Authors: Kato et al.
Journal line: Cureus, November 12, 2025. DOI: 10.7759/cureus.96727
Summary:
This prospective pilot study examined whether glycine-containing remifentanil elevates plasma glycine levels during general anesthesia. The concern arises because remifentanil formulations include glycine, and glycine acts as a co-agonist at the NMDA receptor, potentially contributing to opioid-induced hyperalgesia or postanesthetic shivering. Ten patients undergoing pancreaticoduodenectomy received balanced anesthesia with desflurane, propofol, fentanyl, and remifentanil at various infusion rates.
Plasma glycine was measured before induction, during surgery, at the end of remifentanil, and hourly for three hours after discontinuation. Contrary to expectations, glycine levels did not increase at any infusion rate. Instead, levels were significantly lower two and three hours after stopping remifentanil. In only one patient did glycine exceed the normal reference range, despite normal renal and hepatic function. The study was not powered to assess links between glycine levels and shivering or hyperalgesia. The authors note several reasons why glycine may not have risen: preserved organ function, surgical metabolic shifts that lower amino acid levels, and differences from prior ICU studies where organ dysfunction allowed glycine accumulation.
Overall, glycine-containing remifentanil did not meaningfully raise circulating glycine in this cohort. Because plasma levels did not increase, the study could not evaluate whether elevated glycine might promote NMDA-mediated postoperative effects. Larger studies, especially involving higher remifentanil doses or multiple glycine-containing drugs, are needed.
Key Points:
• Remifentanil contains glycine, raising concern for NMDA-related effects such as hyperalgesia.
• In 9 of 10 surgical patients, plasma glycine did not rise during remifentanil anesthesia.
• Glycine levels actually decreased several hours postoperatively.
• Only one patient exceeded the normal glycine range, without clear explanation.
• Because glycine did not increase, the study could not test whether glycine contributes to postoperative shivering or hyperalgesia.
• Larger studies with higher glycine exposure are needed.
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