Nitrous Oxide In Humans Research Articles

Bitonic dose–response functions for reinforcing and self-reported effects of nitrous oxide in humans

The reinforcing and self-reported effects of nitrous oxide (10%, 30%, and 50% N 2O in O 2) were examined in 13 humans. During each of three sessions, subjects sampled one dose of N 2O and 100% O 2 (placebo) for 10 min each, separated by 30-min recovery periods. The agents were identified by letter code, and later in the session, subjects chose nine times, once every 5 min, among N 2O (e.g., “Agent A”), placebo (e.g., “Agent B”), or “neither” (also 100% O 2, identified as “drug-free air”). Self-reported and psychomotor effects were measured at various times. Dose–response functions varied across subjects and included bitonic, monotonic increasing, monotonic decreasing, U-shaped, and flat dose–response functions for reinforcing and/or self-reported effects. For subjects who showed bitonic reinforcing effects, the descending limb of the dose–response function could not be attributed to behavioral impairment. This study replicates previous studies showing dose-dependent effects of N 2O, as well as between-subject variability in N 2O effects. Bitonic dose–response functions for some subjects extend the generality of the phenomenon of bitonicity of drug effects to N 2O effects in humans.

MAC Does Not Matter to the Patient

MAC Does Not Matter to the Patient To the Editor: We read with interest Dr Eger’s elegant paper elaborating on the effects of temperature and age on minimal alveolar concentration (MAC) of volatile anesthetics and nitrous oxide in humans (1). The concept of MAC, immobility and amnesia, is reproducible, easy to use, and requires minimal equipment. These main characteristics may be acceptable endpoints for the anesthesiologist and a convenient way of self-assurance. However, we would like to question the failure to withdraw to a painful stimulus (immobility) as a result of a change in temperature as this may easily represent a change of pain perception rather than an effect of the anesthetics in question. Further, immobility can be produced by a variety of drugs such a butyrophenones and opioids without a change in the level of consciousness. This withdrawal reflex becomes irrelevant once muscle relaxants are used. Patients undergoing a general anesthesia expect unconsciousness and would prefer not to rely on amnesia for this period. Understanding and eventually measuring unconsciousness must be the primary goal for anesthesiologists. Further adjustments of the MAC value for age, temperature and ambient pressure will improve our prediction of failure to withdraw to a painful stimulus but not that of unconsciousness. T. Engelhardt P.R. Lowe

Depression of Diaphragm Contractility by Nitrous Oxide in Humans

Nitrous oxide is widely used in anesthesia and critical care medicine. The effect of nitrous oxide on diaphragm contractility in humans is unknown. We evaluated the effect of a 50% nitrous oxide–50% oxygen mixture on diaphragm contractility in healthy adult volunteers. The sniff transdiaphragmatic pressure (Sn Pdi) and the twitch transdiaphragmatic pressure (Tw Pdi) elicited by bilateral supramaximal phrenic nerve stimulation were measured before during and after inhalation of a mixture of 50% nitrous oxide and 50% oxygen. Sn Pdi decreased by 15.4% during nitrous oxide inhalation, with a value of 136 ± 21 cm H2O before nitrous oxide and a value of 115 ± 27 cm H2O during nitrous oxide inhalation (P = 0.03). Similarly, Tw Pdi decreased from 21.2 ± 1.8 cm H2O before nitrous oxide inhalation to 16.9 ± 4.1 cm H2O during nitrous oxide inhalation (P = 0.03). The effect of nitrous oxide was totally abolished 20 min after its discontinuation. Nitrous oxide has a short-acting suppressant effect on the pressure generating capacity of the diaphragm in healthy humans.

Depression of diaphragm contractility by nitrous oxide in humans.

