The effects of subanesthetic concentrations of sevoflurane and nitrous oxide, alone and in combination, on analgesia, mood, and psychomotor performance in healthy volunteers.

UNLABELLED: We studied the effects of subanesthetic concentrations of sevoflurane and nitrous oxide, alone and in combination, on analgesia, mood, and psychomotor performance in human volunteers. We hypothesized that nitrous oxide and sevoflurane would produce both opposing and potentiating effects within the same study. Over the course of three sessions, 20 subjects inhaled 0%, 0.2%, or 0.4% end-tidal sevoflurane for a 68-min period that was divided into four 17-min blocks. During either the second or fourth block, 30% end-tidal nitrous oxide was added to the concentration of sevoflurane being inhaled. Pain response, psychomotor performance, and mood were evaluated during the second and fourth blocks. Pain ratings were higher when sevoflurane and nitrous oxide were administered together than when nitrous oxide was administered alone, which indicates that sevoflurane attenuated the analgesic effects of nitrous oxide. Sevoflurane increased self-reported ratings of sleepiness, and the addition of nitrous oxide decreased these ratings. Nitrous oxide potentiated psychomotor impairment that was induced by sevoflurane. The combination of sevoflurane and nitrous oxide produced both opposing and potentiating effects within the same study. The results suggest that nitrous oxide and sevoflurane may act through different neurochemical mechanisms on some end points, such as analgesia and sleepiness. IMPLICATIONS: Healthy volunteers inhaled subanesthetic concentrations of sevoflurane and nitrous oxide. Sevoflurane made nitrous oxide less effective as an analgesic, and nitrous oxide made sevoflurane less effective as a sedative. The two drugs may work at cross purposes on different end points of anesthesia.

Effects of information on the reinforcing, subjective, and psychomotor effects of nitrous oxide in healthy volunteers.

The purpose of this study was to characterize the reinforcing, subjective, and psychomotor effects of nitrous oxide (N2O) in healthy volunteers who were given different amounts of information regarding the drugs they were being administered in the experiment. A choice procedure was used in which subjects first sampled a placebo and a given concentration of N2O and then chose between the two. N2O concentration varied across the four-session experiment from 10-40%. Besides choice, subjective and psychomotor effects served as dependent measures. In the INFORMED group (n = 11), subjects were told at the beginning of each sampling trial what concentration of N2O they were inhaling or whether they were inhaling 100% oxygen (placebo). They were also informed about the prototypic effects of N2O (e.g. tingling or numbing, euphoria, dysphoria) and oxygen (e.g. no discernible effects). In the NON-INFORMED group (n = 11), subjects were only told at the beginning of each sampling trial that the drugs they would be inhaling came from one of six classes of drugs. Thirty percent N2O was chosen by a significantly higher proportion of subjects than expected by chance in the INFORMED group, but not in the NON-INFORMED group. Further, the probability of choosing 20-40% N2O was higher in the INFORMED group than in the NON-INFORMED group. Subjective effects of N2O were not affected by the information manipulation. Psychomotor performance at the highest N2O concentration tested (40%) was impaired to a greater extent in the NON-INFORMED than in the INFORMED group. We conclude that the reinforcing effects of N2O, and perhaps the impairing effects, can be modulated by telling subjects beforehand that they are inhaling N2O and what effects they might be expected to experience from the drug.

Subjective, psychomotor, cognitive, and analgesic effects of subanesthetic concentrations of sevoflurane and nitrous oxide.

BACKGROUND: Sevoflurane is a volatile general anesthetic that differs in chemical nature from the gaseous anesthetic nitrous oxide. In a controlled laboratory setting, the authors characterized the subjective, psychomotor, and analgesic effects of sevoflurane and nitrous oxide at two equal minimum alveolar subanesthetic concentrations. METHODS: A crossover design was used to test the effects of two end-tidal concentrations of sevoflurane (0.3% and 0.60%), two end-tidal concentrations of nitrous oxide (15% and 30%) that were equal in minimum alveolar concentration to that of sevoflurane, and placebo (100% oxygen) in 12 healthy volunteers. The volunteers inhaled one of these concentrations of sevoflurane, nitrous oxide, or placebo for 35 min. Dependent measures included subjective, psychomotor, and physiologic effects, and pain ratings measured during a cold-water test. RESULTS: Sevoflurane produced a greater degree of amnesia, psychomotor impairment, and drowsiness than did equal minimum alveolar concentrations of nitrous oxide. Recovery from sevoflurane and nitrous oxide effects was rapid. Nitrous oxide but not sevoflurane had analgesic effects. CONCLUSIONS: Sevoflurane and nitrous oxide produced different profiles of subjective, behavioral, and cognitive effects, with sevoflurane, in general, producing an overall greater magnitude of effect. The differences in effects between sevoflurane and nitrous oxide are consistent with the differences in their chemical nature and putative mechanisms of action.

