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CommonMigrainePreventiveMedications
Medications Notes Antihypertensives
Betablockers (propranolol,metoprolol, timolol,nadolol)
Avoidinpatientswithlowbaselinebloodpressuresand/orheartrates,aswellasasthma,decompensatedheart failure,andrefractorydepression.Commonsideeffectsincludehypotensionandexerciseintolerance.
Angiotensin-converting enzymeinhibitors,aka ACEinhibitors (lisinopril)
Avoidinpatientswithlowbaselinebloodpressure,renalfailure,hyperkalemia,orahistoryofangioedema.Side effectsincludehypotension,lightheadedness,andcough.
AngiotensinIIreceptor blockers,akaARBs (candesartan)
Avoidinpatientswithlowbaselinebloodpressureandahistoryofhyperkalemia.Sideeffectsincludehypotension andlightheadedness.
Calciumchannel blockers(verapamil)
Avoidinpatientswithlowbaselinebloodpressure,ahistoryofcardiacarrhythmias,renalorhepaticimpairment,or heartfailure.Sideeffectsincludehypotension,light-headedness,andconstipation.
Antidepressants
Tricyclics(amitriptyline, nortriptyline)
Avoidinpatientswithahistoryofcardiacarrhythmiasorsuicidalthinking/behavior.Sideeffectsincludesedation,
weightgain,drymouth,andconstipation. Serotonin­norepinephrinereuptake inhibitors,akaSNRIs (venlafaxine,duloxetine)
Avoidinpatientswithahistoryofrenalorhepaticimpairment,orsuicidalthinking/behavior.Sideeffectsinclude
nausea,light-headedness,insomnia,andsexualdysfunction.
Anticonvulsants
Divalproex sodium/sodium valproate
Avoidinpatientswithhepaticimpairment,thrombocytopeniaandinwomenofchildbearingage(highlyteratogenic;
cancauseneuraltubedefectsandmajorcongenitalmalformations).
Sideeffectsincludeweightgain,nausea,tremor,andfatigue. Topiramate Avoidinpatientswithahistoryofrenalimpairment,nephrolithiasis,orglaucoma.Sideeffectsincludeparesthesias,
weightloss,andword-findingdifficulty(typicallyonlyseenathigherdoses).
CGRPMonoclonalAntibodies
Fremanezumab Galcanezumab ErenumabEptinezumab
Givenmonthly(orevery3months).Injectable(Fremanezumab,Galcanezumab,Erenumab)orintravenous
(Eptinezumab).Theseareremarkablywell-tolerated;commonsideeffectsincludeconstipation(predominantly
associatedwithErenumab)andinjectionsitereactions.Thereislittleevidenceregardinguseinchildrenandin
womenduringpregnancyandlactation.
Sma llMoleculeCGRPAntagonist
Atogepant ThisisadailyoralmedicationthatwasFDAapprovedaboutaweekbeforethisbookwassentofftothepress!
Commonadverseeffectsincludenauseaandconstipation.Safetyinchildrenandinwomenduringpregnancyis
unknown.
Box3.5CGRP
Calcitoningene-relatedpeptide(CGRP)isthenewesttherapeutictargetinmigraine treatment.Itisasmallproteinthatstimulatesreleaseofinflammatorymediators,transmits nociceptive(pain)informationfromintracranialbloodvesselstotheCNS,andactsasa potentvasodilator.LevelsofCGRPincreaseinmigraineursduringamigraineattackandfall whentheattackresolves.
TheCGRPmonoclonalantibodiesarethefirstmigraine-specificpreventivemedications. TargetsincludetheCGRPmoleculeitselfandtheCGRPreceptor.Althoughtheavailable dataarestillrelativelynew,thesedrugsappeartoberemarkablysafeandwell-tolerated. Constipation,alongwithinjectionsitereactions,arethemostcommonlyreportedadverse effects.TheCGRPmonoclonalantibodiesseemtobeaboutaseffectiveastheother prophylacticoptions.
Aboutaweekbeforethisbookwassentofftopress,aCGRPsmallmoleculereceptor antagonist(atogepant)wasalsoapprovedformigraineprevention.TheothertwoCGRP smallmoleculereceptorantagonists(ubrogepant,rimegepant)areapprovedfortheacute treatmentofmigraine(seepage100).Galcanezumab,oneoftheCGRPmonoclonal antibodies,isalsoapprovedforclusterheadacheprevention,andanother(eptinezumab)is
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currentlyintrialsforclusterheadache.
