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Original research
Nitrous oxide for the treatment of complex regional pain syndrome: a randomized blinded trial
  1. Jason Hale1,
  2. Jijun Xu1,
  3. Dong Wang2,3,
  4. Fabio Rodriguez-Patarroyo2,
  5. Omer Bakal2,
  6. Orkun Kopac2,4,
  7. Ece Yamak Altinpulluk2,
  8. Ozkan Onal2,5,
  9. Jack E Brooker2,
  10. Miguel Cruz6,
  11. Marco Maurtua6,
  12. Ruben Agudelo-Jimenez2,7,
  13. Daniel I Sessler2 and
  14. Alparslan Turan2,6
  1. 1Department of Pain Management, Cleveland Clinic, Cleveland, Ohio, USA
  2. 2Department of Outcomes Research, Cleveland Clinic, Cleveland, Ohio, USA
  3. 3Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
  4. 4Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA
  5. 5Department of Anesthesiology and Reanimation, Selcuk Universitesi, Konya, Turkey
  6. 6Department of General Anesthesiology, Cleveland Clinic, Cleveland, Ohio, USA
  7. 7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington, USA
  1. Correspondence to Dr Alparslan Turan, Department of Outcomes Research, Cleveland Clinic, Cleveland, Ohio, USA; turana{at}ccf.org

Abstract

Introduction Complex Regional Pain Syndrome (CRPS) is a debilitating neuropathic condition often refractory to conventional treatments. N-methyl-D-aspartate (NMDA) receptor antagonists have a well-established role in the development and modulation of chronic neuropathic pain. Nitrous oxide is widely used and generally safe anesthetic gas with NMDA receptor antagonist activity. We therefore tested the hypothesis that brief periods of nitrous oxide exposure reduce pain in patients with CRPS.

Methods Patients with a diagnosis of CRPS were randomized to either 2 hours of nitrous oxide exposure on three alternating days (Nitrous Oxide) versus a placebo air/oxygen mixture (Air-Oxygen). Our primary outcome was patient-reported pain scores at 1 week and 1 month. Secondary and exploratory outcomes were physical and mental health (PRMOIS-29 v2 survey), specific neuropathic pain symptoms (McGill short-form questionnaire), and opioid consumption.

Results 44 patients participated in the study; 20 were randomized to Nitrous Oxide and 24 were assigned to Air-Oxygen. Pain scores did not differ significantly, with the estimated difference in means (Nitrous Oxide−Air-Oxygen) of −0.57 (95% CI: −1.42 to 0.28) points, p=0.19. There were also no differences detected in secondary outcomes, with the estimated difference in mean Z-scores for physical health (Nitrous Oxide−Air-Oxygen) of 0.13 (95% CI: −0.16 to 0.43), mental health 0.087 (95% CI: −0.31 to 0.48), and Patient Global Impression of Change score −0.7 (95% CI: −1.85 to 0.46).

Conclusions Compared with air/oxygen, 2 hours of nitrous oxide/oxygen exposure for three sessions did not provide meaningful therapeutic potential for patients with chronic CRPS. Our results do not support using nitrous oxide for the treatment of CRPS.

  • Pain Management
  • Complex Regional Pain Syndromes
  • Pain Perception

Data availability statement

Data are available upon reasonable request. Data are available on reasonable request to the corresponding author.

https://doi.org/10.1136/rapm-2023-104537

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    Data availability statement

    Data are available upon reasonable request. Data are available on reasonable request to the corresponding author.

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    Footnotes

    • Contributors JH and JX contributed to study design and writing of first draft. DW contributed to data analysis. FR-P, OB, OK, EYA, OO, JEB, MC, MM, and RA-J contributed to data interpretation. DIS contributed to writing of first draft. AT is the guarantor and contributed to study design, data interpretation and writing of first draft. All the authors contributed to revising of paper for important intellectual content and approval of final version.

    • Funding Study was supported by a research grant from Reflex Sympathetic Dystrophy Syndrome Association and Cleveland Clinic Catalyst grant. JX is supported by an NIH grant (K08CA228039) and Steve & Melody Golding Foundation.

    • Competing interests DIS is a consultant for Edwards Lifesciences, Sensifree, and Perceptive Medical. None of the conflicts are related to the submitted study. AT was a speaker for Pfizer and consultant for Consentric Medical. None of the conflicts are related to the submitted study. None of the other authors declare competing interests.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.