The effects of alcohol history on the reinforcing, subjective and psychomotor effects of nitrous oxide in healthy volunteers.

The purpose of this study was to characterize the reinforcing, subjective and psychomotor effects of nitrous oxide in healthy volunteers with different alcohol histories. Subjects were divided into two groups: light drinkers (n = 9) and moderate drinkers (n = 10). A choice procedure was used in which subjects first sampled placebo and a given concentration of nitrous oxide, and then chose between the two. Nitrous oxide concentration varied across the four-session experiment from 10-40%. Besides choice, subjective and psychomotor effects served as dependent measures. The majority of subjective effects of nitrous oxide, and its psychomotor-impairing effects, did not vary as a function of drinking group. However, a Wilcoxon rank sum test showed that the median number of times moderate drinkers chose nitrous oxide (three) was significantly higher than the median number of times light drinkers chose nitrous oxide (one). This study provides suggestive evidence that the reinforcing effects of nitrous oxide are modulated by alcohol history.

The reinforcing effects of brief exposures to nitrous oxide in healthy volunteers.

The reinforcing and subjective effects of brief (about 1.5 min) exposures to nitrous oxide, ranging from inspired concentrations of 20-80% in oxygen, were examined in 11 healthy volunteers. A choice procedure was used in which during each of four sessions, subjects first sampled a given concentration of nitrous oxide and placebo oxygen, and then chose between the two. 20, 40, 60 and 80% nitrous oxide were chosen by five, four, three, and three subjects, respectively--these choice levels did not exceed that of chance. All concentrations had psychoactive effects, and in general, concentration-related subjective effects were found. We conclude that in a medical setting, nitrous oxide inhaled in a manner similar to that when used recreationally in a naturalistic setting, does not function as a reinforcer across a wide range of concentrations, in subjects with a modest lifetime history of psychoactive drug use.

Midazolam does not influence intravenous fentanyl-induced analgesia in healthy volunteers.

The effects of saline and intravenous midazolam (0.5, 1, and 2 mg per 70 kg) in combination with intravenous fentanyl (0.1 mg/70 kg) were examined on pain induced by a cold pressor test. Healthy volunteers (six females, six males) were enrolled in a prospective, double-blind, randomized, crossover trial in which mood and psychomotor performance were also examined. Five minutes and 135 min postinjection subjects immersed their forearm in ice cold water for 3 min while assessments of pain were recorded. During the first immersion, subjects reported significantly lower pain intensity and bothersomeness ratings after having been injected with fentanyl, relative to the saline condition, but the addition of midazolam neither increased nor decreased pain reports. During the second immersion (approximately 2.5 h postinjection) pain ratings did not differ between the drug and saline conditions. Mood-altering and psychomotor-impairing effects of the drug combination were dose related. We conclude that midazolam at the doses and route of administration tested neither potentiates nor decreases the analgesia produced by fentanyl in a cold-pressor pain assay.

Awakening, clinical recovery, and psychomotor effects after desflurane and propofol anesthesia.

We compared postanesthetic and residual recovery of desflurane versus propofol anesthesia. Twenty volunteers were anesthetized for 1 h at 1-wk intervals with either propofol (induction) plus desflurane (1.25 minimum alveolar anesthetic concentration) in O2 (PD), propofol plus desflurane in N2O-O2 (PDN), propofol plus propofol infusion with N2O-O2 (PPN), or desflurane (induction) plus desflurane in O2 (DD). Awakening and clinical recovery were measured. Psychomotor skills (attention, coordination, reactive skills, and memory) were tested before and 1,3,5, and 7 h after anesthesia. Awakening was fastest in Group PDN. At 1 h after anesthesia, the subjects given desflurane for maintenance (PD, PDN, and DD) performed significantly (P < 0.05-0.01) better in several psychomotor tests compared with those whose anesthesia was maintained with propofol (PPN). However, subjects met criteria for home readiness as fast after PPN as after PDN anesthesia (mean times +/- SE until fitness for discharge were 126 +/- 20, 81 +/- 14, 70 +/- 7, and 106 +/- 14 min after PD, PDN, PPN, and DD, respectively). Awakening and early psychomotor recovery for as long as 1 h after anesthesia is faster after desflurane than after propofol, but there was no difference in time to home readiness or in residual effects thereafter between propofol and desflurane with N2O in O2.