Nitrous oxide is widely used in anesthesia and critical care medicine. The effect of nitrous oxide on diaphragm contractility in humans is unknown. We evaluated the effect of a 50% nitrous oxide-50% oxygen mixture on diaphragm contractility in healthy adult volunteers. The sniff transdiaphragmatic pressure (Sn Pdi) and the twitch transdiaphragmatic pressure (Tw Pdi) elicited by bilateral supramaximal phrenic nerve stimulation were measured before during and after inhalation of a mixture of 50% nitrous oxide and 50% oxygen. Sn Pdi decreased by 15.4% during nitrous oxide inhalation, with a value of 136 +/- 21 cm H(2)O before nitrous oxide and a value of 115 +/- 27 cm H(2)O during nitrous oxide inhalation (P = 0.03). Similarly, Tw Pdi decreased from 21.2 +/- 1.8 cm H(2)O before nitrous oxide inhalation to 16.9 +/- 4.1 cm H(2)O during nitrous oxide inhalation (P = 0.03). The effect of nitrous oxide was totally abolished 20 min after its discontinuation. Nitrous oxide has a short-acting suppressant effect on the pressure generating capacity of the diaphragm in healthy humans. We investigated whether nitrous oxide (a common component of gas anesthesia) reduces diaphragm strength in humans. Diaphragm strength is reduced by nitrous oxide but the effect wears off within 20 min of administration. Caution is advised when using nitrous oxide without anesthesiologist supervision in patients at risk of ventilatory failure

Effects of naloxone on nitrous oxide actions in healthy volunteers

A number of studies have examined the effects of naloxone on nitrous oxide-induced analgesia with conflicting results. In the present study the effects of a relatively high dose of naloxone was examined to determine its effects on nitrous oxide-induced analgesia, as well as on the subjective and psychomotor effects of nitrous oxide. Fourteen subjects participated in a four-session crossover trial in which they received intravenous injections of either saline or 30mg/70kg naloxone 10min into a 35min period in which they were inhaling either 100% oxygen or 30% nitrous oxide in oxygen. Ten minutes after the naloxone administration, subjects were tested on the cold pressor test. Mood and psychomotor performance were also assessed before, during and after the inhalation period. Subjects reported higher pain ratings after the naloxone injection than the saline injection, but there was no evidence of naloxone reversing the analgesic effects of nitrous oxide. Similarly while naloxone also affected mood and impaired psychomotor performance, there was no evidence of naloxone reversing the effect of nitrous oxide on these measures. The results of this study call into question the role of the opioidergic system in mediating various effects of nitrous oxide in humans.

Comparison of the analgesic potency of xenon and nitrous oxide in humans evaluated by experimental pain

We have compared the analgesic potency of MAC-equivalent concentrations of xenon (10, 20, 30 and 40%) and nitrous oxide (15, 30, 45 and 60%) in humans using a multimodal experimental pain testing and assessment technique. We tested 12 healthy volunteers in a randomized, single-blind, crossover study. The following experimental pain tests were used: nociceptive reflex to repeated stimuli; pain tolerance to maximal effort tourniquet ischaemia; electrical stimulation; mechanical pressure; and cold. Reaction time was also measured. Xenon and nitrous oxide produced analgesia to ischaemic, electrical and mechanical stimulation, but not to cold pain. There was no difference in MAC-equivalent concentrations of xenon and nitrous oxide. Both increased reaction time in a similar manner. Xenon and nitrous oxide evoked nausea and vomiting in a large number of volunteers.

Regional cerebral blood flow (SPECT) during anaesthesia with isoflurane and nitrous oxide in humans

Nitrous oxide and isoflurane have different effects on absolute cerebral blood flow (CBF) and regional distribution of CBF in humans. In this study we examined the effects of isoflurane in combination with nitrous oxide on CBF. We studied 10 patients (two groups of five patients, ASA I) anaesthetized with 50% nitrous oxide and either 0.5 or 1.0 MAC of isoflurane during normocapnia (PaCO2 5.7 kPa) using two-dimensional CBF measurement (CBFxenon) (i.v. 133xenon washout technique) and a three-dimensional method for measurement of regional CBF (rCBF) distribution with SPECT (single photon emission computer-aided tomography with 99mTc- HMPAO). The results were compared with 1.0 MAC of isoflurane from a previous study performed in exactly the same way as the present investigation. During normocapnia, anaesthesia with 50% nitrous oxide and 0.5 MAC of isoflurane resulted in a mean CBFxenon of 45 (SEM 5) ISI units. Increasing the isoflurane concentration to 1.0 MAC had no significant effect on mean CBFxenon (53 (5) ISI units). Both flow values were significantly (P = 0.01) higher than the CBFxenon value obtained when 1 MAC of isoflurane was administered alone (33 (3) ISI units). There were no significant differences in rCBF distribution regardless of whether or not isoflurane was given alone or together with nitrous oxide at 0.5 or 1 MAC. In all situations there were higher relative flows in subcortical regions (thalamus and basal ganglia, 10%) and in the pons (7-10% above average). rCBF in the cerebellum was approximately 10% greater than average. In summary, we have found that mean CBF was greater with combined nitrous oxide and isoflurane anaesthesia than previously found with isoflurane alone; however, relative flow distribution was similar.

