title: Intranasal application of xenon: describing the pharmacokinetics in experimental animals and the increased pain tolerance within a placebo-controlled experimental human study.
abstract: BACKGROUND
  Pain sensitizes the central nervous system via N-methyl-D-aspartate receptors (NMDARs) leading to an enhancement of pain perception. However, the enhanced responsiveness of pain-processing areas can be suppressed by subanaesthetic doses of the NMDAR antagonist xenon. To analyse the strength of the analgesic effect of low-dose xenon using new economical application methods, we tested xenon applied nasally in an experimental human pain setting.
  
  
  METHODS
  We tested 10 healthy volunteers using a multimodal experimental pain testing in a randomized double-blind placebo-controlled repeated measures study. Xenon was administered using a novel low-pressure intranasal application device. Additionally, we measured xenon concentrations in blood samples obtained from intracranial veins of experimental animals to describe the pharmacokinetics of intranasally applied xenon in the cerebral compartment.
  
  
  RESULTS
  Intranasal application of xenon at a rate of 1.0 litre h(-1) for 30 min significantly increased pain tolerance of volunteers to ischaemic (+128%), cold (+58%), and mechanical (+40%) stimulation (P<0.01). However, 60 min after terminating the application of xenon, there was no significant alteration of pain tolerance compared with placebo. Cranial blood concentrations of xenon in pigs reached a steady state of approximately 450 nl ml(-1) after 5 min.
  
  
  CONCLUSIONS
  In this placebo-controlled experimental human study, we described the increased pain tolerance induced by intranasally applied xenon. On the basis of our results, we conclude that intranasally administered xenon has analgesic properties and suggest that the novel application device presented here offers new possibilities for the administration of NMDAR antagonists within a multimodal analgesia approach.
authors.affiliation: Department of Anaesthesiology, University Hospital of Ulm, Steinhoevelstrasse 9, 89075 Ulm, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Froeba
authors.forename: M
authors.initials: M
authors.lastname: Georgieff
authors.forename: E M
authors.initials: EM
authors.lastname: Linder
authors.forename: K J
authors.initials: KJ
authors.lastname: Föhr
authors.forename: H U
authors.initials: HU
authors.lastname: Weigt
authors.forename: T F
authors.initials: TF
authors.lastname: Holsträter
authors.forename: M A
authors.initials: MA
authors.lastname: Kölle
authors.forename: O
authors.initials: O
authors.lastname: Adolph
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D003080:Cold Temperature; D004195:Disease Models, Animal; D004311:Double-Blind Method; D016503:Drug Delivery Systems; D006801:Humans; D007511:Ischemia / Q000150:complications; D008297:Male; D010146:Pain / Q000209:etiology / Q000517:prevention & control; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects*; D010812:Physical Stimulation / Q000379:methods; D011930:Reaction Time / Q000187:drug effects; D034421:Sus scrofa; D014978:Xenon / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
chemical_list: D018712:Analgesics, Non-Narcotic; D018685:Anesthetics, Inhalation; D014978:Xenon