Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids, Part 2 - Effect of epinephrine

Background: The ability of epinephrine to improve the efficacy of epidurally administered drugs is assumed to result from local vasoconstriction and a consequent decrease in drug clearance. However, because drug concentration in the epidural space has never been measured, our understanding of the effect of epinephrine on epidural pharmacokinetics is incomplete. This study was designed to characterize the effect of epinephrine on the epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidurally administered opioids. Methods. Morphine plus alfentanil, fentanyl, or sufentanil was administered epidurally with and without epinephrine (1:200,000) to pigs. Opioid concentration was subsequently measured in the epidural space, central venous plasma, and epidural venous plasma, and these data were used to calculate relevant pharmacokinetic parameters. Results: The pharmacokinetic effects of epinephrine varied by opioid and by sampling site. For example, in the lumbar epidural space, epinephrine increased the mean residence time of morphine but decreased that of fentanyl and sufentanil. Epinephrine had no effect on the terminal elimination half-life of morphine in the epidural space, but it decreased that of fentanyl. and sufentanil. In contrast, in the lumbar intrathecal space, epinephrine had no effect on the pharmacokinetics of alfentanil, fentanyl, or sufentanil, but it increased the area under the concentration-time curve of morphine and decreased its elimination half-life. Conclusions: The findings indicate that the effects of epinephrine on the spinal pharmacokinetics of these opioids are complex and often antithetical across compartments and opioids. In addition, the data clearly indicate that the pharmacokinetic effects of epinephrine in spinal "compartments" cannot be predicted from measurements of drug concentration in plasma, as has been assumed for decades.