyrighted 1999, Ameri-
can Medical Association.)
introduced bias has not been thoroughly con-
sidered in evaluating the "evidence" from clin-
ical trials. Administration of triptans early in
the attack may account for the substantially
augmented responses to triptans in clinical
practice as compared to those reported in clin-
ical trials.20 Recently it has been recommended
that complete cessation of headache ("head-
ache-free criterion"), a more robust and rele-
vant measure of triptan efficacy, be included
in the results of trials.81
The placebo response always needs to be
factored in when evaluating the results of clin-
ical trials. It can confound results often in very
complex ways (see Chapter 13). The triptan
studies consider that responses ascribed to
placebos are controlled for by comparing re-
sponse to active drug with response to placebo.
Accordingly, they define therapeutic gain as
the percentage response for active drug minus
the percentage response for placebo. This mea-
sure, however, can be misleading, as placebo
responses that vary markedly among studies
may disguise the fact that triptans have a lim-
Triptans 351
ited therapeutic response; in other words,
there appears to be a so-called ceiling response
or a limit to the percentage of patients who re-
spond to the drug.46
SUMATRIPTAN
Sumatriptan is efficacious and well tolerated by
the vast majority of patients. Headache relief
rates of approximately 70% have been demon-
strated in clinical trials at 2 hours with SC suma-
triptan, and more than 60% with oral suma-
triptan. Not only are headaches relieved, but
controlled clinical trials have shown that both
oral, intranasal, and SC sumatriptan relieve the
nausea, vomiting, photophobia, and phonopho-
bia associated with migraine attacks. The type
of migraine (with or without aura) does not af-
fect sumatriptan's efficacy.128'134'175'176 Admin-
istration during the aura phase, however, does
not appear to be effective against the symptoms
or duration of the aura and, more important,
does not prevent the headache.2
Subcutaneous Sumatriptan
Sumatriptan is formulated for SC use in a 6 mg
autoinjector. It is rapidly absorbed, with a
mean peak plasma concentration (Cmax) of 69.5
to 80.2 /Ag/L attained in a mean time of 10 to
15 minutes (Table 16-2). Bioavailability is es-
sentially 100%.97 The pharmocokinetics of
sumatriptan in migraine patients are similar to
those in healthy subjects, both young and el-
derly, and are linear over a SC dose range of 1
to 16 mg. Sumatriptan is widely distributed and
has low protein binding. It penetrates the nor-
mal blood-brain barrier poorly. Following SC
administration, 21% of sumatriptan is elimi-
nated unchanged in the urine and 0.6% un-
changed in the feces.50
Headache relief usually begins within 10
minutes; maximal improvement occurs at 2
hours. In a meta-analysis of randomized,
placebo-controlled clinical trials, Saxena and
Tfelt-Hansen calculated that the mean re-
sponse rate for SC sumatriptan (6 mg) was
69%, with a mean placebo response rate of
19%.159 The mean therapeutic gain was 51%
(95% confidence interval [CI] 48% to 53%)
(Table 16-3). Sumatriptan's efficacy is unaf-
fected by age, gender, ethnicity, or migraine
type.
352 Management of Acute Attacks

Figure 16-4. Cumulative proportion of patients returning to normal work performance across an 8-hour work shift af-
ter treating an acute bout of migraine in the workplace with either sumatriptan injection (6 mg) or placebo. The sample
consisted of 135 patients 18 years or older diagnosed with migraine by IHS criteria. They self-adminstered sumatriptan
or a placebo to treat a moderate or severe migraine headache with the first 4 hours of an 8-hour work shift. (Patients'
time to return to normal work performance has been set to the time to the end of the scheduled work shift for patients
not returning to normal work performance.) (Adapted from Cady RC, Ryan R, Jhingran P, O'Quinn S, and Pait DG:
Sumatriptan injection reduces productivity loss during a migraine attack: results of a double-blind, placebo-controlled
trial. Arch Intern Med 158:1013-1018, 1998. Copyrighted 1998, American Medical Association.)

Oral Sumatriptan gating the 100 mg dosage, Saxena and Tfelt-

Oral sumatriptan was released first in a 100 mg
formulation in Europe and later in 25 and 50
mg formulations in the United States (Table
16-3 and Fig. 16-5). In clinical trials investi-
Hansen performed a meta-analysis of its effi-
cacy.159 They calculated the mean therapeutic
gain after 2 hours as 31% (95% CI 28% to
33.5%) (sumatriptan response rate: 59%;
placebo response rate: 28%). Doses of oral

Table 1 6-1 . Cost of Triptans

Average Wholesale
Medication Brand Name Dosage Price ($)

Oral sumatriptan Imitrex 50 mg (1 tablet) 16.01

Intranasal sumatriptan Imitrex 20 mg (1 use) 20.80
Subcutaneous sumatriptan Imitrex 6 mg (1 injection) 49.30
Zolmitriptan Zomig 2.5 mg (1 tablet) 14.01
Naratriptan Amerge 2.5 mg (1 tablet) 16.74
Rizatriptan Maxalt 10 mg (1 tablet) 14.32
Data from 2000 Red Book, Medical Economics Data, Inc. (non-generic prices).
 Triptans 353

Table 16-2. Sumatriptan: Pharmacokinetics

F 'max th *-max AUC

Administration (%) (hours) (hours) (ng/mL) (ng- hours/ml)
Subcutaneous (6 mg) 96 0.17-0.25 1.9-2.0 69.5-80.2 81-90
Oral (50 mg) 14 2.5 2.0 31.3 117.9
Intranasal (20 mg) 15.8 1.0-1.5 1.8-2.0 12.9-16.0 47.5-53.5
AUC, area under the plasma concentration-time curve; Cmax, peak plasma concentration; F, bioavailability; tmax, time
to reach the peak plasma concentration; tv2, elimination half-life.
Data from Duquesnoy et al. (1998),39 Fowler et al. (1991),50 Guttermann et al. (1989),76 Lacey et al. (1995),97 Moore
et al. (1997),121 Visser et al. (1996),184 Vojnar-Horton et al. (1996),191 and Warner et al. (1995).193

sumatriptan larger than 100 mg do not confer Intranasal Sumatriptan

additional therapeutic benefit for moderate or
severe headaches.
Oral sumatriptan displays an absorption pro-
file with a large peak or two main peaks. In
general, with a 50 mg tablet the peak plasma
concentration of 15.5 jug/1 is attained at 2 hours
following administration. Three percent of
sumatriptan is excreted unchanged in the urine
and 9% in the feces.50 Oral bioavailabilty is ap-
proximately 14%.50 Its comparatively low
bioavailability in oral form primarily results
from first-pass metabolism by the liver and, to
a lesser extent, partial oral absorption.34'50 It is
not known whether sumatriptan's bioavailabil-
ity is influenced by concomitant food intake,
but it appears that the gastric stasis which of-
ten occurs during bouts of migraine does not
affect its absorption.21'96'171
Sumatriptan also comes in single-dose devices
that deliver 5 or 20 mg in a 0.1 ml aqueous so-
lution as a spray to a single nostril. Intranasal
sumatriptan was developed to provide a for-
mulation for patients who do not like to take
injections but require rapid delivery. The mi-
crovilli of the nasal epithelium provide a large
surface area for absorption, and the subep-
ithelial layer is highly vascularized. Venous
blood from the nose passes directly into the
systemic circulation. As a result, sumatriptan
absorbed from the nasal cavity is not subjected
to extensive first-pass metabolism as with oral
medications. That fraction of the intranasal
dose not absorbed nasally is absorbed by the
gastrointestinal tract and metabolized in the
fiver. The peak plasma concentration of 14.4

Table 16-3. Clinical Efficacy of Triptans

Response Headache
Rate* (%) Therapeutic Recurrence Rate (%)
Triptan (2 hours) Gain (%) (within 24 hours)
Sumatriptan (50 mg oral) 59 31 26-34
Sumatriptan (20 mg IN) 61 30 28-43
Sumatriptan (6 mg SC) 69* 51 21^5
Zolmitriptan (2.5 mg) 64 34 22^37
Naratriptan (2.5 mg) 48t 21 17-28
Rizatriptan (10 mg) 71 31-39 35-47
Eletriptan (80 mg) 65-80 46-55| 19-34
Frovatriptan (2.5 mg) 38-40 22-25
Almotriptan (12.5 mg) 64 18 18
IN, intranasal; SC, subcutaneous. "Response defined as severe or moderate headache decreased to mild or pain-free.
**1 hour. f4 hours. |Placebo response rate in some trials was very lowone-half of what is seen in most large clinical
trials.
354 Management of Acute Attacks

Figure 165. Percentage of patients with headache relief as a function of time after administration of Sumatriptan tablets
(25, 50, or 100 mg) or placebo. The data were obtained drom 1003 patients enrolled in a multinational controlled trial.
The patients treated up to three migraine attacks. There is no significant differences between 50 and 100 mg tablets, but
both formulations are significantly more effective than the 25 mg tablet. "P < 0.05 vs. placebo; \P < 0.05 vs. 25 mg.
(Adapted from Pfaffenrath V, Cunin G, Sjonell G, and Prendergast S: Efficacy and safety of Sumatriptan tablets (25 mg,
50 mg, and 100 mg) in the acute treatment of migraine: defining the optimum doses of oral Sumatriptan. Headache
38:184-190, 1998, with permission.)

to 16 /tg/1 is achieved in 1 hour. In a meta-
analysis, Saxena and Tfelt-Hansen determined
that the mean response rate for intranasal
Sumatriptan (20 mg) after 2 hours was 61%
compared to a placebo rate of 31% (mean ther-
apeutic gain 30%, 95% CI 25 to 34%).159
(Table 16-3). In smaller doses, intranasal
Sumatriptan is still effective, but less so than
the 20 mg dose.
SECOND-GENERATION
TRIPTANS: TRIALS AND
COMPARATIVE TRIALS
Second-generation triptans have been devel-
oped to provide anti-migraine medications with
faster and more consistent responses, superior
pharmacokinetic properties, fewer coronary ef-
fects, and the ability to penetrate the
blood-brain barrier. Controlled clinical trials
have demonstrated favorable efficacy for
second-generation triptans, and shown that
they are all significantly more efficacious than
placebos. Zolmitriptan, naratriptan, and riza-
triptan were approved in some countries in
1997 and 1998; almotriptan was approved in
2001; eletriptan is being readied for approval;
and frovatriptan may be released in 2002. Avit-
riptan (BMS-180048) was found to be effective
in migraine treatment, but is no longer in clin-
ical development because of its hepatic side ef-
fects. Alniditan was not marketed because pre-
liminary data indicated that it offered no
benefit over sumatriptan.
How well have the aims of the pharmaceu-
tical manufacturers for second-generation
triptans been realized? When compared to
oral sumatriptan (and all are only available in
oral form), in general the second-generation
triptans do have a higher mean oral bioavail-
ability than oral sumatriptan's 14% (Table
16-4). 45,52,97,99,192 the tmax values (the time to
reach the peak plasma concentration) follow-
ing oral zolmitriptan and naratriptan are
longer than the value for oral sumatriptan;
those for eletriptan and possibly rizatriptan are
shorter, but these values do not seem to cor-
relate with the time required for clinical effi-
cacy. The elimination half-lives (t v2) of zolmi-
triptan, naratriptan, and eletriptan, but not
that of rizatriptan, are longer than that of
sumatriptan, but these also do not correlate
well with the recurrence rate.
 Triptans 355

Table 16-4. Second Generation Triptans: Pharmacokinetics

F *imax th t-max AUC

Drug (%) (hours) (hours) (ng/mL) ng-hours/mL
Zolmitriptan (5 mg) 40-46 1.5-2.5 2.6-^3.8 6.6-9.1 35.2-44.1
Naratriptan (2.5 mg) 63-74 0.8-4.1 5.0-6.7 7.8-14.4 86-98
Rizatriptan (10 mg) 3^45 0.7-3.0 i.a-3.o 17.7-28.6 49.6-63.6
Eletriptan (40 mg) 50 1.0-1.5 4.0-5.0 107-190
Frovatriptan (2.5 mg) 22-30 1.2-4 25.7 4.2-7.0 94
Almotriptan (12.5 mg) 70-80 1.4-3.8 3.2-^3.7 33.5-49.5 217.4-266.1
AUC, area under the plasma concentration-time curve; Cmax, peak plasma concentration; F, bioavailability; *max, time
to reach the peak plasma concentration; t\, elimination half-life.
(Data from Buchan et al. (1999),13 Cabarrocas (1997),14 Cabarrocas et al. (1997, 2000),15-16 Cheng et al. (1996),23 Cut-
ler et al. (1999),29 Dixon et al. (1999),35 Dixon and Warrander (1997),37 Farkkla et al. (1996),43 Fuseau et al. (1997),52
Goldberg et al. (1999, 2000),67-68 Kempsford (1997),90 Kempsford et al. (1997),91 Lee et al. (1999),99 Morgan et al.
(1997),122 Palacios et al. (1999),142 Peck et al. (1998),148 Sciberras et al. (1997),162 and Seaber et al. (1996, 1998).163'164

Propranolol affects the pharmacokinetics of fective than sumatriptan (50 mg) in terms of
several second-generation triptans. It increases headache response at 2 and 4 hours, the dif-
the peak plasma concentration of zolmitriptan, ferences were small (zolmitriptan 2.5 mg: 2
although following 2.5 mg doses only negligi- hours 67.1%, 4 hours 83.3%; sumatriptan 50
ble increases are seen in the area under the mg: 2 hours 63.8%, 4 hours 80.8%).55
plasma concentration-time curve (AUC). Pro- Zolmitriptan, however, was significantly more
pranolol reduces the conversion of zolmitrip- effective than sumatriptan in producing sus-
tan to its active N-desmethyl metabolite.147'1^4 tained 24-hour pain relief across six bouts of
Coadminstration of propranolol with rizatrip-
tan results in a 56% increase in the latter's AUC
and a 70% increase in plasma levels; with frova-
triptan, there is a 25% increase in the bioavail-
ability; with eletriptan, a prolonged half life. A
rizatriptan dose reduction is advised in patients
taking propranolol.
A number of controlled clinical studies have
demonstrated favorable efficacy for zolmitrip-
tan 152,170,189 A meta-analysis of phase II/III
studies demonstrated that the 2-hour response
rate for a 2.5 mg dose was 64% (95% CI 59%
to 69%) with a therapeutic gain of 34% (95%
CI 27% to 41%). These data are statistically in-
distinguishable from those of a 5 mg dose (66%
with a therapeutic gain of 37%) (Figs. 16-6 and
16-7).61 Because the 5 mg dose produces a
substantial increase in the rate of adverse
events, the 2.5 mg formulation appears to pro-
vide the optimal balance between efficacy and
Figure 16-6. Comparison of headache responses (mod-
tolerability (Fig. 16-8).41>61>152 Analysis of the erate or severe pain becomes mild or absent at 2 hours
time course of headache responses showed that post-dose) for sumatriptan, naratriptan, and zolmitriptan.
zolmitriptan produced significant headache re- The points are means and the vertical lines are the 95%
lief within 1 hour; increasing benefits occurred confidence intervals (CI). The horizontal dashed lines pro-
vide the 95% CI for sumatriptan at 100 mg. Data from
with time up to 4 hours. Goadsby61 and Saxena and Tfelt-Hansen. 159 (Adapted
Although in a head-to-head comparison, from Goadsby PJ: A triptan too far? J Neurol Neurosurg
zolmitiptan (2.5 mg) was significantly more ef- Psychiatry 64:143-147, 1998, with permission.)
356 Management of Acute Attacks

Figure 16-7. Comparison of therapeutic gains (headache response to drug minus headache response to placebo) at 2
hours postdose for sumatriptan, naratriptan, and zolmitriptan. The points are means and the vertical lines are the 95%
confidence intervals (CI). The horizontal dashed lines provide the 95% CI for sumatriptan 100 mg. (Adapted from Goadsby
PJ: A triptan too far? J Neurol Neurosurg Psychiatry 64:143-147, 1998, with permission.)

migraine. In a large trial, zolmitriptan (5 mg)
was found to be at least as effective as suma-
triptan (100 mg), although the study suffered
from design deficiencies that resulted in a high
placebo response.57
The response rate for naratriptan (2.5 mg),
based on meta-analysis of phase II/III trials,
was 48% (95% CI 45% to 51%) at 4 hours and
its therapeutic gain was comparatively modest
(21%; 95% CI 18% to 24%).fel The compound

Figure 16-8. Comparison of the rate of occurrence of adverse events (expressed as therapeutic penalty: adverse event
rate after drug minus adverse event rate on placebo) at 2 hours post-dose for sumatriptan, naratriptan, and zolmitriptan.
The points are means and the vertical lines are the 95% confidence intervals (CI). The horizontal dashed lines provide
the 95% CI for sumatriptan 100 mg. (Adapted from Goadsby PJ: A triptan too far? J Neurol Neurosurg Psychiatry
64:143-147, 1998, with permission.)

has a slower onset of action than other triptans.
The 2.5 mg dose is very well tolerated, how-
ever: its rate of adverse events is lower than
that for other triptans (Fig. 16-8)equivalent
to the rate for placebos (Fig. 16-8).75 In addi-
tion, a low rate of headache recurrence is
reported.
The most effective dosage of rizatriptan with
a reasonable side-effect profile is 10 mg. The
mean therapeutic gain for 10 mg in placebo-
controlled trials was between 31% and
39% 70,93,179,181,190 Studies snOwed that 2
hours after administration between 6% to 21%
more migraineurs achieved headache relief
from rizatriptan than from sumatriptan.70'181
When rizatriptan (10 mg) was compared to
sumatriptan (100 mg), analysis found that 29%
more patients were likely to be pain-free within
2 hours after rizatriptan than after sumatrip-
tan.181 In several studies, rizatriptan appeared
to provide faster pain relief than sumatriptan,
although the differences are modest, and the
results may have been skewed by inclusion of
sumatriptan non-responders.70'103'181'190 As ex-
pected from naratriptan's slow onset of action,
rizatriptan (10 mg) provided substantially more
relief at 2 hours than naratriptan (2.5 mg) (riza-
triptan: 44.8%; naratriptan: 20.7%).7
Only a few trials of eletriptan's efficacy are
in print or available in abstract. Two hours af-
ter administration of eletriptan (80 mg), 65%
to 80% of patients had headache relief com-
pared to 19% to 25% in placebo groups.77'129
Eletriptan (80 mg) is significantly more effec-
tive than oral sumatriptan (100 mg) at 2 hours
(placebo, 24%; sumatriptan, 55%; eletriptan,
77%).62 It also appears to have a more rapid
onset of action than sumatriptan (100 mg). But
the encapsulated (non-marketed) form of
sumatriptan used to facilitate blinding in these
investigations may have influenced its efficacy.
Headache recurrence following eletriptan varies
between 21% and 33%.
There are only minimal published data about
frovatriptan. Headache response rates for 2.5
mg (considered to be the optimal dose com-
bining efficacy and tolerability) are between
38% and 40%, compared to placebo rates of
22% to 25%.69'156 Headache recurrence rates
at 24 hours range from 9% to 14%.
A 12.5 mg dose of almotriptan appears to
provide the optimum efficacy/safety ratio.44
Following oral almotriptan (12.5 mg), 60% to
70% of patients perceive headache relief by 2
hours (sumatriptan 100 mg, 64%; placebo, 38%
Triptans 357
to 42%).17'145 Adverse event rates following
oral almotriptan (12.5 mg) are not different
from placebo (18% vs. 16% for placebo) and
the headache recurrence rate is 18%.
HEADACHE RECURRENCE
A considerable number of headaches that are
successfully treated with sumatriptan in clini-
cal trials recur within 24 hours.47'153 In clinical
practice as many as 75% of patients may expe-
rience recurrence in at least some of their
sumatriptan-treated attacks.188 Headache re-
currence is a major drawback of triptan ther-
apy. It has a direct impact on patient satisfac-
tion, cited as the reason many patients
discontinue the drug.167
The time to headache recurrence ranges be-
tween 1 and 30 hours, the median being 12
hours after SC treatment and 17 hours after
oral treatment (Fig. 16-9).19'47'63'153-185 The
time to recurrence, but not the frequency of
recurrence, is a function of sumatriptan dos-
age.149 Whether recurrence occurs more fre-
quently in patients treated late rather than
early in an attack is unclear, but as might be
predicted, the phenomenon is more likely in
patients with longer attacks (i.e., normally last-
ing 2 to 3 days without treatment).32'167'188
Headache recurrence is not, however,
unique to sumatriptan. It occurs after other
triptans and non-triptan headache medica-
tions. Recurrence is more frequent with
sumatriptan than with oral ergotamine, par-
enteral dihydroergotamine (DHE), a combi-
nation of aspirin and metoclopramide, or
placebo.19-48'1^5'132'176 The proportion of af-
fected patients varies widely among triptans:
sumatriptan (50 mg), 26% to 34%; zolmitrip-
tan (2.5 mg), 22% to 37%; naratriptan (2.5 mg),
17% to 28%; rizatriptan (10 mg), 28% to 47%;
eletriptan (40 mg), 19% to 34%; almotriptan (5
mg) 18% to 27%; and frovatriptan (2.5 mg)
10% to 18% (but in the same study, the placebo
recurrence rate was 18%, one-half of what has
been reported for most large clinical tri-
a|s\ 3,45,58,82,92,93,104,149,155,160,166,168,179,190,196
Except for naratriptan, and possibly eletriptan
and frovatriptan, the triptans do not have con-
sistent differences in recurrence rates. Head-
ache recurrence is approximately one-third less
frequent for naratriptan (2.5 mg) than for
sumatriptan (100 mg) in controlled trials.3'64
358 Management of Acute Attacks

Figure 16-9. Time to headache recurrence after administration of subcutaneous (SC) and oral sumatriptan. The data
were retrospectively obtained from questionaires given to 453 migraine patients who had used sumatriptan for nearly
28,000 attacks. (Adapted from Visser WH, de Vriend RHM, Jaspers NMWH, and Ferrari MD: Sumatriptan in clinical
practice: a 2-year review of 453 migraine patients. Neurology 47:46-51, 1996, with permission.)

The cause of headache recurrence after trip-
tan administration is unknown. For sumatrip-
tan recurrence has been attributed to its rela-
tively short, 2-hour elimination half-life (fv 2 ).
The short v2 may allow a breakthrough of an
only suppressed, but still ongoing, bout of mi-
graine. The longer 5- or 6-hour t v2 presumably
reduces the proportion of naratriptan-treated
migraineurs who develop headache recurrence
when compared to sumatriptan-treated pa-
tients. It is curious, then, that patients with and
without recurrences following sumatriptan use
have similar pharmacokinetic profiles for the
drug, and that those given rizatriptan and
zomitriptan, drugs that appear to have longer
v2's than sumatriptan, also have frequent head-
ache recurrences (see Tables 16-2 and
16-4).i84 Headache return, however, occurs
with a slightly longer latency after administra-
tion of these latter drugs.
The incidence of headache recurrence is
not reduced by a second dose of sumatriptan
administered as prophylaxis against recur-
rence.47'153 But once recurrence occurs it can
often be effectively treated by an additional
dose.47'65'149'179 Unfortunately, as many as
70% of patients effectively treated in this way
experience additional recurrences. The addi-
tion of a non-steroidal anti-inflammatory drug
(NSAID) at the time of the original adminis-
tration has been demonstrated to reduce suma-
triptan's recurrence rate.94'95 Naratriptan, ad-
ministered at the same time as sumatriptan, has
also been used.
ADVERSE SYMPTOMS
In general, the treatment of acute migraine
with sumatriptan and other triptans is well tol-
erated. Adverse events are frequentas many
as 65% of patients report at least one adverse
event from SC sumatriptanbut they are gen-
erally mild to moderate in intensity, arise soon
after administration, are short-lasting (usual
duration: <15 minutes), and resolve sponta-
neously.38'75 They interfere with treatment in
only a small minority of patients, with long-
term investigations showing that only 6% to
10% of patients stopped sumatriptan or
zolmitriptan because of side effects.73'82'178
Although adverse events induced by suma-
triptan and second-generation triptans have
similar profiles, their rate of occurrence varies
(see Fig. 16-8).159 Among the oral triptans,
zolmitriptan (2.5 mg) produces 15% more
adverse effects than placebo and rizatriptan
(10 mg) 17%; naratriptan's (2.5 mg) rate of

side effects is no higher than that of
placebo.70'152'168'179'181 As expected from the
higher plasma levels after SC administration,
the incidence of adverse events is higher with
SC sumatriptan than with oral or intranasal
sumatriptan: SC sumatriptan (6 mg) has 33%
more adverse events than placebo, oral suma-
triptan (100 mg) has 16%, and intranasal suma-
triptan (20 mg) has 21%.159
All triptans have the potential to cause a col-
lection of adverse symptoms called the triptan
syndrome,118 which consists of paresthesias
(usually tingling) or numbness, sensations of
warmth, heat, burning, or cold, and feelings of
heaviness, tightness, or pressure in the head,
neck, chest, throat, or other body parts21'168'175
(see below). Other common side effects in-
clude dizziness or lightheadness, vertigo, som-
nolence, fatigue, drowsiness, flushing, weak-
ness, and worsening nausea or vomiting. Some
of these symptoms resemble those caused by
the migrainous process itself. The most fre-
quent side effect reported after using in-
tranasal sumatriptan is a bitter or unpleasant
taste that some patients cannot tolerate. When
they inject sumatriptan, most patients feel a
mild pain or stinging or burning sensations at
the injection site lasting 30 seconds.
Triptans cause transient blood pressure ele-
vations in some individuals, but they are gen-
erally smallapproximately 10 mm Hgand
of 30 to 60 minutes duration after SC suma-
triptan; a lesser elevation of approximately 7
mm Hg can occur after oral therapy. Detailed,
invasive hemodynamic studies show that suma-
triptan increases vascular resistance in both
systemic and pulmonary circulations. Aortic
systolic and diastolic pressures are increased by
17% to 20% and 12% to 16%, respectively; pul-
monary systolic and diastolic pressures are in-
creased by 40% to 50% and 33% to 77%, re-
spectively.114'115 Stroke has been reported in
rare patients treated with sumatriptan.85'111
There is no convincing evidence that suma-
triptan or the other triptans can precipitate
acute anaphylaxis or asthma.
Several patients have reportedly developed
the serotonin syndrome following sumatriptan
use in combination with selective serotonin re-
uptake inhibitors (SSRIs).56'120 It consists of
varying neurological manifestations such as
confusion, agitation, weakness, hyperreflexia,
myoclonus, shivering, dystonia, muscle cramps,
tremor, and incoordination. The serotonin syn-
Triptans 359
drome in these cases presumably results from
drug-induced, excess stimulation of 5-HT re-
ceptors. With supportive therapy alone, the
syndrome usually resolves completely within
24 hours after discontinuation of the medica-
tions. Symptomatic treatment with cyprohep-
tidine (4 to 8 mg PO) has been used with suc-
cess.72
CHEST, NECK, AND
THROAT SYMPTOMS
Although they are believed to be fundamen-
tally harmless, symptoms of tightness, heavi-
ness, pressure, stiffness, or pain referable to the
chest, neck, and/or throat are side effects that
often alarm patients. Early clinical investiga-
tions strictly excluded patients with cardiovas-
cular disease; up to 5% of patients who re-
ceived SC sumatriptan and 3% treated orally
complained of chest, neck, and/or throat symp-
toms.12'107'178 Post-marketing surveys of pa-
tients recruited from general practices found
pressure, tightness, or pain even more fre-
quentin up to 8% of individuals.12'80'139'140
Some clinicians report that sensations of tight-
ness and pressure occur at one time or another
in as many as 40% of their patients treated with
SC sumatriptan.31'187
Chest pressure, heaviness, or tightness are
by far the most prevalent chest symptoms,
while actual chest pain or radiating pain are
much more unusual.31'187 Because the symp-
toms may resemble the chest pressure or pain
of angina pectoris, they are disturbing to pa-
tients and to their physicians. In addition, sev-
eral case reports of myocardial ischemia and
infarction associated with sumatriptan use have
been published (see below). These serious
events caused a change in sumatriptan's prod-
uct labeling in 1994 to warn against its admin-
istration if there is a history of coronary artery
disease or significant risk factors for develop-
ing myocardial ischemia.
In general, the chest symptoms develop with
30 minutes and last from 15 minutes to 2
hours.12'107'178-187 More than 2 hours of chest
pressure or pain is unusual and requires eval-
uation with electrocardiography to rule out
myocardial ischemia.138 Subcutaneous admin-
istration causes more frequent chest symptoms
than oral sumatriptan, and they appear
sooner.138 The likelihood that chest symptoms
360 Management of Acute Attacks
will develop after use is, in large measure,
patient-dependent; individuals either usually
or always have chest symptoms or never per-
ceive them.187 Strangely, women, younger pa-
tients, patients with low rather than high body
mass index, and patients without cardiac prob-
lems appear to have a higher risk of develop-
ing sumatriptan-induced chest discomfort than
older men do, but data correlating the proba-
bility of developing chest symptoms with the
incidence of cardiovascular risk factors are in
conflict.11'138'139'187 Naratriptan has a lower
frequency of chest-related symptoms than all
other triptans, but it is not clear if other
second-generation triptans have lower frequen-
cies than oral sumatriptan.40'41'82 Placebo-
controlled investigations reported chest-related
symptoms in up to 4% of patients treated with
second-generation triptans. Most second-
generation triptans have an in vitro pharma-
cology equivalent to that of sumatriptan in
terms of receptor selectivity, potency, and effi-
cacy. Thus from a pharmacologic point of view,
one would expect that the cardiovascular ef-
fects of second-generation triptans will not be
profoundly different from those of sumatriptan.
Serious Adverse Cardiac Events
The incidence of serious adverse cardiac
events from triptans is slight when one con-
siders that millions of patients use the drugs.
The incidence of any type of electrocardio-
graphic (EKG) change after triptan use is low
(e.g., sumatriptan 100 mg, 4%; zolmitriptan 1
to 20 mg, 2% to 3%; placebo, 2%). EKG
changes indicative of myocardial ischemia are
very rare with sumatriptan (0.1 to 0.2%).12 A
small number of disturbing case reports, how-
ever, describe sumatriptan-treated patients
who suffered myocardial ischemia and infarc-
tion<80,98,123,131,l36,138,141,187,194,195 Rare patients
developed ventricular arrhythmias.27 Most of
the adverse cardiac events occurred in patients
with clear evidence of cardiac disease or with
concomitant risk factors for coronary artery dis-
ease (e.g., history of heavy smoking, hypercho-
lesterolemia), patients to whom sumatriptan
should not have been prescribed or who had
been inappropriately dosed. But some serious
cardiac episodes have occurred in patients with
minimal or no coronary artery disease.98'123'131
It has been hypothesized that coronary artery
vasospasm is responsible.
Actions on Coronary Circulation
Because of their potential to cause myocardial
ischemia, much effort has gone into determin-
ing how the triptans act on the coronary cir-
culation. Neither sumatriptan nor naratriptan
cause significant alterations in myocardial per-
fusion in migraineurs.60'101 For patients with-
out obstructive coronary artery disease, eletrip-
tan and naratriptan cause no significant
coronary artery constriction and naratriptan
produced no significant reduction of coronary
artery diameter in patients with known or sus-
pected coronary artery disease.78'124'177 But di-
agnostic angiographic studies in patients with
coronary artery disease or suspected coronary
artery disease, have shown about a 16% re-
duction in mean coronary artery diameter af-
ter intravenous (IV) or SC sumatriptan.114'115
Coronary angiography in two cases of
sumatriptan-induced myocardial infarction re-
vealed either normal coronary arteries or min-
imal luminal irregularities, an indication that
sumatriptan-induced coronary vasoconstriction
produced the infarctions, and that such vaso-
constriction was probably independent of
coronary atherosclerosis.123'131 Why triptan-
induced vasoconstriction occurs in some indi-
viduals and not in others is unknown.
Pharmacological techniques have been used
to describe both 5-HTi and S-HTa receptors
in human coronary arteries just where molec-
ular biological methods show mRNAs corre-
sponding to 5-HTiB and 5-HT2A receptors
expressed in high levels.4'84'130'144 mRNAs cod-
ing for 5-HTiA, 5-HTio, and 5-HTy receptors
are only weakly expressed. Data about the
amount of message for 5-HTiF receptors in
coronary arteries are inconsistent.8 There is
also disagreement about the relative roles that
5-HTi and 5-HT receptors play in 5-HT-
induced vasoconstriction of coronary arteries,
although both types of receptors are thought
to be involved.71 Review of available pharma-
cologic and molecular biologic studies leads to
the presumption that the 5-HTiB receptors lo-
cated on smooth muscle cells of coronary ar-
teries are the 5-HTi receptors activated by
sumatriptan and other triptans.83'88'89'109'130
The role of 5-HT receptors is particularly ev-
ident when concentrations of 5-HT are high,
but sumatriptan and the other triptans have no
significant effects on these receptors.88
The triptans are only partial agonists at hu-
man coronary artery 5-HTiB receptors. In vitro
 Triptans 361

investigations have shown that 5-HT, suma-
triptan, and second-generation triptans con-
strict isolated human epicardial coronary ar-
teries. The constriction appears to be a class
effect for this drug type.4'^108,112,113,116>143,144
Because they are partial 5-HT agonists, the
triptans have low efficacy, and their maximum
coronary artery contractions are smaller than
those evoked by 5-HT. Several second-gener-
ation triptans (zolmitriptan, naratriptan, riza-
triptan, and frovatriptan) are more potent than
sumatriptan in contracting human coronary
arteries in vitro, although their maximum con-
traction is lower than or equal to that of suma-
triptan (Fig. 16-10).26>108>A3'143>158 At concen-
trations equivalent to therapeutic plasma levels
achieved on clinical dosing, there is little no
contraction of coronary arteries.113
The relationship between sumatriptan-
induced contraction and underlying coronary
artery disease in isolated arteries is unclear.
Some studies show that triptan contractile ef-
ficacy is potentiated in the presence of a dys-
functional endothelium, while others report no
association between sumatriptan-induced con-
traction and atherosclerosis. >88>183
Although the precise cause of the triptan-
induced chest tightness that can appear after
administration of triptans is unknown, the
symptom is not thought to be caused by myo-
carcfral ischemia in most cases. Alternative ex-
planations such as esophageal spasm have been
postulated. In healthy normal subjects, SC
sumatriptan causes a significant increase in the
amplitude and duration of esophageal contrac-
tions.49'79 These effects are particularly marked
in patients who suffer chest pain after taking
sumatriptan. Esophageal dysfunction can cause
chest symptoms indistinguishable from those
produced by the triptans and by angina. Data
supporting the esophageal hypothesis are, how-
ever, limited. Other suggested mechanisms in-

Figure 16-10. Contractile effects of 5-HT and triptans on ring preparations of human epicardial coronary arteries ob-
tained from hearts of cardiac transplant recipients. Ordinate: contraction of ring in response to agonist platted as per-
centage of response to 80 mM KCl; abscissa: log concentration of agonist. 5-HT (); zolmitriptan (O); and sumatriptan
(D). Points are the means of 7 to 10 preparations; vertical lines: standard error of the mean. (Adapted from Martin GR,
Robertson AD, MacLennan SJ, et al.: Receptor specificity and trigeminovascular inhibitory actions of a novel 5-HTiB/io
receptor partial agonist 311C90 (zolmitriptan). Br J Pharmacol 121:157-164, 1997, with permission.)
362 Management of Acute Attacks
elude pulmonary vasoconstriction and inter-
costal muscle spasm.
Because the triptans have the potential to
cause coronary vasospasm and cardiac isch-
emia, labeling restrictions indicate that they be
contraindicated in patients with coronary
artery disease. Prudence would dictate that pa-
tients with Prinzmetal's angina (variant angina)
should not be treated with triptans (Table
16-5). In patients with preexisting coronary
artery lesions or Prinzmetal's angina, even a
minor contraction of coronary arteries that
might occur at therapeutic plasma concentra-
tions of triptans could potentially have delete-
rious effects resulting myocardial ischemia. Be-
cause of the possibility of additive and
prolonged vasoconstrictive reactions, triptans
Table 16-5. Contraindications to the
Use of Triptans
Ischemic heart disease
Prinzmetal's angina
Administration of ergotamine, dihydroergotamine,
or methysergide within prior 24 hours
Cerebral vascular disease
Peripheral vascular disease
Hemiplegic, basilar, or retinal migraine or
migraine with prolonged aura
Uncontrolled hypertension
Heart disease (valvular problems, arrhythmias)*
History of analgesic/ergotamine abuse**
Use of selective serotonin reuptake inhibitors t
Risk factors for coronary artery disease
(menopause, men over 40 years of age,
hypertension, obesity, diabetes, smoking, strong
family history)*
Age over 65*
Pregnancy**
Significant hepatic impairment
Significant renal impairment}
Use of propranolol}}
Use of monoamine oxidase inhibitors within prior
2 weeks}}}
Childhood**
'Relative contraindication; use extreme caution. "Rel-
ative contraindication, t Relative contraindication; patients
should be warned of symptoms of serotonin syndrome.
} Relative contraindication; first dose to be given in physi-
cian's office. }Naratriptan only. }}Rizatriptan only; use 5
mg rizatriptan. }}}Sumatriptan, zolmitriptan, and riza-
triptan.
are not to be given concomitantly with vaso-
constrictor drugs such as ergotamine, dihy-
droergotamine, or methysergide, or if the pa-
tient has taken such medications within the
previous 24 hours.105
Many physicians believe that patients in
whom unrecognized coronary artery disease is
possible should have the first dose of a triptan,
particularly SC sumatriptan, administered in a
physician's office. This group includes post-
menopausal women, men over 40 years of age,
and patients with risk factors such as hyper-
tension, hypercholesterolemia, obesity, dia-
betes, a history of smoking, or a strong family
history of coronary artery disease.
CONTRAINDICATIONS
In addition to apprehensions about kidney and
liver impairment and interactions with other
drugs discussed below, there are other con-
traindications to triptan use. Because of con-
cern about vasoconstriction, triptans are not to
be administered to patients with cerebral or
peripheral vascular disease, or to patients with
complicated migraine (basilar, hemiplegic and
retinal migraine, or migraine with prolonged
aura). Triptans have the potential to elevate
blood pressure; they should not be taken by pa-
tients with uncontrolled hypertension. Triptans
should be used with extreme caution in pa-
tients with valvular problems and arrhythmias.
Patients with a history of analgesic or ergota-
mine abuse may also abuse triptans; these
drugs should be prescribed to them with ex-
treme care and careful monitoring. Before trip-
tans are prescribed, patients taking SSRIs
should be warned about the possibility of de-
veloping the symptoms of the serotonin syn-
drome.
METABOLISM AND ITS
CONSEQUENCES
Understanding the metabolism of triptans is
important because of the possibility of drug in-
teractions if the triptan and another agent use
the same metabolic pathways. And because of
their hepatic metabolism and renal excretion,
attention must be paid to the state of these or-
gans when triptans and some of their metabo-
lites are prescribed.

Sumatriptan is extensively metabolized in
the liver and gastrointestinal tract to a phar-
macologically inactive indole-acetic acid analog
via monoamine oxidase A (MAO-A).34'50 The
metabolite is primarily excreted in the urine as
a free acid and as a glucoronide conjugate.
Rizatriptan is also metabolized by MAO-A to
form both an inactive indole-acetic acid me-
tabolite and N-monodesmethyl-rizatriptan, a
minor metabolite with pharmacologic activity
similar to that of rizatriptan and present in a
concentration approximately 14% of the par-
ent compound. Unmetabolized rizatriptan and
its metabolites are excreted primarily in the
urine.192 Zolmitriptan is eliminated principally
by hepatic metabolism followed by urinary ex-
cretion of its metabolites. In contrast to suma-
triptan and rizatriptan, zolmitriptan metabo-
lism occurs by hepatic P-450 enzyme systems
yielding two inactive and one active metabo-
lite. In animal models, the active metabolite, a
N-desmethyl compound, which is several times
more potent than the parent compound in an-
imal models, has plasma concentrations about
one-half to two-thirds of the parent compound
and is likely to contribute to the therapeutic
activity of zolmitriptan.163 Metabolism of the
N-desmethyl metabolite occurs via MAO-A.
Naratriptan is also metabolized by P-450 en-
zyme systems and excreted in the urine.52 Al-
motriptan is metabolized via two primary
routes: cytochrome P-450 is involved in the ox-
idation of the pyrrolidine moiety, and MAO-A
catalyzes the oxidative deamination. A large
amount of the drug is found unchanged in the
urine.142 The metabolism of eletriptan is pre-
dominantly by cytochrome P-450.150 Only a
small percentage is excreted unchanged in the
urine. Its absorption may be slowed as much
as 50% during migraine attacks.86'165 Renal
clearance is the major route of elimination of
frovatriptan; 50% of the dose is excreted un-
changed.
Because MAO-A is the major enzyme re-
sponsible for sumatriptan metabolism, its phar-
macokinetic profile can be altered by concur-
rent administration of monoamine oxidase
inhibitors (MAOIs). The MAOIs may increase
systemic bioavailability and serum sumatriptan
concentrations, particularly for oral and (to a
lesser extent) intranasal formulations that must
pass through the liver after absorption. As a re-
sult, the manufacturer recommends that, as a
rule, oral and intranasal sumatriptan should not
Triptans 363
be given until 2 weeks have elapsed since the
last dose of MAOIs. Similarly, coadministration
of SC sumatriptan and MAOIs is not ordinar-
ily recommended, but if absolutely necessary,
the dose of SC sumatriptan should be reduced.
One study, however, found no increase in ad-
verse events following SC sumatriptan treat-
ment in patients who were taking MAOIs.51
Similarly, because the active N-desmethyl me-
tabolite of zolmitriptan is degraded by MAO-
A, the total dose per day should be limited to
5 mg in patients on MAO I therapy.154 Levels
of rizatriptan may be elevated in patients tak-
ing MAOIs and the drug should not be pre-
scribed for patients taking MAOIs. There is no
interaction of naratriptan with MAOIs.
Triptans should not be prescribed for patients
with significant hepatic impairment.36'37'59 Mild-
to-moderate renal dysfunction is a contraindi-
cation to the use of naratriptan, but not other
triptans.
COMPARISONS WITH
OTHER TREATMENTS
A few investigations have compared the acute
efficacy of triptans with other treatments for
acute relief from migraine attacks. Controlled
studies have shown oral sumatriptan (100 mg)
to be more effective than ergotamine (2 mg
plus caffeine, 200 mg) or aspirin (900 mg plus
metoclopramide, 10 mg). >132 In contrast,
oral sumatriptan (100 mg) is not more effica-
cious at 2 hours than a highly soluble aspirin
salt, lysine acetylsalicylate (1620 mg, equivalent
to 900 mg of aspirin and metoclopramide, 10
mg), or a rapidly absorbed, soluble form of the
NSAID tolfenamic acid (200 mg plus another
200 mg if needed; not available in the United
States).127'180 Sumatriptan nasal spray (20 mg)
is reported to be superior to DHE nasal spray
1 mg plus optional 1 me) at the primary effi-
cacy endpoint of 1 hour.1" Subcutaneous suma-
triptan (6 mg) is reported to have a faster on-
set of action and to be more effective than
DHE nasal spray (1 mg plus optional 1 mg).182
Subcutaneous sumatriptan (6 mg) is superior
to SC DHE (1 mg, plus an optional 1 mg) dur-
ing the first 2 hours; the effects of both med-
ications are similar after 3 and 4 hours, but
there are fewer headache recurrences after
DHE.196 Despite these results, when ques-
tioned, patients prefer SC sumatriptan over
364 Management of Acute Attacks
other acute anti-migraine medications in-
cluding ergotamine, DHE, aspirin, and
NSAIDs.9'11" Rizatriptan (10 mg) has also been
reported by patients to be consistently supe-
rior to standard abortive migraine medica-
tions.6
One consideration when comparing suma-
triptan and the second-generation triptans
to other anti-migraine drugs (e.g., ergots,
NSAIDs) concerns cost (see Tables 14-5,15-1,
and 16-1). Self-administration of SC suma-
triptan with an auto-injection device may, how-
ever, be very cost-effective if it reduces the
necessity for emergency room visits and hos-
pitalizations.173 In this regard, triptans are cost-
effective in patients with severe bouts of
migraine.
EFFICACY AND LONG-TERM
TRIPTAN USE
Not all patients respond to sumatriptan con-
sistently. Only 5% to 7% of patients were con-
sistent non-responders, and a similar number
of'patients do not respond to the new trip-
tans.1?'47'65'185 One study shows that about 9%
of patients using SC sumatriptan and 19% of
patients using the oral formulation, have head-
ache relief only one-third of the time, or even
less often. Sumatriptan's efficacy, moreover,
varies from attack to attack in the same patient.
In one study, 63% of patients responded to
sumatriptan more than 80% of the time, but
only 49% responded over 90% of the time.18
Patients who respond to sumatriptan do not ap-
pear to differ in any significant way from pa-
tients, who do not.167'186 In contrast, patients
for whom triptans always or almost always work
find that efficacy is maintained after repeated,
long-term use. About three-quarters of re-
sponders treat all their attacks with sumatrip-
tan; about 30% of patients eventually discon-
tinue use of sumatriptan.185 The reasons
offered by patients are varied and include ad-
verse events, lack of efficacy, headache recur-
rence, and high cost.
TRIPTAN OVERUSE
As with other anti-migraine medications, ex-
cessive sumatriptan intake can lead to rebound
headaches and the subsequent development of
drug-induced headaches.1'22'87'135'151 It has
been estimated that sumatriptan overuse oc-
curs in between 0.5% and 4.0% of pa-
tients.42'53'54'66'137 Similar problems are re-
ported for zolmitriptan and naratriptan, and
would presumably occur following over-use of
any triptan.102 Some patients overuse the drug
by taking it in anticipation of headaches, in-
stead of at the onset of symptoms. Triptan-
induced headache is most common among
users of SC sumatriptan, especially when there
is a history of previous drug overuse problems
or a mixed migraine-tension-type of headache
problem.42'54
CLINICAL USE OF TRIPTANS
Triptans should be prescribed only after taking
an adequate history of personal and family car-
diovascular disease and risk factors for it. An
EKG is warranted in all patients with risk fac-
tors for unrecognized coronary artery disease
(Table 16-5). With a normal EKG, it is unclear
if further non-invasive cardiac stress testing is
appropriate.117 For asymptomatic patients with
a high risk of atherogenesis, caution must be
exercised. At the least, patients at risk for un-
recognized coronary artery disease should take
their first dose of a triptan under physician
supervision. Some physicians administer an
initial supervised dose when the patient is
headache-free.
Although evidence is far from conclusive,
triptans should be administered as soon as pos-
sible after the onset of headache, but not dur-
ing the aura. Some clinicians believe that nara-
triptan administered during a well-defined
prodrome may prevent attacks and may de-
crease the severity of attacks that subsequently
occur. Triptans are effective in treating well-
established headaches, although they may take
longer to work and may not be as efficacious.
The triptans differ in their pharmacokinetic
profiles and bioavailability, and this may trans-
late into modest-to-moderate differences in ef-
ficacy, side effects, and frequency of headache
recurrence. Although statistically significant
differences have been reported among differ-
ent oral agents, their clinical pertinence is un-
certain. Because clinical experience indicates
large interindividual variability as to how indi-
vidual patients respond to various triptans, and
because interindividual preference for differ-

ent triptans occurs for reasons not evident in
clinical trials, conclusions drawn from compar-
ison data must still be regarded as preliminary.
Well-designed, direct comparative trials are
scarce, and conclusions are frequently based on
small differences in results. Review of the lit-
erature indicates that there are no major dif-
ferences among sumatriptan, zolmitriptan, and
rizatriptan when taken orally at comparable,
appropriate doses.157 As noted previously,
naratriptan has a slower onset. Clinical experi-
ence makes it clear that some patients whose
symptoms are not adequately alleviated by one
triptan may be successfully treated with an-
other.119'1'2 It is not possible, therefore, to pro-
vide precise guidance as to which drug should
be used for specific therapy in individual pa-
tients. The recommended dosages of the trip-
tans are listed in Table 16-6.
Subcutaneous administration is strikingly
more effective: SC sumatriptan given by injec-
tion is simply the most efficacious of all avail-
able triptan formulations. Because its onset of
action is extremely rapid, it is an ideal first-line
medication for patients with severe, rapid-on-
set headaches. The main reason given by pa-
tients for preferring the injection is speed of
relief.74 It is also a valuable rescue medication
for patients with less severe attacks that do not
respond well to other non-triptan (and non-
ergot) medications. It is a preferred prepara-
tion for patients who, because of severe nau-
sea or vomiting, are unable to swallow a tablet.
There is agreement that SC sumatriptan pro-
vides more rapid and more efficacious mi-
Table 16-6. Triptan Dosage Requirements
Recommended
Initial Dose
Agent (mg)
Sumatriptan oral 50
Sumatriptan IN 20
Sumatriptan SC 6 May repeat after
Sumatriptan PRf 25
Oral zolmitriptan 2.5/5
Oral naratriptan 2.5
Oral rizatriptan 10
Oral eletriptan 40-80
IN, intranasal; PR, per rectum; SC, subcutaneous.
"Recommended maximum dosages vary in different reports and reviews and vary in different countries.
t Available in certain European countries.
Tri plans 365
graine relief than either the oral or intranasal
formulations. Unfortunately, the time to re-
currence after parenteral administration is
shorter, and the incidence of side effects is
higher than with other sumatriptan formula-
tions. Parenteral sumatriptan is available in
prefilled, single-dose syringe cartridges (for
use with the IMITREX STATdose Pen) and in
6 mg single-dose vials.
A proportion of migraineurs fear SC> injec-
tions and tolerate them poorly. Intranasal
sumatriptan presents an alternate route for pa-
tients who desire rapid relief, or for those who
suffer from early nausea and vomiting that pre-
clude oral medication, yet are unwilling to use
injections. Intranasal sumatriptan produces
better and faster abatement of symptoms than
the oral preparation. There are some data that,
with the exception of a bitter, unpleasant taste,
the nasal spray is better tolerated than the
tablets. The taste may, however, affect patient
preference. The usual 20 mg dose has been
shown to be optimal in clinical trials. It is also
available in a 5 mg dose.
Oral sumatriptan is best for headaches of
gradual onset and of moderate severity, when
rapid pain relief is not required. Sumatriptan
tablets of 25 and 50 mg are significantly more
effective than placebo, but administration of 50
or 100 mg of sumatriptan is significantly more
effective than sumatriptan tablets of 25 mg
(Fig. 16-5).30-149'174 The 50 mg dosage of
sumatriptan may be as effective as the 100 mg
dosage, with the added advantage of lessening
the incidence of adverse events.133'149'174 The
Maximum Dose
in 24 Hours
Repeat Dose (mg)
May repeat after 2 hours 200-300
May repeat after 2 hours 40
2 hours 12
May repeat after 2 hours 50
May repeat after 2 hours 10
May repeat after 4 hours 5
May repeat after 2 hours 20-30*
80
366 Management of Acute Attacks
50 mg tablet presents the optimum ratio of ef-
ficacy to tolerability.149 It is considered the pre-
ferred initial dose of oral sumatriptan. Al-
though it seems counterintuitive, some data
show that the 100 mg dose may offer advan-
tages in efficacy over the 50 mg dose when used
to treat mild pain.20 Patients who do not re-
spond to an initial administration of sumatrip-
tan (in any formulation) do not typically im-
prove after a subsequent dose of the
medications. If no relief is perceived after the
initial dose, a second dose is usually not given.
(For some individual patients, however, a sec-
ond dose may be effective.19-21'48)
The efficacy at 4 hours appears similar fol-
lowing oral doses of all available triptans. Tri-
als show that at 2 hours, rizatriptan (10 mg),
zolmitiptan (2.5 to 5 mg), and eletriptan (40 to
80 mg) may be more effective than oral suma-
triptan (50 mg), but more data are needed. In
contrast, naratriptan (2.5 mg) has a slow onset
of action and an inferior response rate, al-
though its headache recurrence rate and inci-
dence of side effects are lower.
The recommended dose of rizatriptan is 10
mg.33 Rizatriptan has been formulated as a
tablet and as an oral wafer (rizatripan-MLT)
that rapidly disintegrates on contact with the
surface of the tonguea possible major factor
in patient preference in cases where nausea
and vomiting constitute major symptoms. The
recommended dose of zolmitriptan is 2.5 mg.
The advantage of both compounds appears to
be a faster onset of action and somewhat
greater headache reduction than sumatriptan,
but the differences are small.157 Headache re-
lief is similar at the end of 2 hours with riza-
triptan (10 mg) and zolmitriptan (2.5 mg), but
rizatriptan tends to provide freedom from pain
sooner than zolmitriptan.146 Eletriptan will
take some time to evaluate in clinical practice,
but its efficacy appears to be one of the high-
est among the second-generation triptans. It
also appears to have a low rate of headache re-
currence. Preliminary data indicate that oral al-
motriptan (12.5 mg) is as efficacious as suma-
triptan (100 mg) and may have fewer side
effects, but again, more data are needed. The
slow-onset naratriptan, in the recommended
dosage of 2.5 mg, may be useful for patients
who tolerate other triptan therapies poorly be-
cause of side effects, who have moderate mi-
graine attacks, who have slowly developing,
long-duration headaches, or in whom headache
recurrence is a substantial issue. It would not
be an advisable choice if a rapid onset of ac-
tion were an important goal.
SUMMARY
The therapeutic approach to the treatment of
acute migraine attacks has evolved in the past
several years from the use of nonspecific and
partially specific medications to newer, selec-
tive anti-migraine agentsthe triptans. When
the first one, sumatriptan, was introduced in
1990, its effect on acute migraine attacks was
dramatic. Newer triptans have since been de-
signed with some possibly more appropriate
characteristics. Extensive clinical trials have es-
tablished that all the triptans are effective and
clearly superior to placebo. The success rate
varies between 50% and 70% after 2 hours.
The clinician now has at hand a choice of
agents with different pharmacokinetic and clin-
ical characteristics and routes of administra-
tion. The advent of the triptans has allowed
physicians to shift from stepwise care to more
individually targeted, stratified approaches to
treatment.
But despite their significant palliative effects
against migraine, the triptans have drawbacks.
They do not work well, or at all, in 20% to 25%
of patients, and fail 40% of the time in patients
who are triptan responders. Why this is so is
not understood. A particular problem with all
triptans is recurrence of headache within 24
hours, a phenomenon that may affect 75% of
patients at least some of the time. Our under-
standing of the mechanisms underlying recur-
rence is limited. Adverse events are also fre-
quent, and although most are generally of
mild-to-moderate intensity and interfere with
treatment in less than 10% of patients, there is
a set of disturbing side effects. Pressure or
tightness (and sometimes pain) affects the
chest and neck in many patients. The cause is
unknown, but because of its resemblance to
angina, it raises the specter of myocardial isch-
emia. And indeed, myocardial infarction has
been seen in a small number of triptan-treated
patients, even a few with normal coronary ar-
teries. Patients with coronary artery disease
should not be prescribed triptans and caution
is advised in patients at risk for coronary artery
disease. Triptans are also very expensive med-

ications. Even so, it is hard to underestimate
how significant a contribution the triptans have
made to relieving the pain and other symptoms
of acute migraine.
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167. Sheftell FD, Weeks RE, Rapoport AM, et al.: Sub-
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1225, 1997.
169. Solomon GD, Skobieranda FG, and Genzen JR:
Quality of life assessment among migraine patients
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170. Solomon S, Lipton RB, and Newman LC: The site
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171. Sramek JJ, Hussey EK, Clements B, and Cutler NR:
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175. Subcutaneous Sumatriptan International Study Group:
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176. Sumatriptan Auto-Injector Study Group: Self-
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177. Swan L, Birnie DH, Hood S, et al.: The effects of
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372 Management of Acute Attacks
pulmonary and coronary circulation in patients with
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428, 1997.
178. Tansey MJ, Pilgrim AJ, and Martin PM: Long-term
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179. Teall J, Tuchman M, Cutler N, et al., and the Riza-
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180. Tfelt-Hansen P, Henry P, Mulder LJ, et al.: The ef-
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182. Touchon J, Bertin L, Pilgrim AJ, Ashford E, and Bes
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185. Visser WH, de Vriend RHM, Jaspers NMWH, and
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186. Visser WH, de Vriend RHM, Jaspers NMWH, and
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366 migraine patients. Headache 36:471^75, 1996.
187. Visser WH, Jaspers NMWH, de Vriend RHM, and
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188. Visser WH, Jaspers NMWH, de Vriend RHM, and
Ferrari MD: Risk factors for headache recurrence af-
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Cephalalgia 16:264-269, 1996.
189. Visser WH, Klein KB, Cox RC, Jones D, and Ferrari
MD: 311C90, a new central and peripherally acting
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of migraine: a double-blind, placebo-controlled,
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190. Visser WH, Terwindt GM, Reines SA, et al. for the
Dutch/US Rizatriptan Study Group: Rizatriptan vs
sumatriptan in the acute treatment of migraine. A
placebo-controlled, dose-ranging study. Arch Neurol
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194. Weidmann B, Jansen W, Jansen W, Bojko P, et al.:
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184, 1996.
Chapter 1 7
Mechanism of Action of Ergots
and Triptans
ACTIVATION OF SEROTONIN
RECEPTORS
PUTATIVE SITES OF ACTION
Prejunctional (Presynaptic) Inhibitory
Effects on Trigeminovascular Fibers
Prejunctional 5-HT Receptor Subtypes
For many years it was presumed that ergot al-
kaloids alleviated migraine attacks through po-
tent, selective constriction of painfully dilated
and stretched external carotid arterial vessels.44
Putative evidence that ergotamine constricted
branches of the external carotid artery dates
back more than 60 years to Harold G. Wolff
and his colleagues' early plethysmographic ex-
periments. Wolff not only reported that ergo-
tamine reduced the amplitude of the scalp
artery pulsations but also correlated the
changes with a lessening of head pain. Their
experimental conclusions, however, were in-
validated by findings that there was no corre-
lation between vasoconstriction and decreased
head pain in some of their subjects. This left
an inexact understanding of where and how er-
gots work. The state of our knowledge about
how triptans work is quite different. They were
specifically developed as 5-HT receptor ago-
nists with the ability to constrict intracranial ar-
teries. And as our insight into their mode of ac-
tion has grown, it has also given rise to new
awareness about how ergots work.
Vasoconstriction of Intracranial Arteries
Vascular Locus of Action
Vascular 5-HT Receptor Subtypes
Brain Stem/Spinal Cord Sites of Action
SUMMARY
ACTIVATION OF
SEROTONIN RECEPTORS
However different ergots and triptans may be,
it is now clear that their main therapeutic ef-
fects are exerted via activation of specific 5-HT
receptors. All triptans display high (nanomolar)
affinities at both 5-HTiB and 5-HTiD recep-
tors (Table 17-1). In contrast, ergot alkaloids
are nonselective pharmacological agents that
interact with a number of neurotransmitter re-
ceptors but also possess high affinity for 5-
HTiB/iD sites. Sumatriptan and other triptans
also possess high affinity for 5-HTip receptors
(Table 17-2). Triptans display weaker affinity
for 5-HTiA and 5-HTiE receptors. In fact, at
clinically effective doses, the sumatriptan
plasma concentration (0.1 to 0.2 /u,M) is not
even in the range necessary to activate 5-HTiA
and 5-HTiE receptors, a finding that removes
binding to these receptors from consideration
as a relevant mechanism of action for suma-
triptan (and presumably other triptans as well).
Triptans are essentially inactive at all other
373
374 Management of Acute Attacks

