Migraine Lecture
2002
Jin-Hyeun Huh
Pharmacy Practice Leader
TWH, UHN
What are the patient’s current and / or likely
(potential) undesirable signs and symptoms?
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working 16-18 hours per day
drinking 6-8 cups of coffee daily
skipping meals and eating poorly.
Minimal to no relief with aspirin, ibuprofen and even OTC
acetaminophen with codeine over the last few months
– gave up taking these medications two days ago
the attacks come on suddenly without warning
“a terrible throbbing on one side of her head”.
The headaches are often accompanied by severe nausea and
commonly vomiting.
some relief by taking frequent breaks and going to lie down
with the lights off.
E.T. has been having at least two headaches per week with one
occurrence lasting over twelve hours resolving with sleep. She
had her last headache three days ago
Urgency
• Quality of Life issue
• Prognosis
– Stroke:
• Higher risk with migraine with Aura
Higher risk with hemiplegic migraine
– Epilepsy
• prolonged or chronic headache
– Psychological disorders ( depression, etc.)
Migraine Disability
Assessment Scale (MIDAS)
Are the patient’s signs and symptoms
caused by a drug?
If so, how is it related to drug therapy?
• Triggers
• Vasodilators
• rebound analgesic HA
Medication Induced Headache
• Drugs implicated
– ASA , NSAIDS, Opiods,
acetaminophen,triptans
• Clinical Presentation/Hallmarks
– daily HA , sometimes throbbing
– Frequent use of analgesics
• Treatment:
– Remove offending agents
– Provide effective acute treatment
– Consider prophylaxis
Are the patient’s signs and symptoms
suggestive of a disease process?
• Differential diagnosis
Are the patient’s signs and symptoms
suggestive of a disease process?
– hypoglycemia
– Hypertension emergency
– Ischemic stroke
– Subarachnoid hemorrhage
– meningitis
– head trauma
Risk Factors: Migraine
• Age:
– Peak ages  adolescence or in the 20’s
– By age 50  Most migrainers report complete
remission
– New onset  unlikely after 40
• Sex:
– Females 70-75 % overall are female
– Prior to puberty : incidence is equal
• Family Hx:
– 70% of patients have relatives with Headache
history
Triggers
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Stress
Emotion
Glare
Hypoglycemia
Altered Sleep Pattern
Menses
Exercise
Alcohol
Excess caffeine
/withdrawal
• Foods containing
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MSG
tyramine
nitrates
phenylethylamine
aspartame
• Drugs
– Estrogen (eg. OC)
– Nitroglycerin
– Excess analgesic use or
withdrawal
History of HA :
what questions would you
ask?
History : Profile of HA
• time from onset to
peak
• usual time of onset
(week , month,
season, hour of day)
• frequency & duration
• change over lifetime
• description :
pulsating, pressing,
sharp
• location : unilateral or
bilateral or changing
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severity
precipitating factors
Aggravating factors
factors that relieve the
headache
• effectiveness of
pharmacological or
non-pharmacological
treatments
• Aura
Definition of Migraine
• Migraine:
– recurring headache disorder manifesting in
attacks lasting 4-72 hrs. Typical
characteristics: unilateral (sometimes
bilateral) location, pulsating quality, mod or
severe intensity, aggravation by routine
physical intensity, and association with
nausea, photo- and phono- phobia.
