Headaches and Migraines

Classification of headaches
Headaches with no identifiable causes (e.g., aneurysms, ischemia, blood pressure abnormalities, meningeal infections, brain tumors, etc.), identified based on symptoms -
1. Common
2. Migraine – affects 10 - 20% of the population (~30 million in US)
Both types of headaches result from dysregulated neurotransmission within specific brain regions but with the abnormalities more severe and complex in migraines than in common headaches.

A collection of severe headaches:

occur in distinct stages (~4; not all patients experience all 4 stages).

frequencies, symptoms and pain intensity vary between patients.

pain may be bilateral or unilateral and pulsatile

female:male incidence of 3:1
- common in children, peaks at adolescence.
- mean age at onset: 7.2 yrs for boys, 10.9 yrs for girls
- wanes with age (but usually maximum between 25-50 yrs)
- 60-70% of cases familial.

“Classical migraine”
accounts for ~20 - 30% of all cases
characterized by premonitory aura (varying neurological symptoms, largely visual) that:
- precedes pain onset;
- lasts 20 to 60 minutes

– “Common Migraine”
Lacks aura
Comprises ~70% of cases

rare
Migraine attacks with aura and one-sided motor paralysis
Mutations in genes for:
Voltage sensitive calcium channel subunit (may increase channel activity & be trigger for CSD)
Na+/K+ ATPase
Voltage sensitive Na+ channel subunit

most common
Episodic: Less than 15 per month (22% of all cases), can be 2-12 days/month
Chronic: 15 or more per month (0.9-2.2% of all cases)
69% of men, 88% of all women experience during lifetime
Gradual onset during or after stress
Occur when neck, scalp, face, shoulders muscles become tense
Other triggers: physical, emotional stress; dental problems (teeth grinding, jaw clenching), eye strain, fatigue
Variable frequency, lasting 30 min. to a week (average 12 hrs)
Pain is bilateral, band-like, usually forehead, around temples, back of head, radiates down neck and shoulders
Described as a dull, aching pain

Cortical Spreading Depression (CSD) Hypothesis
A wave of electrophysiological hyperactivity followed by a wave of inhibition, usually in the visual cortex - manifestations include scintillating scotoma (blind spots)

The spreading depression wave progresses across the cortex at approximately 2 - 5 mm/minute.

Neurochemical changes during CSD include increased extracellular potassium ion concentration and glutamate
- both contribute to the initiation and propagation of
CSD.

CSD accounts for the aura of migraine

It’s believed to be caused by a wave of electrical activity that spreads across the cortex of the brain. This wave is then followed by a prolonged suppression of nerve cell activity. This can lead to various changes, such as changes in blood flow, which may lead to migraine symptoms

OnabotulinumtoxinA (BoTox) – injected around cranial dermatomes that are involved in headaches, enters nerve endings, prevents acetylcholine release
Used for chronic migraine
Possibly acts centrally by retrograde and anterograde axonal transport from periphery
Also inhibits release of CGRP, substance P, serotonin, glutamate, GABA, noradrenaline, dopamine, enkephalin and glycine
Down regulates surface expression of nociceptive receptors (e.g. TRPV1).
Agonistic effect on m-opioid receptors.

Specific treatments
- include ergots, triptans and gepants
- are effective in migraine and other types of
headache
- are ineffective against other pain disorders

● Nonspecific treatments
- are effective in migraine
- can be used to treat all types of pain
- include analgesics and opioids

Receptor agonists – block release of CGRP and substance P by acting on presynaptic 5-HT1B/D/F receptors
Stimulation of 5-HT1B receptor – constriction of meningeal, dural, cerebral & pial vessels:
Blocks plasma protein extravasation
Blocks neurogenic inflammation
Can have severe side effects related to binding to “off target” receptors

Ergots have a broader spectrum of adverse effects than triptans: 5-HT1A, 5-HT2, adrenergic, and dopaminergic receptor-binding affinity: ergots >> triptans

• A manifestation of the potent vasoconstrictive effects of ergot compounds that involves:
1 adrenergic receptors
2. 5-HT receptors

• Has a sustained vasospasm component—from direct smooth muscle stimulation:
- vasospasm is not reversible by alpha1 adrenergic or 5-HT
receptor antagonists.
- when cumulative (from overdose/repeated dosing),
vasospasm results in:
a. poor heat exchange -- severe burning sensation;
b. poor tissue perfusion -- ischemia & restricted
blood flow to extremities -- gangrene (may require amputation).
• An associated central dopaminergic and serotonergic
(5-HT) receptor activation -- hallucinations

Lasmiditan (Reyvow) (FDA approved, 10/2019), considered a new class of drug, “ditans”, different scaffold than triptans.
New, highly selective, centrally acting 5-HT1F agonist
Inhibits dural plasma protein extravasation (PPE)
Does not cause vasoconstriction (unlike triptans)
Inhibits second order neurons in trigeminal nucleus (decrease action potential)

lack vasoconstrictive properties (& other) side effects of triptans (remember: CGRP elevated in external jugular venous blood during migraine attack, CGRP receptors located on: meningeal blood vessels, trigeminal ganglion, periaqueductal gray and other brain areas assoc with migraine)

Gepants: selective CGRP receptor antagonists – ubrogepant (Ubrelvy), first of its class to be approved, for acute use.
Rimegepant (Zydis) – for daily or prophylactic use
Atogepant (Qulipta) – FDA approved 9/21, can be used for daily or prophylatic use
Zavegepant (Zavzpret) – first intranasally administered CGRP receptor antagonist, for acute use, approved 3/2023

Anti-CGRP antibodies – against CGRP: fremanezumab-vfrm (Ajovy), galcanezumab (Emgality), eptinezumab (Vyepti) or CGRP receptor; erenumab-aooe (Aimovig), all FDA approved, for prophylactic use on episodic or chronic migraines