1. Indometacin-Responsive Headaches
Manjit S Matharu
Headache Group, Institute of Neurology &
The National Hospital for Neurology and Neurosurgery
London UK
HULL-BASH Headache Meeting
20th January 2011

2. Indometacin-Responsive Headaches
ABSOLUTE RESPONSE
Paroxysmal Hemicrania
Hemicrania Continua
PARTIAL RESPONSE
Primary stabbing headache
Valsalva-induced headache
Primary cough headache
Primary exertional headache
Primary sex headache
Hypnic headache

3. Indometacin Introduced in clinical practice in 1963
Non-steroidal anti-inflammatory drug (NSAID)
Anti-inflammatory, anti-pyretic and analgesic effects
MECHANISM OF ACTION IN INDOMETACIN-RESPONSIVE HEADACHES
Basis of specific action unknown:
Inhibits cyclooxygenase 1 and cyclooxygenase 2 (therefore, the generation of prostaglandins) and leukocyte activity
Decreases both cerebral blood flow and CSF pressure
Indometacin also affects melatonin secretion
Indometacin may have an effect on nitrinergic mechanisms (David Dodick, 1998)

4. Indometacin-Responsive Headaches
ABSOLUTE RESPONSE
Paroxysmal Hemicrania
Hemicrania Continua
PARTIAL RESPONSE
Primary stabbing headache
Valsalva-induced headache
Primary cough headache
Primary exertional headache
Primary sex headache
Hypnic headache

5. Trigeminal Autonomic Cephalalgias
Cluster Headache
Paroxysmal Hemicrania
SUNCT (Short-lasting Unilateral Neuralgiform headache with Conjunctival injection and Tearing)
Unilateral head pain, predominantly V1
Very severe / Excruciating
Cranial autonomic symptoms
Parasympathetic h
Sympathetic i
Attack frequency and duration differs
Treatment responses differ

6. Paroxysmal Hemicrania IHS CLASSIFICATION CRITERIA
Severe
Unilateral
Orbital, supraorbital or temporal pain
2-30 minutes duration
>5 attacks daily at least 50% of the time
Associated symptoms:
-Conjunctival injection
-Lacrimation
-Ptosis
-Miosis
-Eyelid oedema
-Nasal congestion
-Rhinorrhea
-Forehead and facial sweating
Stopped completely by indometacin

7. Trigeminal Autonomic Cephalalgias
Cluster
Headache
Paroxysmal Hemicrania
SUNCT
Lifetime prevalence
1/1000
1/50,000*
1/15,000
F:M ratio 1:
1:1
1:1.5
Age
Mean
Range 30
6-67 37
5-68 48
19-75

8. Trigeminal Autonomic Cephalalgias
Cluster
Headache
Paroxysmal Hemicrania
SUNCT
Attack frequency (daily)
1-8
1-40
3-200
Duration of attack
15-180mins
2-30mins
5-240secs
Pain quality
Sharp, throbbing
Stabbing, burning
Pain intensity
Very severe
Circadian periodicity
70%
45%
Absent

9. Trigeminal Autonomic Cephalalgias
Cluster
Headache
Paroxysmal Hemicrania
SUNCT
Autonomic features
+++
+++*
Migrainous features ++ +
Restless or agitated
90%
80%
65%
Aura
14%
Rare
Triggers
Alcohol
Cutaneous -
Episodic : Chronic
90:10
35:65
10:90

10. Paroxysmal Hemicrania
Trigeminal Autonomic Cephalalgias EVIDENCE FOR HYPOTHALAMIC DYSFUNCTION
Cluster Headache
PET Study
Paroxysmal Hemicrania
PET Study
SUNCT
fMRI Study
May et al, Lancet 1998
Matharu et al, Ann Neurol 2004
May et al, Ann Neurol 1999
Posterior hypothalamic region activation in all trigeminal autonomic cephalalgias

11. Paroxysmal Hemicrania PET STUDY
Posterior Hypothalamus
Ventral Midbrain
Matharu et al, Ann Neurol 2006

12. Adapted from Antonaci et al. Headache 1998;38:122-8
Indometacin Trial
Oral Indometacin trial
25mgs tds for 3 days
50mgs tds for 3 days
75mgs tds for 7 days
Indotest (Intramuscular indometacin) hr
Time
Indomethacin 100mgs intramuscularly
Adapted from Antonaci et al. Headache 1998;38:122-8

