Nitrous oxide analgesia in humans: acute and chronic tolerance

Abstract

Electrical tooth stimulation was used to investigate whether humans develop tolerance to nitrous oxide (N 2 O) analgesia within a single administration as well as over repeated administrations. In a double-blind cross-over experiment, 77 subjects received a 40-minute administration of 38% N 2 O 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 N 2 O administration. In a second double-blind experiment, 64 subjects received both 30-min of placebo gas and 30-min of 35% N 2 O, separated by a 35-min gas wash-out period, during each of 5 sessions. Sensory thresholds were assessed prior to drug or placebo administration (baseline) and between 7-12 min and 25-30 min of gas administration. A control group of 16 subjects received only placebo gas at these 5 sessions. During a sixth session, the experimental procedures were similar to the previous sessions except that the control group received N 2 O 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 N 2 O 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 N 2 O's analgesic effects in humans.

Modification of Behavior With 50% Nitrous Oxide/Oxygen Conscious Sedation Over Repeated Visits for Dental Treatment A 3-Year Prospective Study

“…15,16 In the current study, neither an acute nor a chronic tolerance effect was observed. The aim of these previous experimental studies, however, was to analyze the analgesic effect of nitrous oxide in healthy subjects submitted to a pain stimulus.…”

Individual differences in initial sensitivity and acute tolerance predict patterns of chronic drug tolerance to nitrous-oxide-induced hypothermia in rats

“…Outbred Long-Evans rats exhibit wide betweensubject variation in initial sensitivity and acute tolerance to N 2 O-induced hypothermia (Ramsay et al 1999) and these differences are reliable characteristics of an individual (Kaiyala et al 2001). Chronic tolerance also develops to N 2 O hypothermia (Ramsay et al 1999). …”

The Effect of Nitrous Oxide Anesthesia on Early Postoperative Opioid Consumption and Pain

“…5 In contrast to ketamine the analgesic effect of N 2 O diminishes over time during continuous administration; a phenomenon seen already after 40 minutes of inhalation. 16 N 2 O’s antinociceptive action is partially mediated via activation of central opioidergic neurons in the periaqueductal grey area. Animal studies support the hypothesis that continuous N 2 O exposure might trigger release of endogenous opioid peptide so excessively that depletion occurs.…”

“…5 In contrast to ketamine, the analgesic effect of N 2 O diminishes over time during continuous administration; a phenomenon seen already after 40 minutes of inhalation. 16 release of endogenous opioid peptide so excessively that depletion occurs. 5 As a consequence, descending antinociceptive pathways might not be activated any longer and analgesic action vanishes.…”