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World prevalence of migraineWorld prevalence of migraine
1-year prevalence rates1-year prevalence rates Population-based studiesPopulation-based studies IHS criteria (or modified)IHS criteria (or modified)
USA 12%USA 12%
Chile 7%Chile 7%
Japan 8%Japan 8%Italy 16%Italy 16%
Denmark 10%Denmark 10%
France 8%France 8%††
Switzerland 13%Switzerland 13%
Rasmussen and Olesen (1994); Rasmussen (1995);Rasmussen and Olesen (1994); Rasmussen (1995);Lipton Lipton et al (et al (1994); Lavados and Tenhamm (1997); 1994); Lavados and Tenhamm (1997);
Sakai and Igarashi (1997)Sakai and Igarashi (1997)††Prevalence measured over a few yearsPrevalence measured over a few years
Prevalence of migraine by Prevalence of migraine by sex and agesex and age
FemalesFemalesMalesMales3030
2525
2020
1515
1010
55
00
2020 3030 4040 5050 6060 7070 8080 100100
Migraine prevalence (%)Migraine prevalence (%)
Age (years)Age (years)
Lipton and Stewart (1993)Lipton and Stewart (1993)The American Migraine Study (The American Migraine Study (nn=2479 migraine sufferers)=2479 migraine sufferers)
Cady (1999); Warshaw Cady (1999); Warshaw et alet al (1998) (1998)
Diagnosis of migraineDiagnosis of migraine
Diagnosis depends on patient historyDiagnosis depends on patient history
No specific tests or clinical markers for migraineNo specific tests or clinical markers for migrainePositive diagnosis if attack history fulfils IHS Positive diagnosis if attack history fulfils IHS criteria for migrainecriteria for migraine
Other pointers include:Other pointers include:– family history of migrainefamily history of migraine– age of onset <45age of onset <45– presence of aurapresence of aura– menstrual associationmenstrual association
Organic disease must be excludedOrganic disease must be excluded
Migraine CriteriaMigraine Criteria
5 attacks lasting 45 attacks lasting 4––72 h72 h
2 of the following 42 of the following 4– UnilateralUnilateral– PulsatingPulsating– Moderate or severe intensityModerate or severe intensity– Aggravation by routine physical activityAggravation by routine physical activity
1 of the following1 of the following– Nausea and/or vomitingNausea and/or vomiting– Photophobia and phonophobiaPhotophobia and phonophobia
Not attributable to another disorderNot attributable to another disorder
SULTANS: two from column A, one SULTANS: two from column A, one from column Bfrom column B
evereevere
nini
ateralateral
hrobbinghrobbing
Ctivity worsensCtivity worsens
auseaausea
Lite and sound Lite and sound ensitivityensitivity
What is migraine?What is migraine?Migraine without aura Migraine without aura (MO)(MO) Migraine with aura (MA)Migraine with aura (MA)
Headache Classification Committee of IHS (1988)Headache Classification Committee of IHS (1988)
At least five attacks fulfilling these At least five attacks fulfilling these criteria:criteria:
Headache lasting 4–72 h Headache lasting 4–72 h (2–48 h in children)(2–48 h in children)
At least two attacks fulfilling these At least two attacks fulfilling these criteria:criteria:
At least three of the following:At least three of the following:– one or more fully reversibleone or more fully reversible
aura symptomsaura symptoms– gradually developing orgradually developing or
sequential aura symptomssequential aura symptoms– no one aura symptom lastsno one aura symptom lasts
longer than 1 hlonger than 1 h– headache shortly follows or headache shortly follows or
accompanies auraaccompanies aura Accompanied by at least one of:Accompanied by at least one of:– nausea nausea
– vomitingvomiting
– photophobia and/or photophobia and/or phonophobiaphonophobia
No evidence of organic diseaseNo evidence of organic disease
With at least two of:With at least two of:– unilateral locationunilateral location– pulsating qualitypulsating quality– moderate/severe intensitymoderate/severe intensity– aggravated by activityaggravated by activity
No evidence of organic diseaseNo evidence of organic disease
Clinical features of migraineClinical features of migraine
SleepySleepy
AnorexiaAnorexia nauseanausea Vomiting
Vomiting
yawningyawning
PhonophobiaPhonophobia
PhotophobiaPhotophobia
PhonophobiaPhonophobia
PhotophobiaPhotophobia
OsmophobiaOsmophobia
OsmophobiaOsmophobia
Vomiting
VomitingDeep sleepDeep sleep
HeadacheHeadache
IIIIII IV IVHeadache Resolution Headache Resolution
Blau (1992)Blau (1992)
II II II NormalNormal Prodromes Aura Prodromes Aura
NormalNormal
AppetiteAppetite
Awake/sleepAwake/sleep
Light toleranceLight tolerance
SmellSmell
NoiseNoise
Fluid balanceFluid balance
CravingCraving
TiredTired yawningyawning
HeightenedHeightened
perceptionperception
FluidFluid retentionretention
VVPostdromes NormalPostdromes Normal
Limited
Limited
Light toleranceLight tolerance
NoiseNoise
SmellSmell
Fluid balanceFluid balance
TiredTired
FeelingFeeling
high orhigh or
lowlow
DiuresisDiuresis
AppetiteAppetite
Awake/sleepAwake/sleep
food tolerance food tolerance
NormalNormal
3
Migraine Patients Suffer From Pain and Symptoms
Adapted from Lipton et al. Headache. 2001.
30%
74%
81%
99%
0 20 40 60 80 100
Vomiting
Nausea
Photophobia
Moderate to severe pain
Percentage of patients reporting symptom
77%Phonophobia
5
Migraine Remains Underdiagnosedand Undertreated
Lipton et al. Neurology. 2002.
