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APRIL 2006

A SPECIAL REPORTfrom

CME Activity:A CME ActivitySponsored by ScientaHealthcare Education®

Release Date:April 2006

Expiration Date:April 30, 2007

Estimated Time toComplete Activity:2.0 hours

Targeting Multiple Mechanisms:New Advances in Migraine Treatment� An update on migraine pathophysiology and

mechanism-based pharmacotherapeutics for migraine� Migraine headaches: Treatment limitations and opportunities� Combination therapy in acute migraine treatment:

The rationale behind the current treatment options� Use of combination therapy in migraine: A review of the clinical evidence

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This Postgraduate Medicine Special Report, “TargetingMultiple Mechanisms: New Advances in MigraineTreatment,” was sponsored and prepared for publication by Scienta Healthcare Education® and supported by aneducational grant from GlaxoSmithKline.

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A SPECIAL REPORT STAFF

1MIGRAINE • A POSTGRADUATE MEDICINE SPECIAL REPORT

CONTENTS

Stephen Brunton, MD 4 INTRODUCTION

Roger Cady, MD 5 AN UPDATE ON MIGRAINE PATHOPHYSIOLOGY AND David Biondi, DO MECHANISM-BASED PHARMACOTHERAPEUTICS FOR MIGRAINE

Robert Kaniecki, MD 14 MIGRAINE HEADACHES Susan Hutchinson, MD TREATMENT LIMITATIONS AND OPPORTUNITIES

Stephen Silberstein, MD 20 COMBINATION THERAPY IN ACUTE MIGRAINE TREATMENT Gary Ruoff, MD THE RATIONALE BEHIND THE CURRENT TREATMENT OPTIONS

Frederick Taylor, MD 27 USE OF COMBINATION THERAPY IN MIGRAINE Timothy Smith, MD A REVIEW OF THE CLINICAL EVIDENCE

32 CME POST-TEST

2 MIGRAINE • A POSTGRADUATE MEDICINE SPECIAL REPORT

A SPECIAL REPORT

CME

Statement of needA main therapeutic goal inmigraine is to achieve rapid free-dom from pain, thereby allow-ing return to normal function-ing. Over recent years, muchwork has been done to furtherthis goal. Basic science researchhas yielded new informationabout the pathologic processesunderlying migraine, most ofwhich primarily affect thetrigeminovascular system.Likewise, complementary clini-cal research initiatives have ledto the development and evalua-tion of optimal migraine man-agement strategies. Use of multi-mechanism combination thera-py is one such strategy. Itinvolves aborting migraineattacks via use of more than onepharmacotherapeutic agent sothat limitations of monotherapycan be overcome; for example,multiple mechanisms can be tar-geted and synergy betweenagents can be established. As useof this strategy evolves, deliveryof clinical content and skillstraining through ongoing med-ical education activities is war-ranted. This CME supplementprovides useful information tohelp meet this need.

Educational objectivesAt the conclusion of this activi-ty, participants should be able to • Identify specific mechanisms

that underlie the pathogenesisof migraine.

• Describe the benefits andchallenges associated with useof monotherapy to abortmigraine attacks.

• Explain how using therapy totarget multiple mechanismsin migraine can improvepatient outcome.

Target audienceThis activity is designed for pri-mary care providers, neurolo-gists, headache specialists, andother healthcare professionalswho have an interest in thediagnosis and treatment ofmigraine.

Accreditation Scienta Healthcare Education®

is accredited by theAccreditation Council forContinuing Medical Educationto sponsor continuing medicaleducation for physicians.

Designation statementScienta Healthcare Education®

designates this educational activity for a maximum of 2.0AMA PRA Category 1 Credits™.Physicians should only claimcredit commensurate with theextent of their participation inthe activity.

To receive CME credit and acertificate, participants shouldsubmit a completed post-test atthe conclusion of this activity.Certificates will be mailed within 4 weeks.

SupportedThis CME activity is supportedby an educational grant fromGlaxoSmithKline.

Faculty financial disclosuresIt is the policy of ScientaHealthcare Education® that allparties participating in continu-

ing medical education activitiesare expected to disclose to theprogram audience any (1) realor apparent conflict(s) of inter-est related to the content oftheir articles and (2) mention ofunlabeled or unapproved uses ofdrugs or medical devices.

Parties have disclosed thatthey have financial or other rela-tionships with the followingcompanies, some of which maymanufacture products the facul-ty members intend to discuss.

David Biondi, DO, disclosesthat he is a consultant forAstraZeneca PharmaceuticalsLP; Endo Pharmaceuticals;GlaxoSmithKline; Merck & Co,Inc; and Ortho-McNeilPharmaceutical, Inc. He alsoparticipates in the speakersbureaus of GlaxoSmithKline;Merck & Co, Inc; Ortho-McNeil Pharmaceutical, Inc;and Pfizer Inc. Additionally, hediscloses that as of April 3,2006, he is an employee ofOrtho-McNeil Neurologics, Inc.

Stephen Brunton, MD,discloses that he is a consultantto Abbott Laboratories; Ortho-McNeil Pharmaceutical,Inc; and Sanofi-Aventis.

Roger Cady, MD, disclosesthat he is a consultant forAradigm Corporation;GlaxoSmithKline; and Ortho-McNeil Pharmaceutical,Inc. He participates on advisoryboards for Allergan, Inc; Atrix Laboratories, Inc; Capnia, Incorporated; Endo Pharmaceuticals;GlaxoSmithKline; Johnson & Johnson; MedPointePharmaceuticals; Merck & Co, Inc; Ortho-McNeilPharmaceutical, Inc; andWinston Laboratories, Inc. He further discloses that he


receives research support fromAbbott Laboratories; Allergan,Inc; Alexza Pharmaceuticals;Aradigm Corporation; Capnia,Incorporated; CipherPharmaceuticals Inc; Eisai Inc;Endo Pharmaceuticals; GelStatCorporation; GlaxoSmithKline;Johnson & Johnson; MatrixxInitiatives, Inc; Merck & Co,Inc; Novartis PharmaceuticalsCorporation; Ortho-McNeilPharmaceutical, Inc; Pfizer Inc;POZEN; and VernalisPharmaceuticals, Inc.

Susan Hutchinson, MD,discloses that she is a consultantfor Endo Pharmaceuticals;Forest Pharmaceuticals, Inc;GlaxoSmithKline; Ortho-McNeil Pharmaceutical, Inc;and Pfizer Inc. She receivesresearch support fromGlaxoSmithKline. She furtherdiscloses that she participates as part of the speakers bureausof Endo Pharmaceuticals; Forest Pharmaceuticals, Inc;GlaxoSmithKline; Merck & Co Inc; Ortho-McNeilPharmaceutical, Inc; and Pfizer Inc.

Robert Kaniecki, MD,discloses that he is a consultantfor GlaxoSmithKline andOrtho-McNeil Pharmaceutical,Inc. He receives research support from GlaxoSmithKline.Additionally, he is a speakersbureau participant forGlaxoSmithKline; MerckPharmaceutical, Inc; andOrtho-McNeil Pharmaceutical,Inc. He further discloses that hisspouse is a part-time employeeof GlaxoSmithKline.

Gary Ruoff, MD, has noth-ing to disclose.

Stephen Silberstein, MD, discloses that he receivesresearch support from Abbott

Laboratories; AGA; Allergan, Inc; AdvancedNeuromodulation Systems(ANS), Inc; GlaxoSmithKline;Eli Lilly and Company;Medtronic Inc; MerckPharmaceutical, Inc; Ortho-McNeil Pharmaceutical,Inc; Pfizer Inc; and POZEN.He is a speakers bureau partici-pant for GlaxoSmithKline;Merck Pharmaceutical, Inc;Ortho-McNeil Pharmaceutical,Inc; and Pfizer Inc. He furtherdiscloses that he participates onadvisory boards for Allergan,Inc; GlaxoSmithKline;Medtronic Inc; MerckPharmaceutical, Inc; Ortho-McNeil Pharmaceutical,Inc; Pfizer Inc; and POZEN.

Timothy Smith, MD, dis-closes that he is a consultant forAstraZeneca PharmaceuticalsLP; GlaxoSmithKline; andPfizer Inc. He receives researchsupport from AstraZenecaPharmaceuticals LP;GlaxoSmithKline; MerckPharmaceutical, Inc; Ortho-McNeil Pharmaceutical,Inc; Pfizer Inc; and VernalisPharmaceuticals, Inc. Dr Smithfurther discloses that he partici-pates in the speakers bureaus of Merck Pharmaceutical, Inc;Pfizer Inc; and Ortho-McNeilPharmaceutical, Inc.

Frederick Taylor, MD, dis-closes that he is a consultant forAllergan, Inc; AstraZenecaGlaxoSmithKline; and MerckPharmaceutical, Inc. Hereceives research support fromAllergan, Inc; GlaxoSmithKline;Merck Pharmaceutical, Inc; andOrtho-McNeil Pharmaceutical,Inc. He further discloses that he is a speakers bureau participant for Allergan, Inc;AstraZeneca Pharmaceuticals

LP; GlaxoSmithKline; MerckPharmaceutical, Inc; Pfizer Inc;and Valeant PharmaceuticalsInternational.

Other financial disclosuresGabby Cruze, ScientaAssociate Director of MedicalEducation, has nothing to disclose.

Monique Johnson, MD,Scienta Medical Director, hasnothing to disclose.

Katie Pierson, ScientaSenior Program Manager, hasnothing to disclose.

Kim Vadas, Scienta ProgramManager, has nothing to disclose.

Leslie-Ann Brill, MedicalWriter, has nothing to disclose.

Deborah Due, PhD,Medical Writer, discloses thatshe is a stockholder of TEVAPharmaceutical Industries Ltd.

Ron Gasbarro, MedicalWriter, has nothing to disclose.

Disclosures of unlabeled useThis education activity contains discussion regardingdrugs and/or uses of drugs thatare under investigation and notyet approved by the US Foodand Drug Administration. Forofficial description of eachdrug discussed, please refer to the approved prescribinginformation.

DisclaimerThe opinions expressed hereinare those of the authors. Theydo not necessarily reflect theviews of the CME providerand are not attributable togrant sponsors or to the pub-lisher, editor, or editorial boardof Postgraduate Medicine.

A SPECIAL REPORT


Introduction

Stephen Brunton, MD

■ Over the past decade, thearmamentarium used to treatmigraine has grown, andmigraine care has been greatlyoptimized. Despite enormousprogress, however, use ofmonotherapy to abort migraineattacks leaves room for improve-ment. Thus, multimechanismtherapy—the use of 2 or morecarefully matched therapeuticagents administered togetherand aimed at different underly-ing pathologic processes—hasbecome the focus of increasedattention in recent years and will be spotlighted in this supplement.

Featured in this supplementare 4 important articles thattake the reader from a concep-tual understanding of migrainepathophysiology to an explo-ration of relevant patient out-comes. An authoring teamconsisting of one neurologyspecialist and one generalist has written each article in orderto present a balance of scientif-ic, clinical, and practical per-spectives. I offer sincere thanksto the distinguished facultywho have contributed.

The first article, by Cadyand Biondi, reviews the cur-

rently existing hypothesesregarding migraine pathophysi-ology, with emphasis on specific mechanisms within the trigeminovascular system.Knowledge of these mecha-nisms provides a conceptualframework for understandingthe antimigraine targets that serve as the basis for current and emerging pharma-cotherapy options for migraine.

The second article, byKaniecki and Hutchinson, outlines current empiric dataabout the drug classes anddelivery systems most com-monly used as abortive therapyfor migraine and identifiesexisting and emerging drugformulations. For each classand delivery system, theadvantages are highlighted and the limitations are articu-lated to uncover opportunitiesto improve their usefulness and address clinical challenges.

The latter 2 articles discussthe rational use of multimech-anism polytherapy formigraine and share relevantclinical outcomes data. Thearticle by Silberstein and Ruoff explains how the pharmacodynamic and

pharmacokinetic interplaybetween 2 carefully chosenagents can be capitalized upon to develop enhancedtherapy regimens. This articlepersuasively argues for use ofmultimechanism therapy bypointing out its biologic plausibility and long traditionof successful use for treatingother chronic medical condi-tions. In the concluding arti-cle, Taylor and Smith reviewclinical studies that used dualtherapy or polytherapy formigraine.

Overall, the goal here is toensure that prescribing clini-cians appreciate the comple-mentary modes of action ofagents commonly used asabortive therapy for migraineattacks. That appreciation will help clinicians determinehow agents can be combinedin a multidrug regimen toachieve optimal therapeuticoutcomes. I hope that this supplement will provide youwith timely and insightfulinformation that proves invaluable to your clinicalpractice as you construct optimal therapeutic regimensfor migraine patients. ■

MIGRAINE • A POSTGRADUATE MEDICINE SPECIAL REPORT 5

A SPECIAL REPORT

An update on migrainepathophysiology andmechanism-based pharmacotherapeuticsfor migraine

Roger K. Cady, MD, and David M. Biondi, DO

PreviewThe pathophysiologic mechanisms of migraine are complexbut appear to primarily involve the trigeminovascular system.Within this system, a number of factors may contribute to thegeneration and perpetuation of pathophysiologic changesleading to migraine. Current migraine medications exert theirtherapeutic benefit via actions at various points relating tothese pathophysiologic changes. However, no single agentcurrently exists that targets all the hypothesized anatomicaland cellular mechanisms of the migraine process. A futurestrategy for achieving optimal therapeutic effect and improv-ing clinical outcomes in migraine involves rational targetingof the multiple mechanisms involved in its pathophysiology;conceptually, this may require concomitant use of multiplepharmacotherapeutic agents.

IntroductionMigraine is a common disorderafflicting approximately 9% ofindividuals in western countriesand 11% of Americans in partic-ular.1 Among those individualswith migraine, disability is high,with over half reporting thatmigraine has a severe impact ondaily life.1 Although much of thedisability from migraine can be

attributed to patients who fail toseek treatment, more than twothirds of treated patients reportthat therapy is not consistentlyeffective.1 The advent of triptansinto the marketplace over adecade ago has done much toadvance effectiveness of migrainetherapy; however, triptans arenot a panacea for all patients,and further therapeutic improve-

ments are needed. Often thera-peutic failure is attributable notonly to medication alone butalso to limited understanding ofthe disease process and failure toemploy appropriate treatmentstrategies.

One important key to theimprovement of migraine treat-ment lies in fully understandingmigraine pathophysiology. Thisknowledge will inspire targeteddevelopment of future therapiesand optimal use of currentlyexisting therapies. Unfortu-nately, the pathophysiology ofmigraine is complex and not yetfully understood; however, anumber of neural substrates, circuits, and endogenous sub-stances have been implicated in the various stages of themigraine process. With emerg-ing developments and improvedunderstanding of migrainemechanisms, we can begin toexplain some of the previouslyinexplicable clinical features of amigraine attack and its variableresponse to pharmacologic treat-ments. This article reviews cur-rent hypotheses on the variousprocesses involved in migrainepathophysiology and the phar-macologic actions of commonlyused migraine medications.

Susceptibility to migraineStudies in twins suggest that theorigin of migraine has both agenetic and environmental com-ponent.2 Studies in patients withfamilial hemiplegic migraine, arare form of migraine, have pro-vided insight into a possiblegenetic origin of migraine andindicate that mutations produc-ing neuronal membrane chan-nelopathies may play a role inthe susceptibility to migraine.3

These channelopathies are

hypothesized to produce neu-ronal hyperexcitability; that is,they lower the threshold forneuronal firing in patients withmigraine. Other abnormalitiessuch as mitochondrial dysfunc-tion and low concentrations ofcellular or circulating magne-sium may also play a role inneuronal hyperexcitability.4

Whether any or all of theseabnormalities exist in mostmigraine patients, includingthose with the most commonform of migraine—migrainewithout aura—is unknown.

