Confusable diagnoses · PANCE / PANRE

Migraine vs Cluster Headache

Written & clinically reviewed by Ryan Busch, PA-C · Updated August 2026 · Report an error

Migraine and Cluster Headache are easy to mix up on the boards. Here's a side-by-side comparison — presentation, workup, imaging, and first-line treatment — drawn from our full outlines.

Migraine vs Cluster Headache at a glance

  • Migraine: Recurrent primary headache disorder with unilateral throbbing pain, photophobia, nausea.
  • Cluster Headache: Severe unilateral periorbital headache with ipsilateral autonomic features; 'suicide headache.'

Try two board-style questions on Migraine vs Cluster Headache

Real questions from the FirstPassPA bank, with the full explanation. Pick an answer — no signup, no email.

Question 1NeurologyEasy
A 32-year-old woman has 8 migraine days per month despite trials of sumatriptan and naproxen. She has tried propranolol and topiramate without benefit and would like to start preventive therapy that targets the calcitonin gene-related peptide pathway. Which of the following is the most appropriate medication?
  • AErenumab
  • BOnabotulinumtoxin A
  • CVerapamil
  • DAmitriptyline
Reveal answer & full explanation
Correct answer: A — Erenumab
  • AErenumab✓
  • BOnabotulinumtoxin A
  • CVerapamil
  • DAmitriptyline

Why erenumab is correct

  • Calcitonin gene-related peptide (CGRP) monoclonal antibodies — including erenumab, fremanezumab, galcanezumab, and eptinezumab — are FDA-approved for episodic and chronic migraine prevention and specifically target the CGRP pathway.
  • They reduce migraine days by ~50% in roughly half of patients, with excellent tolerability and no CNS side effects.
  • Most are monthly subcutaneous injections; eptinezumab is administered intravenously quarterly.

Why the others are wrong

  • B) OnabotulinumtoxinA — FDA-approved for chronic migraine prevention (≥15 headache days/month) but does not target the CGRP pathway; this patient has 8 migraine days/month (episodic migraine).
  • C) Verapamil — Used for cluster headache prevention, not the preferred agent for migraine and does not target the CGRP pathway.
  • D) Amitriptyline — A tricyclic antidepressant used as migraine prophylaxis but does not target the CGRP pathway, which is what the patient specifically requests.

Additional high-yield points

  • Gepants (ubrogepant, rimegepant) are CGRP receptor antagonists used for acute treatment and, for some agents, prevention.
Question 2NeurologyEasy
A 28-year-old female has daily unilateral severe headaches around the right eye with ipsilateral tearing, rhinorrhea, and ptosis, each lasting 45-75 minutes, occurring at the same time (2 AM) for 4 weeks. She is normal between episodes. Which of the following is the most appropriate acute treatment?
  • ACarbamazepine
  • BHigh-flow oxygen
  • COral sumatriptan
  • DIndomethacin
Reveal answer & full explanation
Correct answer: B — High-flow oxygen
  • ACarbamazepine
  • BHigh-flow oxygen✓
  • COral sumatriptan
  • DIndomethacin

Why High-flow oxygen is correct

  • Cluster headache presents with strictly unilateral severe periorbital pain with ipsilateral autonomic features (lacrimation, rhinorrhea, ptosis, miosis, conjunctival injection), duration 15-180 minutes, occurring in clusters at the same time daily
  • Circadian pattern is often nocturnal due to hypothalamic activation
  • First-line acute treatment is high-flow 100% O2 via non-rebreather mask for 15-20 minutes
  • Subcutaneous sumatriptan 6 mg is the fastest pharmacologic acute alternative

Why the others are wrong

  • Carbamazepine — used for trigeminal neuralgia, not cluster headache (confused-with trigeminal neuralgia)
  • Oral sumatriptan — the oral route has too slow an onset for cluster headache; subcutaneous sumatriptan is the preferred pharmacologic acute option (right-concept-wrong-route)
  • Indomethacin — hallmark treatment for paroxysmal hemicrania, which has shorter attacks and an absolute indomethacin response, not cluster headache (confused-with paroxysmal hemicrania)

