3rd Editiun
`
`
`
`i
`
`IPR2018—01427
`
`Lilly Exhibit 1311, Page 1 of 24
`
`Eli Lilly & CO. V. Teva Pharms. Int'l GMBH
`
`Jes Olesen
`
`Peter J. Goadsby
`
`Nabih M. Ramadan
`
`Peer TfeIt-Hansen
`
`K. Michael A. Welch
`
`

`

`The Headaches
`Third Edition
`
`

`

`The Headaches
`Third Edition
`
`EDITED Bv
`Jes Olesen, M.D.
`Professor and Chairman
`Department of eurology
`Glostrup Hospital
`University of Copenhagen
`Glostrup, Copen.hagen, Denmark
`Peter J. Goadsby, M.D., Ph.D., D.Sc.
`Professor of Clinical euro1ogy
`Institute of I eurology
`The National Hospital for eurology and Neurosurgery
`London, United Kingdom
`Nabih M. Ramadan, M.D.
`Professor and Chair
`Department of Neurology
`Chicago Medical School
`Vice President
`Interprofessional Advancement
`and Community Relations
`Rosalind Franklin University of Medicine and Science
`Chicago, Illinois
`Peer Tfelt-Hansen, M.D.
`Professor
`Department of 1 ·ew"Ology
`Glostrup Hospital
`University of Copenhagen
`Glostrup, Copenhagen, Denmark
`K. Michael A. Welch, M.D., Ch.B., F.R.C.P.
`Professor
`Department of Neurology
`Chicago Medical School
`President and CEO
`Rosalind Franklin University of Medicine and Science
`Chicago, Illinois
`
`•
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`Library of Congress Cataloging-in-Publication Data
`The headaches/edited by Jes Olesen ... [et al.].- 3rd ed.
`p.; cm.
`Includes bibliographical references and index.
`ISBN 0-7817-5400-3
`I. Headache.
`I. Olesen, Jes.
`[DNLM: L Headache. WL 342 H4329 2006]
`RBl28.H445 2006
`616.8'491- dc22
`
`2005022487
`Care has been token lo confirm the accuracy of the information presented and to describe generally
`accepted practices. However, the authors, editors, and publisher are not responsible for en-ors or
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`profes ional responsiblliLy of the practitionea:
`The author , editors, and publisher have exerted every effort to ensure that drug selection and
`dosage set forth in this text are in accordance with cun-ent recommendations and practice at the
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`the constant now of information relating to drug therapy and dnig reactions, the reader is urged to
`check the package inscn for each drug for any change in indications and dosage and for added
`warnings and precautions. This is particularly impo11ant when the recommended agent is a new or
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`

`

`Contributors xi
`Preface to the First Edition xxv
`Preface xxvii
`
`1 History of the Headache 0 1
`Hansruedi Isler and Pete.r J. Koehler
`2 Classification of Headache 09
`Jes Olesen and Richard B. Lipton
`
`3 Epidemiology of Headache 17
`Lars J. Stovner and Ann I. Scher
`4 Impact of the Headache on the
`Individual and Family 27
`Carl G. H. Dahlof and Glen D. Solomon
`5 Societal Burden of the Headache 35
`Jenny Berg and Nabih M. Ramadan
`6 The History and Examination of Headache
`Patients 43
`Jes Olesen and David W Dodick
`
`7 Principles of Clinical Pharmacology,
`Randomized Controlled Clinical Trials, and
`Evidence-Based Medicine in Headache 55
`Carl G. H. Dahlof, Paul Rolan, and Peer Tfelt-Hansen
`
`8 Ethical Issues in Headache Research and
`Management 63
`Timothy J. Steiner and Pov[ Riis
`
`11 Inhibition and Facilitation of
`Nociception 111
`Jiirgen Sandkiihler
`12 Peripheral and Central Sensitization Related
`to Headaches 121
`Rami Burstein, Dan Levy, Moshe Jakubowski, and
`Clifford J. Woolf
`13 Imaging Pain 131
`Irene Tracey and Martin lngvar
`14 Serotonin and Other Biogenic Amines 143
`Christian Waeber
`15 Nitric Oxide 151
`Andrew A. Parsons
`16 Calcitonin Gene-Related Peptide and Other
`Peptides 159
`Susan Brain and Lars Edvinsson
`17 Sex Hormones 165
`Nancy E. J. Bennan and Michael M. Behbehani
`18 Prostanoids and Other Inflammatory
`Mediators 175
`Christian Waeber
`19 Other Molecules Involved in Pain
`Transmission 183
`Anthony Dickenson
`20 Ion Channels Relevant to Pain 189
`Kevin Shields and Arn van den Maagdenberg
`21 Triptan Signal Transduction 203
`Gareth W John and Peter J. Goadsby
`22 Animal Models of Headache 213
`Andrew H. Ahn and Peter J. Goadsby
`23 Human Models of the Headaches 221
`Christina Kruuse and Shazia Khan Afridi
`
`9 Anatomy of Muscles, Tendons, Joints, Blood
`Vessels, and Meninges 71
`Lars Edvinsson and Marc Abel
`
`10 Anatomy and Physiology of Head Pain 95
`Karl Messlinger, Jonathan 0. Dostrovslcy, and
`Andrew M. Strassman
`
`24 The Migraines: Introduction 231
`Jes Olesen and Peter J. Goadsby
`25 Epidemiology of Migraine 235
`Birthe Krogh Rasmussen
`
`V
`
`