Calcitoningene-relatedpeptide(CGRP)levelsbeforeandduringanacutemigraineattack.
AcuteMigraineTreatmentintheEmergencyDepartment.Youcanimaginethattheemergency department(ED),withitsfluorescentlightsandbeepingmonitors,isthelastplaceonearthanypatient withmigrainewantstobe.ButtheEDisoftenwheretheyendupwhenanacuteattackfailstorespondto treatmentandthepainissevere.
Everyonehastheirpreferred“migrainecocktail”ofmedicationstouseforthesepatients.But—big
picture—thetwomostimportantthingstodointhesesituationsare:
1. Manageexpectations.WecantaketheedgeoffbutareunlikelytofullyresolvetheheadachewhilethepatientisintheED.
2. Arrangecloseoutpatientfollow-up.Thegoalistoestablishasolidtreatmentplanthatwillhopefullykeepthepatientfarawayfromthe lightsandnoisesoftheEDinthefuture.
Box3.6OurEDMigraineCocktail
Firstline(givenincombination):
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IVmetoclopramide
IVdiphenhydramine(topreventanacutedystonicreactionfrommetoclopramide)
IVketorolac
↓
Secondline(whenfirstlinefails;butgiveyourfirst-linemedicationsatleastanhourortwoto work!):
IVmagnesiumsulfateand/or
Repeatfirst-linetreatment
↓
Thirdline(whensecondlinefails):
Option1:IVvalproicAcid+POvalproicacid(thendischargeonaquickoraltaper)
Option2:IVlevetiracetam
↓
Fourthline(whenthirdlinefails):
IVsteroids(thendischargeonaquicktaper;steroidsmaynotdecreasepainacutelybut havebeenshowntodecreasetheriskofheadacherecurrence)
NotesonaFewOtherTreatmentOptions
Opioids.Opioidscarrythehighestriskformedicationoveruseintreatingpatientsforheadache.Patients canquicklybecomedependent,andthemoretheyusethem,theworsetheirheadachesarelikelyto become.Despitethis,opioidscontinuetobeprescribedathighrates.Thereareoccasionalindications— particularlyinpatientswithmultiplecomorbiditiesresultingintheirinabilitytotakeothermedications suchastriptansandNSAIDsandinpatientswithcancer—butingeneral,opioidsshouldbealastresort (orevenanever-resort)treatmentforheadache.
AlternativeTherapies.It’sbeenestimatedthatapproximately25%to40%ofpatientswithmigraine requirepreventivetherapy,butfewerthanhalfofthesepatientsareabletoadheretothesemedications formorethanafewmonths.Thisislikelyduetoacombinationofthesideeffectburdenandthe disappointingresponsetomanyofthesetherapies.Therehas,therefore,beenalotofinterestin identifyingeffectivenonpharmacologictherapies,devices,andlow-riskinterventionsthatcanbeoffered eitherasmonotherapyorasanadjuncttoothertreatments.
Acupuncture,meditationandbiofeedbackarepopularalternativetherapies.Theevidenceislimited (althoughbecomingmorerobustbytheday—particularlywithregardtobiofeedbackandmeditation),but overallseemstosuggestpotentialbenefitwithextremelylittlerisk.Ifapatientisinterested,whynottry? Nerveblocksandneuromodulationdevices(suchastranscranialmagneticstimulation,transcranial supraorbitalstimulation,andnoninvasivevagalnervestimulation)areotheroptionsforpatientswho cannottolerateorwhofailtorespondtopharmacologictherapy.
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Tension-typeHeadache
Tensionheadachesarethe“vanilla”ofheadachemedicine.Thisisnottobelittlethem(forthosewho experiencetensionheadaches,theycanwreakhavoconproductivityanddestroyotherwisegooddays), buttohelpyourememberthattheyareeffectively“featureless”inthattheydonotpresentwithanyofthe symptomsassociatedwithmigraine,suchasnausea,vomiting,photophobia,orphonophobia.Theyare mostoftenbilateral,classicallydescribedasatightening“band-like”sensationaroundthehead,andare mild-to-moderateinintensity.
