Manjit S MatharuHeadache Group, Institute of Neurology &

The National Hospital for Neurology and NeurosurgeryLondon

UK

HULL-BASH Headache Meeting20th January 2011

Indometacin-Responsive HeadachesIndometacin-Responsive Headaches

PARTIAL RESPONSE

Primary stabbing headacheValsalva-induced headache

Primary cough headachePrimary exertional headachePrimary sex headache

Hypnic headache

ABSOLUTE RESPONSE

Paroxysmal HemicraniaHemicrania Continua

IndometacinIndometacin

• 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:

1. Inhibits cyclooxygenase 1 and cyclooxygenase 2 (therefore, the generation of prostaglandins) and leukocyte activity

2. Decreases both cerebral blood flow and CSF pressure3. Indometacin also affects melatonin secretion4. Indometacin may have an effect on nitrinergic mechanisms

(David Dodick, 1998)

Indometacin-Responsive HeadachesIndometacin-Responsive Headaches

PARTIAL RESPONSE

Primary stabbing headacheValsalva-induced headache

Primary cough headachePrimary exertional headachePrimary sex headache

Hypnic headache

ABSOLUTE RESPONSE

Paroxysmal HemicraniaHemicrania Continua

Unilateral head pain, predominantly V1

Very severe / ExcruciatingCranial autonomic symptoms

Parasympathetic Sympathetic

Attack frequency and duration differsTreatment responses differ

Cluster HeadacheParoxysmal HemicraniaSUNCT (Short-lasting Unilateral Neuralgiform headache with Conjunctival injection and Tearing)

• Severe Severe • Unilateral Unilateral • Orbital, supraorbital Orbital, supraorbital

or temporal painor temporal pain• 2-30 minutes 2-30 minutes

durationduration• >5 attacks daily at >5 attacks daily at

least 50% of the timeleast 50% of the time

• Associated symptoms:Associated symptoms:-Conjunctival -Conjunctival

injectioninjection-Lacrimation-Lacrimation-Ptosis-Ptosis-Miosis-Miosis-Eyelid oedema-Eyelid oedema-Nasal congestion-Nasal congestion-Rhinorrhea-Rhinorrhea-Forehead and -Forehead and

facial facial sweatingsweating• Stopped Stopped completelycompletely by by

indometacinindometacin

Cluster Cluster HeadacheHeadache

Paroxysmal Paroxysmal HemicraniaHemicrania SUNCTSUNCT

Lifetime prevalenceLifetime prevalence 1/10001/1000 1/50,000*1/50,000* 1/15,0001/15,000

F:M ratioF:M ratio 1:2.5-7.21:2.5-7.2 1:11:1 1:1.51:1.5

AgeAge• MeanMean• RangeRange 3030

6-676-673737

5-685-684848

19-7519-75

Cluster Cluster

HeadacheHeadacheParoxysmal Paroxysmal HemicraniaHemicrania SUNCTSUNCT

Attack frequency (daily)Attack frequency (daily) 1-81-8 1-401-40 3-2003-200

Duration of attackDuration of attack 15-180mins15-180mins 2-30mins2-30mins 5-240secs5-240secs

Pain qualityPain quality Sharp, Sharp, throbbingthrobbing

Sharp, Sharp, throbbingthrobbing

Stabbing, Stabbing, burningburning

Pain intensityPain intensity Very severeVery severe Very severeVery severe Very severeVery severe

Circadian periodicityCircadian periodicity 70%70% 45%45% AbsentAbsent

Cluster Cluster HeadacheHeadache

Paroxysmal Paroxysmal HemicraniaHemicrania SUNCTSUNCT

Autonomic featuresAutonomic features ++++++ ++++++ +++*+++*

Migrainous featuresMigrainous features ++++ ++++ ++

Restless or agitatedRestless or agitated 90%90% 80%80% 65%65%

AuraAura 14%14% RareRare RareRare

TriggersTriggers• AlcoholAlcohol• CutaneousCutaneous

++++++--

++--

--++++++

Episodic : ChronicEpisodic : Chronic 90:1090:10 35:6535:65 10:9010:90

Cluster HeadacheCluster HeadachePET StudyPET Study

SUNCTSUNCTfMRI StudyfMRI Study

May et al, Lancet 1998 May et al, Ann Neurol 1999

Paroxysmal HemicraniaParoxysmal HemicraniaPET StudyPET Study

Matharu et al, Ann Neurol 2004

Posterior hypothalamic region activation in all trigeminal autonomic cephalalgias