5%
23%
48%
23%
49%
0
25
50
75
100
MD diagnosis Rx medication only
OTC medication only
Both Rx and OTC
No medication
Per
cen
tag
e o
f p
atie
nts
IMPORTANT DIAGNOSTIC IMPORTANT DIAGNOSTIC CONSIDERATIONSCONSIDERATIONS
Recurring moderate to severe headache is migraine until proven otherwise
Russell MB, et al. Cephalalgia. 1996.Pryse-Phillips WEM, et al. Can Med Assoc J. 1997.
No single criterion necessary nor sufficient for diagnosis
15% of patients have a neurological aura
IHS criteria do not require GI symptoms
Vomiting occurs in < 1/3 of patients
41% of migraine patients report bilateral pain
50% of the time, pain is non-pulsating
Premonitory, aura and postdromal Premonitory, aura and postdromal symptomssymptoms
ProdromeProdrome Occurs in 60% of attacksOccurs in 60% of attacks Alterations inAlterations in
– moodmood– alertnessalertness– appetiteappetite
Originate in hypothalamus Originate in hypothalamus and frontal lobesand frontal lobes
Silberstein and Lipton (1994); Silberstein and Lipton (1994);
Lance (1993); Blau (1992)Lance (1993); Blau (1992)
PostdromePostdrome Occurs in 90% patientsOccurs in 90% patients Symptoms can persist for Symptoms can persist for
several daysseveral days– lethargylethargy– exhaustionexhaustion– impaired concentrationimpaired concentration– irritabilityirritability– sluggishnesssluggishness– diminished appetitediminished appetite– euphoriaeuphoria
AuraAura Occur in MA (20% patients)Occur in MA (20% patients) Visual symptomsVisual symptoms
– blurring, ripplingblurring, rippling– spots or flashesspots or flashes– fortification spectrafortification spectra– scotomascotoma
Sensory symptomsSensory symptoms– numbness/tinglingnumbness/tingling
Motor symptomsMotor symptoms– hemiparesishemiparesis
MIGRAINE WITH AURAMIGRAINE WITH AURA(FORMERLY “CLASSIC” (FORMERLY “CLASSIC”
MIGRAINE)MIGRAINE)
Visual > sensory > motor, language, brainstem
Gradual evolution:
5–20 minutes (<60 minutes)
May or may not be associated with headache
Complex array of symptoms reflecting focal cortical or brainstem dysfunction
International Headache Society. Cephalalgia. 1988;8;(suppl 7):1-96.
DIAGNOSIS AND TESTINGDIAGNOSIS AND TESTING
Detailed History and ExaminationDetailed History and Examination
Primary Headache? Preliminary DiagnosisPrimary Headache? Preliminary Diagnosis
NONO
SecondaryHeadacheSecondaryHeadache
DiagnosticTesting
DiagnosticTesting
AtypicalFeatures
YESYES
REASONS FOR REASONS FOR MISDIAGNOSIS OF MIGRAINE MISDIAGNOSIS OF MIGRAINE
AS TTH OR SINUSAS TTH OR SINUSSinus
Raskin NH. Headache. 2nd ed. 1988; Barbanti P, et.al. Cephalalgia. 2001;Kaniecki R. Cephalalgia. 2001.
Migraine is a referred pain syndrome (V1, C1-C3)
Up to 50% of migraine patients report their headaches are influenced by weather
45% of migraine patients report attack related ‘sinus’ symptoms including lacrimation, rhinorrhea, nasal congestion
Tension-Type Headache
75% of migraine patients report posterior neck pain/tightness/stiffness during attacks
Stress/anxiety frequent migraine trigger
Migraine is bilateral in up to 40% of patients
Differential diagnosis of Differential diagnosis of primary headachesprimary headaches
Dubose Dubose et alet al (1995); Goadsby (1999); Marks and Rapoport (1997) (1995); Goadsby (1999); Marks and Rapoport (1997)
Family historyFamily history YesYes
SexSex More femalesMore females
OnsetOnset Variable Variable
LocationLocation Usually unilateralUsually unilateralin adultsin adults
Character/severityCharacter/severity PulsatilePulsatileThrobbingThrobbing
Frequency/Frequency/ 2–72 h/attack2–72 h/attack durationduration 1 attack/year to1 attack/year to
>8 per month>8 per month
AssociatedAssociated Visual auraVisual aurasymptomssymptoms PhonophobiaPhonophobia
PhotophobiaPhotophobiaPallorPallorNausea/vomitingNausea/vomiting
Clinical featureClinical feature MigraineMigraine
NoNo
More malesMore males
During sleepDuring sleep
Behind/aroundBehind/aroundone eyeone eye
Excruciating/Excruciating/sharpsharpSteadySteady
15–90 min/attack15–90 min/attack1–8 attacks/day1–8 attacks/dayfor 3–16 weeks for 3–16 weeks 1–2 bouts/year1–2 bouts/year
SweatingSweatingFacial flushingFacial flushingNasal congestionNasal congestionPtosisPtosisLacrimationLacrimationConjunctival injectionConjunctival injectionPupillary changesPupillary changes
Cluster headacheCluster headache
YesYes
More femalesMore females
Under stressUnder stress
Bilateral in bandBilateral in bandaround headaround head
DullDullPersistent Tightening/pressingPersistent Tightening/pressing
30 min to 7 days 30 min to 7 days 3–4 attacks/week3–4 attacks/weekto 1–2 attacks/yearto 1–2 attacks/year
Mild photophobiaMild photophobiaMild phonophobiaMild phonophobiaAnorexiaAnorexia
Tension headacheTension headache
WORRISOME HEADACHE RED WORRISOME HEADACHE RED FLAGSFLAGS
“SNOOP”“SNOOP”