Table 17-1. Receptor Binding Affinities* of Ergot Alkaloids and

Sumatriptan at Human Recombinant Receptors

Receptor Ergotamine DHE Sumatriptan

5-HT1A 9.3 6.0-6.90
5-HT1B 9.2 7.4-8.1
5-HT1D 8.6 7.9-8.5
5-HTiE 6.2 6.2 5.8-7.6
5-HTiF 6.8 7.0 7.6-7.9
5-HT2A 7.7 8.5
DHE, dihydroergotamine.
'Affinity expressed as either log IQ or log [ICso] (nM).
log KI, negative logarithm of the concentration of drug required to inhibit binding to a re-
ceptor; log [ICso], log [ICso]; negative logarithm of the concentration of antagonist required
for 50% inhibition of agonist binding.
Data from Adham et al. (1993),2 Connor et al. (1997),18 Gupta et al. (1997),47 Johnson et
al. (1997),56 Leysen et al. (1996),63 and Newman-Tancredi et al. (1997).79

serotonin receptor sites and have negligible
affinity for various other neurotransmitter
binding sites. In contrast to the triptans, ergo-
tamine and dihydroergotamine (DHE) are
known to have high or moderate affinity bind-
ing at the following biogenic amine receptor
sites: 5-HT1A, 5-HTiB, 5-HTm, 5-HTiE, and
5-HT2 (Table 17-1), as well as at a r and
2-adrenergic, and Da dopamine receptor
sites.10'24-74'84-90
Most triptans are partial agonists with re-
spect to the endogenous agonist 5-HT.18'71'103
Partial agonists have low efficacy (intrinsic ac-
tivity) in producing full biological responses at
the drug-receptor complex, and as shown in
Figure 17-1, their dose-response curves ex-
hibit a "ceiling effect" at less than the maximal
effect produced by 5-HT.
PUTATIVE SITES OF ACTION
Even though their molecular sites of action are
now known, precisely where and how ergot al-

Table 17-2. Receptor Binding Affinities* of Second-generation Triptans at

Human Recombinant Receptors

Receptor Zolmitriptan Naratriptan Rizatriptan Eletriptan Frovatriptan Almotriptan

5-HT1A 6.5 7.1 6.3 7.4 7.3 7.4
5-HT1B 8.3 8.5-8.7 7.4-8.0 8.0 8.0-8.6 7.2-8.0
5-HT1D 9.2 8.3-8.5 8.0-8.4 8.9 8.4-8.9 8.0
5-HTiE <5.0 7.2 6.5-6.8 7.3 <6.0
5-HTiF 7.1-7.6 8.3 6.6 8.2 7.0-8.0
5-HT2A <5.3
5-HT2C <5.3
5-HT3
5-HT7 6.7
"Affinity expressed as either log Kj or log [ICso] (nM).
log Kj, negative logarithm of the concentration of drug required to inhibit binding to a receptor; log [ICso], "log
[ICso]; negative logarithm of the concentration of antagonist required for 50% inhibition of agonist binding.
Data from Adham et al. (1993),2 Beer et al. (1995),6 Brown et al. (1996),11 Connor et al. (1997),18 Gupta et al. (1996,
1997),47'48 Johnson et al. (1997),56 Leysen et al. (1996),63 Martin et al. (1997),71 Napier et al. (1999),78 and Yocca et al.
(1997).107
 Mechanism of Action of Ergots and Triptans 375

Figure 17-1. Contractile effects of 5-HT and triptans on ring preparations of primate basilar arteries. Ordinate: con-
traction of ring in response to agonist plotted as percentage of response to 80 mM KCl, abscissa: log concentration of ag-
onist. 5-HT (); zolmitriptan (O); and sumatriptan (D). Points are the means of 7 to 10 preparations. Vertical lines: stan-
dard error of the mean. (Adapted from Martin GR, Robertson AD, MacLennan SJ, et al.: Receptor specificity and
trigemino-vascular inhibitory actions of a novel 5-HTiB/io receptor partial agonist 311C90 (zolmitriptan). Br J Pharma-
col 121:157-164, 1997, with permission.)

kaloids and triptans work remains undefined. Prejunctional (Presynaptic)

Three major hypotheses, which are not mutu-
ally exclusive, have been offered to explain the
anti-migraine actions of ergot alkaloids and
triptans:
1. The ergot alkaloids and triptans have in-
hibitory effects at prejunctional (presy-
naptic) 5-HT receptors on trigeminovas-
cular fibers that innervate dural and other
intracranial arteries.
2. The ergot alkaloids and triptans act di-
rectly on 5-HT receptors on intracranial
blood vessels, causing vasoconstriction.
3. Ergots and lipophilic triptans with access
to central components of the trigemino-
vascular system block cranial nociceptive
input by inhibiting release of neuropep-
tides and/or block firing of second-order
trigeminal neurons.
Inhibitory Effects on
Trigeminovascular Fibers
The first hypothesis proposes that migraine
headache pain results from activation of sensory
trigeminal nerves surrounding dural and other
intracranial blood vessels (see Chapter 11).
Perivascular trigeminal sensory nerves, when
activated, are believed to release the neu-
ropeptides calcitonin gene-related peptide
(CGRP), substance P, and neurokinin A. They,
in turn, produce neurogenic inflammation. It
has been shown that ergot alkaloids and triptans
reduce neurogenically mediated dural inflam-
matory responses. For example, at therapeuti-
cally relevant doses, ergot alkaloids and triptans
reduce dural plasma extravasation produced
376 Management of Acute Attacks

Figure 17-2. Sumatriptan-induced block of calcitonin gene-related peptide (CGRP) release produced by stimulation of
trigeminal ganglion in cats. The effect of sumatriptan (85 Atg/Kg intravenously) on the levels of CGRP in blood obtained
from the ipsilateral and the contralateral external jugular veins. The CGRP level was increased by electrical stimulation
of the trigeminal ganglion and reduced by sumatriptan. Each point represents the mean standard error of the mean
for five animals. (Adapted from Goadsby PJ and Edvinsson L: The trigeminovascular system and migraine: studies char-
acterizing cerebrovascular and neuropeptide changes seen in man and cat. Ann Neurol 33:48-56, 1993, with permission.)

by trigeminal stimulation.15'18-45'46'69'70'94'104 creased CGRP levels presumably released

Triptans also reduce the dilatation of menin-
geal blood vessels, mast cell and endothelial al-
terations, and platelet activation that result
when procedures activating trigeminal afferent
fibers produce dural inflammation. To produce
these latter effects, doses higher than those
needed to reduce plasma extravasation may be
required.14'75'93'104"
Ergot alkaloids and triptans do not block
dural plasma leakage or dural vasodilatation
produced by exogenous neurokinins or CGRP,
but diminish release of the trigminovascular
peptide neurotransmitter CGRP produced by
trigeminal ganglion stimulation into the venous
effluent draining from the dura in either ex-
perimental animals or humans. Accordingly,
the anti-inflammatory effects of ergots and
triptans are thought to result from activation of
prejunctional 5-HT receptors on the periph-
eral ends of small-diameter trigeminovascular
fibers, thus reducing the release of neuropep-
tides by these fibers (Fig. 17_2).14,33,59,104 The
clinical relevance of these experimental find-
ings is illustrated by observations that the in-
from trigeminovascular fibers into human cra-
nial venous blood during acute migraine at-
tacks are normalized by sumatriptan concomi-
tant with headache relief (Fig. 17-3).34'35
Prejunctional 5-HT
Receptor Subtypes
The precise identity of the pertinent prejunc-
tional 5-HT receptor remains uncertain. As
noted above, ergot alkaloids and triptans bind
with high affinity to 5-HTiB, 5-HT1D, and 5-
HTiF receptors. Although it has been sug-
gested that any or all of these receptor sub-
types could be responsible for the inhibitory
effects of ergots and triptans, the prevailing
view favors the 5-HTiD subtype.7'9'87 Despite
some conflicting data, there is evidence of both
5-HTiB and 5-HTiD receptors in human
trigeminal ganglia. 5-HTiB mRNA, however,
occurs only in small quantities.9'67'87 In exper-
imental animals, mRNA for both 5-HTiB and
5-HTio receptors is present in trigeminal gan-
 Mechanism of Action of Ergots and Triptans
Figure 17-3. Effect of sumatriptan on calcitonin gene-
related peptide (CGRP) levels during attacks of migraine.
Ordinate: CGRP levels of eight individual patients during
a headache (before treatment) and after sumatriptan (ei-
ther 3 or 6 mg administered subcutaneously). Ah1 but one
patient responded with both decreased headache and re-
duced CGRP sampled from the external jugular vein. In
the one exception, there was neither a response to suma-
triptan nor a change in the CGRP level. (Adapted from
Goadsby PJ and Edvinsson L: The trigeminovascular sys-
tem and migraine: studies characterizing cerebrovascular
and neuropeptide changes seen in man and cat. Ann Neu-
rol 33:48-^56, 1993, with permission.)
glion neurons.7'13 Both subtypes are localized
to neuronal ganglion cells, but differences
among species of experimental animals make
it unclear which specific types of trigeminal
ganglion neurons express which 5-HT recep-
tor subtypes.7'105 Only 5-HTio receptors are
detected in trigeminal nerves projecting pe-
ripherally to the dural vasculature. 7
Selective activation of 5-HTio receptors
may be sufficient to block neurogenic inflam-
mation of the dura. As an example, PNU-
109291, a 5-HT receptor agonist showing 5000-
fold more selectivity for primate 5-HTiD than
for 5-HTiB receptors, effectively reduces dural
plasma extravasation produced by trigeminal
stimulation.23 But the idea that sumatriptan
acts solely at 5-HTio receptors has been chal-
lenged: whereas sumatriptan is effective in re-
ducing plasma protein extravasation produced
by trigeminal ganglion stimulation in wild-type
mice, it is ineffective in knockout mice lacking
5-HTiB receptors.108 Such findings suggest
that activation of 5-HTio receptors is not suf-
377
ficient to mediate triptan-induced blockade of
neurogenic dural inflammation. But caution
must be exerted when extrapolating rodent
data to humans, because the pharmacological
profile of what are called 5-HTiB receptors in
rodents is clearly different from that of human
5-HTiB receptors.3
5-HTiF receptors have also been implicated
in ergot alkaloid and triptan activity. Tables
17-1 and 17-2 illustrate that ergot alkaloids
and triptans display high affinity at this sub-
type.2'56'71 mRNA for 5-HTip receptors is ex-
pressed by trigeminal ganglion neurons.1'9'71
Activation of 5-HTip receptors attenuates
dural plasma extravasation induced by electri-
cal stimulation of the trigeminal ganglion.56'86
Moreover, the potent and specific 5-HTip ag-
onist LY 334,370 is effective in acute migraine,
although only in higher doses.41 Studies with
alniditan, a 5-HTi agonist, indicate, however,
that activation of 5-HTiF receptors is not nec-
essary for either anti-migraine action or inhi-
bition of dural plasma extravasation. Alniditan,
like ergot alkaloids and triptans, possesses high
affinity for 5-HTiB and 5-HTiD receptors, but
in contrast to them, has little affinity for 5-
HTip receptors.63 Yet alniditan is an effica-
cious anti-migraine drug and blocks neuro-
genic dural plasma protein extravasation more
potently than sumatriptan.43'64'66 The role, if
any, of 5-HTip receptors for the actions of the
triptans remains obscure.
Vasoconstriction of
Intracranial Arteries
Unlike the debunked traditional view that di-
latation of the external carotid vasculature
causes migraine pain, an alternative view fo-
cuses on painfully dilated intracranial vessels.
This second hypothesis proposes that normal-
ization of putative blood vessel dilatation is the
most important mechanism for pain relief dur-
ing a migraine headache. It is thought that er-
got alkaloids and triptans confer their thera-
peutic action by reducing the diameter of
painfully distended intracranial blood vessels
whose distension had activated perivascular
nociceptive afferent fibers. Selective constric-
tion of meningeal vessels that are believed to
be inflamed during an attack would modify the
geometric stresses placed on perivascular no-
ciceptive axons in die walls of distended and
378 Management of Acute Attacks
edematous dural blood vessels and would raise
the threshold for nociceptive firing.
Evidence that vasoconstriction may be nec-
essary for anti-migraine action comes from
findings that the 5-HT agonist CP-122,288, a
conformationally restricted sumatriptan ana-
logue, is 1000-fold more effective in reducing
dural neurogenic inflammation than sumatrip-
tan is. But devoid of vasoconstrictive proper-
ties, CP-122,228 is ineffective against acute mi-
graine pain.62'88 Similarly, a conformationally
restricted analogue of zolmitriptan, 4991W93,
is a highly potent blocker of protein extravasa-
tion at doses without vascular effects, but is
clinically inactive in acute migraine.28'32 In
contrast, avitriptan and BMS-181885, 5-
HTiB/iD agonists that are much less potent
than sumatriptan as inhibitors of neurogenic
inflammation, are comparable in clinical effi-
cacy to sumatriptan.20'^06'107 Finally, the en-
dothelin receptor antagonist bosantan, the se-
lective 5-HTiD antagonist PNU-142633, and
NK1 receptor antagonists are also effective re-
ducers of dural plasma extravasation, but these
do not produce vasoconstriction and have no
therapeutic action in migraine.22'42'73'88
Vascular Locus of Action
The precise vasoconstrictive locus of action for
5-HTiB/iD agonists is subject to controversy. It
has been variously ascribed to large cerebral
arteries, dural blood vessels, small resistance
vessels, veins, and arteriovenous anastomoses.
The problem is compounded by questions over
possible differences in the ways 5-HTiB/io ag-
onists act on normal vessels and on vessels pu-
tatively dilated as a result of migraine. Gener-
ally, the evidence is strongest for large arteries.
In experimental animals and humans, for ex-
ample, ergot alkaloids and sumatriptan po-
tently contract large pial conduit arteries such
as the basilar, middle cerebral, and middle
meningeal arteries.18'19'55'77'82'83 Many of these
observations come from in vitro studies of iso-
lated arteries and may not be representative of
5-HTiB/iD agonist effects in vivo.
Data about changes in large human artery
diameters in vivo following ergot or triptan
administration are equivocal. Transcranial Dop-
pler ultrasonography (TCD) studies show er-
got alkaloids and sumatriptan producing either
increased or unchanged blood flow velocity in
internal and external carotid, middle cerebral,
posterior cerebral, basilar, and middle menin-
geal arteries.5'16'27'31'65'97-99-109 Moreover, the
correlation between pain relief and blood flow
velocity are imperfect: patients with total alle-
viation of pain may show no changes in veloc-
ity; patients may show a significant increase in
velocity without changes in the intensity of
their head pain.65'99 Data also vary as to
whether the effects of sumatriptan differ dur-
ing and between attacks.16'98 Finally, the ef-
fects measured by TCD after sumatriptan are
often short-lived, while the headache relief is
not.27
Administration of ergot alkaloids and trip-
tans to some (pig, dog, cat, and rabbit), but not
all (rat), anesthetized experimental animals in-
creases carotid arterial resistance and produces
a profound, persistent reduction in carotid
arterial blood flow without changing blood
pressure, heart rate, or flow in other major
vascular beds.18'26'45'68'81'85-95'103 These latter
findings have been attributed to a flow-
limiting constriction that occurs only in certain
components of the vasculature, namely, the ar-
teriovenous anastomoses or shunts that are
thought to provide a major conduit for carotid
blood flow in the anesthetized state.25'85 Al-
though arteriovenous anastomoses have been
hypothesized to dilate during migraine attacks,
there is no evidence that they serve an impor-
tant role in human craniovascular modula-
tion.51 We do know that a particular 5-HT
agonist's ability to affect arteriovenous anasto-
moses is highly correlated with its clinical
efficacy, but the relevance of such carotid he-
modynamic changes to 5-HTiB/iD agonists'
therapeutic actions is unknown.
As for the small vessels, topically applied er-
got alkaloids and triptans cause reductions in
their diameters. Yet small resistance vessels are
not significantly affected by systemically ad-
ministered 5-HTiB/iD agonists.19 In experi-
mental animals or humans, for example,
systemic administration of ergot alkaloids,
sumatriptan, or other triptans does not affect
regional cerebral blood flow (rCBF).4'30'31'60'68'92
In particular, treatment of migraine attacks
with subcutaneous sumatriptan does not cause
focal ischemia.30 It can be said that the in-
tracranial vasoconstrictor action of sumatriptan
occurs at the level of the large conducting ves-
sels and not at the level of the resistance arte-
rioles in the cerebral circulation.
 Mechanism of Action of Ergots and Triptans
The first hypothesis dealt with the idea that
triptans constrict dural vessels dilated as a re-
sult of the inflammation produced by trigemi-
nal activation, but they do so through prejunc-
tional (presynaptic) effects. The second
hypothesis under discussion concerns direct
effects on dural vessels. Findings measured
by selective arterial angiography that intra-
arterially or intravenously injected sumatriptan
causes vasoconstriction of normal dural vessels
of patients without migraine support this hy-
pothesis.50 A constrictive effect of sumatriptan
can be observed in the perfused isolated
meningeal circulation of human dura removed
postmortem and in biopsied human middle
meningeal arteries.54'102
Vascular 5-HT Receptor Subtypes
A number of investigations provide data that 5-
HTiB receptor activation is responsible for
triptan effects on intracranial vasculature. Us-
ing specific 5-HTiB and 5-HTiD receptor an-
tibodies, human meningeal arteries have been
shown to be rich in 5-HTiB receptors but to
have few, if any, 5-HTio receptors.67 5-HTiB
mRNA and 5-HTiB receptor immunoreactiv-
ity are present in human intracranial blood ves-
sels, but 5-HTiD receptor mRNA has a low ex-
pression.9'49'67-100 Furthermore, 5-HT-induced
contraction of isolated cerebral blood vessels
is comparatively insensitive to antagonism by
ketanserin, a compound with some degree of
selectivity for 5-HTiD compared to 5-HTiB
receptors.58 In contrast, although mRNA
coding for 5-HTip receptors is present in
cerebral blood vessels, selective 5-HTip re-
ceptor agonists are devoid of vasoconstrictor
properties.8-56'90'100
Brain Stem/Spinal Cord Sites
of Action
The third hypothesis presupposes that ergots
and triptans work by inhibiting transmission
through the trigeminovascular system in the
brain stem and spinal cord. Because sumatrip-
tan's hydrophilicity prevents access to the cen-
tral nervous system (CNS) when the blood-
brain barrier is intact, actions in the brain stem
would not appear necessary for its anti-
379
migraine actions. Other second-generation
triptans have no difficulty passing through the
blood-brain barrier. Ergotamine and dihy-
droergotamine penetrate the blood-brain bar-
rier poorly, although small amounts do enter
the cerebrospinal fluid (CSF).29'36
Dihydroergotamine and second-generation
triptans block nociceptive trigeminal sensory
transmission at relay sites in the nucleus cau-
dalis and its caudal extension into the dorsal
horn at Cl and C2.21'37'40-61'80 Sumatriptan has
the same action if the blood-brain barrier is
disrupted.57 This may result from activation of
inhibitory 5-HT receptors on the central ter-
minations of trigeminovascular fibers or on
second-order trigeminal neurons. Presumably,
activation of central prejunctional 5-HT re-
ceptors by ergot alkaloids and triptans would
presynaptically inhibit the release of neu-
ropeptides onto intraparenchymal, second-
order neurons in a manner similar to periph-
eral actions against neurogenic plasma ex-
travasation. Alternatively, as has been shown,
5-HTiB/iD agonists inhibit second-order trigem-
inal neurons directly (Fig. 17-4).52>96
Autoradiography demonstrates that radioac-
tive triptans and ergots label a discrete popu-
lation of trigeminal neurons, indicating that
the trigeminal nucleus caudalis and the sub-
stantia gelatinosa possess binding sites for
them.17'36'39'76'101 These presumably represent
5-HTiB/io receptors. This idea is buttressed
by the detection of 5-HTiB/iD receptor
mRNA and receptor immunoreactivity in
trigeminal neurons and the cervical dorsal
hom 9,12,13,67,72,76 Although both 5-HT1B and
5-HTio receptors are present in the trigemi-
nal nucleus, the receptor responsible for the
central actions of ergot alkaloids and triptans
appears to be the 5-HTiD receptor. This con-
clusion is based on findings that DHE,
zolmitriptan, eletriptan, naratriptan, and riza-
triptan 5-HTiB/D agonists, but not the selective
5-HTiB receptor agonist CP-93,129, inhibit
central nociceptive transmission in the trigem-
inal nucleus of experimental animals.21'38'52 In
addition, immunoreactivity for 5-HTiD recep-
tors is most dense on trigeminal fibers running
through the trigeminal tract and on fibers in
close proximity to second-order neurons.67
It appears that the central prejunctional ef-
fects of ergots on trigeminovascular fibers and
the direct dural vasoconstrictive actions of er-
gots and triptans posited by the first two hy-
380 Management of Acute Attacks

Figure 17-4. Ergot and triptan effects on dorsal horn neurons. Firing of a C2 dorsal horn neuron was suppressed by mi-
crointophoretic application of zolmitriptan (Zolmi), ergotometrine (Ergo), and sumatriptan (Suma). The cell was linked
to the superior sagittal sinus. The excitatory amino acid homocysteic acid (HCA) excited the neuron, but control appli-
cations of saline had no effect. Microiontophoretic applications are indicated by bars. (Adapted from Storer RJ and Goadsby
PJ: Microintophoretic application of serotonin (5HT)iB/io agonists inhibits trigeminal cell firing in the cat. Brain
120:2171-2177, 1997, with permission of Oxford University Press.)

potheses are necessary for the effects of 5-HT
agonists on migraine pain. Because sumatrip-
tan does not penetrate the blood-brain barrier,
yet is an effective anti-migraine medication, in-
hibition of nociceptive transmission in the
trigeminal nucleus, posited by the third hy-
pothesis, would appear unnecessary for the
symptomatic treatment of migraine. Whether
action in the trigeminal nucleus might increase
the efficacy of second-generation triptans is
uncertain.
SUMMARY
Activation of specific 5-HT receptors clearly
underlies the effectiveness of ergots and trip-
tans as anti-migraine agents. But beyond agree-
ment about 5-HT receptor activation, details
about their mechanisms of action remain a
topic of debate.53'89 Despite a great deal of sci-
entific effort, no one has resolved whether the
anti-migraine actions of 5-HTiB/iD agonists re-
late primarily to their prejunctional neuronal
actions or to their vascular (vasoconstrictive)
effects or whether, as is likely, both actions are
necessary. An additional central action against
transmission of trigeminovascular nociceptive
information may also be important. There is
also some controversy concerning the precise
5-HT receptor subtype(s) responsible for anti-
migraine action. These questions may be re-
solved by the development of compounds that
are more selective 5-HTiB or 5-HTiD agonists.
 Mechanism of Action of Ergots and Triptans
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100. Ullmer C, Schmuck K, Kalkman HO, and Liibbert
H: Expression of serotonin receptor mRNAs in blood
vessels. FEES Lett 370:215-221, 1995.
101. Waeber C and Moskowitz MA: [3H]sumatriptan la-
bels both SHTio and 5HTiF binding sites in guinea
pig brain. Naunyn Schmiedebergs Arch Pharmacol
352:263-275, 1995.
102. Whalley ET, Motevalian AA, Parsons AA, Feniuk W,
and Humphrey PPA: The human isolated perfused
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840, 1991.
103. Willems E, De Vries P, Heiligers JP, and Saxena PR:
Porcine carotid vascular effects of eletriptan (UK-
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macol 358:212-219, 1998.
104. Williamson DJ, Shepheard SL, Hill RG, and Har-
greaves RJ: The novel anti-migraine agent rizatriptan
inhibits neurogenic dural vasodilatation and extrava-
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105. Wotherspoon G and Priestley JV: Expression of the
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106. Yocca FD, Buchanan J, Gylys IA, et al.: The pre-
clinical pharmacological profile of the putative
antimigraine agent BMS-180048, a structurally novel
5-HT1D agonist. Cephalalgia 15(Suppl 14):174,1995.
107. Yocca FD, Gylys JA, Smith DW, et al.: BMS-181885:
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ties. Cephalalgia 17(Suppl 18):404, 1997.
108. Yu XJ, Waeber C, Castanon N, et al.: 5-Carboxamido-
tryptamine, CP-122,288 and dihydroergotamine but
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Chapter 1 8
Emergency Department Treatment
NARCOTICS
TRIPTANS
DIHYDROERGOTAMINE
PHENOTHIAZINES, HALOPERIDOL,
AND METOCLOPRAMIDE
Headache is a frequent patient complaint in
emergency departments (EDs). Most patients
whose primary complaint is headache have be-
nign disorders, but as many as 16% have head-
aches indicative of serious intracranial pathol-
ogy.51 Differential diagnoses of meningitis,
encephalitis, subarachnoid or intracerebral
hemorrhage, or brain tumor must be consid-
ered when a patient with severe head pain
even if one is convinced it is acute migraine
has significant fever, rigidity of the neck or
signs of meningeal irritation (Kernig's and
Brudzinki's signs), substantial alteration of con-
sciousness or cognition, oculomotor pareses,
papilledema or fundal hemorrhages, unex-
plained vomiting, an abnormal neurological ex-
amination, excessive elevation of the blood
pressure, or a cranial bruit (Tables 18-1 and
18-2). The ED physician must be especially
concerned if the headache is described as the
worst headache the patient has ever endured,
or if the headache is the first significant head-
ache in the patient's life. A patient with a his-
tory of migraine headaches for many years who
is now experiencing a change in the intensity,
frequency, or character of his or her attacks is
another cause of concern. If a particular head-
ache differs from previously experienced ones,
it should always be investigated. A new, pro-
gressive headache that has persisted for days
also suggests a serious underlying cause. Pre-
PARENTERAL KETEROLAC
CORTICOSTEROIDS
OTHER MEDICATIONS
SUMMARY
cipitation of a new headache by coitus or ex-
ertion may indicate a subarachnoid hemor-
rhage. A history of head trauma, HIV infection,
systemic malignancy, or bleeding disorder
should alert the ED physician to the prospect
of substantial intracranial pathology. Under all
of these circumstances, appropriate diagnostic
tests such as computed tomographic (CT)
scans and lumbar punctures must be per-
formed rapidly.
Migraine is the most common, benign head-
ache disorder seen in the ED, accounting for
approximately 60% of adult and pediatric head-
ache complaints.2'6 One survey found that al-
most 20% of female and more than 13% of
male migraineurs had obtained emergency
care for their headaches.9 It has also been re-
ported that 16% of patients received their di-
agnosis of migraine from an ED physician.53
Anecdotal information indicates that ED users
may represent a distinctive population who
lack access to primary care and specialists, self-
medicate, overuse narcotics, benzodiazepines,
and butalbital, and/or suffer from frequent
headaches of intense severity.35'49 Migraineurs
go to EDs for two major reasons: a particular
headache is intense or prolonged and does not
respond to the usual self-administered med-
ications; or the patient has used up his or her
prescription medications. Many patients have
simply been struck by an unusually severe
385
386 Management of Acute Attacks
Table 1 8-1 . Signs and Symptoms of
High-risk Acute Headaches
Severe, crippling headache in a patient with a
history of significant headaches ("worst
headache")
Uncommon presentation of headache in a patient
with chronic headaches (e.g., precipitous onset,
changed sensorium)
Sudden-onset, first severe headache ("first
headache")
Progressively increasing headache
Presence of a neurological deficit
Change in mental status
Nuchal rigidity or other signs of meningeal
irritation
Alterations in eye grounds (e.g., papilledema,
hemorrhages)
Signs of systemic illness (e.g., fever, rash)
Unexplained vomiting
History of head trauma, HIV infection,
malignancy, or coagulopathy
Precipitation of headache by exertion or coitus
Excessive elevation of blood pressure
Oculomotor pareses
Cranial bruit
headache. Others, however, have been suffer-
ing from the headache for days or even
weeks.15 Individuals in this latter group char-
acteristically find their attacks have been in-
creasing in severity over a substantial period
and have had progressively poorer responses to
their regular medication. Frequently their
headaches are the drug-induced result of re-
bound cycles of narcotic, ergotamine, or bu-
talbital use (see Chapters 12 and 25). These
patients are often emotionally exhausted ("last-
straw syndrome").16 Some migraineurs come
to EDs because of physical or emotional de-
pendence upon narcoticsa far more compli-
cated problem.59 And a percentage are drug-
seeking; although they provide the ED
physician with a history compatible with mi-
graine, they do not suffer from the disorder.
All migraineurs who seek ED help are
desperate for relief of pain, nausea, and vom-
iting. Unfortunately, there seems to be no stan-
dard therapeutic regimen for these situations.
Medication is the mainstay of ED migraine
treatmentmost frequently narcotics, trip-
tans, dihydroergotamine (DHE), phenothi-
zines, and non-steroidal anti-inflammatory
drugs (NSAIDs) (Table 18-3). These drugs all
have limitations imposed by their addiction po-
tential, effectiveness, adverse-event profile, re-
currence rate, and cost.
Patients in the ED with migraine often have
been vomiting excessively and may be dehy-
drated. They may need intravenous fluids as
well as medications. In addition, because the
usual ED environment, with its noise, bright
lights, and bustle, is antithetical to migraine re-
covery, patients should be supplied with an ice
bag and placed in a dark, cool, quiet room if at
all possible. Frequently, however, EDs are too
frenetically busy to provide such appropriate
and necessaryancillary amenities. Patients
with moderate to severe headaches can, how-
ever, usually be treated appropriately in EDs
(although delays in treatment are exceedingly
common), provided that medication toxicity,
dependency, or rebound is not part of the clin-
ical picture; that they are not excessively de-
hydrated, electrolyte depleted, hypotensive, or
suffering from intractable nausea and vomit-
ing; that they have have no concurrent medical
illnesses; and that there is no pattern of multi-
ple ED visits. Patients with these latter prob-
lems frequently have to be hospitalized.
Table 18-2. Differential Diagnosis:
High-risk Acute Headaches
"First" or "Worst" Headache
Subarachnoid hemorrhage
Intracerebral hemorrhage
Meningitis
Encephalitis
Systemic infection
Head trauma
Sinusitis
Carotid/vertebral artery dissection
Recent Onset Recurrent Headaches
Cerebral tumor
Subdural hematoma
Cerebrovascular insufficiency
Brain abscess
Giant cell arteritis
Idiopathic intracranial hypertension
Low cerebrospinal fluid pressure
 Emergency Department Treatment 387

Table 18-3. Emergency Department Treatment of Migraine

Dihydroergotamine (DHE 45) 0.5-1.0 mg IV (after metoclopramide (Reglan) 10 mg IV or IM or
prochlorpromazine 3.5-5 mg IV)
Sumatriptan (Imitrex) 6.0 mg SC
Chlorpromazine (Thorazine) 0.1 mg/kg IV at 15-minute intervals X3 if necessary or 50 mg IM
Prochlorpromazine (Compazine) 10 mg IV or IM
Meperidine (Demerol) 100 mg IM (with promethazine [Phenergan] 25 mg or Hydroxyzine
[Vistaril] 25-50 mg IM)
Keterolac (Toradol) 60 mg IM
Propofol (Diprivan) 110-15 mg IV
Valproate (Depacon) 300 mg IV
Dexamethasone (Decadron) 8-20 mg IV
IM, intramuscular administration; IV, intravenous administration; SC, subcutaneous injection.

Although the medications discussed in this
chapter have for the most part been discussed
elsewhere, this chapter provides an overview
of the treatment strategies available to the ED
physician.
NARCOTICS
Traditionally, parenteral administration of
narcotic analgesics (almost always meperidine
[Demerol]), combined with anti-nausea med-
ications has been the ED treatment for se-
vere migraine attacks. Some reports indicate
that it may still be the most commonly admin-
istered treatment.25'34'49 Patients (including
those who are not seeking drugs) often insist
on an injection of meperidine and an anti-
emetic because that is what they have previ-
ously received. Sufficient amounts of a par-
enteral narcotic enable a proportion of patients
to fall asleep, and many awaken improved.
Many clinicians, however, have significant
reservations about meperidine and other nar-
cotics because of the significant potential for
iatrogenic drug addiction. An unfortunate re-
sult of ED physicians seeing the numbers of
narcotic-seeking patients increase is that gen-
uine migraineurs with substantial headaches
may receive inadequate doses of medication if
they go to an ED where the staff is excessively
apprehensive about gratifying drug-seeking be-
havior and/or naive about the severity of mi-
graine headaches.
Whether opiates are effective medications to
use during acute, refractory bouts of migraine
is a controversial issue. For a significant num-
ber of patients, narcotic injections are often of
little benefit and produce only ephemeral re-
lief. In fact, only a minority of patients may
benefit.3'31'33'54 Headaches frequently either
continue or recur in spite of the treatment. On
occasion, this failure can be attributed to ad-
ministration of an insufficient dose of a nar-
cotic or to its administration in a chaotic, noisy,
brightly illuminated room. But at other times,
even a substantial dose of a narcotic injected
in an appropriate setting will do no more than
sedate the patient for an hour or two; the head-
ache then returns unabated. Opioid use is as-
sociated with side effects such as drowsiness
and nausea. In addition, a pattern of repetitive
opioid treatments in the ED, even when no
more frequent than once a week or so, can pro-
duce a rebound syndrome. As a consequence
of these limitations, narcotics in ED treatment
of acute migraine should give way whenever
possible to other modes of treatment and be
reserved only for patients who do not respond
to other anti-migraine medications or who have
contraindications to them, such as coronary
artery disease or pregnancy.
TRIPTANS
If the patient has no contraindication to the use
of triptans and has not been treated recently
with ergots or triptans, subcutaneous suma-
triptan is an effective, rapidly acting medica-
tion.1 Triptan use is reviewed in Chapter 16.
Parenteral sumatriptan, however, is not com-
388 Management of Acute Attacks
monly used by ED physicians because of its ex-
pense and high rate of headache recurrence.
Oral triptans act too slowly for ED use.
DIHYDROERGOTAMINE
Dihydroergotamine is the standard migraine
treatment in some hospital EDs. It is most ef-
fective when administered intravenously (IV).
As many as 85% of patients with acute migraine
attacks are reported to respond to IV DHE,
and the U.S. Headache Consortium considers
it the ED treatment of choice.7'44'52 The de-
tailed use of IV DHE for acute migraine at-
tacks is discussed in Chapter 15. Intranasal
DHE is not usually suitable for patients with
very intense headaches, the type of headache
seen most often by ED physicians.
PHENOTHIAZINES,
HALOPERIDOL, AND
METOCLOPRAMIDE
A number of dopamine D2 receptor antago-
nists (e.g., prochlorperazine, chlorpromazine,
metoclopramide, droperidol, and haloperidol)
can be used to treat acute migraine at-
tacks.4'8'10 Parenteral phenothizines, in partic-
ular, have become frequently administered
drugs. Although the quality of the data is lim-
ited, a number of both controlled and uncon-
trolled studies indicate that parenteral chlor-
promazine (Thorazine) has efficacy.4'22'31'32'41'50
Successful response rates vary from 81% to
94%, although the headache recurrence rate
may be substantial.8'32 As many as 75% of pa-
tients report complete relief from IV chlor-
promazine.32 The compound has also been re-
ported to be more effective than either DHE
or meperidine.4'31
Chlorpromazine can be given intravenously
in a dose of 0.1 mg/kg at 15-minute intervals;
up to three doses may be necessary.4'8'31-32 It
should be injected slowly (>2 minutes) into the
tubing of a normal saline infusion or diluted in
normal saline for administration as a drip.
Chlorpromazine can also be administered in-
tramuscularly (50 mg). Because this drug can
cause orthostatic hypotension, its major draw-
back in an ED setting, it is advisable to keep
all patients supine for 2 to 4 hours and to record
their blood pressure at frequent intervals. To
prevent possible postural hypotension, some
physicians routinely pretreat patients who have
healthy cardiovascular systems with intra-
venous normal saline (500 to 1000 mL) before
administering chlorpromazine. Other possible
side effects include dysphoria, seizures, dys-
tonic reactions, and akathisia.38 The extrapyra-
midal symptoms are easily treated with ben-
zotropin mesyalte (Cogentin).
Among the other phenothiazines, prochlor-
perazine (Compazine, 10 mg intravenously or
intramuscularly) is also reported to act quickly
and effectively to relieve migraine.10'21'23'^4'47'48
Because it does not appear to produce hy-
potension and is less sedating than chlorper-
azine, it is easier to administer intravenously
and may even be more effective. Akathisia
(restlessness associated with anxiety) however,
is reported to develop in more than 40% of pa-
tients receiving 10 mg of prochlorperazine in-
travenously.13 Prochlorperazine administered
rectally is far less efficacious than intravenous
administration.57
Although the data are sparse, butyrophe-
nones may also be effective. Intravenous
haloperidol (Haldol, 5 mg) has been used with
some success.19 Some physicians preadminis-
ter a 500 to 1000 mL bolus of normal saline to
prevent hypotension. Droperidol (Inapsine),
commonly used as an anti-emetic and as an ad-
junct in regional and general anesthesia, has
been reported to be successful in relieving
symptoms in 74% to 81% of patients treated in
the ED for acute migraine.3'45 Various regi-
mens have been used, including one intra-
muscular injection of 2.5 mg or intravenous ad-
ministration of 2.5 mg every 30 minutes until
three doses are given or the patient is asymp-
tomatic.45'58 When opioids are required, or
when other depressants such as barbiturates or
tranquilizers have been taken, droperidol
should be given in reduced doses because it
potentiates the actions of central nervous sys
tem (CNS) depressants. The most commons
adverse reactions reported to occur with
droperidol are mild-to-moderate hypotension,
drowsiness, and akathisia and other extrapyra-
midal symptoms.
Parenteral metoclopramide has been used
alone for acute migraine attacks with varied re-
sults.8'10'18'23'55'56 Rescue analgesic medication
was necessary in 45% of patients.23 Phenoth-
izines are more effective than metoclopramide.

PARENTERAL KETEROLAC
Keterolac (Toradol) (60 mg, intramuscular) is
a NSAID used by many ED physicians as a
substitute for narcotics.5 Studies of its use
have been inadequately controlled, have em-
ployed only small doses of the NSAID, or
have investigated only small numbers of pa-
tients.11'12'1*'26'33'50 Nonetheless, results sug-
gest that a dose of 60 mg has some efficacy
against acute migraine. Most patients with se-
vere migraine, however, consider keterolac
decidedly inferior to meperidine when the lat-
ter is administered in adequate dosages.
CORTICOSTEROIDS
Some authorities recommend the addition of
parenteral corticosteroids, such as dexametha-
sone (Decadron, 8 to 20 mg IV), to other med-
ications in an ED setting.20'29'30'39 In a limited
study, patients receiving dexamethasone in
combination with treatments such as meperi-
dine or DHE were reported to have better out-
comes than patients who did not receive
steroids. Because no controlled data are avail-
able, the place of steroids remains problematic.
OTHER MEDICATIONS
A heterogeneous group of medications has
been reported to be effective as anti-migraine
medications and some may be suitable for use
in the ED. Unfortunately, most have only been
investigated in open studies and all require fur-
ther investigation before they can be recom-
mended.
Intranasal lidocaine has been reported to of-
fer a therapeutic alternative for some patients
with acute migraine.28'36'37 Installation of 4%
lidocaine achieved success (defined as at least
a 50% reduction in pain) in 55% of patients in
a controlled study. Unfortunately, headache re-
curred in 50% of these patients within the first
hour.37 Although a much lower recurrence rate
was reported in an uncontrolled study, lido-
caine's role, if any, in acute migraine appears
limited.28
The rapid-acting, short-duration anesthetic
propofol (Diprivan), when given intravenously
in subanesthetic concentrations (average dose:
110 to 175 mg), is reported to have a very high
Emergency Department Treatment 389
rate of success as an acute anti-migraine med-
ication.27'42 It can be given in boluses of 10 to
30 mg every 3 to 5 minutes. Propofolol pre-
sumably works as an allosteric modulator and
agonist at specific subtypes of GABAA recep-
tors.
Intravenous infusion of valproate (Depacon)
has been reported to abort both acute and pro-
longed migraine headaches.17'40'46 It may be
particularly valuable in patients who have taken
ergotamine, DHE, or triptans in the preceding
24 hours. Valproate sodium (300 mg) diluted
in 100 ml of IV normal saline may be given as
a rapid drip (20 mg/minute). This can be re-
peated in 8 hours. The procedure produces a
low occurrence of adverse events. Both propo-
folol and IV valproate may also be useful in sta-
tus migrainosus, in breaking the cycle of trans-
formed migraine, and in treating intractable
chronic daily headache.
SUMMARY
The ED physician's first obligation is to dis-
tinguish migraine from headaches indicative of
serious intracranial pathology. Once a diagno-
sis of migraine is established, however, the ED
physician must not let worries about narcotic-
seeking behavior be a deterrent to employing
all means to limit the suffering of the patient.
Narcotics in adequate doses are one weapon in
the anti-migraine armamentarium. But a num-
ber of comparative trials have shown that other
anti-migraine treatments are as effective as, or
more effective than, meperidine. Non-opioid
treatments, including parenteral sumatriptan,
DHE, dopamine antagonist antiemetics, and
parenteral NSAIDs, have evolved as standard
therapy in many EDs. And although no clear
consensus has developed for a specific par-
enteral non-narcotic therapy, all patients
should have a reasonable chance of leaving the
ED in some comfort.
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of refractory headache: a pilot study. Headache Q 10:
55-57, 1999.
44. Raskin NH: Repetitive intravenous dihydroergota-
mine as therapy for intractable migraine. Neurology
36:995-997, 1986.
45. Richman PB, Reischel U, Ostrow A, et al.: Droperi-
dol for acute migraine headache. Am J Emerg Med
17:398-400, 1999.
46. Robbins LD: Intravenous valproate for prolonged mi-
graine headache. Headache 40:427, 2000.
47. Saadah HA: Abortive headache therapy in the office
with intravenous dihydroergotamine plus prochlor-
perazine. Headache 32:143-146, 1992.
48. Saadah HA: Abortive migraine therapy in the office
with dexamethasone and prochlorperazine. Headache
34:366-370, 1994.
49. Salomone JA, Thomas RW, Althoff JR, and Watson
WA: An evaluation of the role of the ED in the man-
agement of migraine headaches. Am J Emerg Med
12:134-137, 1994.
50. Shrestha M, Singh R, Moreden J, and Hayes JE: Ke-
torolac vs chlorpromazine in the treatment of acute
migraine without aura. A prospective, randomized,
double-blind trial. Arch Intern Med 156:1725-1728,
1996.
Emergency Department Treatment 391
51. Silberstein SD: Evaluation and emergency treatment
of headache. Headache 32:369^04, 1992.
52. Silberstein SD for the U.S. Headache Consortium.
Practice parameter: evidence-based guidelines for mi-
graine headache (an evidence-based review). Neurol-
ogy 55:754-763, 2000.
53. Stang PE, Osterhaus JT, and Celentano DD: Mi-
graine. Patterns of healthcare use. Neurology 44(Suppl
4):S47-S55, 1994.
54. Stiell IG, Dufour DG, Moher D, et al.: Methotri-
meprazine versus meperidine and dimenhydrinate in
the treatment of severe migraine: a randomized, con-
trolled trial. Ann Emerg Med 20:1201-1205, 1991.
55. Tek DS, McClellan DS, Olshaker JS, Allen CL, and
Arthur DC: A prospective, double-blind study of
metoclopramide hydrochloride for the control of mi-
graine in the emergency department. Ann Emerg Med
19:1083-1087, 1990.
56. Tfelt-Hansen P, Olesen J, Abelholt-Krabbe A, Mel-
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clopramide in the treatment of migraine attacks. J
Neural Neurosurg Psychiatry 43:369-371, 1980.
57. Thomas SH, Stone CK, Ray VG, and Whitley TW: In-
travenous versus rectal prochlorperazine in the treat-
ment of benign vascular or tension headache: a ran-
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58. Wang S, Silberstein SD, and Young WB: Droperidol
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This page intentionally left blank
PART IV

PROPHYLAXIS
This page intentionally left blank
Chapter 1 9
Overview of Indications
and Guidelines
CRITERIA
DRUG EFFICACY
EFFICACY: INDIVIDUAL PATIENTS
PROPHYLACTIC AGENTS: OVERVIEW
SUMMARY
Many patients with severe or frequent attacks
of migraine require daily prophylactic medica-
tion to control their headache symptoms. Pre-
scribing preventative medication has multiple
aims: to diminish the frequency, intensity, and
duration of bouts of migraine; to reduce dis-
ability; and to enhance the quality of life. Ex-
tensive clinical experience, together with a va-
riety of controlled trials, has established that
prophylactic drugs can lessen the frequency
and severity of migraine attacks, although few
drugs are more than 50% effective. All pre-
ventative drugs have side effects and need to
be prescribed with circumspection. Moreover,
finding the proper medication in its effective
dose for a particular patient is not always an
easy task. The present chapter will provide an
overview of prophylactic medication. The en-
suing chapters will provide detail about the use
of specific prophylactic medications.
CRITERIA
The criteria for initiating preventative medica-
tion vary.5'8'13'15'17'20-21 Some authorities pre-
scribe prophylactic drugs if a patient has more
than one severe, disabling headache a month.
Others feel that daily medication is warranted
only if the frequency is greater than one head-
ache per week. Simple calendar accountings
like this, I think, beg the question. Aspects of
an individual's headache problemother than
frequencymust enter into the equation
(Table 19-1). For example, one would not hes-
itate to prescribe preventative medication for
patients with relatively infrequent attacks if the
headaches were long-lasting, were sufficiently
incapacitating to disrupt the patient's life, were
causing recurrent absences from work, and/or
were interfering with family responsibilities
and activities. Similarly, prophylactic medica-
tions are appropriate when migraine attacks are
accompanied by substantial neurological symp-
toms such as hemiplegia or aphasia. Prophy-
laxis for infrequent attacks would also be war-
ranted if the bouts were not readily controlled
by symptomatic or abortive medication, or if
abortive medications caused untoward side ef-
fects or were medically contraindicated. A pa-
tient overusing abortive medication, and there-
fore suffering from rebound headaches, is
another good candidate, although prophylactic
agents are usually ineffective as long as die pa-
tient continues to overuse analgesics and er-
gots. Drug overuse, therefore, must be treated
before embarking on prophylaxis. If headaches
are infrequent and respond readily to treat-
ment with triptans, ergots, or other medica-
tions, prophylactic therapy is not indicated.
Quite a few individuals are reluctant to use
daily medication. The concept of preventative
395
396 Prophylaxis
Table 1 9-1 . Prophylaxis for Migraine
Guidelines for Starting Prophylactic Medication
Frequent migraine attacks
Attack duration longer than 48 hours
Extreme headache severity or disability (even if
sporadic)
Interference with patient's daily routine, work,
and/or home life
Patient preference for prophylactic medication
Abortive drug overuse (use more than twice a
week)
Contraindication to, or inadequate relief from,
abortive drugs
Adverse events from abortive drugs
Complicated migraine (migraine with prolonged
aura, hemiplegic migraine, basilar migraine,
migrainous infarction)
medication may be foreign to some patients,
particularly if they have been treated with
nothing but analgesics for many years. Fur-
thermore, because prophylactic medications
prevent rather than cure, the relationship be-
tween drug intake and efficacy may not be ob-
vious to some patients. The physician's role is
to explain patiently both the rationale for use
of prophylaxis and the plan of therapy. Com-
pliance with daily prophylaxis is often difficult
unless the patient understands the purpose of
the medication, comprehends the idea that a
prophylactic agent usually does not work im-
mediately, and accepts the possibility that the
medications may have some side effects and
may not be totally effective. Noncompliance
with prophylactic medication is common be-
cause migraineurs frequently experience side
effects before they take a drug long enough to
note its beneficial results.19 Moreover, for un-
known reasons, adverse reactions appear to be
more frequent in migraineurs than in patients
taking the same meoUcation for other reasons.
Migraineurs with longstanding headaches
have often seen many physicians in the quest
for relief from suffering. If they are in a physi-
cian's office, that is prima facie evidence that
they have not found successful treatment (but
it is also evidence that they are still hoping to
find help). Their hope, however, may be tem-
pered by considerable skepticism, for previous
physicians may not have taken the necessary
time or effort to enlighten them appropriately
about the medications and their side effects,
and, as a consequence, these individuals may
distrust all physicians and all medications. The
absolute necessity of educating patients be-
comes even clearer when one factors in data
that approximately half of all patients who go
to a physician for whatever reason either do not
take the prescribed drug at all, do not take it
as prescribed, or stop treatment as soon as they
are feeling better.6
Patients seeking treatment not infrequently
have had previous unsuccessful trials with pre-
ventative medications. Many so-called non-
responders have never been given adequate
doses or have not had preventative medication
administered for a sufficient period of time. In
addition, many patients have been tried on
medications even though they were concomi-
tantly taking daily analgesics, excessive amounts
of ergots, or immoderate quantities of caffeine.
Before judging a patient a non-responder to a
previously prescribed medication, attempts
must be made to obtain all old records, in-
cluding the physician's and pharmacist's records,
to assure that the medication was indeed tried
properly.
DRUG EFFICACY
Although there are exceptions, many prophy-
lactic medications have not been subjected to
intensive investigation in a sufficient number
of good-quality, randomized, double-blind,
placebo-controlled clinical trials (Table 19-
2).2'14 Although propranolol has been investi-
gated in 18 trials, other /3-blockers have been
less well studied (e.g., metoprolol, three trials;
atenolol, three trials; timolol, three trials;
nadolol, one trial). The widely used medica-
tions amitriptyline, verapamil, and methy-
sergide have been appropriately studied in only
three, four, and three trials, respectively.
Moreover, Ramadan and colleagues have ar-
gued that the majority of the controlled trials
of preventative anti-migraine drugs lack scien-
tific rigor.14 And most medications effective in
the prevention of migraine have not been ap-
proved for this purpose by the Food and Drug
Administration (FDA). In general, the manu-
facturer has not performed the necessary in-
vestigations required for FDA approval. Any
approved medication may, of course, be used
 Overview of Indications and Guidelines 397

Table 19-2. Prophylactic Anti-migraine Drugs

Clinical Scientific Proof Side-effect
Medication Efficacy of Efficacy Potential
Amitriptyline 2-3+ 2-3+ 3+
j8-Blockers 4+ 3-4+ 2+
Cyproheptidine 1+ NA 2-3+
Valproate 4+ 4+ 3+
Flunarazine 3-4+ 4+ 2-3+
Fluoxetine 1+ 1+ 1-2+
Gabapentin 2+ 2+ 1+
Lithium 1-2+ 1+ 4+
MAOIs 3-4+ NA 4+
Methysergide 4+ 34+ 4+
Mg2+ 1+ 1+ 1+
NSAIDs 1-2+ 3+ 2+
Pizotifen 2+ 2+ 3+
Prozac 1+ 1+ 2+
Verapamil 2+ 1+ 1+
MAOIs, monoamine oxidase inhibitors; NSAIDs, non-steroidal anti-inflammatory drugs. 1 + ,
slight; 2+, moderate; 3+, high; 4+, very high; NA, not available.
Data in part from Silberstein (2000)^ and Tfelt-Hansen (1997).20

for an unapproved application, but in the final
analysis, physicians' choices of prophylactic
medication are largely empiric.7
EFFICACY: INDIVIDUAL
PATIENTS
Determination of how well a specific medica-
tion is working in an individual patient is im-
portant because only rarely do prophylactic
agents completely eliminate headaches. Ob-
jective evaluation is sometimes very difficult,
but it must be attempted. A headache diary is
very valuable, providing the only objective ev-
idence of efficacy:
1. The beneficial effects of most preventa-
tive agents increase with time. Accordingly,
prophylactic agents must often be tried for sub-
stantial periods before the treating physician
can be sure whether the medication is work-
ing.
2. The natural history of migraine may be
exceedingly erratic. Patients with the disorder
are prone to relapses and remissions, the time
course of which may be exceptionally variable.
3. Drugs prescribed for migraine can have
an impressive, often intense, placebo effect. In
one investigation a decrease in migraine fre-
quency of up to 70% was noted within 3
months among patients assigned to place-
bos.10'11 Migraineurs are particularly prone to
report therapeutic effects when the physician
demonstrates intense personal interest in the
efficacy of the agent, especially when the pa-
tient really wants to believe this medication will
be the one that works. Placebo effects may be
very dramatic in the first few weeks of therapy,
although they often diminish with time.
A headache diary, conscientiously kept, can
document the actual condition of the patient.
This is especially useful when one drug is aban-
doned as unsuccessful and another is tried.
PROPHYLACTIC AGENTS:
OVERVIEW
All prophylactic agents should be started in
low doses and slowly titrated upward until a
therapeutic effect (or significant side effects)
is noted, or until the ceiling dose for the agent
has been reached. The aim is to use the small-
est amount with the fewest side effects. Often
low doses are satisfactory. Some individuals
respond to as little as 10 to 30 mg per day of
398 Prophylaxis
amitriptyline. Depressed individuals may re-
quire 150 to 200 mg per day. There are also
migraineurs who require very high doses for
a therapeutic effect and appear to tolerate
large amounts of medication very well. Pro-
phylactic drugs generally should be avoided in
pregnant patients (see Chapter 25). The physi-
cian must determine whether female patients
practice effective birth control before starting
prophylaxis.
It is commonly held that 1 to 3 months at a
therapeutic, tolerable dosage should be al-
lowed before effectiveness is evaluated. This
may be true for some drugs (such as propra-
nolol and other /3-blockers and calcium-channel
blockers), but some medications (e.g., dival-
proex sodium and methysergide) can work so
rapidly that substantial effects may be noted
during the first few weeks. As noted above, pro-
phylactic medication is frequently ineffective
when patients are overusing analgesics, trip-
tans, or ergots. Limitation of abortive medica-
tions to 1 or 2 days per week is necessary. To
minimize the possibilities of drug interactions
and side effects, prophylactic therapy should
be given as monotherapy. At times, however, a
patient will respond better to two medications
(e.g., a/3-blocker and a tricyclic antidepressant)
than to a single agent. If a given medication is
ineffective in preventing migraine attacks, or if
it is causing intolerable adverse effects, another
prophylactic agent should be tried. Sometimes
a different member of the same class will work;
other times, another type of medication is nec-
essary. Some patients with refractory head-
aches may only respond on the third or fourth
attempt. Sometimes a combination of two
medications is efficacious. For example, a syn-
ergistic effect between propranolol and ami-
triptyline has been described.3'9 Prophylactic
therapy should be reevaluated at 6 months and
if the migraine is controlled, tapering or dis-
continuing the agent should be considered.
The effects of prophylactic medication some-
times last for six months or more after discon-
tinuation.4'12
Unfortunately, there are no published poli-
cies that provide an absolute basis for deciding
which is the most rational agent for a particu-
lar patient. It is impossible to predict which pa-
tient will respond to which prophylactic med
ication (Table 19-3). The treating physician
must individualize therapy based on a number
Table 19-3. Use of Prophylactic Drugs
Determine if there are contraindications to use of
particular agent (coexisting medical conditions,
possible drug interactions)
Use monotherapy wherever possible
Start with low doses
Increase dosage slowly until therapeutic effect
achieved, or significant side effects occur, or
ceiling dose for drug is reached
Allow a therapeutic trial of 1 to 3 months
If initial medication is ineffective, try several
agents in sequence
Be sure that there is no concomitant overuse of
analgesics, triptans, or ergots
Reevaluate at 6 months
If headaches are well controlled, consider slow
taper
Make sure women of childbearing age are not
pregnant or on adequate contraception
of factors. In particular, before prescribing, a
physician must be certain that the proposed
drug is neither medically contraindicated nor
likely to interact with the patient's other
medications, including headache medications
(Table 19-4). Attention must be given not only
to the potential for side effects but also to var-
ious medical conditions such as high or low
blood pressure, obesity, a history of depression,
difficulties with sleep, or untoward previous ex-
periences with the medication under consider-
ation. Some generalizations can be made. /3-
Blockers are contraindicated in patients with
bronchospastic conditions such as asthma and
in individuals with depression or a history of
depression. /3-Blockers should be avoided in
athletes because they limit peak cardiovascular
performance. Methysergide should not be pre-
scribed for patients with angina pectoris or
peripheral vascular disease. Patients with
epilepsy, obesity, or cardiac conduction diffi-
culties should not receive tricyclic antidepres-
sants. Monoamine oxidase inhibitors (MAOIs)
should not be prescribed for hypertensive pa-
tients. Non-steroidal anti-inflammatory drugs
(NSAIDs) should be restricted in patients with
peptic ulcer.
Most authorities generally consider /8-block-
ers a "first-line" prophylactic drug. This opin-
ion is supported by extensive clinical experi-

Table 19-4. Contraindicated Prophylactics and Concomitant
Medical Conditions
Medical Disorder
Arrhythmias
Asthma
Cardiac conduction disturbances
Congestive heart failure
Coronary artery disease
Depression
Epilepsy
Gastrointestinal disease
Hepatic dysfunction
Hypertension
Hypotension
Obesity
MAOIs, monoamine oxidase inhibitors; NSAIDs, non-steroidal anti-inflammatory drugs.
ence and by controlled trials. Calcium-channel
blockers are worthwhile options and should be
tried in patients who have contraindications to
the use of, or intolerable side effects from, j8-
blockers. Hypertensive individuals and patients
with angina may respond well to either )8-
blockers or calcium-channel blockers (Table
19-5).18 Tricyclic antidepressants are often of
value when patients have depressive features,
are clinically depressed, or have sleep distur-
bances accompanying their migraine. They are
most often beneficial for patients with both mi-
graine and tension-type headaches or for pa-
tients with transformed migraine. Divalproex
sodium may be particularly valuable when
epilepsy or bipolar disorder coexist with mi-
Table 19-5. Indicated Prophylactics and Concomitant
Medical Conditions
Medical Disorder
Angina
Bipolar disorder
Depression
Epilepsy
Hypertension
Insomnia
MAOIs, monoamine oxidase inhibitors; SSRIs, selective serotonin reuptake inhibitors.
Overview of Indications and Guidelines 399
Contraindicated Anti-migraine Drugs
Tricyclics
jS-Blockers
j8-Blockers, calcium channel blockers
Calcium-channel blockers
Methysergide
/3-Blockers
Tricyclics
NSAIDs
Valproate
MAOIs
/3-Blockers, calcium-channel blockers
/3-Blockers, tricyclics, valproate,
cyproheptidine, pizotifen
graine. Although many practitioners use
NSAIDs, their efficacy is limited compared to
that of /3-blockers and divalproex sodium. Fi-
nally, because of the large potential for adverse
reactions, methysergide, MAOIs, and lithium
are usually prescribed only for patients unre-
sponsive to other therapies (Table 19-6).
The cost of preventative medications should
also enter the equation (Table 19-7). Adelman
and colleagues recently showed that the more
expensive preventative medications such as di-
valproex sodium, methysergide, and flu-
narazine are cost-effective only at very high
headache rates (e.g., eight attacks per month)
compared to the costs of acute anti-migraine
medication.1
Indicated Anti-migraine Drugs
Calcium-channel blockers
Valproate
Tricyclic antidepressants, SSRIs, MAOIs
Valproate
/3-Blockers, calcium-channel blockers
Tricyclic antidepressants
400 Prophylaxis

Table 1 9-6. Prophylactic Anti-migraine Drugs

Efficacy and Effects Drug(s)
High efficacy /3-Blockers, TCAs, valproate,
Acceptable level of adverse effects flunarazine
High efficacy Methysergide, MAOIs
Significant adverse effects
Low efficacy Verapamil, NSAIDs, SSRIs,
Acceptable level of adverse effects cyproheptidine, gabapentin, magnesium
Low efficacy Lithium
Significant adverse effects
MAOIs, monoamine oxidase inhibitors; NSAIDs, non-steroidal antiinflammatory drugs; SS-
RIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.
Data from Silberstein (1997).15

SUMMARY equivalent clinical headache syndromes react

Prophylactic medication can alleviate the bur-
den of living with migraine, but will only
rarely completely eliminate headaches. While
physicians can select from a considerable
number of pharmaceutical agents, there are
no published rules to ascertain the appropri-
ate preventative drug for a given patient. It
remains unclear why patients with virtually
so differently to the same prophylactic med-
ications. The physician must learn to individ-
ualize therapy. Many years of clinical experi-
ence and the data from a number of trials have
shown that prophylactic drugs, if used appro-
priately, are effective in at least one-half of
patients in lessening the frequency and some-
times the severity and duration of migraine
attacks.