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Tensionheadachesmaybedevoidofspecificdefiningfeatures,buttheycanstillbeunpleasantand distressingifrarelydisabling.
Thepathogenesisisnotreallyunderstood.Despiteitsname,neithernervoustensionnormuscular tensionhasbeenconvincinglyidentifiedasanetiologicfactor.
AcetaminophenandNSAIDsarethetreatmentsofchoice,butyouwillwanttominimizetheiruseas muchaspossibletoavoidpotentialsideeffects.Althoughthereisnoknowncausallinkbetweenstress andtensionheadaches,relaxationtechniquescanbehelpful(andwhat’sthedownside?).Tricyclic antidepressants(mostcommonlyamitriptyline)canbeeffectivepreventiveagents.
Althoughmigraineandtensionheadachearebyfarthemostcommoncausesofprimaryheadache,there areotherprimaryheadachedisordersthatyoushouldbefamiliarwith.Theseincludethetrigeminal autonomiccephalalgias(TACs),theneuralgias,andseveralotherdisordersthatwewilltouchonbriefly.
TrigeminalAutonomicCephalalgias(TACs)
Theseareagroupofheadachedisorderscharacterizedby:
1. Unilateralpaininatrigeminaldistribution(i.e.,involvingtheV1,V2,and/orV3branchesofthetrigeminalnerve),and
2. Ipsilateralautonomicfeatures,whichcanincludelacrimation,conjunctivalinjection,nasalcongestion,rhinorrhea,eyelidedema,ptosis, miosis,andfacialsweating.
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Trigeminalnervedistributions:V1(ophthalmic),V2(maxillary),V3(mandibular).
TherearefourtypesofTACs.Theeasiestwaytokeepthemstraightistoclassifythemby(1)headache duration—withSUNCT/SUNAhavingtheshortestdurationandhemicraniacontinuahavingthelongest duration—and(2)theirresponsetoindomethacin(seetableonthefollowingpage).
1.  SUNCT (short-lasting unilateral neuralgiform headache with conjunctival injection and tearing) and SUNA (short-lasting unilateral neuralgiform headache with autonomic symptoms). Just roll right off the tongue, don’t they? These headaches are characterizedbysudden attacksofstabbing,unilateralpainthatlastonlya few secondsbutcan occurhundredsoftimes a day. The attacksareoftentriggeredbytactileorcutaneousstimuli,suchasbathing,brushing one’shair,orshaving.SUNCTpresentswithboth conjunctival injection and tearing; SUNA presents with other autonomic features, and can include either conjunctival injection OR tearingbutnotboth. These headaches are too brief totreat acutely (althoughIV lidocainecanbeusedin particularly severe cases). Lamotrigineisfirstlineforprophylaxis.
2. ParoxysmalHemicrania.These attacksareclinicallysimilartoSUNCTandSUNA,butlastlonger(2to30minutesper attack)and occur less frequently (1 to 40 attacks/day). The headaches are also too brief to treat acutely but are responsive to indomethacin prophylaxis.
3. ClusterHeadache.ThisisthemostcommontypeofTACbutagainisfarlesscommonthanmigraineortensionheadache.Compared to paroxysmal hemicrania, cluster headaches can last longer (15 minutes to 3 hours) but typically occur less frequently (1 to 8 attacks/day).Theytendtocomeincycleslasting6to12weeks,andoftenpresentinacircadianfashion, withattacksoccurringatthe sametimeeachday.Thepainissevere andis oftenassociatedwithasenseofrestlessness(unlikeinmigraine,whenpatientswantto
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lieverystill).Acutely,clusterheadachescanbetreatedwithoxygen(100%vianonrebreather)andtriptansgivensubcutaneouslyorvia nasal spray. Verapamil is the medication most often used for prevention. Topiramate, valproic acid, lithium, and indomethacin are second-lineoptions.Galcanezumab,oneoftheCGRPmonoclonalantibodies,hasalsobeenapprovedforprophylacticclusterheadache treatment.Becauseittakesthesemedicationsafewweekstokickin,ashortsteroidcourseisoftenusedintheinterim.Occipitalnerve blockshavealsobeenshowntohelpreducethelengthofclusterperiodsforpatients.
