The indomethacin-responsive headache disorders consist of a group of conditions with a particularly good response to indomethacin. Two examples are hemicrania continua and paroxysmal hemicrania. Other conditions are Valsalva-induced headaches (cough headache, exercise headache, and sex headache), primary stabbing headache, and hypnic headache. (VanderPluym, 2015)
This specific response is not well understood but could be related with not only the inhibition of cyclooxygenase, but also with a reduction of cerebral blood flow (CBF), and the inhibition of nitric oxide (NO). NO is one of the fundamental molecules involved in the regulation of cerebral metabolic activity and blood flow. (Villar-Martínez et al, 2021).
To predicted chronic responsiveness to indomethacin therapy. (Baldacci F. et al, 2008)
There are several protocols and the dosages used as a tool for detecting indomethacin responsive conditions vary according to different centers of investigation. (Bordini et al, 2016)
Some examples of protocols and doses are:
Other classes of medications such as selective cyclooxygenase-2 inhibitors (celecoxib), anti-epileptic agents (topiramate), calcium channel blockers (verapamil, flunarizine), melatonin, and local nerve blocks with anesthetic and steroids have been shown to be effective in case reports and series. (Zhu et al, 2015)
There are reports on the efficacy of a serotonin and norepinephrine reuptake inhibitors (SNRI) (Venlafaxine) for hemicrania continua. (Dora et al, 2022)
Villar-Martínez MD, Moreno-Ajona D, Chan C, Goadsby PJ. Indomethacin-responsive headaches-A narrative review. Headache. 2021 May;61(5):700-714. doi: 10.1111/head.14111. PMID: 34105154.
VanderPluym J. Indomethacin-responsive headaches. Curr Neurol Neurosci Rep. 2015;15(2):516. doi: 10.1007/s11910-014-0516-y. PMID: 25467407.
Bordini EC, Bordini CA, Woldeamanuel YW, Rapoport AM. Indomethacin Responsive Headaches: Exhaustive Systematic Review with Pooled Analysis and Critical Appraisal of 81 Published Clinical Studies. Headache. 2016 Feb;56(2):422-35. doi: 10.1111/head.12771. Epub 2016 Feb 8. PMID: 26853085.
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Baldacci F, Nuti A, Cafforio G, Lucetti C, Logi C, Cipriani G, Orlandi G, Bonuccelli U. 'INDOTEST' in atypical hemicrania continua. Cephalalgia. 2008 Mar;28(3):300-1. doi: 10.1111/j.1468-2982.2007.01525.x. PMID: 18254899.
Monta A, Redon S, Fabre C, Donnet A. A retrospective observation on 105 patients with chronic cluster headache receiving indomethacin. Neurol Sci. 2021 Oct;42(10):4175-4182. doi: 10.1007/s10072-021-05114-4. Epub 2021 Feb 5. PMID: 33547540.
Myers KA, Barmherzig R, Raj NR, Berrahmoune S, Ingelmo P, Saint-Martin C, Khan AQ, Kouri M, Morris C, Hershey AD, Kacperski J, Kabbouche MA, Mohamed N, Rao RR, Lagman-Bartolome AM, Gelfand AA, Szperka CL, Orr SL. The spectrum of indomethacin-responsive headaches in children and adolescents. Cephalalgia. 2022 Jul;42(8):793-797. doi: 10.1177/03331024221076483. Epub 2022 Mar 18. PMID: 35302385; PMCID: PMC9218410.
Zhu S, McGeeney B. When indomethacin fails: additional treatment options for "indomethacin responsive headaches". Curr Pain Headache Rep. 2015 Mar;19(3):7. doi: 10.1007/s11916-015-0475-2. PMID: 25754595.
Dora B, Demir-Dora D. Indomethacin Resistant Hemicrania Continua Responsive to Venlafaxine. Neurol India. 2022 Jul-Aug;70(4):1670. doi: 10.4103/0028-3886.355083. PMID: 36076682.