Acute Treatment of Migraine Acute Treatment of Migraine

Acute
Treatment
of Migraine
Robert Shapiro, MD, PhD
Disclosures
• Since 2012:
– Lilly: Clinical Trial Data Monitoring Committee
Desired Properties
of Acute Migraine Therapies
• Prompt freedom from
– headache
– associated symptoms
– disability
• No recurrence of symptoms
• No side effects
• No risk of medication overuse headache
• Convenient formulation
• Consistent efficacy
• Effective for all patients
• Not contraindicated for any patients

Principles of
Acute Migraine Management
 Pharmacological therapies


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
Treat aggressively – “stratify” therapy to migraine burden
Treat early during attacks
Do not treat too often – not more than 8 days per month
Consider combining acute medication classes (e.g. triptan +
NSAID) to improve pain-free response and reduce recurrence.
 Non-pharmacological therapies




hot or cold compresses may help
avoid excess sensation – photophobia, phonophobia, etc.
apply behavioral therapies – cognitive, relaxation, biofeedback
consider acupuncture
Acute PharmacologicTherapies
for Migraine

NSAIDs or aspirin
(e.g. diclofenac, ibuprofen, naproxen sodium, indomethacin, cox-2 inhibitors, etc.)

Dopamine antagonists (e.g. metoclopramide, prochlorperazine, chlorpromazine)

5-HT1 agonists (specific: triptans / non-specific: ergotamines – DHE nasal spray)

Isometheptene / dichloralphenazone / APAP (Midrin)

Caffeine combinations (e.g. APAP/ASA/caffeine, APAP/butalbital/caffeine, etc.)