Table 19-7. Cost of Preventative Miigraine Therapy

Dosage Average Wholesale Price
Medication Brand Name (mg per day) ($ per month)
Amitriptyline Elavil 75 33.63
Doxepin Sinequan 75 35.43
Fluoxetine Prozac 20 79.24
Fluvoxamine Luvox 100 166.99
Gabapentin Neurontin 900 104.47
Methysergide Sansert 6 199.01
Naproxen Naprosyn 500 25.51
Nortriptyline Pamelor 75 105.61
Paroxetine Paxil 20 69.85
Phenelzine Nardil 45 42.36
Propranolol Inderal LA 120 49.51
Sertraline Zoloft 100 72.28
Topiramate Topomax 200 177.19
Trazodone Desyrel 100 201.78
Valproate Depakote 500 49.75
Verapamil Isoptin SR 240 72.87
Data from 2000 RedI Book, Medical Economics Data, Inc. (non-generic prices).

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and Rapoport AM: Migraine preventative medications:
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1999.
3. Dexter JD, Byer JA, and Slaughter JR: The concomi-
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4. Diamond S, Kudrow L, Stevens J, and Shapiro DB:
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633-638, 1989.
11. Migraine-Nimodipine European Study Group (MINES):
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Overview of Indications and Guidelines 401
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up after flunarizine or nimodipine discontinuation in
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18. Solomon GD: Management of the headache patient
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Chapter 20
/J-Blockers andCalcium-channel
Blockers
0-ADRENERGIC RECEPTOR
ANTAGONISTS (0-BLOCKERS)
Adrenergic Receptors
Pharmacokinetics
Guidelines for Use of Propranolol
Effectiveness of Propranolol
Use of Other j3-Blockers
Side Effects
Contraindications
Mechanism of Action of fi-Blockers
CALCIUM-CHANNEL BLOCKERS
Side Effects
/3-Blockers are the most widely prescribed
medications for the prevention of recurrent
bouts of migraine. /3-Blockers are considered
the first line in migraine prophylaxis, and if
there are no contraindications to their use,
most physicians prescribe them first. Con-
trolled trials have convincingly demonstrated
that propranolol (Inderal) and metoprolol (Lo-
pressor) have migraine prophylactic activ-
ity.2,4,16,27,33,45,56,62,66,91,101 jt must be remem.
bered, however, that many clinical trials were
carried out in the 1970s and early 1980s when
clinical trial design was far from standardized.
Nonetheless, clinical experience has confirmed
the validity of these early results. Controlled
trials have also shown timolol (Blocadren),
nadolol (Corgard), and atenolol (Tenormin) to
be effective^20-30'74-86'92 All five of these -
blockers clearly can decrease the frequency of
attacks. Their effects on duration and intensity
of migraine bouts are less clearcut.10 Both pro-
pranolol and timolol are approved by the Fed-
402
Contraindications
Verapamil
Nifedipine and Nimodipine
Diltiazem
Flunarazine
Amlodipine
Mechanism of Action of Calcium-channel
Blockers
SUMMARY
eral Drug Administration (FDA) for use in mi-
graine prevention. In contrast, opinions about
the efficacy of calcium-channel blockers vary,
although some clinicians consider verapamil a
reasonable option for patients who cannot use
/3-blockers. It is a very well-tolerated medica-
tion. Flunarazine is another very valuable cal-
cium-channel blocker, but it is not available in
the United States. Experience with other
agents in this class is limited.
0-ADRENERGIC RECEPTOR
ANTAGONISTS (^-BLOCKERS)
Adrenergic Receptors
Researchers divide adrenergic receptors into
two different typesa and /3based on the
specificity of chemical agents capable of acti-
vating or blocking their respective receptors.
By definition, all /3-blockers demonstrate an

antagonistic action at /3-adrenergic receptors.
j8-Blockers may, however, be additionally cat-
egorized into selective and nonselective types,
depending on their relative abilities to antago-
nize the actions of norepinephrine and sympa-
thomimetic amines at the two major classes of
/3-receptors/3i and ($2. There also 3 recep-
tors, whose exact function is unclear.
j8-Adrenergic receptor antagonists produce
their effects by competitive inhibition of the (3-
receptors. At low concentrations, /3i-selective
antagonists inhibit /3i-receptors located pre-
dominantly in cardiac and adipose tissue, and
have less action at the /^-receptors prevalent
in the bronchi and vascular smooth muscle. At
high doses, selectivity is usually lost, and both
j8i- and ^-receptors may be blocked. Nonse-
lective /3-blockers antagonize both fi\- and fa-
adrenoceptors. Blockade of jSa-adrenoceptors
is responsible for many of the adverse reactions
to /3-antagonists such as bronchospasm, hypo-
glycemia, and increased peripheral vascular in-
sufficiency, although some side effects, includ-
ing bradycardia and postural dizziness, are also
related to /3i-adrenoceptor antagonism.
Propranolol, timolol, and nadolol are non-
selective /3-blockers, while atenolol and meto-
prolol have a greater affinity for /3i- than for
/^-receptors. Although the risk is high, j3i-se-
lective drugs are preferable for patients who
suffer from asthma and other respiratory prob-
lems, who are liable to develop hypoglycemia,
and perhaps who have peripheral vascular dis-
ease. j8i-Selective drugs do not reduce a healthy
individual's physical and exercise tolerance to
the same degree as the nonselective /3-agents do.
Pharmacokinetics
The hydrophilic /3-blockers nadolol and atenol-
ol are not as readily absorbed from the gas-
Table 20-1 . IPharmacolog ical Characteiristics of 0-Bl ockers
Drug /3t -selectivity Lipophilicity
Propranolol No
Metoprolol Yes
Timolol No
Nadolol No
Atenolol Yes
j8-Blockers and Calcium-channel Blockers 403
trointestinal tract as the lipophilic j8-blockers
propranolol, metoprolol, and timolol. Hy-
drophilic j8-blockers are also not as extensively
metabolized as the lipophilic drugs.13 Propra-
nolol is highly lipophilic, well absorbed, and
significantly metabolized by first-pass hepatic
metabolism. It has a short plasma half-life (tv2)
of 3 to 6 hours. As shown in Table 20-1, the
tl/z of other j8-blockers varies over a wide range.
Conventional propranolol tablets produce a
high initial peak plasma level followed by a
swift fall. This means that the drug has to be
administered two to four times a day to achieve
any stability of plasma levels. A sustained-
release formulation (Inderal LA) was devel-
oped to maintain therapeutic concentrations in
plasma throughout a 24-hour period. Indeed,
the long-acting propranolol, with prolonged
absorption and lower peak levels, produces sus-
tained blood levels with much smaller varia-
tions over a 24-hour period than conventional
tablets do. The half-life after a dose of long-
acting propranolol is between 10 and 20
hoursthree to four times that of conventional
propranolol. The sustained release forms ap-
pear, however, to have reduced bioavailability
and total daily doses higher than the doses of
conventional formulations may be required.
Nadolol has an extended half-life and the total
daily dose may be given once a day. Metopra-
nol, timolol, and atenolol should be adminis-
tered in appropnately divided doses.
Plasma levels of propranolol and other /3-
blockers usually vary directly with the dose.
However, the same oral dose of propranolol
may show up to 20-fold variation in plasma lev-
els when given to a number of subjects.12'104
This variation (seen also with other /3-blockers)
is a function of many factors, including extent
of hepatic metabolism, coadministered med-
ications, food ingestion, and length of therapy.
Furthermore, although higher doses of /3-
f/2 Bioavailability
(hours) (%)
High 3-6 30
High 3-^ 35
High 4 50
Low 14-24 50
Low 5-8 40
404 Prophylaxis
blockers are generally more effective than
lower doses, the plasma levels of propranolol
and other /3-blockers do not correlate well with
the clinical responses in migraineurs.12'37'76
This would suggest that clinical response is
contingent in large measure on an individual's
sensitivity to /3-blockers, rather than on the
dosage or the amount of /3-blockade produced.
Guidelines for Use
of Propranolol
The optimal dose of propranolol must be de-
termined for each individual patient (Table
20-2). Some individuals with migraine do very
well with doses as low as 40 mg daily.12'63 But
a number of clinical observations and experi-
mental data indicate that for most patients the
amount of improvement is proportional to
dose.73'74'89 To achieve a therapeutic effect
without undue delay, propranolol can be ini-
tially administered in a dose of 60 to 80 mg
long-acting (LA) per day. Clinical experience
dictates that compliance is much higher with
extended-release preparations than with mul-
tiple doses of conventional formulations.36'82 If
there are no side effects, or if the medication
has not produced a substantial fall in blood
pressure and pulse rate, the dose can be in-
crementally increased at a rate that depends on
the patient's frequency of headaches prior to
starting treatment and the patient's response.
Some clinicians raise the dose every other
week, while others prefer to do it monthly.
Some even use bimonthly intervals, although
this appears to be too long. The long-acting
propranolol is best administered twice a day
when higher doses are used. The latter regi-
men is more likely to prevent headaches that
occur upon awakening or that develop in the
early morning.
Table 20-2. /?-B lockers Used for Migraine Prop hylaxis
/3-blocker Brand Name
Propranolol Inderal
Metoprolol Lopressor
Timolol Blocadren
Nadolol Corgard
Atenolol Tenormin
Prescribing inadequate doses of propranolol
is an important cause of treatment failure. If
efficacy is not seen at low or moderate dosages,
doses of propranolol as high as 240 to 320 mg
per day should be administeredprovided the
individual can tolerate thembefore deciding
that propranolol is an ineffective agent in a par-
ticular patient.56 Some authorities even suggest
trying 480 mg per day, but this may be an ex-
cessive dose. Many migraineurs are sensitive
to the cardiovascular effects of /3-blockers and
cannot tolerate high doses. Some patients have
an unexpected sensitivity, developing dramatic
bradycardia and hypotension even on modest
doses. The patient's blood pressure and pulse
should be taken regularly. A pulse of less than
50 per minute or a systolic blood pressure of
less than 90 mm Hg indicates that a higher dose
should not be used. Failure with propranolol
does not predetermine the response to a sec-
ond or even a third /3-blocker. Sequential tests
of different (3 -blockers are sometimes required
before a significant anti-migraine effect is pro-
duced.
Improvement occurs immediately with some
migraineurs, but the number of patients who
respond to propranolol increases with time.71
Some improvement is almost always seen
within 4 weeks, but propranolol should be
given a 3-month trial at the maximum dose the
patient can tolerate before considering the pa-
tient a non-responder. Before treatment is in-
stituted, every migraineur must comprehend
that relief may not come until a prolonged
course of treatment has been tried. Occasion-
ally, patients indicate that their headaches have
worsened after starting propranolol; but most
of them experience a therapeutic effect with
continued administration. In contrast, some
people for whom propranolol has provided re-
lief notice a loss of efficacy after a period of
time. For them, an increase in the dosage usu-
Starting Dose Maximum Dose
(mg per day) (mg per day)
60-80 240-320
100 250
20 60
40 240
50 200

ally remedies the situation. Once a therapeutic
effect has been attained, one can try reducing
high doses slowly for maintenance purposes.
If propranolol is effective, the drug can be
administered indefinitely. But for some mi-
graineurs, a period of 6 months is sometimes
sufficient to eliminate migraine for an ex-
tended period of time. One long-term investi-
gation of migraineurs who had taken propra-
nolol for 8 to 16 months demonstrated that
46% of them maintained their improvement
when a placebo was substituted for the drug.15
But another investigation showed that the pos-
itive effect of successful prophylaxis lasted only
an average of 6 months (range: 1 to 28 months)
after discontinuation of treatment.103 Anal-
gesic intake appears to be among the most im-
portant prognostic factors in determining the
long-term effects of discontinuing propranolol.
If for any reason propranolol is to be dis-
continued, the dosage should be tapered over
a period of 10 days to 2 weeks, and exercise
should be limited during this period. Because
the number of /3-adrenoceptors may be in-
creased (up-regulated) in individuals taking j8-
blockers, abrupt termination may cause a re-
bound headache, produce adrenergic side
effects, or precipitate angina pectoris in pa-
tients with preexisting coronary artery disease.
Severe consequences of rapid withdrawal are
fortunately infrequent in healthy individuals, as
witnessed by the fact that many migraineurs
suspend their use of propranolol and other
j8-blockers precipitously without deleterious
effects.21
Effectiveness of Propranolol
The results of a number of appropriately con-
trolled trials of propranolol indicate that pro-
pranolol is more efficacious than placebo.
There is a substantial range in these studies,
with between 55% and 93% of patients with
migraine reported to respond well to the med-
ication.64 This range may be overly optimistic
and, because many patients in practice fail
to meet the criteria required of trial patients,
the frequency of response to propranolol in
practice may be lower. For example, a few
studies have even failed to demonstrate a sig-
nificant difference between propranolol and
a placebo.27'94 Meta-analysis has shown that
when daily headache diaries are used to assess
/3-Blockers and Calcium-channel Blockers 405
treatment outcomes, proranolol produces only
a 44% reduction in migraine activity.28'29 In
comparison, placebos cause on average a 14%
decrement in migraine activity.
Investigations that have compared the ef-
fectiveness of propranolol with prophylactic
agents such as other /3-blockers, flunarazine,
valproate, non-steroidal anti-inflammatory
drugs (NSAIDs), amitriptyline, and methy-
sergide and have found essentially equivalent
benefit among the medications.1'22'34'41'62'75'87'97
It still remains for the physician and patient to
work together to find the best agent in each
case. Nevertheless, because of its low side-ef-
fect profile, ease of administration, and low
cost, propranolol will probably remain the
agent first selected by most physicians for mi-
graine prophylaxis.
Use of Other 0-Blockers
Only one investigation has demonstrated that
one j8-blocker had an advantageous effect over
anothernadolol in a dose of 160 mg daily was
found to be better than the same daily dose of
propranolol.97 The results of other direct com-
parison trials have shown that when adminis-
tered in doses that are equally effective in re-
ducing heart rate and blood pressure, the
various j8-blockers are equally efficacious
against migraine.33'60'62'73'97
Side Effects
Although many patients complain of side ef-
fects, the j8-blockers as a group have a consid-
erable safety margin. In general, tolerance to
adverse effects is acquired over a period of
weeks so that there is no need to discontinue
medication immediately if some side effects
such as cold extremities or diarrhea appear.
These usually decrease substantially with time.
Fatigue appears to be the most ubiquitous side
effect, and may occur even with low doses. It,
too, tends to diminish in the course of a few
weeks.
Other side effects do not diminish with time.
Many patients complain of not feeling well
while taking j8-blockers. This feeling may re-
flect sluggishness, decreased alertness, or fa-
tigue.72 Gastrointestinal side effects include
nausea, vomiting, and flatulence. Sexual dys-
406 Prophylaxis
function with impotence has been reported, as
has alopecia. Modest weight gain occurs in
about 30% of patients.
/3-Blockers are capable of causing a number
of unwanted central nervous system (CNS) and
behavioral effects. These include sedation,
drowsiness, lethargy, sleep disorders, night-
mares, and hallucinations. On rare occasions,
delirious states and paranoid psychosis have
been reported.35 Some patients complain of
major memory problems. Although there is
controversy about the incidence, depression,
often of a serious nature, has been seen dur-
ing administration of /3-blockers.6'65 The de-
pression may consist of both mood distur-
bances and neurovegetative symptoms. It may
be unresponsive to therapeutic doses of tri-
cyclic antidepressants and usually requires dis-
continuation of /3-blockers.47
Although all the commonly used /3-blockers
penetrate the CNS to some extent, lipophilic
blockers (propranolol, metoprolol, timolol)
which readily cross the blood-brain barrier
have been postulated to cause more CNS side
effects than hydrophilic ^-antagonists (nadolol,
atenolol) that do not cross the blood-brain bar-
rier with ease.35 But CNS disturbances with
hydrophilic /3-blockers have been reported,
and attempts to correlate the CNS side effects
with the lipid solubility of various /3-blockers
have not been very successful, making the hy-
pothesis difficult to prove.17
Much of the caution about using /3-adrenergic
receptor antagonists centers on their possible ex-
acerbation of asthma and chronic obstructive
pulmonary disease, and for good reason. (32 Re-
ceptors in bronchial smooth muscle are impor-
tant in supporting bronchodilatation. In patients
with bronchospastic diseases, /3-blockers may
produce sufficient blockade of jSa-receptors to
cause both bronchial smooth muscle contraction
and increased airway resistance.
Common short-term cardiac effects of /3-
blockers include a reduction in heart rate and
cardiac output, resulting in a decrease of myo-
cardial oxygen consumption. Reports have also
appeared indicating a decrease in coronary
blood flow and an increase in peripheral vas-
cular resistance. These effects are all re-
versible. Because of their effects on heart rate,
/3-blockers may reduce exercise limits. It is be-
lieved, however, that, despite limitations on el-
evation of heart rate, individuals can enhance
cardiorespiratory fitness with exercise while
taking j8-blockers.25
A few case reports have maintained that
strokes occurred during propranolol adminis-
tration to migraineurs.7'24'49'6' Many of the pa-
tients appear to have had other risk factors that
complicated analysis of the possible linkage be-
tween propranolol and the development of
their strokes. If propranolol does predispose to
the development of cerebrovascular symptoms,
it must do so only very rarely.
Contraindications
Individuals with asthma or chronic obstructive
pulmonary disease should not receive /3-blockers
(Table 20-3). Although /^-selective agents
have been reported to have a lower incidence
of untoward pulmonary effects than similar
doses of nonselective drugs, /^-selective agents
are only comparatively selective, and do have
antagonistic actions at /32-adrenoceptors at
higher doses.68 Selective /3i-blockers may
therefore induce bronchospasm in sensitive pa-
tients with pulmonary problems.
jS-Blockers should not be prescribed for pa-
tients with insufficient cardiac reserve because
such drugs could precipitate congestive heart
failure. The mechanism presumably involves
block of activity in the sympathetic nervous sys-
tem, which furnishes essential support for car-
diac performance when myocardial function is
Table 20-3. Contraindications to the
Use of j8-Blockers
Asthma and chronic obstructive pulmonary disease
Limited cardiac reserve or congestive heart failure
Hypotension (<90 mm Hg systolic)
Atrioventricular conduction disturbances
Bradycardia (<50 beats/minute)
Concomitant use of calcium-channel blockers*
Peripheral vascular disease
Use of methysergide and ergots0
Raynaud's disease
Complicated migraine (migraine with prolonged
aura, hemiplegic migraine, basilar migraine,
migrainous infarction)*
Significant cerebrovascular disease*
Insulin- or oral hypoglycemic-dependent diabetes
mellitus
Hyperthyroidism
Pregnancy*
"Relative contraindication.

impaired. Hypotension (<90 mm Hg) is a con-
traindication. Because of the propensity of )3-
blockers to cause bradycardia, they should not
be taken by individuals with significant atri-
oventricular (AV) conduction disturbances
(greater than first degree AV block), and
should be administered with caution to mi-
graineurs with slow sinus rates (bradycardia
<50 beats/minute). In patients with partial or
complete AV conduction defects, j8-blockers
may cause life-threatening bradyarrhythmias.
Because both /3-blockers and calcium-channel
blockers exert a negative chronotropic effect
on the heart, their combined use increases the
risk for bradyarrhythmias with resultant symp-
toms of cerebral, coronary, and systemic hy-
poperfusion. Moreover, concomitant use of
both agents increases the propensity for im-
paired sinus-node function, AV block, and de-
pression of ventricular function.
j8-Blockers may cause peripheral vasocon-
striction. Accordingly, they should be avoided
by patients who suffer from significant occlu-
sive problems in peripheral arteries. For simi-
lar reasons, ergotamine or methysergide should
be used with caution in patients on high doses
of /3-blockers, because of the increased poten-
tial for significant vasoconstriction.8 Raynaud's
phenomenon may develop in patients taking j8-
blockers. Although it is far from clear whether
j3-blockers predispose to vascular events in mi-
graineurs, these drugs should be used with cau-
tion in patients with complicated migraine or
significant cerebrovascular disease.
Diabetics who take insulin or oral hypo-
glycemic agents may experience difficulty with
/3-blockers because blockade of /3-receptors
can conceal the clinical manifestations of hy-
poglycemia. The use of propranolol and other
/3-blockers by migraineurs with mild diabetes
mellitus who do not need insulin or oral hypo-
glycemic agents is usually safe. /3-Blockers also
mask many of the signs and symptoms of hy-
perthyroidism, and should not be prescribed
for individuals with this condition.
The use of /3-blockers in pregnancy is dis-
cussed in detail in Chapter 24.
Mechanism of Action
of 0-Blockers
No one really knows what mechanisms and loci
of action enable /3-blockers to prevent mi-
graine. Because propranolol blocks /3-receptors
/3-Blockers and Calcium-channel Blockers 407
necessary for peripheral vasodilatation, it has
been assumed that the drug also prevents the
cranial vasodilatation believed by some to be
the cause of migrainous head pain. But pro-
pranolol has little effect on cerebral blood
flow.61 Moreover, a number of investigations
have shown that blockade of /3-adrenoceptors
is not sufficient per se to prevent migraine
headaches. For example, reports correlating
propranolol's ability to reduce the frequency of
headaches with its ability to produce periph-
eral j8-blockade as manifested by reduced heart
rate yield inconsistent data.12'37 A number of
potent /3-blockers, such as pindolol, alprenolol,
oxprenolol, and acetbutolol, have shown no ef-
ficacy as anti-migraine agents.18'19-58'79 These
latter compounds have intrinsic sympath-
omimetic activity (i.e., they are partial /3-
receptor agonists), a property thought to ren-
der them ineffective in migraine prophylaxis.
In contrast, D-propranolol, which has only
slight /3-adrenoceptor activity, may be effective
clinicallythe data are unclear.93'96
Some /3-blockers stabilize the membranes of
peripheral nerve cells and heart. This property
was once thought to be important in explain-
ing anti-migraine efficacy. But because the
membrane-stabilizing effects of /3-blockers is
only seen at concentrations 50- to 100-fold
higher than the levels in plasma necessary to
produce /3-blockade, it probably has little clin-
ical relevance. As further evidence against this
theory, propranolol and metoprolol have mem-
brane-stabilizing activity whereas nadolol and
atenolol do not. Even so, all four agents have
therapeutic actions in patients with migraine.
Affinity for 5-HT receptors has also been
thought relevant to the anti-migraine action of
/3-blockers. This is another untenable asser-
tion. Clinical efficacy does not correlate with
the actions of /3-adrenoceptor antagonists at 5-
HTi binding sites.52'57 Pindolol, alprenolol,
and oxprenolol all interact with 5-HT binding
sites at low concentrations, yet are of no value
in migraine.53 One is forced to conclude that
the therapeutic anti-migraine actions of /3-
adrenergic agents cannot be ascribed to antag-
onism of serotonin receptors.
CALCIUM-CHANNEL BLOCKERS
Calcium-channel blockers (calcium-channel an-
tagonists) are a chemically heterogeneous
group of agents that act at calcium channels to
408 Prophylaxis
block the influx of Ca2+ ions in response to
voltage changes. Calcium-channel blockers of
four different classes have been used for the
prevention of migraine headaches: (1) phenyl-
alkylamines (verapamil), (2) dihydropyridines
(nifedipine, nimodipine), (3) benzothiazepines
(diltiazem), and (4) piperazine derivatives (flu-
narizine). Of the available medications, vera-
pamil and flunarazine are commonly used for
the prevention of migraine.
Some calcium-channel blockers are success-
ful against migraine, mostly as related to head-
ache frequency. Reported reductions in head-
ache severity and duration are less dramatic.
But, with the exception of flunarazine (Sibel-
ium), the published data that show calcium-
channel blockers as being effective anti-mi-
graine drugs are much less convincing than
similar data available for /3-blockers. The num-
ber of patients participating in most controlled
studies of efficacy of calcium-channel blockers
has been low; many of the studies suffer from
design deficiencies, and the drop-out rate has
been high. In addition, calcium-channel block-
ers suffer from a slow onset of action in many
patients. The onset of a clinical response is fre-
quently deferred for 2 to 8 weeks (and in some
patients, several months), which may cause dif-
ficulties with patient compliance. Calcium-
channel blocking agents with disparate chem-
ical structures vary in their effects on cells. As
a result, there are differences both in their clin-
ical effects as anti-migraine drugs and in their
side effects. Despite these confusing details,
for some patients calcium-channel blockers can
be extremely effective preventative medica-
tions. Unfortunately, there is no way to iden-
tify such responders without a trial of calcium-
channel blockers.
Side Effects
The side effects of various calcium-channel
blockers differ, but in general, their untoward
effects are dose-dependent. Side effects pri-
marily arise from unwanted extensions of their
calcium-blocking effects on smooth muscle of
peripheral blood vessels and bowel, on the
CNS, and on the heart. The most common side
effects are due to excessive vasodilatation,
which can lead to dizziness and flushing. Hy-
potension, usually modest and well tolerated,
can also occur.
Table 20-4. Contraindications to the
Use of Calcium-channel Blockers
Congestive heart failure
SA or AV nodal conduction disturbances
Cardiac arrhythmias
Bradycardia (<50 beats/minute)
Hypotension (<90 mm Hg systolic)
Concomitant use of /3-blockers*
Depression or history of depression t
Parkinsonismt
Severe constipation
AV, atrioventricular; SA, sino-atrial. "Relative con-
traindication. fFlunarazine only.
Contraindications
Calcium-channel blockers exert a negative in-
otropic effect on cardiac muscle (Table 20-4).
This effect is rarely evident clinically in indi-
viduals with normal hearts, but in patients with
ventricular dysfunction or congestive heart
failure these agents should not be used as anti-
migraine agents. They are also contraindicated
in patients with sino-atrial (SA) or AV nodal
conduction disturbances because Ca2+ is nec-
essary for the genesis of action potentials in the
specialized conducting cells of the heart. Use
of calcium-channel blockers may result in AV
block and bradycardia. They should not be pre-
scribed for patients with bradycardia (<50
beats/minute). By dilating peripheral arterioles
and reducing the total peripheral resistance,
these agents reduce arterial blood pressure at
rest. They are contraindicated for individuals
with a low systolic blood pressures (<90 mm
Hg). Flunarazine should not be prescribed for
patients with depression or a history of de-
pression or for patients with parkinsonism (see
below). Calcium-channel blockers, particularly
verapamil, are constipating and may cause dif-
ficulties in patients with bowel problems.
Verapamil
Both open and controlled studies, and con-
temporary clinical experience, indicate that ve-
rapamil (Calan, Isoptin, Verelan) is a modestly
effective anti-migraine drug.31'43'51'69'84 It may
be especially useful in preventing complicated
migraine. Data from all types of sources show

that, as with the /3-blockers, the primary im-
provement is in migraine frequency. Little
change in the intensity of head pain has been
noted. In most investigations, the drug has
been shown to work equally well against mi-
graine with and without aura.
Higher doses of verapamil are more effec-
tive than lower doses.83 Many patients tolerate
480 mg a day without difficulty. Verapamil is
available in short-acting and long-acting forms.
Because of reduced bioavailability of the sus-
tained release formulations, the 40 mg or 80
mg pills taken several times a day may be
slightly more effective than the long-acting (ve-
rapamil SR, 120 mg, 240 mg) formulation, but
the once-daily administration of long-acting
medications substantially improves compli-
ance. The starting dose is 120 mg slow release
(SR) per day. This may be raised (provided
there are no side effects and heart rate and
blood pressure are maintained) in 120 mg in-
crements at weekly or biweekly intervals.
Side effects are seen in approximately 40%
of patients, but they are usually not substan-
tial.31 Vascular changes such as edema of the
hands and feet, flushing, and lightheadedness
and cardiac abnormalities such as bradycardia,
hypotension, and atrioventricular conduction
defects are less commonly seen. Verapamil is
among the most constipating of the calcium-
channel blockers, with constipation being the
most commonly reported untoward effect of
the drug. If slight hand tremor develops, the
drug can be administered at night to minimize
daytime symptoms.
Nifedipine and Nimodipine
It is difficult to recommend either nifedipine
(Procardia, Adalat) or nimodipine (Nimotop)
for migraine prophylaxis. Although in open
studies nifedipine has been reported effec-
tive in decreasing migraine attack frequency
in a majority of patients, results from con-
trolled drug trials leave its status as an
anti-migraine medication problematic at the
present time.31'32'44'78 Moreover, its high fre-
quency of side effects argue for trying other
calcium-channel blockers before resorting to
nifedipine.
Nifedipine is responsible for a higher inci-
dence of side effects than other calcium-
channel blockers. As many as 50% to 70% of
/3-Blockers and Calcium-channel Blockers 409
migraine patients report untoward effects, an
incidence of side effects that appears higher
than in patients receiving the drug for cardiac
conditions. The most common adverse effect
is postural hypotension with dizziness, but vas-
cular complaints such as edema or flushing are
also frequent. Patients also report gastroin-
testinal symptoms such as nausea and vomit-
ing, weight gain, non-migrainous headaches,
fatigue, and mental changes including diffi-
culty in concentration.
As for nimodipine, published trials present
unclear data as to whether it is effective for mi-
graine prophylaxis. Open, uncontrolled studies
have reported nimodipine to have anti-
migraine actions, but the results of small, con-
trolled studies conflict: the agent has been
shown to be both better than and no different
from placebo.5'23'26'95 The small sample sizes
of these trials may account for the varying re-
sults. A large, multicenter, double-blind inves-
tigation in Europe concluded that nimodipine
has no or, at most, a very slight prophylactic ef-
fect in migraine. The statistical power of that
study, however, was reduced by a very high rate
of placebo response.54'55
Nimodipine is very well tolerated by most
patients. Small numbers of patients may de-
velop side effects that include myalgia, muscle
cramps, postural hypotension, gastrointestinal
and vascular complaints, headache, fatigue,
menstrual discomfort, and some behavioral al-
terations such as irritability.
Diltiazem
Pilot studies of the anti-migraine actions of dil-
tiazem (Cardizem) have demonstrated positive
results.70'80 While these preliminary results are
encouraging, they need to be corroborated in
appropriately controlled investigations before
the efficacy of the drug can be determined.
Diltiazem is well tolerated, with unwanted
symptoms reported by fewer than 3% of pa-
tients. The most common side effects are head-
ache, nausea, edema, and rash.
Flunarazine
A number of controlled clinical trials have de-
termined that flunarazine (Sibelium) is effica-
cious.39'48'81'85'98 The percentage of patients
410 Prophylaxis
who showed improvement ranged from 30% to
66% in different investigations. Flunarazine is
equally effective in both migraine with aura
and migraine without aura, although the results
of one open investigation appear to show
greater efficacy in patients with aura.14 Some
data indicate that patients respond best to the
drug if they have no previous or present his-
tory of analgesic overuse, a low frequency of
attacks characterized by severe migraine pain,
and a positive family history of migraine.4" Be-
cause of its favorable efficacy/side-effects ratio,
flunarazine is considered by some to be a first-
choice drug in the treatment of migraine. Its
onset of action of flunarazine is slow, but in-
creases progressively over a period of several
months. Several studies have reported that
flunarazine (10 mg per day) is equivalent to
propranolol, other /3-blockers, and methy-
sergide.22'42'88 In other words, flunarazine is an
impressive migraine prophylactic medication.
Flunarazine has a large spectrum of adverse
effects, but these are usually mild. The most
substantial side effects include daytime drowsi-
ness and sedation, gastrointestinal symptoms,
mild vertigo, anxiety, dry mouth, sleep distur-
bances, vivid dreams, muscle fatiguability, and
paresthesias. Weight gain is a prominent com-
plaint. The most serious unwanted effects
depression, parkinsonism, and tardive dyskine-
siaare fortunately rare.11'50
Amlodipine
Anecdotal information and an open label study
indicate that amlodipine (Norvasc) at a dose of
5 to 10 mg daily provides a significant decrease
in the frequency of migraine attacks."
Mechanism of Action of
Calcium-channel Blockers
Although the currently available calcium-chan-
nel blockers are chemically diverse, they share
the common property of blocking the trans-
membrane flow of Ca2+ ions through voltage-
gated, L-type Ca2+ channels.46 Calcium-
channel blockers bind to the ic subunitthe
main pore-forming subunitof L-type chan-
nels. Of presumed pertinence to migraine, L-
type Ca2+ channels are present in the mem-
branes of neurons and vascular smooth muscle
cells. Two different hypotheses of action have
been proposed: that calcium-channel blockers
could affect migraine by acting at either of
these two loci.
In the first hypothesis, the anti-migraine
properties of calcium-channel blockers depend
upon neuronal actions. Ca2+ is of considerable
importance in determining neuronal function.
Its intracellular concentration regulates neuro-
transmitter release and neuronal excitability.
These putative neuronal actions presuppose
that calcium-channel blockers enter the brain.
There is little information as to whether vera-
pamil passes the blood-brain barrier, and opin-
ions on this are conflicting. One study has
found that in schizophrenics the cerebrospinal
fluid (CSF) level of verapamil was only 7% of
the plasma level.59 The CSF levels for schizo-
phrenics receiving 480 mg per day for several
weeks was approximately 11 ng/ml (22 ^iM),
well below the concentration of 50 to 100 fjiM
required for significant in vitro effects on
neurons.
Flunarazine inhibits spreading depression of
electrical activity in experimental animals, but
very high doses are required.77'100 The mech-
anism of this action has not been explored; nor
have the effects of other calcium antagonists
on spreading depression been reported. Flu-
narazine, however, has additional neural ac-
tions that may be important in explaining ei-
ther its efficacy or its side effect profile. On the
basis of its spectrum of side effects, it appears
that flunarazine has actions at a variety of amin-
ergic receptors. Binding data support this con-
tention and show that, at clinically relevant
concentrations, flunarazine binds to serotoner-
gic (5-HT2), dopaminergic (D2), and hista-
minergic (Hi) receptors. >38 Perhaps its anti-
migraine activity depends upon its complex
interaction with several neurotransmitter re-
ceptors rather than on its calcium-channel an-
tagonist action. Single-photon emission com-
puterized tomography (SPECT) studies show
that treatment with flunarazine reduces the do-
pamine D2 receptor binding potential. Flu-
narazine's efficacy in migraine prophylaxis,
however, failed to correlate with the degree
of D2 receptor blockade, implying that flu-
narazine's anti-migraine efficacy may not
involve antidopaminergic mechanisms.102 Flu-
narazine's ability to bind to dopamine recep-
tors is presumably the major reason for its ex-
trapyramidal side effects.
 /3-Blockers and Calcium-channel Blockers
In the second hypothesis of action, calcium-
channel blockers exert their anti-migraine ac-
tions through actions on smooth muscle. Cere-
bral vasoconstriction is thought by some to be
responsible for the migraine aura. Calcium-
channel blockers are hypothesized to work as
anti-migraine drugs when they prevent the ini-
tial vasoconstriction by antagonizing the en-
trance of extracellular Ca2+ into vascular
smooth muscle cells. Calcium-channel block-
ers could thus suppress the putative cerebral
vasospasm postulated by some to be the
causative mechanism in migraine.
If a vascular locus of action is, in fact, re-
sponsible for calcium antagonists' anti-
migraine effects, one would expect that most
vasoactive calcium-channel blockers would be
the most effective anti-migraine agents. But
this does not seem to be the case. Nimodipine,
which has potent actions on cranial blood ves-
sels, is either not at all effective or only mar-
ginally effective as an anti-migraine drug. In
contrast, flunarazine, which has little or no vas-
cular activity, is very effective therapeutically.
SUMMARY
/3-Blockers are the most widely used group of
prophylactic agents for migraine. j8-Blockers
are well tolerated, and in general, propranolol,
metoprolol, timolol, nadolol, and atenolol are
equally effective. If used properly, they are ef-
fective in more than 40% of patients. Failure
to use high enough dosages for long enough
periods of time are major reasons for failure in
clinical practice. Compliance is increased when
extended-release formulations of propranolol
are prescribed. Their mechanism of action as
anti-migraine agents is not well understood. Ev-
idence supporting the effectiveness of calcium-
channel blockers (other than flunarazine,
which is unavailable in the United States) is
much less substantial than that for /3-blockers.
Verapamil does appear to have modest anti-
migraine effects and has few side effects.
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Chapter 21
Antidepressants
TRICYCLIC ANTIDEPRESSANTS
Guidelines
Side Effects
Contraindications
MONOAMINE OXIDASE INHIBITORS
Guidelines, Precautions, and
Contraindications
Antidepressants form an important part of the
therapy for a large proportion of migraine pa-
tients. Several different types of antidepres-
santsthe tricyclic antidepressants, monoamine
oxidase inhibitors (MAOIs), and selective sero-
tonin (5-HT) uptake inhibitors (SSRIs)have
all been used for migraine prophylaxis with
varying degrees of success. Considering their
widespread use as anti-migraine drugs, it is in-
deed surprising that there are so few controlled
data about their efficacy.
TRICYCLIC ANTIDEPRESSANTS
Tricyclic antidepressants, particularly amitrip-
tyline, have proved remarkably beneficial for
migraineurs who suffer from frequent attacks
of migraine with or without aura, from a mix-
ture of migraine and tension-type headaches,
or from chronic daily headaches resulting from
transformed migraine. They are much less use-
ful if a patient's attacks are infrequent. A con-
sistent finding is that the tricyclics' anti-
migraine actions are unrelated to their antide-
pressant effects.12 Even so, these medications
are particularly valuable for patients who are
also depressed and/or who have sleep distur-
bances (Table 21-1).
Side Effects
Combined Use of Monoamine Oxidase
Inhibitors and Tricyclic Antidepressants
SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
MECHANISMS OF ACTION
SUMMARY
Amitriptyline (Elavil, Endep) is the only tri-
cyclic evaluated in controlled investigations of
migraine.5'12'18'26'42'43 Trials have shown it to
decrease the frequency, duration, and severity
of migraine attacks. Amitriptyline is reported
to be as effective a prophylactic agent as pro-
pranolol, although the incidence of side effects
is higher.42 When administered concomitantly,
propranolol and amitriptyline, pointing to dif-
ferent mechanisms of action, appear to act syn-
ergistically.15'24 A number of other tricyclic an-
tidepressants have also been found in clinical
practice to be clearly efficacious anti-migraine
drugs. Indeed, as discussed below, there is
anecdotal information that some tricyclic anti-
depressants have distinct advantages over ami-
triptyline.
Guidelines
Determining which tricyclic antidepressant to
try first depends on how well the pharmaco-
logical characteristics of an agent correspond
to the patient's clinical problems. For example,
amitriptyline appears to be especially useful if
the migraineur also suffers from tension-type
headaches. A migraineur afflicted with insom-
nia will frequently benefit from a tricyclic agent
415
416 Prophylaxis
Table 21-1. Tricyclic Antidepressants:
Indications
Frequent migraine attacks
Combination of migraine and tension-type
headaches
Chronic daily headache syndrome
Transformed migraine
Migraine plus depression
Migraine plus insomnia
with sedative properties, such as amitriptyline
or doxepin (Sinequan). Their sedative action
may also be useful for depressed migraineurs
whose depression includes anxiety. In contrast,
desipramine (Norpramin), nortriptyline (Pam-
elor), and protriptyh'ne (Vivactil) are less se-
dating or nonsedating, and may be adminis-
tered to patients without sleep problems or to
patients who complain of persistent fatigue and
sleepiness from amitriptyline. While not a tri-
cyclic, the low incidence of anticholinergic and
cardiovascular effects with the heterocyclic
compound trazadone (Desyrel) makes this
agent particularly useful in the elderly, in pa-
tients with cardiovascular disease, and in pa-
tients intolerant of other antidepressants.
Because most tricyclic antidepressants have
prolonged, cumulative effects, a single daily
dose is usually effective. Amitriptyline's elimi-
nation half-life (tv2) averages 21.2 hours; peak
plasma concentrations (Cmax) typically are
achieved in an average of 3.6 hours. But be-
cause high doses of amytriptyh'ne and other
strongly anticholinergic meofications can delay
gastric emptying and absorption, the peak may
be delayed for as much as 12 hours. Some pa-
tients become excessively sedated by daytime
administration. A single dose at bedtime usu-
ally allows the major sedative effects to occur
during sleep. Rare patients tolerate the med-
ication better when it is given in split doses dur-
ing the day. Tolerance to the next-day sedative
properties of the tricyclic antidepressants fre-
quently evolves over a period of days to weeks.
To minimize side effects, initial doses of ami-
triptyline should be low. Beginning with too
high a dose substantially decreases compliance
because of the high incidence of side effects.
The recommended starting dose is 10 mg taken
at night. As soon as the morning "hangover" se-
dation has lessened, slow augmentation of the
dose by small weekly or biweekly increments
may also help to lessen the intensity of the side
effects. Steady-state levels are not reached for
4 to 10 days. The way in which individual pa-
tients respond to amitriptyline and other tri-
cyclics varies widely. Because of intolerable
drowsiness, sedation, and fatigue in the morn-
ing, some migraineurs, for example, cannot
abide as little as a 10 mg nocturnal dose of ami-
triptyline. Other patients perceive only modest
adverse effects when 150 to 200 mg a day are
administered. If a patient persists with the
medication, the sedative effects usually subside
to a tolerable level. A final dose of 50 to 75 mg
is often effective, although some individuals,
particularly patients with significant depres-
sion, require very large amounts of amitripty-
line (150 to 200 mg) and may not have signif-
icant side effects at these doses. Doses higher
than 200 mg per day are rarely needed to treat
headache.
If daytime sleepiness occurs despite ami-
triptyline administration at night, another less-
sedating tricyclic (e.g., nortriptyline, desipr-
amine) or a heterocyclic (e.g., trazadone) may
be used. Alternatively, a patient may respond
nicely to a small amount of amitriptyline for
sleep purposes together with a larger amount
of another tricyclic, both taken at bedtime. Pro-
triptyline and desipramine may have mild-to-
moderate stimulant effects in some patients,
and are therefore not generally prescribed as a
single bedtime dose. They may be given either
in the morning or in divided daytime doses.
The plasma concentration of some tricyclic
compounds, including imipramine, desipr-
amine, and nortriptyline, correlates with anti-
depressant efficacy. But in headache patients,
a large interpatient variability of plasma levels
for a given dose of an antidepressant has been
well documented.44 As an example, plasma lev-
els of amitriptyline may vary more than 10-fold
among different headache patients receiving
the same dose. This variation is mainly deter-
mined by genetic factors (e.g., from disparate
drug metabolism rates by the liver). No data
are available that relate plasma levels to anti-
migraine therapeutic efficacy. Monitoring
plasma levels may be useful in treatment-re-
sistant patients, but, in general, regulation of
dosage should depend on changes in symptoms
and development of side effects.
Although treatment of depression usually re-
quires several weeks of therapy, most mi-

graineurs who are going to improve on antide-
pressants derive some pain relief within a week
or 10 days of adequate dosage.12'13 Maximum
anti-migraine effects, however, may not de-
velop until 4 to 8 weeks at the appropriate dos-
age have elapsed.
Side Effects
Tricyclic and heterocyclic antidepressants are
quite safe overall. Almost all treated individu-
als, however, experience some type of side ef-
fect (Table 21-2). Side effects are customarily
mild to moderate in doses used for anti-
migraine therapy, but can be severe enough to
warrant discontinuation. Untoward effects oc-
cur more often when tricyclics are adminis-
tered together with other medications or when
the individual has coexisting medical disorders.
Tricyclic antidepressants should be used with
caution in the elderly because they have a
much higher incidence of side effects than do
younger individuals. Unwanted effects are usu-
ally most pronounced at the beginning of ther-
apy and discourage many patients from con-
tinuing with treatment. Patients should be
reassured that some side effects, such as early
morning sedation, usually decrease over time.
Common adverse responses to tricyclic an-
tidepressants result from actions on the CNS.
While excessive sedation and/or sleepiness are
common problems, a small minority of patients
become anxious and agitated on tricyclic anti-
depressants. Visual and auditory hallucinations,
usually of the hypnagogic variety, as well as
delirium have been reported. They may be al-
Table 21-2. Cyclic Antidepressants: Pharmacologic Features
Anti-cholinergic
Antidepressant Brand Name
Amitriptyline Elavil, Endep
Doxepin Sinequan
Imipramine Tofranil
Nortriptyline Pamelor
Desipramine Norpramin
Protriptyline Vivactil
Trazodone Desyrel
+ , slight; ++, moderate; + + + , high; + 4 - ++, very high.
Antidepressants 417
leviated by dividing the daily dose rather than
administering it entirely at bedtime. About
10% of patients develop a fine, high-frequency
tremor of the upper extremities. It is usually a
postural tremor, most easily observed when the
arms are outstretched. The incidence is much
more common in elderly patients, especially
those on large doses. Myoclonus, either when
conscious or asleep, is also an occasional side
effect. Rare patients develop signs of cerebel-
lar dysfunction with ataxia, dysarthria, and nys-
tagmus.
Increased appetite, craving for sweets,
overeating, binge eating, and concomitant
weight gain develop frequently enough that pa-
tients should be warned before starting treat-
ment. Some patients gain substantial amounts,
reaching levels of 3 to 5 pounds per month.
This may occur with or without subjective ap-
petite stimulation or overeating. Amitriptyline
and imipramine have most often been associ-
ated with increasing body weight during treat-
ment. Ironically, concern over weight gain may
cause enough stress to aggravate the headaches
the tricyclics were meant to treat. Because tol-
erance does not develop, weight gain can sig-
nificantly interfere with long-term therapy and
is often a cause for discontinuation of treat-
ment.
Tricyclic antidepressants may disrupt sexual
desire and function in both men and women.
Decreased libido, impotence, delay of orgasm,
and anorgasmia have been described. Men may
have difficulty achieving or maintaining penile
erection. These symptoms may begin later
rather than earlier in the course of antidepres-
sant use. Endocrine problems such as amen-
Migraine
Orthostatic Dose Range
Effects Sedation Hypotension (mg per day)
++++ + ++ ++ 10-150
++ + ++ ++ 10-150
++ ++ ++ 10-150
++ + + 10-150
+ + + 10-150
+++ + + 15-40
+ ++ + 50-300
418 Prophylaxis
orrhea and galactorrhea have been described.
Trazadone, unlike any of the other cyclic anti-
depressants, can cause priapism and perma-
nent impotence. Should priapism occur, emer-
gency urological treatment is required.
All tricyclic antidepressants appear to lower
the seizure threshold. Infrequent patients will
experience their first seizure while taking these
drugs. Seizures are most often observed when
patients are treated with high doses for long
periods of time or when the dosage is increased
rapidly. Patients with preexisting epilepsy
should be kept on low doses and increments
made more slowly than usual.
All tricyclic agents have substantial anti-
cholinergic (atropine-like) effects. Among the
tricyclic agents as a class, secondary amine tri-
cyclics (e.g., desipramine, nortriptyline) have
less anticholinergic activity and are associated
with fewer anticholinergic side effects than ter-
tiary amine tricyclics (e.g., amitriptyline, imip-
ramine). In the entire group, amitriptyline
causes the most significant anticholinergic ef-
fects: dry mouth, constipation, ileus, delayed
micturition, and urinary retention. Paradoxi-
cally, excessive sweating is a rather frequent
complaint. Dry mouth can often be alleviated
by the use of sugar-free candies and gum or ar-
tificial saliva drops. Dry eyes can be helped
with artificial tears. Constipation can be re-
lieved by increased fluid and fiber intake and
stool softeners. Adding the parasympathetic
medication bethanechol (10 to 50 mg every day
to four times daily) relieves the dry mouth,
blurred vision, urinary hesitancy, and consti-
pation in some patients.
Anticholinergic effects may interfere with
memory and cognition. In fact, cognitive im-
pairment of some degree is an unavoidable,
dose-related complication of tricyclic antide-
pressants. At lower doses, the impairment gen-
erally is minimal. The signs and symptoms
include impaired short-term memory, word-
finding difficulties, impaired concentration,
problems with attention, and even confusion.
If intolerable, the dose may have to be reduced
or the drug replaced with another that has a
lower incidence of anticholinergic side effects.
The anticholinergic actions can also affect
the eye. Tricyclic antidepressants promote
pupillary dilatation which can potentially pre-
cipitate or exacerbate glaucoma. Clinically, this
is a rare occurrence. The threat is probably
highest in elderly patients with undiagnosed
narrow-angle glaucoma. Tricyclic and hetero-
cyclic antidepressants can be used in individu-
als with open-angle glaucoma provided that
they continue to take pilocarpine or other ap-
propriate eye drops. Another common com-
plaint is blurred vision caused by a failure of
accommodation that results from ciliary mus-
cle relaxation. Vision for distant objects is usu-
ally not disturbed. Tolerance sometimes de-
velops after a few weeks of treatment.
In healthy adults, tricyclic antidepressants
are usually free of substantial, untoward car-
diovascular changes except for postural hy-
potension. These agents should, however, be
used with extreme caution in patients with car-
diovascular problems. One of the most com-
mon adverse cardiac effects is tachycardia, pro-
duced when tricyclics block cholinergic vagal
inhibition of the sino-atrial node. The tachy-
cardia may be extreme, but most patients ex-
perience this have rate increases of only 10 to
15 beats per minute.17 Because of amitripty-
line's substantial anticholinergic actions, it is
the tricyclic most likely to cause tachycardia.
Tricyclic antidepressants are reported to in-
crease the risk of myocardial infarction in de-
pressed patients with ischemic heart disease,
but there are no data about the risk for non-
depressed migraineurs with ischemic heart dis-
ease.11
Significant cardiac conduction abnormalities
are not common complications of tricyclic
therapy, although the drugs do cause changes
in some patients; they can slow both atrial and
ventricular depolarization. Tricyclics exert
their major action on intraventricular conduc-
tion. Electrocardiograms (EKGs) show an in-
crease in PR and QRS intervals and a decrease
in T-wave amplitude.17 Tricyclics can also pro-
duce nodal and bundle-branch blocks. Some
antidepressants increase the risk of arrhyth-
mias in patients with preexisting conduction
abnormalities or heart block. A baseline EKG
will identify those patients with cardiac con-
duction disease in whom further slowing of
conduction would be undesirable. A pretreat-
ment EKG should be obtained for any patient
over 50 or who is suspected of having cardiac
disease. EKG monitoring can be valuable to
evaluate the QRS interval when high doses are
required.
Orthostatic (postural) hypotension is an-
other common adverse reaction to tricyclic
therapy, and may be severe enough to require

