Indomethacin-responsive headache syndromes represent a unique group of primary headache disorders characterized by a prompt and often complete response to indomethacin. Indomethacin-responsive headache syndromes are divided into 2 distinct categories in the International Classification of Headache Disorders, 3rd edition (ICHD-3 beta): trigeminal autonomic cephalalgias (paroxysmal hemicrania and hemicrania continua) and other primary headaches, including primary stabbing headache and Valsalva-induced headaches (primary cough headache, primary exercise headache, primary headache associated with sexual activity). In addition, cluster headache and hypnic headache have been described as another 2 primary headache disorders that may respond to indomethacin. The velocity of publications on indomethacin and headache has decreased in recent years. Most papers have been specific to indomethacin and trigeminal autonomic cephalalgias (11).
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Indomethacin-responsive headache syndromes can be divided into 2 groups: (1) trigeminal autonomic cephalalgias (paroxysmal hemicrania, code 3.2 and hemicrania continua, code 3.4) and (2) other primary headaches, including Valsalva-induced headaches (primary cough headache, primary exercise headache, primary headache associated with sexual activity, codes 4.1 to 4.3), and primary stabbing headache (code 4.7).
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Not all hemicrania continua are side-locked and responsive to indomethacin treatment.
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Primary cough headache is usually self-limited.
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Reversible cerebral vasoconstriction syndrome (RCVS) should be considered as possible underlying etiology before the diagnosis of primary headache associated with sexual activity.
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Cluster headache may be also responsive to indomethacin.
Historical note and terminology
Indomethacin is a unique agent that was introduced into clinical practice in 1963. It is a nonsteroidal indoleacetic drug that has antiinflammatory and antipyretic-analgesic properties. It is the only agent in this category that has more anti-inflammatory activity than aspirin (56). It is used for many medical conditions, including patent ductus arteriosus, tocolysis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and gout. Indomethacin is used in ophthalmology for uveitis and postoperative inflammation.
The mechanisms of indomethacin with excellent effect on some headaches are not clear. However, some special characteristics of indomethacin may play an important role in the effect. The mean unbound free plasma concentration of indomethacin reaches its peak at around 2 hours (07). The mean plasma half-life is approximately 7 hours, which usually involves the necessary posology of administration twice or thrice per day (63). Indomethacin has the highest passage of the blood brain barrier when compared to naproxen and ibuprofen. In an animal study, indomethacin could inhibit NO-induced dural vasodilation, but the effect was not found in naproxen and ibuprofen groups (136). A study showed that indomethacin could inhibit the trigeminocervical complex activated by local micro-iontophoresis of L-glutamate or administration of a nitric oxide donor (137). However, naproxen could only inhibit the former, not the latter. The result supports the direct implication of indomethacin in the CNS. It seems indomethacin has more potent vasoconstrictive activity and unique direct neuronal or nitric oxide dependent inhibitory pathway activity (69). Using transcranial Doppler monitoring, decreased mean flow velocity was noted in the middle cerebral artery (17). In addition, indomethacin was found in experiments to have akinetic profile of time dependent tight binding; naproxen shows time dependent weak binding, and ibuprofen acts via competitive inhibition on COX1 and COX2 (42). Some studies also showed that indomethacin could decrease intracranial pressure. The regulation of intracranial pressure may play an important role in the action of some headaches for which intracranial pressure is proposed as the underlying pathophysiology (37; 44; 145). Indomethacin was reported to reduce the CSF opening pressure in patients with idiopathic and posttraumatic intracranial hypertension (37). Indomethacin is also used as a tool for differential diagnosis in headache clinics.
The so-called "indomethacin-responsive headaches are divided into 2 groups in the International Classification of Headache Disorders, 3rd edition (ICHD-3, beta version), which are, (1) trigeminal autonomic cephalalgias (paroxysmal hemicrania, code 3.2 and hemicrania continua, code 3.4) and (2) other primary headaches, including Valsalva-induced headaches (primary cough headache, primary exercise headache, primary headache associated with sexual activity, codes 4.1 to 4.3,), and primary stabbing headache (code 4.7). Indomethacin-responsive headaches can also occur in the pediatric population (80). However, because there are no large clinical trials available focusing on the treatment efficacy, most of these recommendations are based on small trials or clinical observations.