Propofol at conscious sedation doses produces mild analgesia to cold pressor-induced pain in healthy volunteers.

STUDY OBJECTIVE: To determine whether subanesthetic doses of propofol have analgesic effects in healthy volunteers. DESIGN: Prospective, double-blind, placebo-controlled, randomized, crossover trial. SETTING: Human psychomotor performance laboratory within our anesthesia and critical care department. SUBJECTS: 12, non-drug abusing volunteers, aged 22 to 38 years. INTERVENTIONS: Five drug conditions were used in which a loading injection was followed by a 20-minute infusion period: placebo [saline (Intralipid)] injection, Intralipid infusion; propofol 0.125 mg/kg injection, propofol 12.5 mcg/kg/min infusion; propofol 0.25 mg/kg injection, propofol 25 mcg/kg/min infusion; propofol 0.5 mg/kg injection, propofol 50 mcg/kg/min infusion; fentanyl 1.4 mcg/kg injection (positive control), Intralipid infusion. Five minutes into the infusion period and 115 minutes after the infusion period was terminated, subjects immersed their forearms in ice-cold water for three minutes while pain assessments were recorded. MEASUREMENTS AND MAIN RESULTS: Propofol at the two higher doses during part of the first immersion produced a significant reduction (p < 0.05) in pain intensity and bothersomeness ratings. However, relative to fentanyl, the analgesia was mild. Propofol did not affect any ratings on the 15-item short-form McGill Pain Questionnaire, whereas fentanyl reduced 10 of the ratings. CONCLUSION: Our laboratory results are consistent with the commonly accepted clinical practice of supplementing propofol with an opioid in conscious sedation procedures to provide a satisfactory level of pain relief.

Lack of acute tolerance development to the subjective, cognitive, and psychomotor effects of nitrous oxide in healthy volunteers.

A crossover, double-blind trial was conducted using eleven healthy volunteers to determine whether and the degree to which acute drug tolerance occurred to the subjective, cognitive, and psychomotor effects of a range of subanesthetic nitrous oxide doses (0, 10, 20, 30, and 40%). There was little evidence of acute drug tolerance to the subjective measures or to the cognitive/psychomotor impairing effects of nitrous oxide at any of the concentrations tested over the course of the 120-min inhalation.

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.c., 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.

Examining the subjective, psychomotor and reinforcing effects of nitrous oxide in healthy volunteers: a dose-response analysis.

The present study examined the subjective, psychomotor and reinforcing effects of 10%, 20%, 30% and 40% nitrous oxide in oxygen in 16 healthy volunteers using a choice procedure in which sampling (e.g. 20% nitrous oxide and oxygen-placebo) and choice trials (e.g. 20% nitrous oxide vs. oxygen placebo) were within the same session. Across the four-session study, nitrous oxide dose was varied. Nitrous oxide in a dose-related manner altered subjective effects (e.g. increased visual analog scale ratings of "high", "stimulated" and "tingling") and decreased performance on the Digit Symbol Substitution Test. 10%, 20%, 30% and 40% nitrous oxide were chosen over oxygen by 6, 7, 7 and 8 subjects, respectively. We conclude that nitrous oxide across a range of subanesthetic doses did not function as reinforcer in the majority of subjects tested.

The acute and residual effects of subanesthetic concentrations of isoflurane/nitrous oxide combinations on cognitive and psychomotor performance in healthy volunteers.

A blind, randomized, cross-over trial was conducted to determine the degree of psychomotor/cognitive impairment and the recovery profile produced by combinations of subanesthetic concentrations of isoflurane and nitrous oxide in healthy volunteers. In the experiment, subjects (n = 10) inhaled 100% oxygen-placebo, 30% nitrous oxide in oxygen, and 0.2% and 0.4% isoflurane in oxygen, alone, and in combination with 30% nitrous oxide, in different sessions. Dependent measures included psychomotor and cognitive performance. Impairment was profound with the combination of inhaled anesthetics, and from an analysis of control conditions (the anesthetics alone), it appeared that isoflurane produced more impairment than did nitrous oxide. The time course of recovery was extremely rapid, with subjects returning to control-level functioning 5 min after cessation of the drug inhalation. The drug combination of isoflurane and nitrous oxide appears to be a promising candidate for conscious sedation procedures, although its analgesic and mood-altering effects need to be studied more systematically.