Studies employing functionalmagnetic resonance imaging(fMRI) and transcranial magnet-ic stimulation (TMS) supportthe notion of neuronal hyperex-citability in migraine. Stimula-tion of occipital cortex via aTMS device was shown to produce visual phenomena offlashing or sparkling lights(phosphenes) at a stimulationintensity that was lower inpatients with migraine com-pared with control subjects. Furthermore, headaches weretriggered by TMS in the majori-ty of these migraineurs althoughno control subjects reportedheadache.5 fMRI studies ofspontaneous or visually inducedaura also imply an abnormalityin neuronal excitability in theoccipital cortex of migrainepatients.6,7 Results from thesestudies suggest that the electro-physiologic correlate of migrainevisual aura manifests as a slowlyspreading wave of neuronaldepolarization followed by alonger-lasting suppression of neuronal activity in the occipital cortex. This neurogenicphenomenon (termed corticalspreading depression or CSD) wasfirst demonstrated by Aristides

Leao in the 1940s using directstimulation of rabbit cerebralcortex8 and has been observed in a variety of experimental paradigms since that time. Theinitiator of CSD in clinicalmigraine is not known, but it may arise from disruptions in central inhibitory neuromod-ulation incited by migraine trig-gers.9 As this dysmodulation ofinhibitory processes progresses, a critical excitatory threshold isreached, and CSD is initiated.The hypotheses regarding thepotential significance of CSD tothe initiation of the migraineprocess are discussed below.

Initiation of the migraine process

CORTICAL SPREADING

DEPRESSION—To investigate the mechanisms by which CSDmay trigger migraine, Bolay et alstudied CSD in a rat model.10

After a pinprick or electricalstimulation of the cortex, CSDwas propagated across the corti-cal surface. Transient increasesoccurred in cortical blood flowbut prolonged increases in bloodflow were detected in the middlemeningeal artery (MMA). Aftertransecting trigeminal nerveinnervation to the meninges, theexperiment was repeated and theprolongation of increased bloodflow in the MMA was abolished.On the basis of these and otherlaboratory findings, Bolay andcolleagues proposed a mecha-nism for migraine initiationwhereby CSD initiates release ofneuroactive substances (K+, H+,neurotransmitters, nitric oxide,and arachidonic acid) into theextracellular and perivascularspace to cause depolarization of trigeminal nerve endingsaround meningeal blood vessels.10

By this mechanism, it is hypoth-esized that intracerebral events(ie, CSD) are able to triggeractivation of extracerebral neuronal structures (trigeminalnerve terminals) in themeninges. In patients withmigraine aura, CSD is thoughtto occur in cortical areas capableof generating clinical symptomssuch as migrating visual or sen-sory phenomena. In cases ofmigraine without aura, it hasbeen proposed that CSD occursin “silent” brain areas,11 althoughthis has yet to be proved.

AUTONOMIC NERVOUS SYSTEM

DYSFUNCTION—Autonomic nervous system dysfunction isbelieved to play a significant rolein migraine pathophysiology12-14;however, the precise mechanismof its contribution has beenunder considerable debate. Tworecent theories suggest thateither sympathetic15 or, alterna-tively, parasympathetic dysfunc-tion16 play a predominant role inthe triggering of migraine,although these theories mightnot be mutually exclusive.

Peroutka recently reviewedthe published data on auto-nomic function in migraineursand found that many physio-logic measures and clinical fea-tures in these patients (such asplasma norepinephrine [NE]levels, adrenergic receptor supersensitivity, and orthostaticsymptoms) were indicative ofsympathetic nervous systemhypofunction.15 Based on thisreview, he proposed that sympa-thetic hypofunction might beinvolved in the initiation ofmigraine. According to thishypothesis, genetically vulnera-ble individuals, when subjectedto stress, may experience a pro-longed or excessive activation of


the sympathetic nervous system.As demonstrated in animal mod-els, this excessive sympatheticstimulation may eventually resultin depletion of NE, while levelsof sympathetic cotransmitters(for example, dopamine, adeno-sine, and prostaglandins) areincreased. At some point (afteran initial vasoconstrictive phase),the net effect of this process isvasodilation of meningeal vesselsbecause of reduction in the vaso-constrictive effects of NE incombination with vasodilatoryeffects of the cotransmitters. Furthermore, because the sym-pathetic nervous system normallyhas an inhibitory influence onthe trigeminal system, trigeminalneurons might become disinhib-ited by diminished sympatheticfunction. Therefore, trigeminalactivation during a migraineattack could be triggered or facil-itated by changes in the sympa-thetic nervous system duringtimes of stress.15

Burstein and Jakubowski have also suggested that theautonomic nervous system isinvolved in migraine generation,but with a focus on parasympa-thetic dysfunction.16 They citeclinical observations of parasym-pathetic hyperfunction inmigraine patients during attackssuch as the common occurrenceof lacrimation, rhinorrhea, and nasal congestion as well asevidence that blockade of thesphenopalatine ganglion (aparasympathetic ganglion) canreduce migraine pain. Otheranatomic and physiologic evi-dence—such as the dense inner-vation of meningeal bloodvessels by parasympathetic fibersand the ability of meningealnociceptor activation to increaseactivity in the superior salivatory

nucleus (SSN) (a parasympa-thetic nucleus) in the brain-stem—also suggests a potentialfor parasympathetic involvementin migraine. These authors pro-pose that the SSN is a commonlocus in neuronal pathways thatare activated by various potentialmigraine triggers (for example,smells, food or sleep depriva-tion, or stress) via projectionsfrom the cortical, hypothalamic,and brainstem areas related tothose triggers. It is hypothesizedthat impulses from the SSN aretransmitted by parasympatheticefferent fibers to the sphenopala-tine ganglion and, ultimately,the meninges and meningealblood vessels, resulting in terminal release of acetylcholine,vasoactive intestinal peptide(VIP), and nitric oxide, therebyinitiating a cascade that leads totrigeminovascular activation(described in detail below).16

Both Peroutka’s (2004) andBurstein and Jakubowski’s(2005) hypotheses are attractivebecause they have the potentialto explain the pathogenesis of migraine in patients whohave migraine without aura. It has been troubling to someresearchers that the initiation of migraine in patients whodon’t experience aura had to beexplained on the basis that CSDwas occurring in clinically silentbrain areas (with little evidenceto support this theory).17

However, with either of the theories stated above, CSD is not a necessary component of migraine pathogenesis.Migraine can be triggered bystress or other events that lead tomeningeal vasodilation, withoutCSD as a part of the process.

Other differences in the earlysymptoms of migraine with aura

and migraine without auraremain to be explained on thebasis of pathophysiology. Forinstance, migraine with auratypically has an abrupt onset(for example, a visual aura maybe immediately triggered by abright flash of light withheadache emerging shortly afterthe aura), while migraine with-out aura tends to develop moreslowly and may be preceded by a lengthy premonitory orprodrome phase. During thisprodrome, patients experiencenonspecific symptoms such asmood or cognitive changes,increased sensory sensitivity, orfood cravings.9 The physiologicmechanisms underlying thesenonspecific symptoms are notunderstood, but it has beenhypothesized that diffuse, non-focal changes in various brainareas (cortical and hypothalam-ic) and in neurotransmitter systems may be responsible.9

Further study is needed to eluci-date the specific pathophysio-logic mechanisms of prodromeand the differences betweenmigraine with and without aura.

Mechanisms of head pain and other migraine symptoms

NEURAL CIRCUITRY OF HEAD

PAIN AND RELATED SYMPTOMS—The meninges, as intracranialstructures with significant sen-sory innervation, are believedto be a principle source of headpain in migraine. A generallyaccepted pathway for genera-tion of this pain begins withdepolarization of perivasculartrigeminal nerve endings in pia mater—initiated by somedirect trigger or reflex, andpotentially described in any ofthe scenarios above or another,as yet, undefined mechanism.



Activation of pial nerve endingstransmits impulses to the dura, stimulating release ofvasoactive substances (for example, calcitonin gene-relatedpeptide [CGRP], substance P,neurokinin A) in meninges.These impulses also transmitcentrally through the trigeminalganglion to the trigeminalnucleus caudalis (TNC) in thebrainstem. The impulses thencontinue through the TNC via2 pathways: one pathway trans-mits through the thalamus tocortical areas where head pain isperceived, and another pathwaytransmits impulses back up tothe meninges via a parasympa-thetic arc through the SSN and sphenopalatine ganglion(Figure 1).10

Activation within thetrigeminovascular circuit mayalso account for some of the

associated symptoms ofmigraine. Activation of theparasympathetic portion of thepathway may provoke the nasalsymptoms that often accompanymigraine.18 Similarly, the neckpain and stiffness that are commonly reported duringmigraine19 may be generated asa result of functional conver-gence of trigeminal neurons inthe TNC and upper cervicalspinal nerves.20 Recruitment orfunctional convergence withother brainstem regions in close proximity to the TNCmight underlie other migrainesymptoms such as nausea, vomiting, photophobia, andphonophobia.21

Additionally, it is importantto note that nontrigeminalbrainstem nuclei (for example,periaqueductal gray, locusceruleus) may play a role in

the generation or modulation of migraine head pain.3

NEUROGENIC INFLAMMATION

AND PERIPHERAL SENSITIZA-TION—After the initial triggerfor migraine (for example, awave of CSD) and its conse-quential effect on the trigeminalsystem subsides, how does paincontinue to be generated withinthe trigeminovascular system?One explanation suggests that neurogenic inflammationcontributes to the continuedgeneration of head pain.22 Sincetrigeminal and parasympatheticnerve activation stimulates therelease of vasodilatory andinflammatory substances fromnerve terminals (for example,substance P,23 neurokinin A,23

CGRP,23,24 VIP,25 and prosta-glandins24), this theory positsthat vasodilation and plasmaprotein extravasation (PPE) or

Figure 1. Proposed mechanism for the initiation of migraine headache pain by a wave of cortical spreading depression (CSD). CSD causes release of substances (eg, K+, H+, nitric oxide, adenosine, archidonic acid [gray circles]) that activate perivasculartrigeminal afferents sending impulses through the trigeminal ganglion (TG) to the trigeminal nucleus caudalis (TNC) (arrows 1, 3, and 4). Impulses from the TNC transmit rostrally to thalamus and cortical areas that process pain. Activation of TNC also leads tostimulation of the superior salivatory nucleus (SSN) (arrow 5) from which impulses are carried to the sphenopalatine nucleus (SPG)and back to the meninges (arrow 6), where vasoactive substances (VIP, nitric oxide, and acetylcholine [black circles]) are released.Direct or indirect (arrow 2) activation of dural trigeminal nerve endings results in release of substance P, CGRP, and neurokinin A(gray triangles), which may result in vasodilation and plasma protein extravasation.10

Reprinted by permission from Macmillan Publishers Ltd: Nature Medicine. Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA,Moskowitz MA. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med. 2002;8:136-142, ©2002.

TG

3

4 5

SSN

TNC

Duralvessel

blood flowvasodilationprotein extravasation

Dura mater

Cerebral Cortex

Brainstem

Rostral Brain Areas

Pialvessel

CSD

c-fos expression

6

1

2

SPG

a neurogenic inflammatoryprocess is produced in themeninges. After the initial activa-tion of trigeminal nerve termi-nals by the migraine trigger, thisprocess of neurogenic inflamma-tion may take over, producing avicious cycle of neuropeptiderelease and perivascular trigemi-nal nerve activation. Sensoryimpulses would be continuouslygenerated and the ensuing cascade of cellular and molecularevents would produce hypersen-sitivity of trigeminal sensory terminals to stimuli that are normally innocuous, such as pulsating arteries or head move-ment after the original activatingtrigger has ceased.26 Duringmigraine, these stimuli becomethe basis for many of the painfulcharacteristics of migraine suchas throbbing and pain with headmovement. This cycle of activa-tion is the peripheral sensitizationphase of migraine.27

This theory has been chal-lenged recently, however. Someinvestigators have suggested thatthe scientific evidence supportsonly the vasodilatory compo-nent of neurogenic inflamma-tion (primarily an effect ofCGRP) but not PPE as a signifi-cant factor in peripheral sensiti-zation.28,29 Most recently, theimportance of CGRP-inducedvasodilation has been questionedas well. Using electrophysiologicmonitoring in a rat model, Levyand colleagues demonstratedthat topical or systemic adminis-tration of CGRP provokedvasodilation in dural vessels butdid not activate or sensitizemeningeal nociceptors.30

CUTANEOUS ALLODYNIA

AND CENTRAL SENSITIZATION—Sensory signals generated in theskin by normally nonnoxious

stimuli such as hair combing,shaving, or touching the scalpare often reported as painful or unpleasant during migraineattacks.31 This clinical phenome-non is termed cutaneous allody-nia and is believed to result fromsensitization of central trigemi-nal pathways, specifically withinthe TNC. This sensitizationoccurs as a result of the constantbarrage of impulses into theTNC from the already sensitizedtrigeminal nociceptors in thedura. Since the TNC alsoreceives input from peripheralsensory nerves that serve theskin and muscles of the neckand upper torso, sensory signals from these areas can bemisinterpreted and cause theseextracranial regions to becomehypersensitive to sensory stimuli.31 A recently proposedmolecular mechanism for central sensitization stipulatesthat after peripheral nociceptorsbecome sensitized, neurons and glia in the TNC becomeactivated, causing release ofprostaglandins. Neuronal releaseof prostaglandins is believed tofacilitate prostaglandin releasefrom the glia. The release ofprostaglandins from glia com-pletes a self-sustaining loop ofexcitation by promoting hyper-excitability in nearby neurons(neuronal recruitment).32 Viathis mechanism, the TNC canbe activated even in the absenceof input from peripheral noci-ceptors. This mechanism is supported by evidence from aclinical study that showed effec-tiveness of IV ketorolac (a non-steriodal anti-inflammatory drug[NSAID] that prevents forma-tion of prostaglandins) inmigraine patients with allodynia(in other words, after central

sensitization had developed).32

Additionally, in a rat model ofmigraine, electrophysiologicrecordings showed that bothketorolac32 and naproxen33 wereable to desensitize sensitizedTNC neurons. Clinical studieswith oral NSAIDs are needed tofurther test this hypothesis.

Mechanism of action for common abortive migraine therapiesAs noted above, several impor-tant molecules and brain path-ways have been identified aspotentially major contributors tomigraine pathophysiology. Inorder to appreciate the distinctactions of commonly prescribedmigraine therapies, their putativeimpact on these pathophysiologicmechanisms is reviewed below.

TRIPTANS AND ERGOTS—Triptans and ergots are consid-ered migraine-specific medica-tions because of their agonistactions at 5HT1B and 5HT1Dreceptors, receptors believed tobe localized at strategic positionswithin the trigeminovascularsystem. There are at least 3actions of 5HT1B/1D agoniststhat may inhibit potentiallyimportant processes within thismigraine-producing system.21,29

1. Direct vasoconstriction ofmeningeal vessels. Activationof 5HT1B receptors on smoothmuscle in meningeal bloodvessels provides a vasocon-strictive action. This vasocon-striction counteracts thevasodilatory component ofneurogenic inflammation, aprocess that may contributeto peripheral sensitization.

2. Inhibition of neuropeptiderelease in meninges. Activa-tion of presynaptic 5HT1Dreceptors on perivascular


trigeminal nerve endingsinhibits release of substance P and CGRP, therebydecreasing both the PPE andvasodilatory components ofneurogenic inflammation.