Opioid "rescue medications” (e.g. butorphanol)
FDA approved migraine therapies
Level A – “Established as Effective”
• Triptans
• Sumatriptan
•
•
•
•
•
•
Oral 25mg, 50mg, 100mg (generic)
Nasal spray 20mg
Nasal applicator 22mg
Needle injection 4mg, 6mg
Needless injection 4mg, 6mg
Iontophoretic patch
• Naratriptan – Oral 1mg, 2.5mg (generic)
• Zolmitriptan
• Oral 2.5mg, 5mg / oral dissolving 5mg (generic)
• Nasal spray 2.5mg, 5mg
•
•
•
•
Rizatriptan – Oral 5mg, 10mg / oral dissolving 5mg, 10mg (generic)
Almotriptan – Oral 12.5mg (generic)
Eletriptan – Oral 20mg, 40mg, 80mg (generic 2016)
Frovatriptan – Oral 2.5mg (generic)
• DHE
• Nasal spray 2mg
Level A – “Established as Effective”
• NSAIDS / Acetaminophen
–
–
–
–
–
–
Aspirin 500mg
Diclofenac 50mg, 100mg
Ibuprofen 200mg, 400mg
Naproxyn 500mg, 550mg
Refocoxib 25mg
Acetaminophen 1gm
• Opioids
– Butorphanol nasal spray 1mg
• Combinations
– Sumatriptan 85mg / naproxyn 500mg
– Acetaminophen 500mg / aspirin 500mg / caffeine 130mg
– Codeine 25mg / acetaminophen 400mg
Level B – “Probably Effective”
• Ergots - ergotamine 1-2mg, IV DHE 1mg
• NSAIDS - ketoprofen 100mg, IV ketorolac 30mg,
• Isometheptene 65mg,
• Opioids - tramadol 75mg
• Dopamine antagonists – prochlorpramazine 10mg, droperidol,
chlorpromazine, metoclopramide
• Magnesium IV 1-2gm
• Metimizole 1mg
Level C – “Possibly Effective”
• Dexamethasone 4-16mg
• Valproic acid 400-1000mg
• Butalbital 50mg / acetaminophen 650mg
The Limits of Acute Migraine Therapy:
Treat Attacks Early, but Not Too Often
 Triptan efficacy is higher if delivered during the early phase of
migraine before allodynia develops.
Treat early.
 Frequent exposure to analgesics, including triptans, may
transform episodic migraine to chronic daily headache in
susceptible individuals.
Treat no more than 8 days / month.
Avoid opioids and barbiturates if possible.
mild pain /
non-migrainous
NSAIDS
Rational Development of Triptans:
Role of Serotonin in Migraine
 In migraine attacks, blood levels of serotonin drop and
urine levels of serotonin metabolites rise.
 Drugs which deplete platelet serotonin (e.g. reserpine)
may trigger migraine-like attacks.
 Intravenous serotonin relieves migraine.
 Serotonin is implicated in mechanisms for many
conditions co-morbid with migraine (e.g. depression,
sleep, etc.).
Sicuteri Headache 6:109 (1966)
Anthony et al Arch Neurol 16:544 (1967)
Kimball et al Neurol Minneap 10:107 (1960)
Serotonin Receptors
and Migraine Therapies
Serotonin
(5HT)
cAMP
5HT1
5-HT 1A
5-HT 1B
5-HT 1D
5-HT 1E
5-HT 1F
PI
5HT2
5-HT 2A
5-HT 2B
5-HT 2C
Na+
K+
Ca2+
5HT3
cAMP
5HT4
cAMP
5HT5
cAMP
5HT6
cAMP
5HT7
5-HT 5A
5-HT 5B
Agonists block acute migraine (e.g. triptans)
Antagonists prevent migraine (e.g. methysergide)
Antagonists prevent nausea (e.g. ondansetron)
Adapted from: The Triptans . 2001
Trigeminovascular System
Neuropeptide
Release
CORTEX
PAIN
CGRP
THALAMUS
5-HT1D Receptors
5-HT1B Receptors
(on vascular
smooth muscle)
Vasoconstriction
B
B
Trigeminal
Ganglion
VIP, NO
D
Vasodilatation
Nucleus
Caudalis
D
D
5-HT1D Receptors
Trigeminal Inhibition
Superior
Salivatory Nucleus
Recreated from Hargreaves et al. Can J Neurol Sci 1999;26:S12-S19.
Triptans
Agonists at selective
serotonin receptors:
5-HT1b , 5-HT1d , 5-HT1f
Imitrex
Amerge
Zomig
Maxalt
Formulations:
oral, iontophoretic, nasal,
subcutaneous
Response rates:
~70% pain relief @ 2hr
~30% pain-free @ 2 hr
Relpax
Axert
Contraindications:
Concurrent CV risks
Hemiplegic migraine
? Serotonin syndrome risk
Frova
Serotonin
Triptan Considerations…
suma
zolmi riza
nara
almo
Renal Failure
*
Hepatic Failure
Concomitant
MAO Inhibitors
*
Sulfonamide sensitivity
*
Severe Pain and/or
On Awakening
*
*
*
*
SC,
IO, NS
*
SC
*
NS
ele
*
*
*
*
*
*
Menstrual Migraine
(long half-life)
Nausea & Vomiting
*
frova
*
New Sumatriptan Iontophoretic Patch
Vikelis et al. Neuropsychiatr Dis Treat. 2012; 8: 429–434.
New Sumatriptan Inhaler
Triptan Limitations
•
•
•
•
Contraindications
–
Ischemic or vasospastic heart disease
–
Multiple risk factors for CAD
–
Hemiplegic or basilar migraine
–
Uncontrolled hypertension
–
Use within 24 hours of ergot or another triptan
Risks
–
Pregnancy Risk: Category C
–
Medication Overuse Headache
–
Triptan side effect profile
–
Serotonin Syndrome Alert – AHS response: Headache 2010;50:1089-1099
Efficacy
–
Therapeutic responses rarely immediate and may be inconsistent
–
Recurrence common – particularly with subcutaneous formulations
–
~30% of migraineurs do not respond at all
Costly - in spite of availability of generic sumatriptan and naratriptan
Where are All the Triptan-Induced Cardiovascular Events?
http://www.colucid.com/writable/press_releases/file/ims_health_facts_addressing_migraine_market_misperceptions_1_4_16_print.pdf
Sumatriptan (85mg) – Naproxen (500mg)
Fixed Combination
Khoury & Couch Drug Des Dev Ther 4:9 (2010)
Rizatriptan 10mg (RI) vs Dexamethasone 4mg (DE) vs
Rizatriptan 10mg + Dexamethasone 4mg (RI+DE)
Pain Free
Bigal et al Headache 2008; 48:1286
Dexamethasone (10 - 24mg):
24 to 72 hour Headache Recurrence
when added to Standard ER treatment
Colman et al BMJ 2008; 336:1359
Butorphanol Nasal Spray
Pain Free
Hoffert et al Headache 35:65 (1995).
Pain Relief
High abuse potential
Migraine transformation
Unreliable formulation
Prevalent side effects
Rebound
Headache
 Substances which acutely relieve migraine …
may provoke migraine upon their withdrawal ("rebound”)
 opioids, barbiturates, caffeine, triptans, ergots, NSAIDs, etc.
 Frequent exposure may lead to INCREASED headache frequency
in susceptible individuals
 ~4% of adults have chronic daily headache (CDH): ≥ 15 days/mon
 ~80% of patients with CDH have “transformed migraine”
 “Transformed migraine” typically begins with episodic migraine and
gradually develops over months to years to chronic daily headaches.
Evolution of Medication Overuse Headache
Tablets / day of caffeine-containing analgesics over 10 years
Spierings, J Headache Pain 4:111 (2003)
Single-pulse Transcranial
Magnetic Stimulation
Lipton et al Lancet Neurol 9:373 (2010)
Questions?