Nitrous oxide analgesia in humans: acute and chronic tolerance

Ramsay, Douglas S.; Leroux, Brian G.; Rothen, Marilynn; Prall, Christopher W.; Fiset, Louis O.; Woods, Stephen C.

doi:10.1016/j.pain.2004.12.011

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Volume 114, Issue 1 , Pages 19-28, March 2005

Nitrous oxide analgesia in humans: acute and chronic tolerance

Douglas S. Ramsay
- Department of Dental Public Health Sciences, University of Washington, Box # 357475, Seattle, WA 98195-7475, USA
- Department of Orthodontics, University of Washington, Seattle, WA, USA
- Department of Pediatric Dentistry, University of Washington, Seattle, WA, USA
- Corresponding author. Address: Department of Dental Public Health Sciences, University of Washington, Box # 357475, Seattle, WA 98195-7475, USA. Tel.: +1 206 616 5427; fax: +1 206 685 4258.
Brian G. Leroux
- Department of Dental Public Health Sciences, University of Washington, Box # 357475, Seattle, WA 98195-7475, USA
- Department of Biostatistics, University of Washington, Seattle, WA, USA
Marilynn Rothen
- Department of Dental Public Health Sciences, University of Washington, Box # 357475, Seattle, WA 98195-7475, USA
Christopher W. Prall
- Department of Dental Public Health Sciences, University of Washington, Box # 357475, Seattle, WA 98195-7475, USA
Louis O. Fiset
- Department of Dental Public Health Sciences, University of Washington, Box # 357475, Seattle, WA 98195-7475, USA
Stephen C. Woods
- Department of Psychiatry, University of Cincinnati, Cincinnati, OH, USA

Received 13 January 2004; received in revised form 26 September 2004; accepted 1 November 2004.

AIB-400595

Abstract

Electrical tooth stimulation was used to investigate whether humans develop tolerance to nitrous oxide (N₂O) analgesia within a single administration as well as over repeated administrations. In a double-blind cross-over experiment, 77 subjects received a 40-min administration of 38% N₂O at one session and placebo gas at the other. The sessions were separated by 1 week and the order of gas administration was counterbalanced. Acute analgesic tolerance developed for pain threshold but not for detection threshold. There was no evidence of a hyperalgesic rebound effect following cessation of the N₂O administration. In a second double-blind experiment, 64 subjects received both 30-min of placebo gas and 30-min of 35% N₂O, separated by a 35-min gas wash-out period, during each of five sessions. Sensory thresholds were assessed prior to drug or placebo administration (baseline) and between 7–12 and 25–30min of gas administration. A control group of 16 subjects received only placebo gas at these five sessions. During a sixth session, the experimental procedures were similar to the previous sessions except that the control group received N₂O for the first time and the experimental group was sub-divided to test for conditioned drug effects. For both detection and pain threshold measures, acute tolerance developed during the initial N₂O exposure and chronic tolerance developed over repeated administrations. Although chronic tolerance developed, a test for Pavlovian drug conditioning found no evidence of conditioned effects on sensory thresholds. In conclusion, acute and chronic tolerance develop to N₂O's analgesic effects in humans.