Monocyte Transmigration Involves in Remifentanil Induced Mechanical Hyperalgesia in Animal Models and a Randomized Controlled Clinical Trial

Abstract: Remifentanil−induced hyperalgesia (RIH) complicates postoperative pain management under total intravenous anesthesia. Although monocyte transmigration contributes to neuropathic pain, its role in RIH remains undefined. Here, we investigated monocyte dynamics in RIH through preclinical and clinical studies. In male mice, intraperitoneal remifentanil infusion (4 μg/kg/min, 1 h) induced sustained mechanical hyperalgesia (reduced paw withdrawal thresholds, PWTs) over 48 hours, paralleled by a transient decline in circulating monocytes (3 h post−infusion) and increased macrophage infiltration in paw tissues. Critically, monocyte depletion significantly attenuated RIH, implicating monocytes in its pathogenesis. Translating these findings, a randomized trial of 44 patients undergoing minor surgery under sevoflurane−remifentanil anesthesia (0.3 μg/kg/min) revealed that perioperative flurbiprofen axetil (1 mg/kg) attenuated remifentanil−induced mechanical hyperalgesia (peri−incisional and upper limb regions) at 2 h and 24 h postoperatively (p < 0.05). Mechanistically, flurbiprofen axetil prevented remifentanil−driven reductions in circulating monocytes and suppressed plasma CCL3/G−CSF elevations (p < 0.05), despite unchanged monocytic COX− 2 expression. In vitro, remifentanil (1000 ng/mL) directly promoted peripheral blood mononuclear cell migration (p < 0.05) without affecting viability. Collectively, monocyte transmigration underlies RIH in both animal models and humans, while flurbiprofen axetil counteracts hyperalgesia by retaining monocytes in circulation and modulating chemokine signaling. These translational insights highlight monocyte−targeted strategies as a therapeutic avenue for RIH. In this study, we demonstrated that extravascular migration of circulating monocytes is involved in remifentanil-induced hyperalgesia. Flurbiprofen axetil attenuates remifentanil-induced hyperalgesia, possibly by suppressing monocyte extravasation. Keywords: hyperalgesia, monocytes, non−steroidal anti−inflammatory drugs, remifentanil