Consistent with previous accounts, some of the patients visiting our pain clinic during the course of a migraine attack have indicated-without solicitation-that sumatriptan injection initially intensified their headache before they were able to appreciate any pain relief. In this study, those patients who came forward complaining about pain exacerbation were asked to rate their headache intensity every 5 min. Within 5-15 min of sumatriptan injection, 17 of the 31 patients studied (55%) reported that their migraine pain intensified for 10-15 min before they started to notice any pain relief. Similar pattern of pain exacerbation was also observed in migraine attacks treated with oral formulation of almotriptan, eletriptan, rizatriptan, and zolmitriptan. To investigate the possible mechanism underlying this transient exacerbation of pain, we examined whether intravenous administration of sumatriptan can alter the response properties of C- and Adelta-meningeal nociceptors in the rat. Five to twenty minutes after intravenous administration of 300 microg/kg sumatriptan, 8/10 C-units and 2/8 Adelta-units increased their firing rate, and 6/10 C-units and 7/8 Adelta-units developed mechanical hyper-responsiveness to dural indentation. The minimal effective dose for activation and sensitization of meningeal nociceptors by sumatriptan was 3 microg/kg, suggesting that relatively low levels of triptans entering the circulation shortly after their administration can alter the physiological properties of meningeal nociceptors and produce a transient exacerbation of headache.