Indomethacin as a cause of headache in hemicrania continua

We read with interest the recent article in Cephalalgia entitled ‘Indomethacin-induced de novo headache in hemicrania continua—fighting fire with fire?’ by Jürgens et al (1). As the authors point out, because of the lack of absolute response of the unilateral headache to indomethacin, using International Classification Headache Disorders (ICHD) criteria, a diagnosis of hemicrania continua (HC) could be questioned. We agree, however, that the marked improvement up to the maximum tolerated dose was highly suggestive of HC. We have recently reported a case similar in many ways in which an absolute response to indomethacin was obtained but in which indomethacin resulted in a contralateral headache (2). We strongly agree with Jürgens et al. that indomethacin-induced headaches in HC would have the potential to cloud the diagnosis itself if a bilateral headache or an ipsilateral headache developed at doses lower than those required to abolish the HC. We feel the available literature suggests that indomethacin can induce headaches which may be of a migrainous phenotype. The case described by Jürgens et al. did not have a clear prior migrainous history, unlike ours, but we wonder if they had other factors, such as history of travel sickness or susceptibility to ‘hangover’ headaches, which might have suggested a predisposition to migraine?

If indomethacin-induced headache might cloud the interpretation of the indomethacin challenge, how might this be minimised? Older studies soon after the introduction of indomethacin have suggested that avoiding peaks in blood levels of indomethacin may reduce the impact of indomethacin-induced headaches; ensuring that indomethacin is always taken with food delays the absorption, reduces peak blood levels, and may reduce side effects such as headaches (3). Divided doses are already utilised – when 300 mg indomethacin was taken as a single dose all subjects in one study developed a ‘violent’ headache but were unlikely to develop headache in doses under 100 mg in divided doses (3). The problem is higher doses may be required for treatment of HC and yet indomethacin-induced headaches seem more likely at higher doses (3,4). A more gradual building up of dose has been described as being associated with less intense headaches, and sometimes the indomethacin-induced headache could gradually resolve with time, although not always (4,2).

If indomethacin-induced headaches are migrainous in nature, could a triptan be used to help? A small study of seven patients with HC has shown that 6 mg subcutaneous sumatriptan did not result in clear (clinically meaningful) reduction in visual analogue scale values in any individual patient, despite a mild reduction in headache intensity in the group as a whole (5).

Overall therefore we speculate that apparently indomethacin-unresponsive cases of HC might be considered for a slower re-challenge with indomethacin, ensuring this is taken three times daily on a full stomach. It is not known if triptans could help differentiate a case of HC from an indomethacin-induced headache, but given their limited effect in HC, they might then be considered.