`

`vi
`
`Contents
`
`26 Migraine Comorbidity 243
`Kathleen Ries Merikangas, Nancy C. D. Low, and
`Birthe Krogh Rasmussen
`
`27 Genetics of Migraine 251
`Michel D. Ferrari, Joost Haan, and Aarno Palotie
`28 Spreading Depression 269
`Martin Lauritzen and Richard P. Kraig
`29 5-Hydroxytryptamine Involvement in
`Migraines 275
`Edith Hamel and Pramod R. Saxena
`30 Nitric Oxide Involvement in Migraines 281
`Helle U. Iversen and Uwe Reuter
`31 CGRP Involvement in Migraines 289
`Lars Edvinsson and Richard Hargreaves
`32 Channelopathies and Their Possible
`Relation to Migraines 301
`Dennis E. Bulman and Daniela Pietrobon
`33 Neurogenic Inflammatory Mechanisms 309
`Kirk W Johnson and Hayrunissa Bolay
`34 Blood and Spinal Fluid in Migraines 321
`Paola Sarchielli and Flemming W Bach
`35 Influence of Female Hormones on
`Migraines 331
`Helene Massiou and E. Anne MacGregor
`36 Platelets and Immunology of Migraines 343
`Rajiv Joseph, Jacqueline deBelleroche, Giovanni
`D'Andrea, and Andre Pradalier
`37 Hemodynamics and Neuroimaging of
`Migraines 351
`Margarita Sanchez de/ Rio, Jes Olesen, and
`Hans-Christoph Diener
`38 Brain Metabolism in Migraines 363
`Pasquale Montagna and K. Michael A. Welch
`39 Neurophysiology of Migraines 369
`Jean Schoen.en and Sheena Aurora
`40 Autonomic Dysfunction in Migraines 377
`Janne Ludwig, Thorsten Bartsch, Gunnar Wasner, and
`Ralf Baron
`41 Psychological Mechanisms of Migraines 385
`Peter D. Drummond and Jan Passchier
`42 Synthesis of Migraine Mechanisms 393
`Jes Olesen and Peter J. Goadsby
`
`43 Symptomatology of Migraines without
`Aura 399
`Alessandro S. Zagami and Anish Bahra
`44 Migraines with Aura and Their
`Subforms 407
`F. Michael Cutrer and Jes Olesen
`45 Diagnosis and Differential Diagnosis of
`Migraines 423
`Jerry W Swanson and Fumihilco Sakai
`46 Prognosis of Migraines 429
`Birthe Krogh Rasmussen and Richard B. Lipton
`
`4 7 General and Pharmacologic Approach to
`Migraine Management 433
`Ninan T Mathew and Peer Tfelt-Hansen
`48 Psychological and Behavioral Treatments of
`Migraines 441
`Patrick J. McGrath, Donald Penzien, and
`Jeanette C. Rains
`
`49 Nonsteroidal Anti-Inflammatory Drugs in
`the Acute Treatment of Migraines 449
`Peer Tfelt-Hansen and Paul Rolan
`50 Ergot Alkaloids in the Acute Treatment of
`Migraines 459
`Peer Tfelt-Hansen and Pramod R. Saxena
`51 Triptans, 5-HTrn;rn Receptor Agonists in the
`Acute Treatment of Migraines 469
`Pramod R. Saxena and Peer Tfelt-Hansen
`52 Antiemetic, Prokinetic, Neuroleptic, and
`Miscellaneous Drugs in the Acute Treatment
`of Migraines 505
`Peer Tfelt-Hansen, William B. Young, and
`Stephen D. Silberstein
`53 Prioritizing Acute Pharmacotherapy of
`Migraines 515
`Peer Tfelt-Hansen
`
`