Older: new onset and progressive headache, especially in middle-age >50 (giant cell arteritis)
Systemic symptoms (fever, weight loss) or
Secondary risk factors (HIV, systemic cancer)
Neurologic symptoms or abnormal signs (confusion, impaired alertness, or consciousness)
Onset: sudden, abrupt, or split-second
Previous headache history: first headache or different (change in attack frequency, severity, or clinical features)
Headache ‘red flags’Headache ‘red flags’First or worst headacheFirst or worst headache
Significant change from previous headache patternSignificant change from previous headache pattern
– no longer fulfils IHS criteriano longer fulfils IHS criteria
New onset headache in middle age or laterNew onset headache in middle age or later
New or progressive headache that lasts for daysNew or progressive headache that lasts for days
Precipitation of headache by coughing/sneezing/Precipitation of headache by coughing/sneezing/bending downbending down
Systemic symptoms such as myalgia, fever, malaise, Systemic symptoms such as myalgia, fever, malaise, weight loss, scalp tenderness, jaw claudicationweight loss, scalp tenderness, jaw claudication
Focal symptoms, seizures, confusion, impaired Focal symptoms, seizures, confusion, impaired conciousness, physical examination abnormalitiesconciousness, physical examination abnormalitiesPryse-Phillips Pryse-Phillips et alet al (1997) (1997)
SUDDEN ONSET HEADACHESUDDEN ONSET HEADACHE
Primary Secondary
SAH
Pituitary apoplexy
Venous sinus thrombosis
Arterial dissection
Meningoencephalitis
Acute hydrocephalus
Acute hypertension
Spontaneous intracranial hypotension
Idiopathic thunderclap headache (TCH)
Exertional headache
Cough headache
Sexual headache
deBruijn, SF, et al. Lancet. 1996; Lancet. 1998.
LUMBAR PUNCTURELUMBAR PUNCTURE
Headache associated with fever, confusion, meningism, or seizures
Thunderclap headache with negative CT head
Subacute progressive headache
High or low CSF pressure suspected (even if papilledema is absent)
The first unusually severe headache
Evans RE, Rozen TD, Adelman JU. In: Wolff’s Headache And Other Head Pain. 2001.
SENSITIVITY OF CT SCAN IN SENSITIVITY OF CT SCAN IN SUBARACHNOID HEMORRHAGE SUBARACHNOID HEMORRHAGE
(SAH)(SAH)
van Gijn J, van Dongen KJ. Neuroradiology. 1982.Kassell NF et al. J Neurosurg. 1990.
TIME AFTER TIME AFTER HEADACHE HEADACHE
ONSETONSET
PROBABILITYPROBABILITY(%)(%)
DAY 0DAY 0 9595
DAY 3DAY 3 8080
1 WEEK1 WEEK 5050
2 WEEKS2 WEEKS 3030
3 WEEKS3 WEEKS ~0~0
DIAGNOSIS TESTINGDIAGNOSIS TESTINGCT AND MRICT AND MRI
Consensus expert opinion MRI is more sensitive
Role of CT or MRI in patients with nonmigraine headache is unclear
In patients with recurrent migraine, neither CT nor MRI is warranted except in cases where: Recent substantial change in headache pattern History of seizures Focal neurologic symptoms or signs
Report of Quality Standards Subcommittee of AAN. Neurology. 1994.
DIAGNOSTIC TESTING DIAGNOSTIC TESTING ELECTROENCEPHALOGRAPHYELECTROENCEPHALOGRAPHY
EEG may be useful in those patients with Alteration or loss of consciousness Residual focal neurologic defects or
encephalopathy Atypical migrainous aura
EEG is not useful In the routine evaluation of patients with headache
to exclude structural cause
Report of Quality Standards Subcommittee of AAN. Neurology. 1995.
MR AND CONVENTIONAL MR AND CONVENTIONAL ANGIOGRAPHYANGIOGRAPHY
MR Angiography
Acute SAH
Arterial dissection
CNS vasculitis
Angiography
Aneurysm (>5 mm)
Arterial dissection
Venous thrombosis
(MR venography)
AV malformation
Leclerc X et al. Neuroradiology. 1999.
INDICATIONS FOR GADOLINIUM INDICATIONS FOR GADOLINIUM ENHANCED MRIENHANCED MRI
CerebrovascularCerebrovascular– Arterial dissection Arterial dissection
(MRA)(MRA)– Cerebral venous Cerebral venous
sinus thrombosis sinus thrombosis (MRV)(MRV)
– CNS vasculitisCNS vasculitis
TumorsTumors– Posterior fossaPosterior fossa– PituitaryPituitary– LeptomeningesLeptomeninges
Herpes encephalitis
High and low intracranial pressure syndromes
MRA = magnetic resonance angiography.MRV = magnetic resonance venography.
Bousser MG et al; Wall M et al; Mokri B; and Newman C, Solomon S. In: Wolff’s Headache And Other Head Pain. 2001. Tien RD et al. AJR Am J Roentgenol. 1993.
CEREBRAL VENOUS SINUS THROMBOSISCEREBRAL VENOUS SINUS THROMBOSIS
Bousser MG et al. In: Wolff’s Headache And Other Head Pain. 2001.
STRATEGIES FOR MIGRAINE STRATEGIES FOR MIGRAINE TREATMENTTREATMENT
Preemptive treatmentMigraine triggertime-limited and
predictable
Preemptive treatmentMigraine triggertime-limited and
predictable
PreventiveTreatment
Decrease inmigraine frequency
warranted
PreventiveTreatment
Decrease inmigraine frequency
warranted
Acutetreatment
To stop pain and prevent progression
Acutetreatment
To stop pain and prevent progression
Silberstein SD. Cephalalgia. 1997.
