• Andreas Wehrfritz, Marcus Bauer, Nathalie Noel, Juan Fernando Ramirez-Gil, Harald Ihmsen, Johannes Prottengeier, Jürgen Schüttler, and Baptiste Bessiere.
• From the Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Department of Anaesthesiology (AW, HI, JP, JS), Department of Orthopaedic and Trauma Surgery, Erlangen, Germany (MB), Médical R&D, Air Liquide Santé International, Les Loges-en-Josas, France (NN, JFRG, BB).
• Eur J Anaesthesiol. 2021 Dec 1; 38 (12): 1230-1241.

BackgroundRemifentanil is an effective drug in peri-operative pain therapy, but it can also induce and aggravate hyperalgesia. Supplemental administration of N2O may help to reduce remifentanil-induced hyperalgesia.ObjectiveTo evaluate the effect of 35 and 50% N2O on hyperalgesia and pain after remifentanil infusion.DesignSingle site, phase 1, double-blind, placebo-controlled, randomised crossover study.SettingUniversity Hospital, Germany from January 2012 to April 2012.ParticipantsTwenty-one healthy male volunteers.InterventionsTranscutaneous electrical stimulation induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions in a randomised order: 50 to 50% N2-O2 and intravenous (i.v.) 0.9% saline infusion (placebo); 50 to 50% N2-O2 and i.v. remifentanil infusion at 0.1 μg kg-1 min-1 (remifentanil); 35 to 15 to 50% N2O-N2-O2 and i.v. remifentanil infusion at 0.1 μg kg-1 min-1 (tested drug) and 50 to 50% N2O-O2 and i.v. remifentanil infusion at 0.1 μg kg-1 min-1 (gas active control). Gas mixtures were inhaled for 60 min; i.v. drugs were administered for 30 min.Main Outcome MeasuresAreas of pin-prick hyperalgesia, areas of touch-evoked allodynia and pain intensity on a visual analogue scale were assessed repeatedly for 160 min.ResultsData from 20 volunteers were analysed. There were significant treatment and treatment-by-time effects regarding areas of hyperalgesia (P < 0.001). After the treatment period, the area of hyperalgesia was significantly reduced (P < 0.001) in the tested drug and in the gas active control (30.6 ± 9.25 and 24.4 ± 7.3 cm2, respectively) compared with remifentanil (51.0 ± 17.0 cm2). There was also a significant difference between the gas active control and the tested drug sessions (P < 0.001). For the area of allodynia and pain rating, results were consistent with the results for hyperalgesia.ConclusionsAdministration of 35% N2O significantly reduced hyperalgesia, allodynia and pain intensity induced after remifentanil. It might therefore be suitable in peri-operative pain relief characterised by hyperalgesia and allodynia, such as postoperative pain, and may help to reduce opioid demand.Trial RegistrationEudraCT-No.: 2011-000966-37.Copyright © 2021 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.

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