3. Inhibition of central neuro-transmission in the TNC.Activation of presynaptic5HT1D receptors on centralaxonal projections of thetrigeminal nerve to the TNCinhibits release of substance P,CGRP, and glutamate tointerrupt pain impulses fromthe periphery. These actionsmay prevent or inhibit thedevelopment of central sensitization.In clinical studies, early use

of triptans, during mild pain orbefore development of allodynia,has proven more effective thanusing them at later stages. Pain-free response is greater at 2 hours posttreatment34,35 andpain freedom is achieved earlier,36

presumably because central sensitization is avoided. Recentlaboratory work by Levy and colleagues suggests that it is the central actions of 5HT1B/1Dagonists that are the most criticalfor their migraine efficacy. Inelectrophysiologic studies whereinflammatory mediators wereapplied to rat dura mater, sumatriptan was unable to block their peripheral effects(increased firing rates in trigemi-nal ganglia) even when adminis-tered simultaneously with themediators. However, sponta-neous firing rates in central neurons (TNC) were decreasedby sumatriptan when it wasgiven early, before developmentof central sensitization.37

Results from these studieshave thus prompted recommen-dations for early intervention

with triptans. Despite the controversy that has developedaround this treatment strategyregarding the possibility that thedesigns of the clinical studiesthat evaluated early interventionwere biased towards a positiveoutcome,38 our clinical experi-ence continues to suggest thatearly treatment, while migrainepain intensity is still mild,improves outcome.

Other central (but non-trigeminal) sites of action havebeen suggested for 5HT1B/1Dagonists. The periaqueductalgray is a possible site since nara-triptan injections into it decreaseresponse of the TNC to duralstimulation.39 Additionally,5HT1B/1D agonists may exertantiemetic actions via 5HT1Dreceptors in the solitary tractnucleus, a structure known tomodulate pain-induced nauseaand vomiting.21 Whether triptans are able to exert actionin these regions of the central nervous system in routine clinical use is unknown.

Although the mechanismresponsible for the efficacy oftriptans and ergots is similar(related to 5HT1B/1D receptoragonism), their adverse eventprofiles differ because of thenonselective effects of ergots.Ergots’ affinity for other 5HTreceptors, in addition to adren-ergic and dopaminergic recep-tors, is likely responsible fortheir side effect profile. Nausea,vomiting, weakness, and vasculareffects are prominent side effects with ergots, although the tolerability profile of dihydroergotamine is somewhatimproved.21 Both triptans andergots are contraindicated inpatients with ischemic cardiac,cerebrovascular, or peripheral

vascular disease, and concomi-tant use of these drugs is prohibited in all patients.

NSAIDS—NSAIDs are a classof analgesic drugs that reducepain and inflammation at leastin part by inhibiting formationof prostaglandins. This inhibi-tion takes place becauseNSAIDs block cyclooxygenases(specifically COX-1 and/orCOX-2) from converting arachi-donic acid to prostaglandin G, the rate-limiting step in theprostaglandin cascade.40 There-fore, the efficacy of NSAIDs inmigraine41-43 is likely a result oftheir antiprostaglandin effectswithin migraine pathophysiolo-gy. Although the precise role ofprostaglandins within migraineis not established, it is knownthat infusion of prostaglandinE1 precipitates headache in control subjects 44 and prosta-glandins are elevated in thejugular blood of migraineursduring migraine.45 On a molecu-lar level, prostaglandins decreasefiring thresholds of neurons,increase neuronal response to asuprathreshold stimulus, andaugment release of substance P and CGRP, which allows their participation in neurogenicinflammation and hyperalgesia.46

It is possible that prostaglandinsmay affect at least 3 crucialphases of the migraine process as noted in the above discussionof pathophysiology. The effectsof NSAIDs on prostaglandinswithin these phases of migrainemay include the following: 1. Reduction in probability that

a migraine is triggered.NSAIDs may reduce hyperex-citability of neurons and theprobability of triggeringmigraine in at least 2 ways:(1) They may block the


formation of prostaglandinsfrom arachidonic acidreleased by CSD.10 Thisaction would decrease hyper-sensitivity in perivasculartrigeminal nerves, potentiallyavoiding the initial neuralactivation required to gener-ate migraine. (2) Similarly, if migraine patients haveincreased basal (interictal)prostaglandin levels becauseof sympathetic hypofunc-tion,15 NSAIDs may decreasethese levels, thereby reducingthe chances that a migrainewill be triggered. The pro-posed actions of NSAIDs onmigraine initiation mayexplain their efficacy in theprevention of migraine.47-49

2. Inhibition of neurogenicinflammation. Prostaglandinrelease may be stimulated by activation of trigeminalnerves and can contribute toneurogenic inflammation inthe meninges.24 NSAIDs, by blocking prostaglandinsynthesis, would potentiallyreduce peripheral sensitiza-tion via reduction of vasodila-tion and PPE.

3. Abolishment of establishedcentral sensitization. If sensi-tization of the TNC occursbecause of prostaglandinrelease in neurons and glia, asproposed by Jakubowski andcolleagues (see above), thenthe ability of NSAIDs toinhibit this release explainstheir apparent capacity to interrupt established sensitization.32

OPIOIDS—Opioids are narcotic analgesics with wide-spread effects in the nervoussystem. Most opioid analgesicsused for migraine bind prefer-entially to µ-opioid receptors

and are agonists at this recep-tor.50 Butorphanol nasal spray,a mixed �-opioid agonist/µ-opioid partial agonist,50 isthe only opioid with provenefficacy in migraine.51

The mechanism of opioidanalgesia is complex, but theprimary actions in somatic painrelief can be described briefly.Opioids relieve physical painby inhibiting ascending painsignal transmission at the level of the spinal cord dorsalhorn while they also activatedescending pain inhibitorypathways in the periaqueductalgray and medulla that projectto the dorsal horn. Modulationof the emotional componentsof pain (that is, the distresscaused by physical pain) byopioids is believed to occur inlimbic structures.52

A mechanism for opioidanalgesia that is specific tomigraine pain has been recentlyproposed and includes sub-strates that are also involved intriptan pain relief 50:1. Inhibition of CGRP release

in meninges. Animal studiesindicate that opioids blockrelease of CGRP fromtrigeminal nerve endingsand inhibit vasodilationcaused by trigeminal nervestimulation. This action mayinhibit neurogenic inflam-mation and peripheral sensitization.

2. Inhibition of central neuro-transmission in the TNC.Similar to triptans, opioidsare believed to act at presy-naptic receptors on centraltrigeminal projections to pre-vent impulse transmission toTNC neurons. By doing so,opioids may prevent devel-opment of central sensitiza-

tion that occurs followingmeningeal vasodilation. However, it is important to

note that the abuse potentialand sedative properties of opi-oids limit their use, and theyare recommended in migraineonly when other agents arecontraindicated or ineffective.51

BARBITURATES—Barbituratesare CNS depressants withactions throughout the CNS.This depressant effect is primarily mediated viaenhancement of GABAergicneurotransmission at GABAAreceptors and inhibition of glutamateric transmission atAMPA receptors.53 Within the trigeminovascular system,barbiturates may inhibit thetransmission of pain signals in the TNC via GABAAreceptors.54 Whether this action occurs primarily at apresynaptic or postsynapticlocation is unknown; however,evidence suggests that postsy-naptic receptors on the TNCare the most likely site ofaction.55 Barbiturates are alsolikely to impact pain transmis-sion at trigeminovascular sitesvia AMPA receptors.56

Barbiturates are frequentlyprescribed for migraine treat-ment and are often used asfirst-line agents.57 However,use of these agents, particular-ly butalbital combinations, is controversial because their efficacy has not been provenin placebo-controlled trialsand because of their ability tocause medication overuseheadache and drug depen-dence. The US HeadacheConsortium recommends limited use of these com-pounds and only with carefulmonitoring.58



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Migraine prevalence and treatment patterns: the global Migraine andZolmitriptan Evaluation survey.Headache. 2003;43:19-26.

2. Ulrich V, Gervil M, Kyvik KO, Olesen J,et al. Evidence of a genetic factor inmigraine with aura: a population-basedDanish twin study. Ann Neurol.1999;45:242-46.

3. Goadsby PJ. Migraine pathophysiology.Headache. 2005;45 Suppl 1:S14-24.

4. Welch KM. Brain hyperexcitability: the basis for antiepileptic drugs inmigraine prevention. Headache. 2005;45(suppl 1):S25-32.

5. Aurora SK, Cao Y, Bowyer SM, et al.The occipital cortex is hyperexcitable in migraine: experimental evidence.Headache. 1999;39:469-76.

6. Cao Y, Welch KM, Aurora S, et al.

Functional MRI-BOLD of visually triggered headache in patients withmigraine. Arch Neurol. 1999;56:548-54.

7. Hadjikhani N, Sanchez Del Rio M, Wu O, et al. Mechanisms of migraineaura revealed by functional MRI inhuman visual cortex. Proc Natl Acad SciU S A. 2001;98:4687-92.

8. Leao A. Spreading depression of activityin the cerebral cortex. J Neurophysiol.1944;7:359-90.

9. Cady R, Schreiber C, Farmer K, et al.Primary headaches: a convergencehypothesis. Headache. 2002;42:204-16.

10. Bolay H, Reuter U, Dunn AK, et al.Intrinsic brain activity triggers trigeminalmeningeal afferents in a migraine model.Nat Med. 2002;8:136-42.

11. Buzzi MG, Moskowitz MA. The pathophysiology of migraine: year 2005.

J Headache Pain. 2005;6:105-11.12. Shechter A, Stewart WF, Silberstein SD,

et al. Migraine and autonomic nervoussystem function: a population-based,case-control study. Neurology. 2002;58:422-7.

13. Mosek A, Novak V, Opfer-Gehrking TL,et al. Autonomic dysfunction inmigraineurs. Headache. 1999;39:108-17.

14. Yarnitsky D, Goor-Aryeh I, Bajwa ZH,et al. 2003 Wolff Award: Possibleparasympathetic contributions to peripheral and central sensitization during migraine. Headache. 2003;43:704-14.

15. Peroutka SJ. Migraine: a chronic sympathetic nervous system disorder.Headache. 2004;44:53-64.

16. Burstein R, Jakubowski M. Unitaryhypothesis for multiple triggers of thepain and strain of migraine. J Comp

Figure 2 provides an overviewof the mechanisms of actionwithin the trigeminovascular system for the commonly prescribed migraine medications.

ConclusionsThe known pathophysiologicmechanisms underlyingmigraine are complex and multifactorial but allow for

intervention at multiple siteswithin the process to preventor abort migraine attacks.New drugs to target sites notaffected by current therapiesare needed and recent clinicaldata show that some may beon the horizon. Preliminaryefficacy has been demonstratedfor antagonists of CGRP59 andglutamate.60

The targeting of multiplemechanisms simultaneouslywith more than one medica-tion is another logical approachtowards more quickly andeffectively aborting migraine.Early use of triptans or ergotsmay reduce neurogenicinflammation and preventcentral sensitization, whileNSAIDs add the capacity to abort established centralsensitization. Use of opioidsshould be limited because of their abuse potential andsedative effects, but whenother medications fail, opioidsmay play a role similar to that of triptans and ergots inthe disruption of processesunderlying migraine patho-physiology. The role of barbiturates is less clear. ■

Figure 2. Proposed mechanisms of action for migraine medications within thetrigeminovascular system.

NI, neurogenic inflammation; NSAIDs, nonsteroidal anti-inflammatory drugs; TG, trigeminal ganglion; TGN, trigeminal neurons; TNC, trigeminal nucleus caudalis.

meninges

Reduces hyperexcitability of TGN: NSAIDs

Reduces NI: triptansergotsNSAIDsopioids

TNC

TG

thalamus

cortex

Abolishes established central sensitization:

NSAIDsbarbiturates?Blocks pain transmission and prevents

central sensitization:triptansergotsopioidsbarbiturates?


Neurol. 2005;493:9-14.17. Spierings EL. Mechanism of migraine

and action of antimigraine medications.Med Clin North Am. 2001;85:943-58.

18. Cady RK, Schreiber CP. Sinus headacheor migraine? Considerations in making adifferential diagnosis. Neurology. 2002;58:S10-4.

19. Blau JN, MacGregor EA. Migraine andthe neck. Headache. 1994;34:88-90.

20. Biondi DM. Cervicogenic headache:mechanisms, evaluation, and treatmentstrategies. J Am Osteopath Assoc. 2000;100:S7-14.

21. Hargreaves RJ, Shepheard SL.Pathophysiology of migraine—newinsights. Can J Neurol Sci. 1999;26(suppl 3):S12-9.

22. Sanchez del Rio M, Reuter U,Moskowitz MA. Central and peripheralmechanisms of migraine. Funct Neurol.2000;15(suppl 3):157-62.

23. Edvinsson L, Goadsby PJ. Neuropep-tides in migraine and cluster headache.Cephalalgia. 1994;14:320-7.

24. Ebersberger A, Averbeck B, Messlinger K,et al. Release of substance P, calcitoningene-related peptide and prostaglandinE2 from rat dura mater encephali following electrical and chemical stimulation in vitro. Neuroscience. 1999;89:901-7.

25. Edvinsson L, Elsas T, Suzuki N, et al.Origin and co-localization of nitric oxidesynthase, CGRP, PACAP, and VIP in thecerebral circulation of the rat. MicroscRes Tech. 2001;53:221-8.

26. Moskowitz MA. Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. TrendsPharmacol Sci. 1992;13:307-11.

27. Burstein R. Deconstructing migraineheadache into peripheral and central sensitization. Pain. 2001;89:107-10.

28. Peroutka SJ. Neurogenic inflammationand migraine: implications for the therapeutics. Mol Interv. 2005;5:304-11.

29. Goadsby PJ, Hargreaves RJ. Mechanismsof action of serotonin 5-HT1B/D agonists: insights into migraine pathophysiology using rizatriptan. Neurology. 2000;55:S8-14.

30. Levy D, Burstein R, Strassman AM.Calcitonin gene-related peptide does notexcite or sensitize meningeal nociceptors:implications for the pathophysiology of migraine. Ann Neurol. 2005;58:698-705.

31. Burstein R, Cutrer MF, Yarnitsky D.The development of cutaneous allodyniaduring a migraine attack: clinical evidence for the sequential recruitmentof spinal and supraspinal nociceptiveneurons in migraine. Brain. 2000;123( Pt 8):1703-9.

32. Jakubowski M, Levy D, Goor-Aryeh I,et al. Terminating migraine with allodynia and ongoing central sensitization using parenteral administration of COX1/COX2inhibitors. Headache. 2005;45:850-61.

33. Burstein R, Jakubowski M, Levy D.Naproxen suppresses sensitization in thecentral trigeminovascular neurons—implication for migraine therapy. Paperpresented at: The 58th Annual Meetingof the American Academy of Neurology;April 4, 2006; San Diego, Calif.

34. Burstein R, Collins B, Jakubowski M.Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann Neurol. 2004;55:19-26.

35. Cady RK, Lipton RB, Hall C, et al.Treatment of mild headache in disabledmigraine sufferers: results of the Spectrum Study. Headache. 2000;40:792-7.

36. Scholpp J, Schellenberg R, Moeckesch B,et al. Early treatment of a migraineattack while pain is still mild increasesthe efficacy of sumatriptan. Cephalalgia.2004;24:925-33.

37. Levy D, Jakubowski M, Burstein R.Disruption of communication betweenperipheral and central trigeminovascularneurons mediates the antimigraine actionof 5HT 1B/1D receptor agonists. ProcNatl Acad Sci U S A. 2004;101:4274-9.