ACUTE MIGRAINE TREATMENTACUTE MIGRAINE TREATMENT
Discuss problems that arise in the acute management of migraine
Evaluate the general principles of treatment
Review the clinical evidence for acute treatment alternatives
Present an approach for selecting and sequencing acute therapies
Objectives
Patient education and behavioral management Nature and mechanism of the disorder Strategies for identifying and avoiding triggers Behavioral strategies
Regular sleep, exercise, meals Stress management, biofeedback Cognitive behavioral therapy
PRINCIPLES OF MIGRAINE PRINCIPLES OF MIGRAINE MANAGEMENTMANAGEMENT
Establish a therapeutic partnership
Pharmacologic management Acute treatment Preventative strategies
NONPHARMACOLOGIC NONPHARMACOLOGIC TREATMENTSTREATMENTS
Insufficient evidence to recommend: GRADE C Acupuncture TENS Cervical manipulation Occlusal adjustment Hyperbaric oxygen Hypnosis
Goslin RE et al. Behavioral and Physical Treatments for Migraine Headache. 1999.
Effective: GRADE A Relaxation training Thermal biofeedback with relaxation training EMG biofeedback Cognitive behavioral therapy
The benefits of behavioral therapy (eg, biofeedback, relaxation) are in addition to preventive drug therapy (eg, propranolol, amitriptyline): GRADE B
Goals of TreatmentGoals of Treatment
Establish diagnosisEstablish diagnosisEducate patientEducate patientDiscuss findingsDiscuss findingsEstablish reasonable expectationsEstablish reasonable expectationsInvolve patient in decisionsInvolve patient in decisionsEncourage Pt to avoid triggersEncourage Pt to avoid triggersChoose the best treatment (tailoring)Choose the best treatment (tailoring)Create treatment planCreate treatment plan
MIGRAINE TRIGGERSMIGRAINE TRIGGERS
Diet
Hormonal changes
Head trauma
Stress and anxiety
Sleep deprivation or excess
Environmental factors
Physical exertion
ACUTE MIGRAINE MEDICATIONSACUTE MIGRAINE MEDICATIONS
Nonspecific NSAIDs Combination analgesics Opioids Neuroleptics/antiemetics Corticosteroids
Specific Ergotamine/DHE Triptans
ACUTE THERAPIES FOR ACUTE THERAPIES FOR MIGRAINEMIGRAINE
Nonspecific Prescription Medications Butorphanol IN Ibuprofen/Naproxen sodium Prochlorperazine IV
GROUP 1a: Substantial empirical evidence and pronounced clinical benefit in
migraine
Silberstein SD. Neurology. 2000.
Migraine-Specific Medications Triptans DHE
SC, IM, IN, IV (plus antiemetic)
GROUP 2: Moderate empirical evidence and clinical benefit
Opioids Others
ACUTE THERAPIES FOR ACUTE THERAPIES FOR MIGRAINEMIGRAINE
Over-the-Counter Analgesics Aspirin Acetaminophen, aspirin, plus caffeine
Silberstein SD. Neurology. 2000.
GROUP 1b: Substantial empirical evidence of clinical benefit in restricted populations
CONSIDERATIONS IN INITIAL CONSIDERATIONS IN INITIAL ACUTE THERAPYACUTE THERAPY
As disability increases, nonspecific treatments less likely to work
In the most severely afflicted 25% of migraine sufferers, an NSAID-metoclopramide combination is successful in only 25% of patients
Try to get the treatment “right” the first time
Match treatment intensity to attack severity (stratified care)
Ask about migraine disability and impact
Silberstein SD. Neurology. 2000.
Trigeminovascular Trigeminovascular model of migrainemodel of migraine
Adapted from Goadsby and Olesen (1996)Adapted from Goadsby and Olesen (1996)
Dura materDura mater
AfferentAfferent
Trigeminal Trigeminal ganglionganglion
Peptide releasingPeptide releasingneuronesneurones
Dura materDura mater
EfferentEfferent
Trigeminal Trigeminal nervenerve
AfferentAfferent
BloodBloodvesselsvessels
EfferentEfferent
CGRP/SPCGRP/SPreleaserelease
DilatationDilatation
CraniumCranium
Mechanisms for treatmentMechanisms for treatment
CGRPCGRPNKNKSPSP
5-HT5-HT1F1F5-HT5-HT1D1D
5-HT5-HT1B1B
Blood vesselBlood vessel
Trigeminal Trigeminal nervenerve
Adapted from Goadsby (1997)Adapted from Goadsby (1997)
CGRPCGRP calcitonin genecalcitonin gene related peptiderelated peptide
NKNK neurokinin Aneurokinin A
SPSP substance Psubstance P
triptantriptan
CONSTRICTIONCONSTRICTION
INHIBITIONINHIBITION
TRIPTANSTRIPTANS
As a class, relative to nonspecific therapies, triptans provide Rapid onset of action High efficacy Favorable side effect profile
Adverse events and contraindications
Selective 5-HT1B/1D/1F agonists
Silberstein SD. Neurology. 2000.
TRIPTANS:TRIPTANS:TREATMENT CHOICESTREATMENT CHOICES
Are there differences Are there differences between the triptans?between the triptans?
If one triptan fails, will If one triptan fails, will another triptan work?another triptan work?
