Indomethacin Responsive Headaches

Indomethacin-responsive headache disorders are a group of rare conditions characterized by an absolute response to the medication indomethacin. The most notable conditions in this group are paroxysmal hemicrania and hemicrania continua.
==Pathophysiology==
Both paroxysmal hemicrania and hemicrania continua seem to be caused by activation of the trigeminal-autonomic reflex, but they involve different brain networks. Paroxysmal hemicrania involves activation in the contralateral posterior hypothalamic region and contralateral ventral midbrain. Hemicrania continua is characterized by activations in the contralateral posterior hypothalamic region, ipsilateral dorsal rostral pons, and ipsilateral ventrolateral midbrain.
The mechanism of action in these disorders of indomethacin is unclear. It has predominant COX-1 selectivity, but other COX-1 selective drugs are relatively ineffective. Theories include effects on nitric oxide and melatonin-related mechanism.
==Clinical Features==
Paroxysmal hemicrania presents as severe, strictly unilateral attacks of pain that typically last 2 to 30 minutes and occur many times a day. These attacks are associated with cranial autonomic symptoms on the same side of the body as the pain. Hemicrania continua presents as a persistent, strictly unilateral headache that fluctuates in intensity throughout the day. These fluctuations are associated with cranial autonomic symptoms.
==Diagnosis==
===Paroxysmal Hemicrania===
ICHD-3 Diagnostic Criteria for Paroxysmal Hemicrania (ICHD-3)
Criteria 	Description
A 	At least 20 attacks fulfilling criteria B-E
B 	Severe unilateral orbital, supraorbital and/or temporal pain lasting 2 to 30 minutes
C 	Either or both of the following:
 	
1. At least one of the following symptoms or signs, ipsilateral to the headache:
 	a. Conjunctival injection and/or lacrimation
 	b. Nasal congestion and/or rhinorrhoea
 	c. Eyelid oedema
 	d. Forehead and facial sweating
 	e. Miosis and/or ptosis
 	2. A sense of restlessness or agitation
D 	Occurring with a frequency of >5 per day (a)
E 	Prevented absolutely by therapeutic doses of indomethacin (b)
F 	Not better accounted for by another ICHD-3 diagnosis
a During part, but less than half, of the active timecourse of paroxysmal hemicrania, attacks may be less frequent.b In an adult, oral indomethacin should be used initially in a dose of at least 150 mg daily and increased if necessary up to 225 mg daily. The dose by injection is 100 mg to 200 mg. Smaller maintenance doses are often employed.	a During part, but less than half, of the active timecourse of paroxysmal hemicrania, attacks may be less frequent.b In an adult, oral indomethacin should be used initially in a dose of at least 150 mg daily and increased if necessary up to 225 mg daily. The dose by injection is 100 mg to 200 mg. Smaller maintenance doses are often employed.
===Hemicrania Continua===
ICHD-3 Diagnostic Criteria for Hemicrania Continua (ICHD-3)
Criteria 	Description
A 	Unilateral headache fulfilling criteria B-D
B 	Present for >3 months, with exacerbations of moderate or greater intensity
C 	Either or both of the following:
 	
1. At least one of the following symptoms or signs, ipsilateral to the headache:
 	a. Conjunctival injection and/or lacrimation
 	b. Nasal congestion and/or rhinorrhoea
 	c. Eyelid oedema
 	d. Forehead and facial sweating
 	e. Miosis and/or ptosis
 	2. A sense of restlessness or agitation, or aggravation of the pain by movement
D 	Responds absolutely to therapeutic doses of indomethacin (a)
E 	Not better accounted for by another ICHD-3 diagnosis
a In an adult, oral indomethacin should be used initially in a dose of at least 150 mg daily and increased if necessary up to 225 mg daily. The dose by injections is 100 mg to 200 mg. Smaller maintenance doses are often employed	a In an adult, oral indomethacin should be used initially in a dose of at least 150 mg daily and increased if necessary up to 225 mg daily. The dose by injections is 100 mg to 200 mg. Smaller maintenance doses are often employed
== Investigations ==
MRI brain is recommended, specifically asking for pituitary views to rule out adenoma, and also assess pituitary function (prolactin, IGF-1, TFTs). Even those with complete response to indomethacin can have a secondary cause.
==Differential Diagnosis==
==Treatment==
=== Indomethacin ===
If unsure, and not clinically contraindicated, consider a two week trial of (ordinary release) indomethacin. It is often difficult to make the diagnosis prior to seeing the response to Indomethacin. Response is usually prompt, within one to two days of reaching the effective dose.
Typically one starts at 25mg tds, and adjusted up or down as needed. For example 25mg tds for three days, 50mg tds for 3 days, 75mg tds for 3 days as needed for headache resolution, and continue on the lowest effective dose. Reaching 75mg tds without resolution of hte headache is a failed trial. For children under 14 years old the dose is 1 to 2 mg/kg daily given in two divided doses daily.
Indomethacin is an NSAID belonging to the acetic acid class. This is in contrast to propionic acid NSAIDs like naproxen and ibuprofen. In New Zealand Indomethacin is listed as a section 29 drug. There are three preparations listed in the formulary: capsule, slow release capsule, and suppository. 
Properties of Indomethacin Formulations
 	Capsule, ordinary release 	Capsule, modified release 	Suppository
Strength 	25mg 	75mg 	100mg
Dosage in literature 	25 mg to 75 mg 3 times daily 	25 mg to 75 mg 2 times daily 	50 mg to 100 mg 2 times daily
Bioavailability 	100% 	100% 	80%
Plasma half-life 	7 hours 	7 hours 	7 hours
Plasma protein binding	~90% 	~90% 	~90%
Excretion 	Renal: 60%, glucuronidatedBiliary: 40% 	Renal: 60%, glucuronidatedBiliary: 40% 	Renal: 60%, glucuronidatedBiliary: 40%
Distribution 	Blood-brain barrier: permeablePlacenta: permeableBreast milk: small amount	Blood-brain barrier: permeablePlacenta: permeableBreast milk: small amount	Blood-brain barrier: permeablePlacenta: permeableBreast milk: small amount
The primary adverse effects are abdominal pain, dyspepsia, and nausea. Proton pump inhibitors are often useful. At high doses lightheadedness can occur. Some patients can get medication overuse headache. Be cautious if the patient is on lithium as it can raise lithium levels.
===Other ===
Noninvasive Vagus Nerve Stimulation is a potential indomethacin sparing treatment option.
Other medications that are sometimes used are COX-2 inhibitors, topiramate, and melatonin.
==Prognosis==
These conditions are essentially lifelong, except potentially in children.
==Resources==
Category:Head and Jaw Conditions
Category:Headache Disorders