38. Ferrari MD. Should we advise patientsto treat migraine attacks early? Cephalalgia.2004;24:915-7.

39. Bartsch T, Knight YE, Goadsby PJ.Activation of 5-HT(1B/1D) receptor in the periaqueductal gray inhibits nociception. Ann Neurol. 2004;56:371-81.

40. Tulunay FC. NSAIDs: behind the mechanisms of action. Funct Neurol.2000;15 Suppl 3:202-7.

41. Silberstein S, Tepper S, Brandes J, et al.Randomized, placebo-controlled trial ofrofecoxib in the acute treatment ofmigraine. Neurology. 2004;62:1552-7.

42. Acute treatment of migraine attacks: efficacy and safety of a nonsteroidal anti-inflammatory drug, diclofenac-potassium, in comparison to oral sumatriptan and placebo. TheDiclofenac-K/Sumatriptan MigraineStudy Group. Cephalalgia. 1999;19:232-40.

43. Diener HC, Bussone G, de Liano H, et al. Placebo-controlled comparison of effervescent acetylsalicylic acid, sumatriptan and ibuprofen in the treatment of migraine attacks. Cephalalgia. 2004;24:947-54.

44. Carlson LA, Ekelund LG, Oro L.Clinical and metabolic effects of differentdoses of prostaglandin E1 in man.Prostaglandin and related factors. Acta Med Scand. 1968;183:423-30.

45. Sarchielli P, Alberti A, Codini M, et al.Nitric oxide metabolites, prostaglandinsand trigeminal vasoactive peptides ininternal jugular vein blood during spontaneous migraine attacks. Cephalalgia. 2000;20:907-18.

46. Richardson JD, Vasko MR. Cellularmechanisms of neurogenic inflammation.J Pharmacol Exp Ther. 2002;302:

839-45.47. Johnson RH, Hornabrook RW,

Lambie DG. Comparison of mefenamicacid and propranolol with placebo inmigraine prophylaxis. Acta NeurolScand. 1986;73:490-2.

48. Welch KM, Ellis DJ, Keenan PA. Successful migraine prophylaxis withnaproxen sodium. Neurology. 1985;35:1304-10.

49. Sances G, Martignoni E, Fioroni L, et al. Naproxen sodium in menstrualmigraine prophylaxis: a double-blindplacebo controlled study. Headache.1990;30:705-9.

50. Williamson DJ, Shepheard SL, Cook DA,et al. Role of opioid receptors in neurogenic dural vasodilation and sensitization of trigeminal neurones in anaesthetized rats. Br J Pharmacol.2001;133:807-14.

51. Snow V, Weiss K, Wall EM, et al.Pharmacologic management of acuteattacks of migraine and prevention ofmigraine headache. Ann Intern Med.2002;137:840-9.

52. Feldman R, Meyer J, Quenzer L.The Opiates. Principles of Neuropsychopharmacology. Sunderland,MA: Sinauer Associates, Inc.; 1997:495-548.

53. Charney D, Mihic S, Harris R.Hypnotics and Sedatives. In: Hardman J,Limbird L, eds. Goodman and Gilman’s The Pharmacological Basis ofTherapeutics. 10th ed. New York, NY:McGraw-Hill; 2001:399-427.

54. Cutrer FM, Mitsikostas DD, Ayata G,et al. Attenuation by butalbital of capsaicin-induced c-fos-like immuno-reactivity in trigeminal nucleus caudalis.Headache. 1999;39:697-704.

55. Storer RJ, Akerman S, Goadsby PJ.GABA receptors modulate trigeminovas-cular nociceptive neurotransmission in the trigeminocervical complex. Br JPharmacol. 2001;134:896-904.

56. Mitsikostas DD, Sanchez del Rio M,Waeber C, et al. Non-NMDA glutamatereceptors modulate capsaicin induced c-fos expression within trigeminal nucleus caudalis. Br J Pharmacol. 1999;127:623-30.

57. Wenzel RG, Sarvis CA. Do butalbital-containing products have a role in themanagement of migraine? Pharmacother-apy. 2002;22:1029-35.

58. Silberstein SD, McCrory DC. Butalbitalin the treatment of headache: history,pharmacology, and efficacy. Headache.2001;41:953-67.

59. Olesen J, Diener HC, Husstedt IW, et al. Calcitonin gene-related peptidereceptor antagonist BIBN 4096 BS forthe acute treatment of migraine. N EnglJ Med. 2004;350:1104-10.

60. Sang CN, Ramadan NM, Wallihan RG,et al. LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine. Cephalalgia. 2004;24:596-602.

Drug classes used in migraine:Advantages and limitationsNONSPECIFIC AGENTS—

Nonsteroidal Anti-inflammatory Drugs.Nonsteroidal anti-inflammatorydrugs (NSAIDs) are generalanalgesics that reduce inflamma-tion by blocking cyclooxygenase(COX) enzymes, therebyinhibiting prostaglandin synthe-sis. NSAIDs are widely availableand include over-the-counteragents, such as ibuprofen andnaproxen, and prescriptiondrugs, such as ketorolac andindomethacin. They are avail-able as oral, injection, and suppository formulations. Whileoral NSAIDs are recommendedas first-line therapy for mild-to-moderate migraine,1 they aregenerally not as effective forsevere migraine; and patient satisfaction with them for severepain tends to be low.8 AlthoughNSAIDs generally have fewerpotential side effects than manyother migraine treatments, they can cause gastrointestinalproblems, such as nausea, vom-iting, dyspepsia, and ulcer, andcan lead to end-organ toxicity.7,9

Opioids. Opioids, such asmorphine, codeine, and butor-phanol, block specific painreceptors in the brain and spinalcord to inhibit the transmissionof pain signals. Possible sideeffects include sedation, nausea,and constipation, and frequentuse can lead to headache pro-gression (medication overuseheadache) and dependence.Opioids are not recommendedas a first-line treatment formigraine. However, they may beuseful in limited circumstancesas rescue therapy when NSAIDsand migraine-specific agents arecontraindicated or have failed.1,6

A SPECIAL REPORT


Migraine headachesTreatment limitations and opportunities

Robert G. Kaniecki, MD, and Susan Hutchinson, MD

PreviewIn recent years, migraine treatment options have expanded to the extent that the practicing clinician now has a myriad ofpharmacologic agents in varied drug classes and deliverysystems from which to choose. Drug classes most commonlyemployed for treatment of migraine attacks includenon–migraine-specific agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, barbiturates, combination analgesics, and antiemetics, and migraine-specific agents, such as triptans and ergot alkaloids andderivatives. Delivery options range from conventional, orallydisintegrating, and rapid-release tablets to injection, nasalspray, and suppository. The US Headache Consortium offersguidelines classifying migraine treatments into differentgroups based on evidence of clinical benefit (Table 1).1

Clinicians must be aware of the advantages and limitations of each class and delivery system and possible opportunitiesto improve their usefulness in different clinical contexts.

■ Treatment response andpatient satisfaction inmigraine are still not opti-mal.2,3 Patients typically preferoral agents,2,4 but the gastricstasis that occurs duringmigraine5 slows down theirabsorption, and the nauseaand vomiting experienced bymany migraineurs can makeoral agents difficult to takeand/or retain.4 Alternativedelivery systems pose otheradvantages and disadvantages.

Improving treatment outcomesrequires arriving at the bestcombination of agent andstrategy for each patient, andsome troubleshooting may berequired in terms of dosing,delivery system, and individualpatient factors.4,6,7 Opportuni-ties to increase treatment success, such as combiningexisting therapies and using aprokinetic agent to enhancethe absorption of oral agents,are being explored.

Table 1. US Headache Consortium Guidelines for Some Common Migraine Treatments1

Adverse Evidence Drug effects Role (by consensus) group*

Naratriptan Infrequent I

Rizatriptan Occasional

Sumatriptan Occasional

Sumatriptan nasal spray Occasional I

Sumatriptan SC Frequent I

DHE SC/IM Occasional II

DHE IV plus antiemetics Frequent I

DHE nasal spray Occasional I

Ergotamine Frequent III

Metoclopramide IM Infrequent to IIIoccasional

Prochlorperazine PR/IM Occasional II

Acetaminophen Infrequent Pregnant migraineur IV

Ketorolac IM Infrequent Consider in emergency department II

Acetaminophen/aspirin/caffeine Infrequent First line for migraine I

Butalbital/ASA/caffeine Occasional III

Butorphanol nasal spray Frequent I

Opiates—oral combinations Occasional II

Opiates—parenteral Frequent II

* Group I: Proven, pronounced statistical and clinical benefit (at least 2 double-blind, placebo-controlled studies and clinicalimpression of effect); Group II: moderate statistical and clinical benefit (1 double-blind, placebo-controlled study and clinicalimpression of effect); Group III: proven statistically but not clinically effective or proven clinically but not statistically effective (conflicting or inconsistent evidence); Group IV: proven to be statistically or clinically ineffective (failed efficacy versus placebo).

Adapted from Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review):report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55:754-62.

Reserved for emergency department use orrescue medication; limit use

Moderate to severe migraine; less severemigraine when nonopiate medications fail

Moderate to severe migraine; useful whennonoral route needed; less severe migrainewhen nonopiate medications fail

Moderate to severe migraine; useful whennonoral route needed; less severe migrainewhen nonopiate medications fail

Moderate to severe migraine; less severemigraine when nonopiate medications fail

Status migrainosus; therapy of choice inemergency department

Moderate to severe migraine; less severemigraine when nonopiate medications fail; low recurrence

Consider for selected patients with moderateto severe migraine

Adjunct therapy; may be choice for acutetherapy

IM/IV adjunct first-line therapy in emergencydepartment or office; consider PR as adjunct

Occasional use for moderate to severemigraine; limit use because of risk of overuse

Moderate to severe migraine; rescue therapy;limit use

Moderate to severe migraine; rescue therapy;limit use


Opioids are available in oral,injection, nasal spray, and sup-pository formulations.

Barbiturates. These sedativeagents (for example, butalbital),which depress the central ner-vous system by enhancing theaction of gamma aminobutyricacid, are prescribed for occasionaluse in moderate to severemigraine.1 Drowsiness is themost common side effect; lesscommon side effects includedizziness, lightheadedness, andmovement difficulty. Barbitu-rates must be used cautiouslybecause of high rates of depen-dence and gradual headacheescalation via the medicationoveruse (rebound) phenomenon.1

Combination Analgesics.Oral combinations of analgesicsand other nonspecific drugs,including a combination ofisometheptene (a vasoconstric-tor), dichloralphenazone (a seda-tive), and acetaminophen andcombinations of aspirin oracetaminophen with caffeineand butalbital, are also available.Although these fixed combina-tions are commonly used, thereis no evidence to support theuse of butalbital compounds 6,10

and little evidence to supportthe use of isometheptene com-pounds in acute migraine.1,6

Antiemetics. Antiemetics are often used to treat nauseaassociated with migraine attacksand are sometimes used to treat the migraine directly.Specifically, metoclopramide is a dopamine D2 receptor antag-onist, 5-hydroxytryptamine3(5-HT3) receptor antagonist,and 5-hydroxytryptamine4(5-HT4) receptor agonist11

that is often used for nausea inmigraine and can be adminis-tered as IV monotherapy for

pain relief.1 Other antiemeticscommonly used for migrainetreatment include prochlorper-azine and chlorpromazine.1

Side effects of antiemeticsinclude dizziness and sedation,and with the neuroleptic agents,there is a risk of extrapyramidalside effects such as dystonia.Routes of administrationinclude oral, injection, and suppository.1

MIGRAINE-SPECIFIC AGENTS—Triptans. Triptans have gen-

erally become the standard ofcare for many patients withmigraine.1 These selective 5-HT1B/1D receptor agonists are thought to work mainly by reversing vasodilation andinhibiting the transmission ofpain signals peripherally andcentrally by blocking the releaseof neuropeptides. They actdirectly on the migraine painrather than simply alleviatinggeneral pain or providing seda-tion. Triptans have superiorcapability to treat migraine successfully compared witholder treatments, offeringgreater speed of relief and consistency of effect as well asgood tolerability.12 Seven trip-tan agents have been approvedin the United States since theearly 1990s, all of which have comparable efficacy and tolera-bility.7,12 Triptans are availablein conventional tablet, orallydissolving wafer, rapid releasetablet, injection, nasal spray,and suppository formulations.They are also more effectivewhen used early in the courseof the migraine, while pain ismild.6 Early treatment is notappropriate in all attacks forpatients with frequent or dailymigraine, because of the risk ofmedication overuse.3,7

Ergots. Drugs containing theergot alkaloid ergotamine, anonspecific 5-HT1 receptor agonist that works through vasoconstriction of intracranialvessels and by inhibiting therelease of vasoactive neurotrans-mitters,9 can be effective inmoderate to severe migraine.1

Possible side effects include toxicity, cardiovascular compli-cations, nausea and vomiting,dizziness, tingling, musclecramps, and abdominal pain.They are available in oral andsuppository formulations.

Dihydroergotamine (DHE).DHE, a semisynthetic ergotalkaloid, is a treatment option inpatients with moderate to severemigraine, and when it is admin-istered intravenously along withan antiemetic, it is a first-linetherapy for intractable migrainebeing treated on an inpatientbasis.1,13 Colman and colleagues,13

in a systematic review of 11studies, found 3 comparingDHE monotherapy to suma-triptan and phenothiazines. Inthese 3 studies, no benefit wasfound for DHE monotherapyover the other therapies. Regard-ing DHE, contraindicationsinclude ischemic cardiomyopa-thy, arterial hypertension, Ray-naud’s disease, and pregnancy.9

It is available as an injection andas a nasal spray.

Migraine drug delivery systems: Advantages and limitationsThe different routes of adminis-tration of migraine treatmentsoffer many options for deliver-ing the drug to the part of thebody that will help produce thebest relief. Speed and efficacy areoften maximized by nonoral for-mulations, particularly in those


patients with migraine uponawakening, rapidly buildingattacks, or significant gastroin-testinal symptoms.4,6 A combina-tion of more than 1 deliverysystem may be optimal for somepatients, and studies have shownthat patients prefer treatmentoptions providing more than 1 formulation.4,14

ORAL—The oral treatmentroute is the most common andis greatly preferred by mostpatients,15 and all migraine med-ications except DHE are avail-able orally. However, the speedof onset and effectiveness of oralagents may be limited by gastricstasis that occurs during amigraine attack5,16 and interfereswith optimal absorption of thedrug. Because of inconsistenttreatment outcomes, patientscan become dissatisfied and discontinue therapy.4

Migraine has long been asso-ciated with gastric stasis, butuntil recently, no evidence wasavailable to document its pres-ence. Boyle and colleagues,16

using surface electrodes to mea-sure gastric impedance, showedthat there is a significant gastricdelay during migraine attacks,but the measurements were indirect. In 2006, Aurora andcolleagues5 used scintigraphy to determine gastric motilityduring and between migraineattacks in 10 migraine patientsand 10 control patients matchedby sex and age. Scintigraphy wasperformed once in all controlsubjects and migraine subjects in the interictal period and oncein the ictal period in 9 of themigraine patients. The time tohalf emptying (T1/2) both duringand between attacks was longerin migraineurs compared withcontrols. Gastric stasis of

migraineurs between attacks was more severe than it was during attacks (a mean T1/2

of 188.8 minutes versus 149.9 minutes, respectively) and was significantly greaterthan it was in control patients(111.8 minutes; P � 0.05). Gastric delay did not correlatewith nausea. The investigatorstheorize that the gastric stasisthat occurs during and betweenmigraine attacks, as well asmigraine-related nausea, may be caused by autonomic dysfunction.

