Subjective, psychomotor, and physiological effects of cumulative doses of mixed-action opioids in healthy volunteers.

RATIONALE: Conducting complete dose-response evaluations of multiple drugs in a single within-subjects experiment is very time-consuming when a complete session is required for evaluation of each dose. OBJECTIVE: To evaluate a within-session cumulative-dosing procedure as a potentially efficient method for conducting dose-response evaluations of mixed-action opioids. METHODS: Fifteen healthy volunteers received intravenous injections of saline, butorphanol, nalbuphine, pentazocine, or morphine in a randomized, double-blind, crossover design. Subjects received one injection per hour for the first 4 h, and a 3-h recovery period followed. Saline was injected first, then saline or increasing doses of each drug (except pentazocine, see below) were administered every hour for the next 3 h. The absolute doses per injection were morphine and nalbuphine 2.5, 5, and 10 mg/70 kg, butorphanol 0.5, 1, and 2 mg/70 kg, and pentazocine 7.5, 15, and 0 mg/70 kg. (The highest dose of pentazocine was omitted because of the risk of dysphoria and psychotomimesis). These injections resulted in cumulative doses of morphine or nalbuphine 2.5, 7.5, and 17.5 mg/70 kg, butorphanol 0.5, 1.5, and 3.5 mg/70 kg, and pentazocine 7.5 and 22.5 mg/70 kg. Mood, psychomotor performance, and vital signs were assessed. RESULTS: Effects of all opioids were similar, with some exceptions. Butorphanol had the strongest effects on psychomotor performance and some subjective effects. Morphine was associated with delayed or prolonged side effects. CONCLUSIONS: Orderly dose-response functions and replication of results of single-dosing studies confirmed that the cumulative-dosing procedure is an efficient way of determining dose-response functions for multiple opioids within the same subjects.

The relative potency of oral transmucosal fentanyl citrate compared with intravenous morphine in the treatment of moderate to severe postoperative pain.

UNLABELLED: Pharmacokinetic studies have shown that oral transmucosal absorption of fentanyl is relatively rapid compared with gastrointestinal absorption, and it results in increased bioavailability. We designed this study to establish the relative potency of oral transmucosal fentanyl citrate (OTFC) compared with i.v. morphine in 133 postoperative patients. The morning after surgery, patients randomly received one dose of either OTFC (200 or 800 microg) and a placebo i.v. injection or i.v. morphine (2 or 10 mg) and an oral transmucosal placebo unit. Pain intensity, pain relief, time to meaningful pain relief, and time to remedication were recorded. Median time to onset of relief was approximately 5 min for all groups. Over the first hour, little difference among treatment groups was seen for pain intensity and pain relief. By 2 h after study drug administration, 800 microg of OTFC and 10 mg of i.v. morphine generally produced similar analgesia, which was better than the smaller doses. Duration of analgesia with the larger doses (800 microg of OTFC and 10 mg of morphine) was similar and longer that produced by the smaller doses. The larger doses of OTFC and morphine produced better and more sustained analgesia than 200 microg of OTFC or 2 mg of morphine. IMPLICATIONS: The relative potency of oral transmucosal fentanyl citrate (OTFC) to i.v. morphine was 8-14:1. In this postoperative setting, OTFC produced rapid pain relief similar to that produced by i.v. morphine. The larger doses of OTFC (800 microg) and morphine (10 mg) produced better and more sustained analgesia than 200 microg of OTFC or 2 mg of morphine.

Early reversal of rapacuronium with neostigmine.