Table 1. Indomethacin Responsive Headaches (Code based on ICHD-3, beta version)
Trigeminal autonomic cephalalgias
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Paroxysmal hemicranias (3.2)
Episodic paroxysmal hemicrania (3.2.1)
Chronic paroxysmal hemicrania (3.2.2)
Hemicrania continua (3.4)
Other primary headaches
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Primary cough headache (4.1)
Primary exercise headache (4.2)
Primary headache associated with sexual activity (4.3)
Probable primary headache associated with sexual activity (4.3.1)
Primary stabbing headache (4.7)
Other indomethacin-responsive headache disorders have been reported. Moncada and Graff-Radford reported 8 patients with indomethacin-responsive facial pain (78). Some patients with hypnic headache were also reported to be responsive to indomethacin treatment (30; 13; 100; 53). Chronic paroxysmal hemicrania-tic, an association between chronic paroxysmal hemicrania and trigeminal neuralgia, has been reported to respond to indomethacin (152). Rozen reported another new headache syndrome responsive to indomethacin, which is a unique, stereotypical, episodic headache disorder marked by long-lasting autonomic symptoms with associated hemicrania (LASH) (113). However, only 3 cases were reported in 15 years (114). Buzzi and colleagues reported a patient with migraine without aura and exercise secondary headache due to Chiari malformation type I and whose headaches responded to treatment with propranolol and indomethacin (15).
Several case reports demonstrate that some patients with cluster headache are responsive to indomethacin treatment (76; 41; Klimek 1984; 148; DCruz 1994; DAmico et al 1996; Isik and DCruz 2002; 114; 14; 01; 45; 101; 106). One patient with Valsalva-induced cluster headache was reported to improve when treated with indomethacin (Ko and 114). The childhood-onset cluster headache was found to be responsive to indomethacin treatment (04). Prakash and colleagues performed an excellent literature review and found some patients with cluster headache might be wrongly diagnosed as having paroxysmal hemicrania because of apparent response to indomethacin (107). They also concluded that the response to indomethacin in patients with cluster headache may not be as immediate as in other indomethacin-responsive headaches, and patients may need much larger doses than usual used for paroxysmal hemicrania. In patients with coexistent cluster headache and paroxysmal hemicrania, they noted that physicians tended to diagnose patients as having paroxysmal hemicrania if patients were responsive to indomethacin even when their clinical profiles were compatible with cluster headache. In addition, 15% of patients with hemicrania continua with the remitting subtype could be diagnosed as cluster headache (105). Some clues suggest the cluster headache, paroxysmal hemicrania, and hemicrania continua share common pathophysiology. All 3 headache disorders showed similar clinical characteristics and neuroimaging findings (66). One report also showed that patients with hemicrania continua might evolve from cluster headache. The different headache duration and frequency of these disorders might result from different levels of hypothalamic regulation (146).
Three patients with bilateral chronic tension-type headaches have been reported to completely respond to indomethacin (49). Although migraine did not respond to 75 mg of indomethacin a day (02), it was beneficial when given in a larger dosage (150 to 200 mg) (118). Baldacci and colleagues reported 1 patient with nummular headache became pain-free after indomethacin treatment (06).
It is important that clinicians recognize indomethacin-responsive headaches because appropriate therapy with indomethacin may not only be the best treatment, but in some cases, it is the only effective therapeutic option. All patients with strictly unilateral headache should receive an indomethacin trial.
Table 2. Other Headache Disorders That May Respond to Indomethacin
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Chronic paroxysmal hemicrania-tic
Long-lasting autonomic symptoms with associated hemicrania
Chronic tension-type headache