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Headache
7 notes available
1 Last Minute Review 2 Migraine 3 TTH, NDPH & Other Primary Headaches 4 Trigeminal Autonomic Cephalalgias 5 Secondary Headache Red Flags 6 Headache Pharmacology 7 Headache Mimics & Facial Pain
Clinical › Headache

Headache Pharmacology

Headache Pharmacology

What You'll Learn

  • CGRP pathway: released from trigeminal ganglion → meningeal vasodilation + neurogenic inflammation; 4 anti-CGRP mAbs plus 4 gepants are FDA-approved across acute and/or preventive migraine indications: ubrogepant, rimegepant, atogepant, and zavegepant
  • Triptans: 5-HT1B/1D agonists — contraindicated in CAD, uncontrolled HTN, hemiplegic migraine / migraine with brainstem aura, stroke history; sumatriptan SC has fastest onset (~10 min)
  • Gepants: CGRP receptor antagonists — non-vasoconstrictive option when triptans are contraindicated by CAD, stroke, PVD, or hemiplegic/brainstem aura migraine; do NOT describe as risk-free in uncontrolled HTN (monitor for new/worsening hypertension and Raynaud phenomenon per labeling); can be used acutely AND preventively; rimegepant is dual-approved
  • Ditans: 5-HT1F agonist (lasmiditan) — no vasoconstriction, Schedule V controlled substance, 8-hour driving restriction
  • Verapamil: first-line preventive for cluster headache — must monitor ECG with every dose increase (risk of PR prolongation and heart block)
  • Indomethacin: diagnostic AND therapeutic for paroxysmal hemicrania, hemicrania continua, primary cough HA, and primary stabbing HA
  • Pregnancy: ergots absolutely contraindicated (uterotonic); valproate and topiramate are teratogenic; acetaminophen is safest acute option
HighYield Pearls
  • Triptan contraindications: CAD, uncontrolled HTN, hemiplegic migraine / migraine with brainstem aura, recent stroke, PVD; ergot within 24 hr; MAOI within 14 d
  • Sumatriptan SC 6 mg → fastest onset (~10 min) — first-line acute pharmacologic for BOTH migraine and cluster headache
  • Rizatriptan + propranolol → reduce rizatriptan to 5 mg max (propranolol ↑ AUC ~70%); classic interaction question
  • Frovatriptan T½ 26 hr → longest half-life triptan; perimenstrual prophylaxis (start 2 days before menses)
  • Lasmiditan (ditan) → 5-HT1F agonist, NO vasoconstriction, Schedule V, mandatory 8-hour driving restriction
  • Erenumab = only CGRP mAb targeting the receptor; the other 3 (fremanezumab, galcanezumab, eptinezumab) target the ligand
  • Rimegepant = only gepant approved for BOTH acute (75 mg PRN) AND preventive (75 mg every-other-day)
  • Galcanezumab = only CGRP mAb FDA-approved for episodic cluster headache (300 mg SC monthly)
  • OnabotulinumtoxinA (PREEMPT): chronic migraine ONLY; 155–195 U across 31–39 sites in 7 muscle groups q12wk; NOT for episodic
  • Verapamil for cluster prophylaxis (240–960 mg/d) → ECG before initiation and with every dose increase (PR prolongation, AV block)
  • Pregnancy avoid: ergots (uterotonic — absolute), valproate (NTDs), topiramate (oral clefts); avoid NSAIDs at ≥20 wk gestation unless specifically indicated and supervised (oligohydramnios), especially at ≥30 wk (ductus closure); acetaminophen +/- metoclopramide is the usual first-line acute approach
  • MOH thresholds: triptans/ergots/opioids/butalbital ≥10 d/mo; simple analgesics/NSAIDs ≥15 d/mo — AVOID opioids + butalbital for headache
🔍 Quick ReferenceMechanism · Adverse effects · Use / pregnancy