`

`Contents
`
`vii
`
`54 p-Aclrenoceptor Blocking Drugs in Migraine
`Prophylaxis 519
`Peer Tfelt-Hansen and Paul Rolan
`55 Antiserotonin Drugs in Migraine
`Prophylaxis 529
`Peer Tfelt-Hansen and Pramod R. Saxena
`56 Calcium Antagonists in Migraine
`Prophylaxis 539
`Noboru Toda and Peer Tfelt-Hansen
`5 7 Antiepileptic Drugs in Migraine
`Prophylaxis 545
`Stephen D. Silberstein and Peer Tfelt-Hansen
`58 Nonsteroidal Anti-Inflammatory and
`Miscellaneous Drugs in Migraine
`Prophylaxis 553
`Stefan Evers and Ewan J. Mylecharane
`59 Prioritizing Prophylactic Treatment of
`Migraines 567
`Peer Tfelt-Hansen
`60 Potential New Drugs for the Acute and
`Prophylatic Treatment of Migraines
`569
`Peter J. Goadsby and Nabih M. Ramadan
`
`61 Sporadic and Familial Hemiplegic
`Migraines 577
`Anne Ducros and Lise Lykke Thomsen
`62 Basilar Migraines and Retinal Migraines
`589
`Marcelo Bigal and K. Michael A. Welch
`63 Status Migrainosus 595
`James R. Couch and Alessandro S. Zagami
`64 Migrainous Infarction and Migraine
`Triggered Epilepsy 599
`K. Michael A. Welch, Marie-Germaine Bousser, and
`Julien Bogouslavsky
`65 Chronic Migraines 613
`Stephen D. Silberstein and Jes Olesen
`
`66 Tension-Type Headache: Introduction 619
`Jes Olesen and K. Michael A. Welch
`67 Epidemiology of Tension-Type
`Headaches 621
`Rigmor Jensen and David Symon
`
`68 Genetics of Tension-Type Headaches 625
`Michael Bj¢m Russell
`69 Human Studies of Experimental Pain From
`Muscle 627
`Peter Svensson and Messoud Ashina
`70 Sensitization of Myofascial Pain Pathways in
`Tension-Type Headaches 637
`Lars Bendtsen and Rolf Detlef Treede
`71 Neurophysiology of Tension-Type
`Headaches 643
`Jean Schoenen and Lars Bendtsen
`72 Hemodynamics and Muscle Metabolism of
`Tension-Type Headaches 651
`Messoud Ashina and Michael Langemark
`73 Temporomandibular Disorders and
`Tension-Type Headache 655
`Steven B. Graff-Radford
`7 4 Psychological Mechanisms of Tension-Type
`Headaches 663
`Frank Andrasik, David A. Wittrock, and Ja n Passchier
`75 Biochemistry of Blood and Cerebrospinal
`Fluid in Tension-Type Headaches 669
`Flemming W Bach and Michel D. Ferrari
`76 Synthesis of Tension-Type Headache
`Mechanisms 679
`Lars Bendtsen and Jean Schoenen
`
`77 Symptomatology of Episodic Tension-Type
`Headaches 685
`Rigmor Jensen and Werner J. Becker
`
`

`

`viii
`
`Contents
`
`78 Symptomatology of Chronic Tension-Type
`Headaches 693
`Rigmor Jensen and Werner J. Becker
`79 Differential Diagnosis and Prognosis of
`Tension-Type Headaches 701
`Jean Schoenen and Rigmor Jensen
`
`80 General Approach to Treatment of
`Tension-Type Headaches 707
`Richard C. Peatfield and John G. Edmeads
`81 Psychological Treatments of Tension-Type
`Headaches 711
`Kenneth A. Holroyd, Paul R. Martin, and Justin M.
`Nash
`82 Physiotherapy of Tension-Type
`Headaches 721
`Rigmor Jensen and Julie Mills Roth
`83 Acute Pharmacotherapy of Tension-Type
`Headaches 727
`Ninan T Mathew and Messoud Ashina
`84 Prophylactic Pharmacotherapy of
`Tension-Type Headache 735
`Lars Bendtsen and Ninan T Mathew
`
`85 Cluster Headaches: Introduction and
`Epidemiology 743
`Peter J. Goadsby and Peer Tfelt-Hansen
`86 Genetics of Cluster Headaches 747
`Michael Bj¢m Russell and Richard C. Trembath
`87 Anatomy and Pathology of Cluster
`Headaches 7 51
`Jan Erik Hardebo and Norihiro Suzuki
`88 Biochemistry, Circannual and Circadian
`Rhythms, Endocrinology, and Immunology
`of Cluster Headaches 755
`Elisabet Walclenlind and Gennaro Bussone
`89 Neurophysiology and Autonomic
`Dysfunction in Cluster Headaches 767
`Peter D. Drw1L11101ul a11d Massimo Alessandri
`90 Neuroimaging in Trigeminal Autonomic
`Cephalgias 77 5
`Ame May and Peter J. Goadsby
`
`91 Synthesis of Cluster Headache
`Pathophysiology 783
`Elisabet Waldenlind and Peter J. Goadsby
`92 Symptomatology of Cluster Headaches 789
`David F. Black, Carlos A. Bordini, and David Russell
`93 Diagnosis, Differential Diagnosis, and
`Prognosis of Cluster Headaches 797
`Karl Ekbom and Anish Bahra
`94 General Approach to the Management of
`Cluster Headaches 801
`Karl Ekbom and Ninan T Mathew
`95 Acute Treatment of Cluster Headaches 803
`Giorgio Sandrini and Thomas N. Ward
`96 Preventive and Surgical Management of
`Cluster Headaches 809
`Massimo Leone and Allan Rapoport
`97 Paroxysmal Bemicrania 815
`Christopher J. Boes, Maurice Vincent, and David
`Russell
`98 Sudden Unilateral Neuralgiform Pain with
`Conjunctiva! Injection and Tearing 823
`Manjit S. Matharu and Peter J. Goadsby
`
`99 Primary Stabbing, Cough, Exertional, and
`Thunderclap Headaches 831
`David W Dodick and Julio Pascual
`100 Primary Headache Attributed to Sexual
`Activity 841
`Stefan Evers and James W Lance
`101 Hypnic Headaches 847
`Lawrence C. Newman and Amnon Masek
`102 Hemicrania Continua 851
`Juan A. Pareja and Peter J. Goadsby
`103 New Daily Persistent Headache 855
`Todd D. Rozen and Rigmor Jensen
`
`104 The Secondary Headaches:
`Introduction 859
`Jes Olesen and Nabih M. Ramadan
`105 Acute Posttraumatic Headaches 863
`Matthias Keidel and Nabih M. Ramadan
`
`

