{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T05:15:02Z","timestamp":1754111702148},"reference-count":34,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2016,3,31]],"date-time":"2016-03-31T00:00:00Z","timestamp":1459382400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100007542","name":"Air Liquide","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007542","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2016,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Opioids are known to relieve pain, and also aggravate pre\u2010existing hyperalgesia. In animal studies, the <jats:italic>N\u2010<\/jats:italic>methyl\u2010<jats:sc>d<\/jats:sc>\u2010aspartate\u2010receptor antagonist nitrous oxide (N<jats:sub>2<\/jats:sub>O) was able to prevent hyperalgesia. The present study evaluated the effect of N<jats:sub>2<\/jats:sub>O on hyperalgesia after remifentanil infusion in healthy volunteers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twenty\u2010one healthy volunteers were enrolled in this placebo\u2010controlled cross\u2010over study. Transcutaneous electrical stimulation at high current densities induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions: (1) 50\u201350% N<jats:sub>2<\/jats:sub>\u2013O<jats:sub>2<\/jats:sub> and i.v. saline; (2) 50\u201350% N<jats:sub>2<\/jats:sub>\u2013O<jats:sub>2<\/jats:sub> and i.v. remifentanil 0.1\u00a0\u03bcg\/kg\/min; (3) 50\u201350% N<jats:sub>2<\/jats:sub>O\u2013O<jats:sub>2<\/jats:sub> and i.v. saline; (4) 50\u201350% N<jats:sub>2<\/jats:sub>O\u2013O<jats:sub>2<\/jats:sub> and i.v. remifentanil 0.1\u00a0\u03bcg\/kg\/min. Inhaled gas mixtures lasted for 60\u00a0min, i.v. drug administration for 30\u00a0min. Visual analogue scale pain intensity, areas of pinprick hyperalgesia and touch\u2010evoked allodynia were assessed repeatedly for 160\u00a0min.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Data of 19 volunteers were analysed. There were significant time and treatment effects regarding areas of hyperalgesia and allodynia (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.02). The area of hyperalgesia was significantly reduced in the N<jats:sub>2<\/jats:sub>O\u00a0+\u00a0remifentanil session compared to the remifentanil session (35.88\u00a0\u00b1\u00a022.37 vs. 43.55\u00a0\u00b1\u00a018.48\u00a0cm<jats:sup>2<\/jats:sup>, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.004). The area of allodynia was significantly reduced in the N<jats:sub>2<\/jats:sub>O\u00a0+\u00a0remifentanil session compared to the remifentanil session (29.95\u00a0\u00b1\u00a016.15 vs. 34.80\u00a0\u00b1\u00a015.35\u00a0cm<jats:sup>2<\/jats:sup>, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.008). The pain intensity was significantly reduced in the N<jats:sub>2<\/jats:sub>O\u00a0+\u00a0remifentanil session compared to the remifentanil session (37.96\u00a0\u00b1\u00a012.78 vs. 42.15\u00a0\u00b1\u00a013.34\u00a0mm, <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.0001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Nitrous oxide significantly reduced hyperalgesia, allodynia and pain intensity aggravated after remifentanil administration in a human volunteer model.<\/jats:p><\/jats:sec><jats:sec><jats:title>What does this study add?<\/jats:title><jats:p>This study brings the evidence that N<jats:sub>2<\/jats:sub>O reduces the remifentanil aggravated secondary hyperalgesia in human volunteers exposed to a well\u2010known model of electrical pain. N<jats:sub>2<\/jats:sub>O was able to oppose the hyperalgesia, the allodynia and the pain intensity consecutive to remifentanil use in this specific pain model.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ejp.870","type":"journal-article","created":{"date-parts":[[2016,3,31]],"date-time":"2016-03-31T22:28:42Z","timestamp":1459463322000},"page":"1467-1477","source":"Crossref","is-referenced-by-count":7,"title":["A randomized phase I trial evaluating the effects of inhaled 50\u201350% N<sub>2<\/sub>O\u2013O<sub>2<\/sub> on remifentanil\u2010induced hyperalgesia and allodynia in human volunteers"],"prefix":"10.1002","volume":"20","author":[{"given":"A.","family":"Wehrfritz","sequence":"first","affiliation":[{"name":"Department of Anaesthesiology University of Erlangen\u2010N\u00fcrnberg Erlangen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Schaefer","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology University of 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