Migraine Flashcards
Pathophysiology of migraine
Peripheral sensitization: vascular mechanism
- incr blood flow in cerebral arteries, abnormal carotid artery blood flow, abnormal extracranial vascular response
Central sensitization: cutaneous allodynia symptoms (risk factor for transformation of episodic migraine to chronic migraine)
Phases of migraine
- Prodrome
- Aura
- Headache (ictal)
- Postdrome
- Interictal
Duration of migraine
(+ each phase)
Migraine (headache/ictal) phase: 4h-72h
- *All phases may last 7 days
- Premonitory: few hours to days
- Prodrome/postdrome: 48h or less each
- Postdrome: <12-24h
- aura: 5-60min preceding headache phase
Role of trigeminovascular system in migraine
Relays head pain signals to the brain
Periphery: trigeminal ganglion relay trigeminovascular nociceptive input from the meningeal vessels and dura mater to the CNS
Central: trigeminocervical complex receives peripheral trigeminovascular nociceptive pain signal from the trigeminal ganglion and relays it to the cortex via the thalamus, resulting in the experience of pain
=> Migraine may result as a result of a dysfunctional trigeminovacular system
Role of sensitization/hyperexcitability
Pain is experienced when trigeminovascular neurons are activated and relay the migraine pain signal from the periphery to the CNS
Repeated activation => state of hypersensitivity and sustained pain
S&S of prodrome
Patho of prodrome
- fatigue, yawning
- food cravings (changes in appetite)
- nausea and vomiting
- cognitive symptoms
- mood changes
- neck discomfort/pain
- photo/phonophobia
Activation of the hypothalamus involved in physiologic processes + neuropeptides involved in homeostatic functions
=> underlies burdensome non-pain symptoms
S&S of aura
Patho of aura
- Visual aura (scotoma - blind spots, fortification spectrum - zigzag, scintillation)
- Sensory disturbances (pins and needles, numbness)
- Speech disturbances
- Motor symptoms
Cortical spreading depression (CSD) in the cortex
Slow-spreading neuronal depolarization within the grey matter cause neuron hyperexcitation in the cortex and brainstem, which may inhibit cortical activity, causing changes to synaptic activity, extracellular ion concentrations, blood flow, and metabolism, thereby activating the trigeminovascular system, driving aura symptoms
What are some examples of positive and negative aura symptoms?
Positive symptoms:
- Scintillations (visual - flash of light)
- Pins and needles
Negative symptoms:
- Scotoma (partial loss of vision within a normal vision field)
- Numbness
S&S of headache (ictal)
Patho of headache phase
- mod-severe HA
- photo/phonophobia
- Nausea with/without vomiting
- cutaneous allodynia
- neck discomfort
- cranial autonomic symptoms - more a/w cluster HA
- cognitive symptoms
- fatigue
Neuropeptides (e.g., CGRP expressed in trigeminovascular and cranial parasympathetic systems) implicated in the sensitization of the central and peripheral trigeminovascular system, creating a state of hypersensitivity and contributing to pain + non-pain symptoms
Functional and anatomic abnormalities - a/w sensitization of primary nociceptors and central trigeminovascular system => mediate allodynia symptoms
Neural basis of photophobia - retinal and trigeminal nociceptive inputs converge in the thalamus + hypersensitive visual cortex
S&S of postdrome
Patho of postdrome
- photo/phonophobia
- nausea
- fatigue
- cognitive symptoms
- neck discomfort/stiffness
- difficulty concentrating
Unknown pathophysiology
S&S of interictal
Patho of interictal
- photo/phonophobia
- cognitive symptoms
- fatigue
Some regions of the brain (olfactory region, midbrain, hypothalamus, visual cortex) remain abnormally activated after HA cessation
Reduced cerebral bloodflow?