discontinuation. Orthostatic hypotension oc-
curs because tricyclic antidepressants block a-
adrenergic receptor sites on arteries. Patients
may become dizzy or lightheaded or have syn-
copal episodes when they arise from a recum-
bent position. Nortriptyline has much less po-
tential than other tricyclics to cause orthostatic
hypotension. Amitriptyline, and particularly
imipramine, tend to cause significant hypoten-
sion. The problem is greater in older patients
and in patients who are taking other potentially
hypotension-causing drugs such as J3-blockers
and calcium-channel blockers. Subjective com-
plaints of dizziness or lightheadedness fre-
quently decrease during the first few months
of treatment even though the objective fall in
blood pressure tricyclics will not usually di-
minish over time. If orthostasis develops, pa-
tients should be instructed to arise slowly from
lying or sitting positions. Support stockings and
abdominal binders may help by reducing pool-
ing of venous blood in the legs and abdomen.
Administration of sodium chloride tablets (0.5
to 3 g per day) or the mineralocorticoid 9-a-
fluorohydrocortisone (0.025 to 0.05 mg every
day to BID) may help.
Allergic reactions, blood dyscrasias, and
jaundice are infrequent side effects. Although
somewhat elevated levels of alkaline phospha-
tase and transaminases are common, antide-
pressant therapy does not have to be discon-
tinued unless symptoms or signs of hepatic
dysfunction appear.
Contraindications
Tricyclic antidepressants are best avoided in
patients with defects in bundle-branch con-
duction, second-degree heart block, or when
other cardiac depressants are being adminis-
tered to treat heart disease (Table 21-3). The
presence of cardiac arrhythmias does not con-
stitute an absolute contraindication, but most
clinicians will not prescribe these agents in pa-
tients predisposed to arrhythmias. Trazadone,
however, does not appear to slow cardiac con-
duction. Tricyclic antidepressants may be con-
traindicated in patients with ischemic cardiac
disease because they are known to increase the
myocardial infarction risk in depressed pa-
tients. Because these agents lower the seizure
threshold, they should not be used for patients
with uncontrolled seizures. Urinary retention
Antidepressants 419
Table 21-3. Contraindications to the
Use of Cyclic Antidepressants
Cardiac conduction defects
Cardiac arrhythmias
Ischemic heart disease
Uncontrolled seizures
Narrow-angle glaucoma
Prostatism
Age over 65 years*
Obesity*
Pregnancy*
Breast-feeding*
Liver disease
Severe constipation*
"Relative contraindication
caused by anticholinergic effects limit their use
in men with prostatism. Similarly, because of
anticholinergic side effects, they should not be
given to patients with narrow-angle glaucoma.
In addition, elderly patients are often unduly
sensitive to anticholinergic medications. Be-
cause of the weight gain problem, obesity is an-
other contraindication. Pregnancy is a relative
contraindication (see Chapter 24), but they
should probably only be prescribed in low
doses for women who are breast-feeding. Cau-
tion is needed when trazadone is used in pa-
tients with severely impaired hepatic function
or renal failure.
MONOAMINE OXIDASE
INHIBITORS
Monoamine oxidase inhibitors (MAOIs) are a
heterogeneous group of agents that act in the
brain, liver, and other tissues to inhibit the ox-
idative deamination of monoamines by the en-
zyme monoamine oxidase (MAO). Phenelzine
(Nardil), tranylcypromine (Parnate), and iso-
carbxazid (Marplan) are the MAOIs available
in the United States. Contolled investigation of
their use in migraine has been limited. Even
so, many clinicians depend on MAOIs to treat
individuals refractory to other measures and
agents.4'25 In particular, clinical experience has
found MAOIs to be helpful for patients with
chronic daily headaches that result from trans-
formed migraine and for chronic refractory mi-
420 Prophylaxis
graine. They also benefit migraineurs who have
concomitant depression and anxiety.38 Their
usefulness is limited by the frequency of side
effects, the necessity to remain on a tyramine-
free diet, and the potentially serious interac-
tions with other medications. The selective
MAO-B inhibitor selegiline (Eldepryl) used for
parkinsonism is not helpful in the management
of migraine.21
Guidelines, Precautions,
and Contraindications
Phenelzine is the MAOI most frequently pre-
scribed for migraine. The usual dose is 45 to
60 mg a day in divided doses. It is best to be-
gin with 15 mg per day for several days, and
then to increase the dose gradually until either
a therapeutic effect or a dosage of 60 mg is at-
tained. The dosage may then be slowly de-
creased to a lower maintenance level. Patients
should wear a "Medical Alert" bracelet.
Hypertensive crises may develop sponta-
neously, but more frequently result from in-
gestion of vasoactive amines or administration
of sympathomimetic substances or other med-
ications that interact with MAOIs. Phenelzine
should only be prescribed for patients who can
be trusted to restrict their diets and to avoid
medications that have the potential to interact
with phenelzine. Close, regular oversight of the
patient is essential. Because of the potential for
stroke or death from hypertensive crises,
MAOIs should not be used in patients with hy-
pertension, cardiovascular problems, or cere-
brovascular disease. For the same reasons, pa-
tients on MAOIs must follow a restricted diet
very carefully to avoid ingesting exogenous va-
soactive amines, particularly tyramine. The
MAO inhibition in the intestines, blood vessels,
and liver enables vasoactive amines to gain un-
restricted entry to the systemic circulation.
These substances can then cause the excessive
release of norepinephrine and other cate-
cholamines from both sympathetic nerve end-
ings and the adrenal medulla. This excessive
release can produce a substantial hypertensive
reaction with palpitations, vomiting, sweating,
chest pain, stiff or sore neck, and throbbing
headache. Hypertensive crises are the most
hazardous toxic effect of MAOIs, and have
sometimes resulted in intracranial bleeding. In
the most severe cases, death ensued.
Table 21-4. Foods to be Avoided
When Taking Monoamine
Oxidase Inhibitors
Aged, fermented, or smoked foods especially if
left open or unrefrigerated
Unrefrigerated, fermented, dried, or smoked
meats and fish
Some sausages (bologna, salami, pepperoni,
fermented sausage, or liverwurst)
Matured or ripened cheeses
Sauerkraut
Raspberries
Avocados
Some brands of beers and ales, particularly on tap
Chiantis
Vermouth
Meat and yeast extracts
Soy sauce
Bananas
Drinks with large amounts of caffeine or other
methylxanthines (coffee, tea, chocolate, cola)
Patients must eliminate dietary tyramine,
which occurs naturally in some foods and de-
velops in others as the products ripen, age, fer-
ment, or even warm to room temperature
(Table 21^4). Smoked and pickled foods
should be avoided. Matured and ripened
cheeses, unrefrigerated or fermented meats
and fish, sauerkraut, raspberries, avocados,
some brands of beers and ales, chiantis, and
meat and yeast extracts are common foods in
which tyramine occurs naturally. Other amines
are also potentially dangerous: L-DOPA in fava
beans; serotonin, dopamine, and norepineph-
rine in bananas; /3-phenylethylamine in choco-
late, and methykanthines in coffee and tea.
These foods should be limited. Patients should
be provided with a wallet-sized card contain-
ing the list of foods to be avoided (see Chap-
ter 4). Such a card can easily be consulted be-
fore eating. When dietary restrictions are
followed, the risk of a serious hypertensive
problem is significantly reduced.
Patients taking MAOIs must also be
warned about possible drug interactions
(Table 21-5). They must not use proprietary
medications that contain sympathomimetics
(phenylephrine, pseudoephedrine, phenylpro-
panolamine), which are found in nasal de-

Tables 21-5. Medications and Drugs
to be Avoided When Taking
Monoamine Oxidase Inhibitors
Proprietary medications containing
sympathomimetics (e.g., nasal decongestants)
Cold, cough, sinus, allergy, or asthma medications
containing sympathomimetics or
dextromethorphan
Anti-appetite (diet) medications
Local anesthetics with epinephrine
Amphetamines
Cocaine
Meperidine
Sumatriptan, zolmitriptan, and rizatriptan
Isometheptene (Midrin)
Selective serotonin reuptake inhibitors, other
MAOIs, imipramine, desipramine,
anticonvulsants (especially carbamzepine)
Levodopa for parkinsonism
Alcohol*
General anesthetics*
Sedatives*
Antihistaminics *
"Relative contraindication; use caution.
congestants, and cold, sinus, allergy, asthma,
or diet medications. These drugs all cause the
release of norepinephrine from sympathetic
neurons. These patients' dentists should be
aware of the dangers of injecting sympath-
omimetic vasoconstrictors in conjunction with
local anesthesia. Stimulants such as the am-
phetamines and related drugs are contraindi-
cated, as is cocaine, a substance the patient may
avoid discussing. It is incumbent upon the
physiciantactfully, but pointedlyto tell pa-
tients about the danger of even one-time use.
A serious, potentially life-threatening reac-
tion can occur after concomitant administra-
tion of the narcotic meperidine (Demerol).
The reaction is characterized by restlessness,
agitation, seizures, coma, profound hyperther-
mia, and hypo- or hypertension. Other nar-
cotics should presumably be administered
with extreme caution. The antitussive dex-
tromethorphan contained in many over-the-
counter cold and cough remedies may also
cause such a reaction. In addition, MAOIs no-
ticeably potentiate the nervous system symp-
toms of alcohol, general anesthetics, sedatives,
Antidepressants 421
and antihistaminics. Patients should carry a
card in their wallets so that in the event of
emergency surgery, the anesthesiologist will be
forewarned. The medication should be with-
drawn several weeks before elective surgery.
Oral sumatriptan, zolmitriptan, and rizatrip-
tan and intranasal sumatriptan should not be
given until 2 weeks have elapsed since the last
dose of MAOIs. Coadministration of subcuta-
neous sumatriptan and MAOIs is not typically
advisable, but if absolutely necessary, the dose
of subcutaneous sumatriptan should be re-
duced.
Side Effects
Monoamine oxidase inhibitors produce a wide
range of adverse reactions, including drowsi-
ness, headaches, changes in behavior, tremor,
muscle twitching, convulsions, weakness, fa-
tigue, constipation and other anticholinergic
effects, and weight gain. Insomnia is often a
major problem, but can frequently be con-
trolled by taking all of the medication before
3:00 PM. Approximately 10% of men develop
either impotence or inability to ejaculate. Some
women lose sexual desire or the ability to reach
orgasm.
A prominent cardiovascular side effect is or-
thostatic hypotension. This may or may not be
associated with modest elevations of basal di-
astolic and systolic pressures. The orthostatic
hypotension is rarely severe enough to require
discontinuation of therapy.
Combined Use of Monoamine
Oxidase Inhibitors and
Tricyclic Antidepressants
Prescribing tricyclics and MAOIs together has
customarily been contraindicated because of
the supposed potential for dangerous adverse
reactions. Physicians have long been warned to
wait 2 weeks or more between ceasing treat-
ment with tricyclics and initiating MAOIs.
However, combined therapy is safe when ami-
triptyline, nortriptyline, and doxepin (but not
imipramine or desipramine) and an MAOI are
used in conservative dosages and when patients
are carefully supervised. Such a combination is
thought to be effective for some patients whose
migraine is refractory to treatment with
422 Prophylaxis
Table 2 1-6. Selective Serotonin Reuptake Inhibitors
SSRI Brand Name
Fluoxetine Prozac
Sertraline Zoloft
Paroxetine Paxil
Venlafaxine Effexor
Fluvoxamine Luvox
MAOIs alone, although the usefulness of this
treatment has not been tested in controlled in-
vestigations. If the drugs are given properly,
the occurrence of interactions is unlikely.36'40
Some authorities feel that the incidence of side
effects from MAOIs is lower when both types
of agents are used. The tricyclic antidepressant
should be started first in low dosages, and the
MAOI added a few days later.2 The dosage of
both drugs can be increased slowly. The use of
MAOIs and selective serotonin reuptake in-
hibitors (SSRIs) is contraindicated and at least
5 weeks should pass after stopping SSRIs be-
fore instituting MAOI therapy.
SELECTIVE SEROTONIN
REUPTAKE INHIBITORS
As a group, SSRIs have not proven very effec-
tive for migraine prophylaxis. Fluoxetine
(Prozac) was reported in one open and two
controlled studies to produce improvement,
but another controlled trial saw no ef-
fect.1'7'14'34 Anecdotal reports indicate that
high doses (40 to 80 mg) occasionally work. De-
spite the lack of clinical evidence, however,
fluoxetine is used extensively for migraine pre-
vention, especially in patients with comorbid
depression. There are some case reports that
paroxetine (Paxil) is effective and fluvoxamine
(Luvox) may have some prophylactic effects,
but further studies are needed. >8>19 Sertraline
(Zoloft) does not appear to have prophylactic
efficacy.22 In sum, although widely used in the
treatment of migraine, their value appears
limited to the treatment of psychiatric prob-
lems comorbid with migraineobsessive-
compulsive disorder, eating conditions, panic
attacks, and anxiety disorders.
Selective serotonin reuptake inhibitors are
well tolerated by many patients, but patients
Starting Dose Maximal Dose
(mg per day) (mg per day)
5-10 60-80
25 150
10 50
75 225
50 200
do differ in their ability to tolerate them. An
individual may respond badly to one, but ac-
cept another without difficulty. Patients should
be started on low doses (e.g., 5 to 10 mg per
day of fluoxetine) to minimize sedation and
anxiety. The dosage should be very gradually
increased every 5 to 7 days (Table 21-6).
In contrast to tricyclic antidepressants,
SSRIs have few anticholinergic effects and pro-
duce little orthostatic hypotension or drowsi-
ness. In fact, some patients feel more ener-
getic, a phenomenon that provides the
rationale for morning administration. Other
patients complain of fatigue and lethargy.
However, SSRIs may cause restlessness, anx-
iety, agitation, insomnia, heart-burn, decreased
appetite, diarrhea, headache, and nausea. They
should be taken after food to minimize possi-
ble nausea. Many male patients have com-
plained of impotence, and a large minority of
women experience a decreased libido and in-
ability to attain orgasm. Extrapyramidal side ef-
fects are described, including akathisia and
restlessness, dyskinesias, dystonia, and bradyki-
nesia. Because of the controversy surrounding
fluoxetine's psychological side effects and po-
tential for causing behavioral changes includ-
ing suicide, many patients may be unwilling to
try SSRIs unless these matters are openly dis-
cussed.
MECHANISMS OF ACTION
Antidepressants affect biogenic amine neuro-
transmitters in various ways. Most hypotheses
about antidepressant mechanisms of action re-
late to changes in receptor responses. Several
different actions have been described: inter-
ference with the transport or metabolism of
biogenic amines; changes in the up- or down-
regulation of receptors; receptor antagonism;

and changes in firing rates of specific sets of
neurons.
Uptake of biogenic amines by the presynap-
tic terminals from which they were released is
the major way by which amines are inactivated.
Tricyclic antidepressants and SSRIs potentiate
the actions of central nervous system (CNS)
biogenic amine neurotransmitters by inhibiting
their reuptake at presynaptic nerve terminals.
They do this by binding to an allosteric site
close to the neurotransmitter transporter,
thereby preventing the transmitter from bind-
ing to the transporter. As a result, 5-HT and
norepinephrine cannot be shuttled back into
the presynaptic terminal. Remarkable differ-
ences have been observed among the tricyclic
compounds as to their potency and selectivity
in inhibiting neuronal transmitter transport.
Desipramine and nortriptyline, for example,
are potent blockers of norepinephrine uptake,
and inhibit its uptake more effectively than that
of 5-HT. In contrast, amitriptyline inhibits nor-
epinephrine and 5-HT uptake equally well.
Fluoxetine and other SSRIs have selective ef-
fects on reuptake of 5-HT.
How interference with the uptake of specific
amines is related to migraine prophylaxis re-
mains somewhat ambiguous. The SSRIs that
specifically block 5-HT uptake are not very
effective anti-migraine medications. Both clo-
mipramine (Anafranil), a tricyclic antidepres-
sant, and femoxitine, a nontricyclic antidepres-
sant, have selective inhibitory actions on 5-HT
uptake, but were found to be inactive in con-
trolled trials of migraine prevention.23'27'30'41 It
may be that interference with uptake of 5-HT
and norepinephrine is necessary for anti-mi-
graine activity. In contrast to tricyclic antide-
pressants, MAOIs do their work by blocking
oxidative monoamine deamination by mito-
chondria! MAO. The MAOIs used to treat mi-
graine block two forms of MAO (MAO-A and
MAO-B) located in the intestines, liver, brain,
platelets, and blood vessels.
Preventing the neuronal uptake of biogenic
amines, or blocking their metabolism, prolongs
their effects at synapses, presumably enhanc-
ing their postsynaptic effects. It is unclear,
however, whether block of uptake or metabo-
lism has much to do with how antidepressants
function as antimigraine agents. Blockade of
amine uptake occurs promptly (within hours)
after administration of tricyclic antidepres-
sants, but the onset of anti-migraine effects
usually takes at least a week or two. Similar ob-
Antidepressants 423
servations have been made for MAOIs. In ex-
perimental animals, peak tissue increases in the
concentrations of norepinephrine and 5-HT
usually occur within the first week of treat-
ment. Then levels decline over a 6-week pe-
riod, even though the degree of uptake block-
ade and MAO inhibition is maintained.10'33
Thus, the degree of transport or enzyme inhi-
bition, as well as the transmitter concentra-
tions, does not appear to correlate with the
clinical effects. Such findings lend support to
the hypothesis that secondary adaptive changes
(such as changes in the regulation of recep-
tors), observed only after chronic drug admin-
istration, play a significant, and possibly criti-
cal, role in determining antidepressant effects.
The second proposed antidepressant mech-
anism of action concerns up- or down-
regulation of receptors. Anti-migraine and an-
tidepressant actions of tricyclic, MAOI, and
serotonin-uptake-blocker antidepressants may
be related to indirectly mediated actions on
biogenic amine receptors. A leading hypothe-
sis for the delay in response to antidepressants
hinges on the observation that in experimental
animals prolonged uptake blockage leads to a
down-regulation of inhibitory presynaptic re-
ceptors on 5-HT nerve terminals. This adapta-
tion may allow increased release of 5-HT. An-
imal experiments also show that long-term
administration of tricyclics causes both down-
regulation of 5-HTaA receptors and augmented
central neuronal responsiveness to !-
adrenergic agonists. The latter phenomenon
is considered to result from increased concen-
tration of adrenergic ai-binding sites (up-
regulation).3 Long-term administration of
some, but not all, tricyclic antidepressants and
MAOIs also produces a decreased number of
/3-adrenergic binding sites (down-regulation);
SSRI effects on j8-adrenoceptor density in ex-
perimental animals are inconsistent.9'31 The
most frequently reported effect of chronic flu-
oxetine exposure is down-regulated neuronal
5-HTi receptors, but the drug also up-regu-
lates 5-HT uptake sites.6'20 As for how antide-
pressants affect other types of neurotransmit-
ter receptors, the data are contradictory:
muscarinic, histaminergic, and dopaminergic
receptors are sometimes altered, but not con-
sistently. Although the association between
adaptive changes in receptors and the emer-
gence of therapeutic anti-migraine responses is
not yet understood, it is considered a prereq-
uisite for antidepressant effects.3
424 Prophylaxis
In the third proposed mechanism of action
receptor antagonism occurs. Tricyclic antide-
pressants may not only produce changes in reg-
ulation of some receptor sites, they may also
act as antagonists at various neurotransmitter
receptors. This group of drugs possesses
moderate-to-high affinity for, and antagonistic
actions at, muscarinic, aj-adrenergic, and HI
histaminergic receptors. It has also been shown
that tricyclics produce an open-channel block
of A/-methyl-D-aspartate (NMDA) receptors,35
which are important in mediating central hy-
perexcitability associated with pain states (see
Chapter 11).
The fourth hypothesis regarding antidepres-
sant action has to do with changes in central
noradrenergic and serotonergic neuron firing
rates. Electrophysiological studies in experi-
mental animals have shown that administration
of either tricyclic antidepressants or MAOIs re-
duces the firing rate of neurons in the locus
coeruleus and in the raphe nuclei.28'32'37 These
effects are probably mediated by presynaptic
autoreceptors. In view of hypotheses that im-
plicate initiation of migraine attacks with al-
tered activity in brain stem areas containing the
locus coeruleus and raphe nuclei, these firing-
rate changes may be the basis for the anti-
migraine actions of antidepressants. Unfortu-
nately, no hard data support this view.
Cyclic antidepressants also have analgesic
and antinociceptive properties that may play a
role in their anti-migraine actions.29 It appears
that antidepressants that affect both 5-HT and
norepinphrine uptake may have a more con-
sistent antinociceptive effect than those with
purely serotonergic effects.16 How antidepres-
sants might produce such therapeutic actions
(or, for that matter, their adverse reactions) is
not known with certainty. Two speculations
have been proposed about the processes in-
volved in the antidepressant analgesic effect.
First, because depression makes all pain more
distressing, alleviating an accompanying de-
pression could very well also alleviate pain. An-
tidepressants, however, have analgesic proper-
ties when administered in doses smaller than
those usually effective for treating depression.
Moreover, a consistent finding is that the anti-
migraine effect of tricyclic antidepressants is
unrelated to the antidepressant effect.12'13
And, in the absence of antidepressive actions,
antidepressants can decrease pain both for pa-
tients who have no signs of depression and for
depressed patients. The second hypothesis
speculates that antidepressants modify the en-
dogenous pain-modulating systems. Central
descending monoaminergic pathways, particu-
larly those that use 5-HT and norepinephrine
as neurotransmitters, are involved in the ros-
tral transmission of pain impulses. The inhibi-
tion of synaptic 5-HT and norepinephrine up-
take could potentiate the action of these
descending pathways, producing an inhibition
of the trigeminal and spinal transmission of no-
ciceptive impulses.
SUMMARY
Without doubt, some antidepressants are suc-
cessful prophylactic treatments for migraine.
Tricyclic antidepressants are especially valu-
able management tools for patients with fre-
quent migraine headaches and chronic daily
headaches resulting from transformed mi-
graine. They are also effective in patients with
intermittent migraine, particularly if accompa-
nied by anxiety, depression, or insomnia. Their
long-term use is limited by side effects. The
MAOIs are worth trying with patients whose
refractory, recurrent, or transformed migraine
has not responded to other more easily ad-
ministered medications. Caution must attend
their use because of the substantial potential
for adverse events. As for SSRIs, controlled
studies have demonstrated little in the way of
efficacy, but they may benefit individual pa-
tients, notably those with depression or anxiety
disorders who cannot tolerate the older anti-
depressants.
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rat brain: an autoradiographic study. Synapse 14:324-
331, 1993.
21. Kuritzky A, Zoldan Y, and Melamed E: Selegeline, a
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22. Landy S, McGinnis J, Curlin D, and Laizure SC: Se-
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23. Langohr HD, Gerber WD, Koletski E, Mayer K, and
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38. Turkewitz LJ, Casaly JS, Dawson GA, and Wirth O:
Phenelzine therapy for headache patients with con-
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A: Chronic administration of antidepressant drugs in-
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41. Zeeberg I, Orholm M, Nielsen JD, Honore PLF, and
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a randomised comparison with placebo. Acta Neurol
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42. Ziegler DK, Hurwitz A, Hassanein RS, et al.: Migraine
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43. Ziegler DK, Hurwitz A, Preskorn S, Hassanein R, and
Seim J: Propranolol and amitriptyline in prophylaxis of
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Chapter 22
Anticonvulsants
VALPROATE
Guidelines
Side Effects
Contraindications
GABAPENTIN
Guidelines
Side Effects
Anticonvulsant medications have been pre-
scribed as preventative treatment for migraine
for many years on the basis of anecdotal re-
ports. Phenytoin (Dilantin), in particular, was
favored for migraine prophylaxis in children.43
One controlled study did show that carba-
mazepine (Tegretol) was more effective as an
anti-migraine drug than placebo, but these re-
sults could not be corroborated.2'48 In fact,
phenytoin and carbamzepine have little place
in the current management of migraine. But
after the first report that valproate (Depakote)
had promise as a preventative medication, in-
terest in anticonvulsants grew.53 Other newer
anticonvulsantsgabapentin (Neurontin), top-
iramate (Topamax), and possibly lamotrigine
(Lamictal)also appear valuable (Table 22-1).
Anticonvulsants, as preventative migraine
medications, have the distinct advantages that
they can be used when j8-blockers are con-
traindicated.
VALPROATE
Valproate has been approved by the Food and
Drug Administration (FDA) for patients with
migraine. Five oral preparations are currently
marketed in the United States: (1) valproic acid
426
TOPI RAM ATE
LAMOTRIGINE
MECHANISMS OF ACTION
SUMMARY
(Depekene capsules, 250 mg); (2) sodium
syrup (Depekene syrup, 250 mg/5 mL); (3) di-
valproex sodium (Depakote tablets, 125 mg,
250 mg, 500 mg), an enteric-coated, stable co-
ordination compound composed of equal pro-
portions of valproate and valproic acid; (4) di-
valproex sodium extended-release (Depakote
ER), an extended-release formulation of de-
pakote; and (5) divalproex sprinkle capsules
(Depakote Sprinkle Capsules), which may be
opened and sprinkled on food.
A number of placebo-controlled, double-
blind trials have demonstrated valproate's effi-
cacy when compared to placebo.22'25'29'40
These investigations and several open, retro-
spective studies concluded that valproate is an
effective prophylactic against migraine head-
aches with and without aura, and is generally
well tolerated.8'11'16'17'34 The compound not
only reduces the frequency of migraine attacks,
but for some patients also reduces the inten-
sity and duration of their attacks. Migraine fre-
quency is cut in half for 40% to 80% of pa-
tients.25'29'34 It is equally effective in reducing
the frequency of severe, frequent attacks and
less severe ones. Valproate also appears to help
patients who have derived little or no benefit
from other preventative medications.17 For the
prophylaxis of migraine without aura, valproate

Table 22-1 . Anticonvulsants Used for Migraine Prophylaxis
Anticonvulsant Brand Name
Divalproex sodium Depakote
Gabapentin Neurontin
Topiramate Topamax
Lamotrigine Lamictal
works as well as propranolol and might well be
in competition with it as the first-line prophy-
lactic if it weren't for some of its side effects.26
Guidelines
Valproate is the only drug approved for mi-
graine prevention that has no direct cardiovas-
cular effects. It may be considered as first-line
medication in situations where j3-blockers are
contraindicated (asthma, cardiac conduction
defects, congestive heart failure, hypotension,
peripheral vascular disease, brittle diabetes).
Nor does it affect exercise tolerance, so it can
be prescribed for athletes. In addition, this
medication is often indicated when there is co-
morbid epilepsy or bipolar disease.
The recommended initial dosage of val-
proate prescribed for headache prevention is
250 to 500 mg per day in divided doses, taken
with food to minimize gastrointestinal prob-
lems. The dose may be increased at weekly in-
tervals by 125 to 250 mg per day until head-
aches are under control or intolerable
side-effects occur. The maximum dose is be-
tween 1 and 2 g per day. Some patients appear
to benefit substantially from low doses of val-
proate.59 Clinical experience has shown that
many patients who are incomplete responders
at lower doses may experience further improve-
ment at higher doses, while non-responders
continue to remain unresponsive even at large
doses.17 Divalproex sodium extended release
(Depakote ER) is effective and may be used
for convenience and to increase patient com-
pliance.64 It is also believed to produce fewer
side effects.
Clinical experience indicates that effective
doses range from 500 to 2000 mg per day. Pub-
lished data are unclear about this, but plasma
Anticonvulsants 427
Starting Common Adult
Dose Maintenance Dose
(mg per day) (mg per day)
250-500 500-2000
300 900-3600
50 200-600
25 100-200
concentration does not appear to correlate with
anti-migraine efficacy.8'-17'22'25'34'53 The poor
correlation presumably results from nonlinear,
concentration-dependent protein binding. As a
result, monitoring of plasma levels cannot fur-
nish a dependable measure of the active, free
valproate, but plasma levels may be obtained
as needed to avoid toxicity and to check for
compliance. Valproate is heavily (90%) bound
to serum albumin, and until a concentration of
50 /Ag/ml is reached, the albumin binding sites
are not saturated. The therapeutic range for
epilepsy treatment is between 50 and 100
jAg/ml. Some patients with migraine may re-
quire dosages that produce even higher blood
levels (125 /tg/ml).52
It is uncertain how long treatment with val-
proex should be continued. A "carry-over" ef-
fect with relief of headache after discontinua-
tion of therapy has been both reported and
denied.25'27'49^
Side Effects
Although valproate is better tolerated than tri-
cyclic antidepressants, there can be side ef-
fects. Drowsiness, sedation, dizziness, asthenia,
anorexia, dyspepsia, diarrhea, nausea, and
vomiting can occur, but most are mild to mod-
erate, and many subside over time. When val-
proate is administered with food, the incidence
of gastrointestinal problems is lower. The cen-
tral nervous system (CNS) side effects develop
infrequently and, as a rule, respond to a de-
crease in dosage. A dose-related hand tremor
affects approximately 10% of patients, but is
rarely severe enough to limit treatment. Alope-
cia occurs in 5% to 6% of patients.5 It usually
responds to dose reduction or, if necessary, dis-
continuation.
428 Prophylaxis
More than half the patients receiving val-
proate gain weight during treatment. The
weight gain does not abate with continued
therapy, but may improve with dose reduction.
Increased appetite is thought to be the under-
lying mechanism, although the precise patho-
genetic mechanism is unknown. It maybe re-
lated to increased levels of insulin and leptin,
a protein secreted by adipocytes that is a key
molecule in the feedback loop that regulates
energy balance.61
Potentially worrisome are reports that val-
proate can have effects on hepatic function, but
the fear of hepatotoxicity is largely unfounded
in healthy adults. The asymptomatic, dose-
related elevation of plasma transaminase en-
zymes seen during the first several months of
therapy in up to 20% of patients is unaccom-
panied by any symptoms of hepatic dysfunc-
tion or other liver function abnormalities.20
The elevation usually subsides spontaneously
or following a temporary reduction in dosage.
An uncommon complicationmainly seen in
very young children, especially in those re-
ceiving polytherapy for epilepsy or who have
metabolic disorders or degenerative brain dis-
easesis a frequently fatal, fulminant hepati-
tis. It has not been reported in healthy adults.
Nonetheless, the drug should not be pre-
scribed as an anti-migraine medication in
any patient with a history of hepatitis or other
liver disease. Serious hepatotoxicity may be
preceded by nonspecific symptoms such as
malaise, weakness, lethargy, anorexia, and
vomiting. Pancreatitis is another rare compli-
cation of treatment with valproate. Cases have
been reported both after initial administration
as well as after several years of use.
Hematologic toxicity can be produced by
large doses administered for prolonged peri-
ods.41 It is frequent with serum valproate lev-
els greater than 100 /^M/ml.1 Hematologic
manifestations include thrombocytopenia, ab-
normal coagulation factors (e.g., low fibrinogen
levels), leukopenia, hemolytic anemia, bone
marrow suppression, and macrocytosis. These
abnormalities are dose related and usually re-
verse once the drug is withdrawn or the dos-
age reduced.
Monitoring liver function and hematologic
measures has become standard practice, and
appear as recommendations in the United
States Physicians Desk Reference. Monitoring
is considered the standard of practice from a
medicolegal point of view, despite findings
from various trials that laboratory monitoring
rarely forecasts serious drug reactions and that
routine blood testing to detect hepatic or
hematologic problems is not useful. None-
theless, it is recommended that patients should
have liver and hematologic studies (including
complete blood count with differential and
platelet count, prothrombin time [PT] and par-
tial thromboplastin time [PTT]) before initiat-
ing therapy, and should then be monitored at
infrequent intervals.52
Polt/cystic ovary syndrome is a potential
complication of long-term valproate therapy
for epilepsy and presumably for long-term use
in migraineurs. It is characterized clinically
by hirsutism and other signs of hyperandro-
genism, polycystic ovaries, and menstrual dis-
orders. About 30% to 50% of the patients are
obese. The prevalence in the general female
population varies in different reports from 3%
to 19%. The pathogenesis of polycystic ovary
syndrome seems to be multifactorial, with both
genetic and environmental influences. The in-
creased frequency in patients taking valproate
is attributed to valproate-induced weight gain,
which, in turn, produces hyperinsulinemia and
low serum levels of insulin-like growth factor
binding protein 1. These changes lead to de-
velopment of the syndrome.
Valproate is teratogenic. Neural tube defects
including spina bifida are reported following
dosage during the first trimester of pregnancy,
especially with high doses. The incidence is es-
timated at 1% to 2% of epileptics who take val-
proate early in pregnancy.
Contraindications
Because of its putative effects on the liver, val-
proate should not be used in patients with liver
disease or a history of hepatitis (Table 22-2).
Because of its teratogenic effects, valproate
must be prescribed cautiously in women of re-
productive age. Female patients must be em-
ploying suitable contraceptive methods. It
should be discontinued in pregnant patients
and in those seeking to become pregnant.
Valproate displaces diazepam from its
plasma binding sites and slows its metabolism.
Similarly, valproate interferes with the metab-
olism of barbiturates. The blood level of both
drugs is significantly increased and excessive

Table 22-2. Contraindications to
the Use of Valproate
History of hepatitis or other liver disease
Pregnancy
Use of inadequate birth control methods in
women
Childhood*
Barbiturates and benzodiazepinesf
"Relative contraindication. Careful monitoring of liver
and hematologic function is required if given to children
under 10 years of age. tRelative contraindication. May
cause excessive sedation.
sedation may result. Diazepam and barbitu-
rates should be used with caution when taking
valproate.
GABAPENTIN
An initial, open-label study showed that
gabapentin (Neurontin) substantially reduced
the number of headache days per month in pa-
tients with migraine and transformed mi-
graine.38 Two controlled investigations dem-
onstrated gabapentin to have efficacy as a
prophylactic agent.13'39
Guidelines
Gabapentin should be started gradually. Most
younger adults easily tolerate 300 mg at bed-
time the first day; 300 mg twice a day the sec-
ond day; and 300 mg three times a day the third
day. Upward titration at a moderate rate in
older patients is recommended, and reduction,
if necessary, should also be performed slowly
in all individuals to avoid withdrawal symp-
toms. A maximum amount of 3600 mg per day
in divided doses may be tried. A target plasma
concentration for migraine has not been es-
tablished.
Side Effects
Gabapentin has a low side-effect profile. The
most common adverse reactions are somno-
lence, dizziness, ataxia, nausea, and fatigue.
Some patients complain of memory and cog-
Anticonvulsants 429
nitive problems. Reports of movement disor-
ders including tremor, retrocollis, oculogyric
crises, opisthotonus, myoclonus and chor-
eiform movements have appeared, but these
problems are very rare.46 Occasional patients
develop edema of the feet and hands. Weight
gain is reported.
Because more than 95% of the drug is ex-
creted unchanged in the urine, the dosage
must be adjusted in patients with impaired re-
nal function and in elderly patients who gen-
erally have a decreased creatinine clearance.
TOPIRAMATE
Two controlled studies and several retrospec-
tive analyses have shown that topiramate
(Topamax) is an efficacious preventative agent
for chronic migraine headaches.14'30'51'56 It has
been found effective in patients whose mi-
graines were considered refractory to preven-
tative therapy. In clinical practice, effective
dosages range from 100 to 200 mg per day.
Some clinicians have used much higher doses
in individual patients. Patients should be tri-
trated upward weekly in 25 mg increments. To
date, no serious systemic side effects (e.g., rash,
hepatotoxicity, cardiotoxicity, serious gastroin-
testinal problems, or aplastic anemia) have
been reported. The most common adverse ef-
fects involve the CNS: dizziness, ataxia, nys-
tagmus, paresthesias, drowsiness, fatigue, and
difficulty with concentration have all been
seen. Drowsiness and fatigue are generally
mild to moderate, appear early in therapy, and
often resolve. Word-finding difficulty seems to
be a fairly specific problem with topiramate
and is reported as an adverse effect in up to a
third of all patients. Diarrhea, altered taste, and
decreased appetite have also been reported.
Loss of up to approximately 10% of body
weight occurs in one-half to two-thirds of pa-
tients. Weight loss, however, may peak at 15 to
18 months and be followed by slow weight gain.
Weight loss is greatest in women and in pa-
tients who are overweight at the start of treat-
ment. The adverse events are minimized by ini-
tiating treatment with a low dosage followed by
slow titration.
Kidney stones develop in 1.5% of patients,
presumably because topiramate is a weak car-
bonic anhydrase inhibitor. Patients should
maintain an adequate fluid intake to minimize
430 Prophylaxis
kidney stone risk. Because 70% of this drug is
excreted unchanged in the urine, patients with
impaired renal function should receive half of
the usual adult dose. Topiramate also should
be used with caution when hepatic disease is
present.
LAMOTRIGINE
Reports differ about how effective lamotrigine
(Lamictal) is as a preventative anti-migraine
medication. One controlled investigation dem-
onstrated that it did not reduce the frequency
of migraine attacks with or without aura.55 In
contrast, two open studies that specifically ad-
dressed migraine with aura showed that lam-
otrigine reduced the frequency of attacks.10'31
In general, lamotrigine is well tolerated.
Common side effects are ataxia, nausea and
vomiting, indigestion, fash, somnolence, and
dizziness. Insomnia troubles some patients.
The adverse reaction that most frequently re-
quires drug withdrawal is an allergic skin reac-
tion. Rashes develop in about 12% of patients,
and typically within the first 8 weeks of ad-
ministration. Rare side effects include hyper-
sensitivity reactions associated both with mul-
tiorgan dysfunction and with various degrees
of hepatic failure. Caution is advised when us-
ing the drug for patients with hepatic or renal
dysfunction. Low starting doses and slow titra-
tion upward should be used in patients pre-
scribed lamotrigine.
MECHANISMS OF ACTION
Although several different cellular mechanisms
of action have been described for anticonvul-
sant drugs administered for migraine prophy-
laxis, it is difficult to relate their cellular and
membrane actions to their efficacy as anti-
migraine agents. It is also clear that all anti-
convulsants have more than one action. The
mechanisms vary among anticonvulsants, fit-
ting into several broad categories that include
effects on neurotransmitters and on Na+ and
Ca2+ channels.
1. Facilitation ofsynaptic transmission me-
diated by the inhibitory neurotransmitter
gamma-aminobutyric acid (GABA). Valproate,
gabapentin, and topiramate have effects on
GABAergic neurons or synapses. A large num-
ber of reports show that valproate works presy-
naptically to enhance GABAergic inhibition. In
particular, because valproate stimulates GABA
formation in presynaptic terminals by activat-
ing the GABA synthetic enzyme glutamic acid
decarboxylase (GAD), the drug significantly
raises GABA levels in the whole brain of
experimental animals.35 In addition, valproate
reduces GABA degradation by blocking the
enzyme succinic semialdehyde dehydroge-
nase.19'21'23'31'60 As a result, action potentials
presumably release more GABA from
GABAergic nerve terminals, resulting in en-
hancement of GABAergic inhibition in the
brain.3 Evidence about valproate's ability to po-
tentiate GABA-mediated inhibition at the post-
synaptic level has been conflicting.4'37'44
Gabapentin is a GABA derivative and was
originally designed to be a GABA agonist. De-
spite this, it is inactive at, and does not bind to,
GABAA and GABAB receptors or to GABA up-
take transporters.47'57 At relevant concentra-
tions, however, gabapentin increases GAD ac-
tivity in vitro, and this increases the apparent
rate of GABA synthesis in several regions of
the brain of experimental animals.36'58 In vivo
nuclear magnetic resonance (NMR) spec-
troscopy provides evidence that gabapentin el-
evates brain GABA concentrations in hu-
mans.45
As for topiramate, there are convincing data
that it enhances GABA responses at the post-
synaptic side of GABAergic synapses. Topira-
mate acts as an allosteric modulator at the
GABA receptor/Cl~ complex. Single-channel
recordings have been shown it to increase the
frequency of GABA-produced Cl~ channel
openings.63
Exactly how increased inhibitory transmis-
sion in the brain helps to prevent migraine is
unclear. Valproate attenuates neurogenic
meningeal inflammation in experimental ani-
mals by a mechanism that involves GABAA re-
ceptors.33 It also attenuates trigeminal nucleus
caudalis neuron activation produced by
meningeal inflammation.9 Valproate presum-
ably does this by increasing GABA-mediated
inhibition of the transmission of nociceptive in-
formation from meningeal afferents to the nu-
cleus caudalis. Whether gabapentin and topi-
ramate have similar effects is not known.
2. Voltage-dependent block of Na+ chan-
nels. In clinically relevant concentrations, val-

proate, topiramate, and lamotrigine have the
capacity to block voltage-sensitive Na+ chan-
nels.6'4^'62 Gabapentin has the same effect, but
only after prolonged exposure. Na+ channel
block limits sustained, high-frequency, repeti-
tive firing of action potentials. Anticonvulsant-
induced block reduces the Na+ channels' abil-
ity to recover from the inactivated state that
follows depolarization-induced Na + channel
activation.6"32'65 It is not known whether each
of the anticonvulsants acts by a similar mech-
anism or if they vary in their selectivity for the
various subunits that make up Na + channels.
However, it does not appear that the effects
that valproate, gabapentin, topiramate, and
lamotrigine have on Na+ channels are central
to their actions as anti-migraine agents; the an-
ticonvulsants phenytoin and carbamazepine
also effectively block voltage-dependent Na +
channels, but are largely ineffective for mi-
graine prophylaxis.
3. Effects on voltage-dependent Ca2+ chan-
nels. Gabapentin, valproate, and topiramate af-
fect Ca2+ channels, but all act in different
ways. Gabapentin binds to the o^S subunit of
high-threshold, voltage-activated Ca2+ chan-
nels.15 Although functional Ca2+ channels re-
quire only an a\ subunit, significant changes in
channel function are effected by coexpression
with 0128 subunits. In particular, when coex-
pressed with a\ subunits, the a%d subunit sub-
stantially increases the amplitude of Ca2+ cur-
rents and alters their kinetics. Although data
showing the inhibition of high-threshold neu-
ronal Ca2+ channels by gabapentin are con-
flicting, it is tempting to speculate that gaba-
pentin controls neuronal excitability through a
modification of Ca2+ channel activity.^0'54
Other Ca2+ channels are acted upon by val-
proate and topiramate: valproate modestly re-
duces low-threshold, T-type Ca2+ neuronal
currents; topiramate decreases high-threshold
L-type Ca2+ currents.28'66 Whether these ef-
fects damp down the putative cortical hyper-
excitability that is said to be characteristic of
migraineurs is not known.
4. Antagonism of excitatory glutamatergic
transmission. Activation of AMPA and kainate
receptors [subtypes of ionotropic glutamate re-
ceptors (iGluRs)] is responsible for rapid
synaptic transmission at many central synapses,
lontophretically applied gabapentin antago-
nizes neuronal responses to AMPA.7 At a ther-
apeutically relevant concentration, topiramate
Anticonvulsants 431
blocks currents evoked when kainate iGluRs
are activated.18
SUMMARY
The role of anticonvulsants as prophylactic
drugs is expanding rapidly. Although only val-
proate has been thoroughly tested in controlled
studies, the other medications discussed in this
chapter show much promise. Valproate has
proven itself to be a first-line drug when /3-
blockers and tricyclic antidepressants cannot
be used. In addition, valproate is the only ap-
proved drug for migraine prophylaxis that has
no direct cardiovascular effects.
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Chapter 23
Antiserotonergics, Non-steroidal
Anti-inflammatory Drugs, and
Miscellaneous Medications
METHYSERGIDE
Guidelines
Side Effects
Fibrotic Disorders
Contraindications
METHYLERGONOVINE
PIZOTIFEN
CYPROHEPTADINE
MECHANISMS OF ACTION OF
ANTISEROTONERGICS
NON-STEROIDAL ANTI-
INFLAMMATORY DRUGS
Side Effects
Contraindications
This chapter considers a variety of compounds
used for migraine prophylaxis: antiserotoner-
gics, non-steroidal anti-inflammatory drugs
(NSAIDs), lithium, magnesium, riboflavin, bac-
lofen, and botulinum toxin. Some of them are
extremely useful against migraine, others are
not. The most effective ones are either limited
by side effects of toxicity and/or must be used
with extreme care. Methysergide, methyler-
gonovine, pizotifen, and cyroproheptidine are
hypothesized to act as antagonists at 5-HT re-
ceptors, although it is not clear which 5-HT re-
ceptors they antagonize or which structures
house the receptors. Nonetheless, these med-
ications are frequently referred to as antisero-
tonergics. Lithium inhibits enzymes required
for phosphoinositide signalling. Of the re-
434
LITHIUM
Guidelines
Side Effects
Contraindications
Mechanisms of Action
MISCELLANEOUS PROPHYLACTIC
TREATMENTS
Magnesium
Riboflavin
Botulinum Toxin
Other Medications
SUMMARY
maining agents discussed in this chapter, each
has a different mode of action.
METHYSERGIDE
Methysergide (Sansert) is an extremely effec-
tive agent for the prevention of migraine at-
tacks, approved since the 1960s by the Federal
Drug Administration (FDA) for this purpose
(Table 23-1). In fact, clinical experience indi-
cates that this drug may be one of the most ef-
ficacious prophylactic, anti-migraine medica-
tion available. It has been proven effective in
older, controlled studies, although trials carried
out with modern techniques have not been
performed.1'42-53-60'69'74 Methysergide, how-
 Antiserotonergics, NSAIDs, and Miscellaneous Medications
Table 23-1. Miscellaneous Medications Used for
Migraine Prophylaxis
Drug Brand Name
Methysergide Sansert
Methylergonovine Methergine
Pizotifen Sandomigran
Lithium Eskalith
Lithobid
Eskalith CR
Magnesium
"Maximum dose depends on blood level.
ever, also has potential for serious side effects,
and this potential has led to its unwarranted
avoidance by many physicians. This is unfortu-
nate because there are some patients who re-
spond to methysergide but not to any other
prophylactic medications. Methysergide is ex-
ceptionally valuable for patients with intense,
recurrent bouts of migraine that have not re-
sponded to other medications such as j8-
blockers and valproate. The agent appears to
be particularly useful for prophylaxis when at-
tacks are frequent.17 Open studies have shown
that when used properly, more than 60% of mi-
graineurs have positive responses to methy-
sergide.16'17'24 It is said to suppress migraine
completely in more than 25% of patients.17
After oral administration, methysergide is
demethylated to an active metabolite methyl-
ergometrine (methylergonovine) during a first
pass through the liver.7 The concentrations and
terminal half-life of the metabolite are much
greater than those of the parent drug.7 For this
reason, methylergometrine is thought to be the
active principle responsible for the therapeu-
tic effectiveness of methysergide.7'46
Guidelines
Patients should be started on methysergide
graduallyone or one-half tablet (1 to 2 mg)
a day at first, with the addition of one or one-
half tablet every 3 or 4 days until a total has
been reached of 2 mg three or four times a day.
Gradual dosage build-up limits the appearance
of some side effects, particularly those related
to the gastrointestinal tract. Once benefit has
435
Starting Dose Maximum Dose
(mg per day) (mg per day)
1-2 8
0.8 1.6
0.5 1.5
300-600 900-1200
400-600 400-600
been attained, some patients can reduce the
daily dose to less than three or four tablets.
Methysergide must be administered in divided
doses because it is a relatively short-acting
agent, with a half-life of only about 2 hours. It
frequently causes nausea and indigestion; for
this reason, methysergide should be taken with
meals and with some food if taken at bedtime.
Its efficacy usually becomes apparent within 2
or 3 days, but, on occasion, beneficial effects
are not seen before 3 or 4 weeks.
Side Effects
Numerous side effects limit the methysergide's
usefulness. Most patients develop them on the
first or second day of therapy. Approximately
45% have at least one minor side effect such
as abdominal discomfort or muscle cramps.
Many minor adverse reactions are temporary
and may abate with continued use. But even
though most are minor in terms of danger to
the patient, they cause enough discomfort that
approximately 10% of patients discontinue the
medication.
Adverse gastrointestinal effects such as
nausea, vomiting, abdominal pain, diarrhea,
and constipation are frequent. Methysergide
can affect the central nervous system (CNS),
causing such symptoms as drowsiness, vertigo,
giddiness, ataxia, insomnia, vivid dreams, anx-
iety, poor concentration and difficulty think-
ing, confusion, a sense of unreality, feelings
of depersonalization, and depression. In rare
patients, the first dose of methysergide may
bring on frightening hallucinatory experiences
436 Prophylaxis
comparable to those during recreational use
of the related compound lysergic acid diethy-
lamide (LSD). Musculoskeletal symptoms
such as muscle cramps, myalgia, arthralgia,
and joint stiffness may appear. Cardiovascu-
lar side effects with vasoconstriction have
been reported. Excessive vasconstriction can
induce pain, pallor, coldness, numbness, and
paresthesias of the extremities. Peripheral
pulses may be diminished or absent. Rarely,
the vasoconstriction caused by long-term use
can cause arterial insufficiency of the lower
extremities with claudication of the legs. Con-
striction of the coronary arteries with angina-
like pain and gangrene of the intestine have
been described. A number of miscellaneous
side effects can develop including hair loss,
weight gain, pedal edema, nasal congestion,
flushing, and sweating.
Fibrotic Disorders
Fibrotic complications of methysergide are un-
common, but long-term, uninterrupted use can
provoke the development of extra connective
tissue in the retroperitoneal space, lungs, and
endocardium.25'26*3 Infrequent instances of
constrictive pericarditis, constriction of the
great vessels, and rectosigmoid strictures have
also occurred.
The overall incidence of fibrotic complica-
tions has been estimated to be as low as 1 in
5000 patients.25 Many patients who developed
fibrosis when the drug was first used in the
1960s took more than the recommended max-
imal dose of 8 mg daily, and did so for many
months to years. In recent years, reports of fi-
brotic complications of chronic methysergide
therapy are very infrequent.8'76 Although sup-
porting data are sparse, this reduction has been
attributed to the current practice of using
lower doses and intermittent use. At present,
methysergide is usually administered for no
longer than 4 to 6 months at a time, discon-
tinued for 4 to 8 weeks, and reinstituted if nec-
essary. Because some of the fibrotic changes
may be partly, or even largely, reversible when
methysergide treatment is discontinued, the
"drug holiday" presumably provides time for
regression of fibrotic lesions that may have
formed.25 Methysergide should always be with-
drawn gradually to avoid rebound effects.
Physical findings attributable to excessive
growth of fibrous tissue are usually nonspecific.
Retroperitoneal fibrosis typically does not pro-
duce clinical symptoms or signs early in its
course. Later, when it produces ureteral ob-
struction and hydronephrosis, it may be asso-
ciated with fatigue, weight loss, fever, and dys-
uria. The most frequent complaint is dull,
non-colicky pain localized to the back, flank, or
abdomen. Retroperitoneal fibrosis may also
cause constipation if it involves the bowel, and
claudication, edema, and muscular atrophy if
it affects the aorta, vena cava, and common il-
iac vessels. The clinical course may be indolent
or rapidly progressive. An elevated ESR and C-
reactive protein are common. Pleuropul-
monary fibrosis may cause symptoms of chest
pain, dyspnea, and fever. Physical examination
may reveal signs of pleural effusion with a fric-
tion rub. Endocardial fibrosis of the aortic
valve, mitral valve, or root of the aorta can pro-
duce systolic or diastolic cardiac murmurs.
To monitor the possible development of fi-
brotic complications, patients being treated
with methysergide should be evaluated by
means of careful cardiac auscultation, palpa-
tion of peripheral pulses, a chest X-ray, and an
enhanced computed tomographic (CT) scan or
enhanced magnetic resonance imaging (MRI)
of the retroperitoneal space (Table 23-2).
These tests should be performed every 6
months for at least the first several years that
a patient is taking methysergide. An intra-
venous pyelogram (IVP) should be obtained in
patients with symptoms suggestive of retroperi-
toneal fibrosis even if imaging studies are
normal.
Table 23-2. Monitoring of Patients on
Methysergide or Methylergonovine
Cardiac auscultation for new murmurs
(echocardiogram if abnormality suspected)
Palpation of peripheral pulses for peripheral
vascular abnormality
Chest X-ray for pleuropulmonary fibrosis
Enhanced abdominal CT or enhanced MR
imaging for retroperitoneal fibrosis (IVP if
patient has symptoms even if imaging is
unremarkable)
Recommended for patients on continuous therapy for 6
months or more.
Data from Saper et al. (1999).63
 Antiserotonergics, NSAIDs, and Miscellaneous Medications
Contraindications
Methysergide is contraindicated in patients for
whom vasoconstriction may pose a problem
(Table 23-3). The drug should not be pre-
scribed for individuals with peripheral vascular
disease, coronary artery disease, Raynaud's dis-
ease, or uncontrolled hypertension. Because of
the higher incidence of vascular disease, it
should be not used in elderly patients. Many
patients take ergotamine, dihydroergotamine
(DHE), or triptans during methysergide ther-
apy, but probably should not take these drugs
because of methysergide's predilection to po-
tentiate the action of vasoconstrictive agents.
Methysergide is also a potent venoconstrictor;
therefore patients with a history of throm-
bophlebitis should avoid the medication. And
because it can increase gastric acid secretion,
methysergide may activate peptic ulcers. It
should not be given to patients with either ac-
tive ulcer disease or a history of peptic ulcer.
Its propensity to cause fibrotic reactions con-
taindicates methysergide use when valvular
heart disease, chronic pulmonary disease, col-
lagen vascular diseases, or other fibrotic con-
ditions are present. Renal and hepatic impair-
ments also limit its use. It should not be
administered to pregnant women or to women
who are not using appropriate contraception.
Table 23-3. Contraindications to
the Use of Methysergide and
Methylergonovine
Peripheral vascular disease
Coronary artery disease
Raynaud's disease*
Uncontrolled hypertension
Older patients
Use of ergotamine, dihydroergotamine, or triptans
History of thrombophlebitis
Peptic ulcer disease
Valvular heart disease
Chronic pulmonary disease
Collagen vascular disease
Renal or hepatic impairment
Pregnancy
"Relative contraindication.
437
METHYLERGONOVINE
Methylergonovine maleate (methylergometrine
maleate, Methergine) is the major metabolite
of methysergide. Although not widely used and
not approved by the FDA for the prophylactic
treatment of migraine, it has been found ef-
fective as an prophylactic agent.3'23'58 Unfor-
tunately, no controlled data are available. Sev-
eral authors cite the potency, lower dose
requirements, and better side-effect profile as
potential advantages over the parent drug,
methysergide. Its most distinct advantage is the
lack of significant peripheral vasoconstrictor
properties.
The usual dosage is 0.2 to 0.4 mg four times
daily. It should be started in low dosages and
increased gradually. Fibrotic reactions, similar
to those seen with methysergide, occur with
methylegonovine. An appropriate drug holiday
every 4 to 6 months should be prescribed.
Monitoring for possible fibrotic complications
should be performed (Table 23-2). The drug
is otherwise very well tolerated. The most com-
mon adverse effects are gastrointestinal upset,
lower extremity muscle cramps, and dizziness.
It is contraindicated in patients with coronary
artery disease, peripheral venous disease, and
anticipated or established pregnancy (Table
23-3).
PIZOTIFEN
The efficacy of pizotifen (Sandomigran, not
available in the United States, but widely used
in Canada and Europe) is a matter of con-
flict.2'4'6'10'13'61'7373 Different controlled studies
have shown it to be either no better than or su-
perior to placebo. One report indicates that if
the patient has four or fewer migraine attacks
per month, pizotifen may not improve migraine
beyond the benefit provided by oral sumatrip-
tan.13
Pizotifen is usually started with a dose of 0.5
mg at bedtime. The dose can be gradually in-
creased to 0.5 mg three times a day or, because
it has a long half-life (23 hours), it can be ad-
ministered as a single nocturnal dose of 1.5 mg.
The dose can be increased to 3 to 6 mg per day
if necessary.
Pizotifen is not well tolerated. The drug en-
hances appetite in almost all patients. Weight
438 Prophylaxis
gain is therefore exceedingly frequent. It may
also cause fatigue and drowsiness. Abnormal
liver function tests have been reported. Pizo-
tifen is associated with a high rate of with-
drawal as a result of side effects. The drug is
contraindicated in patients taking monoamine
oxidase inhibitors (MAOIs).
CYPROHEPTADINE
The antihistamine cyproheptadine (Periactin)
is of limited use as a migraine prophylac-
tic.17'41'58 There are few controlled data de-
scribing its efficacy, although clinical experi-
ence indicates that it may be of help in some
patients.57 In particular, it is said to be bene-
ficial for preventing migraine in children. But
despite its widespread use for this purpose,
convincing data are lacking.
The medication is frequently given in di-
vided doses because of its tendency to cause
drowsiness. The usual adult dosage is 2 to 4 mg
three or four times a day. An occasional mi-
graineur can tolerate a total dosage of 32 mg
per day. Because of its prolonged duration of
action, cyproheptidine can also be given once
daily at bedtime. Stimulation of appetite with
subsequent weight gain occurs frequently dur-
ing extended or even acute administration of
the drug. Sedation often interferes with patient
compliance. Other side effects result from its
anti-cholinergic properties and include urinary
retention and dry mouth. Cyproheptidine is
contraindicated in all situations where anti-
cholinergic side effects should be avoided (e.g.,
closed-angle glaucoma, symptomatic prostatic
hypertrophy) and in patients taking MAOIs. It
has additive effects with CNS depressants such
as alcohol, hypnotics, sedatives, and tranquiliz-
ers. Because it can reverse the effects of anti-
depressant medication, it should be adminis-
tered with caution to depressed patients on
standard antidepressants.
MECHANISMS OF ACTION OF
ANTISERONTONERGICS
The mechanism(s) of action of methysergide,
methylergonovine, pizotifen, and cyprohepta-
dine as preventative anti-migraine agents is far
from clear. Undoubtedly, methysergide (and
its active metabolite methylergonovine), pizo-
tifen, and cyproheptadine have effects at 5-HT
receptors, but which ones? Methysergide and
methylergonovine have both agonist and an-
tagonist actions at different 5-HT receptors;
methylergonovine, pizotifen, and cyprohepta-
dine have additional effects at receptors for
other neurotransmitters. Pizotifen and cypro-
heptadine, for example, have antagonist effects
at histamine receptors and at muscarinic
cholinergic receptors, and methylergonovine
has effects at dopamine receptors.20
The basis for methysergide's action was be-
lieved to be antagonism of 5-HT2 (now desig-
nated 5-HTA) receptors. Several antagonists
that are considered moderately selective for 5-
HTA receptors (ketanserin, mianserin, ser-
golexole) are, however, ineffective in migraine
therapy. It is now thought that properties other
than 5-HT2A receptor antagonism may be more
important in determining methysergide's effi-
cacy against migraine.11'45 Because the cloned
5-HT2A receptor shares extensive sequence ho-
mology with the 5-HT2B and 5-HT2c recep-
tors, presumably these additional properties
include actions at 5-HT2B/2C receptors.
Reasonable data indicate that methysergide
does have high affinity for, and is an antagonist
at, 5-HT2B/2C receptors (Table 23-4).22 Methyl-
ergometrine, pizotifen, and cyproheptidine
also demonstrate high affinity for these recep-
tors.31'47 For a number of drugs with antimi-
graine properties, there is a significant corre-
lation between their log dose and measures of
their affinity for 5-HT2B/2C receptors (pA2 val-
ues for the 5-HT2B receptor, pKo values for
the 5-HT2C receptor). This correlation sug-
gests that migraine prophylaxis can be pro-
duced by 5-HT2B/2c antagonism.36 It is not
known precisely how 5-HT2B/2C receptor an-
tagonism produces migraine prophylaxis. It has
always been assumed that methysergide and
methylergonovine act on blood vessels. Both
compounds are potent antagonists of 5-HT-
induced contraction of vascular smooth mus-
cle.47'77 They may exert these effects on 5-
HT2B receptors on cerebral artery endothe-
lium, and on the smooth muscle of cerebral
vessels. Methylergonovine has a 5-HT antago-
nistic action on isolated segments of the hu-
man temporal artery that is 40 times greater
than that of methysergide.77 It is not under-
stood how such actions would prevent mi-
graine. However, chronic methysergide admin-
istration diminishes dural plasma extravasation
 Antiserotonergics, NSAIDs, and Miscellaneous Medications 439