`

`106 Chronic Posttraumatic Headaches 873
`Nabih 1\11. Ramadan and Miguel J. A. Lainez
`107 Headache Attributed to Whiplash
`Injury 879
`Helge Kasch and Nabih M. Ramadan
`
`119 Headache Attributed to Infection 981
`Joerg R. Weber and Fumihiko Sakai
`120 Headache Attributed to a Disorder of
`Homeostasis 989
`David W Dodick and Paul T. G. Davies
`
`Contents
`
`ix
`
`108 Ischemic Stroke and Spontaneous
`Intracerebral Hematoma 885
`Panayiotis Mitsias and Troels Staehelin Jensen
`109 Unruptured Vascular Malformation and
`Subarachnoid Hemorrhage 893
`John R. (/Jstergaard and Nabih M. Ramadan
`110 Arteritis 901
`Michael Wall and James John Corbett
`111 Carotid or Vertebral Artery Pain 911
`Valerie Biousse and Panayiotis Mitsias
`112 Cerebral Venous Thrombosis 919
`Gretchen E. Tzetjen
`
`113 High Cerebrospinal Fluid Pressure 925
`Deborah I. Friedman and James John Corbett
`114 Low Cerebrospinal Fluid Pressure 935
`Steinar T. Vilming and Bahram Mokri
`115 Pseudomigraine with Pleocytosis 945
`Dimas D. Mitsikostas and Julio Pascual
`116 Intracranial Neoplasms 949
`Sarah Kirby and R. Allan Purdy
`
`121 Disorder of the Skull and Cervical
`Spine 1003
`Hartmut Gobel and John G. Edmeads
`122 Ocular Disorder 1013
`Robert L. Tomsak and Robert B. Daro-ff
`123 Disorder of Ear, Nose, and
`Sinus 1019
`Hartmut Gobel and Robert W Baloh
`124 Headache Attributed to
`Orofacial/Temporornandibular
`Pathology 1029
`Steven B. Graff-Radford and
`Dermot W Canavan
`125 Headache Attributed to Psychiatric
`Disorder 103 7
`Nutan Vaidya and K. Michael A. Welch
`
`126 Pain of Cranial Nerve and Cervical Nerve
`Origin Other Than Primary Neuralgias
`1043
`Nikolai Bogduk
`127 Trigeminal Neuralgia and Other Facial
`Neuralgias 1053
`Turo J. Nurmiklw and Troels Staehelin Jensen
`128 Central Pain in the Face and
`Head 1063
`Jorgen Boivie and Kenneth L. Casey
`
`117 Headache Associated with Acute Substance
`Use or Exposure 959
`Jose M. Pereira Monteiro, Stewart Tepper, and
`Robert E. Shapiro
`118 Medication Overuse Headaches 971
`Hans-Christoph Diener and Stephen D. Silberstein
`
`129 History and Examination of Infants,
`Children, and Adolescents with
`Headaches 1069
`Paul Winner and Vincenza Guidetti
`
`