Zolmitriptan Tablet (2.5, 5 mg) Nasal spray (5 mg)
Rizatriptan Tablet (5, 10 mg)
Naratriptan Tablet (1, 2.5 mg)
Question and Answer
AlmotriptanTablet (6.25, 12.5 mg)
FrovatriptanTablet (2.5 mg)
Sumatriptan Tablet (25, 50, 100 mg) Injection (6 mg) Nasal spray (5, 20 mg*)
* Pediatric efficacy shown Ferrari MD et al. Lancet. 2001.
EletriptanTablet (20, 40 mg)
ROUTES OF ADMINISTRATIONROUTES OF ADMINISTRATION
Suppositories: antiemetics, ergots, opioids
Oral therapies: most medications
Nasal sprays: sumatriptan, DHE, butorphanol, zolmitriptan
Injectable (SL, IM, IV) sumatriptan, DHE, injectable NSAIDs, opioids, neuroleptics
FORMULATION: ONSETFORMULATION: ONSET
Increasing SpeedIncreasing Speed
ParenteralParenteralOralOral
TabletTablet
SLSL
ININ
PRPR
IM/SCIM/SC IVIV
SumatriptanSumatriptan
Sumatriptan (Glaxo Wellcome) Sumatriptan (Glaxo Wellcome) – 5-HT5-HT1B/1D1B/1D agonist agonist
N
H
NMe2
MeNHSO2
Major advance – good efficacy with Major advance – good efficacy with subcutaneous formulationsubcutaneous formulation
Slow onset (2–4 h p.o.); LogD -1.5Slow onset (2–4 h p.o.); LogD -1.5
Short tShort t1/21/2 (2 h) (2 h)
Ferrari Ferrari et alet al (1995) (1995)
22
Efficacy of Eletriptan: Comprehensive Relief at 2 Hours
Relief of Photophobia, %
Headache response, %
Relief of Nausea, %
Relief of Phonophobia, %
Pain-free response, %
Placebo
0
20
40
60
4030
80
2010
40
60
80
80
40
60
80
Adapted from Mathew et al. Headache. 2003.
Sumatriptan was blinded using encapsulation. Encapsulated sumatriptan was bioequivalent to commercial tablets.
60
*†
*†
*†*†
*†
*
*
*
* *
*P<.001 vs placebo. †P<.05 vs sumatriptan.
Sumatriptan 100 mgEletriptan 40 mg
20 20
2040
24
Incidence of Adverse Events*
*Events experienced by 2% of patients. Incidence following a single dose of study medication.
Relpax® (eletriptan HBr) Prescribing Information. Data on file. Pfizer Inc., New York, NY.
Placebo 20 mg 40 mg 80 mg(n=988) (n=431) (n=1774) (n=1932)
10%5%4%3%Asthenia
4%2%1%1%Chest tightness/pain/pressure
4%3%2%2%Dry mouth
4%3%3%2%Paresthesia
4%3%4%3%Headache
7%6%3%3%Dizziness
7%6%3%4%Somnolence
8%5%4%5%Nausea
Eletriptan
The maximum recommended single dose of eletriptan is 40 mg.
00
2020
4040
6060
8080
100100
00 11 22 33 44
PlaceboPlacebo
Time post dose (h)Time post dose (h)
nn=563=563
Headache responses continue to Headache responses continue to improve over time after eletriptan improve over time after eletriptan
dosingdosingTime course for headache responseTime course for headache response
Pfizer, data on filePfizer, data on file
% Patients with response% Patients with response
20 mg eletriptan20 mg eletriptan
40 mg eletriptan40 mg eletriptan
Study 314Study 314****PP<0.05 vs placebo for all doses<0.05 vs placebo for all doses
80 mg eletriptan80 mg eletriptan****
****
****
ACUTE TREATMENT ACUTE TREATMENT PRINCIPLESPRINCIPLES
Early intervention
Use correct dose and formulation
Use a maximum of 2–3 days/week
Use preventive therapy in selected patients
stratified care
Silberstein SD. Neurology. 2000; Lipton RB, et al. JAMA. 2000.
BASIS OF STRATIFICATIONBASIS OF STRATIFICATION
Symptom profile Prominent nausea and vomiting may require parenteral
therapy
Headache frequency Consider risk of medication overuse
Patient history and preferences Consider adverse events and prior experience
Headache onset and severity Fast onset may benefit from parenteral therapy Disability predicts treatment needs
Silberstein SD. Neurology. 2000.
MIDAS ScoreMIDAS ScoreDays in Last 3 monthsDays in Last 3 months
You’ve missed work or school due to your headaches? You’ve missed work or school due to your headaches? Your productivity at work or school reduced by half or more due to Your productivity at work or school reduced by half or more due to your headaches? your headaches? (Please do not include days you counted in (Please do not include days you counted in question 1 where you missed work or school)question 1 where you missed work or school) You not do household work because of your headaches? You not do household work because of your headaches? Your productivity in household work reduced by half or more Your productivity in household work reduced by half or more because of your headaches?because of your headaches? (Do not include days you counted in (Do not include days you counted in question 3 where you did not do household work)question 3 where you did not do household work) You missed family, social or leisure activities because of your You missed family, social or leisure activities because of your headaches? headaches? A. Had a Headache? If a headache lasted more than one day count A. Had a Headache? If a headache lasted more than one day count each day. each day.
B. On a scale of 1-10 on average how painful were those B. On a scale of 1-10 on average how painful were those headaches? (Where 0 is no pain, 10 is as bas as pain could be??headaches? (Where 0 is no pain, 10 is as bas as pain could be??
