BACKGROUND Remifentanil 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. OBJECTIVE To evaluate the effect of 35 and 50% N2O on hyperalgesia and pain after remifentanil infusion. DESIGN Single site, phase 1, double-blind, placebo-controlled, randomised crossover study. SETTING University Hospital, Germany from January 2012 to April 2012. PARTICIPANTS Twenty-one healthy male volunteers. INTERVENTIONS Transcutaneous 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% N-2-O-2 and intravenous (i.v.) 0.9% saline infusion (placebo); 50 to 50% N-2-O-2 and i.v. remifentanil infusion at 0.1 mu g kg(-1) min(-1) (remifentanil); 35 to 15 to 50% N2O-N-2-O-2 and i.v. remifentanil infusion at 0.1 mu g kg(-1) min(-1) (tested drug) and 50 to 50% N2O-O-2 and i.v. remifentanil infusion at 0.1 mu g kg(-1) min(-1) (gas active control). Gas mixtures were inhaled for 60 min; i.v. drugs were administered for 30 min. MAIN OUTCOME MEASURES Areas of pin-prick hyperalgesia, areas of touch-evoked allodynia and pain intensity on a visual analogue scale were assessed repeatedly for 160 min. RESULTS Data 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 cm(2), respectively) compared with remifentanil (51.0 +/- 17.0 cm(2)). 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. CONCLUSIONS Administration 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.

BACKGROUND Remifentanil 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. OBJECTIVE To evaluate the effect of 35 and 50% N2O on hyperalgesia and pain after remifentanil infusion. DESIGN Single site, phase 1, double-blind, placebo-controlled, randomised crossover study. SETTING University Hospital, Germany from January 2012 to April 2012. PARTICIPANTS Twenty-one healthy male volunteers. INTERVENTIONS Transcutaneous 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 MEASURES Areas of pin-prick hyperalgesia, areas of touch-evoked allodynia and pain intensity on a visual analogue scale were assessed repeatedly for 160 min. RESULTS Data 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. CONCLUSIONS Administration 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 REGISTRATION EudraCT-No.: 2011-000966-37.

BackgroundOpioids are known to relieve pain, and also aggravate pre-existing hyperalgesia. In animal studies, the N-methyl-d-aspartate-receptor antagonist nitrous oxide (N2O) was able to prevent hyperalgesia. The present study evaluated the effect of N2O on hyperalgesia after remifentanil infusion in healthy volunteers.MethodsTwenty-one healthy volunteers were enrolled in this placebo-controlled cross-over 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) 50-50% N-2-O-2 and i.v. saline; (2) 50-50% N-2-O-2 and i.v. remifentanil 0.1g/kg/min; (3) 50-50% N2O-O-2 and i.v. saline; (4) 50-50% N2O-O-2 and i.v. remifentanil 0.1g/kg/min. Inhaled gas mixtures lasted for 60min, i.v. drug administration for 30min. Visual analogue scale pain intensity, areas of pinprick hyperalgesia and touch-evoked allodynia were assessed repeatedly for 160min.ResultsData of 19 volunteers were analysed. There were significant time and treatment effects regarding areas of hyperalgesia and allodynia (p<0.02). The area of hyperalgesia was significantly reduced in the N2O+remifentanil session compared to the remifentanil session (35.8822.37 vs. 43.5518.48cm(2), p=0.004). The area of allodynia was significantly reduced in the N2O+remifentanil session compared to the remifentanil session (29.95 +/- 16.15 vs. 34.80 +/- 15.35cm(2), p=0.008). The pain intensity was significantly reduced in the N2O+remifentanil session compared to the remifentanil session (37.96 +/- 12.78 vs. 42.15 +/- 13.34mm, p<0.0001).ConclusionsNitrous oxide significantly reduced hyperalgesia, allodynia and pain intensity aggravated after remifentanil administration in a human volunteer model.What does this study add?This study brings the evidence that N2O reduces the remifentanil aggravated secondary hyperalgesia in human volunteers exposed to a well-known model of electrical pain. N2O was able to oppose the hyperalgesia, the allodynia and the pain intensity consecutive to remifentanil use in this specific pain model.

Wehrfritz, A. P.; Richebe, P.; Noel, N.; Apiou - Sbirlea, G.; Koppert, W. Author Information

European Journal of PainVolume 13, Issue S1 p. S124-S124 410 A RANDOMIZED PHASE I TRIAL EVALUATING THE ANTI-HYPERALGESIC AND ANALGESIC EFFECTS OF 50%–50% N2O—O2 A. Wehrfritz, A. Wehrfritz Department of Anaesthesiology, University hospital, Erlangen, GermanySearch for more papers by this authorP. Richebe, P. Richebe Department of Anesthesiology and Pain Medicine, University of Washington MC, Seattle, United StatesSearch for more papers by this authorN. Noel, N. Noel CRCD, Air Liquide, Jouy-en-Josas, FranceSearch for more papers by this authorG. Apiou-Sbirlea, G. Apiou-Sbirlea CRCD, Air Liquide, Jouy-en-Josas, FranceSearch for more papers by this authorW. Koppert, W. Koppert Department of Anaesthesiology, University hospital, Erlangen, GermanySearch for more papers by this author A. Wehrfritz, A. Wehrfritz Department of Anaesthesiology, University hospital, Erlangen, GermanySearch for more papers by this authorP. Richebe, P. Richebe Department of Anesthesiology and Pain Medicine, University of Washington MC, Seattle, United StatesSearch for more papers by this authorN. Noel, N. Noel CRCD, Air Liquide, Jouy-en-Josas, FranceSearch for more papers by this authorG. Apiou-Sbirlea, G. Apiou-Sbirlea CRCD, Air Liquide, Jouy-en-Josas, FranceSearch for more papers by this authorW. Koppert, W. Koppert Department of Anaesthesiology, University hospital, Erlangen, GermanySearch for more papers by this author First published: 12 January 2012 https://doi.org/10.1016/S1090-3801(09)60413-4Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume13, IssueS1September 2009Pages S124-S124 RelatedInformation