Classification
• 2 major types
– Classic : migraine with aura
– Common: migraine without aura
• Other less common
– Hemiplegic
– Status Migrainosus
– Menstrual
Diagnosis
Migraine without Aura
• Number of attacks
• Associated symptoms
Diagnosis
Migraine without Aura
• 5 attacks ; each lasting 4- 72 hrs
• each attack to be accompanied by one of the
following:
• nausea or vomiting
• phonophobia
• photophobia
• 2 of the 4 pain characteristics
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unilateral location
pulsating quality
moderate to severe intensity
aggravation by physical activity
Diagnosis:
Migraine with aura
• Number of attacks
• Associated symptoms
Diagnosis:
Migraine with aura
• At least 2 attacks
• Include any 3 of the following
– one or more fully reversible aura symptoms
– aura developing over more than 4 minutes
– aura lasting less than 60 minutes
– headache following aura with a free
interval of less than 60 minutes
Pathophysiology:
3 Systems
• Sympathetic
– NE
• Parasympathetic
– NO , VIP
• Trigeminal
– CRGP
Pathophysiology:
Triggers
Triggers
Emotional
Physical
Chemical
Locus Cerulus
Sympathetic System
Dorsal Raphe
Release of NE
Release of 5-HT
Vasoconstriction
stimluation of 5-HT 2B or 5Ht 7
stimulates chemo center
Vasoconstriction
Nausea & vomiting
Response to Vasoconstriction
Vasoconstriction
stimulation of PNS
release of NO
from neurons
Peripheral
Trigeminal
afferents
vasodilation
effect thalamus
HA
HA
Trigeminal
Nucleus c
Spinal
Trigeminal
Cervical Muscle
causing
head & neck pain
CGRP
Hypothalmus
vasodilation
cervical inflammation
Headche
Headache
Photophobia
Phonophobia
Treatment Strategies & Goals
• Acute Treatment (Abortive)
• Prophylaxis
Treatment Strategies & Goals
• Acute Treatment
– decrease duration of attack
• Prophylaxis
– decrease severity, duration and frequency
• Based on severity & frequency of migraine
attacks
Non-pharmacological methods
• Effective > 50%
– Diet, education re: triggers,relaxation
• Moderately effective 30-50%
– Stop smoking, exercise, riboflavin
• Ineffective <30%
– Avoiding tyramine, aspartame,chocolate
– Magnesium, feverfew
Drug related problems
• MH is suffering from migraine and
requires effective acute therapy .
• MH may be experiencing headache
due to analgesic overuse and requires
effective acute therapy.
Treatment Strategies:
Acute Treatment
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Analgesics :Acetaminophen, NSAIDS
Analgesics with barbiturates
Analgesics with OPIODS
ergotamine derivatives
“triptans or 5-HT1 agonists
neuroleptics
antiemetics
Misc. (divalprolex, lidocaine, magnesium,
NOSI, propofol)
Treatment :
Factors influencing efficacy
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Severity of migraine
Time to onset
Efficacy
Duration of effect/headache recurrence
Side effects
Acetaminophen
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Severity of migraine: mild
Time to onset: 1-2 hrs
Effiacy : 1st line agent
Duration of effect/ headache recurrence
• 2-3 hrs
• with increasing frequency of use ,
effectiveness may decrease
• Side effects:
– well tolerated
– liver problems > 4g daily
NSAIDS
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Severity of migraine : mild
Time to onset:
depends on agents 1-2 hrs
Efficacy : partial
Duration of effect/ headache recurrence :
• depends on agents
• with increasing frequency of use ,
effectiveness may decrease
• Side Effects
• GI bleeding
• renal dysfunction
Ergotamine derivatives
Severity of migraine :
Time to onset:
severe
IN, SC, PO, IV, IM
15 min -2 hrs
Efficacy :
50-70 %
Duration of effect/ headache recurrence
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• 4 hrs
• 2-3 hrs
• Side effects
• N&V
-incr BP
-incr. MI, stroke
1st generation 5-HT1 agonist
Sumatriptan
• Severity of migraine :
Severe
• Time to onset:
10 min -60 min
