Lecture 21: Migraine Flashcards
What is the definition of a migraine?
leading cause of disability worldwide, particularly in those under 50
primarily headache disorder characterized by recurring headaches that are moderate to severe, pulsating in nature, last from 2-72 hours
sensitivity to normal sensory input (light, sound, head movement)
sometimes nausea and vomiting
What is migraine aura?
migraine sometimes (~20%) preceded with aura (visual disturbances consisting of flashing lights or zigzag lines moving across the field of vision)
thought to be driven by cortical spreading depression: wave of neuronal depolarization followed by desensitization (“depression”) that propagates across the cortex
What is migraine epidemiology?
migraine risk a mix of genetic and environmental factors
affects women more than men
increase incidence in women after puberty (hormones?)
some genetic contribution: familial hemiplegic migraines
What is familial hemiplegic migraine?
migraine that includes weakness of half of the body
autosomal dominant inheritance
3 known genetic mutations associated with FHM: P/Q-type calcium channel, Na+/K+ATPase, Na+ channel subunit
mutations lower the threshold for cortical spreading depression
What is the trigeminal system?
trigeminal nerve is the largest cranial nerve
peripheral processes divided into three branches - ophthalmic, maxillary, and mandibular
What are the three purposes of the trigeminal system?
senses pain and temperature in the head region
innervates the dura mater (membrane that surrounds the brain)
controls cerebral blood vessels (trigeminovascular system)
What is the mechanism of migraine?
pain in head detected by ophthalmic branch of the trigeminal nerve innervating dura mater and associated blood vessels
cause of migraine still unknown, but thought to be a neurovascular disease
- extracerebral vessels dilate during migraine attack
- cranial blood vessel stimulation provokes headache
- vasoconstrictor drugs alleviate pain
What is the relationship between serotonin and migraine?
release of 5-HT leads to vasoconstriction
low 5-HT levels in migraineurs between attacks
5-HT is released during migraine attacks
What is the relationship between CGRP and migraine?
calcitonin gene-related peptide (CGRP) located in trigeminal peripheral afferents
released from afferents in response to pain, leads to vasodilation
CGRP elevated in those with migraines
What are the two treatment strategies for migraines?
treatment strategies incorporates both prophylactic and abortive strategies
prophylactic treatments are taken daily to prevent attacks, abortive treatments taken once an attack occurs
What are non-pharmacological prophylactic interventions?
identify triggers (diet, exercise, consistent sleep, avoiding excessive caffeine and alcohol, minimize stress)
What are pharmacological prophylactic interventions?
beta blockers (propanolol), anticonvulsants (gabapentin), antidepressants (amitriptyline)
What are abortive treatment strategies?
non-specific analgesics (asprin, acetaminophen, NSAID, opioids)
risk of medication overuse headache
What is the relationship between caffeine and migraine?
caffeine is an adenosine receptor antagonist
leads to vasoconstriction
increases absorption of some analgesics (acetaminophen, ergotamines)
improves migraine treatment during attack
but may also trigger headaches or result in rebound headache (withdrawal)
What are ergotamines?
ergot alkaloid (like LSD)
first specific anti-migraine agents (introduced in 1926), but no longer first line therapy
agonists for 5HT-1b/d receptors that inhibit neurogenic inflammation
but, low degree of receptor selectivity which increases the risk of experiencing a drug-induced side effect
What are the side effects of ergotamines?
ergotamine can produce coronary vasoconstriction, often with associated ischemic changes and anginal pain in patients with coronary artery disease
contraindicated in patients with peripheral vascular disease, coronary heart disease, uncontrolled hypertension, stroke
What is the absorption and distribution of ergotamines?
large first pass metabolism via oral administration leads to low bioavailability (<1%), caffeine can improve both rate and extent of absorption
What is the metabolism of ergotamines?
metabolized by liver by poorly defined enzymes
half life is 2 hours
What is the excretion of ergotamines?
excreted in bile
What are triptans?
first line migraine therapy (i.e. Sumatriptan)
selective 5-HT1b/d agonist
two mechanisms: vasoconstriction and inhibition of trigeminal nerve
avoids many of the side effects of ergotamine
What is the absorption and distribution of triptans?
bioavailability around 14% when taken orally, 96% when given subcutaneously (because first pass metabolism)
What is the metabolism of triptans?
metabolized by monoamine oxidase in the liver in indoleacetic acid
half life around 2 hours
What is the excretion of triptans?
cleared in the urine
What are migraine treatment strategies that are under development?
small molecule CGRP antagonists
monoclonal antibodies to CGRP or CGRP receptor
several potential drug candidates have been developed and currently under investigation
What are CGRP antibodies?
monoclonal antibodies to either the CGRP receptor or CGRP itself
inhibits CGRP signaling leading to vasoconstriction
between May and September 2018, three new CGRP antibodies approved for use of migraine in US and Canada
What is the CGRP antagonist BIBN4096 (Olcegepant)?
good efficacy at treating migraine
poor bioavailability (particularly orally) which limited clinical efficacy; abandoned at phase II clinical trial
What is the CGRP antagonist MK-0974 (Telcagepant)?
several Phase III clinical trials support anti-migraine efficacy and safety
problem emerged with daily dosing (elevation of liver aminotransferase); abandoned at phase III clinical trial
What is the CGRP antagonist Rimegepant (Nurtek)?
is one of the few remaining small molecule CGRP receptor antagonists that remains in clinical development
effective migraine treatment
less effect on liver aminotransferase levels (safer for longterm use)