`

`X
`
`Contents
`
`130 Childhood Migraine and Related
`Syndromes 1073
`Ishaq Abu-Arefeh and Eric Pearlman
`131 Tension-Type Headaches and Other
`Nonmigraine Primary Headaches in the
`Pediatric Population 1079
`p9ek Woeber-Bingol and Andrew D. Hershey
`132 Secondary Headaches in the Pediatric
`Population 1083
`David Symon and Mirja L. Hamalainen
`
`133
`
`Headache During Pregnancy and
`Lactation 1091
`Elizabeth W Loder and Helene Massiou
`
`134 Headaches and Sleep 1099
`Poul Jennum and Teresa Paiva
`135 Headaches in the Elderly 1105
`John G. Edmeads and Shuu-Jiun Wang
`136 Headache in Patients with Coexisting Other
`Pain Disorder 1111
`David M. Biondi and Mario F Peres
`137 Headaches in Patients with Coexisting
`Psychiatric Disease 1117
`Donald Penzien, Richard C. Peatfield, and
`Gay L. Lipchik
`138 Headaches in Patients with Coexisting
`Medical Disease 1125
`Vincent Martin and Markus Farkkila
`139 Headaches in the Emergency Room 1133
`Dominique Valade
`Index 1139
`
`

`

`Nonsteroidal Anti-Inflammatory
`and Miscellaneous Drugs in
`Migraine Prophylaxis
`
`Stefan Evers and Ewan ]. Mylecharane
`
`INTRODUCTION
`
`In addition to the recognized drugs of first choice For rni(cid:173)
`oraine prophylaxis such as /3-adrenoceptor blockers, an(cid:173)
`;iserotonin drugs, calcium antagonists, and antiepileptic
`drugs, many other drugs and remedies have been tested in
`migraine prophylaxis. Most of these other drugs have not
`been tested in controlled randomized clinical trials. How(cid:173)
`evc1~ their use is sometimes recommended even in modern
`handbooks. This chapter aims to p1·esenl the data on mis(cid:173)
`cellaneous drugs that have been tested for migraine pro(cid:173)
`phylaxis and for which controlled randomized tri_als ~re
`available. For drugs with established efficacy in m1grame
`prophylaxis, details of their therapeutic use are mentioned
`briefly. The description will focus on the clinical evidence
`for efficacy of these drugs rather than on their pharrnaco(cid:173)
`logic properties.
`
`NONSTEROIDAL ANTIINFLAMMATORY
`DRUGS (NSAIOS)
`
`The rationale for using NSAIDs in the prophylaxis of rni(cid:173)
`oraine is based on the observation that some palienls Lak(cid:173)
`~g NSAIDs for other reasons (e.g., secondary prophy(cid:173)
`laxis of stroke) experience fewer migraine attacks and
`on the possible general involvement of proslaglandins in
`the inflammalory pathophysiologic components of the mi(cid:173)
`graine process. The NSAIDs that have been most exten(cid:173)
`sively tested in migraine prophylaxis are acetylsalicylic
`acid ·(ASA) (aspirin), naproxen and naproxen sodium, and
`Lolfenarnic acid.
`
`Pharmacologic Background
`
`The pharmacologic actions of the NSAJDs relevant to
`migraine prophylaxis are described in Chapter 49. BrieOy,
`NSAIDs possess anliinRammatory, analgesic, and anti(cid:173)
`pyretic properties. They exert their effect by inhibiting the
`ubiquitous cyclooxygenase- l and cyclooxygenase-2 en(cid:173)
`zymes, thereby preven Ling the synthesis of prostaglanclins
`a·nd thrornboxanes from ASA. The inhibition by ASA, but
`nol other NSAIDs, is irreversible because ASA acetylates
`cyclooxygenase. The NSAIDs usually are classified as
`peripheral analgesics, al though they have central effects
`as well.
`Absorption al'ler oral ASA, as with other NSAIDs, is
`high, in excess of 80% ( 1 ). ASA is metabolized rapicUv
`bv plasma and tissue eslerases lo salicylic acid belore il
`reaches the systemic circulation. The peak plasma concen(cid:173)
`tration of ASA is achieved 15 minutes after oral aclmin(cid:173)
`islralion, whereas the peak concentration of salicylale is
`reached after 30 lo 60 minutes. The plasma half-life of ASA
`is 15 to 30 minutes. Salicylic acid exhibits dose-dependent
`kinetics; thus, its half-life after 250 mg of ASA is about
`3 hours and after I g about 6 hours. The range of bioavail(cid:173)
`abilit vis between greatel' than 90% for naproxen/naproxen
`sodiu·m and 60% for LolFenamic acid. The plasma half-lives
`of these NSAIDs are in the range of 2 lo 4 hours, with the ex(cid:173)
`ception of naproxen, which has a half-Ii Fe of 12 Lo 15 hours.
`
`Possible Mode of Action in
`Migraine Prophylaxis
`The mode of action of NSAIDs in migraine therapy and
`whether this mode of action involves prostaglanclins in
`the migraine process are discussed in Chapter 49. One of
`
`553
`
`