Table 23-4. Prophylactic Drugs and 5-HT Receptors

Log Dose 5-HT2A 5-HT2B 5-HT2B

Drug (pKi) (pA2) (pKi) (pKD) 5-HT2C

Methysergide 0.48 8.6 8.9-9.2 8.9 8.6-8.9

Methylergometrine 8.7
Pizotifen 0.78 7.8 7.5-8.0 8.5 7.8-8.1
Cyproheptadine 1.23 8.5 7.5 7.9 7.5-8.4
Amitriptyline 1.75 6.4 6.8
Propranolol 2.23 6.1-6.5 6.5 6.2
pKi, pA2, pKi; and pKD are direct or indirect measures of the affinity of an agonist or an antagonist for a receptor.
Modified from Kalkman (1994)36 and Silberstein (1998).70 Data from Clineschmidt et al. (1985),14 Gorlitz and Frey
(1973),22 Hoyer (1988),33 Kalkman and Fozard (1991),37 Schechter and Weinstock (1974),64 and Schmuck et al. (1996).65

produced by stimulation of the trigeminal gan-
glion.62 Findings that the 5-HT2 family of re-
ceptors is up-regulated or sensitized by chronic
exposure to antagonists may be the basis for
this phenomenon.59 Methysergide and pizo-
tifen bind to, and are partial agonists at, 5-
HTiA sites.48'51 Methysergide also has weak
vasoconstrictor effects, but it is not known
whether these reflect its action at 5-HTi or at
5-HT receptors.75 It has also been suggested
that methysergide, pizotifen, and cyprohepta-
dine block meningeal vasodilation involved in
the pathogenesis of migraine, but supportive
data are lacking.
NON-STEROIDAL ANTI-
INFLAMMATORY DRUGS
INFLAMMATORY
Although NSAIDs are reasonably effective
agents for migraine prophylaxis, they should be
used infrequently as preventative agents be-
cause they have untoward effects on the kid-
neys and gastrointestinal tract when taken for
prolonged periods. Most controlled investiga-
tions comparing NSAIDs and placebo for the
prevention of migraine indicate that NSAIDs
are significandy superior to placebo.5'18'19'34'78'79
Trials of naproxen (Naprosyn), ketoprofen
(Orudis), fenoprofen (Nalfon), and mefenamic
acid (Ponstel) have all demonstrated efficacy in
reducing the frequency of migraine attacks.
Naproxen is probably the NSAID most pre-
scribed for migraine prevention (Table 23-5).
Prophylactic use of the new COX-2 inhibitors
has not been evaluated.
Aspirin, either by itself or combined with
dipyridamole (Persantine), has also been used
for migraine prophylaxis. Most trials, both open
and controlled, have shown aspirin to have a
small, but significant, benefit in reducing the
frequency and sometimes the intensity of mi-
graine attacks.9'43'50'55 The largest trials have,
however, been performed in men; convincing
data showing efficacy in women are not avail-
able. Aspirin is not as potent as more frequently
used therapeutic agents such as /3-blockers.27
Low-dose aspirin used for prevention of car-

Table 23-5. Non-steroidal Anti-inflammatory Drugs Used for

Migraine Prophylaxis

Starting Dose Maximum Dose

NSAID Brand Name (mg per day) (mg per day)
Naproxen Naprosyn 550 1000
Ketoprofen Orudis 75 150
Fenoprofen Nalfon 800 2400
Mefamic acid Ponstel 500 1000
Acetylsalicylic acid Aspirin 300 900
440 Prophylaxis
diovascular disease may not have efficacy in mi-
graine prevention.32
The NSAIDs are of particular value in pa-
tients who cannot tolerate the sedating effects
of/3-blockers or tricyclic antidepressants. They
also have merit in treatment of patients with
associated muscle or joint pain. The NSAIDs
should be taken with food to minimize gastric
problems.
Side Effects
The side effects of short-term NSAID therapy
are discussed in Chapter 10. Chronic use is as-
sociated with a higher incidence of adverse re-
actions than when these compounds are used
occasionally for acute migraine attacks. Ad-
verse renal effects, for example, have been re-
ported during continual use. These include in-
terstitial nephritis, the nephrotic syndrome,
and renal papillary necrosis. Gastrointestinal
effects are not uncommon. Individuals who re-
ceive long-term therapy with traditional
NSAIDs have more gastrointestinal hemor-
rhages and other ulcer-related complications,
hospitalizations, and deaths than the general
population.72 Serious adverse reactions are
more prevalent in the elderly. Gastrointestinal
toxicity, hyperkalemia, renal insufficiency, and
mental status changes are particularly associ-
ated with geriatric use of NSAIDS.
Contraindications
These are also discussed in Chapter 10. Be-
cause the untoward renal effects of NSAIDs
are more likely to occur in patients with pre-
existing renal dysfunction, patients must have
normal renal function before starting chronic
NSAID treatment.
LITHIUM
Although lithium's effectiveness as migraine
treatment has not been ascertained in con-
trolled trials, both open studies and clinical ex-
perience point toward efficacy.12'49 Patients
whose attacks have a cyclical pattern respond
well to lithium.44 This cyclical pattern can be
identified when a patient reports having inter-
vals of almost daily headaches for a few weeks
which alternate with intervals during which he
or she is free, or relatively free, of headaches.
Lithium has obvious value for treating mi-
graineurs who also suffer from bipolar symp-
toms or depression. In contrast, one report has
indicated that for some patients with ordinary
migraine, lithium exacerbates headaches.52
Guidelines
In the United States, lithium preparations
include immediate-release (Eskalith, Litho-
nate, Lithotabs), slow-release (Lithobid), and
controlled-release (Eskalith CR) forms of
lithium carbonate, as well as a lithium citrate
syrup. Because of its small margin of safety and
its short half-life, lithium carbonate or citrate
is administered in divided doses. Even the
slow-release preparations of lithium are given
two to three times a day. The initial dose is usu-
ally 300 mg once or twice daily. After check-
ing blood levels, the amount may be increased
by 300 mg every 4 or 5 days. Because blood
levels in the therapeutic range are crucial for
safe use of lithium, it is only suitable for pa-
tients who are willing and able to have blood
drawn repeatedly on a fixed schedule. To com-
pare blood levels from one test to the next, each
venipuncture must be made at approximately
the same number of hours after the last dose
of lithium. Patients who cannot or will not com-
ply with such a regimen should not be consid-
ered candidates for a trial of lithium therapy.
The concentration of the cation in the blood
needs monitoring because levels must stay
within a definite, narrow range. Adverse reac-
tions may occur at levels that are close to ther-
apeutic levels. It is presently thought that be-
tween 0.75 and 1.25 mEq/L are the optimum
serum concentrations. These are levels ob-
tained 10 to 12 hours after the last oral dose of
the day. Lithium levels fluctuate between
doses. Therefore, the interval between the lat-
est dose of lithium and the drawing of blood
samples should remain constant to keep the re-
sults of repeated blood samples comparable.
The dosage needed to maintain a safe level
varies among different individuals, but usually
ranges between 900 mg and 1500 mg per day
of lithium carbonate.
Lithium is rapidly and completely absorbed,
with serum concentrations peaking in 1 to ll/%
hours with standard preparations, and in 4 to
 Antiserotonergics, NSAIDs, and Miscellaneous Medications
4x/2 hours with the slow and controlled release
forms. It is excreted almost entirely by the kid-
neys, with an elimination half-life of between
18 and 24 hours. Pharmacokinetic data indi-
cate that several days are required to achieve
a steady state after initiating therapy or chang-
ing the dosage.15 Accordingly, until therapeu-
tic levels are obtained, lithium levels should be
drawn every 4 or 5 days. Dosage adjustment
based on serum levels obtained before a steady
state has been reached can be both deceptive
and harmful unless the physician is aware of
the pharmacokinetics of lithium. After a dose
schedule that produces therapeutic levels has
been established, blood levels should continue
to be monitored every month for the first 6
months and every 2 or 3 months thereafter.
Side Effects
A number of adverse reactions can attend
lithium therapy. Many occur initially and are
generally not serious. These include nausea,
loose (but not frequent) stools, polyuria, and
polydipsia, fine tremor of the hands, lethargy,
muscular weakness, and memory problems.
The polyuria is secondary to a defect in urine
concentrating ability caused by lithium's effect
on renal tubular function. Polyuria and poly-
dipsia, while typically mild and transient, are
occasionally a major problem and may persist
throughout treatment. The tremor is made
worse by sustained posture of the extremities
or by the performance of activities requiring
fine motor control. Although the tremor usu-
ally appears when therapy is initiated and de-
creases over time, it may persist from the be-
ginning of treatment, appear at any time, or
recur. Taking lithium after meals and subdi-
viding doses may reduce some of these side ef-
fects.
More serious side effects occur when lithium
levels are too high. Gastrointestinal symptoms,
such as abdominal pain, marked vomiting, and
diarrhea, may be prodromal; they sometimes
herald impending toxicity. Serious side effects
affect the central nervous and neuromuscular
systems. These include drowsiness, generalized
coarse tremors, ataxia, nystagmus, dysarthria,
hyperactive tendon jerks, mental confusion,
seizures, and coma. Permanent neurological
damage (often cerebellar) may result from
lithium intoxication.
441
Some side effects that develop during ther-
apy are not related to dose or blood level. For
example, some patients develop diffuse and
non-tender enlargement of the thyroid gland.
Most patients typically remain euthyroid, but
obvious hypothyroidism can be observed in
10% of patients, more frequently in women
than in men.35 Thyroid function tests should
be obtained for all patients receiving long-
term lithium treatment. Headache, peripheral
edema, alopecia, and rashes have also been
seen. Weight gain, often of 20 or more pounds,
is reported in many patients on lithium ther-
apy. It has been attributed to the drug's com-
plex effects on carbohydrate metabolism.
Contraindications
Because lithium is eliminated mainly by the
kidneys, this cation should not be given to pa-
tients with renal or cardiovascular disease
(Table 23-6). Sodium depletion augments the
cation's reabsorption by the renal tubules, and
for this reason patients should not receive di-
uretics or be on salt-restricted diets, or lithium
may accumulate to toxic levels. Thiazide di-
uretics have great potential to increase lithium
concentrations25% to 40% increases in
lithium concentration have occurred after ini-
tiation of thiazide therapy. Similar elevations of
blood lithium levels may occur during bouts of
diarrhea or during excessive sweating. Lithium
should not be used in patients with hypothy-
roidism. Anecdotal reports have linked nu-
merous medications, including anticonvulsants
and calcium antagonists, with the development
of neurotoxicity. These medications have been
Table 23-6. Contraindications to
the Use of Lithium
Renal disease
Cardiac failure
Concomitant use of diuretics
Salt-restricted diet
Hypothyroidism
Concomitant use of anticonvulsants or calcium-
channel blockers"
Pregnancy
Breast-feeding
"Relative contraindication.
442 Prophylaxis
implicated in a sufficient number of case re-
ports to warrant concern. The relative risk of
serious interactions appears low, but caution is
advised. Because lithium is reported to cause
a high malformation and perinatal death rate,
it is contraindicated in pregnant and lactating
women. Lithium use in early pregnancy is as-
sociated with a several-fold increase in the in-
cidence of cardiovascular anomalies (particu-
larly Ebstein's anomaly, a tricuspid valve
dysplasia with downward displacement of the
valve into the right ventricle) in the newborn.
Mechanisms of Action
Lithium has a number of effects on signal trans-
duction and on neurotransmitter systems, but
which of the cation's molecular mechanisms are
related to its therapeutic actions is not known.
At therapeutically relevant concentrations in
brain, Ithium inhibits enzymes required for
phosphoinositide signalling. In particular, it is a
potent inhibitor of the enzymes inositol
monophosphatase and inositol polyphosphate
1-phosphatase, key enzymes for the de novo
synthesis and recycling of inositol.28 Lithium-
induced inhibition of these enzymes reduces
the free pool of inositol, leading to a lowered
cellular concentration of the second-messenger
inositol(l,4,5)-triphosphate,. attenuated neuro-
transmitter-induced increases in the concen-
tration of inositol(l,4,5)-triphosphate, and ulti-
mately to a reduced mobilization of intracellular
Ca2+.
Lithium also produces changes in the 5-HT
system. It has been reported to affect several
serotonergic processes including synthesis, re-
lease, and uptake of S-HT.30'38-39 Both long-
and short-term treatment with lithium has
been shown to increase brain 5-HT turnover,
although some investigations have indicated a
decreased concentration of 5-HT. Chronic
lithium treatment decreases the number of 5-
HT receptor sites in the hippocampus and
striatum, but not in cortex or hypothalamus.
MISCELLANEOUS
PROPHYLACTIC TREATMENTS
Magnesium
The rationale for using magnesium as a pro-
phylactic agent is to correct low levels of the
cation putatively found in migraineurs. Mag-
nesium is well tolerated and inexpensive, but
its use is controversial. Anecdotal reports attest
to magnesium's efficacy for some patients.
Magnesium oxide, magnesium diglycinate, and
slow-release magnesium chloride seem to work
for some patients when used in a 400 to 600
mg daily dose. However, the results of con-
trolled studies carried out to determine
whether magnesium has efficacy in migraine
prevention are conflicting.21'54'5" The negative
investigation apparently used a poorly ab-
sorbed salt of magnesium, as almost half of the
patients in the active group had diarrhea. No
significant correlation was found between
serum magnesium levels prior to treatment and
changes in attack frequency.54
Riboflavin
Because impairment of mitochondrial respira-
tion may be characteristic of some migraine
subtypes, riboflavin, the precursor of flavin
mononucleotide and flavin adenenine nucleo-
tide needed for the activity of flavoenzymes in-
volved in the electron transport chain, has been
tried for the prevention of migraine attacks. In
a controlled study, high doses of riboflavin (400
mg per day) were superior to placebo in re-
ducing attack frequency.66 Little is known
about its use in clinical practice.
Botulinum Toxin
Injection of botulinum toxin type A (BOTOX)
into the pericrania! muscles is a new thera-
peutic option for the prophylaxis of migraine.
A controlled study has shown that injection of
25 U or 75 U of BOTOX into the frontalis, tem-
poralis, and glabellar muscles is significantly
superior to placebo in reducing migraine sever-
ity and frequency.71 The beneficial effects are
seen mainly at 2 and 3 months following the
injection, and there do not seem to be any sig-
nificant side effects. The duration of the effect
is not known.
Botulinum neurotoxin interrupts transmis-
sion at neuromuscular junctions by blocking
the release of acetylcholine from motor nerve
terminals. As a result, the muscles become
weak and somewhat atrophic. The affected
nerve terminals do not degenerate, but the
blockage of acetylcholine release is irre-
 Antiserotonergics, NSAIDs, and Miscellaneous Medications
versible. Function is restored by sprouting of
nerve terminals and the development of new
synaptic contacts, a process that usually takes
2 to 3 months. How injection of the toxin pre-
vents migraine is unknown.
Other Medications
Preliminary pilot studies suggest efficacy of
montelukast sodium (Singulair) and baclofen in
migraine prevention.29'*9'68 Montelukast, a
specific D4 leukotriene receptor antagonist, is
a well-tolerated anti-inflammatory drug used to
treat asthma. A prospective, open label study
of a small number of patients found that about
half experienced reduction of greater than 50%
in the frequency of severe attacks on mon-
telukast (10 to 20 mg QD).68 Further investi-
gation is needed.
The results of an open pilot study found bac-
lofen, an analogue of GABA that activates
GABAe receptors, to be effective in 86% of pa-
tients with migraine with or without aura. Ad-
ministered in divided dosages totaling 15 to 40
mg per day, the compound significantly re-
duced the frequency of attacks.29 Anecdotal
use for migraine prophylaxis has also been re-
ported.
In a controlled study, the antihyperten-
sive drug lisinopril (Zestril), an angiotensin-
converting enzyme (ACE) inzyme inhibitor,
has been reported to produce a significant re-
duction in the frequency of migraine attacks.67
Side effects were few and mild, being mostly
related to lowering of blood pressure.
SUMMARY
Methysergide is a very effective prophylactic
medication when appropriately used for pa-
tients with intractable migraine that has not re-
sponded to other agents. Its use is limited by
a high incidence of side effects. Methyler-
gonovine, the major metabolite of methy-
sergide, is better tolerated and has many fewer
side effects, but only small amounts of pub-
lished data support its usefulness as an anti-mi-
graine prophylactic. The NSAIDs have a lim-
ited role in migraine prophylaxis and must be
used with care. Lithium also has value as a mi-
graine preventative in refractory migraine, es-
pecially migraine with a cyclical pattern or ac-
companied by depression or bipolar disease. As
443
for magnesium, riboflavin, baclofen, and botu-
linum toxin, the other agents mentioned above,
information is available either in only small
amounts or it is equivocal.
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PART V

SPECIAL TOPICS
This page intentionally left blank
Chapter 24
Migraine in Women
MIGRAINE ASSOCIATED WITH
MENSTRUATION
Therapy for Acute Attacks
Preventative Medications
Behavioral Therapy
Hormonal Therapy
Treatment of Premenstrual Syndromes
ORAL CONTRACEPTIVES
THE PREGNANT MIGRAINEUR
Acute Migraine Attacks
There is little doubt that hormonal changes
caused by menstruation, pregnancy, meno-
pause, or oral contraceptive use frequently af-
fect migraine. Hormonal factors involved in the
genesis of migraine were considered in detail
in Chapter 6. This chapter deals with the prob-
lems specifically associated with treating
women whose headaches are particularly sen-
sitive to changes in hormonal levels.
MIGRAINE ASSOCIATED
WITH MENSTRUATION
Approximately 60% of women patients report
an association between menstruation and their
migraine attacks. Although most of them have
attacks throughout the cycle, the number in-
creases in the perimenstrual period (menstru-
ally related migraine}. Fewer than 15% of
women patients report headaches limited only
to the time of menstruation (menstrual mi-
graine}. Menstrual and menstrually related mi-
graines are frequently difficult to manage. For
example, many women remark that standard
prophylactic medications such as propranolol
Prophylactic Medication
THE NURSING MIGRAINEUR
Pharmacokinetics
Acute Migraine Attacks
Prophylactic Medication
THE POSTMENOPAUSAL MIGRAINEUR
SUMMARY
are efficacious in eliminating their head-
achesexcept for the one headache a month
they suffer from just before or during their
mensesan indication that headaches associ-
ated with menstruation may be especially re-
sistant to prophylactic treatment.61 No univer-
sally effective treatment is available for
migraine attacks associated with menstruation
(Table 24-1). However, in most studies, trip-
tans have been found to be equally effective in
menstrual and non-menstrual migraine.35 In
addition, more than 90% of women mi-
graineurs suffer from premenstrual symptoms
of one type or another.57'60 This comorbidity
may require additional therapeutic measures.
Patients need insight into the relationship
between their bouts of migraine and normal
hormonal variation. They must understand that
because of the monthly nature of the problem,
the physician has only one opportunity per
month to see if prescribed treatment works.
Months of medication trials may be necessary
before the most effective treatment is found.
The avoidance of trigger factors during the peri-
menstrual period of risk must be emphasized.
In particular, the intake of caffeine and alco-
449
450 Special Topics
Table 24-1. Treatment Options for
Menstrual Migraine
NSAIDs
Ergotamine and dihydroergotamine
Triptans
Perimenstrual use of established preventative
medications
Perimenstrual use of NSAIDs, ergotamine, or
triptans
Biofeedback
Hormonal therapy
Estrogens (transdermal patches, estradiol gel)
Synthetic androgens (danazol)
Antiestrogens (tamoxifen)
Medical menopause (GnRH analogues)
Dopamine agonists (bromocriptine)
GnRH, gonadotropin-releasing hormone; NSAIDs,
non-steroidal anti-inflammatory drugs.
Data from Silberstein and Merriam (1991).87
hol should be reduced. The diet should be
carefully monitored. Regular exercise may be
of great benefit.
Therapy for Acute Attacks
Symptomatic approaches to acute menstrual
and menstrually related migraine are the same
as the treatment for any other acute attack
of migraine: anti-emetics, non-steroidal anti-
inflammatory drugs (NSAIDs), analgesics, er-
gots, and triptans are used in precisely the same
way. Aspirin and acetaminophen, when com-
bined with caffeine (Excedrin Migraine; ace-
taminophen 250 mg, aspirin 250 mg, caffeine
65 mg), has been shown to be more effective
than placebo against menstrual migraine.84
Controlled studies have demonstrated that
both oral and subcutaneous sumatriptan are ef-
fective.28'35'91 In a retrospective investigation,
zolmitriptan was efficacious for menstrual mi-
graine, and no less so than for non-menstrual
migraine.19'81 Rizatriptan is also effective.86
Parenteral and intranasal dihydroerogatime
(DHE) are also demonstrably more effective
than placebo in menstrual and menstrually re-
lated migraine.62
Patients who are afflicted with migraine that
occurs exclusively at the time of their menses
may be treated freely with analgesics because
use at only one time of the month does not ap-
pear to cause analgesic rebound headaches.
For this small group of menstrual migraineurs,
narcotics or compound preparations of simple
analgesics, caffeine, and butalbital may be very
effective.
Preventative Medications
Only a small percentage of women require spe-
cific prophylaxis or hormonal therapy directed
specifically at their bouts of migraine associ-
ated with their periods. Prophylactic treatment
strategies vary depending upon the regularity
of menstruation and the predictability of mi-
graine attacks. If periods are regular and mi-
graine attacks are predictable, preventive med-
ications can be used perimenstrually and may
not be necessary all month. But although most
menstrual cycles during the middle reproduc-
tive years are between 25 and 30 days, the in-
terval between cycles can vary both in an indi-
vidual and among women. This obviously
complicates perimenstrual administration of
prophylactic agents. The greatest variability is
found in the years shortly after menarche and
immediately preceding menopause, when it is
difficult to estimate when menstruation will
occur.
For women whose cycles are reasonably pre-
dictable, premenstrual medication is worth try-
ing. Preemptive prophylaxis may be valuable,
but its value is largely supported by anecdotal
information. The NSAIDs are often very ef-
fective when administered in adequate doses
on a regular basis about the time of vulnera-
bility. They are especially useful for women
who also suffer from dysmenorrhea. Naproxen
sodium (Anaprox, 550 mg twice daily started 3
or 4 days before the expected menses through
the third day of menstrual flow) is reported to
be efficacious in reducing headache intensity
and duration.78 Fenoprofen (Nalfon) and
mefenamic acid (Ponstel) have also been
shown to have value.1'64 Variability in respon-
siveness make it imperative to try different
classes of NSAIDs if the first one is ineffective.
Women who are not already taking daily pro-
phylactic medication throughout the month
may also use /3-blockers, calcium-channel
blockers, amitriptyline, or methysergide peri-
menstrually.27 The medication is usually begun

3 to 5 days before menstruation, continued
through menstruation, and the dosage then ta-
pered. If a women is already taking a prophy-
lactic medication, its dose can be increased
during the period of risk.
As with analgesics, ergot or triptan depen-
dence does not pose a problem if the medica-
tion is given prophylactically on a daily basis
only during the vulnerable period. A Cafergot
tablet, twice a day, or half a suppository at bed-
time may be prescribed for the days at risk.
Alternatively, one tablet twice a day of Beller-
gal-S, a sustained-release tablet containing er-
gotamine (0.3 mg), phenobarbital (40 mg), and
belladonna (0.2 mg), is useful in some men-
strual migraine patients. Sumatriptan (25 mg
three times a day), or any of the second-gen-
eration triptans (especially narartriptan, 1.0 mg
daily), can also be prescribed to start 2 or 3
days before the expected headache and con-
tinued for 5 days.67'68
Behavioral Therapy
Only a few investigations have explored the
value of biofeedback and other behavioral
methods for the treatment of menstrual mi-
graine. Although there is conflict among re-
sults, most studies attribute equivocal value to
behavioral therapy.32'33'49'90
Hormonal Therapy
Hormonal therapy may be required for men-
strual migraine if all simpler symptomatic and
prophylactic treatments are of no avail. A num-
ber of different strategies have been tried with
varying degrees of success. Because physiolog-
ical withdrawal of estrogen in the premenstrual
phase of the cycle is thought to be the causative
event, numerous attempts have been made to
elevate estrogen levels artificially. Efforts to
prevent migraine by raising estrogen levels,
however, have not only generated contradic-
tory data as to efficacy, but in the past, estro-
gens usually produced serious menstrual irreg-
ularities as side effects.23'24'58'73'89'92-94 A large
part of the reported variability stems from dif-
ferent estrogen administration methods pro-
ducing different hormone levels. A stable, ad-
equate plasma level throughout each full day
may be necessary to induce a therapeutic ef-
Migraine in Women 451
fect without disturbing the menstrual cycle.23
Oral estrogens usually produce a peak 1 to 2
hours after administration, followed by a fall
within a few hours. Their poor beneficial re-
sults may be attributed to their failure to main-
tain such stable levels. Percutaneous estradiol
(Oestrogel, estradiol gel, 1.5 mg estradiol ini-
tiated 48 hours before the menses and contin-
ued for 7 days, not available in the United
States) appears to be an effective method of
achieving high and stable estrogen levels. Con-
trolled trials have shown its efficacy.23'25 Al-
ternatively, doses of estrogen (for 3 to 6 days
during menses or just before menses) supplied
by transdermal patch may be effective, but
high-concentration patches (Estraderm trans-
dermal systems, 0.1 mg per day; Climara 25
cm2 system, 0.1 mg per day) appear neces-
sary.73'89 Estrogen supplements should not be
prescribed for women who are at risk for preg-
nancy or who have undiagnosed vaginal bleed-
ing or estrogen-dependent tumors.
Although some older, and mostly anecdotal,
studies did show that progesterone preparations
suppressed menstrual migraine attacks, the
results have been largely inconsistent.20'34'55'88
At the present time there is little enthusiasm
for this form of treatment.
Suppression of the ovulatory cycle has also
been used as therapy for menstrual migraine.
Danazole (Danocrine), tamoxifen (Nolvadex),
and leuprolide acetate (Lupron) are reportedly
effective, although they have not been sub-
jected to controlled clinical trials. All three
medications have many side effects and cannot
be recommended for routine use. Danazole, a
synthetic androgen, is an ethyltestosterone de-
rivative that suppresses the enzymatic synthe-
sis of ovarian sex steroids and binds competi-
tively to both androgen and progesterone
receptors. It prevents the elevation of both es-
trogen and progesterone levels in the ovulatory
and midluteal phases of the menstrual cycle
and, as a result, maintains a constant low level
of estrogen.39'95 An unacceptable rate of ad-
verse effects, including weight gain, fluid re-
tention, acne, hot flashes, hair loss, and de-
creased breast size, occurs when danazole is
administered in doses of 800 mg per day. But
a recent uncontrolled investigation reported
that 400 mg administered daily for 25 days each
month is effective treatment for menstrual mi-
graine in women unresponsive to previous
therapies.53 Sixteen percent of patients, how-
452 Special Topics
ever, withdrew from the study because of se-
vere side effects, including joint pain and acne.
Tamoxifen, given in doses of 10 to 20 mg per
day for the 7 to 14 days preceding menstrua-
tion followed by 5 to 10 mg per day for 3 days
during menses, has been reported in an open
trial to be effective against menstrual mi-
graine.70 Tamoxifen is a non-steroidal triph-
enylethylene derivative that has antiestrogenic
properties. The most frequent adverse effects
include hot flashes, nausea, and vomiting. If
used for more than 1 year, a higher risk of uter-
ine cancer develops.
For the most severe cases of menstrual mi-
graine, gonadotropin-releasing hormone (GnRH)
agonists that cause medical menopause may be
considered. Two small, open studies found that
administration of leuprolide acetate depot,
with or without added estrogen and progester-
one, was effective in reducing menstrual mi-
graine.53'65 Leuprolide results in an initial stim-
ulation followed by a prolonged suppression of
pituitary gonadotropin secretion. Repeated
dosing results in decreased secretion of ovar-
ian steroids and selective suppression of men-
strual cyclicity. The GnRH analogues also in-
duce hypogonadism with reduction of estrogen
levels. Many of the same short- and long-term
effects as those from menopause resulthence
the need for replacement estrogen with or
without progesterone. In some women, leu-
prolide has the potential to produce severe
daily headache.
There is one other medication, not part of
the usual armamentarium of anti-migraine
therapy, that can be considered for perimen-
strual use. Bromocriptine (Parlodel), a dopa-
mine Dg agonist and inhibitor of prolactin re-
lease, may limit the symptoms of the
premenstrual syndrome and headache when
prescribed in dosages of 2.5 mg twice a day
from the time of expected ovulation to the start
of menstruation.5'6'13 The results of open stud-
ies indicate, however, that continuous bromo-
criptine therapy may be more effective than in-
termittent administration.40'41 The incidence
of side effects (e.g., nausea, headache, dizzi-
ness, fatigue) is high, but these are generally
mild to moderate in degree.
Surgical oophorectomy has been suggested
as treatment in those women who respond to
hormonal therapy. This is to be avoided if at
all possible; the procedure is reported to exac-
erbate migraine in about two-thirds of cases,
and to improve migraine in only about one-
third.66
Finally, it should be pointed out that a num-
ber of generally ineffective treatments are
widely prescribed for patients with menstrual
migraine. Because bouts of migraine are often
accompanied by fluid retention, practitioners
often hypothesize that premenstrual fluid re-
tention is somehow connected to the monthly
headaches. Diuretics can reduce such fluid re-
tention but do not prevent menstrually related
migraine. Nor has the efficacy of pyridoxine
(vitamin B6) been established in controlled
studies.
Treatment of
Premenstrual Syndromes
The vast majority of menstruating women with
migraine suffer from premenstrual symptoms
of one variety or another.57'60 Although we do
know that a normal ovarian endocrine cycle is
necessary for premenstrual symptoms to de-
velop, the large number of approaches to
managing the symptoms probably reflects our
inadequate understanding of the precise
causative mechanisms (see Chapter 6). Be-
cause it is thought that premenstrual problems
are related to a 5-HT deficit, fluoextine has
been used, with reports of efficacy.102 Sup-
pression of the ovarian cycle by continuous
high doses of exogenous estrogen administered
as implants or patches has also been success-
ful.98'^9 The risk of endometrial hyperplasia
from unopposed estrogen is too high for long-
term use, and unfortunately, when a protesto-
gen is added, premenstrual symptoms recur.
Interference with the synthesis of ovarian sex
hormones or suppression of the ovarian cycle
by administration of danazol or GnRH ana-
logues resolves symptoms in most women.36'37
ORAL CONTRACEPTIVES
The relative risk of occlusive stroke for women
of reproductive age who use modern, low-
estrogen oral contraceptives is small (see Chap-
ter 6). Among migraineurs, however, investi-
gations show a further increased stroke risk. As
a consequence, administration of these com-
pounds must be done with caution and

Figure 24-1. The use of combined oral contraceptives (COCs) in patients with migraine. (Adapted from MacGregor EA
and Guillebaud J: Recommendations for clinical practice: combined oral contraceptives, migraine and stroke. Br J Fam
Plan 24:53-60, 1998, with permission.)
thought. The risk of stroke is a problem that
physicians treating migraine patients fre-
quently encounter. One must take into account
the type of migraine, the frequency and sever-
ity of attacks, and the presence of other vas-
cular risk factors. In general; the following fac-
tors should be kept in mind:
1. Combined oral contraceptives should not
be prescribed for women with migraine with
aura or complicated migraine.56'63 The risk of
ischemic stroke in patients with aura is greater
than the risk of stroke associated with preg-
nancy.
2. In the absence of any other risk factors
for stroke, such as a family history of arterial
or venous disease in a first-degree relative
younger than 45 years of age, hypertension, di-
abetes mellitus, obesity or lipid disorder, low-
dose (<50 /Jig ethinyl estradiol) combined oral
contraceptives may be prescribed for a woman
Migraine in Women 453
with migraine without aura, provided that she
does not smoke and is less than 35 years of age
(Fig. 24-1).12'56 The putative liabilities of oral
contraceptives must be discussed, regular su-
pervision must be supplied by periodic visits,
and the patient has to be made aware that she
must contact her physician rapidly if the char-
acter of her attacks changes, if the duration,
severity, or frequency of her headaches in-
creases, or if she develops any neurological
symptoms either during or between headaches.
3. If attacks of migraine worsen, an aura or
other accompanying neurological symptoms
develop, or severe or frequent non-migrainous
headaches occur while on contraceptives, dis-
continuation should be strongly advised.
4. If a woman with migraine without aura
has only one additional risk factor for stroke,
the disadvantages of combined oral contracep-
tives are assumed to outweigh their advantages
454 Special Topics
Table 24-2. Additional Risk Factors
for Ischemic Stroke in Female
Migraineurs Using Combined
Oral Contraceptives
Age >35 years
Ischemic heart disease
Cardiac disease with embolic potential
Diabetes mellitus
Family history of arterial disease <45 years
Hyperlipidemia or hypercholesterolemia
Hypertension
Migraine aura
Complicated migraine
Obesity (body mass index >30)
Smoking
Systemic diseases associated with stroke (e.g.,
sickle cell disease, connective tissue disorders)
Data from International Headache Society (2000).43
(Table 24-2). They should be used in such
women with great caution.56
5. The presence of multiple risk factors is
an absolute contraindication for combined oral
contraceptive use in patients with migraine.
6. Progestin oral contraceptives are recom-
mended for women with a risk factor for
stroke.56 Although controlled data are unavail-
able, clinical observations suggest that such
contraceptives are not associated with an in-
creased risk of ischemic stroke.
THE PREGNANT MIGRAINEUR
Management of migraine in pregnant women
is especially difficult because some anti-
migraine medication is potentially teratogenic.
Many drugs have been shown to cross the pla-
cental barrier, producing pharmacological or
teratogenic effects in the fetus. The most crit-
ical period for minimizing fetal drug exposure
is during organogenesisfrom the fourth
through tenth weeks of pregnancy. The fetus
is most vulnerable to medications during this
period of time. Exposure to dangerous med-
ications before organogenesis either causes
death of the embryo or the fetus develops with-
out abnormalities. Drug effects later in preg-
nancy often lead to developmental syndromes,
intrauterine growth retardation, or multiple-
organ involvement. Some medications may in-
fluence the physiology of pregnancy itself. The
NSAIDs, for example, have been reported to
decrease the volume of amniotic fluid, to de-
lay the start of labor, or cause premature clo-
sure of the ductus arteriosus, placing the new-
born at risk for development of pulmonary
hypertension. Accordingly, the majority of anti-
migraine drugs should not be prescribed for
pregnant patientsor for patients who are try-
ing to conceive.
Fortunately for 75% of women, migraine
ameliorates during pregnancy and may even
stop, particularly during the second and third
trimester. Several non-pharmacological thera-
pies including relaxation training, biofeedback,
and physical therapy have been demonstrated
to be effective in pregnant women.59'79 Should
pharmacological therapy be necessary, all at-
tempts should be made to avoid medications
during the first trimester. If possible, pharma-
cological therapy other than acetaminophen
and meperidine should be reserved only for
women in the second and third trimesters who
have frequent and severe attacks accompanied
by vomiting and possible dehydration.
Acute Migraine Attacks
Acetaminophen appears benign enough to ad-
minister to women with acute attacks of mi-
graine who are pregnant or attempting to be-
come pregnant. Acetaminophen crosses the
placenta, but has not been found to cause prob-
lems.50 It has no known teratogenic proper-
ties.8 It is unclear why it has been classified as
a Federal Drug Administration (FDA) Cate-
gory C drug for use in pregnancy (Table 24-3;
for a drug to be Category C, studies indicate
teratogenic or embryocidal risk in animals, but
no controlled studies have been done in
women, or there are no controlled studies in
animals or humans).
All narcotics cross the placenta and have the
potential to cause dependence and withdrawal
symptoms in the fetus and newborn if used reg-
ularly or abused.4 They should never be used
for prolonged periods of time during preg-
nancy. As for meperidine, there have been no
large prospective studies of possible association
between its limited use and teratogenic
changes in fetuses. Neither are there reports
of any increased malformations in the offspring
 Migraine in Women 455

Table 24-3. Migraine Medications and Pregnancy Risk

FDA PREGNANCY RISK CATEGORY

B c D X

Aspirin Acetaminophen/butalbital Atenolol Ergots

Doxepin Actaminophen Divalproex sodium Methysergide
Fluoxetine Amitriptyline Lithium
Meperidine Aspirin/butalbital/caffeine
Metoclopramide Botulinum toxin type A
Non-steroidal anti-inflammatory drugs Codeine
Dexamethasone
Gabapentin
Keterolac
Metoprolol
Nadolol
Naratriptan
Nortriptyline
Paroxetine
Prochlorpromazine
Promethazine
Propranolol
Rizatriptan
Sertraline
Sumatriptan
Timolol
Topiramate
Trazadon
Verapamil
Zolmitriptan
Federal Drug Administration (FDA) Category B, no evidence of risk in humans; FDA Category C, risk cannot be ruled
out; FDA Category D, positive evidence of risk; FDA Category X, contraindicated in pregnancy.

of women who took meperidine (and other nar-
cotics) during the first trimester.46 Meperidine
therefore appears to be relatively safe, pro-
vided its administration is tightly controlled by
the physician and it is prescribed in only lim-
ited amounts. The compound, however, has
poor oral potency. A 50 mg oral dose is only
equivalent to 650 mg of aspirin. An infrequent
injection of meperidine is probably safe for
acute attacks of migraine. But because it causes
neonatal depression, meperidine should not be
used close to term.
Almost all other drugs have potential for side
effects for the fetus. First-trimester exposure
to aspirin and other NSAIDs does not pose ap-
preciable teratogenic risk, but can lead to pre-
mature constriction or closure of the ductus ar-
teriosus, which is ordinarily maintained in the
dilated state by prostaglandins. Aspirin can be
used sparingly during the first two trimesters
but must be avoided near term, because it can
increase intrapartum blood loss and impair
neonatal hemostasis. The latter can lead to
neonatal bleeding disorders and to intracranial
hemorrhage in premature infants.96 If used in
the third trimester, aspirin and other NSAIDs
may also increase the mother's hemorrhagic
risk. And because NSAIDs reduce fetal urine
output, their use may lead to oligohydramnios.
In sum, aspirin and other NSAIDs should be
avoided if at all possible, especially in the third
trimester.
Codeine used during the first or second
trimester may produce cleft lip and palate, in-
456 Special Topics
quinal hernia, cardiac and respiratory system
defects, and dislocated hips.15 Withdrawal
symptoms have been reported in the infants of
mothers who used excessive amounts of
codeine late in pregnancy. Codeine is classified
by the FDA as a Category C drug, and should
not be used indiscriminately during pregnancy,
particularly during the first trimester, chroni-
cally, or close to term.
Sporadic administration of drugs containing
butalbital is presumably safe, but the repetitive
administration of barbiturates during preg-
nancy may cause neonatal withdrawal symp-
toms, hypotonia, reduced responsiveness, and
feeding problems.97 Barbiturates are classified
by the FDA as Category C drugs.
Ergot preparations including ergotamine
and DHE are contraindicated during preg-
nancy.42 Increased prenatal mortality and
growth retardation have been described. The
teratogenic effects of ergots are uncertain. Al-
though doses much larger than those used for
migraine are needed to produce uterine con-
tractions and abortion, pregnancy constitutes
an absolute contraindication to the use of er-
gots.
Considering its placental transfer of only
15% in 4 hours and its short half-life, suma-
triptan may prove safe in pregnancy, but pres-
ent data are conflicting.26'80 There is no
evidence of embryotoxicity, fetotoxicity, or ter-
atogenicity in rats and rabbits receiving high
doses of sumatriptan.30 Three small prospec-
tive studies noted no difference in rates of live
births, spontaneous abortions, or major birth
defects and no difference in perinatal and preg-
nancy outcome between patients who had and
those who had not used sumatriptan after con-
ception.72'76'82 In contrast, a Danish investiga-
tion reported that sumatriptan exposure dur-
ing pregnancy was apparently associated with
increased risk of preterm delivery and low birth
weight.71 The latter investigation, however, has
been criticized on methodological grounds.31
It is still unclear how safe sumatriptan is dur-
ing pregnancy and, for the time being, it should
probably be avoided. The FDA has classified
sumatriptan as a Category C drug.
Nausea and vomiting may be extremely de-
bilitating for the pregnant migraineur. Meto-
clopramide may be used. It is classified as an
FDA Category B drug (Category B: animal
studies do not indicate a fetal risk or animal
studies do indicate a teratogenic risk, but well
controlled human studies have failed to dem-
onstrate a risk). In more severe instances,
trimethobenzamide, prochlorpromazine, or
promethazine can be administered orally, by
suppository, or parenterally. They are Category
C drugs.
Prolonged, excessively severe attacks of mi-
graine must be managed in an aggressive fash-
ion.85 Hospitalization may be necessary if in-
travenous fluids are needed for hydration.
Prochlorperazine (10 mg) maybe administered
intravenously to reduce vomiting and alleviate
head pain. Parenteral meperidine can also be
used. Steroids may be considered.83 Most cor-
ticosteroids cross the placenta, but prednisone
and prednisolone are inactivated by the pla-
centa.69 No increase in the rate of fetal mal-
formations has been reported in pregnant
women exposed to corticosteroids.
Prophylactic Medication
Preventative medication should be reserved for
those patients whose migraine significantly in-
creases in severity and frequency and is asso-
ciated with substantial nausea and vomiting.
Prophylaxis should not be undertaken lightly,
and may be justified only as a last resort. A full
discussion with both parents is necessary.
Propranolol (FDA Category C) has been
used for migraine prophylaxis during preg-
nancy, even though untoward effects of )8-
blockers on pregnant migraineurs have not
been adequately investigated. From their ex-
tensive use in the treatment of hypertension
and other cardiovascular-related conditions
during pregnancy, one can infer that /3-block-
ers are usually safe.77 Propranolol, however,
may be associated with intrauterine fetal
growth retardation, prematurity, prolonged la-
bor, respiratory depression, hypoglycemia, and
hyperbilirubinemia.44'74 The incidence of re-
tardation of uterine growth is low, probably less
than 5%.75'77 And no one really knows to what
extent these unfortunate effects may be a
consequence of fetal distress developing in
high-risk, hypertensive obstetric patients. Pro-
pranolol may cause neonatal bradycardia, hy-
poglycemia, and apnea, but these symptoms
can be circumvented by discontinuing the drug
at least 2 weeks before the estimated date of
delivery.74
Although tricyclic antidepressants are classi-
fied as FDA Category C drugs, associations be-
tween tricyclic antidepressants and birth de-

fects in large human population studies are dif-
ficult to establish. From animal data, however,
there is evidence of significant changes at the
receptor level in animals exposed to tricyclics
prenatally, including decreased adrenergic re-
ceptor binding and decreased density of 5-HT
receptors.22'4^The implications of these find-
ings for the developing human fetus are un-
clear. Nonetheless, amitriptyline is considered
to be a relatively safe drug to administer in
pregnancy, although in cases where the mother
took tricyclics until the time of birth, neonatal
dyspnea, cyanosis, tachypnea, irritability,
tachycardia, and feeding difficulties have been
seen.50
Insufficient data about verapamil, flunara-
zine, and fluoxetine prevent any firm statement
about their safety in pregnant women. Limited
anecdotal evidence suggests that verapamil
may be an effective prophylactic drug for preg-
nant migraineurs. All calcium-channel blockers
are classified as FDA Class C drugs. Valproate
is known to be teratogenic in humansthere
is a definite risk of neural tube defects if the
drug is used between days 17 and 30 after fer-
tilization.15 Lithium can cause cardiac abnor-
malities if the fetus is exposed during the first
trimester. Methysergide is closely related to
ergots and is contraindicated for use during
pregnancy.
THE NURSING MIGRAINEUR
Although the lactating woman with migraine
may expect her physician to guide her about the
risks her drug therapy poses to the neonate,
such guidance is fraught with difficulty. There
is no adequate information about many med-
ications. With the exception of ergots, which are
absolutely contraindicated, the available litera-
ture does not provide sufficient data to rule
most medications out totally. Consultation be-
tween the mother's physician and the baby's pe-
diatrician is probably prudent in most cases.
Nursing may have to be discontinued if the
mother is crippled by migraine that cannot be
treated effectively out of concern for her infant.
Pharmacokinetics
The pharmacokinetics of medication excretion
into breast milk and the subsequent handling
Migraine in Women 457
of that substance by a nursing infant are com-
plex, and depend upon a number of factors:
1. Lipophilicity. Medications ingested by a
nursing mother enter the blood-stream where
the free non-protein-bound fraction readily
passes into breast milk. The best predictor of
medication concentrations available in breast
milk is the lipid solubility of the particular drug:
more lipophilic agents will diffuse more rapidly
into the milk.
2. Maternal protein binding. Because only
free drug is able to leave the maternal circula-
tion, drugs that are highly protein bound are
less likely to be transferred into breast milk
than drugs that are less protein bound.
3. Rate of infant metabolism and liver func-
tion. Because the neonate is metabolically im-
mature, the newborn is less able than adults to
metabolize most medications and high levels
can develop. For example, babies have a very
low rate of hepatic glucuronidation.
4. Infant kidney function. The glomerular
filtration rate and tubular secretion rates are
functionally immature and therefore slower
than those of adults, leading to higher serum
steady-state levels.
5. Infant protein binding. The decreased
protein binding by infants compared to that in
adults results in an increased concentration of
free drug in the infant circulation.
Acute Migraine Attacks
A number of anti-migraine drugs pass into
mother's milk from the plasma and therefore
have the potential to affect the nursing infant.
For example, breast-feeding mothers should
avoid aspirin because of the theoretical risk
of Reye's syndrome in babies (Table 24-4).
Aspirin has also been reported to produce
metabolic acidosis in infants.18 With the ex-
ception of aspirin, however, non-narcotic
analgesics (such as acetaminophen) and
NSAIDs (such as ibufrofen and naproxen) are
considered little risk to the nursing infant.3
Acetaminophen does enter breast milk, but
the maximal fetal dose is less than 2% of the
maternal dose. It is compatible with breast-
feeding when taken in short courses at ther-
apeutic doses.
Moderate ingestion of caffeine (equivalent
to two cups a day) does not seem to affect the
infant. Breast milk usually contains less than
1% of the maternal level of caffeine. Excessive
458 Special Topics
Table 24-4. Antimigraine Drugs and Nursing: American Academy of
Pediatrics (AAP) Classification
Drugs that are contraindicated during
breast-feeding
Drugs whose effect on nursing infants is unknown
but may be of concern
Drugs that have been associated with significant
effects on some nursing infants and should be
given to nursing mothers with caution
Maternal medications usually compatible with
breast-feeding
Data from American Academy of Pediatrics (1994).a
use of caffeine may cause increased wakeful-
ness and irritability in the infant.29
One case report has documented symptoms
of ergotism in an infant exposed to ergotamine
through breast-feeding. Other reports of vom-
iting and diarrhea have appeared. The Ameri-
can Academy of Pediatrics (AAP) classifies er-
gots as contraindicated in nursing mothers.2
Metoclopramide is not concentrated in hu-
man milk, but its effects on infants are not
known. The doses received by a nursing infant
are much less than the therapeutic doses ad-
ministered to infants.14 Chronic metoclo-
pramide use increases serum prolactin in
women and increases milk production. Meto-
clopramide does not, however, change pro-
lactin levels in nursing infants.48 The AAP does
not recommend its use during the nursing
period.
Barbiturates such as butalbital may cause se-
dation in infants, but are considered compati-
ble with breast-feeding. Opioids are excreted
into breast milk. Pharmacokinetic analysis has
shown that the concentrations of codeine and
Ergotamine
Lithium
Amitriptyline, desipramine, doxepin, imipramine
Chlorpromazine
Fluoxetine
Fluvoxamine
Haloperidol
Metoclopramide
Trazadone
Aspirin
Acetaminophen
Butalbital
Caffeine
Codeine, meperidine, morphine, propoxyphene
Ibuprofen, keterolac, naproxen
Indomethacin
Propranolol
Valproic acid
Verapamil
morphine in breast milk are equal to or even
greater than maternal plasma concentrations.29
Nonetheless, the AAP considers use of many
narcotics including codeine, meperidine, and
morphine to be compatible with breast feed-
ing. It is possible that codeine and meperidine
excreted in breast milk can cause sedation and
respiratory depression in infants.
The use of sumatriptan in nursing mothers
has not been studied in detail. The breast milk
concentrations of sumatriptan are quite low
0.24% of a 6 mg subcutaneous dose.26'101
Even this minor exposure to sumatriptan may
be avoided if the breast milk is expressed and
discarded for 8 hours after the dose of suma-
triptan.101
Prophylactic Medication
/S-Blockers are excreted in breast milk and may
cause bradycardia and hypoglycemia in infants.
This must be a rare occurrence because the av-
erage neonatal exposure to a maternal dose of