Mechanism of action
  • Triptans → 5-HT1B/1D agonists — cranial vasoconstriction + inhibition of trigeminal CGRP/substance P release
  • Ditans (lasmiditan) → selective 5-HT1F agonist — central pain modulation, NO vasoconstriction
  • Gepants (ubrogepant, rimegepant, atogepant, zavegepant) → CGRP receptor antagonists (small molecule)
  • Erenumab → mAb against the CGRP receptor (CLR/RAMP1 complex)
  • Fremanezumab / galcanezumab / eptinezumab → mAbs against the CGRP ligand
  • DHE / ergotamine → non-selective 5-HT1B/1D + multi-receptor (also α-adrenergic, dopaminergic)
  • Topiramate → Na+ channel + GABA enhancement + AMPA/kainate inhibition + carbonic anhydrase inhibition
  • Valproate → Na+ channel + GABA + glutamate modulation
  • Amitriptyline → 5-HT / NE reuptake inhibition (+ anticholinergic, antihistaminic)
  • Onabotulinumtoxin-A → cleaves SNAP-25 → blocks acetylcholine + peripheral CGRP release
Adverse effects / contraindications
  • Chest tightness / paresthesias / dizziness → triptans (also avoid in CAD, uncontrolled HTN, hemiplegic migraine / migraine with brainstem aura)
  • “Dopamax” cognitive slowing + word-finding difficulty + kidney stones + paresthesias + oligohidrosis + metabolic acidosis → topiramate
  • Weight gain + tremor + alopecia + thrombocytopenia + hyperammonemia + hepatotoxicity → valproate
  • Constipation + injection-site reaction + HTN → erenumab
  • Sedation + dry mouth + urinary retention + QT prolongation + weight gain → amitriptyline (avoid in elderly)
  • Acute dystonia / akathisia → metoclopramide, prochlorperazine (pre-treat with diphenhydramine)
  • PR prolongation / AV block / bradycardia → verapamil — ECG with every dose increase
  • Narrow therapeutic window + renal + thyroid monitoring → lithium (cluster: 0.4–0.8 mEq/L)
  • Medication overuse headache + bounce-back / tolerance / dependence → opioids + butalbital (avoid)
  • Mandatory 8-hour driving restriction + sedation → lasmiditan (Schedule V)
Use / pregnancy / pearls
  • Fastest acute migraine + cluster abortive → sumatriptan SC 6 mg (~10 min onset)
  • Menstrual migraine perimenstrual mini-prophylaxis → frovatriptan (longest T½ 26 hr; alt: naratriptan)
  • Status migrainosus IV protocol → DHE (Raskin) + metoclopramide pre-treatment
  • Non-vasoconstrictive acute migraine option when triptans are contraindicated (CAD, prior stroke, PVD, hemiplegic/brainstem aura migraine) → gepants or ditans; monitor for new/worsening HTN and Raynaud phenomenon per labeling — not risk-free in uncontrolled HTN
  • Dual acute + preventive oral agent → rimegepant (75 mg PRN or every-other-day)
  • Episodic cluster headache CGRP option → galcanezumab 300 mg SC monthly (only mAb with cluster FDA indication)
  • Chronic migraine PREEMPT → onabotulinumtoxin-A q12wk (NOT for episodic)
  • Cluster prophylaxis first-line → verapamil; bridge with brief prednisone taper ± GON block; lithium for chronic cluster
  • Pregnancy first-line acute → acetaminophen + metoclopramide (magnesium also safe; GON block safe)
  • Pregnancy absolute contraindication → ergotamine / DHE (uterotonic → uterine contractions / fetal distress)
  • Pregnancy acceptable preventives → propranolol + amitriptyline (monitor neonatal β-blockade syndrome at delivery)
  • CGRP mAbs + conception → discontinue ≥5 half-lives (~5 months) before planned pregnancy
CGRP Pathway & Mechanism