Differential acute tolerance development to effects of nitrous oxide in humans

The analgesic, subjective, and psychomotor effects of 0, 10, 20, 30, and 40% nitrous oxide in oxygen were studied in 10 volunteers to determine if acute tolerance developed differentially to these variables. In this prospective, randomized, crossover, double-blind study, volunteers inhaled either placebo (100% oxygen) or one of the aforementioned doses of nitrous oxide for 120 min. During this period, volunteers immersed their non-dominant forearm, for 3 min, in ice-cold water at 25, 70 and 115 min from the onset of the inhalation. At other prescribed time intervals throughout the session, mood and psychomotor performance were assessed. Subjects reported less pain intensity from the cold-water stimulus and reported the pain bothered them less as a function of increasing nitrous oxide dose; in addition, this analgesia was significantly less as the inhalation period progressed (i.e., acute tolerance). Some subjective effects of nitrous oxide that could be considered hedonic in nature (elation, drug liking) also showed evidence of acute tolerance. In contrast, other subjective effects and the psychomotor-impairing effects of nitrous oxide did not change significantly during the inhalation period (i.e., no acute tolerance). The differential acute tolerance observed in this study suggests that different effects of nitrous oxide may be mediated by different neurochemical substrates.

Flumazenil may attenuate some subjective effects of nitrous oxide in humans: A preliminary report

Two double-blind, randomized, crossover trials were conducted to study whether the benzodiazepine antagonist, flumazenil, would interact with the subjective and psychomotor effects of nitrous oxide in healthy volunteers. In both experiments, eight subjects inhaled 30% nitrous oxide in oxygen for 35 min and were challenged, 10 min into the inhalation, with flumazenil. Experiment 1 tested a range of flumazenil doses used clinically (0, 0.25, 0.5, and 1.0 mg/70 kg) whereas Experiment 2 tested a supraclinical flumazenil dose (0 and 5.0 mg/70 kg). Nitrous oxide increased mood ratings of “high,” “drunk,” and “tingling,” and decreased psychomotor performance as assessed by the Digit Symbol Substitution Test. Flumazenil, at the supraclinical dose, significantly lowered the mood rating of “high.” Decreases, though not significant ( p < 0.10), were also obtained on the ratings “drunk,” “elated,” and “drug liking”. Flumazenil, in both experiments, did not interact with the psychomotor effects of nitrous oxide. It appears that flumazenil, at a dose higher than that used clinically, may antagonize some of the subjective effects produced by nitrous oxide in humans.

Effects of marijuana history on the subjective, psychomotor, and reinforcing effects of nitrous oxide in humans

An experiment using marijuana users and non-users was conducted to assess whether the reinforcing, subjective, or psychomotor effects of nitrous oxide were influenced by a subject's drug history. Subjects in the first four sessions sampled 40% nitrous oxide in oxygen and 100% oxygen (placebo), and then over the next three sessions, chose which agent they wished to inhale. Choice distributions between the two groups did not differ significantly, and nitrous oxide choice rates were less than 50% in both groups. However, a history of marijuana use appeared to intensify some of the subjective effects induced by nitrous oxide inhalation.