propranolol is less than 1% of the therapeutic
dose.11 Atenolol, however, does pose a risk to
the suckling infant because a significant quan-
tity of the drug passes into milk.52 Other (3-
blockers appear to be safe.
The risk of using verapamil is low because
the amount passing into the milk is small (max-
imum 0.4% to 1.1% of the weight-adjusted ma-
ternal daily dose).7 Although the effect of tri-
cyclic antidepressant drugs on nursing infants
is unexplored, these agents do appear in hu-
man milk (but in very small amounts), may be
of concern, and probably should not be pre-
scribed in more than modest doses. Valproate
is excreted into human milk at low concentra-
tions (approximately 15% of the mother's
serum concentration). It is considered com-
patible with breast-feeding.3 The risk to the in-
fant of administering lithium is significant;
large quanities of the cation pass into milk and
neurological effects have been noted in in-
fants.14 The AAP considers lithium to be con-
traindicated during nursing.
THE POSTMENOPAUSAL
MIGRAINEUR
Migraine is frequent in menopausal and post-
menopausal women (see Chapter 6). In fact,
some women develop migraine for the first time
during the perimenopausal period. Hormonal
changes that characterize the menopause and
succeeding years and the introduction of ex-
ogenous estrogen make migraine's manifesta-
tions at this time of life more complex.
The way in which changing hormonal levels
during menopause affect the severity and fre-
quency of migraine has not been clarified by
studies of estrogen therapy in menopausal
women. Both therapeutic improvement and in-
creased incidence of headache have been re-
ported among different series of estrogen-
treated women.9'16'17'21'47'51 On the whole,
hormone replacement therapy seems to
worsen rather than improve migraine; dis-
parate findings may be a function of the type,
dose, route of administration, and timing of the
hormone therapy. To offset the augmented risk
of endometrial adenomatous hyperplasia, a
precursor of endometrial cancer associated
with daily estrogen therapy, estrogen is regu-
larly coupled with a small, daily amount of pro-
Migraine in Women 459
gestin and prescribed in a cyclical fashion: used
for 21 to 25 days and then stopped for 5 to 7
days. Although clear-cut data are unavailable,
such cyclic estrogen therapy with progestin is
thought by many clinicians to worsen head-
aches. The headaches are believed to be more
prominent during estrogen-free days. In con-
trast, daily administration of the hormone, with
or without progesterone, may benefit some mi-
graineurs.51
Oral administration with its unavoidable
daily fluctuations in plasma hormone levels
may exacerbate migraine. For women affected
in this way, several options are available:87
1. The dose of estrogen can be reduced. Be-
cause the frequency of migraine headache ap-
pears inversely correlated with the dosage of
estrogen, the amount of estrogen should be re-
duced to the minimal dose that controls meno-
pausal symptoms.24
2. The type of estrogen can be changed from
conjugated estrogen to pure estradiol or es-
trone. Conjugated equine estrogens (Premarin,
Estratab) are the most widely used preparation
for oral estrogen replacement therapy in the
United States today. Still most commonly ob-
tained from natural sources, including extrac-
tion from the urine of pregnant mares, this
preparation is actually a combination of up to
10 different, naturally occurring estrogenic
compounds. The bioavailability and metabo-
lism of such a mixture is, of course, complex.
Substitution of a simpler form of estrogen may
alleviate migraine symptoms. A number of
other estrogens can be used:
a. 17/3-Estradiol. This is a potent, naturally
occurring estrogen. Natural estradiol, when
given orally, is poorly absorbed and undergoes
rapid metabolism to estrone because of passage
to the liver from the intestine. Because of this,
most marketed estradiol products are in ester-
ified, microionized, or sulfated formulations.
b. Estriol. This is a naturally occurring ste-
roid hormone that cannot be converted to
estradiol. It is of low potency, short acting, and
rapidly metabolized, but if given daily in di-
vided doses, the estrogenic effect is reported
to be substantial.
c. 17-Ethinyl estradiol. Ethinyl estradiol
(Estinyl) is a synthetic estrogenic steroid that
is much more potent than estradiol.
d. Mestranol. This is a derivative of ethinyl
estradiol. It is metabolized to, and exerts its es-
trogenic effects as, the parent compound.
460 Special Topics
3. The oral dosing (intermittent dosing) can
be changed to transdermal (continuous) ad-
ministration. Estrogen implants and transder-
mal patches may keep the concentration of es-
trogen more uniform. There is a surge in serum
estrogen values after tablet ingestion. The
serum half-life of estrone and estradiol is ap-
proximately 4 to 6 hours; to achieve serum val-
ues within a therapeutic range, a high estrogen
dose is required with once-daily administra-
tion. In addition to keeping more uniform lev-
els, transdermal estrogen therapy maintains a
physiologic ratio of serum estradiol to estrone.
4. Androgens can be added. Estrogen-
androgen combinations may decrease the fre-
quency of migraine attacks, but these combi-
nations detrimentally decrease serum levels of
high-density lipoprotein (HDL) cholesterol.100
5. Estrogens can be discontinued. Discon-
tinuation of replacement estrogens may result
in a marked improvement for many mi-
graineurs, although the improvement may take
months to become apparent.24'51 Recommen-
dations to terminate estrogen replacement are
difficult to make, however, when benefits for
the heart and the bones are considered, as well
as estrogen's ability to obviate severe meno-
pausal symptoms.10'38
Various schedules for the administration of
estrogen and progestins are used. A commonly
employed regimen consists of estrogens on the
first 25 days of each month, with progestins
added on the 14th or 16th through 25th days.
Many clinicians prescribe estrogen in continu-
ous 28-day cycles and the progestin is added
for 10, 12, or 14 days of each cycle. An in-
creasingly common regimen is to use both es-
trogen and progestin daily without interrup-
tion, which, with estrogen provided in patch
form, may be the best regimen for a mi-
graineur.
SUMMARY
Women have more migraine than men.
Women consistently report more distress from
their headaches than men do, describing head-
aches that are more severe and of longer du-
ration. Estrogen appears to be a key determi-
nant in the differences between headaches in
women and men. Changes in estrogen levels
are also a prime factor in the production of
headaches during menstruation, pregnancy,
and after menopause. The treatment of head-
aches occurring as a result of hormonal changes
requires subtle approaches that may be very
different from the treatments for migraine in
men.
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Migraine in Women 463
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Chapter 25
Intractable Headaches and
Medication Overuse
EXCESSIVE USE OF ANTI-MIGRAINE
MEDICATION
Prevention of Drug-induced Headache
Treatment
Medications During and After Withdrawal
Success Rate
After Medication Withdrawal
One of the most difficult therapeutic chal-
lenges facing those who treat patients with re-
current migraine headaches is migraine trans-
formed into chronic daily headache. A number
of patients note that over time the number of
headaches between their major bouts of mi-
graine increases (see Chapter 4). Some gradu-
ally discover that their previously episodic pat-
tern has been superseded by daily headaches,
with or without superimposed migraine at-
tacks. For others, their typical migraine head-
aches start to occur several times a week, or
even every day.
EXCESSIVE USE OF
ANTI-MIGRAINE MEDICATION
Almost any medication used for the treatment
of acute migraine attacks taken in excessive
amounts for prolonged periods has the ability
to both cause and sustain headache.3-5 When a
daily pattern of chronic headaches is caused by
excessive medication, it has been variously des-
ignated as drug-induced headache, analgesic
rebound headache, or analgesic abuse head-
ache. Most patients are caught up in a vicious
464
STATUS MIGRAINOSUS
Treatment
CHRONIC INTRACTABLE HEADACHES
SUMMARY
cycle of daily headache and medication
overuse. In addition, their headaches have be-
come refractory to prophylactic medications.
Some patients use only one kind of drug, but
a substantial number use two or more. The
headachemedication cycle is characterized
by daily headache together with daily or almost
daily ingestion of one or more compounds:
over-the-counter (OTC) analgesics, butalbital-
containing drugs, narcotic medications, non-
steroidal anti-inflammatory drugs (NSAIDs),
triptans, and/or ergotamine (Table 25-1 ).13'25'38
Excessive caffeine intake may complicate the
picture. Not only do many of their medications
contain caffeine but additionally, many patients
with this syndrome often drink substantial
quantities of coffee. Nicotine and alcohol are
also used by considerable numbers; both con-
tribute to the headache. Other medications
that can contribute to the problem include
nasal sprays, sinus medications, antihistamines,
and tranquilizers consumed to excess, or even
daily.
A period of at least 3 months of excessive
medication use is probably necessary before a
daily headache develops, but most of these
problems evolve over a period of several years.
 Intractable Headaches and Medication Overuse
Table 25-1. Medications That Can
Lead to Drug-induced Headaches
Aspirin and aspirin-containing medications
Acetaminophen and acetaminophen-containing
medications
Butalbital-containing compounds with or without
caffeine
Ergotamine tartrate
Dihydroergotamine
Narcotics
Caffeine
Non-steroidal anti-inflammatory drugs
Isometheptene mucate
Sedative or hypnotics
Benzodiazepines
Nasal decongestants
Triptans
Migraineurs frequently practice self-medication,
taking excessive amounts of both prescribed
and OTC drugs for headache. Many have been
using analgesics and other medications in grad-
ually increasing amounts since childhood or
adolescence. Moreover, some patients make a
distinction between prescription and OTC
medications. They mistakenly believe that if
they take prescriptions properly, they are fol-
lowing doctor's orders. But because OTC med-
ications fall outside the need for physician ap-
proval, they are perceived as harmless products
that can be taken as often as "needed."
Sufferers of chronic daily headache fre-
quently ingest medication at the onset of the
slightest symptoms. All too frequently a family
member reminds them that it is time to take
medication before the "next" headache ap-
pears. The excessive ingestion of medication
often provides a rhythm not only to the pa-
tients' daily lives but often to those around
them. In contrast, many other patients hide
their drug-taking behavior. Countless patients
anticipate and dread an impending headache
and, as a result, premedicate themselves every
day in an attempt to ward off a bout of head
pain. Apprehension over losing one's job be-
cause of headache-caused absence is another
excuse for what they view as "prophylactic" in-
take of analgesic and anti-migraine drugs. Most
patients have significant emotional and physi-
cal dependence on analgesics and ergots, while
465
at the same time they have developed toler-
ance to their anti-migraine actions. Drug tol-
erance then leads patients to taking larger and
larger quantities in a futile endeavor to salvage
a constantly diminishing therapeutic effect.
Anti-migraine drugs were first prescribed for
many patients by well-meaning physicians who
were unfortunately unaware that misuse of
analgesics, narcotics, ergots, and triptans can
worsen headaches. Such physicians often did
not set limits on their use, so that the medica-
tions were used in progressively larger quanti-
tiesultimately in unmistakable excess. Sym-
pathetic physicians may have unwittingly
contributed to the problem by urging patients
to take anti-migraine medications at the first
sign of a headache or even in anticipation of
pain in stressful situations. It is now widely con-
ceded, however, that the daily use of anal-
gesics, narcotics, ergots, and triptans worsens
and maintains head pain, thereby playing an
important role in the transformation of
episodic headache to daily headache. In other
words, such headaches are drug-induced head-
achesameliorated, often in a dramatic fash-
ion, after drug intake is stopped. This endorses
the argument that the headache was, in fact,
produced by excessive amounts of medications.
Butalbital-containing preparations are among
the most regularly overused compounds.30 It is
not unusual for patients to take 30 tablets per
week, but some ingest 85 or more tablets per
week.23 Many of these patients ingest substan-
tial quantities of OTC medications6 to 10
tablets or more in a day. But patients may de-
velop a chronic daily headache by overcon-
suming nothing other than aspirin or acet-
aminophen.20'2^ The critical threshold dosage
at which acetaminophen or aspirin induces
daily headache is estimated to be approxi-
mately 1000 mg per day. The two compounds
are equally effective in their capacity to stim-
ulate chronic headaches.
Ergotamine overuse, with subsequent phys-
ical dependence and chronic headache, evolves
at an inconstant pace in migraine patients.
Overuse frequently worsens headaches, short-
ens the duration of headache relief it produces,
and renders ineffective previously effective mi-
graine prophylaxis.1'16'4* Ergotamine overuse is
generally seen when a migraineur takes the
compound more than two or three times a
week.39 This is a weekly dose of more than 10
mg in most cases, although some patients take
466 Special Topics
as much as 10 to 15 mg per day.3Q Especially
susceptible individuals may develop drug-
induced daily headaches by taking only 0.5 to
1.0 mg several times a week.1'39 Very few pa-
tients who use ergots excessively show clinical
evidence of significant peripheral ischemia.
But findings of subclinical ergotismalter-
ations of the peripheral circulation and changes
in the cardiovascular system and the elec-
troencephalogram (EEC)may follow contin-
troncephalogram
uous weekly ergotamine doses of more than 7
>16
to 10 mg.11,16 Of interest are reports that the
intensity of withdrawal symptoms does not
appear to correlate with the dose or the length
of ergotamine overuse.1 Dihydroergotamine
(DHE), when administered for extended peri-
ods of time, can also induce chronic headaches,
but this is unusual.44
Because excessive ingestion of caffeine can
factor into the production of chronic daily
headaches, patients must avoid overconsump-
tion of coffee and caffeine-containing soft
drinks and medications. Many migraineurs
consume a lot of caffeine because it relieves
migraine-induced fatigue and irritability and
improves performance and mood. Moreover,
the psychostimulating effects of caffeine can
offset the lethargy produced by excessive doses
of analgesic, narcotic, and sedative drugs.
Many chronic headache patients ingest caf-
feine amounts equivalent to more than three
or four cups of strong coffee per daysome,
the equivalent of 6 to 10 cups, or even more.44
Regardless of its source, caffeine cessation, or
even a dose decrease, produces a caffeine-
withdrawal headache. When this occurs, pa-
tients find that rapid relief can be obtained by
drinking caffeine. This sustains the vicious cy-
cle of caffeine overuse. Moreover, avoiding
caffeine-withdrawal headaches may well con-
tribute to the overuse of caffeine-containing
combination drugs.6
Prevention of Drug-induced
Headache
To keep drug-induced headaches from devel-
oping, doctors must know thoroughly the dan-
gers inherent in indiscriminate prescription of
certain headache remedies. The quantity and
frequency of use must also be plainly specified
to every patient. Each patient must be clearly
warned about the dangers of medication
overuse; the phenomenon of analgesic rebound
needs to be explained in detail. And each pa-
tient must comprehend that this warning ex-
tends to OTC products as well. Patients must
accept the fact that overuse of analgesics, nar-
cotics, ergots, triptans, and caffeine not only
has the potential to lead to daily headache but
will also prevent potentially beneficial preven-
tative medications from functioning effectively.
To err on the side of caution, analgesics
should probably not be used more often than
4 days a month, and limited to two unit doses
per week.43 Ergotamine should probably be
confined to one unit dose per week.43 Unfor-
tunately, clear-cut guidelines as to the limits of
drug administration have not been agreed
upon. To prevent rebounding and physical de-
pendence, physicians should prescribe the low-
est dose of an analgesic or narcotic and the least
potent agent that has an effect.38 The number
of tablets or pills that are required between vis-
its should be reviewed at each visit and the
headache diary evaluated. Call-in requests for
additional medication should be discouraged.
Treatment
The initial step in treating drug-induced head-
ache consists of withdrawing all of the offend-
ing drug or drugs.24 First, however, the af-
fected individual has to be convinced that the
daily headache cannot be alleviated without
detoxification. Convincing the patient usually
requires much effort and time. The physician
must be sympathetic but persuasive, because
treatment for this problem will not succeed un-
less the patient wants the treatment enough to
stay with it despite considerable discomfort.
The patient must realize that effective preven-
tion of migraine is not possible until all
overused medications and preparations have
been eliminated from his or her body and
lifestyle.
Withdrawal procedures vary according to
different authorities and at different centers.
Medications can be withdrawn suddenly or
gradually over a period of weeks, but there is
no uniformity of opinion about which method
is preferable. Whatever method is used, all
analgesics and ergots must ultimately be elim-
inated for the program to be successful. De-
pending on the amount and type of drug
overuse, as well as the patient's psychological,
 Intractable Headaches and Medication Overuse
economic, and social circumstances, the with-
drawal can be managed in an outpatient or an
inpatient situation. Outpatient treatment is far
less expensive, but poor patient compliance is
often a problem. Hospitalization ensures com-
pliance. If withdrawal is done abruptly, close
supervision is usually required and can usually
only be done in a hospital setting. Abrupt with-
drawal may, however, be effective in an out-
patient setting if sufficient explanation is pro-
vided to patients as to what to expect and how
to deal with the discomfort.15 Only patients
with substantial motivation should be treated
as outpatients. Inpatient treatment is required
for patients who have repeatedly failed outpa-
tient withdrawal.
When the individual has been taking large
amounts of abortive medication (particularly
opiates, butalbital, and benzodiazepines), drug
withdrawal may be difficult, if not impossible
and hazardous, on an outpatient basis because
of the severity of the withdrawal symptoms and
the possibility of precipitating seizures. Hospi-
talization is also necessary to provide support-
ive measures such as intravenous fluids for the
control of the alterations in fluid and elec-
trolyte balance resulting from vomiting. Pa-
tients with substantial medical problems (e.g.,
cardiac disease, epilepsy, hyper- or hypoten-
sion) should be hospitalized. Hospitalization in
a specialized headache unit is probably ideal,
because it allows both the parenteral treatment
to interrupt the headache cycle and the devel-
opment of a simultaneous medical and behav-
ioral multidisciplinary treatment plan.19
Abrupt cessation of butalbital-containing
medications, ergotamine, narcotics, and caf-
feine consistently results in an increase in the
severity of head pain. The headache is usually
disabling and is accompanied by nausea. The
withdrawal headache ordinarily begins within
24 to 48 hours following discontinuation of the
drug. The typical headache and withdrawal
symptoms last 2 to 10 days. Some patients ex-
perience worsening of headache, others expe-
rience withdrawal symptoms for a month.7 The
latter can include nausea, vomiting, diarrhea,
tremor, abdominal and leg cramps, arterial hy-
potension, tachycardia, sleep disturbances, and
emotional distress characterized by restless-
ness, anxiety, and nervousness.21'30
Symptoms that may accompany withdrawal
from codeine and other narcotics include
sweating, depression, and severe abdominal
467
aches and pains. Clonidine (two 0.2 mg trans-
dermal patches changed after 1 week and dis-
continued after 2 weeks) can be used to ame-
liorate some of the symptoms of narcotic
detoxification. Clonidine does not, however, al-
leviate the general aches and narcotic craving
characteristic of narcotic withdrawal. Such
withdrawal symptoms may persist for weeks
and, in some cases, months. Benzodiazepine
withdrawal symptoms include anxiety, agita-
tion, paresthesias, muscle cramps, myoclonic
jerks, sleep disturbances, and, following high-
dose usage, seizures and delirium. Patients who
have been on low-dose benzodiazepines usu-
ally have modest side effects upon discontinu-
ation. Most patients taking moderate-to-high
doses of benzodiazepines require inpatient ob-
servation and the use of phenobarbital or car-
bamazepine to prevent seizures. Seizures have
been reported to follow abrupt withdrawal of
butalbital in patients taking very large daily
doses. Phenobarbital (30 mg three times a day
for the first 2 days; 30 mg every day for the
next 2 days) should be administered to patients
who have had abrupt discontinuation of
butalbital-containing medications.36 Otherwise,
barbiturate-withdrawal symptoms resemble
those of benzodiazepines.
After withdrawal, the daily headaches grad-
ually decrease in intensity, frequency, and du-
ration over a period of several weeks. With-
drawal from chronic use of medication alone
may suffice to eliminate or significantly reduce
the daily headache. In two series of cases, with-
drawal from ergotamine and analgesics, with-
out further therapy for 3 months, eradicated
the daily headache in more than 60% of cases,
although in most patients the migraine re-
mained.6'8
Medications During and
After Withdrawal
The Raskin repetitive, intravenous DHE pro-
tocol is of great benefit during the early stages
of withdrawal, but it requires hospitaliza-
tion.28'33'45 Its use has greatly shortened the
time required for detoxification and made pa-
tients' lives more tolerable. Figure 251 shows
how the dose of DHE is determined. After a
10 mg intravenous (IV) dose of metoclo-
pramide, 0.5 mg of DHE is administered IV.
If nausea occurs, no more DHE is given for 8
 468 Special Topics

DIHYDROERGOTAMINE PROTOCOL
Metoclopramide 10 mg IV;
DHE 0.5 mg IV (over 2-3 min)

Nausea Head pain persists; Head pain stops;

no nausea no nausea

No DHE for 8 hours then Repeat DHE 0.5 mg IV DHE 0.5 mg IV

give 0.3 or 0.4 mg q 8 hours in 1 hour q 8 hours for 3 days plus
for 3 days plus (without metoclopramide) metoclopramide 10 mg
metoclopramide 10 mg

Nausea No nausea

DHE 0.75 mg DHELOmg

q 8 hours for 3 days q 8 hours for 3 days
plus plus
metoclopramide 10 mg metoclopramide 10 mg
Figure 25-1. Algorithm for the determination of the appropriate dosage of parenteral dihydroergotamine (DHE) for pa-
tients with drug-induced headache. (Adapted from Raskin NH: Treatment of status migrainosus: the American experi-
ence. Headache 30 (Suppl 2):550-553, 1990, with permission.)

hours. After 8 hours, depending on the inten-
sity and duration of the nausea following the
initial DHE, the next DHE dose ought to be
0.3 or 0.4 mg given with metoclopramide. For
those patients whose head pain vanishes and
nausea does not develop, the dose is continued
at 0.5 mg every 8 hours with metoclopramide.
If, on the other hand, the headache is not sub-
stantially reduced after the first 0.5 mg dose of
DHE, another 0.5 mg dose is administered 1
hour later without metoclopramide. If nausea
occurs after this second 0.5 mg dose, 0.75 mg
is selected to be the final 8-hour dose. If nau-
sea does not occur after the second 0.5 mg
dose, the final dose is 1.0 mg given with 10 mg
metoclopramide. Patients older than 60 years
should have electrocardiographic (EKG) mon-
itoring during the first two IV injections of
DHE. Most patients become headache-free
within 2 to 3 days.
Repetitive DHE causes few serious side ef-
fects. Diarrhea occurs in about half of the pa-
tients. The diarrhea usually responds to ad-
ministration of diphenoxylate and atropine
(Lomotil). Nausea, muscle cramps, and ab-
dominal discomfort may appear, but are usu-
ally eliminated by reducing the dose of DHE.
Some few patients note initial worsening of
their headaches.29
Although there are few controlled studies,
there are reports that NSAIDs, phenothi-
azines, benzodiazepines, corticosteroids, val-
proate, and anti-emetics have been used
more or less successfully to ease the pain and
symptoms of withdrawal for those who can-
not tolerate DHE or for whom DHE is
contraindicated, or for outpatient withdrawal.
In particular, parenteral phenothiazine med-
ications may be used as alternatives to DHE.
Chlorpromazine (7.5 to 20 mg in a slow >2
minute IV injection two or three times daily)
or prochlorpromazine (5 to 10 mg IV in a slow
>2 minute IV injection two or three times a
day) have proved effective. Orthostatic hy-
 Intractable Headaches and Medication Overuse
potension is a potential adverse reaction to
parenteral chlorpromazine, and it is prudent
to keep all patients supine for 2 to 4 hours
and to record their blood pressure at frequent
intervals. Dystonia may appear after use of
phenothizines, but it is easily treated with
benzotropin mesyalte (Cogentin). Sedatives
may also be valuable to counteract the with-
drawal symptoms. The short-term use of par-
enteral narcotics may be necessary. Antinau-
sea remedies are essential for rapid
detoxification. Parenteral sumatriptan is re-
ported to be effective during the withdrawal
phase, but headache recurrence is a prob-
lem.10 A single subcutaneous dose, however,
may alleviate the headache for as long as 6 to
10 hours.
During the withdrawal period, or once the
withdrawal headache has diminished, effective
prophylactic medication such as j8-blockers,
tricyclic antidepressants, or divalproex sodium
should be administered to prevent the recom-
mencement of self-medication with analgesics
and ergots. Amitriptyline appears to be the
agent of choice. Effective prevention is gener-
ally possible after detoxification and removal of
analgesics and ergots, whereas the same pro-
phylactic medications were ineffective in the
presence of daily symptomatic medication.
Some practitioners prescribe prophylactic medi-
cations for several weeks before starting drug
withdrawal, but no data are available showing
that this is more effective than starting pro-
phylaxis during withdrawal.
Success Rate
In different series of patients, the success
rate for analgesic, narcotic, and ergot
withdrawal has varied between 48% and
96% 1,15,21,23,26,27,28,31,46-48 These reported
differences largely reflect the duration of the
follow-up period, the criteria used to deter-
mine success, and the particular drugs from
which the patients under study were with-
drawn. The mean long-term rate of headache
relief appears to be approximately 50% to
80% 2,8,tt,19,26,42,46,47 jn addition to reduction
of head pain, irritability and insomnia are fre-
quently reduced, apathy and depression are
typically alleviated, and general health usually
improves. Significant reductions in days lost to
pain occur.l
469
After Medication Withdrawal
Every patient, no matter how enthusiastic over
achieving a detoxification status, must face con-
tinuing problems of psychologic as well as
physiologic dependence on drugs. Perceptions
based on years of belief that the headache
would be even worse without large amounts of
medication must be changed. For patients who
used sedative or hypnotic medications, the
drugs may have served to distance them from
real-life stresses that are caused by migraine
and also exacerbate it. Accordingly, new cop-
ing mechanisms need to be developed. Any
program, whether inpatient or outpatient,
ought to be integrated with education, behav-
ioral therapy, and psychologic support to aid
patients in the complete management of their
headache problems. Biobehavioral interven-
tions involving relaxation training, biofeedback,
and cognitive therapy are commonly employed
in headache clinics. Individual behavioral
counseling, family therapy, physical exercise,
dietary instructions, and information about
avoiding trigger factors are all necessary.22
Detoxed patients must be warned against re-
lapsing back to their former medication prac-
tices. They must also understand that acute mi-
graine attacks are to be treated with care and
circumspection. The NSAIDs, aspirin, or acet-
aminophen in combination with metoclo-
pramide should be the mainstay of abortive
treatment. Triptans may also be of great help
for many of these patients if their use is con-
trolled. Ergotamine should be used in a very
curtailed manner, its use should be restricted
to those who persist in having severe migraine
attacks despite appropriate prophylactic ther-
apy. Medications containing butalbital or nar-
cotics should be prohibited or, at the least, se-
verely limited.9
STATUS M1GRAINOSUS
Status migrainosus (acute intractable mi-
graine) is the designation applied to severe, un-
relenting bouts of migraine that persist for
more than 72 hours. The headache is continu-
ous throughout the attack, or is interrupted by
headache-free intervals that last fewer than 4
hours.14 The same medication overuse that
gives rise to the chronic daily headache syn-
drome is considered an important factor in
470 Special Topics
many cases of status. Some attacks of pro-
longed migraine headaches, however, develop
without any cause, while others follow head
trauma, the use of oral contraceptives, systemic
illness, high fever, or aseptic meningitis.4 Still
other cases result from the development of co-
morbid intracranial disease or cervical prob-
lems. Status migrainosus typically includes in-
tense nausea, persistent vomiting, prostration,
dehydration, electrolyte imbalance, and signif-
icant emotional distress. The pain, nausea, and
vomiting of these sieges do not respond either
to the usual analgesic and anti-emetic medica-
tions or to appropriate parenteral medication
administered in a physician's office. Many such
patients will have already made multiple trips
to emergency departments (EDs).
Treatment
Patients in status migrainosus generally require
hospitalization away from the chaos of the ED
(Table 25-2). In particular, hospitalization is
necessary if patients are dehydrated, elec-
trolyte depleted, hypotensive, or experiencing
drug withdrawal; have intractable vomiting or
diarrhea; or suffer from a concurrent medical
illness. Intracranial pathology should be ruled
out by appropriate investigation. The patient
should be put to rest in a darkened, quiet room.
Intravenous fluids are usually necessary to cor-
rect the alterations of fluid and electrolyte bal-
ance that result from vomiting and excessive
sweating. Anti-emetics should be used in ap-
propriate doses. Most patients with status do
Table 25-2. Treatment of Status
Migrainosus
Hospitalization
Organic disease must be ruled out
Rehydration with intravenous fluids
Control of nausea and vomiting with anti-emetics
Discontinuation of any abused medications
Intravenous dihydroergotamine (raskin protocol)
If Dihydroergotamine is contraindicated:
Parenteral phenothiazines
Parenteral keterolac
Rectal indomethacin
Consider intravenous corticosteroids
Start preventative medications if appropriate
not obtain much relief from narcotic analgesics
even when they are administered parenterally
in adequate doses. Ergotamine is usually of no
help because of the duration of the symptoms.
In fact, many patients are in status because of
drug overuse. Any overused drugs must be
withdrawn with appropriate supportive mea-
sures.
The repetitive injection of intravenous DHE
every 8 hours has transformed the treatment
of status migrainosus.32'33 It usually eliminates
such headaches within 48 hours. The Raskin
protocol for DHE use in status migrainosus is
identical to that used for drug withdrawal (Fig.
25-1). If DHE is contraindicated, parenteral
phenothiazines, intramuscular (IM) ketorolac
(60 mg IM three times daily), or indomethacin
(50 mg rectal suppositories three times daily)
may be used for analgesia. (The use of pheno-
thiazines is discussed above and in Chapter 18).
Subcutaneous sumatriptan may be used, pro-
vided no ergot has been taken within 24 hours.
Some clinicians recommend the addition of
parenteral corticosteroids to other treatments,
although no consensus about the dose or
method of administration has been reached.
Some use 100 to 500 mg of hydrocortisone ad-
ministered by injection over about 10 minutes
into the IV tubing of a drip of normal saline.
Others inject dexamethasone in a dosage of 8
to 20 mg either intramuscularly or intra-
venously. A repeat parenteral dose, or its oral
equivalent, may be necessary in 8 to 12 hours,
but, in general, if corticosteroids have not
ended status within 24 hours, it is improbable
that they will do so and they should be dis-
continued. Migraine prophylaxis should be im-
plemented.
Other medications that are potentially of
value in status migrainosus and in breaking the
cycle of transformed migraine include intra-
venous valproate and propofol (see Chapter
18).
CHRONIC INTRACTABLE
HEADACHES
A group of patients with migraine do not re-
spond to any of the standard treatments for
headache, or even to medications that are less
frequently used, such as methysergide or
monoamine oxidase inhibitors. Many of these
patients have been tried on a dozen or more
prophylactic regimens without success. They
 Intractable Headaches and Medication Overuse
have had biofeedback or other biobehavioral
therapies and been placed on an assortment of
diets without success. They have often been
through nerve block injections, physical ther-
apy, and chiropractic manipulation. Although
most suffer from transformed migraine with
overuse of analgesic medication, the usual
detoxification procedures have been ineffec-
tive. These patients may truly be said to have
chronic intractable headaches.
There are a number of putative reasons for
failure of treatment in these patients. They may
have any one of the following condition:
1. An undiagnosed secondary headache dis-
order. Organic brain disease (e.g., intracranial
hypertension) may mimic both migraine with
or without aura and transformed migraine,
thereby producing a sustained and persistent
headache.
2. A misdiagnosed primary headache disor-
der. For example, apparent "transformed mi-
graine" may in fact be misdiagnosed as hemi-
crania continua, cervicogenic headache, or
pseudotumor cerebri. Such patients may never
have had appropriate therapy.
3. An undiagnosed medical illness. Con-
comitant medical problems (e.g., sleep apnea,
chronic fatigue syndrome, HIV, hormonal dis-
turbances) may complicate the picture, con-
founding the treatment of headache. Such
medical conditions require treatment before
headaches can be expected to respond to anti-
migraine therapy. Other medical conditions
(e.g., severe coronary artery disease, severe hy-
pertension, brittle diabetes) may produce sub-
stantial limitations on treatment.
4. Problems with non-headache medica-
tions. Patients may be taking a prescribed agent
that can cause headaches as a side effect. Oral
contraceptives may be a major factor. Even
third-generation, low estrogen-containing oral
contraceptives can increase both the severity
and frequency of migraine headaches in be-
tween 3% and 5% of women (see Chapter 6).
5. Noncompliance. Patients may be non-
compliant with a prescribed treatment plan.
6. Illicit drug use. Headaches are not un-
common among cocaine, heroin, and mari-
juana users.
7. Unhealthy dietary or deleterious lifestyle
trigger factors. Patients may persist in, but
deny, irregular eating and sleeping habits.
Chronic sleep deprivation may be a major fac-
tor in adolescents or college students. Patients
may be working irregular shifts. Unreported al-
471
coholism can be a factor, as can addiction to
chocolate.
8. Addiction to prescribed narcotics, butal-
bital, or benzodiazepines. Because they feel
embarrassment or shame, some patients may
not give a history of substantial or frequent
analgesic, tranquilizer, or sedative overuse de-
spite repeated questioning. Many addicted pa-
tients try to hide problematic use of analgesic
medication from medical care providers for
fear that their access to drugs will be limited.
Other patients use symptomatic headache
medication for relief of intolerable psycholog-
ical symptoms. The diagnosis of addiction is
sometimes difficult in migraineurs because ev-
idence of compulsive drug use and the pattern
of drug-seeking behavior may be absent in pa-
tients who receive prescribed pain medication
from several different medical sources.
9. Psychiatric comorbidity. Psychiatric dif-
ficulties often portend unyielding headaches.
In particular, behavioral and psychological
problems may become entangled with the
headache disorder. Physical, psychological, or
sexual abuse, parental alcohol abuse, and a high
level of depression are highly correlated with
poor response to migraine management.21
Some patients with intractable headaches have
obsessive-compulsive disorder, panic or anxiety
disorders, or bipolar illness.
10. Excessive number of psychosocial stres-
sors. Patients may be stuck in intolerable fam-
ily situations with abusive or alcoholic or ad-
dicted spouses or other impaired family
members.
11. An inappropriate social situation. Fam-
ily members sometimes refuse to eliminate en-
vironmental triggers such as tobacco smoke,
perfumes, or colognes. In addition, they often
unwittingly sustain or reinforce illness and
headache behaviors in patients with chronic
headaches.18
12. An ill-adapted reaction to pain. Inap-
propriate reactions to continued headache pain
(and to headache care providers) may compli-
cate treatment. Patients may be overwhelmed
by feelings of hopelessness, anger, and rage.
They may be angry at, or feel victimized by,
past experiences with physicians.
Patients with chronic intractable headaches
who do not respond to aggressive management
require intense evaluation. The history has to
be re-evaluated with probing for details about
medications, analgesics, illicit drugs, and med-
ical problems that may have developed since
472 Special Topics
the original history was taken. A complete neu-
rological and general physical examination
should be performed. Particular attention must
be paid to the condition of the neck. If clinical
re-evaluation suggests the possibility of serious
medical or neurologic illness, appropriate di-
agnostic testing is indicated. A toxicological
screen for drugs and medications may be nec-
essary. Consultation with a psychiatrist is often
valuable. If no new physical problem emerges,
many patients with chronic intractable head-
aches may need the advanced and sustained in-
tervention available at tertiary headache care
centers where a comprehensive, team-oriented,
coordinated interdisciplinary approach is
used.41 The necessary combination of detoxifi-
cation, headache interruption, psychological
intervention, use of multiple pharmacologic
agents and non-pharmacologic intervention,
and development of preventative programming
is simply unavailable in the usual primary and
secondary treatment situations. Individuals
with chronic intractable headaches require ex-
tensive commitments of time at a facility with
experienced staff. A substantial proportion of
patients treated at comprehensive, multidisci-
plinary centers experience sustained, signifi-
cant reductions in pain and depression.19 Their
use of drugs for symptomatic relief and their
visits to EDs are significantly reduced. Many
return to work.
Some clinicians advocate the use of long-
acting opioids taken as preventatives several
times a day as an option for patients with chronic
intractable headaches.17>34>35 This approach is
very controversial. Morphine compounds (MS
Contin), oxycodone (OxyContin), and metha-
done (Dolophine) have all been used, but the
doses must be kept low (MS-Contin, 45 mg per
day; oxycodone, 30 mg per day; methadone, 2.5
to 30 mg per day). These medications appear
safe if they are not overused. The major side ef-
fects that lead to discontinuation are constipa-
tion, nausea, fatigue, and somnolence. Opioid
toxicity, declining function, and aberrant or ad-
dictive behavior are definite dangers. Most pa-
tients will develop physical dependence and tol-
erance to opioids. Some patients worsen and,
depending upon the medication, are at risk for
narcotic overuse or misuse. Only a minority of
these patients achieve long-lasting relief.12'40 It
is difficult to recommend chronic opioid use at
the present time because data are lacking about
criteria for patient selection and the hazards of
long-term use.
SUMMARY
Headaches induced by the excessive use of
analgesic medication continue to be of major
concern. As long as commercials for analgesics
encourage those with pounding heads and up-
set stomachs to use analgesics, and as long as
physicians remain ignorant about the deleteri-
ous effects of analgesics on headache, individ-
uals with frequent headaches will continue to
transform themselves into victims of a daily
pattern of chronic headaches. Physicians will
continue to face individuals who need relief
from intense suffering.
The approach to drug-induced headache is
based on the triad of drug withdrawal, treat-
ment of the withdrawal symptoms, and insti-
tution of appropriate prophylactic therapy.
Complete cessation of the offending medica-
tion is necessary if success is to be achieved.
Withdrawal can be performed gradually or
abruptly, as an outpatient or an inpatient pro-
cess, according to the needs of the patient, the
amount and type of excessively used medica-
tion, and the presence of concomitant medical
problems. Long-term success can be achieved
in more than half the patients. Patients who do
not respond (i.e., have chronic intractable
headaches) may require referral to a tertiary
headache care center. A comprehensive, team-
oriented, coordinated interdisciplinary ap-
proach to the problem is necessary for them.
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fractory chronic daily headache: quality of life assess-
ment. Headache Q 8:234-236, 1997.
36. Sands GH: A protocol for butalbital, aspirin and caf-
feine (BAG) detoxification in headache patients.
Headache 30:491-496, 1990.
37. Saper JR: The mixed headache syndrome: a new per-
spective. Headache 22:284-286, 1982.
38. Saper JR: Medicolegal issues: headache. Neurol Clin
17:197-214, 1999.
39. Saper JR and Jones JM: Ergotamine tartrate depen-
dency: features and possible mechanism. Clin Neu-
ropharmacol 9:244-256, 1986.
40. Saper JR, Lake AE, Hamel RL, et al.: Long-term
scheduled opioid treatment for intractable headache:
a 3-year outcome report. Cephalalgia 20:380, 2000.
41. Saper JR, Lake AE, Maddeb SF, and Kreeger C: Com-
prehensive/tertiary care for headache: a 6-month out-
come study. Headache 39:249-263, 1999.
42. Schnider P, Aull S, Baumgartner C, et al.: Long-term
outcome of patients with headache and drug abuse af-
ter inpatient withdrawal: five-year follow-up. Cepha-
lalgia 16:481^85, 1996.
43. Schoenen J, Lenarduzzi P, and Sianard-Gainko J:
Chronic headaches associated with analgesics and/or
ergotamine abuse: a clinical survey of 434 consecutive
out-patients. In Clifford Rose F (ed): New Advances
in Headache Research. Smith-Gordon, London, 1989,
pp 255-259.
44. Scholz E, Diener HC, and Geiselhart S: Does a criti-
cal dosage exist in drug-induced headache? In Diener
HC and Wilkinson M (eds): Drug-Induced Headache.
Springer-Verlag, Berlin, 1988, pp 29-43.
45. Silberstein SD, Schulman EA, and Hopkins MM:
Repetitive intravenous DHE in the treatment of re-
fractory headache. Headache 30:334-349, 1990.
46. Silberstein SD and Silberstein JR: Chronic daily head-
ache: long-term prognosis following inpatient treat-
ment with repetitive IV DHE. Headache 32:439-445,
1992.
47. Suhr B, Evers S, Bauer B, et al.: Drug-induced head-
ache: long-term results of stationary versus ambulatory
withdrawal therapy. Cephalalgia 19:44-49, 1999.
48. Tfelt-Hansen P and Krabbe A: Ergotamine abuse. Do
patients benefit from withdrawal? Cephalalgia 1:29-
32, 1981.
Chapter 26
Migraine in Children and the Elderly
MIGRAINE IN CHILDREN
Acute Attacks
Prophylactic Therapy
Analgesic Rebound Headaches
Behavioral Therapy
Migraine Equivalents
When migraine is severe, we tend to think of
it as a disorder of young and middle-aged
adults. Yet headache is one of the most fre-
quent physical complaints of children and ado-
lescents. It is also among the most common
reasons that parents seek medical attention for
their children. But despite its high frequency,
both parents and physicians tend to underesti-
mate migraine as a cause of headache, and
childhood migraine is generally undertreated.
At the other end of the age spectrum, head-
aches are also frequent in the elderly. Although
somatic disease is a common cause of head pain
in this age group and clinicians usually look
elsewhere for the source of the head pain, mi-
graine does occur among the elderly and can
be as severe as that in younger adults. Older
patients deserve thorough evaluation and,
when diagnosed, their migraine requires age-
appropriate treatment.
MIGRAINE IN CHILDREN
Migraine attacks can include symptoms that
frighten children and their parents. Because
most families are unaware that migraine occurs
in childhood, parents often come to physicians
terrified that their child is suffering from some
serious organic disease. Reassuring both par-
474
ELDERLY
MIGRAINE IN THE ELDERLY
Guidelines
Acute Attacks
Prophylactic Therapy
SUMMARY
ent and child is crucial. Once other causes of
headache have been excluded, the family must
be persuaded that no serious medical or neu-
rological disease is present, and that no further
specialized diagnostic tests are necessary. At
that point, the cause of the head pain and other
symptoms can be explained to them. After the
parents are convinced that their youngster is
not gravely ill, they can begin to be educated
about how to help their child minimize the
number and intensity of migraine attacks. Par-
ents must be informed about general measures
that affect migraine: diet, sleep, and trigger fac-
tors.
For the most part, the same approach used
to modify adult lifestyles is appropriate for chil-
dren. Fatigue, exercise, noise, glare, missed
meals, and studying have been identified as
major trigger factors. Emphasis should be
placed on determining and eliminating areas of
stress at school and at home.9'42 Parental dis-
cord and/or coercion may be important trig-
gering factors. Migraine is more frequent dur-
ing the school year than during the summer,
because school is a major source of childhood
stress. Emphasis on achieving high grades at
the expense of enjoyable learning is an addi-
tional source of stress. Many children are over-
loaded with activities, and this burden should
be lightened. If stress is not recognized and

dealt with, medications may be of little value.
Excessive computer time and long hours of
watching television may also be important de-
terminants.7 Physicians should detail a home
schedule that includes a reasonable amount of
extracurricular, extraschool, free-time activity,
an early bedtime, and regular meals (including
breakfast). Children often consume far more
"junk" food (full of chemical additives and col-
orings) than adults do. Eliminating these prod-
ucts may be very helpful. Most parents find
that unless they provide "competing snacks"
either homemade or purchased from a health
food storeit may be impossible to keep the
child away from potential precipitants.
Many medications for symptomatic relief
and for prophylaxis are recommended for
childhood migraine, but clinical decisions
about the type of therapy are difficult to make
because most commonly used preparations
have not been properly investigated in chil-
dren. We lack data about their effectiveness
against childhood migraine; information is also
limited about preventative medications in chil-
dren. Moreover, a number of useful drugs have
not been approved for children under 12 years
of age. Evaluating anti-migraine therapy in
children is also difficult because many children
show a progressive reduction in headache fre-
quency regardless of the form or type of treat-
ment. For acute migraine, the adolescent can
usually be medicated with adult dosage.
Acute Attacks
Even more so than in adults, children require
rest for acute migraine attacks. Sleep should be
encouraged, as it can greatly expedite im-
provement. Many children, especially younger
children, fall asleep during a bout of migraine
and most awake free of symptoms.1 Rest in a
dark room and ice or cold packs may be suffi-
cient for mild attacks.
The pharmacologic treatment for the acute
attack is complicated by a number of factors.
Abortive drugs, for example, should be used
early in a bout of migraine, but young children
are often unable to recognize the early phase
of their attack. Even when youngsters are old
enough to recognize early symptoms, there can
be obstacles. Although many attacks occur dur-
ing school hours, students are often not per-
mitted to bring medicine to school or to take
Migraine in Children and the Elderly 475
it without supervision. Nor will most schools
administer medications. And even when the
situation enables them to have their medica-
tion with them, young children are unable to
take the responsibility for administering it
safely and properly. Thus, abortive medication
is often not an option at the very onset of an
attack. It is necessary for the physician to in-
form the child's school about the necessity of
early medication. In addition, it has been doc-
umented that adolescents frequently delay tak-
ing analgesic medication after the onset of pain,
presumably hoping it will go away by itself.15
The necessity for early treatment must be
stressed.
Once an attack is underway, simple anal-
gesics frequently can reduce the pain of mild-
to-moderate headaches, and if at all possible,
treatment should be limited to them (Table
26-1). The primary drug of choice for migraine
in children is acetaminophen.23 It can even be
administered to children as drops or syrup. In
therapeutic doses (10 to 15 mg/kg) adverse ef-
fects are extremely rare in children. Ibuprofen
(10 to 20 mg/kg) and other non-steroidal anti-
inflammatories (NSAIDs) are reasonable op-
tions. A controlled study reported that ace-
taminophen may have had a more rapid onset
than ibuprofen, but the latter is more likely to
produce a pain-free state at 2 hours.23 Al-
though aspirin may be useful against childhood
migraine, it should not be ingested by children
under the age of 12 because Reye's syndrome
may develop should the child be suffering from
an unnoticed, subclinical virus infection. Con-
sisting of severe hepatic dysfunction and en-
cephalopathy, Reye's syndrome is a rare, but
frequently fatal consequence of infection with
various viruses, particularly the influenza virus.
Salicylate use has been strongly implicated in
the development of Reye's syndrome in chil-
dren. Controversy exists about the ages during
which Reye's syndrome is a risk factor. Some
authorities recommend that aspirin be with-
held until age 16, or even 18.
If nausea and vomiting are conspicuous com-
ponents of the attack, anti-emetics such as
prochlorperazine (Compazine) and metoclo-
pramide (Reglan) can be given. Younger chil-
dren occasionally develop intense and un-
pleasant dystonic reactions to metoclopramide.
These include oculogyric crises and muscle
spasms. Prochlorperazine may also cause extra-
pyramidal symptoms. Accordingly, the lowest
476 Special Topics

Table 26-1. Medications for Acute Migraine Attacks in Children

Agent Brand Name Dosage Pediatric Form

Aspirin* 7-10 mg/kg Chewable tablets

(maximum 30-65 mg/kg per day)
Acetaminophen Tylenol 10-15 mg/kg; Elixir, syrup
Tempra may repeat in 2 hours suspension,
(maximum 30-40 mg/kg per day) chewable tablets
Ibuprofen Motrin 10 mg/kg; Suspension,
Advil may repeat in 4-6 hours chewable tablets,
(maximum 40 mg/kg per day) concentrated drops
Isometheptene Midrin 1-2 capsules;
Acetaminophen repeat hourly
Dichloralphenazon (maximum ^5 capsules per day)
Metoclopramide Reglan 2-10 mg Syrup
(maximum 10-15 mg per day)
Prochlorperazine Compazine 2.5 mg one to three times daily Suppository,
(maximum 7.5-15 mg per day) syrup
Promethazine Phenergan 0.25 mg/kg four times daily Suppository,
(maximum 1.0 mg/day) syrup
Sumatriptan Imitrex Pediatric dosage, safety, and
efficacy not established
Ergotamine Cafergot 6-9 years: 0.1-0.15 mg/dose (suggested) Suppository
Wigraine 9-12 years: 0.2 mg/dose (suggested)
1216 years: 0.25 mg/dose (suggested)
"Contraindicated in children <12 years of age because of danger of developing Reye's syndrome; see text.

effective dosage of each should be adminis- young as 6 years of age.29 Recommended

tered. Promethazine (Phenergan) supposito-
ries are often helpful, and are less likely to pro-
duce dystonia.
The utility of triptans in children is unclear.
Oral triptans do not appear to be effective,
most probably because of the short duration of
many attacks.22 Two open studies showed effi-
cacy of subcutaneous sumatriptan in modified
dosage (0.06 mg/kg).30>33 Controlled investiga-
tions have demonstrated the efficacy of in-
tranasal sumatriptan in adolescents.5*'61 Oral
triptans are also widely used for adolescents.31
Ergotamine preparations should be used in
low doses and are best avoided altogether for
children below the age of 6. In older children
the drug should be reserved for those uncom-
mon patients with infrequent, exceptionally se-
vere, long-lasting bouts of migraine that do not
respond to triptans. Unfortunately, the recom-
mended dose of ergotamine has not been de-
termined for children. Intravenously-adminis-
tered dihydroergotamine (DHE) is now being
used successfully by some pediatric neurolo-
gists to treat refractory migraine in children as
dosages are as follows: age 6 to 9 years, 0.1 to
0.15 mg/dose; 9 to 12 years, 0.2 mg/dose; 12 to
16 years, 0.25 mg/dose. DHE nasal spray may
be prescribed for older children. It can be used
empirically at half the adult dose.
The fact that a variety of symptomatic treat-
ments are available for acute migraine attacks
in childrenand that no one is favored except
for Tylenolprovides confirmation that man-
agement of such attacks is sometimes unsatis-
factory. No preparation is efficacious for all
children, and some patients may be refractory
to all agents or develop intolerable side effects.
This latter group of children require prophy-
lactic medication.
Prophylactic Therapy
The primary element when recommending
prophylactic therapy is the frequency and
severity of the attacks and their associated dis-
ability. Prophylaxis should be offered to chil-
dren who have several severe, prolonged head-
 Migraine in Children and the Elderly 477

Table 26-2. Prophylactic Medications for Migraine in Children

Agent Pediatric Form Initial Dose Maximum Dose

Cyproheptidine Syrup 0.25 mg/kg per day 2-6 years: 4-12 mg per day
(Periactin) 7-14 years: 8-16 mg per day
Propranolol 1-4 mg/kg per day 5 mg/kg per day
(Inderal)
Amitriptyline 0.25-0.5 mg/kg per day
(Elavil)
Verapamil 4-10 mg/kg per day
(Calan, Isoptin)
Valproate Syrup, 10 mg/kg per day <60 mg/kg per day
(Depakene, Depakote) sprinkles
Gabapentin 20^40 mg/kg per day
(Neurontin)
Topiramate Sprinkles 30 mg per day 0.25-1.0 mg/kg per day
(Topamax)

aches per month, who do not respond well to
symptomatic medication, and for whom head-
aches are disrupting school attendance, inter-
rupting sports activities, and interfering with
their relations with other children. Among the
drugs in use for childhood migraine prophy-
laxis are cyproheptadine, anticonvulsants, (3-
blockers, amitriptyline, calcium-channel block-
ers, as well as other medications effective for
adult migraineurs (Table 26-2). Gabapentin
and topiramate have been approved for use in
very young children and may potentially be
used in children with migraine. Unfortunately,
there have been few well-designed, controlled
investigations in children to offer guidance for
appropriate prophylaxis.
Probably from force of habit, cyproheptidine
(Periactin) remains a popular therapy for
childhood migraine. In fact, despite a dearth
of published informationonly two uncon-
trolled pilot studies have reported efficacy
cyproheptidine may be the most frequently
prescribed medication.10'12 Depending on age,
the usual dosage is 2 to 4 mg two or three times
a day. As in adults, drowsiness, appetite stim-
ulation, and anticholinergic effects can occur.
Because of its propensity to stimulate appetite,
it should not be used for obese children. Nor
is it recommended for use in very young chil-
dren (particularly those less than 2 years old)
because antihistaminics may cause hallucina-
tions, convulsions, or central nervous system
(CNS) depression in young children.
In years past, anticonvulsant agents, partic-
ularly phenobarbital and phenytoin, were pre-
ferred for the preventative treatment of child-
hood migraine.5'38'46 Some practitioners still
prescribe them, but neither phenobarbital nor
phenytoin has been exposed to thorough test-
ing for anti-migraine effectiveness. Moreover,
the use of these drugs is limited by their sub-
tle effects on attention, learning, and behavior.
Valproate (Depakote, Depekene) has been ap-
proved by the Federal Drug Administration
(FDA) for use in adult patients with migraine.
An open study reported efficacy in children.13
Caution must be employed when using this
medication for migraine prophylaxis in chil-
dren. In the very young, it can produce a ful-
minant hepatitis.
The two controlled investigations of propra-
nolol (Inderal) in childhood migraine produced
quite different treatment outcomes: effective-
ness in one; little value in the other.19'32 None-
theless, propranolol is considered an important
prophylactic drug for the therapy of childhood
migraine. Pediatric patients should be started
on 1 to 2 mg/kg per day, and the dose gradu-
ally increased to 5 mg/kg per day unless a ther-
apeutic effect is reached at a lower dose. There
seem to be fewer side effects in children and
adolescents than in adults.
All of the other medications used for mi-
graine prophylaxis in adults are potentially use-
ful against childhood migraine. Only flunara-
zine (Sibelium) and pizotifen (Sandomigran)
478 Special Topics
however, have been shown superior to placebo
in controlled studies, and neither is available in
the United States.14'35'45'52 One controlled trial
of nimodipine (Nimotop) in children demon-
strated it to be ineffective.6 Methysergide
(Sansert) is not recommended because of the
high incidence of side effects. Although there
have been no controlled studies, tricyclic anti-
depressants have a role in the treatment of chil-
dren who have frequent attacks or mixed types
of headaches.25'51
Because migraine in children has a high re-
mission rate, attempts should be made to dis-
continue prophylactic medication at the end of
6 months or at the end of the school year. Ther-
apy can be recommenced if headaches recur.
Analgesic Rebound Headaches
Analgesic rebound headaches are a well-
recognized and widespread complication among
adult migraineurs. We now know that analgesic
rebound headaches, as well as analgesic abuse,
also occur in pediatric and adolescent mi-
graineurs.53'59 Daily or near-daily headaches
can be associated with the daily use of anal-
gesics in children. The clinical picture is com-
parable to that seen in adults. No ideal treat-
ment plan has been devised for children and
adolescents, but all analgesics must be stopped.
Behavioral Therapy
A smaller percentage of children than adults
are treated prophylactically because of the in-
grained hesitancy of physicians to treat grow-
ing children with medication for a prolonged
period of time. Fortunately, behavioral therapy
appears to be valuable for childhood mi-
graineurs, particularly if the parents and physi-
cians are disinclined to use medications or if
pharmacotherapy has been tried and found in-
effective.48 Relaxation training, thermal bio-
feedback, and other behavioral modalities all
work, although their relative efficacy is uncer-
tain.24'36'48 Some uncontrolled stuclies involv-
ing only small numbers of children suggest that
children may respond to behavioral therapy
better than adults.24 Children under the age of
8, however, may not be able to follow compli-
cated treatment protocols.
Migraine Equivalents
Several syndromes of childhoodbenign parox-
ysmal vertigo, abdominal migraine, and cyclic
vomitingare regarded by many as migraine
equivalents (see Chapter 4). A few stuclies in-
dicate that prophylaxis with anti-migraine
drugs may be effective and should be at-
tempted if a child has symptoms that disrupt
normal activity. No trials have assessed pro-
phylactic medication for benign paroxysmal
vertigo. For abdominal migraine, propranolol
and pizotifen are reported to provide effective
prophylaxis, whereas the efficacy of other pro-
phylactic drugs is limited to anecdotal re-
ports.44'54'55-62 Prophylactic treatment of cyclic
vomiting with cyproheptidine, pizotifen, phe-
nobarbital, and amitriptyline is often effec-
tive.2'18'21'44 Data about other prophylactic
drugs are not available. Over 65% of the chil-
dren considered to have cyclic vomiting are
said to respond to sumatriptan.28
MIGRAINE IN THE ELDERLY
The prevalence of migraine may decline with
advancing age, but migraine headaches are not
uncommon in elderly patients. Although treat-
ment principles discussed in earlier chapters
remain the same, the options are somewhat re-
duced. Chronic illness and the medications
needed to treat them, age- and illness-related
contraindications to various medications, and
sleep problems may all interfere with migraine
treatment. Approximately 80% of individuals
65 years of age and over suffer from at least
one chronic disease. Most prevalent are arthri-
tis, hypertension, heart disease, visual difficul-
ties, and cerebrovascular diseaseeach is
found in at least 10% of the elder population.58
Compared to younger individuals, those in the
over-65 group have a relatively high consump-
tion of medications, accounting for about 30%
of all prescription drugs.3 Non-prescription
drug use similarly increases with age, with about
two-thirds of the elderly self-medicating.27
Some data indicate that the average older
American takes three prescription drugs and
four doses of over-the-counter (OTC) medica-
tions daily.8 Not only does the possibility of
drug-drug interaction interfere with migraine
treatment, daily anlgesic ingestion, such as for

arthritis, often transforms migraine. Noncom-
pliance with prescribed regimens does not
necessarily increase with advancing age, but its
likelihood increases as the number of different
medications rises. Studies have reported med-
ication adherence rates in the elderly that
range from 26% to 59%.4 Noncompliance may
result in failure of migraine treatment and drug
efficacy and/or medication overdosage. A reg-
ular sleep schedule is essential for migraine
prevention. Thirty to fifty percent of older per-
sons complain of some sort of sleep distur-
bance.47 Like other medical problems, these
sleep disorders can exacerbate migraine.
Various physiological changes associated
with aging have implications for anti-migraine
therapy:
1. Age-related untoward responses to drugs.
Physiological changes associated with aging
may adversely alter the responses to drugs. A
clear illustration of this is the postural hy-
potension commonly seen with tertiary amine
tricyclic antidepressants. In a young individual,
this may not be noted or may be only a trivial
side effect; in older patients, however, the
heart may have limited capacity to accelerate
its rate in response to decreased blood pres-
sure and, as a result, orthostatic hypotension
may have serious consequences.
Table 26-3. Physiologic Changes in the Elderly Associated with
Altered Pharmacokinetics
Organ System Change
GI tract J, Intestinal and splanchnic
blood flow
Circulatory | Plasma albu
concentration
| i-acid glycopro
I Total body water
Kidney IGFR
Muscle | Lean body m
t Adipose tissue
Liver | Activity of dr
metabolizing enzymes
I Hepatic blood flow
GFR, glomerular filtration rate; GI, gastrointestinal.
(Adapted from DeVane CL and Pollock BG: Pharmacokinetic considerations of antidepressant use in the elderly. J Clin
Psychiatry 60(Suppl 20):38^4, 1999. Copyright 1999, Physicians Postgraduate Press. Reprinted with permission.)
Migraine in Children and the Elderly 479
2. Reduction of ability to metabolize and ex-
crete drugs. The elderly (even in good health)
have a reduced ability to metabolize and ex-
crete drugs, increasing the risk of adverse drug
effects unless drug doses are appropriately ad-
justed. In other words, as people age, they need
smaller doses of medication; unless practition-
ers take account of age, there is danger of over-
medication. As a result of inadvertent over-
dosage, the elderly also have a greater potential
for the development of drug side effects. The
overall incidence of adverse drug reactions is
two to three times that found in young adults.40
3. Alterations in pharmacokinetics. The
pharmacokinetics, binding, and excretion of
drugs will be affected in various ways in geri-
atric migraineurs (Table 26-3). Age may alter
the pharmacokinetics of drugs because of
changes in lean body mass, plasma protein
binding, hepatic blood flow, and renal function.
For example, lean muscle mass and total body
water decrease, while body fat increases rela-
tive to total body weight in the elderly.11 Many
drugs used in the treatment of migraine (e.g.,
antidepressants, some /3-blockers, neuroleptics,
anticonvulsants, barbiturates) are fat-soluble
(lipophilic) compounds. A given dose of one of
them will be distributed more extensively in
the peripheral body tissues of an elderly pa-
Pharmacokinetic Consequences
| Rate of drug absorp
Possible | bioavailab
| or | free concentra
drugs in plasma
| Renal clearance of d
| Plasma concentra
Altered volume of distribution
| Hepatic cleara
Plasma concentration
480 Special Topics
tient than in that of a younger patient, and this
has consequences for how the body clears the
drugs. The elimination half-life (v2) of a drug
is a function of the volume of distribution (Vj).
An increase in Va prolongs f v2 even if the clear-
ance is unchanged. In other words, one would
expect the levels of a lipophilic drug to be pro-
longed in the elderly. Several other factors may
be associated with clinically observed increases
in drug toxicity in older patients, namely age-
related decreases in plasma albumin concen-
tration, with a concomitant reduced capacity
for drug binding; in hepatic microsomal oxi-
dizing capacity, which reduces the first-pass
metabolism of oral drugs, and in renal blood
flow and glomerular filtration rate, thus re-
ducing renal clearance of drugs and metabo-
lites. The plasma levels of a number of med-
ications used for migraine treatment, including
amitriptyline and other tricyclics, lithium, and
paroxitine, are increased as a result of these al-
terations.26'39
4. Changes in neurotransmitterfunction. As
for neurotransmitters, there are changes in the
concentration of 5-HTiA and 5-HTA recep-
tors, the 5-HT transporter responsible for in-
activation of 5-HT at serotonergic synapses in
aged human brains. As a result, the level of
brain 5-HT is altered.34'37-50'60 The effects of
various medications that act on serotonergic
systems will also presumably be altered.
Guidelines
Some of the obstacles to successful pharmaco-
logic treatment of older migraineurs can be re-
duced if a set of procedures are routinely em-
ployed:
1. Identify all medical problems.
2. Take a careful drug history, including the
use of OTC medications. This may involve
questioning caregivers and relatives. Regular
updates must be displayed in a prominent lo-
cation in the patient's chart.
3. Educate patients, caregivers, and rela-
tives about all prescribed medicines and their
potential adverse reactions.
4. Prescribe medications one at a time.
Limit starting doses to less than the minimum
dose recommended for young adults.
5. Raise dosages very carefully and very
slowly.16
6. Avoid polypharmacy.
7. Monitor compliance.
8. Suspect an adverse drug reaction if there
is a deterioration in the patient's physical or
cognitive state.
Effective and safe use of anti-migraine drugs
in geriatric patients is a matter of careful indi-
vidualization of the therapeutic regimen, and
of constant vigilance.
Behavioral techniques are often valuable, al-
though they appear to work less well in older
individuals than in younger adults. Older pa-
tients frequently take longer to master the
techniques and often require protocol modifi-
cations.
Acute Attacks
There are no rules for treating migraine in
older individuals. Their headaches can be just
as severe as in younger individuals and ade-
quate treatment is necessary. But some med-
ications used for the symptomatic relief of mi-
graine headaches may cause difficulty in
elderly patients (Table 26-4). The selection of
anti-migraine medication depends on assorted
factors, especially the concomitant medical sta-
tus of the patient and the potential for serious
cardiac, peripheral vascular, and renal prob-
lems. Because triptans and ergot derivatives
must be used conservatively and with caution,
reliance is placed more on symptomatic pain
medications. In addition to the contraindica-
tions listed in Table 26-4, other caveats are in
order.
Acetaminophen is particularly useful in
elderly patients because of its high safety
profile. Nonetheless, physicians must be aware
of potential problems when prescribed
acetaminophen-containing medications are
supplemented with self-administered OTC
acetaminophen. An elderly patient taking a
prescribed combination of propoxyphene and
acetaminophen, if taken approximately every 4
hours for a migraine attack along with one or
two OTC 500 mg acetaminophen tablets, may
easily ingest 4 to 6 g of acetaminophen in 8 to
12 hours. The recommended maximum for an
adult in a 24-hour period is 4 g; for the elderly
even 4 g may be excessive.
Non-steroidal anti-inflammatory drugs (in-
cluding aspirin) should be used much more
sparingly because the chance of causing con-
gestive heart failure, renal failure, or gastroin-

