Terminating Migraine With Allodynia and Ongoing Central Sensitization Using Parenteral Administration of COX1/COX2 Inhibitors

Abstract

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...

Sensitization of central trigeminovascular neurons: Blockade by intravenous naproxen infusion

“…Thus, as inhibitors of COX activities that regulate prostaglandin biosynthesis, naproxen (present study) and ketorolac (Jakubowski et al, 2005) are well positioned to counteract the sensitization of central trigeminovascular neurons that mediate migraine with allodynia. That activity-independent central sensitization can be terminated using NSAID infusion but not triptan therapy is compatible with our earlier observation that patients having migraine with periorbital allodynia (a sign of central sensitization) became pain-free within 1 h of ketorolac infusion after failing to respond to triptan therapy earlier in the same migraine attack (Jakubowski et al, 2005).…”

“…Allodynic patients from our earlier study (Jakubowski et al, 2005) who were rendered painfree using parenteral ketorolac -the only intravenous formulation of NSAID currently approved in the US -testified that ingestion of oral NSAID formulations did nothing in the way of aborting their migraine attacks. Given that oral and intravenous administration of COX inhibitors result in similar profiles of plasma concentration (Jung et al, 1988, Pasloske et al, 1999, McAleer et al, 2007, and that intrathecal doses that block pain caused by peripheral inflammation are less than 100th of the doses required systemically (Malmberg and Yaksh, 1992), we suggest that non-parenteral administration somehow leads to sub-optimal concentration of NSAIDs in the dorsal horn.…”

“…Notwithstanding, attacks with allodynia can be effectively terminated, provided that the patient vigilantly resorts to triptan therapy before or soon after the onset of allodynia, but not after allodynia has become firmly established . On the other hand, allodynic patients who had missed the critical window for effective triptan therapy, can still be rendered pain-free using intravenous infusion of the non-steroidal anti-inflammatory drug (NSAID) ketorolac (Jakubowski et al, 2005).…”

“…Preliminary data obtained in a single-unit recording study in the rat have suggested that infusion of ketorolac, a non-specific cyclooxygenase (COX) inhibitor, can block peripheral and central trigeminovascular neurons that were previously sensitized by stimulating the dura with a mixture of inflammatory agents (Jakubowski et al, 2005). Using the same rat model in the present study, we tested whether naproxen, another non-specific COX inhibitor, would terminate ongoing central sensitization, and also block the induction of such sensitization when given preemptively before stimulating the dura with inflammatory agents.…”

Diclofenac potassium for oral solution (CAMBIA®) in the acute management of a migraine attack: clinical evidence and practical experience

“…5 The effectiveness of triptans may also be decreased in the presence of central sensitization and cutaneous allodynia (a clinical indicator of central sensitization) as the migraine attack progresses. 11 In this advanced phase of migraine, levels of cyclooxygenases (COXs) in the spinal cord are increased; NSAIDs, such as diclofenac, inhibit the activity of these COXs and may offer benefit to migraineurs with allodynia and central sensitization. 11 Here, we will review patient treatment goals, as well as the pharmacologic, pharmacokinetic, efficacy, and safety data for diclofenac potassium in patients with migraine, with a focus on the soluble formulation of diclofenac potassium (CAMBIA ® , Depomed, Inc., Newark, CA, USA).…”