Calcitonin Gene-Related Peptide (CGRP)

  • CGRP = 37-amino-acid neuropeptide; most potent endogenous vasodilator known
  • α-CGRP — predominant in trigeminal ganglion and central nervous system (relevant to headache)
  • β-CGRP — predominant in enteric nervous system
  • Trigeminovascular activation → CGRP released from trigeminal ganglion → meningeal vasodilation, mast cell degranulation, plasma protein extravasation, neurogenic inflammation
  • CGRP receptor: heterodimer of CLR (calcitonin receptor-like receptor) + RAMP1 (receptor activity-modifying protein 1)
  • IV CGRP infusion triggers migraine-like attacks in susceptible individuals — proof-of-concept for CGRP as migraine mediator
💎 Board Pearl
  • CGRP levels are elevated in jugular venous blood during migraine attacks and normalize with successful triptan treatment — this finding validated the CGRP pathway as a therapeutic target
  • The CGRP receptor requires both CLR and RAMP1 for function — erenumab targets this receptor complex; the other 3 mAbs target the CGRP ligand itself
Acute Migraine Treatment — Master Table

Comprehensive Acute Treatment Overview

Stratified care (match treatment to attack severity) is superior to step care. Treat within 60 minutes of onset for best efficacy.

Drug Class Agent Mechanism Dose Onset Key Features Contraindications
Triptans Sumatriptan SC 5-HT1B/1D agonist 6 mg SC ~10 min Fastest onset of all triptans; widest formulations (SC, nasal, oral, patch) CAD, uncontrolled HTN, hemiplegic migraine, migraine with brainstem aura, stroke, PVD, pregnancy (relative)
Sumatriptan nasal 20 mg ~15 min Good for nausea/vomiting; bitter taste
Sumatriptan oral 50–100 mg ~30 min Most commonly prescribed form
Zolmitriptan 2.5–5 mg PO/nasal ~15 min (nasal) Nasal form effective for cluster HA; also available as ODT
Rizatriptan 5–10 mg ODT ~30 min Fastest-onset oral triptan; reduce dose to 5 mg with propranolol
Eletriptan 40–80 mg ~30 min Highest oral efficacy; CYP3A4 substrate — avoid with strong CYP3A4 inhibitors
Naratriptan 2.5 mg ~60 min Gentle onset, fewer side effects; long T½
Triptans (cont.) Frovatriptan 5-HT1B/1D agonist 2.5 mg ~60 min Longest T½ (26 h) — best for menstrual migraine prophylaxis Same as above
Almotriptan 5-HT1B/1D agonist 12.5 mg ~30 min Fewest side effects; best tolerability profile Same as above
Gepants Ubrogepant (Ubrelvy) CGRP receptor antagonist 50–100 mg ~60 min Acute only; may repeat ×1 after ≥2 h; CYP3A4 substrate No vasoconstrictive contraindication, but monitor for new/worsening HTN and Raynaud phenomenon per labeling; avoid strong CYP3A4 inhibitors
Rimegepant (Nurtec) 75 mg ODT ~60 min Dual-approved: acute (75 mg PRN) + preventive (75 mg EOD)
Ditans Lasmiditan (Reyvow) 5-HT1F agonist 50, 100, or 200 mg PO; max 1 dose per 24 h (do NOT repeat) ~60 min NO vasoconstriction; Schedule V — no driving for at least 8 hours after each dose; sedation, dizziness No vasoconstriction, but monitor per labeling; caution with CNS depressants
NSAIDs Ketorolac IV/IM COX inhibition 30–60 mg IV/IM ~15–30 min ER workhorse; no sedation; short course only Renal disease, GI bleeding; avoid NSAIDs at ≥20 weeks gestation unless specifically indicated and supervised (FDA 2020), especially at ≥30 weeks (ductus closure)
Naproxen 500–750 mg ~30–60 min Long-acting; good with triptan (SumaRT combination)
Ibuprofen 400–800 mg ~30 min First-line for mild–moderate attacks
Ergots DHE IV/nasal 5-HT1B/1D + multi-receptor DHE 0.5–1 mg IV q8h (status migrainosus, Raskin protocol); nasal Migranal 2 mg total per attack (1 spray each nostril, repeat in 15 min); nasal Trudhesa 1.45 mg ~15–30 min (IV) Status migrainosus (repetitive IV protocol); low headache recurrence CAD, HTN, pregnancy, CYP3A4 inhibitors; separate triptan and ergot by ≥24 h (in either direction)
Anti-emetics Metoclopramide D2 antagonist 10–20 mg IV ~15 min Prokinetic; enhances oral drug absorption; also effective as monotherapy Dystonia, akathisia (pre-treat with diphenhydramine); QT risk with chlorpromazine
Prochlorperazine 10 mg IV ~15 min Highly effective ER monotherapy for migraine; evidence rivals triptans
Chlorpromazine 12.5–25 mg IV ~15 min Potent; risk of hypotension — give with IV fluids
Corticosteroid Dexamethasone Anti-inflammatory 10 mg IV Hours Prevents headache recurrence (NNT ~6); does NOT abort the acute attack itself Hyperglycemia; not for repeated use
💎 Board Pearl
  • Triptans are contraindicated in hemiplegic migraine and migraine with brainstem aura due to theoretical vasoconstriction risk — gepants and ditans are non-vasoconstrictive alternatives
  • Dexamethasone in the ER prevents headache recurrence but does NOT abort the acute migraine — always give an abortive agent alongside
Status Migrainosus Management
  • Definition: >72 h debilitating migraine
  • IV fluids
  • IV ketorolac
  • IV metoclopramide or prochlorperazine + diphenhydramine (pretreat for dystonia/akathisia)
  • IV magnesium 1–2 g
  • IV dexamethasone 10–20 mg
  • DHE Raskin protocol (0.5–1 mg IV q8h)
🔒

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