Table 26-4. Contraindications to Anti-migraine Medication in the Elderly
Medication
Abortive Drugs
Aspirin
Non-steroidal anti-inflammatory drugs
Acetaminophen
Codeine
Barbiturates
Isometheptene
Ergotamine, dihydroergotamine
Triptans
Prophylactics
Tricyclics
/3-Blockers
Calcium-channel blockers
Methysergide
Adapted from Edmeads (1990),16 by courtesy of Marcel Dekker, Inc.
testinal hemorrhage is augmented in patients
of advanced age.17>41'56 Although prostaglan-
dins have both vasodilator and vasoconstrictor
actions, the overall inhibitory effect of NSAIDs
on prostaglandin synthesis is to raise systemic
vascular resistance. In individuals with im-
paired ventricular function, the increased vas-
cular resistance may be sufficient to produce
congestive heart failure. Increased vascular re-
sistance also reduces renal perfusion. In addi-
tion, NSAIDs in the elderly are associated with
a wide range of tubular, interstitial, glomeru-
lar, and vascular renal problems. In particular,
nephropathy is more likely to occur when older
individuals take excessive amounts of analgesic
mixtures containing at least two antipyretic
analgesics combined with caffeine and/or
codeine. Increasing age is also associated with
many alterations in gastrointestinal physiology
that may contribute to an increased risk of
Migraine in Children and the Elderly 481
Contraindication
Peptic ulcer
Peptic ulcer
Renal or hepatic disease
Constipation
Mental slowing and confusion
Hypertension, cardiac or peripheral
vascular disease
Coronary heart disease, uncontrolled
hypertension, peripheral vascular disease,
Raynaud's disease, cerebrovascular disease
Coronary heart disease, uncontrolled
hypertension, peripheral atherosclerotic
vascular disease, Raynaud's disease,
cerebrovascular disease
Glaucoma, prostatism, cardiac arrhythmias,
sedation
Heart block, bronchospasm, hypotension,
heart failure, depression
Heart block, heart failure, peripheral edema,
hypotension, constipation
Retroperitoneal and pleuropulmonary
fibrosis, peripheral vascular disease,
renal disease, ischemic cardiac disease,
cardiac valvular disease
NSAID-induced gastropathy. Levels of gas-
trointestinal prostaglandins are reduced with
age. The lower basal levels of prostaglandins
leads to greater fragility of the mucosa. Small,
elderly women seem to be most susceptible to
the development of gastritis and ulcer forma-
tion with its attendant risk of hemorrhage.
NSAID therapy should be limited to those
situations where it is deemed to be absolutely
necessary. One must use the lowest feasible
dose for the shortest period of time, employ-
ing gastrointestinal prophylactic therapy (e.g.,
misoprostol [Prilosec]) and using non-NSAID
alternatives (e.g., acetaminophen) as the first-
line analgesic therapy as soon as possible.
These are currently the best-supported strate-
gies for reducing the risk of NSAID-ielated ad-
verse events in the elderly patient population.
Barbiturates, such as the butalbital in anal-
gesic-sedative combination drugs (e.g., Fiore-
482 Special Topics
cet, Esgic), usually have no acute deleterious
actions in younger patients, but in elderly in-
dividuals they may produce depression, confu-
sion, and sometimes paradoxical excitement.
These medications should not be used to treat
migraine in the elderly if alternatives are avail-
able. If butalbital-containing medications are
used, they must be prescribed in very small
quantities. Isometheptene mucate (Midrin) is
less sedating than barbiturates and appears to
be tolerated by elderly migraineurs. It should
be used with caution in patients with hyper-
tension, cardiac probelms, or peripheral vas-
cular disease.
The clinical effects of codeine do not appear
to change with age. Codeine may be pre-
scribed in older patients provided each one is
clearly warned about the dangers of medica-
tion overuse. Codeine is O-demethylated to its
active metabolite morphine by the P-450
isoenzyme CYP2D6. The activity of this isoen-
zyme is unaltered by age, but is subject to in-
hibition by some medications frequently used
by the elderly, such as the selective serotonin-
reuptake inhibitors (SSRIs), fluoexetine
(Prozac) and paroxetine (Paxil). Narcotics
stronger than codeine have an increased risk
in the elderly of adverse effects such as cog-
nitive disturbances, respiratory depression,
and constipation.
Ergotamine, even in modest doses, can
cause vasoconstriction sufficient to produce
signs and symptoms of vascular insufficiency in
the extremities, heart, and brain. Problems of
this type are much less frequent in younger
people. In older individuals, who may have pre-
existent, but asymptomatic, vascular disease,
ergot derivatives (including DHE) may cause
symptoms referable to coronary artery insuffi-
ciency. In general, ergots should not be pre-
scribed for patients older than 60 years.
The triptans must be used sparingly. Special
care must be taken when administering trip-
tans to individuals who may have vascular dis-
ease affecting the heart, periphery, or cere-
brum or have clinically relevant risk factors for
development of vascular disease. Half-tablets
of triptans may be tried first in a physician's of-
fice. Despite the fact that triptan-induced chest
discomfort and pain are not believed to be car-
diac in origin, if chest pain does result from ad-
minsitration of the first dose, the medicine
should probably not be prescribed even if the
electrocardiogram (EKG) is normal.
Prophylactic Therapy
Elderly individuals with severe or frequent at-
tacks of migraine may need daily prophylactic
medication to control their headache symp-
toms. Even when given in lower dosages, such
medications are often capable of greatly im-
proving the quality of life in older patients.
Chapters 19 to 23 contain specific details about
preventative medications. Cautions similar to
those for symptomatic medications attend the
prescription of preventative medications with
regard to both dose and contraindications
(Table 26-4).
1. (3-blockers. Although adverse effects of
/3-blockers are more common in elderly mi-
graineurs, they still may be used with appro-
priate monitoring. Dosing should begin with 60
mg long-acting (LA) once a day.
2. Calcium-channel Mockers. Verapamil is a
useful prophylactic agent in the elderly. It is
generally safe, but its clearance is reduced in
elderly patients, and as a consequence, its neg-
ative chronotropic and dromotropic effects are
more common.49 Its constipating properties
also pose problems in this age group. A start-
ing dose of 90 mg sustained-release (SR) (one-
half of a 180 mg SR tablet) or 120 mg SR
should be used.
3. Tricyclic antidepressants. Although some
elderly patients may require the same doses as
younger adults, the variability in pharmacoki-
netics is such that the responses of elderly pa-
tients to tricyclics are less predictable than
those of younger adults. Dosage requirements
will most often be reduced in the geriatric mi-
graineur. Good clinical practice specifies initi-
ating antidepressants at a reduced dose: 10 mg
per day of amitriptyline and other tricyclics. In
general, they should not be administered as a
single nightly dose (unless patients are taking
small amounts [10 to 50 mg per day] because
of an increased incidence of side effects when
the entire dose is given at one time.
Secondary amine tricyclics, particularly nor-
triptyline and desipramine, are generally
preferable to tertiary amine tricyclics (ami-
triptyline, imipramine, doxepin) in older pa-
tients because their side effects are milder and
their metabolism is less complex. The low fre-
quency of anticholinergic and cardiovascular
effects makes the quatracyclic trazadone prac-
tical for use in the elderly. In contrast, the an-
ticholinergic side effects of tricyclic antide-

pressants are especially troublesome. There
may be central side effects (causing confusion,
delirium, excessive sedation, and cognitive im-
pairment) or peripheral ones (causing dry
mouth, blurred vision, tachycardia, urinary re-
tention, constipation, and orthostatic hypoten-
sion).
The elderly are more prone to develop or-
thostatic hypotension, which can cause falls,
fractures, strokes, or coronary occlusion.20 In-
deed, an increased incidence of femoral neck
fracture in older patients treated with tricyclics
has been attributed to orthostatic hypotension.
The risk of hip fracture appears greatest shortly
after initiation of antidepressant therapy, and
declines over time. The most serious side ef-
fect of tricyclic antidepressant treatment in
older individuals is cardiotoxicity. At higher
plasma levels, these drugs interfere with car-
diac conduction and can produce bundle-
branch or atrioventricular (AV) block. Pre-
treatment EKGs are strongly recommended,
and frequent EKG monitoring during the
course of treatment is important.
4. Valproate. Free valproate levels are in-
creased in the elderly. At least two separate
mechanisms are involved: a decrease in plasma
protein binding and a reduction of drug me-
tabolizing capacity that results in decreased
clearance of free drug by the liver.43 More
gradual escalation should be used in elderly pa-
tients (e.g., 125 mg the first day and changes
of 125 mg made every few days).
5. Gabapentin. This drug is well tolerated
by older individuals, but some become lethar-
gic or confused. Because it is cleared by renal
excretion, gabapentin levels may be higher be-
cause elderly patients have a decreased renal
blood flow and glomerular filtration rate. The
drug should be administered in low doses (100
mg daily) and gradually increased to therapeu-
tic levels. The amounts vary widely, from 300
mg to 3600 mg per day.
6. Monoamine oxidase inhibitors (MAOIs).
These drugs may be used in elderly patients,
but they or their caregivers must fully under-
stand the dietary and medication restrictions.
7. Lithium. The elimination half-life is pro-
longed in the elderly because of the age-related
decrease in glomerular-filtration rate. Conse-
quently, older patients tend to need lower than
usual doses to reach a given serum concentra-
tion and require longer than usual to reach a
steady state.
Migraine in Children and the Elderly 483
SUMMARY
Many children with migraine are undertreated
because parents and physicians tend to under-
diagnosis migraine and to underestimate the
significance of the problem. While it is true
that many children respond to reassurance,
general suggestions, and basic remedies, many
other children suffer severe, long-lasting, fre-
quent attacks that require vigorous attention.
Treating childhood migraine is made difficult
by a lack of verifiable information about com-
mon medications in children. Prophylactic
treatment for children is also far from satisfac-
tory. Compassion and understanding are
needed in large measure.
Equally difficult is the treatment of migraine
in older patients. Treatment is complicated by
the frequency of chronic medical illnesses, the
relatively high medication consumption, and
age-related changes in the pharmacokinetics of
drugs and in neurotransmitter function. None-
theless, older patients can be managed suc-
cessfully if sufficient attention is paid to details
in treatment, especially with regard to the dif-
ferent doses and regimens the elderly often
require.
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Chapter 27
Afterword
If this book has fulfilled its purpose, it has dis-
tilled the way this practicing academic neurol-
ogist/bench scientist views migraine. With
more than 30 years of basic research behind
me on a variety of neurophysiological and
neuropharmacological processes, prominent
among them the identification and mecha-
nisms of action of neurotransmitters, my goal
has been to combine my clinical observations
of headache patients with my scientist's eye
and with my academic inclination to try to read
as much as possible of what has been published
about this topic. The bibliography has been cut,
of course, but the text reflects my attempt to
evaluate and synthesize the historical, tradi-
tional, and most modern views of migraine. I
have found that much of what is stated about
migraine, and particularly about its pathophys-
iology, is not fact at all, but can only be put
forth as working hypotheses that need further
observation and experimentation. I have tried
to point this out. Various chapters have con-
sidered migraine's clinical presentations and
epidemiology, the basic aspects of its patho-
physiology, a compassionate approach to the
management of migraine patients, and the pros
and cons of the various pharmaceutical thera-
pies. Here too, despite the considerable
progress made in recent decades toward un-
derstanding migraine, a great deal remains un-
clear about its diagnosis, definition, pathogen-
esis, and treatment. I have concentrated on
topics that seem to me of fundamental signifi-
cance or that have important implications for
future developments. Certain points bear rep-
etition.
Although the prevalence may vary, epi-
demiological investigations have shown that
migraine is a common cause of pain and has
486
serious effects on the functional capacity of
migraineurs in all societies and at all socioeco-
nomic levels. Adult women more ordinarily
experience migraine than adult men do. Col-
lected data from recent population-based in-
vestigations appear more accurate than earlier
data; the estimate now is that during the pre-
vious 1-year period in North America and
Western European countries, 15% to 18% of
women and 6% to 7% of men suffered from all
types of migraine combined. Various studies
estimate prevalence of migraine in childhood
at between 3.5% and 5.0%, then rising during
adolescence to approximately 15%. Whether
migraine with and without aura represents the
same entity or different entities is still a con-
tentious issue. Migraine is comorbid with sev-
eral medical, neurologic, and psychiatric con-
ditions, including depression, anxiety, epilepsy,
stroke, mitral valve prolapse, hypertension, and
Meniere's disease. The basis for such comor-
bidity requires inquiry.
Reasonable diagnostic criteria, formulated
by the International Headache Society, offer
more precise definitions of various migraine
syndromes than what we previously had. The
criteria reflect an effort to make migraine di-
agnosis more objective, despite its lack of spe-
cific pathology or definitive diagnostic tests.
Even with these advances in classification,
skepticism is still voiced over discriminating
between migraine and tension-type headaches.
Some epidemiologists and clinicianswho
have focused on the severity of head painfeel
that it may not be possible to develop classifi-
cations that discretely separate them. Head
pain, however, is just one attribute of a com-
plex affliction. Migraine attacks can be divided
into five stages: prodrome, aura, headache, res-

olution, and postdrome. Each has its own char-
acteristic spectrum of clinical phenomena and
accompanying symptoms. In particular, today
we know that premonitory or prodromal phe-
nomenaoften vague symptoms, poorly rec-
ognized by both patients and physiciansoc-
cur in many patients days to hours before the
headache. Modern clinicians should recognize
prodromes as an integral part of the migraine
attack. They also must be cognizant that, in ad-
dition to the commonly recognized visual, sen-
sory, and motor symptoms, migrainous auras
can consist of often poorly recognized cogni-
tive and psychologic symptoms, and migraine
is frequently accompanied by metabolic, auto-
nomic, and systemic disturbances.
Advances in understanding the genesis of
migraine attacks have revealed the complicated
interactions between genetic substrate, med-
ical conditions, external irritants and triggers,
and lifestyle practices. There is convincing ev-
idence that migraine has a genetic component.
In particular, at least half of the families with
familial hemiplegic migraine show genetic link-
age to mutations in a neuronal voltage-gated
P/Q-type calcium-channel IA subunit gene
(CACNA1A) located on chromosome 19pl3.
The same gene may also be implicated in some
families whose migraine is of a more common
type. Modern data show, however, that only
40% to 50% of the probability that one will de-
velop a common form of migraine can be as-
cribed to genetic factors, an indication that the
inheritance of migraine is multifactorial. Both
internal and environmental elements are pre-
sumed to act on a susceptible nervous system
predisposed to develop migraine by an inher-
ited alteration in the biologic threshold to cer-
tain stimuli. The intrinsic central defect may
still be unknown; medical ways to counter it
are not. Patients with migraine headaches can
be effectively managed if their trigger factors
are identified and known precipitants are re-
moved. Different patients find their attacks
triggered by different agents or processes.
Practicing physicians should be ableand will-
ingto educate their patients about how to lo-
cate and circumvent these provocative factors.
Far too much effort has been expended try-
ing to identify personality traits shared by mi-
graineurs and to assign migraine causation to
character defects or psychologic makeup. Am-
ple evidence demonstrates that no one per-
sonality type is characteristic of all migraineurs.
Afterword 487
Migraine treatment must be individualized be-
cause migraineurs vary considerably in both
the ways they deal with stresses that trigger
headaches and the ways they cope (or fail to
cope) with the recurrent torment of migraine
attacks.
Despite attempts to develop an objective
test that could make or confirm the diagnosis,
no biological marker for migraine has been
found so far. The diagnosis of migraine is made
by careful questioning and listening. Unless
the history reveals a need to rule out other dis-
ease, for the vast majority of patients labora-
tory tests are unnecessary. Nonspecific abnor-
malities are seen with considerable frequency
in computed tomographic (CT) scans, mag-
netic resonance (MR) imaging, electroen-
cephalograms (EEGs), evoked potentials, and
thermograms, but the abnormalities are rarely
significant. They are certainly not diagnostic
of migraine. Far too many examinations are
performed on migraineurs simply because the
tests are available.
The two principal, and seemingly compet-
ing, hypotheses of migraine causationthe
vascular and neurogenic theorieshave now
been integrated. A consensus has been evolv-
ing that die migraine process begins in the
neural substrate of the brain and then pro-
gresses to implicate intra- and extracerebral
blood vessels. By what mechanisms all this oc-
curs, however, is still the subject of debate.
Much work has focused on decreases in
cerebral blood flow observed during attacks of
migraine with aura. The nature of the
changesthe anterior expansion of the areas
of low blood flow as attacks progress (so-called
spreading oligemia) and the apparent failure of
this expansion to respect major cerebral arte-
rial boundarieshas led to the as-yet unproven
working hypothesis that the alterations in blood
flow are secondary to neuronal changes that are
possibly caused by the process of spreading de-
pression. In migraine without aura, positron
emission tomographic (PET) measurements of
regional blood flow during the headache phase
of spontaneous attacks demonstrate increased
blood flow in midline brain stem structures. Al-
though we do not yet know what activates the
brain stem structures, the activated area has
been postulated to represent a "migraine gen-
erator" in the brain stem.
Important progress has been made in un-
derstanding the nociceptive mechanisms that
488 Afterword
operate during migraine attacks. Much new ev-
idence points to the trigeminovascular sys-
temthe trigeminal nerve and its connections
with the intra- and extracranial vasculature
as the final common link in the migrainous pro-
cess. Neurogenic inflammation affecting the
dura, associated with and possibly triggered by
vasodilatation of dural arteries, appears to fol-
low activation of trigeminal sensory fibers and
the subsequent release of vasoactive neu-
ropeptides including substance P, neurokinin
A, and calcitonin gene-related peptide. The in-
flammatory process is initiated by peptide re-
lease from trigeminovascular fibers and gener-
ated by the release or formation of multiple
inflammatory mediators involving mast cells,
blood vessels, and tissue cells. This sequence
of events is believed to sensitize trigeminal no-
ciceptors and to produce and maintain the pain
of migraine headache.
Neurogenic and vascular mechanisms of mi-
graine genesis and maintenance undoubtedly
include changes in neurotransmission or neu-
rotransmitter function. The association be-
tween serotonin and migraine is based on a
substantial aggregate of circumstantial bio-
chemical, pharmacological, and anatomical ev-
idence. Early research efforts concentrated on
changes in the concentrations of platelet sero-
tonin and urinary 5-hydroxyindoleacetic acid
during a migraine attack. More recent work has
focused on the actions of a number of agents
that can either precipitate or relieve migraine
attacks by effects variously believed to be ex-
erted on serotonergic neurons or on seroton-
ergic receptors located on trigeminovascular
fibers, bloodvessels, and platelets. But because
the locus of the alterations in serotonin activ-
ity that inaugurate the migrainous process is
unknown, the precise role that serotonin plays
in migraine remains enigmatic. As an alterna-
tive to the serotonergic hypothesis, a re-
spectable aggregate of suggestive data impli-
cates dopamine in the migraine pathogenesis.
Findings that nitroglycerin (which is con-
verted to nitric oxide [NO]) induces intracra-
nial arterial dilatation and can produce exper-
imental headaches in both normal volunteers
and migraineurs and that administration of NO
synthase inhibitors can reduce the severity of
migraine pain have led to the intriguing pro-
posal that NO plays a significant role in the
pathogenesis of migraine. Other suggestive
data implicate interictal cerebral cortical hy-
perexcitability, changes in Mg2+ levels, and de-
creased mitochondrial energy reserves in the
pathogenesis of migraine. It must be realized,
however, that at present all hypotheses about
migraine pathophysiology are based on cir-
cumstantial evidence.
Physicians treating patients with migraine
must become aware of how profoundly mi-
graine attacks can degrade the lives of children,
adolescents, adults, and the elderly. Family in-
teractions, work, social activities, and leisure
projects are all affected negatively. So much
time is lost from productive work and actual
living that migraine has serious consequences
for society. The management of patients so
afflicted deserves and requires much time, per-
sistence, and understanding. Simply prescrib-
ing medication is insufficient. Adequate treat-
ment requires support, counseling, education,
and advice about behavior and lifestyle. The
patient must be guided to make reasoned judg-
ments about eliminating, or altering exposure
to, precipitating factors and about changing
lifestyle.
Migraine management also consists of the
judicious administration of appropriate med-
ications. Therapy at the initial visit should be
based on the patient's account of the severity
of symptoms. Patients with severe, prolonged,
incapacitating headaches unresponsive to sim-
ple analgesics should be prescribed triptans,
provided there are no contraindications. Pa-
tients with mild-to-modest headaches should
be started on the simplest medications and, if
unsuccessful, be advanced to more potent
agents until a response is obtained. The emer-
gency department treatment of migraine
should de-emphasize the traditional adminis-
tration of parenteral narcotics and stress the
use of dihydroergotamine, phenothizines, and
triptans.
Excessive use of symptomatic anti-migraine
therapy is hazardous; it is appropriate to focus
attention on the problems it creates. Treatment
of recurrent migraine headaches is often
complicated by drug dependence and the
development of chronic daily headaches. A
medication-abuse cycle with daily headache
and daily use of over-the-counter anal-
gesics, prescribed preparations containing bu-
talbital, non-steroidal anti-inflammatory drugs
(NSAIDs), narcotics, ergotamine, or even trip-

tans can develop unless both the physician and
patient understand the dangers of medication
overuse.
A large number of effective medications
j8-blockers, calcium-channel blockers, antide-
pressants, antiserotonergics, and othersare
now available for the prevention of migraine
and should be used for all patients with fre-
quent bouts of migraine or with headaches suf-
ficiently incapacitating to disrupt the patient's
life. Choice of medication is determined in
large part by coexisting medical conditions and
by potential side effects. Prophylactic drugs,
when used appropriately, are capable of de-
creasing both the frequency and severity of mi-
graine in most migraineurs. All prophylactic
Afterword 489
drugs have side effects and need to be pre-
scribed with circumspection. They may be
used alone, or concomitant with behavioral
techniques. In fact, behavioral techniques such
as biofeedback and simple relaxation therapy
are often exceedingly helpful by themselves in
decreasing the frequency and intensity of bouts
of migraine.
In sum, migraine is a potentially disabling
illness that is yielding to our understanding of
it and to new methods of treatment. Treat-
ment, however, remains "low-tech" and time-
consuming. But patience and compassion can
alleviate much suffering and can transform the
lives of a significant cohort of the population,
making them happier, more productive people.
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Index

A "t" following a page number indicates a table; an "f" indicates a figure.

Abdominal migraine Almotriptan, efficacy, 357

clinical features of, 81-82 Alniditan
diagnostic criteria for, 82t affinity for 5-HTiB/iD receptors, 377
Abortive medications, contraindications to use, 319t affinity for 5-HTiF receptors, 377
Abortive migraine. See Migraine aura without headache effects on dural plasma extravasation, 377
Abortive treatment, 319t in migraine attacks, 377
aims, 315t Alternating hemiplegia of childhood, 84-85
cost of, 321t Alternative medicine
Acalculia, as an aura, 55 acupuncture, 308
Acephalgic migraine. See Migraine aura without chiropractic, 308
headache feverfew, 309
Acetaminophen herbal remedies, 309
geriatric patients, 480 hypnosis, 308
inhibition of fatty acid cycloxygenase, 333 transcutaneous electrical nerve stimulation, 308
migraine attacks, 323 Amerge. See Naratriptan
migraine attacks in children, 475 American Council for Headache Education (ACHE),
nursing migraineurs, 457 299
during pregnancy, 454 Amitriptyline
side effects of, 325 clinical trials of, 415
Acetylcholine, in parasympathetic nerves, 210 daytime sleepiness, 416
Achromatopsia, as an aura, 52 depression, 416
Acquired immunodeficiency disease, headache and, 113 depression and anxiety, 416
Activities of daily living, effects of migraine, 18 dosage, 416
Acupuncture, for migraine, 308 efficacy versus propranolol, 405
Acute confusional migraine, 62 menstrual migraine, 450-451
Acute intractable migraine. See Status migrainosus migraine, 416-417
Ad Hoc Committee on Classification of Headache, 4 migraine with tension-type headaches, 415
Adalat. See Nifedipine pharmacokinetics of, 416
Addiction prophylactic use, 397-398, 415-416
butalbital-containing analgesics, 328 sedative properties, 416
butorphanol, 331 synergism with propranolol, 415
opioids, 329-330 Amlodipine, for migraine prophylaxis, 410
propoxyphene, 330 Amyl nitrate, and auras, 190
Adenosine, induction of headache, 223 Analgesic overuse/abuse headache, 464
Adie's pupil, in migraine attacks, 60 prevention, 466
Adolescents, migraine, 15-16 treatment, 466-469
Adrenergic receptors, 402-403 Analgesic rebound headache, 464
Adverse reactions. See Side effects in children, 478
Advil. See Ibuprofen Analgesics. See also specific drugs
Age of onset, migraine, 12-13, 13f menstrual migraine, 450
Aging, physiological changes, 479-480 migraine attacks in children, 475
Alcohol, as a migraine trigger, 100 overuse in children, 478
Alexia without agraphia overuse/abuse, 320-321
as an aura, 55 Anaphylaxis, migraine and, 102
in migraine attacks, 63 Anaprox. See Naproxen
Alice in Wonderland phenomena, 52, 53f Aneurysms, headaches and, 179
Allergy Angina, migraine and, 82-83
complement and migraine, 102 Angiography
migraine and, 24 arterial dissection, 182
as a migraine trigger, 102 arterial occlusion, 157
serum levels of IgE in food allergy, 102 hemiplegic migraine, 70
skin tests in food allergy, 102 migraineurs, 157-158
Alleve. See Naprosyn migrainous infarction, 74
Allodynia, 253-254 risk in migraineurs, 158

491
492 Index

Anisocoria, migraine and, 150 central actions, 333

Anterior meningeal nerves, innervation of cerebral combined with acetaminophen and caffeine, 324
vessels, 231-232 dosage, 324
Anterior visual pathway migraine. See Retinal migraine effects on platelets, 333
Anticardiolipin antibodies. See Antiphospholipid effervescent, 324
antibodies efficacy, 324
Anticonvulsants. See also specific drugs efficacy versus j8-blockers, 439
dosage, 427t efficacy versus sumatriptan, 363-364
mechanisms of action, 422-424, 430 for migraine prophylaxis, 439^140
prophylaxis in children, 477 nursing migraineurs, 457
Antidepressants. See also specific drugs pharmacokinetics of, 322, 324
neuronal firing, 424 during pregnancy, 455
neurotransmirter receptor regulation, 423-424 prostanoid synthesis, 332-333
transport of amines, 423 side effects of, 324-325
Anti-emetic medications. See also specific drugs Aspisol. See Lysine-acetylsalicylic acid
for children, 475^176 Asthenopia. See Eyestrain
chlorpromazine, 322-323 Ataxia
delayed gastric emptying, 322 episodic ataxia type 2, 35
mechanisms of action, 332 familial hemiplegic migraine and, 33
metoclopramide, 322 spinocerebellar ataxia type 6, 35
in migraine attacks, 323t Atenolol
during pregnancy, 456 clinical trials of, 402
prochlorperazine, 322-323 for migraine prophylaxis, 402
promazine, 322-323 Auditory evoked potentials, in migraineurs, 156
promethazine, 322-323 Auditory hallucinations, as auras, 53
trimethobenzamide hydrochloride, 322-323 Auras
Antiepileptics. See Anticonvulsants acalculia, 55
Antimigraine medications. See also specific drugs achromatopsia, 52
dosage in children, 476t acute onset, 45
choices, 316-319 alexia without agraphia, 55
cost of, 320 Alice in Wonderland phenomena, 52, 53f
factors influencing choice of, 318-319 aphasia, 55
overuse, 320-321, 464-466 arteriovenous malformations and, 172
Antiphospholipid antibodies auditory hallucinations, 53
ischemic stroke, 75-76 aura without headache, 45
migrainous infarction, 75-76 basilar migraine, 45
Antiserotonergics, mechanisms of action, 438-439 central scotoma, 50f
Anxiety, migraine and, 21t, 22 characteristics, 49
Aphasia cheiro-oral paresthesias/sensory loss, 53f, 53-54
as an aura, 55 children, 48
in migraine attacks, 63 cognitive disturbances, 5455
Apomorphine, 284 complex visual hallucinations, 52
Arachidonic acid cortical spreading depression hypothesis, 194f,
changes in calcium levels, 218 195-196
eicosanoid synthesis, 217-218 deja vu, 54-55
metabolism of, 218-219, 29f delirium, 5455
phospholipase A, 218 differentiation from transient ischemic attacks, 180
Area postrema, and vomiting, 263 digito-lingual paresthesias, 53-54
Arterial dissection distinguished from prodrome, 45
angiography in, 182 dizziness, 54
carotid artery, 181 dreamy states, 54-55
causes, 181-182 dysarthria, 54, 55
magnetic resonance imaging of, 182 effect of amyl nitrate, 190
vertebral artery, 182 familial hemiplegic migraine, 33, 45
Arteriovenous anastomoses fortification spectrum, 50f, 51
ergots, 378 functional magnetic resonance imaging, 199-201
triptans, 378 hemiparesis, 54
Arteriovenous malformations (AVMs) Hildegard of Bingen, 52f
headaches and, 179 homonymous hemianopia, 50, 50f
producing migrainous auras, 172 limb pain, 54
Aspartame, as a migraine trigger, 101-102 macropsia, 52
Aspirin macrosomatognosia, 52
absorption, 324 metamorphopsia, 52
migraine attacks, 323-324 micropsia, 52
migraine attacks in children, 475 microsomatognosia, 52
caffeine and, 325 olfactory hallucinations, 53
 Index 493

palinopsia, 52 migraine, 303-305

permanent neurological deficits, 202 during pregnancy, 454
photopsias, 49, 50f thermal, 304
positron emission tomography, 198-199 Blitz migraine. See Crash migraine
primary neuronal hypothesis, 190 Blocadren. See Timolol
produced by brain tumors, 173 /3-Blockers. See also specific drugs
prolonged aura, 45 contraindications to use, 406-407, 406t
scintillating scotomas, 51 dosages, 404t
scotomas, 49, 50-51 hydrophilic agents, 403
somatosensory auras, 53-54, 53f, 54f lipophilic agents, 403
teichopsias, 51 mechanisms of action, 407
telopsia, 52 menstrual migraine, 450-451
types, 49t for migraine prophylaxis, 397t, 398, 402
vasospasm, 203 nursing, 458-459
vertigo, 54 pharmacokinetics of, 403404
visual auras, 49-52 pharmacological characteristics, 403t
Wolff hypothesis, 190 side effects of, 405-406
Autonomic innervation, cerebral vasculature, 208f /3-endorphin, distribution, 259
Autonomic nervous system Blood flow velocities, in migraine, 240f
activation as a migraine trigger, 285-286 Blurred vision, in migraine, 51
changes in migraine attacks, 60 Borderline migraine. See Migrainous disorder
cluster headache, 168 Bosentan
dysfunction as a cause of migraine, 285-286 effects on dural plasma extravasation, 377
Avoidance, migraine and, 94 in migraine attacks, 221, 377
Axert. See Almotriptan Botulinum toxin (BOTOX), for migraine prophylaxis,
442-443
Baclofen, for migraine prophylaxis, 443 Bradykinin
Basal nucleus of Meynert, and cerebral blood flow, 216 arachidonic acid cascade, 222
Basilar artery migraine. See Basilar migraine cerebral arteries, 222
Basilar migraine nociceptor activation by, 251
clinical features of, 71-72 Bradyphrenia, in migraine attacks, 61
complications, 72 Brain tumor
criteria for diagnosis, 71t auras caused by, 173
differential diagnosis of, 7273 characteristics of headache, 172-173
electroencephalographic abnormalities in, 154 differentiation from migraine, 173
epidemiology of, 72 Bromocriptine, 284
hearing loss, 72 use in menstrual migraine, 452
Behavior, in migraine, 18-19, 62 Buildup, of scotomas, 51
Behavioral therapy Bulbospinal monamine pathways, 259
biofeedback, 303-305 Butalbital
children, 478 acetaminophen and, 327
cognitive-behavioral training, 306 acetaminophen and caffeine and, 327
indications, 303 in analgesic medications, 327-329
menstrual migraine, 451 aspirin and, 327
during pregnancy, 454 aspirin and caffeine and, 327
relaxation therapy, 305 bultalbital-containing analgesics, 328t
Bellergal-S. See Ergotamine caffeine and, 327
Benign exertional headache, 104 contraindications to use, 328-329, 328t
Benign intracranial hypertension. See Idiopathic Food and Drug Administration approval, 327
intracranial hypertension geriatric patients, 481482
Benign orgasmic cephalgia, 105 mechanism of action, 333-334
Benign paroxysmal torticollis in infancy, 81 nursing migraineurs, 458
Benign paroxysmal vertigo of childhood potential for addiction, 328
clinical features of, 79-80 during pregnancy, 456
migraine and, 79 removal from market, 328
symptoms of, 80f side effects, 328
Benign recurrent vertigo in adults Butorphanol
clinical features of, 80-81 in migraine attacks, 331
migraine and, 80 potential for addiction, 331
triggers of, 80 side effects of, 331
Benign sex headache, 105
Bickerstaff s migraine. See Basilar migraine
Bilious headache. See Cyclic vomiting syndrome CACNA1A, 33
Biofeedback CADASIL. See Cerebral autosomal dominant
electromyographic, 304 arteriopathy with subcortical infarcts and
mechanisms of, 304-305 leukoencephalopathy
494 Index

Cafergot. See Ergotamine as a source of pain, 229-230

Caffeine
as an adenosine receptor antagonist, 99
beverages, 99t
ergotamine and, 342
inhibition of phosphodiesterase, 99
as a migraine trigger, 98-99
nursing migraineurs, 457-458
over-the-counter medications, 325
in prescription analgesics, 325
withdrawal headaches, 99
Calan. See Verapamil
Calcitonin gene-related peptide (CGRP)
activation of adenylyl cyclase, 211
effect of triptans on release, 376
levels after sumatriptan, 377f
levels in migraine, 243-244, 243f
nociception and, 238-239
release, 376
in trigeminal ganglia, 238
trigeminovascular fibers containing, 211, 238-239
vasodilatation, 211
Calcium antagonists. See Calcium channel blockers
Calcium channel blockers. See also specific drugs
clinical trials, 408
contraindications to use, 408, 408t
mechanisms of action, 410-411
menstrual migraine, 450-451
prophylaxis, 397t, 398
side effects of, 408
Calcium channels
anticonvulsants and, 431
subunits comprising, 34f
Capsaicin, and nociceptive nerve fibers, 243
Carbamazepine, for migraine prophylaxis, 426
Carbon dioxide, and cerebral blood flow, 222
Cardiac migraine, 82-83
Cardizem. See Diltiazem
Carotid arterial blood flow
effect of ergots, 378
effect of triptans, 378
Carotid artery microganglia/miniganglia, 210
Carotid artery tenderness, in migraine, 57
Carotodynia, 57-58
Cataflam. See Diclofenac-potassium
Celebrex. See Celecoxib
Celecoxib, in migraine attacks, 327
Central scotoma, as an aura, 50f
Central sensitization
allodynia, 253-254
c-fos, 255
glutamic acid, 254-255
hyperalgesia, 253
intracellular calcium, 254
nitric oxide synthase, 254
NMDA receptors, 254
phenotype of low-threshold afferents, 255
protein kinase C, 254
sensory receptive fields, 254-255
activation of silent synapses, 255
substance P, 254-255
windup, 254
Cerebral arteries
and bradykmin, 222
innervation of, 207
parasympathetic innervation of, 209
sympathetic innervation of, 208-209
Cerebral autoregulation, during aura, 193-194
Cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy
(CADASIL), migraine and, 36, 37f
Cerebral blood flow (CBF)
during aura, 192
Basal nucleus of Meynert, 216
cerebral autoregulation during aura, 193-194
cortical spreading depression, 196
definition, 191
factors regulating, 207-208
histamine, 222
hyperemia during aura, 193
interictal measurements, 192
locus coeruleus, 212
in migraine attacks, 193f, 241, 487-488
nitric oxide synthase antagonism, 216
prostanoids/prostaglandins, 219
protons, 222
response to CO during aura, 193-194
single-photon emission computed tomography, 192
spreading hypoperfusion during aura, 192-196
spreading oligemia during aura, 192-196
trigeminal ganglion, 212
133
Xe methods of measurement, 191-192
Cerebral hyperexcitability, as a cause of migraine,
274-275
Cerebrospinal fluid, in acute attacks, 158
Cervical joint dysfunction, in headaches of cervical
origin, 170
Cervical spondylosis, headaches and, 109-110
Cervicogenic headache
characteristics of headache, 169-170
symptoms of, 170t
Cheese, as a migraine trigger, 97
Cheiro-oral paresthesias/sensory loss, as auras, 53-54, 53f
Chemical sensitivity syndromes, 107108
Childhood epilepsy with occipital paroxysms
electroencephalographic abnormalities, 22-23
migraine and, 22-23
visual hallucinations, 22
Children
acetaminophen for migraine attacks, 475
acute confusional migraine, 62
age of migraine onset, 15
analgesic abuse, 478
analgesic rebound headaches, 478
analgesics for migraine attacks, 475
anticonvulsants, 477
anti-emetics, 475-476
aspirin use, 475
avoidance of trigger factors, 474-475
behavioral therapy, 478
biofeedback, 303
cyproheptidine for prophylaxis, 477
diagnostic criteria for migraine, 15-16
dosage of antimigraine medications, 476
duration of migraine attacks, 16
ergots, 476
flunarazine, 477-478
frequency of migraine attacks, 46
gastrointestinal disturbances in migraine attacks, 59
guidelines for prophylaxis, 476-478
methysergide, 478
 Index 495

metoclopramide, 475-476 head pain, 167-168

migraine, 15-16 subtypes of, 167
migraine and gender, 15 Cluster migraine, 78
migrainous head pain, 16, 57 Cocaine, headaches and, 109
nimodipine, 478 Cocoa, caffeine in, 98-99
non-steroidal anti-inflammatory agents, 327, 475 Codeine
phenytoin, 426 geriatric patients, 482
pizotifen, 477-478 migraine attacks, 330, 330t
prevalence of migraine, 486 during pregnancy, 455^56
prochlorperazine, 475-A76 Coffee, caffeine content, 98-99
prognosis of migraine, 16, 16f Cognitive changes
promethazine, 475-476 as an aura, 54-55
prophylaxis, 477t in migraine attacks, 61-62
propranolol, 477 Coital cephalgia, 105
rest in migraine attacks, 475 Coitus
trigger factors for migraine attacks, 91 low cerebrospinal fluid pressure headache and, 105
triptans, 476 as a migraine trigger, 105
valproate, 477 tension type headaches and, 105
Chinese restaurant (Kwok's) syndrome, 101 Cold-stimulus headache, 107
Chiropractic Combined oral contraceptives
for migraine treatment, 308-309 migraine and, 134136
spinal manipulation, 308 migraine exacerbation, 133
vertebral arterial dissection, 308-309 migraine improvement, 133
rn-Chlorophenylpiperazine (mCPP) new onset migraine, 133
activation of 5-hydroxytryptamine receptors, 283 risk of cerebral infarction, 134-136
as a 5-hydroxytryptamine agonist, 283 risks, 133-136
effect on 5-hydroxytryptamine transport, 283 Common migraine. See Migraine without aura
induction of headaches, 282 Comorbid conditions, 486
induction of migraine, 282 migraine and allergy, 24
Chlorpromazine migraine and anxiety, 21t, 22
as anti-emetic, 322-^323 migraine and depression, 21, 21f
use in emergency care, 388 migraine and epilepsy, 22,
Chocolate migraine and hypertension, 23,
craving for during prodrome, 98 migraine and Meniere's disease,
migraine trigger, 98 migraine and mitral valve prolapse, 24
Chronic daily headache, 464, 488 migraine and panic attacks, 21t, 22
analgesic overuse and, 77-78 migraine and phobias, 21t, 22
clinical features of, 77 migraine and Raynaud's phenomenon, 24
depression in, 78 migraine and stroke, 23, 23t
epidemiology of, 77 migraine and systemic lupus erythematosus, 24
transformed/evolved from migraine, 77-78 Compazine. See Prochlorperazine
Chronic fatigue immunodysfunction syndrome. See Compliance
Chronic fatigue syndrome with migraine prophylaxis, 396
Chronic fatigue syndrome (CFS), 112-113 with treatment, 296
Chronic intractable headaches Complicated migraine
evaluation of, 471-472 hemiplegic migraine, 70
possible causes of, 471 use of ergotamine, 342
response to antimigraine medications, 470-471 use of oral contraceptives, 453
treatment in comprehensive, multidisciplinary centers, varieties, 69-76
472 Computed tomography (CT)
use of long-acting opioids, 472 abnormalities in migraineurs, 151-153
Circadian periodicity, onset of migraine, 47f hypodense areas, 152
Classic migraine. See Migraine with aura migraine diagnosis, 151-152
Classification, migraine, 45. 45t migrainous infarction, 74
Climara. See Transdermal estrogen patches Constipation, in migraine attacks, 60
Clinical examination of migraineurs, 149-150 Consultation with physicians, migraine, 9t
Cluster headache Consultations for headache, 294t
autonomic nervous system involvement during attacks, Contingent negative variation (CNV), 157f
168 in migraineurs, 156
behavior during attacks, 168 Coping mechanisms, 94
characteristics of attacks, 167 Corgard. See Nadolol
definition of, 167 Coronary arteries
diagnostic criteria for, 167t 5-HTiB receptors, 360
differentiation from migraine, 168 5-hydroxytryptamine receptors, 360-361
epidemiology of, 168 triptans effects on, 360-361
facial characteristics of patients, 168 Cortical hyperexcitability, and migraine, 488
496 Index

Cortical spreading depression Depekene. See Valproate

as a cause of auras, 195-196, 488 Depo-Provera, and headaches, 133
cerebral blood flow changes during, 196, 198f Depression
glutamate, 196-197 chronic daily headache and, 78
in humans, 201 migraine and, 21-22, 21t, 78
ionic changes during, 196, 197f Desipramine, for migraine prophylaxis, 416
magnetoencephalography in, 198 Desyrel, for migraine prophylaxis, 416
meningeal C-fibers, 247 Diagnosis, of migraine, 6f, 9f
nitric oxide, 221 Diagnostic criteria, for migraine, 486
potassium ions, 196, 196-197 Dialysis, headaches and, 113
Corticosteroids Dichloralphenazone, 329
migraine attacks, 331 Diclofenac-potassium, in migraine attacks, 326
osteonecrosis, 331 Dietary migraine, 95-102
use in emergency care, 388 Differences, migraine with and without aura, 46
Cost Digito-lingual paresthesias, as auras, 53-54
abortive treatment, 32 It Dihydroergotamine (DHE)
antimigraine medications, 320 clinical use, 345
dihydroergotamine, 340 contraindications to use, 346
ergotamine, 340 cost of, 340
prophylactic medications, 399. 400t drug-induced headache, 467-468
sumatriptan, 349 emergency care, 388
triptans, 352t, 364 intranasal use, 345
Costen's syndrome. See Oromandibular dysfunction metabolism of, 345
CP-122,288 nasal spray, efficacy versus sumatriptan nasal spray,
effects on dural neurogenic inflammation, 378 363-364
lack of vasoconstriction, 378 nucleus caudalis, 379^380
in migraine attacks, 378 parenteral use, 345
CP-93,129 pharmacokinetics of, 345
as a 5-HTiB agonist, 379 side effects of, 346
trigeminal nucleus, 379 status migrainosus, 470
Craniomandibular dysfunction. See Oromandibular subcutaneous, versus subcutaneous sumatriptan,
dysfunction Dilantin. See Phenytoin
Crash migraine, 180 Dilated pupil, in migraine attacks, 60
Cyclic guanosine monophosphate (cGMP), 211 Diltiazem
Cyclic vomiting clinical trials of, 409
clinical features of, 81 for migraine prophylaxis, 409
migraine and, 81 side effects of, 409
as a migraine equivalent, 81 Diprivan. See Propofol
precipitating factors, 81 Dipyridamole, use with aspirin, 439
Cyproheptadine Disappearance of migraine with age, 139f
children, 477 Distribution of auras, 49f
dosage, 438 Divalproex sodium. See Valproate
mechanisms of action, 438-439 Dizziness, in migraine attacks, 61
prophylaxis, 397t, 438 Dolophine. See Methadone
side effects of, 438 Domperidone, 284
Dopamine
Daily hassles, as function of headache type, 94f D2 antagonists, 284
Daily mixed headache. See Transformed migraine effect of agonists in migraineurs, 283284
Danazol and migraine, 283, 488
dosage, 452 Dopamine receptors, activation and migraine symptoms,
in menstrual migraine, 451^452 284f
side effects of, 452 Dorphanol. See Butorphanol
Danocrine. See Danazol Dorsal horn, nociceptive neuron, 234f
Darvocet-N 100. See Proproxyphene, with Dorsal root reflexes, release of neuropeptides, 247
acetaminophen Dorsolateral pontine tegmentum (DLPT)
Darvon. See Propoxyphene periaqueductal gray, 256
Darvon Compound 65. See Proproxyphene, with aspirin spinal cord projections, 257
and caffeine Doxepin. See Sinequan
Deja vu, as an aura, S4--55 Dreamy states, as auras, 54-55
Delirium, as an aura, 5455 Drop attacks, basilar migraine, 72
Delivery, headaches and, 136 Droperidol, emergency care, 388
Demerol. See Meperidine Drug-induced headache
Demographics, migraine in adults, 8-14 abrupt cessation, 466-467
Depacon. See Valproate analgesic limitation, 466
Depakote. See Valproate butalbital as a cause, 465
Depakote ER. See Valproate caffeine as a factor, 464, 466
 Index 497

duration of drug use, 464 phenothiazines, 388

ergotamine as a cause, 465 prochlorperazine, 388
medications during withdrawal, 468-469 triptans, 387-388
over-the-counter medications, 465 Emergency departments. See Emergency care
physician participation, 465 Endep. See Amitriptyline
prevention, 466 Endogenous pain modulating systems
prophylactic medication for, 469 bulbospinal monamine pathways, 258-259
Raskin dihydroergotamine protocol, 467468, 468f descending pathways, 257f
relapse after withdrawal, 469 endogenous opioid peptides, 259-260
self-medication, 465 and migraine, 255
treatment of, 466-467 on- and off-cells, 257-258
treatment success rate, 469 periaqueductal gray, 256
withdrawal of medications, 466-467 Endothelial-derived hyperpolarizing factor (EDHF), and
withdrawal symptoms, 467 vasodilatation, 216
Dura, innervation of, 231 Endothelin
Dural arteries, vasodilatation, 488 effects on cerebral blood vessels, 220
Dural blood vessels, innervation, 245f levels in migraine, 221
Dural inflammation. See Neurogenic inflammation of receptor antagonism and migraine, 221
dura synthesis of, 220f
Dural plasma extravasation and vascular endothelium, 216
alniditan, 377 Endothelium-derived relaxing factor (EDRF), 210
bosentan, 377 Engorged turbinates, in migraine attacks, 150
ergots, 376 Enterochromaffin cells, 276
5-HT1F receptors, 377 Environmental factors
NK1 receptor antagonists, 377 chemical sensitivity syndrome, 107t
Duration of attacks, migraine, as migraine triggers, 105-108
Dynorphin Environmental illness, 107
distribution, 260 Epidemiology
role in nociception, 260 basilar migraine, 72
Dysarthria, as an aura, 54, 55 chronic daily headache, 77
Dysmenorrhea, in migraineurs, 122 cluster headache, 168
Dysphrenic migraine, 61 giant cell arteritis, 173
D.H.E. 45. See Dihydroergotamine migraine, 486-487
Epilepsy, migraine and, 22
Eating, in migraine attacks, 60 Episodic ataxia type 2 (EA2), 35
Education, migraine, 14 P/Q calcium channels and, 35
Effort migraine, 104 Epistaxis, in migraine attacks, 60
Elavil. See Amitriptyline Equivalents, migraine, 15
Eldepryl. See Selegiline Ergomar. See Ergotamine
Electroencephalograms (EEGs) Ergotamine
in basilar migraine, 154 bioavailability, 340, 342
in childhood epilepsy with occipital paroxysms, 22-23 caffeine and, 342
ictal patterns, 155 causing vasospasm, 343
indications, 155-156 clinical trials of, 340
interictal patterns, 154 clinical use of, 342
migraineurs, 153-155 complicated migraine, 342
photic driving, 155 contraindications to use, 344
spectral analysis, 154 cost of, 340
Eletriptan efficacy versus aspirin, 340
efficacy, 357 efficacy versus non-steroidal anti-inflammatory agents,
efficacy versus sumatriptan, 357 340
Emergency care efficacy versus sumatriptan, 363-364
chlorpromazine, 388 efficacy versus triptans, 340
corticosteroids, 388 encephalopathy caused by overuse, 343
dehydration, 386 ergotism, 343
dihydroergotamine,388 first-pass effect, 339
droperidol, 388 metabolism of, 339-340
emergency departments, 385-387 migraine with aura, 342
haloperidol, 388 migraine with prolonged aura, 342
intravenous valproate, 388 overuse of, 344
keterolac, 388 pharmacokinetics of, 340, 341t, 342
medication for migraine, 387t preparations of, 341t
meperidine, 387 side effects of, 343
metoclopramide, 388 Ergots. See also specific drugs
narcotic seeking, 386 arteriovenous anastomoses, 378
patient complaints, 385-386 autoradiography, 379
498 Index

