title: Chronic postsurgical pain in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial.
abstract: BACKGROUND
  Previous animal and clinical studies showed that nitrous oxide may produce long-term analgesia. The aim of this study was to evaluate the effect of nitrous oxide in preventing chronic postsurgical pain. We also explored whether methylenetetrahydrofolate reductase gene polymorphisms (1298A>C, 667C>T) would enhance nitrous oxide analgesia.
  
  
  METHODS
  We conducted a telephone interview at 12 months after surgery on 2924 (41.1%) patients enrolled in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia-II trial. Pain at the wound site was recorded using the modified brief pain inventory and the neuropathic pain questionnaire. General health status was measured using the EQ-5D questionnaire. Genotyping was performed in a subset of 674 Asian patients in Hong Kong.
  
  
  RESULTS
  At 12 months after surgery, 356 (12.2%) patients reported chronic postsurgical pain at the wound site and 112 (3.8%) patients had severe pain and required regular analgesic interventions. Nitrous oxide did not affect the rate of chronic postsurgical pain (11.8% nitrous oxide group; 12.5% no nitrous oxide group), relative risk (95% confidence intervals): 0.94 (0.75-1.17), P=0.57. However, in a planned subgroup analysis, nitrous oxide reduced the risk of chronic postsurgical pain in Asian patients, relative risk (95% confidence intervals): 0.70 (0.50-0.98), P=0.031. Patients who were homozygous for either gene polymorphism and who received nitrous oxide during surgery were less likely to report chronic postsurgical pain.
  
  
  CONCLUSIONS
  Nitrous oxide administration had no impact on chronic postsurgical pain, but benefits may still be possible in Asian patients and patients with variants in methylenetetrahydrofolate reductase gene.
  
  
  BACKGROUND
  NCT00430989.
authors.affiliation: Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China mtvchan@cuhk.edu.hk.
authors.forename: M T V
authors.initials: MT
authors.lastname: Chan
authors.affiliation: Department of Anaesthesia, Austin Hospital, Melbourne, Victoria, Australia.|Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Peyton
authors.affiliation: Department of Anaesthesia and Perioperative Medicine, The Alfred Hospital, Melbourne, Victoria, Australia.|Department of Anaesthesia and Perioperative Medicine, Monash University, Melbourne, Victoria, Australia.|Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
authors.forename: P S
authors.initials: PS
authors.lastname: Myles
authors.affiliation: Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.|Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Melbourne, Victoria, Australia.|Anaesthesia, Perioperative and Pain Medicine Unit, and.|Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Leslie
authors.affiliation: Department of Anesthesia, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Buckley
authors.affiliation: Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Kasza
authors.affiliation: Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Perth, Western Australia, Australia.|School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Paech
authors.affiliation: Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada.|Department of Anaesthesia, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: W S
authors.initials: WS
authors.lastname: Beattie
authors.affiliation: Department of Outcomes Research, Anesthesiology Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: D I
authors.initials: DI
authors.lastname: Sessler
authors.affiliation: Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Forbes
authors.affiliation: Department of Anaesthesia and Perioperative Medicine, The Alfred Hospital, Melbourne, Victoria, Australia.|Department of Anaesthesia and Perioperative Medicine, Monash University, Melbourne, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Wallace
authors.affiliation: Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.|Li Ka Shing Institute of Health Sciences, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.|State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: W K K
authors.initials: WK
authors.lastname: Wu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000758:Anesthesia / Q000379:methods*; D018685:Anesthetics, Inhalation / Q000627:therapeutic use*; D059350:Chronic Pain / Q000188:drug therapy*; D005260:Female; D006723:Hong Kong; D006801:Humans; D007407:Interviews as Topic; D008297:Male; D008875:Middle Aged; D009609:Nitrous Oxide / Q000627:therapeutic use*; D010149:Postoperative Pain / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D018685:Anesthetics, Inhalation; D009609:Nitrous Oxide
keywords: chronic pain; nitrous oxide; polymorphism; single nucleotide; surgery