`

`554
`
`The Migraines
`
`the major obstacles to inhibilion oF cyclooxygenase being
`responsible for the prophylaclic efficacy of these agents
`is the lack of effect of lhe polenl NSAID indomethacin
`in a double-blind, placebo-conlrolled trial in migraine pa(cid:173)
`tients (2).
`Il has been suggested that lhe prophylactic usdulnesc
`of NSAIDs in migraine could be through the inhibition
`of platelet aggregation, thereby correcting an underlying
`hyperaggregability (3,4). Howevec high oral closes of ASA
`(650 to 1300 mg daily) in combination with 75 to 300 mg
`dipyridamole daily were marginally superior to placebo
`in migraine prophylaxis in one trial (5) and superior to
`placebo in another (3 ), but these effects were not correlated
`with whelher the patients had byperaggregable platelets.
`In one placebo-controlled crossover trial in which a low
`close of ASA ( 160 mg) was evaluated for migraine prophy(cid:173)
`laxis (see below), the active meclicalion was oF no bene(cid:173)
`fit despile inhibition of platelet 11111ction (6). In the Physi(cid:173)
`cians' Health Sludy (7) of ASA (325 mg on al ternate clays),
`howeve1; a 20% reduction in the incidence o[ migraine was
`suggested compared with placebo (see below). No corre(cid:173)
`lation was observed between lhe degree of platelet inhibi(cid:173)
`lion and the efficacy as a migraine prophylactic drug for
`naproxen (8). Therefore, il is most unlikely lhat an action
`of platelels is responsible for lhe beneficial prophylactic
`effecl of NSAJDs. Thus, lhe mode or action of NSAIDs in
`migraine proplwlaxis is-as it is for any other migraine
`prophylactic drug-still not fully understood.
`
`Results of Controlled Clinical Trials
`
`A summary ol' 20 conlrollecl double-blind randomized tri(cid:173)
`als on the efficacy oF oral NSAIDs in migraine prophylaxis
`is given in Table 58- l. All but two lrials (3, 10) included
`migraine patients both with and withoul aura; the two ex(cid:173)
`ceptions did not include any aura patients.
`Higher closes of aspirin ( 1300 mg and 900 mg daily,
`respectively) showed superior dficacy compared with
`placebo ( l l) and were apparen lly comparable in efficacy
`lo propranolol (9) in two small trials ( l:Z palienls in each),
`although lhe latter trial was too small lo demonstrate com(cid:173)
`parabilily. In another lrial, howeve1; ASA ( 1500 mg daily)
`was less eff eclive than meloprolol ( I 0). This was confirmed
`by a recent large trial showing a superiority of 200 mg of
`meloprolol over 300 mg of ASA for all efficacy parameters
`(J2). The oulcome results for ASA were regarded by the
`investigalors as in lhe range of typical placebo response.
`Trials of low closes o[ ASA have also foiled Lo provide con(cid:173)
`vincing evidence of efficacy. ASA ( 160 mg daily) did not
`achieve belter results than placebo (6), and no correlalion
`was found between the number of allacks and inhibi tion
`of adenosine diphosphate (ADP)-induced plalelet aggre(cid:173)
`gation. In children aged 7 lo 17 years, lhe effect of ASA
`( I 00 to 200 mg daily) was comparable lo that of flunar(cid:173)
`izine ( l3); howeve1; because no placebo was used in this
`
`lrial, conclusions concerning the efficacy of ASA cannol be
`made.
`There are three large cohort studies with a comparison
`between ASA and placebo not primarily designed to exan, ..
`ine the influence on migraine prophylaxis but showing in(cid:173)
`teresting relevanl results. The Physicians' Health Study (7)
`indicaled some effect of low-close ASA (325 mg every other
`day for the prevention of cardiovascular disease) with the
`finding that 6% of subjects reported migraine compared
`with 7.4% of subjects taking placebo during a 60-month
`period (i.e., a 20% reduction in migraine frequency) . Sim(cid:173)
`ilar resulls were obtained in the earlier British Doctors
`Trial showing a reduction of migraine attacks by about
`30% in the group taking 500 mg of ASA (14). Howeve1; in
`the Women's Health Study, 100 mg of ASA daily did not
`result in a significant recluclion of migraine frequency as
`compared to placebo, but showed a lrend to a decr~ase
`in severitv, duration, and migraine-related incapacitation
`(15). The sludy result was regarded as only a small treal(cid:173)
`ment effect of ASA in the prophylaxis of migraine among
`middle-aged women. The question of whelher low-close
`ASA has a minor effect in migraine prophylaxis thus re(cid:173)
`mains open.
`In lhe l'irst lrial of naproxen (500 mg daily), this
`drug proved only questionably belter than placebo ( 16).
`Naproxen sodium (1100 mg daily), howeve1; was demon(cid:173)
`strated to have better efficacy than placebo in three trials
`( 4,8, 17), and in one of these trials ( 17) it was comparable lo
`pizotifen. In another lrial ( 18), naproxen sodium (1100 mg
`daily) was comparable lo propranolol, but the superior(cid:173)
`i t_v of both drugs over placebo was restricted to patients'
`evaluations. Comparabilily in each of these trials was nol
`substantiated by narrow confidence intervals.
`Tolfenamic acid had significantly better results than
`placebo ( I 9,20), and comparabilily to proprnnolol was in(cid:173)
`dicaled in one of lhe trials (20) by rathet" narrow confi(cid:173)
`dence intervals. In another trial (21 ), tol fenarnic acid was
`con,parable lo propranolol , but no placebo control was
`included.
`Only single trials are available for the remaining
`NSAIDs listed in Table 58-1. Ketoprofen showed margi(cid:173)
`nally superior resul ts compared with placebo in a group of
`severe!)' afnictecl migraine patients (22). In one small trial
`( 17 patients), mefenamic acid hacl superior efficacy com(cid:173)
`pared with placebo (23), but the claimed comparabilitv to
`prnpranolol cannot be substantiated From a trial lhat in(cid:173)
`cluded so few palients. Fenoprofen ( 1800 mg daily but not
`600 mg daily) was superior to placebo (24), indobufen also
`had greater effecls than placebo in one trial (25), and even
`nurbiprofen led to a significant decrease of headache inten(cid:173)
`sil_v but not frequency in a double-blind placebo-controlled
`trial (26). Very recen tly, the new selective cyclooxygenase-
`2 inhibitor rofecoxib was studied for migraine prophy(cid:173)
`laxis. In a double-blind, placebo-controlled trial wilh 175
`randomized (147 evaluated) patients, rofecoxib 25 mg/clay
`
`