Oral Triptan Formulations.Although triptans have greatlyimproved migraine treatment,outcomes with oral triptans stillleave room for improvement. Ina meta-analysis of 53 trials withoral triptans, Ferrari and col-leagues12 reported that a mean of59% (95% CI, 57%-60%) ofpatients treated with sumatrip-tan 100 mg respond to treat-ment (from moderate or severeto mild or no pain) within 2 hours, 29% (95% CI, 27%-30%) achieve a pain-freeresponse at 2 hours, 20% (95% CI, 18%-21%) have asustained pain-free response over24 hours, and 67% (95% CI,63%-70%) have a consistentresponse at 2 hours in 2 out of 3 attacks. Similar results wereseen with other triptans.

Of the oral-triptan formula-tions, the orally dissolving wafer,which can be taken withoutwater and melts in the mouth,may provide convenience anddiscretion. The fact that it meltsquickly can be an advantage for patients with nausea andvomiting or those who have difficulty swallowing tablets.4

However, because it is still swallowed (with saliva), it does

not provide faster relief thanconventional tablets.4 Addition-ally, some patients consider thetaste of an orally dissolvingwafer to be unpleasant.17

The rapid-release tablet, bydissolving and dispersing morerapidly within the gastrointesti-nal tract, can provide faster reliefand make it more likely that thedrug will take effect during thecrucial window of time early in the attack.18-20 Sheftell andcolleagues18 conducted 2 ran-domized, double-blind, parallel-group studies of 2,696 patientsreceiving rapid-release sumatrip-tan 50 mg or 100 mg or place-bo. Results demonstrated thatpain relief was achieved as earlyas 20 minutes for 100 mg andas early as 30 minutes for 50 mgsumatriptan (P ≤0.05).

Regardless of brand or for-mulation, evidence supportsimproved efficacy of oral trip-tans when administered duringthe earliest stages of acutemigraine.3,6

INJECTION—Injection is generally the fastest and mosteffective delivery system. Thus,it is a viable alternative forpatients whose symptomsprogress quickly, who awakenwith symptoms that are alreadysevere, or who cannot swallow atablet because of severe nauseaand vomiting.4 Issues with injec-tions are that the actual injec-tion can be painful, discomfortlocal to the injection site canoccur, and many patients dislikeneedles. These issues may makeit unlikely that this form oftreatment will become wide-spread,4 yet patients do some-times prefer it because of itsspeed and effectiveness.18

NASAL SPRAY—Nasal spraysprovide a faster onset of action


than oral agents and anotheroption for patients with nauseaand vomiting4,21 without theinvasiveness and inconvenienceof an injection,22 and they canalso be useful in patients withsinus symptoms.7 Nasal sprayscan cause a bad or bitter taste inmany patients,21 which couldworsen nausea,4 and they canirritate the nasal mucosa.

Intranasal sumatriptan israpidly absorbed, with 60% ofthe maximum plasma concentra-tion occurring 30 minutes after a 20-mg dose.22 Peikert and colleagues, comparing intranasalsumatriptan with placebo in 544 patients in a multicenter,randomized, double-blind, placebo-controlled, parallel-group study, showed thatintranasal sumatriptan (at dosesof 5 mg, 10 mg, and 20 mg) issignificantly better than placeboat providing 2-hour headacherelief (P ≤ 0.01) and is well tolerated.21 Most patients experi-enced a bad taste, which lastedup to 30 minutes in approxi-mately 50% of patients, and72% of patients who receivedthe 20-mg dose said they wouldbe willing to take it again.22

Zolmitriptan, another triptan, isalso available as a nasal spray.The dose is 5 mg, and efficacy iscomparable to that of sumatrip-tan nasal spray. Dodick and col-leagues assessed the effectivenessof intranasal zolmitriptan in amulticenter, double-blind studyof 2,122 patients randomized toreceive zolmitriptan 5 mg nasalspray or placebo; the zolmitrip-tan group had a 2-hour responserate of 66.2% versus 35.0% forthe placebo group (P � 0.001),and the drug was well tolerated.23

Other nasal spray optionsinclude opioids and DHE.

Intranasal butorphanol has been associated with abuse and dependence, but it is stillrecommended as an optionwhen other medications cannotbe used or as a rescue medica-tion if significant sedationwould not pose a problem.1

SUPPOSITORY—The rectalroute is another option forpatients with severe nausea andvomiting. Sumatriptan supposi-tory is not presently available inthe United States. Disadvantagesof suppositories include erraticabsorption, possible rectal irrita-tion, fewer choices of agents, anda lower patient acceptance rate.4

Overcoming clinical challenges: Considerations for improving treatment outcomesMigraine is a challenging disorder for both patients andclinicians. Improving treatmentoutcome will mean that clini-cians will need to avoid diagnos-tic pitfalls, prescribe the optimaldose for the patient, and strong-ly consider use of multimecha-nism combination therapy.

AVOID DIAGNOSTIC PITFALLS—Migraine can initially be mistak-en for tension or sinus head-aches.6 Becoming familiar with a patient’s pattern of headachesand symptoms can help the clin-ician and patient learn whenearly treatment might be war-ranted.7 Failing to diagnose arebound headache is anotherpotential misstep. If the patientis already using an over-the-counter drug, it can renderother drugs ineffective and leadto medication overuse headache.Some patients may benefit frombeing evaluated for preventivetreatment, particularly whenattacks occur more frequently

than 1 to 2 days per week.CHOOSE OPTIMAL DOSING—

The optimal dose for treatingmigraine is generally the highestdose as listed on the packageinsert, except for very small orelderly patients.7 Titrating up,while common, may not beeffective enough to stop theheadache from progressing.

USE COMBINATION

THERAPY TO TARGET MULTIPLE

MECHANISMS—Combiningexisting therapies represents apossible opportunity to improvetreatment response, as discussedin the article on combinationtherapy in this supplement. Thisstrategy can target the multiplemechanisms and neurologicpathways that contribute to amigraine attack. The first articlein this supplement discusses thesepathways. Combination therapyis becoming the standard of carein many clinical conditions, andmany combinations are alreadybeing used in migraine treat-ment.24,25 The last 2 articles inthis supplement will providerational argument for and clinicaldata supporting use of multi-mechanism combination therapy.

ConclusionsClinicians must be aware of theclinical advantages associatedwith the therapeutic classes ofagents and routes of administra-tion most commonly used totreat migraineurs. Additionally,they must appreciate the limita-tions associated with currentlyavailable agents and formula-tions and stay abreast of newstrategies being investigated toovercome these limitations. Suchawareness will enable cliniciansto design individualized treat-ment plans and provide appro-priate patient counseling. ■



References1. Silberstein SD. Practice parameter:

evidence-based guidelines for migraineheadache (an evidence-based review):report of the Quality Standards Subcommittee of the American Academyof Neurology. Neurology. 2000;55:754-62.

2. Lipton RB, Hamelsky SW, Dayno JM.What do patients with migraine wantfrom acute migraine treatment?Headache. 2002;42(suppl 1):3-9.

3. Moschiano F, D'Amico D, Allais G, et al. Early triptan intervention inmigraine: an overview. Neurol Sci.2005;26(suppl 2):S108-10.

4. Worthington I. Delivery systems foracute migraine medications. Can FamPhysician. 2001;47:322-9.

5. Aurora SK, Kori SH, Barrodale P, et al.Gastric stasis in migraine: more than just a paroxysmal abnormality during amigraine attack. Headache. 2006;46:57-63.

6. Kaniecki R. Intercepting migraine:results of early therapy with nonspecificand migraine-specific agents. Curr TreatOptions Neurol. 2006;8:3-10.

7. Taylor FR. Migraine headache: optionsfor acute treatment. Curr Neurol Neurosci Rep. 2005;5:86-92.

8. Ceballos Hernansanz MA, Sanchez Roy R, Cano Orgaz A, et al. Migrainetreatment patterns and patient satisfaction with prior therapy: a substudy of a multicenter trial of rizatriptan effectiveness. Clin Ther.2003;25:2053-69.

9. Higelin F, Annoni JM. Medical

treatment of migraine: from mechanismsof action to contraindications. SchweizMed Wochenschr. 1998;128:374-83.

10. Loder E. Fixed drug combinations forthe acute treatment of migraine: place intherapy. CNS Drugs. 2005;19:769-84.

11. MacGregor EA. Anti-emetics. Curr MedRes Opin. 2001;17(suppl 1):S22-5.

12. Ferrari MD, Roon KI, Lipton RB, et al.Oral triptans (serotonin 5-HT(1B/1D)agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet.2001;358:1668-75.

13. Colman I, Brown MD, Innes GD, et al.Parenteral dihydroergotamine for acutemigraine headache: a systematic review of the literature. Ann Emerg Med.2005;45:393-401.

14. Kaniecki RG. Mixing sumatriptan: aprospective study of stratified care usingmultiple formulations. Headache. 2001;41:862-6.

15. Lipton RB, Stewart W. Acute migrainetherapy: do doctors understand whatpatients with migraine want from therapy? Headache. 1999;39(suppl 2):S20-6.

16. Boyle R, Behan PO, Sutton JA. A correlation between severity ofmigraine and delayed gastric emptyingmeasured by an epigastric impedancemethod. Br J Clin Pharmacol. 1990;30:405-9.

17. Dowson AJ, Almqvist P. Part III: theconvenience of, and patient preferencefor, zolmitriptan orally disintegratingtablet. Curr Med Res Opin. 2005;21(suppl 3):S13-7.

18. Sheftell FD, Dahlof CG, Brandes JL, et al. Two replicate randomized, double-blind, placebo-controlled trials of thetime to onset of pain relief in the acute treatment of migraine with a fast-disintegrating/rapid-release formulation of sumatriptan tablets. Clin Ther. 2005;27:407-17.

19. Barbanti P, Carpay JA, Kwong WJ, et al. Effects of a fast disintegrating/rapidrelease oral formulation of sumatriptanon functional ability in patients withmigraine. Curr Med Res Opin. 2004;20:2021-9.

20. Walls C, Lewis A, Bullman J, et al.Pharmacokinetic profile of a new form ofsumatriptan tablets in healthy volunteers.Curr Med Res Opin. 2004;20:803-9.

21. Peikert A, Becker WJ, Ashford EA, et al.Sumatriptan nasal spray: a dose-rangingstudy in the acute treatment of migraine.Eur J Neurol. 1999;6:43-9.

22. Fuseau E, Petricoul O, Moore KH, et al. Clinical pharmacokinetics ofintranasal sumatriptan. Clin Pharmacokinet. 2002;41:801-11.

23. Dodick D, Brandes J, Elkind A, et al.Speed of onset, efficacy and tolerabilityof zolmitriptan nasal spray in the acutetreatment of migraine: a randomised,double-blind, placebo-controlled study.CNS Drugs. 2005;19:125-36.

24. Krymchantowski AV. Acute treatment of migraine. Breaking the paradigm ofmonotherapy. BMC Neurol. 2004;4:4.

25. Peroutka SJ. Beyond monotherapy:rational polytherapy in migraine.Headache. 1998;38:18-22.

NOTES

effect is altered, compared withthe effect of either drug alone.A pharmacodynamic interac-

tion may occur when combining2 drugs with differing mecha-nisms of action that produce the same effect.1 For example,the combination of aspirin (aninhibitor of platelet function)and warfarin (an inhibitor of Vitamin K–dependent clot-ting factors) will result in anincreased anticoagulant effect.2

Drugs that compete for the samereceptor (but with opposingeffects at that receptor) may alsointeract pharmacodynamically.This type of reaction has beenexploited in the treatment ofopioid-induced respiratorydepression with naloxone (a µ-opioid receptor antagonist).1

The effect of combining 2drugs can be classified as addi-tive, synergistic, or antagonistic.1

• An additive effect occurswhen the efficacy or sideeffects are equal to the sum ofthe effects of either drug alone

• A synergistic effect occurswhen the efficacy or sideeffects are greater than the sumof the effects of either drugalone

• An antagonistic effect occurswhen the efficacy or sideeffects are decreased com-pared with using either drugalone A drug-drug interaction,

whether it is a pharmacokineticor pharmacodynamic one, istypically considered undesirable.In many situations (but not all),pharmacokinetic interactionsshould be avoided. Using a drugwith a narrow therapeutic indexin combination with a drug thatwill alter its rate of metabolismor excretion may result in toxiceffects if the rate is decreased

A SPECIAL REPORT


Combination therapy in acutemigraine treatmentThe rationale behind the current treatment options

Stephen D. Silberstein, MD, and Gary Ruoff, MD

PreviewCombination therapy is used to treat many disorders; for someconditions, it has become first-line treatment or the standard ofcare. The development and use of novel drug combinations willgrow as the understanding of disease pathophysiology anddrug pharmacokinetics and pharmacodynamics progresses.

In the acute management of migraine, existing drug combinations have proven to be effective, safe, and tolerable.They may offer distinct advantages compared with mono-therapy, including both enhanced therapeutic benefits andfewer adverse events (AEs). This article discusses the typesof interactions that can occur with combination therapy and their potential effects on efficacy and tolerability. Therationale for using combination therapy will first be discussedwithin the context of clinical conditions in which it is alreadythe standard of care. This will be followed by a discussion ofthe rationale for use in migraine.

Characterizing drug-druginteractions and their role in combination therapyWhen 2 drugs are combined in the treatment of a disorder(or multiple disorders), a drug-drug interaction may occur.That interaction is character-ized, based on its mechanism, aseither a pharmacokinetic or apharmacodynamic interaction.1

• In a pharmacokineticinteraction, drug absorption,distribution, metabolism orexcretion is altered for at leastone of the drugs being com-bined, compared with whenthe drugs are used alone.

• In a pharmacodynamic inter-action, drug pharmacokinet-ics remain unchanged, butthe combined pharmacologic

or in inefficacy if the rate isincreased. Pharmacokinetic inter-actions often occur with agentsthat are hepatically metabolizedvia the cytochrome P450 system.A medication that is an inhibitoror inducer of the particularenzymes that participate in thebiotransformation of anotheragent may increase or decrease(respectively) the serum levels of that agent and negativelyimpact its safety or efficacy pro-file. Similarly, concomitant useof two drugs that are metabo-lized through the same CYP3A4or CYP2D6 enzyme pathwayincreases the potential for a pharmacokinetic interaction.3

Pharmacodynamic interac-tions may also produce unwant-ed effects—some of thempotentially life-threatening. Asnoted above, combining warfarinwith aspirin will increase antico-agulant effects and in some cases,these increased effects may resultin bleeding.2 Combining 2 drugsthat both produce CNS depres-sion may also result in a seriousinteraction. For instance, com-bining an opioid analgesic and abenzodiazepine hypnotic mayproduce extreme somnolence,respiratory depression, or worse(coma and death). Dosageadjustments of either or bothdrugs may be required whenthere is a need to combine drugsthat produce excessive effectswhen used together.4

On the other hand, drugcombinations can be, and arebeing, rationally designed toproduce beneficial drug-druginteractions. The ideal drugcombination would have syner-gistic efficacy effects but antago-nistic effects on toxicity. Mostdrug combinations have beendevised with the intent of pro-

ducing better efficacy.5 Mostcommonly, an additive effect onefficacy is achieved via a phar-macodynamic interaction. Useof combination therapy has beenstandard treatment for a varietyof disorders that are inadequate-ly controlled by monotherapy.

