David C. Flemming

Subjective and Psychomotor Effects of Sub anesthetic Doses of Propofol in Healthy Volunteers

Propofol is increasingly being used in medical and surgical procedures in which conscious sedation of the patient is desired. The mood-altering and psychomotor effects of subanesthetic concentrations of propofol have not been well characterized. Therefore, we examined the effects of intravenous infusions of different subanesthetic doses of propofol on mood and psychomotor/cognitive performance in healthy volunteers (n = 10). A prospective, randomized, placebo-controlled, double-blind, crossover design was used in which subjects first were administered an intravenous loading dose of propofol or placebo (Intralipid) and then were infused over a 20-min period with a given dose of propofol or placebo. Each subject received placebo (Intralipid loading dose and infusion), low-dose propofol (0.08 mg/kg loading dose and 0.5 mg.kg-1.h-1 infusion), moderate-dose propofol (0.16 mg/kg loading dose and 1.0 mg.kg-1.h-1 infusion), and high-dose propofol (0.32 mg/kg loading dose and 2.0 mg.kg-1.h-1 infusion) in four sessions spaced approximately 1 week apart. Propofol induced changes in mood in a dose-related fashion. Some of these mood-altering effects lingered for as long as 30 min after termination of the infusion, but, in general mood had returned to baseline levels 1 h after termination of the infusion. Intralipid induced no changes in mood during the infusion period. Psychomotor functioning was impaired during, and anterograde amnesia was present after, the high-dose propofol infusion. These results suggest that propofol as a sedative has a spectrum of effects that are well-suited for ambulatory surgery (e.g., sedation, amnesia, and rapid and complete recovery).

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 drugs 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.

Subjective, behavioral and physiological responses to intravenous meperidine in healthy volunteers

Meperidine is a mu opiate agonist that is frequently used to treat pain. We examined in healthy volunteers (N=10) the effects of intravenous meperidine (0, 0.25, 0.5, and 1.0 mg/kg) on mood and psychomotor performance. A randomized, placebo-controlled, crossover design was used in which subjects were injected with meperidine or saline in a double-blind fashion. Subjects completed several subjective effects questionnaires commonly used in abuse liability testing studies before drug injection and at periodic intervals for up to 5 h after drug injection. Subjects also completed several psychomotor tests. Meperidine produced a constellation of subjective effects in a dose-related fashion, including increases in ratings of “sedated,” “coasting or spaced out” and “feel drug effect” ratings. Many of the drugs subjective effects persisted up to 4 or 5 h after administration of the 1.0 mg/kg dose. Drug liking ratings assessed on a visual analog scale were increased after meperidine injection in about half of the subjects (P=0.09). Eye-hand coordination was affected slightly by meperidine but other indices of psychomotor functioning were unaffected. Miosis increased in a dose-related fashion. Other physiological parameters, such as vital signs, were not affected by meperidine. We conclude that meperidine in healthy volunteers has robust and long-lasting effects on mood, but may have weaker effects on psychomotor performance.

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

BackgroundDuring 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. MethodsTwelve 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. ResultsBoth 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. ConclusionsBased 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.