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IN/SC PO
• Efficacy :
70- 80 %
• Duration of effect/ headache recurrence
• 2 hrs
• 40-50%
• Side effects
• N&V
• dizziness
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- chest tightness
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Sumatriptan (Imitrex)
• Dosage forms: PO, IN, SC
• pharmacokinetic:
– T½
– Onset
– Metabolism
:2 hr
:10 min –1hr
:MAO
• Pharmacodynamic
– Efficacy at 2 hrs
• Pain free
• Sustained effect
22-32 % 25-100mg
17-20% 25-100mg
Assessment of 2nd generation
triptans
Dosage forms: bioavailability
Pharmacokinetic:
T½
Onset
Metabolism
Pharmacodynamic
Efficacy at 2 hrs
Rizatriptan (Maxalt)
Dosage forms:
pharmacokinetic:
T½
Onset
Metabolism
Pharmacodynamic
Efficacy at 2 hrs
Pain free
Sustained effect
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Rizatriptan (Maxalt)
Dosage forms: Po tablets , wafers
pharmacokinetic:
T½
Onset (peak)
Metabolism
:2 hrs
:1 hr
:MAO
Pharmacodynamic
Efficacy at 2 hrs
Pain free
Sustained effect
30-40% 5-10 mg
19-25% 5-10 mg
Zolmitriptan
(Zomig, -Rapimelt)
• Dosage forms:
• pharmacokinetic:
– T½
– Onset
– Metabolism
• Pharmacodynamic
– Efficacy at 2 hrs
• Pain free
• Sustained effect
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Zolmitriptan
(Zomig, -Rapimelt)
Dosage forms: Po tablets ,
pharmacokinetic:
T½
Onset (peak)
Metabolism
:3 hrs
:4 hr
:MAO/CYP450
Pharmacodynamic
Efficacy at 2 hrs
Pain free
Sustained effect
30-32% 2.5-5 mg
20-22% 2.5-5 mg
Naratriptan (Amerge)
Dosage forms:
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pharmacokinetic:
T½
Onset (peak)
Metabolism
Pharmacodynamic
Efficacy at 2 hrs
Pain free
Sustained effect
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Naratriptan (Amerge)
Dosage forms: Po tablets ,
pharmacokinetic:
T½
Onset (peak)
Metabolism
:5-6.3 hrs
:2-3 hr
:renal 70%
CYP450
Pharmacodynamic
Efficacy at 2 hrs
Pain free
Sustained effect
20% 2.5 mg
15% 2.5 mg
Triptans comparison
N Engl J Med,Vol.346,N .4 ·January 24,200
Triptans comparison
N Engl J Med,Vol.346,N .4 ·January
Triptans comparison
N Engl J Med,Vol.346,N .4 ·January 24,200
Triptans comparison
N Engl J Med,Vol.346,N .4 ·January 24,200
Triptans Side Effects
Common Reasons for
Prophylactic Treatment failure
• Analgesic or ergot overuse
• Inadequate trial duration
– 8 weeks at effective doses
• Inadequate trial of non-pharmacological
regimens
• DI interactions
• Inaccurate diagnosis
Criteria for Migraine
Prophylaxis
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2-3 attacks/month
duration of attack is greater than 48 hrs
extreme severity
inadequate relief / side effects with
acute medication
• migraine attacks occur after a prolonged
aura
Treatment Strategies:
Prophylaxis
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Beta-blockers
Antidepressants
Calcium channel blockers
Anti-convulsants
Serotonin antagonists
Natural products
Newer treatments ( BOTOX)
Prophylaxis
• Beta blockers
– dose/frequency:
– efficacy:
– side effects:
• Calcium channel blockers
– dose/frequency:
– efficacy:
– side effects:
Prophylaxis
• Antidepressants (TCA)
– dose/frequency
– efficacy
– side effects
• valproate
– dose/frequency
– efficacy
– side effects
Prophylaxis
• Natural products
– feverfew
– magnesium
– vitamin B
• Newer treatments
– Botox
Outcomes
• Clinical Outcomes
– Improve quality of life
– Decrease frequency of migraine attacks
– Decrease severity of attacks
• Pharmacotherapeutic Outcomes
Pharmacotherapeutic
Endpoint
Therapeutic Plan
• Acute treatment /Prophylaxis ?
• Acute therapy
– Which triptan ? Why ?
– Route of triptan ?
– Dose of triptan ?
– Time frame to assess efficacy
• Cafergot
Therapeutic Plan
• Prophylaxis
– Which agent? Why ?
– BB : propanolol, metoprolol,atenolol
– TCA: amitriptyline
• Metoprolol prn
Monitoring Plan
• Side effects of medication
• Oral contraceptives