Effects of naloxone 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," 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.

Comparing the subjective, psychomotor and physiological effects of intravenous butorphanol and morphine in healthy volunteers.

The purposes of this study were to characterize the subjective, psychomotor and physiological effects of butorphanol in healthy nondrug-abusing volunteers and to compare and contrast the effects of butorphanol to those of morphine. Into an antecubital vein, the subjects (seven men and five women), who had no history of opiate dependence, were injected with 0, 0.5, 1.0 or 2.0 mg/70 kg of butorphanol or 10 mg/70 kg of morphine; a randomized, double-blind, crossover design was used. The subjective effects of butorphanol included increased scores on the Pentobarbital-Chlorpromazine-Alcohol Group scale and Lysergic Acid Diethylamide scale of the Addiction Research Center inventory; increased visual analog scale ratings of "sedated," "coasting or spaced out" and "difficulty concentrating;" increased adjective checklist ratings of "sweating," "skin itchy" and "sleepy;" and increased "feel drug effect" and drug-liking ratings. Morphine had some subjective effects of a magnitude similar to those of an equianalgesic dose of butorphanol (2 mg) (e.g., "strength of drug effect," "sedated," "heavy or sluggish feeling" and "high"). However, other effects of morphine were lesser in magnitude (e.g., "coasting or spaced out," "drunken" and "lightheaded") than those of butorphanol. Also, morphine did not affect a number of ratings that were affected by butorphanol (e.g., "confused," "dreamy," "stimulated," "difficulty concentrating," "floating" or "sweating"). The psychomotor impairing effects of butorphanol, as measured by the Maddox Wing test, an eye-hand coordination test, and the Digit Symbol Substitution Test, were dose related; in contrast, morphine had no effect on psychomotor functioning. Both butorphanol and morphine induced miosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Time course of effects of brief inhalations of nitrous oxide in normal volunteers.

Nitrous oxide is commonly used (abused) recreationally by inhaling it in a bolus form (i.e. single or several breaths). The time course of the psychoactive effects of nitrous oxide, via this mode of inhalation, has not been adequately characterized and thus formed the basis for this study. Twelve healthy volunteers participated in four sessions, using a randomized, cross-over, placebo-controlled design. In each session one of the following four measures were assessed: self-reported strength of drug effects, mood, memory and psychomotor performance. Within sessions, subjects were exposed to four different concentrations of nitrous oxide in a randomized fashion: 0% (oxygen-placebo), 40%, 60% and 80%. At each concentration, or "trial", subjects took four deep breaths of the gas. Peak drug effects, as reported by our subjects, occurred within 30 seconds after the last inhalation of nitrous oxide, persisted for about a minute, and then gradually subsided to near-baseline levels by 5 minutes post-inhalation. Certain aspects of mood were briefly affected by nitrous oxide, generally in a dose-related fashion with increases in visual analog scale ratings of "anxious", "stimulated", "coasting (spaced out)", "lightheaded", "confused", and "high". Free recall of wards that had been presented between 30 and 60 seconds post-inhalation was significantly reduced after 80% nitrous oxide, relative to oxygen-placebo. There was a trend towards psychomotor impairment (Concentration x time: p = 0.08), as measured by the Digit Symbol Substitution Test, with peak decrements in performance (about a minute after inhalation) being greater after 80% nitrous oxide than after 0% nitrous oxide. Our results suggest that there arc acute, albeit brief, adverse effects of inhaling bolus concentrations of nitrous oxide.

A dose-response analysis of the subjective, psychomotor and physiological effects of intravenous morphine in healthy volunteers.

The purpose of this study was to characterize the subjective, psychomotor and physiological effects of morphine in healthy volunteers. Subjects (10 males and 2 females) without histories of opiate dependence were injected in an antecubetal vein with 0, 2.5, 5.0 or 10 mg/70 kg of morphine, by using a randomized, double-blind, cross-over design. Subjective effects, psychomotor performance and physiological measures were assessed immediately before the injection and for up to 5 hr afterward. Morphine increased the Pentobarbital-Chlorpromazine-Alcohol Group, Amphetamine, the Lysergic Acid Diethylamide and the Morphine-Benzedrine Group scores and decreased Benzedrine Group scores on the Addiction Research Center Inventory. Increased visual analog scale ratings of "stimulated," "high," "sedated," "coasting or spaced out" and "drunken" were also obtained. On an opiate adjective checklist, subjects reported increased ratings of "flushing," "dry mouth" and "tingling." Drug liking was not significantly altered by morphine, but there was substantial intersubject variability with this measure. Some aspects of psychomotor performance (reaction time, Digit Symbol Substitution Test and Maddox Wing) were impaired by morphine; however, eye-hand coordination was not. Miosis was induced by morphine. Most effects of morphine were dose-related, some effects peaked soon after morphine injection (e.g., increased stimulated and high ratings) and dissipated gradually, whereas other effects did not peak until later into the session (sedation or exophoria). Our results are fairly consistent with other studies examining morphine effects in healthy volunteers, and also indicate that the profile of morphine effects differ between healthy volunteers and those with a history of opiate dependence.

