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