4. HemicraniaContinua.Theseheadachespersistfordaystomonthsatatime.Theyarecharacterizedbyaconstant,mild-to-moderate baselinepainthatisintermittentlypunctuatedbyamoresevere,sharp,andstabbingpain.Theycanbeaccompanied byaforeignbody sensationor itchingof the eye,as wellas othermore typical migrainousfeaturessuch as nausea,vomiting,photo- andphonophobia. Associatedautonomic symptomsare present but are oftenless prominent than with the other TACs. Hemicrania continuaisalways indomethacin-responsive:iftheheadachedoesnotimprovewithindomethacin,itisn’themicraniacontinua.
SUNCT/SUNA Parox ysmalHemicrania Cluster HemicraniaContinua
Headacheduration 1–600seconds 2–30minutes 15minutes–3hours Days–Months Headache frequency
1–200/day 1–40/day 1–8/day Continuous
Demographics M>F,ageofonset40s–
70s
F>M,ageofonset20s– 40s
M>F,ageofonset20s– 40s
F>M,ageofonset20s– 40s
AcuteTreatment IVlidocaine None O2
SQ/nasaltriptans
None
Preventive Treatment
Lamotrigine Indomethacin Verapamil,
Galcanezumab
Indomethacin
IndomethacinisanNSAIDthatcanbetoughtotolerateforlongperiodsoftime.Alternativeoptions
includemelatonin(whichhasaverysimilarchemicalstructure)andtopiramate.
Althoughtheseareallexclusivelyclinicaldiagnoses,anMRIiswarrantedbeforemakingthediagnosis inordertoexcludeunderlyingcraniallesions.Pituitarylesionsinparticularcancausesimilartrigeminal­distributionpain.
Box3.7ClusterversusMigraineHeadache
Clusterheadachesareoftenconfusedwithmigraines.Theyshouldn’tbe.Bothare intermittentandseverebutinalmostallotherwaystheyaredistinct.Clusterheadaches occurwithapredictablepatternoveraperiodofseveralweeks,whereasmigrainescome andgowithfarlessregularity.Andoneofthemostusefuldistinguishingfeaturesisonewe havealreadyalludedto—migrainesmakeyouwanttoliedownandescapefromtheworldof sensations,whereasclusterheadachestypicallymakeyouwanttomovearound.
SinusHeadache
Alwaysaniffydiagnosis.Althoughmanypatientsthinkoftheirheadachesas“sinusheadaches,”andmany physicianscontinuetomakethisdiagnosis,inrealityveryfewheadachesaredirectlyassociatedwith acuteorchronicsinusitis.Stuffynose,headfullness,andheadpressureareactuallycommonfeaturesof migraine,whichismoreoftenthannotthecorrectdiagnosisinthesepatients.
Doesthismeanthatpatientswithactualupperrespiratoryinfectionsdon’tgetheadaches?Ofcourse not.Thepointisthatmanypatientswith“sinus”-typeheadachesdonothaveupperrespiratoryinfections oracutesinusitis,andarehavingmigrainesinstead.
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Painaroundthesinuses,withoutevidenceofanupperrespiratoryinfection,israrelyasinusheadache, butfarmoreoftenamanifestationofmigraine.
Neuralgias
Neuralgiasarecharacterizedbysharp,shock-likepainthatfollowsthecourseofanerve.Their presentationisquitedistinctandthediagnosisisusuallyclearfromthepatient’shistory.Thetwomost commonneuralgiasaretrigeminalneuralgia(TN)andoccipitalneuralgia.
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Painfultrigeminalnerveirritation.
TrigeminalNeuralgia(TN),TNpresentswithunilateral,briefepisodesofshock-likepainthatoccurin thedistributionofoneormoredivisionsofthetrigeminalnerve;themaxillaryandmandibularbranches (V2andV3)aremorecommonlyaffectedthantheophthalmicdivision(V1).SimilartoSUNCTand SUNA,TNcanbetriggeredbyinnocuouscutaneousstimulisuchasbrushingone’shairoralightgustof wind.Attacksareshort,lastingapproximately10secondsto2minutes;unlikeSUNCTandSUNA, however,theyarefollowedbyarefractoryperiodduringwhichattackscannotoccur.TNisclassified intothreebroadcategories:
1.  Classical TN. Classical TN is due to neurovascular compression causing morphologicalchanges in the trigeminal nerve root. An abnormal vascular loop compresses the trigeminal nerve around its dorsal root entry zone into the pons, resulting in destructive demyelinationandpain.
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