GradeDefinitionScoreGradeDefinitionScore
I Minimal or infrequent disability 0-5I Minimal or infrequent disability 0-5
II II Mild or infrequent disability 6-10Mild or infrequent disability 6-10
III III Moderate disability 11-20Moderate disability 11-20
IV IV Severe disability 21+Severe disability 21+
DISABILITY IN STRATEGIES OF DISABILITY IN STRATEGIES OF CARE (DISC) STUDYCARE (DISC) STUDY
Step care across attacks ASA + M Assess response after 3 attacks Escalate treatment to zolmitriptan if ASA + M fails 2/3 or 3/3
Stratification based on disability MIDAS Grade II—ASA + M MIDAS Grade III, IV—Triptan (zolmitriptan)
Step care within attacks ASA + M Assess response at 2 hours
Rescue with zolmitriptan prn
Stratified care produces better headache response less disability time
Disability can be used to predict treatment needs
Compared 3 strategies of migraine management over 6 attacks
Lipton RB et al. JAMA. 2000.
TREAT MIGRAINE WHEN PAIN IS MILDTREAT MIGRAINE WHEN PAIN IS MILD
Retrospective analysis of 3 studies confirmed triptan treatment while pain is mild provided higher pain-free response at 2 h than ergotamine plus caffeine or aspirin plus metoclopramide, and reduced need for redosing
Prospective rizatriptan study of 1919 patients confirms triptan effectiveness at all levels of pain but enhanced benefit if taken while pain is mild
Post-hoc analysis of Spectrum study (26 patients) showed sumatriptan provided more effective relief with less recurrence when taken while pain was still mild
Cady RK et al. Headache. 2000; Cady RK et al. Clin Ther. 2000; Hu XH et al. Headache. 2002.
In patients with migraine, sumatriptan effectively treats all 3 types
TRIPTANS IN THE SPECTRUM TRIPTANS IN THE SPECTRUM OF MIGRAINEOF MIGRAINE
In patients with pure TTH, sumatriptan is not effectiveIn migraine sufferers TTH, has a migraine-like mechanism, whereas pure TTH has a different mechanism
Patients with disabling migraine have different headache types, including migraine, migrainous, and tension-type headache (TTH)
Lipton et al. Headache. 2000; Cady RK et al. Cephalalgia. 1997.
Therefore, sumatriptan can effectively treat TTH in migraine sufferers, probably because it is a form of mild migraine
RECURRENCE & REBOUNDRECURRENCE & REBOUND
Rebound: Recurring headache induced by repetitive and chronic overuse of acute headache medication
Recurrence: Return of episodic headache during the same attack following acute treatment Prevention: Treat early, add NSAID. Use long
duration triptan or DHE
Treatment: Repeat initial acute headache drug; almost always effective
Tfelt-Hansen P et al. Drugs. 2000; Capobianco DJ et al. Headache. 2001.
APPROACH TO DIFFICULT APPROACH TO DIFFICULT HEADACHE PROBLEMSHEADACHE PROBLEMS
Problem Strategy
Headache recurrence Treat earlier, add NSAID, increase dose, change triptans (consider naratriptan or frovatriptan), or switch to DHE
Elderly Use acetaminophen, COX 2 inhibitors, opioids, atypical neuroleptics
Pregnancy Use acetaminophen, opioids, corticosteroids, neuroleptics
Adverse effects Switch triptans, use a different class
Lack of response Treat earlier, increase dose, add metoclopramide or NSAID, change formulation or triptan. Add preventive.
Silberstein SD et al. Wolff’s Headache and Other Head Pain. 2001.
SUMMARY OF ACUTE SUMMARY OF ACUTE MIGRAINE MANAGEMENTMIGRAINE MANAGEMENT
Identify coexistent conditions that influence therapy
Make a specific, credible diagnosis and communicate it
Assess migraine severity and it’s impact on the patient
Determine the patient’s preferences and needs (eg, fast relief, adverse effects tolerance)
Develop a therapeutic partnership with realistic expectations
Create plan based on migraine type and severity, as well as patient’s needs, preferences, and comorbidities
Consider need for preventive treatment
26
Eletriptan Dosing and Administration
• RELPAX should be taken at the onset of a migraine headache.
• RELPAX can be taken with or without food.• RELPAX should not be used within at least 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir and nelfinavir.
• Studies have shown that the pharmacokinetics of eletriptan are generally unaffected by age, gender, or menstrual cycle.
Relpax® (eletriptan HBr) Prescribing Information. Pfizer Inc., New York, NY.
7
Eletriptan: Key Clinical Trials
Phase II/III/IIIPhase II/III/III--b b clinical programclinical program8 trials; N=81058 trials; N=8105
Eletriptan8 trials; n=4704
20 mg2 trials; n=434
40 mg8 trials; n=2797
80 mg6 trials; n=1473
PlaceboPlacebo8 trials; n=15088 trials; n=1508
Cafergot®
1 trial; n=203Sumatriptan
4 trials; n=1690
25 mg1 trial; n=180
50 mg2 trials; n=362
100 mg3 trials; n=1148
Data on file. Pfizer Inc., New York, NY.
Double-blind, Placebo-controlled, Randomized Trials
The maximum recommended single dose of eletriptan is 40 mg.
16
Efficacy of Eletriptan:Pain-free at 2 Hours
Sumatriptan100 mg(n=799)
Placebo(n=406)
Eletriptan40 mg
(n=782)
0
10
20
30
40
50
5%
27%*
36%*†
Per
cen
tag
e o
f p
atie
nts
Sumatriptan was blinded using encapsulation. Encapsulated sumatriptan was bioequivalent to commercial tablets.
Adapted from Mathew et al. Headache. 2003.Data on file. Pfizer Inc., New York, NY.
*P<.0001 vs placebo. †P<.001 vs sumatriptan.