The legacy of combination therapyUse of multiple drugs to treat asingle disorder is not a new con-cept. Combination therapy hasbeen used in some clinical condi-tions for many years. It has thepotential to improve outcomecompared with monotherapy bytargeting different parts of thepathophysiologic process. Anadditive or synergistic effect maybe achieved, ideally with noworsening or even with improve-ments in tolerability. Drugbioavailability or rate of absorp-tion may also be improved whenpharmacokinetic interactions areexploited. Use of combinationtreatments is common or insome cases, standard of care, fora number of disorders treated inprimary care including diabetes,hypertension, and various infec-tious diseases, particularly HIV.

TREATMENT OF TYPE 2 DIABETES: EMPLOYING A

PHARMACODYNAMIC

INTERACTION TO PRODUCE

ADDITIVE EFFICACY EFFECTS—In patients with Type 2 (non–insulin-dependent) diabetes,blood glucose levels are elevatedbecause of 2 physiologic defects:resistance to the actions ofinsulin and impaired �-cell func-tion in the pancreas resulting indecreased insulin production.Monotherapy for this disorder isassociated with a high treatmentfailure rate, especially as the dis-ease progresses.6

A multimechanisticapproach to the treatment of Type 2 diabetes with oraltherapy employs beneficialpharmacodynamic interactionsbetween antidiabetic agents to target multiple aspects ofdiabetes pathophysiology.• Sulfonylureas and non-

sulphonylurea secretagogues(repaglinide, nateglinide)bind to the ATP-dependentpotassium channel complexin the membranes of �-cellswhere they are able to potentiate glucose-dependentinsulin secretion.7

• Biguanides (metformin) act through an uncertainmechanism that results in the potentiation of the suppressive effects ofinsulin on hepatic glucoseproduction.7

• Alpha-glucosidase inhibitorsslow the absorption of glu-cose by impairing the actionof enzymes that break downcomplex carbohydrates in thesmall intestine.7

• Thiazolidinediones bind toperoxisome-proliferator–activated receptor-� whichalters gene expression andleads to an increase in insulin sensitivity in fat, liver, and muscle.7

Various combinations ofthese agents produce additiveefficacy. For example, non-sulfonylurea secretagogues,which potentiate glucose-dependent insulin secretion(controlling postprandial hyper-glycemia), are combined withmetformin, which suppresseshepatic glucose production(controlling fasting hyper-glycemia), to produce an additive effect on glycemic control.6


TREATMENT OF HYPERTEN-SION: EMPLOYING PHARMACO-DYNAMIC INTERACTIONS TO

PRODUCE ADDITIVE OR SYNER-GISTIC EFFICACY EFFECTS—Treatment of hypertension also benefits from a multimecha-nistic approach since its patho-physiology is complex andmultifactorial.8 A common physiologic abnormality inhypertensive patients involvesthe renin-angiotensin system. In some patients, increased levelsof renin and angiotensin II are a part of the pathophysiology driving hypertension. �-blockersare useful in this populationbecause of their ability to sup-press renin release, in addition to decreasing cardiac output.8

However, �-blockers also causeretention of sodium and water.To counteract this problem, clinicians combine a �-blockerwith a thiazide diuretic, takingadvantage of the diuretic’s abilityto increase sodium excretion anddecrease blood volume. Thesediuretics also stimulate reninrelease, but this effect is counter-acted by the �-blocker.9 Studies indicate that this combinationmay be additive or even synergis-tic, in the case of combiningbisoprolol with hydrochlorothi-azide. Low doses of each havebeen combined to produce sub-stantial antihypertensive effects,but with a low incidence of sideeffects,9 suggesting a possibleantagonistic effect on toxicity.

TREATMENT OF HUMAN

IMMUNODEFICIENCY VIRUS/ACQUIRED IMMUNODEFICIENCY

SYNDROME (HIV/AIDS): EMPLOY-ING PHARMACODYNAMIC AND

PHARMACOKINETIC INTERAC-TIONS TO INCREASE EFFICACY—Disease processes may involvemultiple, and often cyclical,

phases. Individual agents may bemost effective against a specificphase of the disease cycle; ifcombined, these agents mayinterrupt the disease processacross multiple phases. Oneexample of a pharmacodynamicinteraction that drives effectivecombination therapy by attack-ing multiple phases of the disease process is the use of anti-retroviral combinations to treatHIV/AIDS.

Combination therapy is thestandard of care even for the ini-tial treatment of HIV/AIDS.Quadruple-agent and triple-agent therapy is used to targetmultiple mechanisms and phasesof the replication cycle of HIV.Currently recommended anti-retroviral agents fall into 3 maincategories, based on mechanismof action10:• Nucleoside reverse transcrip-

tase inhibitors (NRTIs ornucleoside analogs)

• Non-nucleoside reverse tran-scriptase inhibitors (NNRTIs)

• Protease inhibitors (PIs)NRTIs and NNRTIs target

the same early phase of the HIVreplication cycle, but via slightlydifferent mechanisms. NRTIsinterfere in the viral replicationcycle during the conversion ofRNA to DNA. They inhibitreverse transcriptase from com-pleting its function by compet-ing with the natural nucleosides,which allows incorporation ofthe NRTI itself into DNA andterminates chain formation.Without the ability to replicateits own DNA, HIV cannotinfect the cell. NNRTIs alsointerfere with reverse transcrip-tase but by binding directly to itand preventing it from convert-ing RNA to DNA. PIs havetheir effect near the end of the

replication cycle: they preventreplication of mature, infectiousHIV by blocking the enzyme(protease) that cleaves longchains of polyproteins (imma-ture, noninfectious precursors)into smaller, functional chainsthat are able to infect othercells.11 Current recommenda-tions suggest initial therapy with at least 3 drugs, either 1NNRTI + 2 NRTIs or 1-2 PIs +2 NRTIs.12

Pharmacokinetic interactionsare also exploited in HIV/AIDStreatment by using ritonavir, aPI with inhibitory effects on the CYP3A4 enzyme, to “boost”the effects of other PIs that are metabolized via the sameenzyme. Metabolism of thesedrugs is slowed, causingincreased exposure.12 Use ofcombination therapy for HIVhas been highly successful insuppressing viral replication,improving immune function,and reducing morbidity andmortality in patients with HIV.13

Combination therapy in the acute treatment of migraine headacheCombination therapy has a longtradition as migraine manage-ment.14,15 Combination therapyfor acute migraine headachetakes advantage of both pharma-cokinetic and pharmacodynamicdrug-drug interactions toachieve better efficacy or tolera-bility. Some combinations use amultimechanistic approach thattargets different aspects of thepathophysiologic mechanism,taking advantage of pharmaco-dynamic interactions to improveoutcome. With other drug combinations for migraine,pharmacokinetic interactions areexploited to speed up drug


absorption or slow down drugelimination. In some cases,migraine drug combinationshave been designed in order toproduce both pharmacodynamicand pharmacokinetic interac-tions that are beneficial to treat-ment. These interactions mayproduce either additive or syner-gistic effects on efficacy.

Combination therapy formigraine offers a variety ofpotential advantages when com-pared to traditional monothera-py for headache. A few examplesof drug combinations formigraine and the rationale fortheir use are discussed below.

COMBINATIONS OF

TRIPTANS AND NAPROXEN: A PHARMACODYNAMIC AND

POTENTIAL PHARMACOKINETIC

INTERACTION—Triptans interactpharmacodynamically withNSAIDs since these medicationsare believed to impact differentparts of the trigeminovascularsystem, the system thoughtresponsible for the generation ofmigraine head pain through itsconnections with the meninges(for review, see the article titled “An update on migrainepathophysiology and mechanism-based pharmacotherapeutics formigraine” by Cady and Biondiin this supplement). Triptans are believed to interrupt themigraine process in 3 ways: bydirect vasoconstriction ofmeningeal vessels, by inhibitingrelease of vasoactive substances(eg, CGRP) in the meninges,(reducing neurogenic inflamma-tion), and by inhibiting centraltransmission of nerve impulsesto the trigeminal nucleus cau-dalis (TNC). This is achievedvia activation of 5HT1B/1Dreceptors.16 Triptans decreasepain and prevent the develop-

ment of central sensitization(self-sustaining activation of the TNC) if taken early in amigraine attack.17 NSAIDs mayalso inhibit neurogenic inflam-mation by blocking formation ofprostaglandins in the meninges,but additionally, they may havethe capacity to interrupt estab-lished central sensitization sincethey may interfere with the glialproduction of prostaglandins.18

A pharmacokinetic interactionbetween triptans and NSAIDsmay also play a role since coad-ministration of sumatriptan andnaproxen appears to slow theelimination of naproxen fromplasma.19

Two recent studies have evaluated the combination of a triptan and an NSAID for acutetreatment of migraine. An open-label study compared rizatriptanmonotherapy to 2 rizatriptancombinations: one that includedrofecoxib (a COX-2–specificNSAID) and another thatincluded tolfenamic acid (a traditional NSAID). Pain-freerates at 2 hours were significantlybetter for the combination thatincluded rofecoxib comparedwith rizatriptan alone. The tolfe-namic acid combination was notsignificantly better than mono-therapy.20 Since rofecoxib wasnot studied as monotherapy, thenature of this interaction (syner-gistic versus additive) cannot bedetermined. Adverse event rateswere similar for the rofecoxibcombination and rizatriptanmonotherapy groups. The sec-ond study was double-blind andplacebo-controlled.21 Sumatriptan (50 mg) plus naproxen (500 mg)was compared with sumatriptanalone, naproxen alone, andplacebo. The combination wassignificantly more effective than

all other treatments for the primary endpoint, 24-hour (sustained) pain relief response.Our analysis of the differencesin sustained relief rates (relativeto placebo, ie, therapeutic gain)suggests a synergistic interactionbetween sumatriptan andnaproxen (see Table 1). Theoverall adverse event rate wassimilar in the combination(23%) and sumatriptanmonotherapy (24%) groups.

The caveats of using a triptan-NSAID combination thus farappear to be the same as usingeither agent alone since adverseevents rates were not increased by use of the combinations. Traditional NSAIDS have beenassociated with gastrointestinalside effects22 and triptans are contraindicated in patients withischemic cardiac, cerebrovascular,or peripheral vascular disease.23

Rofecoxib has been withdrawnfrom the market because of itsincreased cardiovascular risk.23

Caffeine-containing combinations: A pharmacokinetic andpotential pharmacodynamicinteractionIn the acute treatment of pain,caffeine has been shown toenhance the effect of a variety of analgesics.24 The mechanismresponsible for this enhancementis not fully known, but mayinvolve both a pharmacokineticand a pharmacodynamic interac-tion. Pharmacokinetic studieshave shown that caffeine increas-es the rate or extent of absorp-tion of aspirin,25 ergotamine, andacetaminophen,24,26 which couldexplain the faster onset andincreased pain relief obtainedwith the combinations. Thepharmacodynamic contribution



of caffeine to increased efficacyis less clear because caffeine asmonotherapy has not beenproven effective in migraine,although it has shown someefficacy in other headachetypes.27 The mechanism under-lying any potential pharmaco-dynamic (multimechanistic)effect of caffeine may be relatedto its ability to block adenosinereceptors.28

Three studies have comparedthe efficacy of an analgesic withand without caffeine. In a studyof patients with migraine with-out aura, diclofenac (anNSAID) plus caffeine was sig-nificantly better than placebo,whereas diclofenac alone wasnot. Whether this improvedefficacy represented synergismor just an additive effect couldnot be determined since caf-feine as monotherapy was notstudied.24 Another placebo-controlled study compared atriple combination of aceta-minophen, aspirin, and caffeineto each agent alone and also tothe combination of aspirin andacetaminophen in patients with migraine or tension-type

headache. The triple combina-tion was significantly moreeffective than all the othertreatments for the primary end-point “time to 50% pain relief.”Adverse event rates were similaracross groups.29 Our analysis ofthe median time to 50% painrelief for the triple combinationgroup compared with the dou-ble combination and caffeinemonotherapy suggests that theaddition of caffeine to aceta-minophen and aspirin pro-duced an additive, rather than asynergistic effect on efficacy(see Table 1). In the third study,a combination of tolfenamicacid and caffeine was comparedwith either agent alone andwith placebo. Again, the com-bination therapy produced bet-ter efficacy than either agentalone (for migraine severity at1.5 hours), although the differ-ences were not statistically sig-nificant. Numerical data werenot provided, but visual inspec-tion of the graphic data sug-gested that the combinationwas only marginally better thantolfenamic acid alone and therewas no synergistic effect.30

Antiemetic-containing combinations: A pharmacokinetic and pharmacodynamic interaction The nausea and vomiting associ-ated with migraine is commonand may be as disabling as theheadache itself. Antiemeticagents such as metoclopramidehave been used to treat theseassociated symptoms.31

Metoclopramide is a proki-netic agent that stimulates gas-tric motility and acceleratesgastric emptying. Its prokineticeffects are thought to be mediat-ed primarily by actions at theserotonin 5-HT4 receptors inthe upper gastrointestinal tract.Metoclopramide also has anantiemetic effect that stemsfrom blockade of dopamine D2receptors in the CNS.32 Botheffects may contribute to theadded efficacy that has beenseen with metoclopramide com-binations. A pharmacokineticinteraction would be producedby the increased gastric motilitysince the coadministered agentwould be absorbed more rapidly,while the antiemetic effects ofmetoclopramide would reduce

Table 1. Analysis of Effects of Combined Therapy Versus Individual Components

Therapeutic Gain (active response Type of Study Efficacy Result* by Treatment Group minus placebo response) Effect†

Smith et al SUM/NPX SUM NPX PLA SUM/NPX SUM NPX Synergistic

46% 29% 25% 17% 29 12 8 29 > 20

Diener et al ASA/AC/C ASA/AC C PLA ASA/AC/C ASA/AC C Additive

65 min 73 min 107 min 133 min -68 -60 -26 68 < 86

* Primary efficacy variable was percent of patients with 24-hour (sustained) pain relief for the Smith et al study; for the Diener et alstudy, it was median time to 50% pain relief (in minutes).

† If the therapeutic gain in the combination group (ASA/AC/C or SUM/NPX) was greater than the sum of the therapeutic gains ofthe components comprising the combination, the combination was considered synergistic. If the gain in the combination groupwas less than or equal to the sum of the gains in the components, the combination was considered to have additive effects.

AC, acetaminophen; ASA, aspirin; C, caffeine; NPX, naproxen; PLA, placebo; SUM, sumatriptan.


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5. Nies AS. Principles of therapeutics. In:Hardman JG, Limbird LE, GoodmanGilman A, eds. Goodman & Gilman’sThe Pharmacological Basis of Therapeutics. 10th ed. New York, NY:McGraw-Hill Medical Publishing Division;2001:45-66.

6. Van Gaal LF, De Leeuw IH. Rationaleand options for combination therapy in the treatment of Type 2 diabetes. Diabetologia. 2003;46(suppl 1):M44-50.

7. Riddle MC. Glycemic management oftype 2 diabetes: an emerging strategywith oral agents, insulins, and combinations. Endocrinol Metab Clin North Am. 2005;34:77-98.

8. Abernethy DR. Pharmacological properties of combination therapies forhypertension. Am J Hypertens. 1997;10:13S-16S.

9. Skolnik NS, Beck JD, Clark M. Combination antihypertensive drugs:

recommendations for use. Am FamPhysician. 2000;61:3049-56.

10. Tapper ML, Daar ES, Piliero PJ, et al.Strategies for initiating combination antiretroviral therapy. AIDS Patient CareSTDs. 2005;19:224-38.

