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Western blots show the constitutive expression of COX-1 and COX-2 in the rat spinal dorsal and ventral horns and in the dorsal root ganglia. Using selective inhibitors of cyclooxygenase (COX) isozymes, we show that in rats with chronic indwelling intrathecal catheters the acute thermal hyperalgesia evoked by the spinal delivery of substance P (SP; 20 nmol) or NMDA (2 nmol) and the thermal hyperalgesia induced by the injection of carrageenan into the paw are suppressed by intrathecal and systemic COX-2 inhibitors. The intrathecal effects are dosedependent and stereospecific. In contrast, a COX-1 inhibitor given systemically, but not spinally, reduced carrageenanevoked thermal hyperalgesia but had no effect by any route with spinal SP hyperalgesia. Using intrathecal loop dialysis catheters, we showed that intrathecal SP would enhance the release of prostaglandin E 2 (PGE 2 ). This intrathecally evoked release of spinal PGE 2 was diminished by systemic delivery of nonspecific COX and COX-2-selective inhibitors, but not a COX-1-selective inhibitor. Given at systemic doses that block SP-and carrageenan-evoked hyperalgesia, COX-2, but not COX-1, inhibitors reduced spinal SP-evoked PGE 2 release. Thus, constitutive spinal COX-2, but not COX-1, is an important contributor to the acute antihyperalgesic effects of spinal as well as systemic COX-2 inhibitors.Key words: cyclooxygenase inhibitor; intrathecal injection; thermal hyperalgesia; NK-1; substance P; NMDA; ibuprofen; Tissue injury results in a heightened sensitivity to subsequent noxious input (hyperalgesia). In behavioral models of injuryinduced hyperalgesia, nonsteroidal, anti-inflammatory drugs (NSAIDs) normalize the otherwise sensitized pain thresholds . Early work showed that systemically delivered NSAIDs were effective inhibitors of cyclooxygenase (COX) (Smith and Willis, 1971;Vane, 1971) and that peripheral prostanoids could sensitize the peripheral terminal. This suggested that hyperalgesia arose from a peripheral afferent sensitization.Tissue injury also evokes persistent afferent traffic that initiates a spinal sensitization. Studies on the pharmacology of this sensitization using intrathecal drug delivery indicate that the hyperalgesia results in part from a complex cascade starting with the activation of spinal neurokinin-1 (NK-1) and NMDA receptors secondary to the spinal release of substance P (SP) and glutamate. Among several elements, this cascade activates spinal phospholipases and generates prostanoids by spinal COX , leading to spinal prostanoid release (Yang et al., 1996a,b;Willingale et al., 1997;Ebersberger et al., 1999). The hyperalgesic effects (Yaksh, 1982; Malmberg and Yaksh, 1992a,b) and the spinal release of prostaglandins (Malmberg and Yaksh, 1995a,b) are diminished by spinal COX inhibitors at doses that have no systemic action. Consistent with the hypothesized spinal organization, intrathecal SP and NMDA, in the absence of tissue injury, induce a transient thermal hyperalgesia (Malmberg and Yaksh, 1992b;Dirig and Yaksh, 1996) and an...

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor–induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.

Calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated clinical efficacy in the treatment of acute migraine. Herein, we describe the design, synthesis, and preclinical characterization of a highly potent, oral CGRP receptor antagonist BMS-927711 (8). Compound 8 has good oral bioavailability in rat and cynomolgus monkey, attractive overall preclinical properties, and shows dose-dependent activity in a primate model of CGRP-induced facial blood flow. Compound 8 is presently in phase II clinical trials.

ObjectiveTo provide the first clinical report that 2 calcitonin gene-related peptide (CGRP) therapies, a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody, can be used concomitantly to treat refractory migraine.MethodsCase reports are presented of 2 patients participating in a long-term safety study of rimegepant 75 mg oral tablets for acute treatment (NCT03266588). After Food and Drug Administration approval of erenumab, both patients started subcutaneous erenumab monthly as allowed per protocol.ResultsPatients were women 44 and 36 years of age with ≥2 decades of self-reported suboptimal response to multiple migraine medications. Patient 1 used rimegepant for 6 months and then started erenumab 70 mg subcutaneous monthly. Despite a response to preventive treatment with erenumab, she experienced substantial relief treating 7 of 7 acute attacks with rimegepant and eliminated regular, frequent use of ibuprofen and a caffeinated analgesic. Patient 2 used rimegepant for 60 days before starting erenumab 140 mg subcutaneously monthly. While on erenumab, 9 of 9 attacks treated with rimegepant responded. She stopped near-daily use of injectable ketorolac and diphenhydramine. While using rimegepant alone or together with erenumab, patients reported no related adverse events.ConclusionsRimegepant 75 mg may be effective for acute treatment during concomitant erenumab preventive administration. The mechanism underlying the benefits of concomitant use of a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody is unknown and requires further study.ClinicalTrials.gov identifierNCT03266588.Classification of evidenceThis study provides Class IV evidence that for patients with migraine using erenumab, rimegepant is effective for acute treatment.

Objective Evaluate the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a monoclonal antibody (mAb) targeting the calcitonin gene‐related peptide (CGRP) ligand or receptor (CGRP mAb) for the preventive treatment of migraine. Background The efficacy of CGRP mAbs for the preventive treatment of migraine and the small molecule CGRP receptor antagonist rimegepant for acute treatment has been demonstrated in randomized controlled clinical trials. Over the past few years, the US Food and Drug Administration has approved 4 CGRP mAbs for the preventive treatment of migraine and 2 small molecule CGRP receptor antagonists for the acute treatment of migraine. A previous case report of 2 patients receiving concomitant treatment with rimegepant and erenumab suggested that rimegepant may be safely used as acute treatment in patients who are also receiving a preventive regimen involving CGRP mAbs. We report here 13 additional patients with migraine who simultaneously used rimegepant and either erenumab, fremanezumab, or galcanezumab and assess the rate of on‐treatment adverse events (AEs). Methods This was a substudy nested within a multicenter, open‐label, long‐term safety study in adults with 2‐14 monthly migraine attacks of moderate to severe pain intensity. A subgroup experiencing 2‐8 monthly attacks and taking a stable dose of a CGRP mAb also took rimegepant 75 mg as needed up to once daily for acute treatment for 12 weeks. Results The 13 patients (11 women [85%]; mean age 49.9 years) enrolled in the substudy were being treated with CGRP mAbs (erenumab [n = 7], fremanezumab [n = 4], or galcanezumab [n = 2]). Mean (SD) time in the rimegepant treatment period was 9.6 (4.6) weeks. Mean (SD) 4‐week rimegepant exposure was 7.8 (5.5) doses; a total of 224 doses were taken. Five (38%) patients reported ≥1 on‐treatment AE. Of these, 2 (15%) patients had mild or moderate nasopharyngitis; no other AEs occurred in ≥2 patients. Three patients had AEs of mild or moderate severity that were considered potentially treatment‐related. No patients had serious AEs, AEs leading to discontinuation, or aminotransferase levels >3× the upper limit of normal. Conclusion Rimegepant, when used as an oral acute treatment in patients receiving CGRP mAbs as preventive treatment, was well tolerated; no safety issues were identified. Studies involving larger patient populations are needed to confirm these findings.