title: A randomized phase I trial evaluating the effects of inhaled 50-50% N2 O-O2 on remifentanil-induced hyperalgesia and allodynia in human volunteers.
abstract: Opioids are known to relieve pain, and also aggravate pre-existing hyperalgesia. In animal studies, the N-methyl-d-aspartate-receptor antagonist nitrous oxide (N2 O) was able to prevent hyperalgesia. The present study evaluated the effect of N2 O on hyperalgesia after remifentanil infusion in healthy volunteers.
  
  
  
  Twenty-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% N2 -O2 and i.v. saline; (2) 50-50% N2 -O2 and i.v. remifentanil 0.1 μg/kg/min; (3) 50-50% N2 O-O2 and i.v. saline; (4) 50-50% N2 O-O2 and i.v. remifentanil 0.1 μg/kg/min. Inhaled gas mixtures lasted for 60 min, i.v. drug administration for 30 min. Visual analogue scale pain intensity, areas of pinprick hyperalgesia and touch-evoked allodynia were assessed repeatedly for 160 min.
  
  
  
  Data 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 N2 O + remifentanil session compared to the remifentanil session (35.88 ± 22.37 vs. 43.55 ± 18.48 cm(2) , p = 0.004). The area of allodynia was significantly reduced in the N2 O + remifentanil session compared to the remifentanil session (29.95 ± 16.15 vs. 34.80 ± 15.35 cm(2) , p = 0.008). The pain intensity was significantly reduced in the N2 O + remifentanil session compared to the remifentanil session (37.96 ± 12.78 vs. 42.15 ± 13.34 mm, p < 0.0001).
  
  
  
  Nitrous 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 N2 O reduces the remifentanil aggravated secondary hyperalgesia in human volunteers exposed to a well-known model of electrical pain. N2 O was able to oppose the hyperalgesia, the allodynia and the pain intensity consecutive to remifentanil use in this specific pain model.
authors.affiliation: Department of Anaesthesiology, University of Erlangen-Nürnberg, Erlangen, Germany. andreas.wehrfritz@kfa.imed.uni-erlangen.de.
authors.forename: A
authors.initials: A
authors.lastname: Wehrfritz
authors.affiliation: Department of Anaesthesiology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schaefer
authors.affiliation: Department of Anaesthesiology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Troester
authors.affiliation: Medical R&D, Air Liquide Santé International, Les Loges-en-Josas, France.
authors.forename: N
authors.initials: N
authors.lastname: Noel
authors.affiliation: Medical R&D, Air Liquide Santé International, Les Loges-en-Josas, France.
authors.forename: B
authors.initials: B
authors.lastname: Bessiere
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, USA.|Department of Dermatology, Harvard Medical School, Boston, USA.
authors.forename: G
authors.initials: G
authors.lastname: Apiou-Sbirlea
authors.affiliation: INCIA UMR 5287, CNRS, Université Bordeaux, Bordeaux, France.
authors.forename: G
authors.initials: G
authors.lastname: Simonnet
authors.affiliation: Department of Anaesthesiology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Schuettler
authors.affiliation: Department of Anaesthesiology, Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, QC, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Richebé
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid; D018592:Cross-Over Studies; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D007262:Infusions, Intravenous; D008297:Male; D009609:Nitrous Oxide / Q000627:therapeutic use*; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines; D000077208:Remifentanil; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D010880:Piperidines; D009609:Nitrous Oxide; D000077208:Remifentanil