Tension (v. migraine)Tension (v. migraine)
10 attacks lasting 30 min–7 days
2 of the following 4– Bilateral– Not pulsating– Mild or moderate intensity– Not aggravated by routine physical activity
No nausea or vomiting
One or neither photophobia or phonophobia
Not attributable to another disorder
MIGRAINEMIGRAINEADDITIONAL FEATURESADDITIONAL FEATURES
Abatement with sleep
Stereotyped premonitory symptoms
Characteristic triggers
Positive family history
Childhood precursors (motion sickness, episodic vomiting, episodic vertigo)
Osmophobia
Predictable timing around menstruation (or ovulation)
Pryse-Phillips WEM, et al. Can Med Assoc J. 1997.
UNDIAGNOSED MIGRAINE SUFFERERS UNDIAGNOSED MIGRAINE SUFFERERS OFTEN RECEIVE OTHER MEDICAL OFTEN RECEIVE OTHER MEDICAL
DIAGNOSESDIAGNOSES
Lipton RB et al. Headache. 2001.
42%
32%
0% 10% 20% 30% 40% 50%
Sinus HA
Tension-type HA
AURA: MIMICS AND AURA: MIMICS AND SECONDARY CAUSESSECONDARY CAUSES
TIA
Carotid artery dissection
Venous sinus thrombosis
Vasculitis
Tumor
Simple partial seizure
AVM
Bousser MG et al. In: Wolff’s Headache And Other Head Pain. 2001; Campbell JK, Sakai F. In: The Headaches. 2000; Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. 2002.
LATE-LIFE MIGRAINE LATE-LIFE MIGRAINE ACCOMPANIMENTS VS TIAACCOMPANIMENTS VS TIA
Mild headache in 50%
Progression from one accompaniment to another
Repetition (2 similar attacks)
Duration 15–25 minutes
Characteristic midlife flurry of attacks
Build up of scintillations—“march” of paresthesias
Fisher CM. Can J Neurol Sci. 1980; Silberstein SD, Saper JR, Freitag FG. In: Wolff’s Headache And Other Head Pain. 2001.
MIGRAINE AND STROKEMIGRAINE AND STROKE
Clinical manifestations of underlying disease (MELAS, CADASIL)
Causal
Comorbid
Coexistent
Bousser MG et al. In: Wolff’s Headache And Other Head Pain. 2001.
CSF XANTHOCHROMIA AFTER SAH SPECTROPHOTOMETRYCSF XANTHOCHROMIA AFTER SAH SPECTROPHOTOMETRY
Vermeulen M et al. J Neurol Neurosurg Psychiatry. 1989.
TIME AFTER TIME AFTER HEMORRHAGEHEMORRHAGE
PROBABILITYPROBABILITY(%)(%)
12 HOURS12 HOURS 100100
1 WEEK1 WEEK 100100
2 WEEKS2 WEEKS 100100
3 WEEKS3 WEEKS >70>70
4 WEEKS4 WEEKS >40>40
GUIDELINES: WHEN TO USE GUIDELINES: WHEN TO USE PREVENTIVE MANAGEMENTPREVENTIVE MANAGEMENT
Uncommon migraine conditions
Silberstein SD et al. Wolff’s Headache And Other Head Pain. 2001.
Migraine significantly interferes with patient’s daily routine, despite acute Rx
Acute medications contraindicated, ineffective, intolerable AEs, or overused
Frequent headache (2 attacks per week)
Patient preference
Cost considerations
GOALS OF PREVENTIVE GOALS OF PREVENTIVE TREATMENTTREATMENT
Silberstein SD et al. Headache in Clinical Practice. 2nd ed. 2002.
Decrease attack frequency (by 50%), intensity, and duration
Improve responsiveness to acute Rx
Improve function and decrease disability
GENERAL PRINCIPLES OF GENERAL PRINCIPLES OF PREVENTIVE TREATMENTPREVENTIVE TREATMENT
Evaluate therapy Use headache calendar (diary) Attempt to taper and discontinue treatment when
headaches well controlledSilberstein SD et al. Headache in Clinical Practice. 2nd ed. 2002.
Start low and increase dose slowly Use long-acting formulation if compliance an issue
Adequate trial (2–3 months) at an appropriate dosage
Avoid interfering, overused, and contraindicated medications
PREVENTIVE MEDICATIONS:PREVENTIVE MEDICATIONS:DRUG CLASSESDRUG CLASSES
Ca2+-Channel blockers
Silberstein SD. Cephalalgia. 1997.
Anticonvulsants
Antidepressants
-Blockers
NSAIDs
5-HT antagonists
Other Vitamins Minerals Herbs Botulinum
Toxin A
GENERAL PRINCIPLES OF GENERAL PRINCIPLES OF PREVENTIVE TREATMENTPREVENTIVE TREATMENTAssess Coexisting Conditions
Be aware of drug interactions
Silberstein SD et al. Headache in Clinical Practice. 2nd ed. 2002.
Select drug to treat both disorders
Do not use migraine drug if contraindicated for other condition
Do not use drug for other condition that exacerbates migraine
Special concern for women of childbearing potential
COMORBID AND COEXISTENT COMORBID AND COEXISTENT CONDITIONSCONDITIONS
Coexistent disorders are commonly present
Silberstein SD et al. Headache in Clinical Practice. 2nd ed. 2002.
