Chronic postsurgical pain after nitrous oxide anesthesia

Pain. 2011 Nov;152(11):2514-2520. doi: 10.1016/j.pain.2011.07.015. Epub 2011 Sep 1.


Nitrous oxide is an antagonist at the N-methyl-D-aspartate receptor and may prevent the development of chronic postsurgical pain. We conducted a follow-up study in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA) trial patients to evaluate the preventive analgesic efficacy of nitrous oxide after major surgery. The ENIGMA trial was a randomized controlled trial of nitrous oxide-based or nitrous oxide-free general anesthesia in patients presenting for noncardiac surgery lasting more than 2 hours. Using a structured telephone interview, we contacted all ENIGMA trial patients recruited in Hong Kong (n=640). We recorded the severity of postsurgical pain of at least 3 months' duration that was not due to disease recurrence or a pre-existing pain syndrome, using the modified Brief Pain Inventory. The impact of postsurgical pain on quality of life was also measured. Pain intensity, opioid and other analgesic requirements during the first week of surgery, were retrieved from the trial case report form and medical records. A total of 46 (10.9%) patients reported pain that persisted from the index surgery, and 39 (9.2%) patients had severe pain. In addition, patients with chronic pain rated poorly in all attributes of the quality-of-life measures compared with those who were pain free. In a multivariate analysis, nitrous oxide decreased the risk of chronic postsurgical pain. In addition, severe pain in the first postoperative week, wound complication, and abdominal incision increased the risk of chronic pain. In conclusion, chronic postsurgical pain was common after major surgery in the ENIGMA trial. Intraoperative nitrous oxide administration was associated with a reduced risk of chronic postsurgical pain.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anesthetics, Inhalation / administration & dosage*
  • Chronic Pain / epidemiology
  • Chronic Pain / metabolism
  • Chronic Pain / prevention & control*
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Neuralgia / epidemiology
  • Neuralgia / prevention & control
  • Nitrous Oxide / administration & dosage*
  • Pain, Postoperative / epidemiology
  • Pain, Postoperative / metabolism
  • Pain, Postoperative / prevention & control*
  • Prevalence
  • Prospective Studies
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors


  • Anesthetics, Inhalation
  • Receptors, N-Methyl-D-Aspartate
  • Nitrous Oxide