IMPAIRED MEMORY AND BEHAVIORAL PERFORMANCE WITH FENTANYL AT LOW PLASMA-CONCENTRATIONS

Fentanyl is commonly administered to conscious patients by continuous epidural or intravenous (IV) infusions, or by the transdermal route, w hich result in relatively constant, low, concentrations of the drug. P revious studies of memory and cognitive effects have not been performe d at constant plasma concentrations of fentanyl. Based on simulated in fusions using the pharmacokinetic modeling program IV-SIM, we administ ered fentanyl or placebo to nine healthy volunteers (aged 21-45 yr) by continuous IV infusion, targeting plasma concentrations of 1, 1.5, an d 2.5 ng/mL in succession. A battery of memory and psychomotor tasks w as administered at each plasma concentration of fentanyl, and at two p oints in the recovery phase while drug levels were decreasing. At incr easing plasma concentrations of fentanyl, we found the following effec ts on memory (in comparison with placebo): a progressive decline in ve rbal learning (P < 0.03); decreased delayed recognition of words prese nted at different test times (P < 0.02); and decreased spontaneous rec all of pictures shown during infusion (P < 0.03). Fentanyl at concentr ations above 2.5 ng/mL caused a performance decrement of 15%-30% relat ive to baseline on all the psychomotor tests administered. Plasma conc entrations less than 2.25 ng/mL had negligible effects on performance with the exception of the critical flicker fusion frequency, which dec reased by 5 Hz at plasma concentrations between 1.5 and 2.25 ng/mL. Vi sual analog scale (VAS) measures of mental and physical sedation were significantly affected by fentanyl, but euphoria was not demonstrable. All subjects receiving fentanyl experienced severe nausea and four of six had one or more episodes of emesis (P < 0.03). We conclude that e ven though patients experiencing constant, low plasma concentrations o f fentanyl appear to be awake, they could have significantly impaired memory.