Chronic pain after bone fracture and orthopedic surgery is often refractory to most analgesics currently in use, thus emphasizing the urgent need for improved therapeutic medications. Chemokine-dependent neuroinflammation is critical for excitatory synaptic plasticity and central nociception sensitization. Recent studies have focused on the inhibition of inflammatory responses by artesunate, the first anti-malaria drug extracted from artemisinin. The present study investigated the analgesic effects and potential targets of artesunate in a mouse model of chronic pain induced by tibial fracture and orthopedic surgery. Three injections of artesunate were intrathecally administered on a daily basis from days 4 to 6 after fracture. We reported that repetitive exposure to artesunate (10 and 100 μg but not 1 μg) dose-dependently prevented fracture-induced mechanical and cold allodynia. Moreover, single intrathecal injection of artesunate (100 μg) alleviated the established chronic pain on day 14 after fracture surgery. Intraperitoneal artesunate (10 and 50 mg kg⁻¹) therapy was effective against chronic fracture pain. Intriguingly, artesunate inhibited the upregulation of spinal chemokine CCL21, triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12) expressions and microglia activation in fracture mice. Furthermore, spinal CCL21 neutralization attenuated the severity of fracture-associated post-surgical pain. Exogenous CCL21-induced acute inflammatory pain was impaired by artesunate therapy. Additionally, the pharmacological blockage of TREM2 reduced recombinant CCL21-elicited behavioral hypernociception. The present findings demonstrate that artesunate therapy reduces the initiation and maintenance of fracture-associated chronic postoperative pain by inhibiting CCL21-dependent TREM2/DAP12 inflammatory signaling and microglia activation, thus suggesting that artesunate could emerge as a therapeutic strategy for fracture pain management.

Background: Remimazolam, a novel ultra-short-acting benzodiazepine, is a potential sedative for non-general anesthesia surgery in the elderly. This study aimed to investigate the appropriate sedative dosage of remimazolam and its effects on perioperative cognitive function in elderly patients undergoing non-general anesthesia surgery.Methods: This multicenter, placebo-controlled trial enrolled 330 elderly patients undergoing non-general anesthesia procedures at eight centers in China from July 2021 to February 2022, with 238 ultimately completing the study. The primary endpoints were the dose of successful sedation with remimazolam and the changes in perioperative cognitive function. Adverse events were recorded to assess drug safety.Results: The induction dose of remimazolam for sedation in spinal anesthesia in elderly patients was 5.38 mg (95% confidence interval [CI], 5.20–5.56), maintained at a rate of 0.223 mg·kg⁻¹·h⁻¹ (95% CI, 0.201–0.237) with no serious adverse effects. Compared with the standard saline group, there was no statistical difference in the MMSE scores on Day 2 morning (P = 0.886), Day 2 afternoon (P = 0.864), and Day 7 (P = 0.613), and no statistical difference in the MoCA scores on Day 2 morning (P = 0.687), Day 2 afternoon (P = 0.827), and Day 7 (P = 0.483) in remimazolam group.Conclusion: Remimazolam besylate is an effective sedative for elderly patients undergoing neuraxial anesthesia. It was successfully induced at a dose of 5.38 mg and maintained at 0.223 mg·kg⁻¹·h⁻¹, demonstrating a good safety profile without affecting short-term postoperative cognitive function.Clinical Trial Registration: http://www.chictr.org.cn (ChiCTR2100048744).