Effects of naloxene on the subjective and psychomotor effects of nitrous oxide in humans

The effects of naloxone on the mood-altering and psychomotor-impairing effects of nitrous oxide were examined in two studies. Each of the double-blind, randomized trials tested effects of three doses of naloxone or saline placebo during inhalation of 30% nitrous oxide in oxygen or 100% oxygen placebo. Experiment 1 tested a range of naloxone doses used clinically to reverse opiate-induced respiratory depression (0, 0.01, 0.1, 1.0 mg/70 kg) and Experiment 2 included a dose approximately 25 times higher than that needed to reverse opiate-induced respiratory depression (0, 1.0, 3.0, 10 mg/70 kg). Nitrous oxide increased subject-rated reports of “feel drug effect”, “carefree,” “drunk,” “sedated,rd and “high,” and decreased psychomotor performance in both experiments. Naloxone had no effects by itself in either experiment, and, for the most part, did not significantly interact with nitrous oxide-induced changes in mood or psychomotor performance. Naloxone, in doses of 10 mg or less, does not appear to affect the subjective and psychomotor effects of nitrous oxide.

Minimum Alveolar Concentration of Nitrous Oxide in Humans

Minimum Alveolar Concentration of Nitrous Oxide in Humans

Stressful Conditions Affect Acceptance of Nitrous Oxide in Humans

Stressful Conditions Affect Acceptance of Nitrous Oxide in Humans

Marijuana Use and the Effects of Nitrous Oxide in Humans

Marijuana Use and the Effects of Nitrous Oxide in Humans

Acute Tolerance to Nitrous Oxide in Humans

The goal of this research was to determine whether the level of analgesia produced by nitrous oxide remains constant for the duration of a typical dental procedure or whether acute tolerance reduces the drug's efficacy. A computer-controlled stimulator delivered brief (approx. 1 msec) electrical pulses to a vital maxillary incisor which had been found to have normal sensitivity in a preliminary session. Subjects were trained to indicate the occurrence of a barely perceptible sensation (i.e., detection threshold) as well as a minimally painful sensation (i.e., pain threshold). On the experimental day, all subjects breathed a non-odorized placebo gas mixture during a 10-min baseline condition, and were then randomly assigned to receive either an odorized placebo gas mixture or an odorized 35-40% nitrous oxide/oxygen gas mixture for 46 min. Detection and pain thresholds were assessed repeatedly during the baseline and gas exposure conditions. Placebo control subjects had little change of either sensory threshold. Subjects breathing nitrous oxide significantly increased both detection and pain thresholds within 2-8 min following the onset of the drug. However, maintenance of the drug's effect was not consistent between subjects, despite continuous administration of a constant concentration of nitrous oxide. Some subjects had a relatively constant elevation of sensory thresholds throughout the nitrous oxide administration period, and others returned to baseline sensitivity values and therefore were acutely tolerant.

Subjective and psychomotor effects of bolus doses of nitrous oxide in humans

AbstractNitrous oxide, commonly used in medical settings for its anxiolytic, analgesic, and anesthetic effects, is also used recreationally. One method of using this agent recreationally is to inhale a pure bolus of nitrous oxide (N2 O) one or more times in succession. The effects of such an inhalation mode (i.e. brief inhalation of higher concentrations of N2 O) have not been adequately characterized. The present experiment examined the subjective and psychomotor effects of short duration (or bolus) administrations of a range of concentrations of N2O in healthy volunteers. We used a prospective, placebo‐controlled, double‐blind, crossover design in which N2O was administered to subjects for 45 s in concentrations of O (oxygen‐placebo), 20, 40, and 80 per cent. A number2 of subjective effects, including increased VAS ratings of ‘high,’ ‘tingling,’ ‘stimulated,’ and ‘confused’ and increased ‘euphoria’ and ‘psychedelic effects’ scores on an Inhalant Drug Effects post‐session questionnaire were found with higher concentrations of N2O (i.e. 40 per cent and 80 per cent). Subjective effects were short‐lived and had usually dissipated within several minutes of inhalation. Psychomotor performance did not differ between the first time that we measured it postinhalation (2.5 min) and pre‐inhalation (baseline), but the self‐reported time course of effects of N2O suggested that we tested post‐inhalation psychomotor performance when effects were subsiding (i.e. not when they were at their peak). We conclude that bolus concentrations of N2O produce a range of subjective effects which is consistent with its recreational use (abuse).

