Indomethacin Responsive Headaches

woman with headache

The indomethacin-responsive headache disorders consist of a group of conditions with a particularly good response to indomethacin. Two of the trigeminal autonomic cephalalgias are included, which are hemicrania continua and paroxysmal hemicrania. Other conditions are Valsalva-induced headaches (i.e. cough headache, exercise headache, and sex headache), primary stabbing headache, and hypnic headache. (VanderPluym, 2015)

This exact mechanism of action is not yet well understood; however, some explanations have been proposed. Since indomethacin is a strong non-steroidal anti-inflammatory, its effect could be related to the inhibition of the cyclooxygenase enzymes. Other reasons include the reduction of cerebral blood flow and the inhibition of nitric oxide. Nitric oxide is one of the fundamental molecules involved in the regulation of cerebral metabolic activity and blood flow. (Villar-Martínez et al, 2021).

Why to perform an indomethacin test (Indotest)

To predict the chronic responsiveness to indomethacin therapy. (Baldacci F. et al, 2008)

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How to perform the test

There are several protocols and dosages that have been used to detect indomethacin responsiveness. (Bordini et al, 2016) A parenteral dose of 100 mg should provide headache relief in no more than 30 minutes. (Antonaci F. et al, 2003) ‎A lower parenteral dose of 50 mg takes around 50 minutes to be effective. ‎(Baldacci F. et al, 2008) ‎In addition, oral indomethacin could be used as a test as well. 100 mg orally per day is expected to reduce the frequency of headache attacks by 50% within at least seven days‎ (Monta A. et al, 2021). Despite the benefit of the Indotest, the incidence of adverse events is high. For this reason, patients must be co-treated with a gastroprotective agent. (Myers et al, 2022)‎

What to do if it fails

Other classes of medications such as selective cyclooxygenase-2 inhibitors (e.g., celecoxib), anti-epileptic agents (e.g., ‎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) Furthermore, there have been several reports on the efficacy of serotonin and norepinephrine reuptake inhibitors (e.g., ‎Venlafaxine) for hemicrania continua. (Dora et al, 2022)

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  • 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.
  • Antonaci F, Costa A, Ghirmai S, Sances G, Sjaastad O, Nappi G. Parenteral indomethacin (the INDOTEST) in cluster headache. Cephalalgia. 2003 Apr;23(3):193-6. doi: 10.1046/j.1468-2982.2003.00495.x. PMID: 12662186.
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  • 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.
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Posted: April 6, 2023
<a href="" target="_self">Jack Botros, DDS</a>

Jack Botros, DDS

Jack Botros graduated as a dentist in Alexandria, Egypt. He continued his professional development obtaining a Master of Science at McGill University, Canada. Currently, he is a resident in the Orofacial Pain program at Herman Ostrow School of Dentistry of USC.
Mariela Padilla

Mariela Padilla

Dr. Padilla obtained her DDS in 1989 at UCR, and in 1998 completed a Residency Program in Orofacial Pain at UCLA. In 2005, she obtained her Master’s Degree in Education and Curriculum Design. Dr. Padilla started her clinical practice as a general dentist in 1990, and then dedicated herself solely to Orofacial Pain and Temporomandibular Disorders. As an Assistant Director of Online Education at Herman Ostrow School of Dentistry of USC, she designs programs and academic experiences for working professionals, and contributes with learning innovation and teaching development.

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