Ergots (Continued) Fenfluramine, and induction of migraine, 282

binding affinities, 374t Fenoprofen
blood-brain-barrier, 379 in menstrual migraine, 450
calcitonin gene-related protein release, 376 for migraine prophylaxis, 439
carotid arterial blood flow, 378 Feverfew, for migraine prophylaxis, 309
causing vasoconstriction, 377-379 Fibromyalgia, 112-113
children, 476 Fioricet. See Butalbital, with acetaminophen and caffeine
contraindications to use, 344t Fiorinal. See Butalbital, with aspirin and caffeine
dural inflammation, 376 Fiorinal #3. See Acetaminophen, with aspirin, caffeine,
dural plasma extravasation, 376 butalbital, and codeine
effects on dorsal horn neurons, 380f First headache, 386t
geriatric patients, 482 Fluid retention, in migraine attacks, 60-61
external carotid artery constriction, 373 Flunarazine
nucleus caudalis binding sites for, 379 clinical trials of, 409-410
nursing, 458 efficacy versus merhysergide, 410
during pregnancy, 456 efficacy versus propranolol, 405, 410
prejunctional/presynaptic 5-HT receptors, 375-377 for migraine prophylaxis, 397t
substantia gelatinosa binding sites for, 379 prophylaxis in children, 477-478
Esgic. See Butalbital, with acetaminophen and caffeine side effects of, 410
Esgic Plus. See Butalbital, with acetaminophen and Fluoxetine
caffeine clinical trials of, 422
Eskalith. See Lithium for migraine prophylaxis, 422
Estraderm transdermal systems. See Transdermal Focal neurological deficits, migraine, 69
estrogen patches Follicle stimulating hormone (FSH), levels during
Estradiol, menstrual migraine and, 123-124, 124f menstrual cycle, 126-127
Estrogen, synthesis of, 130f Food and Drug Administration (FDA), release of
Ethmoidal nerves, innervation of cerebral vessels, triptans, 349
231-232 Food triggers, lOOf
European Medicines Evaluation Agency (EMEA), aspartame, 101-102
release of triptans, 349 caffeine, 98-99
Evidence-based medicine, 297-298 chocolate, 98
Evolutive migraine. See Transformed migraine citrus, 99
Excedrin Migraine. See Aspirin, combined with elimination diet, 102
acetaminophen and caffeine migraine as food allergy, 102
Exercise monosodium glutamate, 100-101
headache trigger, 104 phenolic flavenoids, 98
migraine treatment, 306 sodium nitrite, 101
Extension-flexion injury to the neck. See Whiplash j8-phenylethylamine in chocolate, 98
Eyestrain, headache and, 113 tyramine, 96-98
Footballer's migraine, 109
Facial migraine, 57 Fortification spectrum, 50f, 51
Factor analysis, headache symptoms, 7 Free interval, after aura, 45, 55
Familial hemiplegic migraine (FHM) Frequency of migraine attacks, 46-47, 47f
abnormality of calcium channels, 487 Frovatriptan, efficacy, 357
auras in, 33 Functional magnetic resonance imaging (fMRI)
cerebellar ataxia and, 33 during auras, 200
chromosome 19 and, 33 BOLD technique, 200-201
clinical features of, 33
genetics of, 33 Gamma-aminobutyric acid (GABA) receptors,
headache, 33 barbiturates, 333-334
P/Q calcium channels and, 33, 35f Gamma-aminobutyric acid synthesis, and
specific chromosomes, 33 anticonvulsants, 430
Family history, 31 GABAergic transmission, and anticonvulsants, 430
Fasting Gabapentin
as a headache trigger, 99 clinical studies of, 429
causing hypoglycemia, 103-104 dosage of, 429
as a migraine trigger, 102-103 geriatric patients, 483
during Ramadan, 103 guidelines for use, 429
tension-type headaches and, 103 mechanisms of action, 430
during Yom Kippur, 103 for migraine prophylaxis, 397t, 426
Fatigue, as a migraine trigger, 104 side effects of, 429
Fatty acid cycloxygenase, 332-333 Gastric emptying, migraine, 60
acetaminophen, 333 Gastrointestinal complaints, in migraine, 59-60
aspirin, 332-333 Gender
isoforms of, 332 migraine, 11-12, 12f
non-steroidal anti-inflammatory agents, 332-333 prevalence of migraine, 486
 Index 499

Genetics calcitonin gene-related peptide levels, 243-244

chromosome 19p locus and migraine, 36 cerebrospinal fluid pleocytosis, 176
migraine, 32-33 as a continuum, 7-8, 7f
migraine as X-Iinked, 32 CP122,288, 244
Geriatric patients emergencies, 178
acetaminophen, 480 external carotid artery, 229
biofeedback, 303 high risk, 386t
j8-blockers, 482 intensity and specific triggers of, 92f
butalbital, 481-482 neurogenic inflammation, 242244
codeine, 482 nitroglycerin, 246
contraindications to antimigraine medication, 481 positron emission tomography, 242
ergots, 482 prevalence of, 10
gabapentin, 483 sexual activity and, 104-105
headaches in, 478-479 substance P antagonists, 244
isometheptene, 482 superficial temporal artery, 190
lithium, 483 trigeminal rhizotomy, 231
monoamine oxidase inhibitors, 483 vasodilatation of cerebral arteries, 240-241
narcotics, 482 Headaches of cervical origin
neurotransmitter function in, 480 causes, 169, 170-171
non-steroidal anti-inflammatory agents, 327, 480-481 cervical joint dysfunction, 170
pharmacokinetics of, 478-479, 479t diagnosis, 169
physiological changes, 479t myofascial trigger points, 170
prophylaxis, 482 non-specific headaches, 170
treatment guidelines for, 480 responsible structures, 170
tricyclic antidepressants, 482-483 Health costs, migraine, 18
triptans, 482 Hearing loss, in migraine, 61
valproate, 483 Heat/cold applications, 316
verapamil, 482 Hemicrania, 56
Giant cell arteritis Hemicrania continua
diagnostic criteria for, 174t autonomic nervous system involvement, 169
epidemiology of, 173 characteristics of headache, 168-169
erythrocyte sedimentation rate in, 174 differentiation from migraine, 169
head pain in, 173 indomethacin, 169
jaw claudication in, 174 Hemiparesis, as an aura, 54
scalp arteries, 173 Hemiplegic migraine. See also Familial hemiplegic
visual loss in, 173-174 migraine
Glaucoma, 176-177 angiography, 70
Glutamate. See Glutamic acid aphasia, 70
Glutamic acid clinical features ot, 70-71
anticonvulsants and, 431 computed tomography, 70
central sensitization and, 254-255 confusion, 70
Glutamic acid receptors, 238-239 differential diagnosis of, 71
Gonadotrophin-releasing hormone (GnRH) epidemiology of, 70
agonists in menstrual migraine, 452 homonymous hemianopia, 70
location of GnRH neurons, 125 magnetic resonance imaging, 70
modulation of secretion, 125, 126 teichopsias, 70
rhythmic firing of GnRH neurons, 125, 127f Hemorrhagic vascular disease, headache in, 180-181
Greater superficial petrosal nerve, 208f, 210 Herbal remedies, for migraine, 309
Guanylate cyclase, activation by nitric oxide, 211 Heroin, headaches and, 109
Hildegard of Bingen, visions, 52, 52f
Habituation, evoked potentials in migraineurs, 156 Histamine
Haldol. See Haloperidol effects on cerebral blood flow, 222
Haloperidol, for emergency care, 388 headache induction, 222. 246-247
Harold G. Wolff, hypothesis of migraine, 190, 228-229, levels in migraine, 222
373 mast cells as a source of, 222
Hassles nociceptor activation by, 248-249
migraine and, 93-94 Histaminic cephalgia. See Cluster headache
onset of headaches and, 93-94 Histocompatibility leukocyte antigen, migraine and, 39
types of, 93 History taking, 145-147
Head trauma, migraine and, 109 Homonymous hemianopia, as an aura, 50, 50f
Headache diary, 300, 301f Hormonal therapy, in menstrual migraine, 451^152
migraine prophylaxis, 396 Hormone replacement therapy, in menopause, 459
Headache recurrence, 316 Homer's syndrome, in migraine attacks, 60, 150
after triptan use, 357-358 Horton's headache. See Cluster headache
Headaches 5-HTiB receptors
bosentan, 244 and coronary arteries, 360
500 Index
5-HTiB receptors (Continued)
and meningeal arteries, 379
mRNA in intracranial blood vessels, 379
in trigeminal ganglia, 376-377
5-HTiB/iD receptors
affinity of alniditan, 377
affinity of ergots, 373-374
affinity of triptans, 373X374
mRNA in cervical dorsal horn, 379
mRNA in trigeminal neurons, 379
5-HTio receptors
dural inflammation, 376X377
trigeminal ganglia, 376-377
5-HTip receptors
affinity of alniditan, 377
affinity of triptans, 373-374
and dural plasma extravasation, 377
mRNA in intracranial blood vessels, 379
mRNA in trigeminal neurons, 377
Human immunodeficiency virus (HIV), 113
Human leukocyte antigens (HLA), migraine and, 39
Hunger, as a migraine trigger, 102-103
5-Hydroxyindoleacetic acid (5-HIAA)
excretion in migraine attacks, 279f
levels in migraine, 278
5-Hydroxytryptamine (5-HT)
administration in migraine, 282
effects of fenfluramine, 282
effects of reserpine, 282
in enterochromaffin cells, 276
initiation of migraine attacks, 275-276
innervation of cerebral blood vessels, 213f
levels in migraine attacks, 279f, 280f
in mast cells, 276
metabolism of, 277f
monoamine oxidase, 277
nociceptor activation by, 251
in platelets, 276-277
and raphe nuclei, 212
and sympathetic nerves, 213
synthesis, 276, 276f, 282
5-Hydroxytryptamine receptor agonists, triptans as,
373-374
5-Hydroxytryptamine receptors
classification of, 214t
coronary arteries, 360-361
cyproheptidine, 438-439
distribution, 214t, 215
methergonovine, 438-439
methysergide, 438-439
nomenclature, 214-215, 214t
pizotifen, 438-439
and prophylactic drugs, 439t
subtypes of, 214-215
transduction mechanisms, 214t
Hyperalgesia, 253
Hyperosmia, migraine, 59
Hypertension
headaches and, 178
migraine and, 23
Hypnosis, for migraine, 308
Hypoglycemia
idiopathic postprandial reactive hypoglycemia, 103
migraine and, 103-104
use of glucose tolerance tests, 103
Hypothalamic-pituitary-ovarian axis, 125
Hypothalamus, gonadotrophin-releasing hormone-
secreting neurons, 126f
Hypotheses of migraine causation, 487-488
Ibuprofen, in migraine attacks, 326
Ice cream headache, 107
Ice pick-like pains. See Idiopathic stabbing headache
Ictal examination, in migraine attacks, 150
Idiopathic intracranial hypertension
cerebrospinal fluid pressure, 175
diagnostic criteria for, 175t
differential diagnosis of, 175
headache in, 174-175
loss of vision, 175
papilledema, 175
sixth nerve palsy, 175
Idiopathic stabbing headache
age of onset, 58f
areas of pain, 58f
characteristics of, 58
in hemicrania continua, 169
Illicit drugs, headaches and, 109
Imaging procedures
indications for, 151
for migraine diagnosis, 150-153
Imitrex. See Sumatriptan
Inapsine. See Droperidol
Incidence, migraine, llf, 14f
Inderal LA. See Propranolol
Inderal. See Propranolol
Indocin. See Indomethacin
Indomethacin
hemicrania continua, 169
migraine attacks, 326
paroxysmal hemicrania, 168
side effects of, 326
Initiation, of migraine, 90-91
Innervation of cerebral vessels
anterior meningeal nerves, 231-232
carotid microganglia/miniganglia, 232
ethmoidal nerves, 231-232
middle meningeal nerves, 232
nervus spinosus of Luschka, 232
nervus tentorii, 231
ophthalmic division, trigeminal nerve
tentorial nerve of Arnold, 231
Intelligence, migraine, 14
International Headache Society (IHS), 4
classification of migraine, 5, 5t
diagnostic criteria for, 5, 6, 15-16, 71t, 76, 167t, 174t,
176t, 486
Internet, information about migraine, 298-299
Interval headaches, 7. See also Tension-type headaches
Interviews, 10
Intracranial vessels, referred pain, 230f
Ischemic stroke
headache and, 23
migraine and, 23, 23t
Ischemic vascular disease
diagnostic criteria for, 180
differential diagnosis of, 180-181
headache in, 180-181, 181f
Isocarboxazid, for migraine prophylaxis,
Isometheptene mucate
contraindications to use, 329, 329t
geriatric patients, 482
 Index 501

migraine attacks, 329 LY 334,370

side effects of, 329
Isoptin. See Verapamil
Jabs and jolts. See Idiopathic stabbing headache
Jaw claudication, in giant cell arteritis, 174
as a 5-HTip- receptor agonist, 377
for migraine attacks, 377
Lysine-acetylsalicylic acid, in migraine attacks, 323
L-arginine, as nitric oxide precursor, 210

Keterolac Macropsia, as an aura, 52

for emergency care, 388 Macrosomatognosia, as an aura, 52
in migraine attacks, 326 Magnesium
Ketoprofen, for migraine prophylaxis, 439 levels in migraine, 284, 488
Knock-out mice for migraine attacks, 332
effect of sumatriptan, 377 for migraine prophylaxis, 397t, 442
5-HTiB receptors, 377 Magnetic resonance imaging
arterial dissection, 182
Laboratory studies, migraine, 487 hemiplegic migraine, 70
Lactation migraine diagnosis, 152153
endocrinology of, 136-137 migrainous infarction, 74
migraine and, 137 ophthalmoplegic migraine, 83
Lamictal. See Lamotrigine primary intracranial hypotension, 176
Lamotrigine white matter abnormalities, 152
clinical studies of, 430 white matter hyperintensities, 153f
for migraine prophylaxis, 426 Magnetic resonance spectroscopy (MRS), 285
for migraine with aura, 430 Magnetoencephalography
side effects of, 430 auras, 198
Late-life migrainous accompaniments, 69 cortical spreading depression, 198
Let-down migraine, 95 Major life events, migraine and, 93
Leukbtrienes Marijuana, migraine and, 109
levels in migraine, 218 Marplan. See Isocarboxazid
vascular smooth muscle and, 218 Mast cells
Leu-enkephalin, distribution, 260 effect of neuropeptides, 249f
Lidocaine, for migraine attacks, 388 histamine in, 222
Lifestyle, of migraineurs, 18-19 5-hydroxytryptamine in, 276
Light,,as a migraine trigger, 106 location in dura, 249
Limb pain, as an aura, 54 Maxalt. See Rizatriptan
Lisinopril, for migraine prophylaxis, 443 Media, information about migraine, 298-299
Lithium Medications, as headache triggers, 108t
blood levels of, 440-441 Medulla
contraindications to use, 441-442, 441t fos, 262f
cyclical migraine, 440 nociceptive neuron, 238f
dosage of, 440-441 Mefenamic acid
for migraine prophylaxis, 397t, 440 menstrual migraine, 450
geriatric patients, 483 migraine prophylaxis, 439
guidelines for use, 440-441 MELAS. See Mitochondria! encephalopathy, lactic
5-hydroxytryptamine receptors, 442 acidosis, and stroke-like episodes
mechanisms of action, 442 Menarche, and onset of migraine, 120
monitoring, 440-441 Meniere's disease, migraine and, 24
nursing, 459 Meningeal C-fibers
phannacokinetics of, 440-441 activation by vasodilatation, 244
phosphoinositides, 442 cortical spreading depression, 247
during pregnancy, 457 nitric oxide, 244-247
side effects of, 441 parasympathetic nerves, 244
Lithobid. See Lithium primary afferent depolarization (PAD), 247
Lithonate. See Lithium Meningeal hydrops. See Idiopathic intracranial
Lithotab's. See Lithium hypertension
Locus cperuleus, and cerebral blood flow, 212 Meningitis, 182
Locus coeruleus, blood vessel innervation, 212 Menopause, 138-140
Lopressor. See Metoprolol clinical features of, 138t
Lower half pain, in migraine, 57 hormone replacement therapy for, 459-460
Lumbar puncture headache, 175 hormone secretion during, 138-139
Lumbarpuncture, in migraine attacks, 158 migraine during, 139
Luprolide acetate, menstrual migraine, 452 migraine reduction after, 140f
Lupron.'See Luprolide acetate Menstrual cycle
Lupus anticoagulant. See Antiphospholipid antibodies endocrinology of, 125-130
Luteinizing hormone (LH), levels during menstrual headache days during, 123f
cycle, 126-128 hormonal levels during, 124, 127f
502 Index

Menstrual cycle (Continued) guidelines, 435

length of, 121f mechanisms of action, 438-439
pain modulation during, 124 menstrual migraine, 450-451
Menstrual migraine. 449-450 metabolism of, 435
amitriptyline, 450-451 for migraine prophylaxis, 397t
analgesics, 450 monitoring, 436, 436t
avoidance of trigger factors, 449 during pregnancy, 457
behavioral therapy, 451 rapidity of prophylactic action, 398
/3-bloekers, 450-451 side effects of, 435-436
bromocriptine, 452 vasoconstriction caused by, 435
calcium channel blockers, 450-451 Metoclopramide
danazol, 451-452 anti-emetic use, 322
definition of, 122 children, 475-476
estradiol, 124f effects on aspirin absorption, 322, 322f
estrogen levels, 123-124, 451 emergency care, 388
fenoprofen, 450 for migraine attacks treatment, 322
gonadotropin-releasing hormone (GnRH) agonists, 452 nursing migraineurs, 458
hormonal therapy, 451-452 prokinetic effects of, 322, 332
luprolide, 452 side effects of, 322
mefenamic acid, 450 Metoprolol
methysergide, 450-451 clinical trials of, 402
migraine without aura, 122-123 for migraine prophylaxis, 402
naproxen sodium, 450 Me*-enkephalin, distribution of, 260
non-steroidal anti-inflammatory agents, 450 Micropsia, as an aura, 52
oophorectomy, 452 Microsomatognosia, as an aura, 52
percutaneous estradiol gel, 451 Middle cerebral artery, balloon inflation of, 230f
premenstrual prophylaxis, 450-451 Middle meningeal nerves, innervation of cerebral vessels
progesterone, 451 by, 232
prophylaxis, 450-451 Midrin. See Isometheptene mucate
tamoxifen, 452 Migraine accompagnee, 70. See Complicated migraine
transdermal estrogen patches, 451 Migraine associee, 70. See Complicated migraine
treatment of, 450 Migraine aura status, 70
treatment options, 450t Migraine aura without headache
triptans, 450 clinical features of, 69
Menstrually-related migraine, 122, 449 gender, 69
Menstruation, cycles, 120 prevalence, 69
Meperidine Migraine cluster. See Cluster migraine
emergency care, 387 Migraine dissociee. See Migraine aura without headache
for migraine, 330 Migraine equivalents, 79-83
monoamine oxidase inhibitors, 421 treatment of, 478
during pregnancy, 454-455 Migraine generator, 487
MERFF. See Myoclonic epilepsy with ragged red fibers positron emission tomography, 260
Metamorphopsia, as an aura, 52 Migraine history, elements of, 147t
Methadone, chronic intractable headaches, 472 Migraine minus one. See Migrainous disorder
Methylergometrine. See Methylergonovine Migraine prophylaxis, during pregnancy, 456-457
Methylergonovine Migraine sine hemicrania. See Migraine aura without
clinical reports of, 437 headache
contraindications to use, 437t Migraine with aura, 5
dosage of, 437 diagnostic criteria for, 46t
fibrosis caused by, 437 without headache, 68-69
mechanisms of action, 438-439 oral contraceptives, 453
as a methysergide metabolite, 435 subtypes, 45
for migraine prophylaxis, 437 types of visual auras, 50f
monitoring, 436t, 437 Migraine with interparoxysmal headache. See
side effects of, 437 Transformed migraine
Methysergide Migraine with prolonged aura
children, 478 ergotamine, 342
clinical studies of, 434 International Headache Society Criteria, 70
contraindications to use, 437, 437t Migraine without aura, diagnostic criteria for, 45t
coronary artery constriction caused by, 435 Migraineurs, medication use, 315f
dosage of, 435 Migraine-associated dizziness. See Benign recurrent
efficacy of, 434-135 vertigo in adults
efficacy versus flunarazine, 410 Migraine-related vestibulopathy
efficacy versus propranolol, 405 clinical features of, 79
fibrosis caused by, 436 differential diagnosis of, 79
fibrotic disorders, 436 vestibular testing in, 79
 Index 503

Migraine-sans-migraine. See Migraine aura without Mood changes, in migraine attacks, 61

headache Motion, as a migraine trigger, 106
Migrainous disorder Motion sickness, 79, 106
in children, 7 Motrin. See Ibuprofen
prevalence of, 7 MS Contin, for chronic intractable headaches, 472
Migrainous head pain Multifactorial inheritance, of migraine, 487
duration, 55 Multiple chemical sensitivity syndrome, 107
intensity, 55-56 Muscle contraction headaches. See Tension-type
location, 56-57 headaches
quality, 55 Muscle tenderness, in migraineurs, 7
Migrainous infarction Muscle tenderness, in patients with tension-type
angiography, 74 headaches, 7
antiphospholipid antibodies, 75-76 Myoclonic epilepsy with ragged red fibers (MERFF),
computed tomography, 74 migraine and, 38
diagnostic criteria for, 74 Myofascial pain syndromes, 110
differential diagnosis of, 75 clinical characteristics of, llOt
epidemiology of, 74 Myofascial pain-dysfunction syndrome. See
magnetic resonance imaging, 74 Oromandibular dysfunction
posterior cerebral arteries, 74 Myofascial trigger points, 11 If
risk factors for, 74-75 causing headaches of cervical origin, 170
Migrainous vertigo. See Benign recurrent vertigo in adults injection of, 307
Migranal. See Dihydroergotamine jump sign, 110-111
Minnesota Multiphasic Personality Inventory (MMPI), as migraine triggers, 110
migraine, 17 oromandibular dysfunction, 171
Minor daily hassles. See Hassles pain caused by, 110
Missed work days, because of migraine, 18. 19f physical therapy for, 307
Mitochondria! encephalopathy, lactic acidosis, and posture training for, 307
stroke-like episodes (MELAS), migraine and 38 treatment of, 307
Mitochondria! respiration, in migraineurs, 285
Mitral valve prolapse Nadolol
migraine and, 24 clinical trials of, 402
prevalence of, 24 efficacy versus propranolol, 405
Mixed tension-vascular headache. See Transformed for migraine prophylaxis, 402
migraine Nalbuphine, in migraine attacks, 330
Mode of inheritance, migraine, 32 Nalfon. See Fenoprofen
Monoamine oxidase (MAO) Naproxen
metabolism of triptans, 363 absorption of, 325
platelet levels of, 96 for migraine prophylaxis, 439
Monoamine oxidase inhibitors, 97 menstrual migraine, 450
anxiety, 419 migraine attacks, 325-326
chronic daily headaches, 419 Naproxen sodium
contraindications to use, 420-421 absorption of, 325
depression, 419 migraine attacks, 325-326
dosage of, 420 Naratriptan, efficacy, 356-357
drug interactions, 420-421 Narcotics
foods to be avoided, 420-421, 420t acetaminophen and, 330
geriatric patients, 483 agonist-antagonist narcotics, 330-331
guidelines for use, 420-421 aspirin and, 330
hypertensive crises, 420 chronic intractable headaches, 472
medications to be avoided, 42 It emergency care, 386
meperidine, 421 geriatric patients, 482
for migraine prophylaxis, 397t, 419 migraine attacks, 329-331, 330t
monoamine oxidase block, 423 monoamine oxidase inhibitors, 421
narcotics, 421 nursing, 458
precautions, 420-421 potential for addiction, 329-330
side effects of, 421 during pregnancy, 454-455
sympathomimetics, 420 side effects of, 331
transformed migraine, 419 Nardil. See Phenelzine
tricylic antidepressants and, 421-422 National Headache Foundation (NHF), 299
triptans, 421 Nausea, in migraine attacks, 60
tyramine, 420-421 Neck, myofascial trigger points, 110-111
vasoactive amines, 420 Neck pain, as a migraine trigger, 110
Monosodium glutamate (MSG) Needle-in-the-eye syndrome. See Idiopathic stabbing
foodstuffs containing, lOlt headache
as a migraine trigger, 100-101 Needs, of headache patients, 146t
Montelukast sodium, for migraine prophylaxis, 443 Nerve growth factor, nociceptor activation by, 252
504 Index

Nervus spinosus of Luschka, innervation of cerebral Nociceptin/orphanin FQ (OFQ/FN), 335

vessels by, 232 Nociception
Nervus tentorii, innervation of cerebral vessels by, 231 calcitonin gene-related peptide, 238-239
Neurogenic inflammation of dura, 488. See also Dural neurokinin A, 238-239
plasma extravasation neuropeptides, 238-239
axon reflexes, 242 substance P, 238-239
effect of ergots, 376 Nociceptive afferent fibers
effect of triptans, 376 capsaicin, 243
effects of CP-122,288 trigeminal nerve, 231
headaches and, 242244 upper cervical nerves, 233
5-HTiD receptors and, 376-377 Nociceptive neurons
NK1 receptor antagonists, 377 nociceptive specific, 235
plasma extravasation in, 242 wide dynamic range, 235
release of neuropeptides, 242243 Nociceptors
trigeminovascular system, 242 activation of, 248f
vasodilatation, 242-243 activation and neurogenic inflammation, 247-248
Neurokinin A algesic/algogenic chemicals, 248
nitric oxide, 211-212 arachidonic acid metabolites, 249-251
trigeminovascular fibers containing, 211-212 bradykinin, 251
vasodilatation, 211-212 histamine, 248-249
Neurontin. See Gabapentin 5-hydroxytryptamine, 251
Neuropeptide Y (NPY), in sympathetic nerves, 209 nerve growth factor, 252
Neuropeptides phosphorylation of sodium channels, 253
mast cells and, 249f prostanoids, 249
neurogenic inflammation, 242-243, protein kinase A, 253
release by trigeminovascular fibers, 488 protein kinase C, 253
Neuropsychologic testing, in migraineurs, 158 protons, 251-252, 252f
Neurosteroids, 130 sensitization of, 248f
synthesis of, 131f sodium currents in, 251, 253
Nifedipine, for migraine prophylaxis, 409 Nocturnal migraine, 104
Night terrors, migraine and, 104 Noise, as a migraine trigger, 106
Nimodipine Nolvadex. See Tamoxifen
children, 478 Non-steroidal antiinflammatory agents (NSAIDs). See
for migraine prophylaxis, 409 also specific drugs
Nimotop. See Nimodipine children, 327, 475
Nitric oxide (NO) contraindications to acute use, 327, 327t
activation of guanylate cyclase, 211 contraindications to chronic use, 440
calcium levels in smooth muscle, 211 COX-2 inhibitors and, 327
cortical spreading depression, 221 dosages of, 439t
endothelium, 210 fatty acid cycloxygenase selectivity, 332t
migraine, 488 geriatric patients, 327, 480-481
neurons, 221 menstrual migraine, 450
neurotransmitter receptors and synthesis, 216 migraine attacks, 326t
smooth muscle cells, 218f migraine prophylaxis, 397t, 439
sources of, 210f nursing migraineurs, 457
synthesis in endothelial cells, 216, 218f during pregnancy, 455
vasodilatation, 210 prostaglandins, 327
Nitric oxide synthase prostanoid synthesis, 333
antagonism and cerebral blood flow, 216 side effects of, 326-327, 440
antagonists and cortical spreading depression, 221 Norepinephrine
calcium/calmodulin, 210 cerebral arteries, 209
central sensitization, 254 sympathetic nerves, 208-209
distribution of, 210 Norplant, and headaches, 133
Nitroglycerin Norpramin. See Desipramine
headache induction, 246f Nortriptyline, for migraine prophylaxis, 416
as a migraine trigger, 109 Norvasc. See Amlodipine
nitric oxide release, 246 Nubain. See Nalbuphine
vasodilatation, 245 Nucleus caudalis, 233-235
NK1 receptor antagonists glutamic acid in, 239
dural plasma extravasation, 377 neuropeptides in, 239
in migraine attacks, 377 Nucleus interpolaris, 233-235
N-methyl-D-aspartate (NMDA) receptors Nucleus of descending tract of trigeminal nerve, 233
Mg2+ block of, 254, 285 Nucleus of the solitary tract, and vomiting, 262
in nucleus caudalis, 239 Nucleus oralis, 233-235
role in central sensitization, 254 Nursing
NO synthase. See Nitric oxide synthase acetaminophen, 457
 Index 505

antimigraine drugs, 458t N-methyl-D-aspartate receptors, 132

aspirin, 457 plasma levels of, 129t
/3-blockers, 458-^59 Over-the-counter medications (OTCs)
butalbital, 458 caffeine in, 325
caffeine, 457-458 drug-induced headache, 465
ergots, 458 use of, 323
lithium, 459 Overuse, of medications, 320-321
metoclopramide, 458 Oxycodone
migraine prophylaxis, 458-459 acetaminophen and, 330
narcotics, 458 aspirin and, 330
non-steroidal anti-inflammatory agents, 457 chronic intractable headaches, 472
pharmacokinetics of, 457 Oxycontin. See Oxycodone
sumatriptran, 458
tricyclic antidepressants, 459 P300, in migraineurs, 156
valproate, 459 Pain
verapamil, 459 central pathways, 236f
dura as a source of, 229
Obstructive sleep apnea, migraine and, 104 intracranial arteries, 229-230
Occipital lobes, hyperexcitability, 274 intracranial pain-sensitive structures, 229-231
Occipital neuralgia, 171 myofascial trigger points and, 110
Occlusal adjustment, for migraine 307 venous sinuses, 229, 231
Octopamine, in citrus, 99 Pain transmission, psychological influences, 26If
Ocular migraine. See Retinal migraine Palinopsia, as an aura, 52
Odors, as a migraine trigger, 106-107 Pamelor. See Nortriptyline
Oestrogel. See percutaneous estradiol gel Panic attacks, migraine and, 21t, 22
Olfactory hallucinations, as auras, 53 Papilledema, in idiopathic intracranial hypertension,
On- and off-cells, 258f 175
Oophorectomy, in menstrual migraine, 452 Parabrachial nucleus, 236
Ophthalmic migraine. See Retinal migraine Parasympathetic innervation, regulation of cerebral
Ophthalmodynia periodica. See Idiopathic stabbing blood flow, 209
headache Parlodel. See Bromocriptine
Ophthalmoplegic migraine Parnate. See Tranylcypromine
clinical features of, 83 Paroxetine, for migraine prophylaxis, 422
differential diagnosis of, 84 Paroxysmal hemicrania
magnetic resonance imaging, 83-84 characteristics of attack, 160
oculomotor nerve in, 83 indomethacin responsiveness, 160
Tolosa-Hunt syndrome, 84 Paroxysmal hemiparesis of childhood. See Alternating
Opioid peptides, 259-260 hemiplegia of childhood
levels in migraine, 260 Pattern of attacks, migraine, 46-47
Opioid receptors, 334-335 Paxil. See Paroxetine
characteristics of, 334t Pentazocine, in migraine attacks, 330
Opioids, mechanisms of action, 334-335 Percocet. See Oxycodone, with acetaminophen
Optic neuritis, 177 Percodan. See Oxycodone, with aspirin
Oral contraceptives, 133-136 Percutaneous estradiol gel, menstrual migraine, 451
complicated migraine, 453 Percutaneous transcranial magnetic stimulation,
migraine, 23, 453 274-275, 275f
migraineurs, 453f Periaqueductal gray (PAG),
risk factors for stroke, 453, 454t behavior and, 260-262
risk of thrombotic stroke, 135t connections of, 262
smoking and, 453 dorsolateral pontine tegmentum, 256
stroke, 452-454 fear, 260-262
worsening of migraine, 453 forebrain limbic system, 262
Ornithine transcarbamylase deficiency, migraine and, 39 inputs to, 256
Oromandibular dysfunction, myofascial trigger points in, migraine, 262
171 rostral ventromedial medulla, 256
Orudis. See Ketoprofen stimulation of, 256, 262
Osmophobia, during migraine attacks, 59 stress and, 260-262
Otic ganglion, 208f, 210 Pericrania! muscle tenderness
Otitic hydrocephalus. See Idiopathic intracranial interictal examination, 149
hypertension during migraine attacks, 57, 150
Ovarian, life cycle, 128f during tension-type headaches, 165
Ovarian follicles, 127, 128f Periorbital ecchymoses, in migraine attacks, 60
Ovarian hormones Perivascular nerves, 207
endothelial NO release, 133 Persantine. See Dipyridamole
gamma-aminobutyric acid receptors, 132 Personality, migraine, 16-17
genetic effects of, 132 Personality traits, in migraineurs, 487
506 Index

Pharmacokinetics Positron emission tomography (PET)

amitriptyline, 416 midline brain stem, 260
aspirin, 322 migraine, 487-488
dihydroergotamine, 345 migraine aura, 198-199
ergotamine, 340, 341t, 342 migraine generator, 260, 487
geriatric patients, 478-480, 479t Postconcussive syndrome
intranasal sumatriptan, 353-354 after head injury, 76
lithium, 440-441 whiplash and, 112
nursing, 457 Postdrome, after migraine attacks, 45, 63
oral sumatriptan, 353 Postictal headaches, 85
propranolol and triptans, 355 Posttraumatic headaches
second-generation triptans, 354-355 classification of, 76
subcutaneous sumatriptan, 351 criteria for, 76
sumatriptan, 353t migraine, 76
triptans, 355t Posttraumatic syndrome, 76
Phenelzine, for migraine prophylaxis, 417 Precipitating events. See Trigger factors
Phenergan. See Promethazine Precordial migraine. See Cardiac migraine
Phenolsulfotransferases (PSTs), platelet levels, 96 Pregnancy, 136
Phenothiazines acetaminophen, 454
as anti-emetics, 322-323 amelioration of migraine, 454
for emergency care, 388 anti-emetics, 456
side effects of, 322-323 aspirin, 455
Phenytoin, for migraine prophylaxis, 426 behavioral therapy during, 454
Pheochromocytoma, 178 butalbital, 456
Phobias, migraine and, 21t, 22 codeine, 455456
Phonophobia, migraine, 59 delivery, 136
Phosphenes, 51, 275 ergots, 456
Phosphocreatine, in migraineurs, 285 fetal drug exposure, 454
Photophobia lithium, 457
dazzle, 59 meperidine, 454-455
facial stimulation and, 263f methysergide, 457
mechanisms of, 263 migraine and, 136
migraine, 59 narcotics, 454-455
Photopsias, 49, 50f nausea and vomiting, 456
Phrenilin. See Butalbital, with acetaminophen non-steroidal anti-inflammatory agents, 455
Phrenilin Forte. See Butalbital, with acetaminophen prophylaxis during, 456-457
Physical therapy, for migraine, 307 propranolol, 456
Physician characteristics desired by patients, 293t risk of medications during, 455t
Physician-patient relationship, 145-147 severe migraine attacks during, 456
Pituitary gonadotrophs, 125 sumatriptan, 456
Pizotifen tricyclic antidepressants, 456-457
children, 477-478 valproate, 457
clinical studies of, 437 verapamil, 457
dosage of, 437 Premenstrual disorders, clinical symptoms of, 122t
mechanisms of action, 438^139 Premenstrual dysphoric disorder, 121-122
for migraine prophylaxis, 397t, 437 Premenstrual symptoms, 121-122
side effects of, 437-438 Premenstrual syndrome (PMS), treatment of, 452
Placebos, 296-297 Premonitory symptoms, migraine. See Migraine,
prophylaxis, 396 prodrome
response to, 296f Prevalence
Platelet disorders, headache and, 113 effects of gender, 486
Platelets migraine, 10, 486
activation of, 277-278, 278f migraine in children, 486
5-hydroxytryptamine in, 276-277, 278-281 migraine with aura, 10-11
5-hydroxytryptamine transport, 281 migraine without aura, 10
microggregates in migraine, 280-281 mitral valve prolapse, 24
morphology of, 278f Primary afferent depolarization (PAD), meningeal C-
Pleuropulmonary fibrosis, from methysergide, 436 fibers, 247
PNU-109291 Primary intracranial hypotension, 175-176
effects on dural plasma extravasation, 377 cerebrospinal fluid pressure, 176
as a 5-HT1D agonist, 377 headache in, 175-176
migraine attacks, 377 meningeal enhancement, 176
Polymyalgia rheumatica Probable migraine. See Migrainous disorder
clinical characteristics of, 174 Procardia. See Nifedipine
giant cell arteritis and, 174 Prochlorperazine
Ponstel. See Mefenamic acid as an anti-emetic, 322-323
 Index 507

children, 475-476 tricyclic antidepressants, 397t. See also specific drugs

emergency care, 388 use of, 398t
Prodromes, 47-48 valproate, 397t, 426-429, 483
causes, 189-190 verapamil, 397t, 408-409, 482,
clinical characteristics of, 47-48 Propofol, migraine attacks, 388
to migraine, 45, 48t, 487 Propoxyphene
Progesterone, menstrual migraine, 124, 451 migraine attacks, 330
Progestin oral contraceptives, 133 potential for addiction, 330
Prokinetic medications. See Anti-emetics Propranolol
Prolactin levels, 136-137 children, 477
Promazine, anti-emetic, 322-323 clinical trials of, 402
Promethazine discontinuation of, 405
as an anti-emetic, 322-323 dosage of, 404
children, 475-476 efficacy of, 405
Prophylaxis efficacy versus amitriptyline, 405
aims of, 395 efficacy versus flunarazine, 405
amitriptyline, 397-398, 415, 416-417 efficacy versus methysergide, 405
amlodipine, 410 efficacy versus nadolol, 405
anticonvulsants, 426-430. See also specific drugs efficacy versus other /3-blockers, 405
aspirin, 439-440 efficacy versus valproate, 405
baclofen, 443 guidelines for use, 404-405
j8-blockers, 397t, 398, 403-407, 482 plasma levels of, 403-404
calcium channel blockers, 397t, 398, 407-408. See also during pregnancy, 456
specific drugs side effects, 405
children, 476-478 Prostacyclin, and vasodilatation, 216
clinical trials, 396-397 Prostacyclin (PGI2), and vascular endothelium, 216
compliance, 396 Prostaglandin endoperoxide synthase. See Fatty acid
concomitant medical conditions, 399t cycloxygenase
cost of, 399, 400t Prostaglandins. See also Prostanoids
criteria for use, 395 cerebral blood flow, 219
cyproheptadine, 397t, 438 headache, 220
diltiazem, 409 Prostanoid receptors, sensory nerve endings, 250f
dosage in children, 477t Prostanoids
efficacy, 395, 396-397, 397t, 400t blood levels in migraine, 220
fenoprofen, 439 cerebral blood flow, 219
flunarazine, 397t, 409-410 nociceptor activation by, 249
gabapentin, 397t, 426, 483 synthesis of, 332-333
geriatric patients, 482 Protons
guidelines, 398t cerebral blood flow, 222
headache diary, 397 nociceptor activation by, 251-252
ketoprofen, 439 Protriptyline, for migraine prophylaxis, 416
lamotrigine, 426 Prozac. See Fluoxetine
lisinopril, 443 Pseudotumor cerebri. See Idiopathic intracranial
lithium, 397t, 440, 483 hypertension
magnesium, 397t, 442 Psychologic inventories, in migraineurs, 17
mefenamic acid, 439 Psychological factors, as migraine triggers, 93-95
menstrual migraine, 450-451 Psychotherapy, 306
methylergonovine, 437 Purine receptors
methysergide, 397t cerebral blood vessels, 223
migraine, 488-489 meningeal blood vessels, 223
monoamine oxidase inhibitors, 397t, 419-421, 483 on platelets, 223
montelukast sodium, 443
non-responders, 396
Quality of life, migraine, 18
non-steroidal anti-inflammatory agents, 397t, 439,
Questionnaires, 10
480-481. See also specific drugs
nursing, 458-459 Quintothalmic tract. See Trigeminothalmic tract
overview, 397-400
phenylzine, 419 Race, migraine and, 14
phenytoin, 426 Raphe nuclei, and 5-hydroxytryptamine, 212
pizotifen, 397t, 437 Rapid eye movement (REM) sleep, migraine and, 104
placebo effects, 396 Rapid eye movements (REMs), 104
riboflavin, 442 Raynaud's phenomenon, migraine and, 24
scientific proof of efficacy, 397t Referred pain, theories, 236-237, 237f
side effect potential, 397t Regional cerebral blood flow (rCBF). See Cerebral blood
side effects of, 400t flow (CBF)
topiramate, 426 Reglan. See Metoclopramide
508 Index

Relaxation therapy, 305-306 Singulair. See Montelukast sodium

autogenic training, 305 Sinusitis, 177-178
breathing exercises, 305-306 acute, 177-178
during pregnancy, 454 chronic, 177
progressive relaxation, 305 Sleep
Rescue medication, 320 abortion of migraine attacks, 104
indications for use, 320t breathing disorders, migraine and, 104
Research Group on Migraine and Headache, 4 as a migraine trigger, 104
Reserpine, and induction of migraine, 282 as treatment for migraine attacks, 316
Resolution, migraine, 45 termination of migraine attack, 63
Retinal migraine, 73-74 Sluder's neuralgia. See Cluster headache
clinical features of, 73 Smoking, migraine and, 107
criteria for diagnosis of, 73t Smooth muscle, calcium levels and nitric oxide, 211
differential diagnosis of, 73-74 Snoring, migraine and, 104
fundus examination, 73 Socio-economic status, migraine and, 1314
infarction of anterior visual pathways, 73 Sodium channels, anticonvulsants and, 430^31
Retroperitoneal fibrosis, from methysergide, 436 Sodium nitrite/nitrate, as migraine triggers, 101
Riboflavin, for migraine prophylaxis, 442 Somatosensory evoked potentials, in migraineurs, 156
Rizatriptan Somnambulism, migraine and, 104
efficacy of, 357 Sparine. See Promazine
efficacy versus sumatriptan, 357 Sphenopalatine ganglia, 208f, 210
Rofecoxib, in migraine attacks, 327 Sphenopalatine neuralgia. See Cluster headache
Rolandic (centrotemporal) epilepsy, migraine and, 23 Spinal tract of the trigeminal nerve, 233
Rostral ventromedial medulla (RVM) Spinocerebellar ataxia type 6 (SCA6), P/Q calcium
nucleus caudalis projections, 257 channels and, 35
periaqueductal gray, 256 Spontaneous intracranial hypotension. See Primary
spinal cord projections, 256 intracranial hypotension
Spreading depression. See Cortical spreading depression
Stadol. See Butorphanol
Salivatory nuclei, 210, 208f Stages of migraine attack, 486-487
Sandomigran. See Pizotifen Status migrainosus, 78-79
Sansert. See Methysergide causes of, 469-470
Scintillating scotoma clinical features of, 78-79
aura, 51 definition of, 78
sequential changes during, 195f dihydroergotamine, 470
Seasons, migraine and, 105 hospitalization for, 470
Selective serotonin reuptake inhibitors (SSRIs) medication overuse, 469-470
dosage of, 422 medications used for, 470
for migraine prophylaxis, 422 precipitating factors of, 79
side effects of, 422 treatment of, 470, 470t
transport of amines, 423 Stepped care, 316-318, 317f
Selegiline, lack of effect in migraine prophylaxis, 420 Step-care-across attacks, 316-318, 318f
Sentinel headache, 179 Stepped care-within-attacks, 316-318, 317f
Sequence of attack, migraine, 44 Stratified care, 316-318, 317f, 318f
Serotonin hypothesis of migraine, 275-276 Stress, migraine and, 93-95
Serotonin syndrome, triptans, 359 Stress headaches. See Tension-type headaches
Serotonin. See 5-Hydroxytryptamine Stressors, migraine and, 93-95
Serous meningitis. See Idiopathic intracranial Stress-coping training. See Cognitive-behavioral training
hypertension Stroke, and migraine 75f
Sertraline, for migraine prophylaxis, 422 Subarachnoid hemorrhage, sentinel headache, 179
Severity Subconjunctival hemorrhages, in migraine attacks, 60
headache classification, 486 Substance P
migraine, 20f central sensitization, 254255
migraine attacks, 56f nitric oxide, 211-212
Sharp short-lived head pains. See Idiopathic stabbing in trigeminovascular fibers, 211-212
headache vasodilatation, 211-212
Short-lasting unilateral neuralgiform headache attacks Sumatriptan, 349
with conjunctiva! injection, tearing, sweating, and administration during aura, 351
rhinorrhea (SUNCT), 58 calcitonin gene-related peptide levels, 377f
Sibelium. See Flunarazine clinical trials of, 350-354
Sick building syndrome, 107 cost effectiveness, 349
Side effects, of antimigraine medications, 319-320. See cost of, 349
also specific drugs during pregnancy, 456
Sinequan, for migraine prophylaxis, 416 efficacy, 350-354, 352f, 354f
Single-photon emission computed tomography (SPECT), efficacy of nasal spray versus dihydroergotamine nasal
cerebral blood flow, 192 spray, 363364
 Index 509

efficacy of subcutaneous preparation versus posterior complex, 235

dihydroergotamine nasal spray, 363-364 ventral medial nucleus (VMpo), 236
efficacy of subcutaneous preparation versus ventrobasal complex, 235
subcutaneous dihydroergotamine, 363-364 ventroposterolateral nucleus (VPL), 235
efficacy versus aspirin, 363-364 ventroposteromedial nucleus (VPM), 235
efficacy versus eletriptan, 357 Therapeutic gain, 351
efficacy versus ergotamine, 363-364 Thermography, 156-157
efficacy versus rizatriptan, 357 Thoracic migraine, See Cardiac migraine
efficacy versus tolfenamic acid, 363-364 Thorazine. See Chlorpromazine
efficacy versus zolmitriptan, 355-356 Thromboxane A
improvement of symptoms, 351f vascular endothelium, 216
nursing, 458 yasoconstriction, 216
pharmacokinetics of, 351, 353-354, 353t Thunderclap headache, 179-180
plasma concentration, 373 Tigan. See Trimethobenzamide hydrochloride
quality-of-life and, 349, 350f Timplol
return to normal work, 351f clinical trials of, 402
time to headache recurrence, 358f fpr migraine prophylaxis, 402
workplace productivity, 349 Tofranil. See Imiprarnine
SUNCT. See Short-lasting unilateral neuralgiform Tolfenamic acid, efficacy versus sumatriptan, 363-364
headache attacks with conjunctiva! injection, Tolosa-Hunt syndrome, 84
tearing, sweating, and rhinorrhea Topamax. See Topiramate
Sunlight, as a migraine trigger, 106 Topiramate
Sympathetic dysfunction theory, 285-286 clinical studies of, 429
Sympathetic innervation, cerebral arteries, 208-209 dosage of, 429 >
Sympathetic nerves, regulation of cerebral blood flow, 209 mechanisms of action, 430
Syncope, during migraine attacks, 62 for migraine prophylaxis, 426
Synephrine, in citrus, 99 side effects of, 429-430
Synthesis of estrogen, 129 Toradpl, See Ketorolac
Systemic lupus erythematosus (SLE), Toxic vascular headaches, 182
scintillating scotomas in, 24 Tract of Lissauer, 233
migraine and, 24 Tramadol, in migraine attacks, 331
Transcranial Doppler ultrasonography (TCD)
Talwin. See Pentazocine cerebral blood flow changes, 240-241
Tamorifen effects of ergots, 378
dosage of, 452 effects of triptans, 378
in menstrual migraine, 452 Transcutaneous electrical nerve stirrtulation (TENS), for
side effects of, 452 migraine, 308
Tea, caffeine in, 98-99 Transdermal estrogen patches, menstrual migraine, 451
Tegretol. See Carbamazepine Transformational migraine. See Transformed migraine
Teichopsias, as auras, 51 Transformed migraine, 77-78
Telopsia, as an aura, 52 age of onset, 166f
Temporal arteritis. See Giant cell arteritis clinical features of, 77
Temporomandibular joint Transient global amnesia, 82
disease of, 171 clinical features of, 82
dysfunction of, 171-172 migraine and, 82
symptoms and signs, 171-172 transient ischemic attack, 82
Temporomandibular joint pain dysfunction syndrome. Transient ischemic attacks
See Oromandibular dysfunction differentiation from auras, 180
Tenormin. See Atenolol headache in, 180
Tension headaches. See Tension-type headaches Tranylcypromine, for migraine prophylaxis,
Tension-type headaches, 7 Trauma-triggered migraine, 109
chronic, age of onset, 166f Trazadone. See Desyrel
coexisting migraine, 7 Treatment
diagnostic criteria for, 164, 165, 165t acupuncture, 308
differentiation from migraine, 164-165, 166-167 aims of, 314
episodic, 165-166 alternative medieine, 307-308
head pain during, 165 avoidance of trigger factors, 300
migraine and, 166 behavioral therapy, 303-306
muscle contraction as a cause, 7 biofeedback, 303-305
pericranial muscle tenderness, 165 chiropractic, 308
prevalence of, 165 cognitive-behavioral training, 306
severity of, 56f compliance with, 295-296
Tentorial nerve of Arnold, innervation of cerebral diary, 300
vessels, 231 dietary changes, 300-502
Thalamus discontinuation of oral contraceptives, 302
intralaminar nuclei, 235 discontinuation of smoking, 302
510 Index

Treatment (Continued) Trigeminovascular system, 488

drug-induced headaches, 466-467 Trigger factors. See also specific triggers
elimination of environmental factors, 302-303 headaches in non-migraineurs, 91-92
evidence-based medicine, 297-298 identification of, 92-93
exercise, 306 migraine in children, 91, 93
geriatric patients, 480 Trimethobenzamide hydrochloride, as anti-emetic,
heat/cold applications, 316 322^323
herbal remedies, 309 Triptan syndrome, 359
hypnosis, 308 Triptans. See also specific drugs
lifestyle changes, 299 administration with selective serotonin reuptake
menstrual migraine, 450-451 inhibitors, 359
migraine equivalents, 478 affinity for 5-HT1A receptors, 373-374
missed meals, 302 affinity for 5-HT1B/m receptors, 373^374
myofascial trigger points, 307 affinity for 5-HT1E receptors, 373-374
non-pharmacologic treatments, 300 affinity for 5-HTiF receptors, 373-374
occlusal adjustment, 307 arteriovenous anastomoses, 378
ophthalmological factors, 307 autoradiography, 379
patient education, 299 basilar artery contraction, 375f
physical therapy, 307 binding affinities of, 374t
placebos, 296-297 blood pressure elevation, 359
psychotherapy, 306 blood-brain-barrier, 379
relaxation therapy, 305-306 calcitonin gene-related peptide release, 376
sleep, 316 carotid arterial blood flow, 378
sleep patterns, 302 chemical structures, 350f
status migrainosus, 470, 470t chest pressure/pain, 359-360
substitution of medications, 302 chest symptom mechanisms, 360-361
transcutaneous electrical nerve stimulation, 308 children, 476
Tricyclic antidepressants. See also specific drugs clinical use, 364-366
children, 478 contraindications to use, 362, 362t
contraindications to use, 419, 419t coronary artery constriction, 360-361, 361f
depression, 415 cost of, 352t, 364
geriatric patients, 482^83 dorsal horn neurons, 380f
guidelines for use, 416 dosage of, 365t
insomnia, 415 dural inflammation, 376
for migraine prophylaxis, 397t, 415 dural plasma extravasation, 376
monoamine oxidase inhibitors, 421-422 efficacy of, 355f
neurotransmitter receptor antagonism, 423-424 electrocardiographic changes, 360
nursing, 459 emergency care, 387-388
pharmacologic features of, 417t geriatric patients, 482
plasma levels of, 416 5-HT receptor agonists, 373-374
during pregnancy, 456-457 long-term use of, 364
side effects of, 417-419 menstrual migraine, 450
transport of amines, 423 metabolism by monoamine oxidase, 363
Trigeminal afferent fibers, and glutamic acid, 238 metabolism of, 362-363
Trigeminal ganglion monoamine oxidase inhibitors, 363, 421
calcitonin gene-related peptide, 238 myocardial ischemia/infarction, 360
cerebral blood flow, 212 myocardial perfusion, 360
5-HT receptor subtypes, 376-377 nucleus caudalis, 379-380
location of, 231 nucleus caudalis binding sites for, 379
neurokinin A, 238 overuse of, 364
stimulation of, 212 as partial 5-HT agonists, 374
substance P, 238 pharmacokinetics of, 354-355, 355t
Trigeminal nerve prejunctional 5-HT receptor subtypes, 376-377
divisions of, 232f prejunctional/presynaptic 5-HT receptors, 375-377
innervation of cerebral vessels, 231-233 propranolol and pharmacokinetics of, 355
Trigeminal neuralgia, 58, 174 recurrence of headache, 357-358
Trigeminal root reflexes, release of neuropeptides, 247 serotonin syndrome, 359
Trigeminal sensory nucleus, subdivisions, 233, 233f side effects of, 356f, 358-^359
Trigeminothalamic tract, 235 substantia gelatinosa binding sites for, 379
Trigeminovascular fibers, 211-212 vasoconstriction, 377-379
afferent sensory fibers, 211 True menstrual migraine, 122
calcitonin gene-related peptide, 211, 238-239 Tryptophan-5-hydroxylase, 213
neurokinin A, 211-212, 238-239 Twins, concordance rates of migraine in, 32
origin of, 231 Tylenol #3. See Acetaminophen, with codeine
peripheral release of peptides, 210 Tylenol #4. See Acetaminophen, with codeine
substance P, 211-212, 238-239 Tylenol. See Acetaminophen
vasomotor fibers, 211 Tylox. See Oxycodone, with acetaminophen
 Index 511

Tyramine geriatric patients, 482

in foodstuffs, 97t for migraine prophylaxis, 397t
as a migraine trigger, 96-98 nursing, 459
monoamine oxidase inhibitors and, 420, 420f during pregnancy, 457
Tyrosine, 97 side effects of, 409
Tyrosine decarboxylase, 97 Verelan. See Verapamil
Vertigo, as an aura, 54
Ultram. See Tramadol Vestibular migraine. See Benign recurrent vertigo in
Unemployment, migraine, 19f adults
Urea cycle, 39f Vicodin. See Hydrocodone, with acetaminophen
Uveitis-iritis, 177 Vicodin ES. See Hydrocodone, with acetaminophen
Vidian neuralgia. See Cluster headache
Vahlquist criteria, 15 Vioxx. See Rofecoxib
Valproate Visual discomfort, in migraine attacks, 59f
"carry-over" effect of, 427 Visual evoked potentials (VEPs), 155-156
clinical trials of, 426 abnormalities in migraineurs, 155
contraindications to use, 428-429, 429f Visual hallucinations
dosage of, 427 auras, 52
efficacy versus propranolol, 405 childhood epilepsy with occipital paroxysms, 22
geriatric patients, 483 Vivactil. See Protriptyline
guidelines for use, 427 Voltage-gated calcium channels
intravenous use in migraine attacks, 388 familial hemiplegic migraine and, 33
laboratory monitoring of, 428 P/Q calcium channels, 34
mechanisms of action, 430 subunits, 34
for migraine prophylaxis, 397t, 426 types, 34
nursing, 459 Volteran. See Diclofenac-sodium
plasma concentration of, 427 Vomiting
during pregnancy, 457 area postrema, 263
prophylaxis in children, 477 central pattern generator, 262
rapidity of prophylactic action, 398 during pregnancy, 456
side effects of, 427-428 migraine attacks, 60
teratogenicity of, 428 neural pathways, 262-263
Variant angina, migraine and, 83 nucleus of the solitary tract, 262
Variants, migraine, 15 vomiting center, 262
Vascular endothelium
endothelial-derived hyperpolarizing factor, 216 Weather, as a migraine trigger, 105-106
endothelin-1, 216 Web sites, information about migraine, 299
prostacyclin, 216 Weekend headaches, 95, 99
thromboxane Ag, 216 Whiplash, 111-112
Vascular smooth muscle Wigraine. See Ergotamine
endothelial vasodilators, 217f Windup, 254
nitric oxide effects on, 218f Wolff hypothesis of migraine, 190, 373
Vasoactive amines, as migraine triggers, 96 Worst headache, 386t
Vasoactive intestinal polypeptide (VIP), 211
cerebral blood flow, 211 Zestril. See Usinopril
in parasympathetic nerves, 211 Zolmitriptan
plexus around blood vessels, 211 efficacy, 355
vasodilatation, 211 efficacy versus sumatriptan, 355-356
Vasoconstriction Zoloft. See Sertraline
ergots, 377-^379 Zomig. See Zolmitriptan
triptans, 377-379
Vasodilatation, dural arteries, 488 4991W93
Vasospastic amaurosis fugax. See Retinal migraine migraine attacks, 377
Verapamil protein extravasation, 377
clinical studies of, 408-409 Vasoconstriction, 377