Additional high-yield points

  • Prophylaxis: verapamil (first-line); suboccipital steroid injection as a short-term bridge; lithium for chronic cluster; galcanezumab for episodic cluster
  • Distinguish from paroxysmal hemicrania: shorter duration (2-30 min), more frequent attacks, absolute indomethacin response
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Side-by-side comparison

FeatureMigraineCluster Headache
At a glanceRecurrent primary headache disorder with unilateral throbbing pain, photophobia, nausea.Severe unilateral periorbital headache with ipsilateral autonomic features; 'suicide headache.'
Classic presentationPOUND mnemonic: Pulsatile, One-day duration (4-72 h), Unilateral, Nausea, Disabling — 4 of 5 features highly suggest migraine.; Prodrome (hours-days before): mood changes, food cravings, neck stiffness, yawning, urinary frequency; Aura (~25%): visual (scintillating scotoma, fortification spectra, hemianopia), sensory (paresthesias…Severe unilateral periorbital pain + ipsilateral autonomic features + restlessness, attacks clustered in time.; Excruciating ('worst pain imaginable,' 'ice pick in the eye') unilateral periorbital/temporal pain; Duration 15-180 minutes per attack; Frequency: 1 every other day to 8 per day, often at the same time(s) daily; Cluster…
Workup / key labsICHD-3 criteria for migraine without aura: ≥5 attacks lasting 4-72 hours, with ≥2 of [unilateral, pulsating, moderate-severe, aggravated by activity] AND ≥1 of [nausea/vomiting, photophobia + phonophobia]. Migraine with aura: ≥2 attacks of fully reversible aura symptoms (most often visual, sensory, or speech/language) with typical…ICHD-3: ≥5 attacks, severe unilateral orbital/supraorbital/temporal pain lasting 15-180 min (untreated), with ≥1 ipsilateral autonomic feature OR sense of restlessness, occurring once every other day to 8 per day.; Not typically helpful for diagnosis
ImagingNeuroimaging NOT routinely indicated for typical migraine with normal exam; MRI brain indicated for: red flags (SNOOP: Systemic symptoms/Secondary risk factors, Neurologic signs, Onset sudden/thunderclap, Older age >50 with new headache, Pattern change/Progressive/Positional/Precipitated by Valsalva); Lumbar puncture if SAH or…MRI brain with pituitary protocol recommended at least once for all patients with cluster headache to exclude structural lesion (pituitary tumor, carotid lesion, AVM); Consider MRA if dissection suspected
First-line treatmentAbortive: NSAIDs (ibuprofen 400-800 mg, naproxen 500 mg) for mild-moderate attacks; Triptan (5-HT1B/1D agonist: 1B causes cranial vasoconstriction, the basis of its cardiovascular contraindications; 1D inhibits trigeminal CGRP and substance P release) — sumatriptan 50-100 mg PO (also 6 mg SC, 20 mg nasal), rizatriptan 10 mg, eletriptan…Acute (abortive): high-flow 100% oxygen 12-15 L/min via non-rebreather mask for 15-20 min (works in ~70-80%; very well tolerated — no smoking or open flame near the oxygen, caution in CO2-retaining COPD); Triptan — sumatriptan 6 mg SC (most effective formulation) or 20 mg intranasal, zolmitriptan 5-10 mg nasal — faster routes preferred…

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Full outlines

Migraine Cluster Headache All 514 diagnoses

Educational use only. This outline is a study aid for PA students and is not medical advice or a substitute for clinical judgment. FirstPassPA is an independent study tool and is not affiliated with, endorsed by, or sponsored by NCCPA or PAEA. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants; End of Rotation™ is a program of the Physician Assistant Education Association.