`

`(continued)
`
`propranolol for all parameters
`
`Both > run-in; tolfenamic acid=
`
`acid > propranolol = placebo for severity
`for frequency and medication; tolfenamic
`Tolfenamic acid= propranolol > placebo
`
`parameters
`
`Migraine days, duration, severity
`
`(4 wk washout)
`
`12wk x 2
`
`medication
`
`Frequency, duration, severity,
`
`12 wk x 3
`
`preference
`
`(2 wk washout)
`
`Tolfenamic acid > placebo for all
`
`Frequency, severity, duration,
`
`10 wk x 2
`
`Naproxen, sodium= pizotifen > placebo
`
`> placebo for patients' evaluation
`severity; naproxen, sodium= propranolol
`placebo ns for headache days and
`Naproxen, sodium vs propranolol vs
`
`Headache unit index
`
`12 wk
`
`Headache days, severity, overall
`
`14wk
`
`evaluation
`
`for all parameters
`
`days with severe headache
`
`(2 wk washout)
`
`Rating of efficacy, headache index, Naproxen, sodium> placebo
`
`Bwk x 2
`
`for all parameters
`
`naproxen, sodium > placebo
`
`parameters dubious
`
`indexc, duration, medication
`
`(2 wk washout)
`
`rating of efficacy, headache
`
`Bwk x 2
`
`indexc, preference
`
`(1 wk washout)
`
`Naproxen > placebo for preference, other
`
`Frequency, duration, headache
`
`decrease
`
`Metoprolol > ASA; both > run-in
`
`Frequency, 50% frequency
`
`12 wk x 2
`
`both > run-in
`
`ASA vs flunarizine, ns;
`
`ASA vs placebo, ns
`
`both > run-in
`
`ASA vs propranolol, ns;
`
`ASA> placebo
`
`Conclusions
`Investigators'
`
`Frequency
`
`3 mo
`
`Frequency, severity
`
`Frequency, headache index•
`
`(2 wk washout)
`
`Frequency
`
`Parameter
`Efficacy
`
`Treatment
`Duration of
`
`m
`
`4 wk (no drug)
`
`Nil
`
`Nil
`
`76 (56)
`
`39 (31)
`
`38 (31)
`
`8 wk placebo
`
`176 (151)
`
`2 wk placebo
`
`170 (129)
`
`2 wk placebo
`
`2 wk placebo
`
`6wk x 2
`
`2 mo (no drug)
`
`8wk
`
`4 wk open
`
`3 mo x 2
`
`Nil
`
`3 mo x 2
`
`30 days open
`
`3 mo x 2
`
`Nil
`
`51 (33)
`
`34 (28)
`
`28
`
`28 (21)
`
`30(29)h
`
`38 (27)
`
`18 (12)
`
`12
`
`co
`
`co
`co
`
`Pa
`
`Pa
`
`co
`co
`co
`co
`Pa
`
`co
`co
`co
`
`Propranolol 40 tid
`Tolfenamic acid 100 tid
`Placebo tid
`Propranolol 40 tid
`Tolfenamic acid 100 tid
`Placebo tid
`Tolfenamic acid 100 tid
`Placebo tid
`Pizotifen 0.5 tid
`Naproxen-sodium 550 bid
`
`Placebo
`Propranolol 40 tid
`Naproxen-sodium 550 bid
`Placebo bid
`Naproxen-sodium 550 bid
`Placebo bid
`Naproxen-sodium 550 bid
`Placebo bid
`Naproxen 250 bid
`ASA 1,500 ad
`Metoprolol 200 od
`Flunarizine 5-10 od
`ASA 100-200 ad
`Placebo ad
`ASA 160 od
`Propranolol 0.6/kg tid
`ASA 4.5/kg tid
`Placebo bid
`ASA 650 bid
`
`(21)
`
`(20)
`
`(19)
`
`(17)
`
`(18)
`
`(8)
`
`(4)
`
`(16)
`
`(10)
`
`(13)
`
`(6)
`
`(9)
`
`(11)
`
`(no. Evaluated) Run-in Period
`
`Design
`Study No. of Patients
`
`Trial Dosage {mg)
`
`Drug and
`
`with Placebo and Other Drugs in the Prophylaxis of Migraine
`t\ TABLE 58-1 Double-Blind Randomized Clinical Trials Comparing NSAIDs
`
`