11. Pietrandoni G. How HIV drugs work101. Positively Aware. 2001;12:26-9.

12. Panel on Clinical Practices for Treatment of HIV Infection. Guidelinesfor the use of antiretroviral agents inHIV-1-infected adults and adolescents.Available at: http://AIDSinfo.nih.gov/Guidelines/Default.aspx?MenuItem=Guidelines. Accessed March 29, 2006.

13. Kress KD. HIV update: emerging clinical evidence and a review of recommendations for the use of highlyactive antiretroviral therapy. Am J HealthSyst Pharm. 2004;61(suppl 3):S3-16.

14. Krymchantowski AV. Acute treatment of migraine: breaking the paradigm

nausea and vomiting. Theantiemetic effects contributed bymetoclopramide could be con-sidered a pharmacodynamicinteraction, although that inter-action does not occur within thepain-producing sites associatedwith migraine (ie, the trigemino-vascular system). Injectabledopamine antagonists haveshown effects on migraine painas well31; however, it is unlikelythat oral agents could contributeto headache pain relief.33

Two double-blind studieshave evaluated the effects of oralmetoclopramide in combinationtherapy for migraine. In a pilotstudy, Schulman and Dermottcompared sumatriptan alone (50 mg) to a combination withmetoclopramide in migrainepatients who were previouslyunresponsive to triptans. Theyfound a higher rate of headacherelief at 2 hours with the meto-clopramide combination (44%)than with sumatriptan alone(31%).34 The difference was nottested for statistical significance.Without a placebo group or ametoclopramide monotherapygroup, it is not possible to deter-

mine if the addition of metoclo-pramide produced a synergisticor additive effect. In the secondstudy, Tokola and colleaguesstudied metoclopramide in com-bination with tolfenamic acid.The combination was statistical-ly superior to metoclopramidealone (for migraine severity at1.5 hours), but the differencecompared with tolfenamic acidmonotherapy did not reach sta-tistical significance. Whetherany synergism occurred with thecombined product could not bedetermined because numericaldata were not presented.30

Because of its prokineticeffects, metoclopramide has thepotential to be especially helpfulin migraine because it mayreverse the gastric stasis that hasbeen documented in patientsduring migraine attacks.35 How-ever the side effects of metoclo-pramide such as sedation,orthostatic hypotension, andextrapyramidal symptoms maylimit its usefulness.36

ConclusionsCombination therapy is used totreat many disorders and is often

the most commonly used andeffective treatments or, in somecases, the standard of care. Theeffectiveness of this strategy isderived from pharmacokineticor pharmacodynamic interac-tions that produce either addi-tive or synergistic effects. Manydrug combinations, includingthose used in migraine, targetmultiple mechanisms within thedisease process. The result isoften increased efficacy withsimilar or better tolerabilitycompared with monotherapy.

Combination therapy foracute migraine treatment is notuncommon: many combina-tions are recommended fortreating headache in addition tothe above examples.31 However,although the efficacy and safetyof some combination treatmentsfor migraine have been demon-strated, combination therapy isnot yet considered the standardof care. Further study is neededto provide more information oncombination therapy and maypromote this strategy to “first-line” in patients with moderateto severe migraine. ■


of monotherapy. BMC Neurology.2004;4:1-5.

15. Loder E. Fixed drug combinations forthe acute treatment of migraine: place intherapy. CNS Drugs. 2005;19:769-84.

16. Hargreaves RJ, Shepheard SL.Pathophysiology of migraine—newinsights. Can J Neurol Sci. 1999;26(suppl 3):S12-9.

17. Burstein R, Collins B, Jakubowski M.Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann Neurol. 2004;55:19-26.

18. Jakubowski M, Levy D, Goor-Aryeh I,et al. Terminating migraine with allodynia and ongoing central sensitization using parenteral administration of COX1/COX2inhibitors. Headache. 2005;45:850-61.

19. Wargin W, Littlefield D, Taylor D, et al. Pharmacokinetic profile of sumatriptan RT technology™ andnaproxen sodium—new single-tablet formulation. Poster presented at: 47thAnnual Scientific Meeting of the American Headache Society; June 23-25,2005; Philadelphia, Pa.

20. Krymchantowski AV, Bigal ME.Rizatriptan versus rizatriptan plus rofecoxib versus rizatriptan plus tolfenamic acid in the acute treatment of migraine. BMC Neurol. 2004;4:10.

21. Smith TR, Sunshine A, Stark SR, et al.Sumatriptan and naproxen sodium forthe acute treatment of migraine.Headache. 2005;45:983-91.

22. Roberts LJ, Morrow JD. Analgesic-

antipyretic and antiinflammatory agentsand drugs employed in the treatment ofgout. In: Hardman JG, Limbird LE,Goodman Gilman A, eds. Goodman &Gilman’s The Pharmacologic Basis ofTherapeutics. 10th ed. New York, NY:McGraw-Hill Medical Publishing Division; 2001:687-732.

23. Dogne JM, Hanson J, Supuran C, et al.Coxibs and cardiovascular side-effects:from light to shadow. Curr Pharm Des.2006;12:971-5.

24. Peroutka SJ, Lyon JA, Swarbrick J, et al.Efficacy of diclofenac sodium softgel 100 mg with or without caffeine 100 mgin migraine without aura: a randomized,double-blind, crossover study. Headache.2004;44:136-41.

25. Thithapandha A. Effect of caffeine onthe bioavailability and pharmacokineticsof aspirin. J Med Assoc Thai. 1989;72:562-6.

26. Iqbal N, Ahmad B, Janbaz KH, et al. The effect of caffeine on the pharmacokinetics of acetaminophen inman. Biopharm Drug Dispos. 1995;16:481-7.

27. Ward N, Whitney C, Avery D, et al.The analgesic effects of caffeine inheadache. Pain. 1991;44:151-5.

28. Sawynok J. Pharmacological rationale for the clinical use of caffeine. Drugs.1995;49:37-50.

29. Diener HC, Pfaffenrath V, Pageler L, et al. The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the

treatment of headache: a multicentre,randomized, double-blind, single-dose,placebo-controlled parallel group study.Cephalalgia. 2005;25:776-87.

30. Tokola RA, Kangasniemi P, Neuvonen PJ, et al. Tolfenamic acid,metoclopramide, caffeine and their combinations in the treatment ofmigraine attacks. Cephalalgia. 1984;4:253-63.

31. Silberstein SD. Practice parameter: evidence-based guidelines for migraineheadache (an evidence-based review):report of the Quality Standards Subcommittee of the American Academyof Neurology. Neurology. 2000;55:754-62.

32. Pasricha PJ. Prokinetic agents, antiemetics, and agents used in irritablebowel syndrome. In: Hardman JG, Limbird LE, Goodman Gilman A, eds. Goodman & Gilman’s The Pharmacologic Basis of Therapeutics.10th ed. New York, NY: McGraw-HillMedical Publishing Division; 2001:1021-36.

33. Fox A, Kori S. Pharmacokinetic opportunities for combination therapy inmigraine. Neurology. 2005;64:S21-5.

34. Schulman EA, Dermott KF.Sumatriptan plus metoclopramide intriptan-nonresponsive migraineurs.Headache. 2003;43:729-33.

35. MacGregor EA. Anti-emetics. Curr MedRes Opin. 2001;17(suppl 1):S22-5.

36. Flake ZA, Scalley RD, Bailey AG.Practical selection of antiemetics. AmFam Physician. 2004;69:1169-74.

NOTES

caffeine 130 mg with the singleagent sumatriptan 50 mg in 171 migraineurs.2 Patients keptdiaries, which investigators usedto ascertain whether the agentswere effective in the early treat-ment of migraine. The resultsshowed that the combinationregimen was significantly moreeffective than sumatriptan in theearly treatment of migraine, asshown by superiority in painintensity reduction beginning at2 hours after dosing and continu-ing throughout the 4-hour treat-ment period (P ≤ 0.011), use ofrescue medication (P � 0.043),and degree of disability by 4 hours postdose (P � 0.044).Additional comparator trialswould be helpful in clinical practice decision making.

Triptans combined with other agentsThe thrust of current research has been to combine the triptanswith other medications. Thetherapeutic rationale is to countermore than one of the neurobio-logic mechanisms related tomigraine pathophysiology.

SUMATRIPTAN AND

NAPROXEN—Sumatriptan and the other triptans are very effec-tive in both the acute treatmentof a migraine attack and as initialtreatment choice in patients withmoderate to severe migrainepain.3 They block pain transmis-sion in the trigeminal system,cause vasoconstriction, and whengiven early in the attack, may prevent development of centralsensitization.4,5 However, whilethey prevent the release of inflam-matory substances from nerveendings, they do not appear toaffect inflammatory substancesalready released or inflammatoryprocesses already activated.5

PreviewThe previous article in this supplement sets forth a compellingargument for use of multimechanism combination pharmaco-therapy as a strategy to improve outcomes for patients withmigraine. This article picks up where the previous one left off byproviding a concise review of data regarding use of combinedagents to treat migraine. Included in this review are clinical studies of both over-the-counter (OTC) and prescription agentswhose performance in combination has been assessed in com-parison to placebo and/or monotherapy. Also, this review is notlimited to fixed drug combinations; studies that used differentsingle-agent tablets administered together are also included.

MIGRAINE • A POSTGRADUATE MEDICINE SPECIAL REPORT 27

A SPECIAL REPORT

Use of combination therapy in migraineA review of the clinical evidence

Frederick Taylor, MD, and Timothy Smith, MD

OTC agents used in combinationSeveral studies using nonprescrip-tion agents have shown a benefitof combination therapy overmonotherapy. A multicenter, randomized, double-blind, single-dose, placebo-controlled,parallel-group study compared theefficacy, safety, and tolerability of(1) 500 mg aspirin plus 400 mgacetaminophen and 100 mg caffeine, (2) 500 mg aspirin plus 400 mg acetaminophen, (3) 1000 mg aspirin, (4) 1000 mgacetaminophen, (5) 100 mg caf-feine, and (6) placebo in anintent-to-treat set of 1,743 pa-tients who were accustomed to

treating their episodic tension-type headache or migraine attackswith nonprescription analgesics.1

For the primary endpoint “timeto 50% pain relief,” the fixedcombination of aspirin, acetamin-ophen, and caffeine was signifi-cantly superior to the combina-tion without caffeine (P � 0.02)and to the single substances,aspirin (P � 0.04), acetamino-phen (P � 0.002), caffeine (P � 0.0001), and placebo (P � 0.0001). The incidence of adverse events was low and tolerable.

Another study compared thecombination of acetaminophen500 mg, aspirin 500 mg, and

Nonsteroidal anti-inflammatory drugs (NSAIDs)are also effective migraine thera-pies,3 and in addition to theirability to prevent prostaglandinproduction, they can prevent the extravasation of plasma byacting on neuropeptide-inducedchanges in vascular permeabilityand/or smooth muscle contractil-ity, as has been shown in preclini-cal studies.6 Thus, because oftheir different mechanisms ofaction on headache, a rationaleexists for combining a triptanand an NSAID as an improvedtreatment over monotherapy.Srinivasu and colleagues demon-strated that naproxen did notalter the pharmacokinetics ofsumatriptan when these agentswere used concomitantly inhealthy volunteers.7 However, in2005, Wargin and colleaguesdemonstrated that naproxenpharmacokinetics were altered inhealthy volunteers when naprox-en was administered with suma-triptan. Specifically, absorption ofnaproxen was delayed.8

Several studies have been per-formed to assess the efficacy ofsumatriptan and naproxen inmigraine. A prospective study of67 patients involved the adminis-tration of sumatriptan 100 mgand naproxen sodium 550 mgand assessed the recurrence rateof migraine.9 The patients hadpreviously used sumatriptan 100 mg alone with success totreat prestudy migraines with a recurrence rate of 62.5%. This rate dropped to 14.2% (P � 0.0001) when the combi-nation was used. In a double-blind substudy of that trial, 26patients were randomized to begiven sumatriptan plus placeboor sumatriptan plus naproxen at the aforementioned doses. The

recurrence rate of the triptanmonotherapy was 59%, com-pared with 26% for the combi-nation (P � 0.0003).

Another randomized study,which was double-blind, doubledummy, and placebo controlled,involved 972 participants whoeach treated a single migraineepisode with encapsulated suma-triptan 50 mg plus naproxensodium 500 mg, each of thecomponents used as monothera-py, or placebo.5 In the combina-tion group, 46% of patientsreached 24-hour pain reliefresponse, which was significantlymore effective than sumatriptanalone (29%), naproxen sodiumalone (25%), or placebo (17%)(P � 0.001). Two-hour headacheresponse was also significantlybetter in the combination group(65%) than in the sumatriptangroup (49%), the naproxen sodi-um group (46%), or the placebogroup (27%) (P � 0.001). Theincidence of headache recurrenceup to 24 hours after treatmentwas lowest in the combinationgroup (29%), compared withsumatriptan alone (41%; P � 0.05), naproxen sodiumalone (47%; P � 0.004), orplacebo (38%; P � 0.08).

A recently developed suma-triptan tablet formulation hasbeen shown to be bioequivalentto the conventional tablet; how-ever, because of technology thatcauses rapid release and disper-sion of drug, it has more rapidabsorption than the conventional-tablet sumatriptan.10 In 2 identi-cal randomized, double-blind,placebo-controlled, parallel-group, single-attack studies ofadult migraineurs, patients weregiven the combination of therapid-release sumatriptan 85 mgplus naproxen sodium 500 mg,

each component used singly, orplacebo.11 At 2 hours, the combi-nation regimen was more effec-tive compared with placebo asmeasured by pain-free and pain-relief rates (P � 0.001). In achiev-ing sustained pain-free responses,the combination was more effec-tive than either component orplacebo (P � 0.001). Sustainedtherapeutic gain was higher forthe combination (16.4%) thanfor sumatriptan (7.6%) ornaproxen (3.7%). Overall, thecombination of the fixed-dosereformulated sumatriptan plusnaproxen offered improved 24-hour benefits over mono-therapy. The sustained pain-freetherapeutic gain suggested to theinvestigators a potential synergis-tic clinical benefit with the com-bination regimen.

SUMATRIPTAN, NAPROXEN, AND

DEXAMETHASONE—Although thesumatriptan-naproxen studiesshow that the combination ofthese 2 drugs can lower the recur-rence rate of migraine, somepatients who take the combina-tion still have persistent attacks.Intravenous (IV) dexamethasonehas been reported anecdotally tobe useful in the treatment ofmigraine and status migrain-osus.12 A small study was con-ducted in patients who had a his-tory of migraine recurrence,defined as returning of pain with-in 2 to 24 hours following thesingle use of sumatriptan 100 mg,zolmitriptan 2.5 mg, or rizatrip-tan 10 mg in at least 5 consecu-tive attacks and a reduction inrecurrence rate less than 21% fol-lowing the combination of tolfe-namic acid 200 mg or rofecoxib25 mg in addition to their triptanregimen.13 Each of the 20 patientswho completed the study pre-sented with frequent recurrence


(that is, recurrence following 60%or more of their migraine attacks).The patients treated 6 consecutivemigraine attacks with their usualtriptan and NSAID regimen plusdexamethasone 4 mg, takensimultaneously, a maximum of 2 times per week. The resultsshowed that 2 patients experi-enced recurrence in 50% of 6attacks, while the remaining 18patients experienced recurrence in 1 or 2 dexamethasone-treatedattacks (mean 23.4%; P � 0.001).The investigators stated that thecautious use of oral dexametha-sone may be useful for a limited population of migraine patientspresenting with recurrence follow-ing the combination of a triptanand an NSAID. However, largerstudies with a randomized, dou-ble-blind design are necessary toconfirm these observations.