13. Paroxysmal Hemicrania vs. Cluster Headache
FEATURE CH PH
Duration (min)
2 – 30
Frequency (attacks/day)
1- 8
1 - 40
Indometacin - +
Trial of Indometacin if:
Attack frequency > 5 daily
Attack duration < 30 minutes
Chronic subtypes
Medically intractable

14. Trigeminal Autonomic Cephalalgias INVESTIGATIONS
Cittadini and Matharu, Neurologist 2009
Literature review of symptomatic TACs published between
Identified 37 symptomatic cases of TACs (CH 24, PH 3, SUNCT 10)
Pituitary tumours: CH 7, PH 3, SUNCT 7
Levy et al, Brain 2005
84 pituitary tumour patients with headaches
Studied in TERTIARY REFERRAL NEUROSURGICAL CENTRE
4% had CH; 5% had SUNCT (76% had migraine)
Investigate all TAC patients for pituitary tumours?
Prevalence of pituitary tumours in TACs is unknown
1 in 10 of the population have an incidental pituitary micro-adenoma (< 1cm diameter) on MRI pituitary
1 in 500 have a macro-adenoma

15. Paroxysmal Hemicrania TREATMENTS
Indometacin
Persistence of efficacy; investigate if efficacy wears off
23% develop GI side effects with chronic treatment
Other NSAIDs
COX-II inhibitors
Topiramate
Verapamil
Greater occipital nerve blocks
Neuromodulation
Occipital nerve stimulation
Posterior hypothalamic region (midbrain tegmentum) DBS

16. Hemicrania Continua IHS DIAGNOSTIC CRITERIA
Headache for >3 months
B. All of the following characteristics:
1. unilateral pain without side-shift
2. daily and continuous, without pain-free periods
3. moderate intensity, but with exacerbations of severe pain
C. At least one of the following autonomic features occurs during exacerbations and ipsilateral to the side of pain:
1. conjunctival injection and/or lacrimation
2. nasal congestion and/or rhinorrhoea
3. ptosis and/or miosis
D. Complete response to therapeutic doses of indomethacin

17. Hemicrania Continua TREATMENTS
Indometacin (25-300mgs)
Other NSAIDs
Piroxicam, Naproxen, Ibuprofen, Aspirin
COX II Inhibitors
Topiramate
Gabapentin
Verapamil
Occipital nerve stimulation

18. Hemicrania Continua OCCIPITAL NERVE STIMULATION
Burns B, Watkins L, Goadsby PJ. Lancet Neurol 2008
Results
5/6 (83%) reported meaningful benefit
Benefit built up over 2 days -3 months
Worsened rapidly when stimulator off
Degree of Improvement % 
Number
Substantial
80-95% 4
Moderate
30% 1
Worse*
-20%
* Patient has migraine not hemicrania continua

19. Hemicrania Continua PET STUDY
Posterior Hypothalamus
Dorsal Rostral Pons
Ventrolateral Midbrain
Matharu et al, Headache 2004

20. Primary Stabbing Pain
Not especially rare – 3% of general population, 42% of migraineurs. Also commoner in cluster, HC, TTH
Stabbing or jabbing pain
Ophthalmic trigeminal distribution
Last a few seconds (rarely up to 1 minute)
May be unifocal or move around the head
Occurs at irregular intervals
Important to differentiate from:
Trigeminal Neuralgia: TN is triggerable, Vii /Viii
SUNCT – longer runs of stabbing pain, cranial autonomic symptoms
Treatment (if required): Indometacin Celecoxib Melatonin
Gabapentin

21. Primary Cough Headache
4/19/ :37 AM
Primary Cough Headache
Previously known as benign cough headache, Valsalva headache
Sudden headache triggered (not worsened) by coughing/Valsalva
Lasts 1 second-30mins
Associated features uncommon
Approx 40% of cough headache is secondary, usually due to Chiari malformation
Essential to exclude structural lesions, especially in posterior fossa
Mean age of onset 67 (range in one series)
Treatment: Indometacin
Acetazolamide, Methysergide
Lumbar puncture – can be curative, may need repeating
© 2007 Microsoft Corporation. All rights reserved. Microsoft, Windows, Windows Vista and other product names are or may be registered trademarks and/or trademarks in the U.S. and/or other countries.
The information herein is for informational purposes only and represents the current view of Microsoft Corporation as of the date of this presentation. Because Microsoft must respond to changing market conditions, it should not be interpreted to be a commitment on the part of Microsoft, and Microsoft cannot guarantee the accuracy of any information provided after the date of this presentation. MICROSOFT MAKES NO WARRANTIES, EXPRESS, IMPLIED OR STATUTORY, AS TO THE INFORMATION IN THIS PRESENTATION.