`

`ASA= aspirin; ns = not significant; ad= once daily; bid= twice daily; tid = three times daily; co= crossover;
`
`pa= parallel-groups comparison; wk= week(s); mo= month(s); > = more effective than.
`
`c= frequency x severity.
`b= children, 7 to 17 years old
`a= frequency x severity x duration
`
`Flurbiprofen > placebo for intensity but
`
`Intensity, frequency
`
`not for frequency
`
`for frequency
`
`Rofecoxib > placebo for responders; ns
`
`Responders, frequency
`
`Metoprolol > ASA for all parameters
`
`lndobufen > placebo for all parameters
`
`ns
`parameters; fenoprofen 200 vs placebo,
`
`Fenoprofen 600 > placebo for all
`
`Frequency, responders
`
`index', evaluation of treatment
`
`Frequency, duration, headache
`
`medication
`
`Frequency, headache index,
`
`(2 wk washout)
`
`8 wk x 2
`
`3 mo
`
`4 mo
`
`Nil
`
`2 mo
`
`4 wk placebo
`
`3 mo
`
`4 wk (no drug)
`
`23
`
`175 (147)
`
`270 (115)
`
`42 (35)
`
`co
`Pa
`
`Pa
`
`Pa
`
`12 wk
`
`4 wk placebo
`
`118(110)
`
`Pa
`
`> placebo; severity and duration, ns
`
`Frequency, mefenamic acid= propranolol
`
`parameters
`
`Frequency, duration, severity
`
`Ketoprofen > placebo for both
`
`Headache index', headache days
`
`3 mo x 3
`
`(1 wk washout)
`
`6wk x 2
`
`1 mo open
`
`Nil
`
`29 (17)
`
`26 (24)
`
`co
`co
`
`Placebo bid
`Flurbiprofen100 bid
`Placebo bid
`Rofecoxib 12.5 bid
`Metoprolol 200 od
`ASA 300 ad
`Pl bid
`lndobufen 200 bid
`Placebo tid
`Fenoprofen 600 tid
`Fenoprofen 200 tid
`Placebo tid
`Propranolol 80 tid
`Mefenamic acid 500 tid
`Placebo tid
`Ketoprofen 50 tid
`
`(26)
`
`(27)
`
`(12)
`
`(25)
`
`(24)
`
`(23)
`
`(22)
`
`Conclusions
`Investigators'
`
`Parameter
`Efficacy
`
`Treatment
`Duration of
`
`Run-in Period
`
`(no. Evaluated)
`No. of Patients
`
`Design
`Study
`
`Trial Dosage (mg)
`
`Drug and
`
`(Continued)
`with Placebo and Other Drugs in the Prophylaxis of Migraine
`. TABLE 58-1 Double-Blind Randomized Clinical Trials Comparing NSAIDs
`
`~
`u,
`
`

`

`Nonsteroidal Anti-Inflammatory and Miscellaneous Drugs in Migraine Prophylaxis
`
`557
`
`was superior to placebo with respect to the responder rate
`but not to the absolute decrease of migraine frequency;
`there were no sign incant differences in the rate of adverse
`events between rofecoxib and placebo (27).
`Gastrointestinal problems were the most common side
`effects during NSAID lreatment, including dyspepsia and
`diarrhea, bul Lheir frequencies of occt11Tence were gene1-(cid:173)
`ali) not greater than those encountered in SL1bjects who
`took placebo, probably because of the relatively mall size
`0 (' the trials. In only one trial (naproxen sodium) was
`it necessary for a patient to withdraw because of peptic
`ulceration ( 17). The possibility that rofecoxib (recently
`withdrawn in everal countries) and other elective
`cvclooxvgenase-2 inhibitors may increase the risk of ad(cid:173)
`verse cardiovascular events might preclude their use in
`migraine prophylaxis.
`
`Menstrual Migraine
`Since about 50% of women migraineurs suff