Main summary of headache patho:
Cortical spreading depression in the cortex – neurons depolarization, neurons hyperexcitation in the cortex and the brainstem, (inhibit cortical activity, activate trigeminovascular system), cause dilation of blood vessels, activation of nociceptors, activate ascending pain pathways
Migraine diagnosis (ICHD-3 criteria)
> = 5 migraine attacks during a lifetime that fulfills the following 4 criteria:
- duration 4h-72h
- > =2 of the following 4 characteristics
- unilateral
- pulsating
- mod-severe pain
- aggravation
- If no aura, >=1 of the following non-headache symptoms
- nausea and/or vomiting
- photophobia and phonophobia
- Not better accounted for by another ICHD-3 diagnosis
Episodic migraine
> = 5 migraine in lifetime, <15 MMD/MHD per month
Chronic migraine
> =15 MHD for >3 months, of which >=8 are MMD
Risk factors for progression of episodic to chronic migraine
- Baseline HA frequency
- Frequency in which individuals use acute meds
- Presence of cutaneous allodynia
- Presence of nausea
- Effectiveness of acute meds (less optimal response to acute med => more likely to progress overtime)
Episodic migraine without aura
At least 5 attacks fulfilling the following 4 criteria:
- duration 4h-72h
- > =2 of the following 4 characteristics
- unilateral
- pulsating
- mod-severe pain
- aggravation
- If no aura, >=1 of the following non-headache symptoms
- nausea and/or vomiting
- photophobia and phonophobia
- Not better accounted for by another ICHD-3 diagnosis
Episodic migraine with aura
At least 2 attacks fulfilling the following 3 criteria:
- At least 1 of the following fully reversible aura symptoms:
- visual
- sensory
- speech/language
- motor
- brainstem
- retinal
- At least 2 of the following 6 characteristics:
- at least 1 aura symptom spreads gradually over >=5min
- 2 or more aura symptoms occur in succession
- each indiv aura symptom lasts 5-60min
- at least 1 aura symptom is unilateral
- at least 1 aura symptom is positive
- the aura is accompanied, or followed within 60min, by headache
- Not better accounted for by another ICHD-3 diagnosis
Acute treatment of migraine
- Goal of acute tx of migraine
- Abort migraine attack
- Treat at first sign of pain to achieve rapid freedom from pain and associated symptoms
- Restore ability to function
Acute treatment of migraine
- What are the acute migraine meds?
Analgesics
NSAIDs
Triptans
Ergotamines
Ditans (stimulates 5HT1F receptor)
Gepants (mAb that blocks CGRP receptors)
acute meds are PRN
Acute treatment of migraine
- For other medications with no consensus across guidelines for their use, what should be considered:
- Potential adverse events
- Risk of dependencies and tolerance
- Risk of med overuse headache
- Patient-specific contraindications
- DDIs
Acute treatment of migraine
- Explain the use of NSAIDs
MOA: anti-inflammatory, some anti-pyretic properties, mediated by blockade of COX enzymes, subsequent inhibition of prostaglandin synthesis
OTC NSAIDs shown to be efficacious
Acute treatment of migraine
- Explain the use of analgesics
OTC paracetamol and aspirin can provide pain relief in acute headache
Acute treatment of migraine
- Triptan therapy (place in therapy)
1st line for acute tx of migraine for pt whom did not achieve pain relief from OTC analgesics/NSAIDs
Efficacy:
- Pain relief within 2h
- 24h sustained pain relief, 24h hour sustained headache response
Acute treatment of migraine
- Why triptans > ergots
- Ergots have not shown relationship with CGRP and central pain process involvement. While Triptans can inhibit vasoactive peptide release (e.g., CGRP) and normalize elevated CGRP levels.
- Better SE profile of Triptans
Acute treatment of migraine
- Triptan therapy (cautions, CI - due to vasoconstriction)
Powerful vasoconstrictor effects - use cautiously in cardiovascular pathologies
CI in arterial hypertension, coronary heart disease, Raynaud’s disease, hist of ischemic stroke
Acute treatment of migraine
- can Triptans be used in pregnancy and lactation
Sumatriptan:
- Pregnancy: not first line, possible incr in rate of preterm birth, caution use
- Lactation: (SubQ) excreted into breastmilk, minimize infant exposure by avoiding breastfeeding for 12h after treatment (Lactmed: 8h, U2D: 12h, PIL:24h)
Acute treatment of migraine
- Triptans DDI
- do not use within 2 weeks after MAOi discontinuation (serotonin syndrome)
- do not use within 24h of ergot/other triptans (vasospastic rxn)
Acute treatment of migraine
- Ergot alkaloids
- MOA: tonic action on vascular smooth muscles in the external carotid network, leading to vasoconstriction by stimulating alpha-adrenergic and 5-HT receptors (esp 1B and 1D), prevent release of neuropeptide and inflammatory mediators
- Inferior to triptan therapy on the outcome of headache relief at 2h
- CI: CVD, CHD, cerebrovascular disease, uncontrolled HTN
Acute treatment of migraine
- Opioids
- Not recommended by some guidelines as non-specific to migraine + abuse potential
- more commonly able to cause MOH
- indiscriminate activation of opioid signaling can have adverse effects such as hyperalgesia, allodynia, worsening of nausea
- however, for pt who do not respond to migraine-specific agents, opioids may be indicated intermittently during acute episodes
Adjunct treatment in migraine
Antiemetics (e.g., Metoclopramide)
- improve N/V symptoms, esp when combined with analgesics
Criteria for preventive migraine treatment (AHS vs EHF)
AHS: based on number of headache days per month + degree of disability caused by the attacks
EHF: impair QoL + not controlled with acute therapy, risk of overuse of acute therapy
Preventive treatment of migraine
- Goal of preventive tx of migraine
Reduce frequency, duration, severity of attacks, esp if QoL impaired
Preventive treatment of migraine
- When might preventive treatment be started (generally)
- Attacks significantly interfere with pt daily routine despite acute treatment s
- Frequent attacks (.=4MHDs)
- CI to / failure of / overuse of acute treatment
- Adverse effects with acute treatment
- Patient preference - cost, lifestyle, SEs
Preventive treatment of migraine
- Preventive meds (class + examples)
- Anticonvulsants: Sodium valproate, Topiramate
- Beta-blockers (B1 antagonist shown to reduce HA attacks): Propranolol (non-selective), Metoprolol (selective B1)
- CGRP monoclonal antibodies (mAbs)
Others:
- Neuromodulation devices
- Neurotoxins
- ARBs
- Triptans
*Pharmacologic, interventional, biobehavioral, neurostimulation, nutraceuticals, lifestyle modifications
What is the role of vasoactive peptide, CGRP in migraine?