Therapeutic opportunities Treat two disorders with a single drug
Hypertension or angina—use -blocker Depression—use TCAs or SSRIs Epilepsy or mania—use divalproex or topiramate
Therapeutic limitations Avoid -blockers with depression, asthma, or
hypotension
COMORBID CONDITIONCOMORBID CONDITION
DRUGDRUG EFFICACY*EFFICACY*SIDE SIDE
EFFECTS*EFFECTS*RELATIVE RELATIVE
CONTRAINDICATIONCONTRAINDICATION RELATIVE RELATIVE INDICATIONINDICATION
AnticonvulsantsAnticonvulsants
DivalproexDivalproex 4+4+ 2+2+ Liver disease, bleeding Liver disease, bleeding disordersdisorders
Mania, epilepsy, Mania, epilepsy, impulse controlimpulse control
TopiramateTopiramate 3+3+ 2+2+ Kidney stonesKidney stones Epilepsy, mania, Epilepsy, mania, neuropathic painneuropathic pain
GabapentinGabapentin 2+2+ 2+2+ Epilepsy, neuropathic Epilepsy, neuropathic painpain
AntidepressantsAntidepressants
TCAsTCAs 4+4+ 2+2+ Mania, urinary retention, Mania, urinary retention, heart blockheart block
Other pain disorders, Other pain disorders, depression, anxiety depression, anxiety disorders, insomniadisorders, insomnia
SSRIsSSRIs 2+2+ 1+1+ ManiaMania Depression, OCDDepression, OCD
MAOIsMAOIs 2+2+ 4+4+ Unreliable patientUnreliable patient Refractory depressionRefractory depression
PREVENTIVE TREATMENT:PREVENTIVE TREATMENT:DRUG CHOICEDRUG CHOICE
Silberstein SD et al. Headache in Clinical Practice. 2nd ed. 2002.Gray RN et al. Drug Treatments for the Prevention of Migraine. 1999.
*On a scale of 0 to 4
COMORBID CONDITIONCOMORBID CONDITION
DRUGDRUG EFFICACY*EFFICACY*SIDE SIDE
EFFECTS*EFFECTS*RELATIVE RELATIVE
CONTRAINDICATIONCONTRAINDICATIONRELATIVE RELATIVE
INDICATIONINDICATION
AntiserotoninAntiserotonin
MethysergideMethysergide 4+4+ 4+4+ Angina, PVDAngina, PVD Orthostatic Orthostatic hypotensionhypotension
-Blockers-Blockers 4+4+ 2+2+ Asthma, depression, CHF, Asthma, depression, CHF, Raynaud’s disease, diabetesRaynaud’s disease, diabetes
HTN, anginaHTN, angina
Calcium channel Calcium channel blockersblockers
VerapamilVerapamil 2+2+ 1+1+ Constipation, hypotensionConstipation, hypotension Migraine with Migraine with aura, HTN, aura, HTN, angina, asthmaangina, asthma
PREVENTIVE TREATMENT:DRUG CHOICEPREVENTIVE TREATMENT:DRUG CHOICE
Silberstein SD et al. Headache in Clinical Practice. 2nd ed. 2002.Gray RN et al. Drug Treatments for the Prevention of Migraine. 1999.
*On a scale of 0 to 4
COMORBID CONDITIONCOMORBID CONDITION
DRUGDRUG EFFICACY*EFFICACY*SIDE SIDE
EFFECTS*EFFECTS*RELATIVE RELATIVE
CONTRAINDICATIONCONTRAINDICATIONRELATIVE RELATIVE
INDICATIONINDICATION
NSAIDsNSAIDs
NaproxenNaproxen 2+2+ 2+2+ Ulcer disease, gastritisUlcer disease, gastritis Arthritis, other Arthritis, other pain disorderspain disorders
OtherOther
RiboflavinRiboflavin 2+2+ 1+1+ Preference for Preference for natural productsnatural products
FeverfewFeverfew
Botulinum Botulinum Toxin AToxin A
2+2+
2+2+
2+2+
1+1+ Myasthenia gravisMyasthenia gravis Dystonia orDystonia orSpasticitySpasticity
PREVENTIVE TREATMENT:DRUG CHOICEPREVENTIVE TREATMENT:DRUG CHOICE
*On a scale of 0 to 4
Silberstein SD et al. Headache in Clinical Practice. 2nd ed. 2002.Gray RN et al. Drug Treatments for the Prevention of Migraine. 1999.
PREVENTIVE TREATMENT: PREVENTIVE TREATMENT: USE OF ACUTE MEDICATIONUSE OF ACUTE MEDICATION
Can use acute and preventive treatment together Limit acute drug use to prevent drug-induced
headache Certain drugs require caution or cannot be
used together Acute medications may have more benefit
Silberstein SD. Cephalalgia. 1997.
Preventive treatment does not eliminate all attacks
Breakthrough attacks need treatment
CAUTIONS IN ACUTE CAUTIONS IN ACUTE MEDICATION USEMEDICATION USE
PREVENTIVEPREVENTIVE CAUTIONCAUTION CONTRAINDICATIONCONTRAINDICATION
MethysergideMethysergide Ergots, TriptansErgots, Triptans
MAOIsMAOIs Sumatriptan Sumatriptan (subcutaneous) (subcutaneous) and zolmitriptanand zolmitriptan
Meperidine, Midrin, Meperidine, Midrin, sumatriptan (po, IN) and sumatriptan (po, IN) and rizatriptanrizatriptan
PropranololPropranolol RizatriptanRizatriptan
NSAIDsNSAIDs Other NSAIDs or Other NSAIDs or ASAASA
DivalproexDivalproex ButalbitalButalbital
Silberstein SD. Cephalalgia. 1997.
NONPHARMACOLOGIC NONPHARMACOLOGIC TREATMENT:TREATMENT:
POTENTIAL INDICATIONSPOTENTIAL INDICATIONS
Goslin RE et al. Behavioral and Physical Treatments for Migraine Headache. 1999.
Patient preference
Poor tolerance, response, or contraindications to drug therapy
Pregnancy, planned pregnancy, or nursing
History of overuse
Significant life stress or deficient stress-coping skills