When indomethacin fails: additional treatment options for "indomethacin responsive headaches"

Indomethacin has been used for the treatment of headache disorders since the 1960's, shortly after it was introduced as a treatment for pain and joint swelling in rheumatologic conditions. A subgroup of primary headache disorders, often refractory to other pharmacologic treatment such as triptans and the usual non-steroidal anti-inflammatories, was noted to be exquisitely and absolutely responsive to the analgesic effects of indomethacin. These disorders have been better characterized over the past decade and classified into primary headache disorders of paroxysmal hemicrania (PH) and hemicrania continua (HC). Since the current ICHD-3 beta requires response to indomethacin as a diagnostic criterion, studies on alternative treatments in HC and PH generally occur in patients with intolerance to its gastro-intestinal side effects rather than loss of analgesia effectiveness. More rarely, the development of new headaches have been reported in chronic indomethacin use. In these settings, 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. We review the literature and provide our clinical recommendations on alternative therapies for the "indomethacin-responsive headaches".