BACKGROUND: Rapacuronium is a rapid-onset, short-acting neuromuscular relaxant. This multiple-center study determined neuromuscular recovery when neostigmine was given 2 or 5 min after rapacuronium. METHODS: One hundred seventeen patients were randomized to receive two different doses of rapacuronium and to receive neostigmine in two different doses and at two different times. During propofol anesthesia with nitrous oxide, oxygen, and fentanyl, 1.5 or 2.5 mg/kg rapacuronium was given 1 min before tracheal intubation. Neuromuscular block was measured by train-of-four ulnar nerve stimulation every 12 s: The adductor pollicis force of contraction was recorded mechanomyographically. Two or five minutes after rapacuronium was administered, 0.05 or 0.07 mg/kg neostigmine was administered and recovery was compared with that of control patients who received no neostigmine. RESULTS: Both doses of rapacuronium produced 100% block in all but one patient, who exhibited 97% block. Neostigmine accelerated recovery in all groups. After 1.5 mg/kg rapacuronium, the time to 25% T1 twitch recovery decreased from a mean of 16 min in control patients to mean values of 8-10 min in the treatment groups: The time to train-of-four ratio of 0.7 decreased from 38 min to 17-19 min. After 2.5 mg/kg rapacuronium, the time to 25% T1 was reduced from 23 min to 11-12 min, and the time to train-of-four ratio of 0.7 decreased from 54 min to 26-32 min. Recovery was not different among the the groups that received different doses and timing of neostigmine. CONCLUSIONS: Recovery of intense rapacuronium block was accelerated by early neostigmine administration. When given 2 min after rapacuronium, neostigmine was as effective as after 5 min, and 0.05 mg/kg neostigmine was comparable to 0.07 mg/kg neostigmine.

Improving the efficiency of survey research in postoperative patients.

STUDY OBJECTIVE: To increase the contact rate with eligible patients for quality assurance/improvement surveys by modifying survey rounds to accommodate the schedules of individual nursing units. DESIGN: Two-phase, interventional time series study. SETTING: Postoperative inpatients at a university hospital. PATIENTS: 498 adult postoperative inpatients who remained hospitalized during the second postoperative day. INTERVENTIONS: Between the first and second measurement periods, efforts were made to learn the schedule of each nursing unit and to improve the efficiency of survey rounds so that a larger proportion of patients could be contacted. MEASUREMENTS AND MAIN RESULTS: The contact rate for eligible patients was improved from 66% to 80% (p < 0.01). Improvement during the second period was attributed to fewer patients being away from the nursing unit (20% vs. 12%, p < 0.05) or otherwise occupied by attending physicians on rounds (9% vs. 4%, p < 0.05). CONCLUSION: Strategies individualized to patient care units can improve the efficiency and credibility of inpatient survey research. We describe the strategies most helpful in improving the efficiency of survey rounds at one medical center.

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.

The effects of transnasal butorphanol on mood and psychomotor functioning in healthy volunteers.

Transnasal butorphanol is effective in relieving migraine and postoperative pain. The extent to which this drug preparation impacts on cognitive and psychomotor performance, as well as mood, has not been examined. Accordingly, the cognitive and psychomotor, subjective, and physiological effects of two clinically relevant doses of transnasal butorphanol (1 and 2 mg) were compared to that of placebo, and a common analgesic drug combination given for pain relief in ambulatory settings, 600 mg of acetaminophen and 60 mg of codeine, in healthy volunteers (n = 10). The larger transnasal butorphanol dose impaired psychomotor performance for up to 2 h, and produced subjective effects for up to 3 h. The smaller dose had no psychomotor-impairing effects, but had subjective effects (including increased ratings of "sleepy"). All three active drug conditions including miosis. These laboratory results suggest that patients should use caution when using the 1-mg dose of transnasal butorphanol, and should curtail certain activities if they administer the 2-mg dose of transnasal butorphanol for analgesia.

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.

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 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 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.

The subjective, behavioral and cognitive effects of subanesthetic concentrations of isoflurane and nitrous oxide in healthy volunteers.

A prospective, crossover, double-blind trial was conducted in nine healthy volunteers in which the subjective, psychomotor and memory effects of isoflurane (0.0, 0.3 and 0.6%) and nitrous oxide (N2O) (0, 20 and 40%) were examined. Dependent measures included visual analog scales and a standardized drug effects inventory (subjective effects), reaction time and eye-hand coordination (e.g., psychomotor performance), and immediate and delayed free recall (memory). There were some similarities in subjective effects between the two inhaled drugs (e.g., increased ratings of "drunk" and "spaced out"), but isoflurane had effects which N2O did not have. Isoflurane but not N2O increased visual analog scale ratings of "confused," "sedated," and "carefree," and decreased ratings of "in control of thoughts" and "in control of body." An odor was detected with isoflurane and it was disliked. Psychomotor performance was more grossly impaired during isoflurane inhalation than during N2O inhalation. Psychomotor recovery from both agents was rapid and complete so that 5 min after the inhalation period had ceased, performance had returned to baseline levels. Both isoflurane and nitrous oxide impaired immediate and delayed free recall. The feasibility of using isoflurane in conscious sedation procedures is discussed.

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.