Reinforcing effects of extended inhalation of nitrous oxide in humans

The subjective, psychomotor and reinforcing effects of nitrous oxide at subanesthetic doses (30% and 40% in oxygen) were determined in normal healthy volunteers using a choice paradigm. Thirty percent nitrous oxide was chosen no more often than oxygen (41.6% choice rate), indicating that, for most of the subjects tested, extended inhalation of this nitrous oxide concentration was no more reinforcing than oxygen inhalation. Forty percent nitrous oxide was chosen significantly less often than oxygen (22% choice rate), indicating that, for most of the subjects tested, extended inhalation of this nitrous oxide concentration was less reinforcing than oxygen. Nitrous oxide produced robust subjective effects (e.g., increased ratings of ‘high,’ ‘tingling,’ and ‘dizzy’). Subjects who chose nitrous oxide reported pleasant subjective effects and liked it, while those who chose placebo reported unpleasant subjective effects and disliked it. Both concentrations of nitrous oxide impaired psychomotor performance in all subjects. The lack of reinforcing effects noted in the present study, given nitrous oxide's known abuse potential, is discussed.

Acute tolerance to nitrous oxide in humans

The goal of this research was to determine whether the level of analgesia produced by nitrous oxide remains constant for the duration of a typical dental procedure or whether acute tolerance reduces the drug's efficacy. A computer-controlled stimulator delivered brief (approx. 1 msec) electrical pulses to a vital maxillary incisor which had been found to have normal sensitivity in a preliminary session. Subjects were trained to indicate the occurrence of a barely perceptible sensation (i.e., detection threshold) as well as a minimally painful sensation (i.e., pain threshold). On the experimental day, all subjects breathed a non-odorized placebo gas mixture during a 10-min baseline condition, and were then randomly assigned to receive either an odorized placebo gas mixture or an odorized 35–40% nitrous oxide/oxygen gas mixture for 46 min. Detection and pain thresholds were assessed repeatedly during the baseline and gas exposure conditions. Placebo control subjects had little change of either sensory threshold. Subjects breathing nitrous oxide significantly increased both detection and pain thresholds within 2–8 min following the onset of the drug. However, maintenance of the drug's effect was not consistent between subjects, despite continuous administration of a constant concentration of nitrous oxide. Some subjects had a relatively constant elevation of sensory thresholds throughout the nitrous oxide administration period, and others returned to baseline sensitivity values and therefore were acutely tolerant.

Progressive Changes in Electroencephalographic Responses to Nitrous Oxide in Humans

The possibility of acute tolerance to nitrous oxide was examined during halothane anesthesia in humans. Nitrous oxide was added to the inspired gas twice. The first admixture induced three successive stages of electroencephalogram (EEG): delta-waves lasting for 13 +/- 12 min, theta-waves lasting for 41 +/- 21 min, and, finally, spindle-type waves. The spindle-type EEG was similar to that of halothane anesthesia in configuration, but smaller in amplitude and faster in frequency than that seen during halothane anesthesia. The second admixture, given after a 20-30-min interval, induced a continuous delta-wave EEG in one patient, theta-waves followed by spindle EEG in eight patients, and spindle-type EEG in four patients. The successive changes of electroencephalographic response during the first admixture indicate that an alteration of central nervous system function occurred. The altered state was maintained in the absence of nitrous oxide: responses to a second admixture were characteristic of the later, altered, stages of responses seen after the first admixture. These findings support the view of acute tolerance to nitrous oxide.

Cardiovascular Effects of Desflurane and Nitrous Oxide in Humans

Cahalan, M K MD; Weiskopf, R B MD; Yasuda, N MD; Eger, E I II MD; Ionescu, P MD; Rampil, I J MD; Lockhart, S MD; Caldwell, J MD; Holmes, M A AB; Freire, B BS; Johnson, B H MS; Laster, M DVM; Kelley, S MD; Peterson, N Author Information