Matharu et al, Ann Neurol 2006

Posterior Hypothalamus Ventral Midbrain

Oral Indometacin trial

25mgs tds for 3 days

50mgs tds for 3 days

75mgs tds for 7 days

Indotest (Intramuscular indometacin)

Indomethacin 100mgs intramuscularly

11.1+3.5 hr

Time

Adapted from Antonaci et al. Headache 1998;38:122-8

Trial of Indometacin if:Trial of Indometacin if:

• Attack frequency Attack frequency >> 5 daily 5 daily• Attack duration Attack duration << 30 minutes 30 minutes• Chronic subtypesChronic subtypes• Medically intractableMedically intractable

FEATUREFEATURE CHCH PHPH

Duration (min)Duration (min) 15 - 18015 - 180 2 – 302 – 30

Frequency (attacks/day)Frequency (attacks/day) 1- 81- 8 1 - 401 - 40

IndometacinIndometacin -- ++

Cittadini and Matharu, Neurologist 2009Literature review of symptomatic TACs published between 1975-2007Identified 37 symptomatic cases of TACs (CH 24, PH 3, SUNCT 10)Pituitary tumours: CH 7, PH 3, SUNCT 7

Levy et al, Brain 200584 pituitary tumour patients with headaches Studied in TERTIARY REFERRAL NEUROSURGICAL CENTRE4% had CH; 5% had SUNCT (76% had migraine)Investigate all TAC patients for pituitary tumours?

Prevalence of pituitary tumours in TACs is unknown1 in 10 of the population have an incidental pituitary micro-adenoma (< 1cm

diameter) on MRI pituitary1 in 500 have a macro-adenoma

IndometacinPersistence of efficacy; investigate if efficacy wears off23% develop GI side effects with chronic treatment

Other NSAIDsCOX-II inhibitorsTopiramateVerapamilGreater occipital nerve blocksNeuromodulation

Occipital nerve stimulationPosterior hypothalamic region (midbrain tegmentum) DBS

A. Headache for >3 months

B. All of the following characteristics:1. unilateral pain without side-shift2. daily and continuous, without pain-free periods3. 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 lacrimation2. nasal congestion and/or rhinorrhoea3. ptosis and/or miosis

D. Complete response to therapeutic doses of indomethacin

Indometacin (25-300mgs)Other NSAIDs

Piroxicam, Naproxen, Ibuprofen, AspirinCOX II InhibitorsTopiramateGabapentinVerapamilOccipital nerve stimulation

Burns B, Watkins L, Goadsby PJ. Lancet Neurol 2008Results

5/6 (83%) reported meaningful benefit

Benefit built up over 2 days -3 monthsWorsened rapidly when stimulator off

Degree of Improvement %  Number

Substantial 80-95% 4

Moderate 30% 1

Worse* -20% 1

* Patient has migraine not hemicrania continua

Matharu et al, Headache 2004

Posterior Hypothalamus Ventrolateral MidbrainDorsal Rostral Pons

Previously known as benign cough headache, Valsalva headacheSudden headache triggered (not worsened) by coughing/ValsalvaLasts 1 second-30minsAssociated features uncommonApprox 40% of cough headache is secondary, usually due to Chiari malformationEssential to exclude structural lesions, especially in posterior fossaMean age of onset 67 (range 44-81 in one series)Treatment: Indometacin

Acetazolamide, MethysergideLumbar puncture – can be curative, may need repeating

IHS criteria:Pulsating headacheLasting from 5 minutes to 48 hoursBrought on by and occurring only during or after physical exertionNot attributed to another disorder

On first occurrence, essential to exclude SAH/dissectionTreatment: Indomethacin

PropranololErgotamine (pre-emptive)Flunarizine

Preorgasmic Headache:Dull ache in the head and neck associated with awareness of neck and/or jaw muscle contractionOccurs during sexual activity and increases with sexual excitement

Orgasmic Headache:Sudden severe ("explosive") headache occurring at orgasmOn first occurrence, essential to exclude SAH/dissection

Treatment: Pre-emptive or prophylactic IndometacinPropranolol/MetoprololDiltiazem

Naratriptan 2.5mg

IHS DIAGNOSTIC CRITERIAA. Dull headache B. Develops only during sleep, and awakens patientC. At least two of the following characteristics:

1. occurs >15 times per month2. lasts ≥15 minutes after waking3. first occurs after age of 50 years

D. No autonomic symptoms and no more than one of nausea, photophobia or phonophobia

TREATMENTSCaffeine, Indometacin, Lithium, Flunarizine

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 headachesShort-lasting unilateral or bilateral headaches