RIZATRIPTAN AND

ROFECOXIB—Rizatriptan hasproved to be highly effective in migraine. In a placebo-controlled, outpatient study, the percentage of patients withpain relief at 2 hours postdosewas significantly higher after riza-triptan 5 mg (62%) or 10 mg(71%), compared with placebo(35%).14

Rofecoxib is an NSAID that selectively inhibits cyclooxygenase-2 (COX-2) andhas a relatively long half-life ofapproximately 17 hours,15 whichpotentially makes it valuable inpreventing migraine recurrence.In an open-label pilot study, 56triptan-naive migraineurs wererandomized with instructions totake either rizatriptan 10 mg orrizatriptan 10 mg plus rofecoxib25 mg for 3 consecutive moder-ate or severe attacks.16 While nostatistically significant differencein absence of headache was

observed at 1, 2, or 4 hours post-dose, recurrence (based on allattacks of those patients whoachieved pain relief at 4 hours)was observed in 53% of theattacks in the rizatriptan-onlygroup but only 20% in the combination group (P � 0.001).Double-blind, placebo-controlledtrials are warranted to confirmthese results.

ZOLMITRIPTAN VERSUS ASPIRIN

PLUS METOCLOPRAMIDE—Oralzolmitriptan has proved to beeffective in double-blind, placebo-controlled trials, with the2.5-mg dose demonstrating anoptimal balance between efficacyand tolerability as initial therapyfor acute treatment of migraine.17

Aspirin is also considered usefulin treating acute attacks ofmigraine.3 Metoclopramide is anantiemetic that has the additionaladvantage of increasing gastroin-testinal motility and, hence,absorption of simultaneouslyingested medication, a processwhich might otherwise be ham-pered by vomiting or gastric stasisduring an attack.18 A double-blind, randomized study was performed that comparedzolmitriptan 2.5 mg with a com-bination of aspirin 900 mg andmetoclopramide 10 mg as acutetherapy for 3 migraine attacks.18

The percentage of patients with a 2-hour headache response afterthe first dose for all 3 attacks was 33.4% with zolmitriptan and32.9% with aspirin plus metoclo-pramide (P � 0.72). However,the overall 2-hour pain-freeresponse rate was higher for thezolmitriptan group than for the aspirin-metoclopramide regimen (34.6% versus 27.9%;OR � 1.40; 95% CI, 1.09-1.78;P � 0.007). Adverse events were reported by 40.8% of

zolmitriptan-treated patients and29.1% of those treated withaspirin plus metoclopramide,although the discontinuation ratewas very low. In this study,zolmitriptan was at least as effec-tive as the comparator regimen interms of achieving a 2-hourheadache response, making boththerapies viable options forpatients with acute migraine.

SUMATRIPTAN AND METOCLO-PRAMIDE—IV metoclopramideadministered aggressively—that is, given up to 4 times over 2 hours as needed for persistentsevere headaches that present inan emergency room environ-ment—has been shown to be aseffective at 2 and 24 hours assubcutaneous sumatriptan 6 mgin the same setting.19 In a double-blind, crossover study involving 16 triptan-nonresponsive mi-graineurs, patients were random-ized to receive oral sumatriptan50 mg plus oral metoclopramide10 mg or oral sumatriptan 50 mg plus placebo and wereinstructed to medicate themselveswhen pain was moderate orsevere in intensity.20 Meaningfulrelief was experienced in 10(63%) of 16 migraines treatedwith the combination regimen,compared with 5 (31%) of 16migraines treated with sumatrip-tan alone. Headache response at2 hours was achieved in 7 (44%)of 16 migraines with the combi-nation, compared with 5 (31%)of 16 migraines treated withsumatriptan alone. Thus, com-bining sumatriptan with meto-clopramide provided relief inpatients who failed to achievepain remission with triptanmonotherapy. However, morestudies need to be done to assesswhether using a higher dose ofsumatriptan and/or initiating


therapy earlier in the acute phasewould have provided additionalor more rapid relief.

Other agents used in combination

INDOMETHACIN, PROCHLOR-PERAZINE, AND CAFFEINE—Most migraineurs who seek med-ical care develop cutaneous allo-dynia during the course of theattack, a sensory abnormalitymediated by sensitization of central trigeminovascular neuronsin the spinal trigeminal nucleus.21

Treatment with triptans canrelieve pain in allodynic migrain-eurs within a narrow timeframe—20 to 120 minutes—thatbegins with pain onset and endswith the establishment of centralsensitization. Indomethacin-responsive headache syndromesare a unique group of primaryheadache disorders characterizedby a prompt and often completeresponse to indomethacin, anability not shared by otherNSAIDs nor medications usuallyeffective in treating other primaryheadache disorders.22 Suchmigraine-like disorders include a select group of trigeminal-autonomic cephalgias, valsalva-induced headaches, and primarystabbing headache (ice-pickheadache or jabs-and-jolts syndrome).22 Indomethacin,alone and in combination withprochlorperazine, a phenoth-iazine antipsychotic and anti-emetic that has been used in thetreatment of acute severe head-ache,23 and caffeine, a vasodilator,has been shown to abolishperipheral and central sensitiza-tion in migraine in vivo models.24

In a multicenter, randomized,crossover trial of 112 migrain-eurs, patients were instructed totreat 2 attacks with a rectal

indomethacin-prochlorperazine-caffeine formulation and 2attacks with rectal sumatriptanand to record the results.25 Theresults showed greater pain reliefat 2 hours in the combinationgroup than in the triptan group(49% versus 34%; P � 0.01).Compared with the sumatriptanalone, the combination was sta-tistically superior in time to apain-free response (that is, itresulted in a higher percentage of attacks that became pain freefrom 0.5 hours postdose to 5 hours postdose) and in sus-tained pain-free response (that is,it resulted in a higher percentage of attacks that became pain freeat 2 hours postdose without useof rescue medication or relapseswithin 48 hours). The combina-tion also alleviated nausea moreeffectively. No commerciallyavailable combination supposito-ry of this type is available in theUnited States, but a compound-ing pharmacy can formulate oneupon a physician’s prescriptionorder.

TRAMADOL AND ACETAMIN-OPHEN—Tramadol is a centrallyacting synthetic opioid analgesicthat, when given intramuscularly,has been found to be an effectiveand reliable alternative treatmentoption for acute migraine attacksthat present in an emergencyroom setting.26 A randomized,placebo-controlled trial assessedthe combination of oral tra-madol 75 mg and acetamino-phen 650 mg for the treatmentof acute migraine pain.27

Treatment response was higherfor the dual-drug regimen than for placebo at 2 hours postdose (55.8% versus 33.8%;P � 0.001) and at every otherassessment from 30 minutes(12.3% versus 6.6%) through

6 hours (64.9% versus 37.7%)(all P ≤ 0.022). Patients in theactive-drug group were morelikely than those in the placebogroup to experience relief of painat 2 hours (22.1% versus 9.3%),6 hours (42.9% versus 25.2%),and 24 hours (52.7% versus37.9%) (all P ≤ 0.007). Regard-ing associated symptoms, fewerpatients taking the tramadol-acetaminophen combinationexperienced moderate to severephotophobia (P � 0.003) andmoderate to severe phonophobia(P � 0.008), but rates ofmigraine-associated nausea weresimilar. The combination may bea viable treatment option forpatients who experience migrainewith minimal nausea or thosewho have contraindications tomigraine-specific therapies.

DOMPERIDONE AND ACETA-MINOPHEN—Domperidone hasantiemetic properties. Studies onacetaminophen alone as an anti-migraine agent are mixed regard-ing efficacy.28,29 A study comparedthe effectiveness and tolerabilityof a fixed combination of dom-peridone and paracetamol withsumatriptan 50 mg in moderateto severe migraine.30 To do this,120 patients were recruited from23 primary care practicesthroughout the United King-dom. Patients were randomizedto one of the comparator regi-mens (used to treat their firstmigraine attack) and thenswitched to the alternative treatment for their second attack. The 2 treatments were comparable in efficacy(≤15% difference) in relievingheadache and reducing nauseaand vomiting at 2 hours and 4 hours postdose, and bothwere well tolerated with no serious adverse effects.



ConclusionsThe clinical evidence reviewedhere attests to the potential forcombining various medicationsto manage migraine headache,much in the same way multi-drug regimens are used to treatother medical diseases and disor-ders, including cancer, asthma,diabetes, hypertension, and HIVinfection. Because migraine ispathophysiologically complex,the concept of rational combina-tion therapy deserves additionalstudy. Finding the optimal drugcombinations (possibly includingfuture, in-the-pipeline products),timing their administration withregard to phase of migraineepisode, and balancing an effec-tive dose while minimizing sideeffects are the challenges faced asmore studies are designed andperformed. The most promisingcombinations thus far appear tobe the triptan-NSAID regimensthat have been studied in dou-ble-blind, placebo-controlled tri-als and that appear to offerimproved 24-hour benefits overmonotherapy. ■

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23. Jones J, Sklar D, Dougherty J, et al. Ran-domized double-blind trial of intravenousprochlorperazine for the treatment of acuteheadache. JAMA. 1989;261:1174-6.

24. Ghelardini C, Galeotti N, Grazioli I, et al.Indomethacin, alone and combined withprochlorperazine and caffeine, but notsumatriptan, abolishes peripheral and central sensitization in in vivo models ofmigraine. J Pain. 2004;5:413-9.

25. Di Monda V, Nicolodi M, Aloisio A, et al.Efficacy of a fixed combination ofindomethacin, prochlorperazine, and caffeine versus sumatriptan in acute treatment of multiple migraine attacks: a multicenter, randomized, crossover trial.Headache. 2003;43:835-44.

26. Engindeniz Z, Demircan C, Karli N, et al. Intramuscular tramadol vs. diclofenacsodium for the treatment of acute migraineattacks in emergency department: aprospective, randomised, double-blindstudy. J Headache Pain. 2005;6:143-8.

27. Silberstein SD, Freitag FG, Rozen TD, et al. Tramadol/acetaminophen for thetreatment of acute migraine pain: findingsof a randomized, placebo-controlled trial.Headache. 2005;45:1317-27.

28. Lipton RB, Baggish JS, Stewart WF, et al.Efficacy and safety of acetaminophen inthe treatment of migraine: results of a ran-domized, double-blind, placebo-controlled, population-based study. Arch Intern Med.2000;160:3486-92.

29. Leinisch E, Evers S, Kaempfe N, et al.Evaluation of the efficacy of intravenousacetaminophen in the treatment of acutemigraine attacks: a double-blind, placebo-controlled parallel group multicenterstudy. Pain. 2005;117:396-400.

30. Dowson A, Ball K, Haworth D.Comparison of a fixed combination of domperidone and paracetamol (Domperamol) with sumatriptan 50 mgin moderate to severe migraine: a randomised UK primary care study. Curr Med Res Opin. 2000;16:190-7.

A SPECIAL REPORT


8. With regard to combining caffeine with an analgesic, apotential pharmacodynamicinteraction may be based onthe ability of caffeine to block_____ receptors.A. AdenosineB. CGRPC. Dopamine D2D. 5-HT

9. In 2 recent randomized, con-trolled trials measuring the performance of a sumatriptan-naproxen combination product, A. The combination was more

effective than placebo basedon pain-free and pain reliefrates at 2 hours.

B. The combination was moreeffective than placebo oreither component based on sustained pain-free rates.

C. The combination was moreeffective than either compo-nent based on sustained therapeutic gain.

D. All of the above are correct.

10. An open-label pilot study published in 2002 by Krymchantowski and col-leagues showed that coadminis-tered rizatriptan and rofecoxibwas superior with regard to______ than rizatriptan alone.A. 2-hour pain-free ratesB. 24-hour pain-free ratesC. Recurrence ratesD. Occurrence of GI upset

CME POST-TESTTargeting Multiple Mechanisms:New Advances in Migraine Treatment

1. Neuronal membrane chan-nelopathies, mitochondrial dysfunction, and low concentra-tions of cellular or circulating______ may play a role in theneuronal hyperexcitability associated with migraine.A. CalciumB. MagnesiumC. PhosphorousD. Sodium

2. Of the following statementsregarding cortical spreadingdepression (CDS), which one isNOT a proposed hypothesis?A. CDS initiates the release of

neuroactive substances.B. CDS manifests as a rapidly

spreading wave of neuronal hyperpolarization.

C. CDS occurs in “silent” brainareas in cases of migrainewithout aura.

D. CDS occurs in visual and sensory cortical areas in casesof migraine with aura.

3. Cutaneous allodynia, the clini-cal phenomena in which nor-mally innocuous tasks such asfacial grooming are painful during migraine attacks, ismediated via _____.A. Central sensitizationB. Peripheral sensitization

4. Which of the following phrasesdescribes an action of triptansand ergots that may be impor-tant to inhibiting migraine?A. Inhibition of neurogenic

inflammationB. Propagation of peripheral

neurotransmission in thetrigeminal nucleus caudalis

C. Vasoconstriction ofmeningeal vessels

D. All of the above

5. All of the following are advantages associated with orally dissolving wafer formulations EXCEPTA. They can be taken without

water.B. They can be administered

conveniently and discretely.C. They may be well suited for

treating migraine associatedwith nausea and vomiting.

D. They provide faster reliefthan conventional tablets.

6. TRUE or FALSE. Opioids arerecommended as first-line treatment for migraine.A. True B. False

7. Regarding the combination of a triptan and an NSAID, coadministration of sumatrip-tan and naproxen appears toslow the ______ of naproxen.A. AbsorptionB. MetabolismC. EliminationD. Excretion

CME Reply Form

To request AMA PRA Category 1 Credit™, please circle yourpost-test answers, complete the evaluation, and mail or faxthis form by April 30, 2007, to:

Scienta Healthcare Education®

2511 Old Cornwallis RoadSuite 290Durham, NC 27713

Fax: (919) 544-2416

For questions concerning this CME activity, please contactDonna Pratt, CME Administrator at (919) 544-0052.

Participant Information

Name: Credentials: Address:

City: State: ZIP:

Scienta Healthcare Education® designates this educational activityfor a maximum of 2.0 AMA PRA Category 1 Credits™. Physiciansshould only claim credit commensurate with the extent of their participation in the activity.

To receive CME credit and a certificate, participants should submit acompleted post-test at the conclusion of this activity. Certificates willbe mailed within 4 weeks.

Credits ClaimedPlease round up to the nearest half hour of credit.

■■.■■■■ Signature: (Required)

■■ I am a non-physician healthcare provider who completed theCME activity, and I wish to receive a certificate of completion.

Post-Test Answers

Evaluation(Required)

Please evaluate this CME activity by circling your response.1. How do you rate this activity in

enabling participants to achieve the stated learning objectives?a. Identify specific mechanisms that

underlie the pathogenesis of migraine.

Excellent Very Good Good Fair Poor5 4 3 2 1b. Describe the benefits and

challenges associated with use of monotherapy to abortmigraine attacks.

Excellent Very Good Good Fair Poor5 4 3 2 1c. Explain how using therapy to

target multiple mechanisms inmigraine can improve patient outcome.

Excellent Very Good Good Fair Poor5 4 3 2 1

2. How do you rate the content withrespect to clinical relevance?


3. How do you rate this format for presenting the information?


4. Will the information presented changethe way you practice?Yes No Not Sure

5. Do you feel the content was fair, balanced, and free of commercialbias?Yes No Not Sure

6. What other topics related to migrainecare are of interest to you?

7. Additional Comments:

1. A B C D2. A B C D3. A B 4. A B C D5. A B C D

6. A B 7. A B C D8. A B C D9. A B C D

10. A B C D

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