Terminating migraine with allodynia and ongoing central sensitization using parenteral administration of COX1/COX2 inhibitors.
OBJECTIVE
To determine whether delayed infusion of COX1/COX2 inhibitors (ketorolac, indomethacin) will stop migraine in allodynic patients, and suppress ongoing sensitization in central trigeminovascular neurons in the rat.


BACKGROUND
The majority of migraineurs seeking secondary or tertiary medical care develop cutaneous allodynia during the course of migraine, a sensory abnormality mediated by sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus. Triptan therapy can render allodynic migraineurs pain free within a narrow window of time (20 to 120 minutes) that opens with the onset of pain and closes with the establishment of central sensitization. Can drugs that tackle ongoing central sensitization render allodynic migraineurs pain free after the window for triptan therapy has expired?


METHODS
Patients exhibiting migraine with allodynia were divided in two groups (n=14, each): group 1 received delayed sumatriptan injection (6 mg) 4 hours after onset of attack--which failed to render them pain free-and ketorolac infusion (two 15-mg boluses) 2 hours later; group 2 received delayed ketorolac monotherapy 4 hours after onset of attack. Pain intensity (visual analog scale) and skin sensitivity (quantitative sensory testing) were measured when the patients were migraine free (baseline); 4 hours after onset of migraine (just before treatment); 2 hours after sumatriptan; 1 hour after ketorolac. In the rat, we tested whether infusion of ketorolac (0.4 mg/kg) or indomethacin (1 mg/kg) will block ongoing sensitization in peripheral and central trigeminovascular neurons. The induction of sensitization (using topical application of inflammatory soup on the dura) and its suppression by COX1/COX2 inhibitors were assessed by monitoring changes in spontaneous activity and responses to mechanical and thermal stimuli.


RESULTS
Patients had normal skin sensitivity in the absence of migraine, and presented cutaneous allodynia 4 hours after onset of migraine. In group 1, all patients continued to exhibit allodynia 2 hours after sumatriptan treatment, and none of them became pain free. However, 71% and 64% of the patients in groups 1 and 2, respectively, were rendered free of pain and allodynia within 60 minutes of ketorolac infusion. Nonresponders from both groups, in contrast to the responders, had had a history of opioid treatment. In the rat, infusion of COX1/COX2 inhibitors blocked sensitization in meningeal nociceptors and suppressed ongoing sensitization in spinal trigeminovascular neurons. This inhibitory action was reflected by normalization of neuronal firing rate and attenuation of neuronal responsiveness to mechanical stimulation of the dura, as well as mechanical and thermal stimulation of the skin.


CONCLUSIONS
The termination of migraine with ongoing allodynia using COX1/COX2 inhibitors is achieved through the suppression of central sensitization. Although parenteral administration of COX1/COX2 inhibitors is impractical as routine migraine therapy, it should be the rescue therapy of choice for patients seeking emergency care for migraine. These patients should never be treated with opioids, particularly if they had no prior opioid exposure.
Department of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Moshe
M
Jakubowski
Dan
D
Levy
Itay
I
Goor-Aryeh
Beth
B
Collins
Zahid
Z
Bajwa
Rami
R
Burstein
D000293:Adolescent; D000328:Adult; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects* / Q000503:physiopathology; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D007263:Infusions, Parenteral; D020910:Ketorolac / Q000008:administration & dosage* / Q000494:pharmacology; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use*; D012867:Skin / Q000187:drug effects / Q000503:physiopathology; D018170:Sumatriptan / Q000627:therapeutic use*; D016896:Treatment Outcome
D016861:Cyclooxygenase Inhibitors; D017366:Serotonin Receptor Agonists; D018170:Sumatriptan; D007213:Indomethacin; D020910:Ketorolac