Reinforcing effects of extended inhalation of a low nitrous oxide concentration in humans.

The reinforcing, subjective, and psychomotor effects of 30 min of inhalation of 20% nitrous oxide were determined in 12 healthy volunteers using a choice paradigm with 100% oxygen as placebo. Nitrous oxide was chosen on only 22% of choice occasions, indicating that, in general, this concentration did not function as a reinforcer. Nitrous oxide produced changes in mood, but had no effect on psychomotor performance. Three out of the 12 subjects chose nitrous oxide on at least two out of the three choice sessions, and during a poststudy debriefing interview, reported pleasant effects of the drug. The other nine subjects reported unpleasant acute effects of the drug (e.g., drowsiness) or residual (postsession) effects of the drug which, they said, influenced their drug choice. The present results are compared to those results obtained in a previous study in which higher concentrations of nitrous oxide (30 and 40%) also produced relatively low choice rates. The apparent lack of reinforcing effects of extended inhalation of nitrous oxide is discussed.

The interaction between alcohol and the residual effects of thiopental anesthesia.

BACKGROUND: During ambulatory surgery, barbiturates, such as thiopental, may impair psychomotor performance several hours after administration. It was hypothesized that if patients drink alcohol 4 h after thiopental injection, the increase in psychomotor impairment would be greater than that seen after alcohol ingestion alone. METHODS: Twelve healthy men volunteered to participate in a double-blind, placebo-controlled, crossover study with a Latin square design. On each testing day, the subjects received intravenous injections of either 5 mg/kg of 2.5% thiopental or an equal volume of saline for 30 s. Four hours after injection, the subjects consumed a beverage with or without 0.7 g/kg alcohol. Psychomotor performance and mood were assessed at five times: prior to injection, at 1 h and 3 h after injection, and at 1 h and 3 h after consumption of beverage. RESULTS: Both thiopental and alcohol had strong independent effects on the dependent measures in this study. In addition, body sway, one of the nine psychomotor tests used to assess impairment, was greater after thiopental and alcohol than after alcohol alone. Of eleven adjectives used to assess mood, lightheadedness was cited most frequently after a combination of thiopental and alcohol than after each alone. CONCLUSIONS: Based on our tests of performance and mood, an interaction between thiopental and alcohol is evident; in addition, the interaction between both drugs may exert deleterious effects on higher levels of central nervous system integration.

Assessing the behavioral effects and abuse potential of propofol bolus injections in healthy volunteers.

Propofol is a recently introduced intravenous anesthetic agent, commonly administered to surgical patients because it induces anesthesia smoothly (i.e., provides loss of consciousness rapidly and usually with no complications) and is associated with rapid recovery. Propofol has psychoactive effects that could be construed as pleasant, although little abuse liability testing has been done on this agent in humans. Accordingly, we examined various effects of this agent at different subanesthetic doses (0.2-0.6 mg/kg) in order to characterize this drug's abuse potential (for recreational use or potential for diversion). Using a double-blind, randomized, crossover design, healthy normal volunteers (N = 10) were injected intravenously with the drug or with placebo. Before the injection and for up to 1 h afterwards, mood (including drug liking), memory and psychomotor performance were assessed. Propofol impaired memory and psychomotor performance and produced changes in 10 of 20 VAS mood ratings. Although there was variability in self-reported drug liking, some subjects clearly liked the effects of propofol, especially at the two higher doses. At the debriefing interview held after completion of the study, five subjects said if they had to participate in one more session in which they were given a choice between being injected with the highest dose (0.6 mg/kg) or a placebo, they would choose propofol. These preliminary results suggest that this agent may have some potential for abuse/diversion and perhaps stricter accountability procedures should be established for this drug in settings where general anesthesia or conscious sedation procedures are done.