Paroxysmal Hemicrania
Paroxysmal hemicrania (PH) is a trigeminal autonomic cephalalgia characterized by frequent, short-lasting, severe unilateral headache attacks with ipsilateral autonomic features. The defining characteristic of PH is its absolute response to indomethacin — this response is both diagnostic and therapeutic. If the headache does not respond completely to indomethacin at adequate doses, the diagnosis should be reconsidered. PH occurs in episodic and chronic forms, with the chronic form being more common.
Bottom Line
- Attack profile: Severe unilateral orbital/temporal pain lasting 2-30 minutes, occurring ≥5 times per day (range 1-40), with ipsilateral autonomic features
- Indomethacin response is absolute and required for diagnosis — complete resolution at therapeutic doses (up to 225 mg/day). This is an ICHD-3 criterion.
- Dose: Indomethacin 25 mg TID, increase to 50-75 mg TID if needed. Most respond within 1-2 days.
- Key differentiators from cluster: Shorter attacks (2-30 min vs 15-180 min), higher frequency (≥5/day vs 1-8/day), female predominance (vs male in cluster), complete indomethacin response (not seen in cluster)
- Long-term management: Indomethacin maintenance at the lowest effective dose. GI protection with PPI.
ICHD-3 Criteria
- A. At least 20 attacks fulfilling B-E
- B. Severe unilateral orbital, supraorbital, and/or temporal pain lasting 2-30 minutes
- C. Either or both:
- At least one ipsilateral autonomic sign: conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead sweating, miosis, ptosis, eyelid edema
- Restlessness or agitation
- D. Frequency ≥5 attacks per day for more than half the time
- E. Prevented absolutely by therapeutic doses of indomethacin
- F. Not better accounted for by another ICHD-3 diagnosis
| Subtype |
Pattern |
| Episodic PH (3.2.1) |
Attacks occurring in bouts lasting 7 days to 1 year, separated by pain-free remissions of ≥3 months |
| Chronic PH (3.2.2) |
Attacks for >1 year without remission or with remissions <3 months. More common form (~80%). |
Differentiating PH from Other TACs
| Feature |
Paroxysmal Hemicrania |
Cluster Headache |
SUNCT/SUNA |
Hemicrania Continua |
| Attack duration |
2-30 min |
15-180 min |
1-600 sec |
Continuous with exacerbations |
| Frequency |
≥5/day |
1-8/day |
≥1/day (often dozens-hundreds) |
Continuous |
| Sex ratio |
Female > male |
Male > female (3:1) |
Male > female |
Female > male |
| Indomethacin |
Absolute response |
No response |
No response |
Absolute response |
| Oxygen/triptan |
No response |
Respond |
No response |
No response |
The Indomethacin Trial
How to Perform an Indomethacin Trial
- Step 1: Start indomethacin 25 mg TID with food
- Step 2: If no complete response in 3 days, increase to 50 mg TID
- Step 3: If no complete response in 3 more days, increase to 75 mg TID (225 mg/day)
- Expected response: Complete cessation of attacks within 1-2 days of reaching the effective dose. Partial response is not sufficient — the response should be absolute.
- If no response at 225 mg/day for 1 week: Reconsider the diagnosis. PH without indomethacin response does not meet ICHD-3 criteria.
- Confirmation: After response, withdraw indomethacin — if attacks recur, and resolve again upon reinstatement, the diagnosis is confirmed.
- IM/IV test: Indomethacin 50-100 mg IM can be used as a rapid diagnostic test (response within 30-60 minutes). Useful in urgent or unclear cases.
Treatment
Indomethacin (First-Line and Only Proven Treatment)
- Maintenance dose: After achieving complete suppression, titrate down to the lowest effective dose (typically 25-100 mg/day)
- Long-term use: Chronic PH patients may need indomethacin indefinitely. Reassess periodically by briefly reducing dose to confirm continued need.
- GI protection: Co-prescribe a PPI (omeprazole 20 mg or equivalent) in all patients on maintenance indomethacin. Risk of gastric ulceration and GI bleeding increases with duration.
- Renal monitoring: Check creatinine and electrolytes periodically (every 6-12 months). Indomethacin can impair renal function, particularly in elderly or patients with pre-existing kidney disease.
Side Effects of Indomethacin
| Side Effect |
Frequency |
Management |
| GI upset / dyspepsia |
Very common |
Take with food; co-prescribe PPI |
| Gastric ulceration / GI bleeding |
Uncommon but serious |
PPI prophylaxis; monitor for black stools, anemia |
| Headache (paradoxical) |
Uncommon |
Usually resolves with dose adjustment |
| Dizziness / lightheadedness |
Common |
Usually transient; take with food |
| Renal impairment |
Dose-dependent |
Monitor creatinine; avoid in CKD |
| Hypertension |
Uncommon |
Monitor BP; may antagonize antihypertensives |
When Indomethacin Cannot Be Tolerated
In the rare patient who cannot tolerate indomethacin due to GI or renal side effects, the following alternatives have been reported in case series (none have RCT evidence):
- Celecoxib 200-400 mg/day — COX-2 selective; lower GI risk. Partial responses reported. Not as reliable as indomethacin.
- Verapamil — some case reports of partial benefit
- Topiramate — anecdotal partial responses
- Melatonin 3-10 mg — rare reports of benefit
- Greater occipital nerve block — transient benefit reported
- None of these are considered adequate replacements for indomethacin — if indomethacin truly cannot be used, reconsider the diagnosis and evaluate for other causes
Important Considerations
- MRI brain with pituitary views should be obtained in all patients with a new diagnosis of PH to exclude structural lesions (particularly pituitary tumors and posterior fossa lesions) that can cause symptomatic PH
- Secondary PH has been reported with pituitary adenomas, arteriovenous malformations, cavernous sinus lesions, and collagen vascular disorders — imaging is mandatory
- PH can coexist with trigeminal neuralgia (“PH-tic syndrome”), analogous to cluster-tic syndrome. Both conditions must be treated independently.
References
- Cittadini E, et al. Paroxysmal hemicrania: a prospective clinical study of 31 cases. Brain. 2008;131(4):1142-1155.
- Boes CJ, et al. Paroxysmal hemicrania, SUNCT, and hemicrania continua. Semin Neurol. 2006;26(2):260-270.
- Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211.
- Antonaci F, et al. Chronic paroxysmal hemicrania and hemicrania continua: parenteral indomethacin as a diagnostic test. Headache. 1998;38(2):122-128.