22. Primary Exertional Headache
4/19/ :37 AM
Primary Exertional Headache
IHS criteria:
Pulsating headache
Lasting from 5 minutes to 48 hours
Brought on by and occurring only during or after physical exertion
Not attributed to another disorder
On first occurrence, essential to exclude SAH/dissection
Treatment: Indomethacin
Propranolol
Ergotamine (pre-emptive)
Flunarizine
© 2007 Microsoft Corporation. All rights reserved. Microsoft, Windows, Windows Vista and other product names are or may be registered trademarks and/or trademarks in the U.S. and/or other countries.
The information herein is for informational purposes only and represents the current view of Microsoft Corporation as of the date of this presentation. Because Microsoft must respond to changing market conditions, it should not be interpreted to be a commitment on the part of Microsoft, and Microsoft cannot guarantee the accuracy of any information provided after the date of this presentation. MICROSOFT MAKES NO WARRANTIES, EXPRESS, IMPLIED OR STATUTORY, AS TO THE INFORMATION IN THIS PRESENTATION.

23. Primary Headache associated with Sexual Activity
4/19/ :37 AM
Primary Headache associated with Sexual Activity
Preorgasmic Headache:
Dull ache in the head and neck associated with awareness of neck and/or jaw muscle contraction
Occurs during sexual activity and increases with sexual excitement
Orgasmic Headache:
Sudden severe ("explosive") headache occurring at orgasm
On first occurrence, essential to exclude SAH/dissection
Treatment: Pre-emptive or prophylactic Indometacin
Propranolol/Metoprolol
Diltiazem
Naratriptan 2.5mg
© 2007 Microsoft Corporation. All rights reserved. Microsoft, Windows, Windows Vista and other product names are or may be registered trademarks and/or trademarks in the U.S. and/or other countries.
The information herein is for informational purposes only and represents the current view of Microsoft Corporation as of the date of this presentation. Because Microsoft must respond to changing market conditions, it should not be interpreted to be a commitment on the part of Microsoft, and Microsoft cannot guarantee the accuracy of any information provided after the date of this presentation. MICROSOFT MAKES NO WARRANTIES, EXPRESS, IMPLIED OR STATUTORY, AS TO THE INFORMATION IN THIS PRESENTATION.

24. Hypnic Headache IHS DIAGNOSTIC CRITERIA TREATMENTS Dull headache
4/19/ :37 AM
Hypnic Headache
IHS DIAGNOSTIC CRITERIA
Dull headache
Develops only during sleep, and awakens patient
At least two of the following characteristics:
occurs >15 times per month
lasts ≥15 minutes after waking
first occurs after age of 50 years
No autonomic symptoms and no more than one of nausea, photophobia or phonophobia
TREATMENTS
Caffeine, Indometacin, Lithium, Flunarizine
© 2007 Microsoft Corporation. All rights reserved. Microsoft, Windows, Windows Vista and other product names are or may be registered trademarks and/or trademarks in the U.S. and/or other countries.
The information herein is for informational purposes only and represents the current view of Microsoft Corporation as of the date of this presentation. Because Microsoft must respond to changing market conditions, it should not be interpreted to be a commitment on the part of Microsoft, and Microsoft cannot guarantee the accuracy of any information provided after the date of this presentation. MICROSOFT MAKES NO WARRANTIES, EXPRESS, IMPLIED OR STATUTORY, AS TO THE INFORMATION IN THIS PRESENTATION.

25. Indometacin-Responsive Headaches
Rare but important group of headache syndromes to recognize in view of therapeutic response to Indometacin
Consider trial of Indometacin in:
Strictly unilateral paroxysmal or continuous headaches
Short-lasting unilateral or bilateral headaches