CGRP is a nociceptive vasodilative peptide released from trigeminal neurons. CGRP release triggers a cascade of central pain spreading, central pain amplification process.
=> pain transmission, vasodilation of cerebral blood vessels, neurogenic inflammation
In migraine, CGRP levels are elevated
Therefore, drugs that inhibit CGRP activity are effective in treating migraine
List the drugs that work by inhibiting CGRP
- Erenumab (anti-CGRP receptor antibody) - targets CGRP receptors
- Anti-CGRP antibodies - targets CGRP proteins
- Gepants - small molecules that antagonize CGRP receptors
Where is CGRP found in the body?
Not just brain, also found in external jugular veins and throughout the body
Where are CGRP receptors found?
- 2nd order neuron (1st oder trigeminal neurons release CGRP to 2nd order neurons => nociception)
- smooth muscle cells (vasodilation of cerebral blood vessels)
- mast cells (trigger neurogenic inflammation)
What are some concerns/risks related to CGRP inhibitors?
CGRP has been hypothesized to act as a vasodilator safeguard during ischemia
Hence, if inhibited long-term, may worsen mild and transient ischemic events, could possibly worsen HTN control
Limitations to CGRP therapy atm
- Expensive ($2000/month)
- SubQ injection monthly
- Clinical benefit within 3 months
- Not yet approved for use in pt <18yo
- Lack of long term safety data
Recommendations for initiating CGRP mAbs (e.g., Erenumab)
*Based on migraine day frequency + treatment history
4-7 monthly migraine days and both:
- inability to tolerate, or inadequate response to 8-week trial of two prior treatment classes
- at least mod diasbility (MIDAS >=11, HIT-6 >50)
8-14 monthly migraine days and:
- inability to tolerate, or inadequate response to 8-week trial of two prior treatment classes
Chronic migraine and either:
- inability to tolerate, or inadequate response to 8-week trial of two prior treatment classes OR
- inability to tolerate, or inadequate response to a minimum of two quarterly injections (6 month) of onabotulinumtoxinA
Criteria for continuation of CGRP mAbs
Either of the 2 criterias are met:
- Reduction in mean monthly headache days or headache days of at least mod severity of >=50% relative to the pretreatment baseline
- Clinically meaningful improvement in ANY of the following validated migraine-specific patient-reported outcome measures: MIDAS (reduction of >=5 points when baseline 11-20, >=30% when baseline >20), MPFID (reduction of >= 5 points), HIT-6 (reduction of >= 5 points)
Assessing migraine treatment efficacy
- headache diary (frequency, severity, acute meds use, symptoms, SEs, adherence)
- PRO tools - disability assessments (e.g., MIDAS)
- adverse effects from meds
MIDAS grade
I: 0-5 (little to no disability)
II: 6-10 (mild disability)
III: 11-20 (mod disability)
IV: >20 (severe disability)
Follow-ups
AHS guidelines recommend
- every 3 months after starting monthly tx
- every 6 months after starting quarterly tx
Assess change in frequency and severity of attacks, evaluate migraine-related symptoms, identify and address adverse events to the treatment, monitor med use, ensure adherence
Success for migraine preventive treatment (AHS guidelines)
*Any of the following
- 50% reduction in frequency
- sig dcr in attack duration (defined by pt)
- sig dcr in attack severity (defined by pt)
- improved response to acute tx
- reduction in migraine-related disability
- improvement in QoL
