A pharmacokinetic approach to resolving spinal and systemic contributions to epidural alfentanil analgesia and side-effects

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Abstract
A pilot study was conducted in 7 normal volunteers to demonstrate the feasibility of employing pharmacokinetic tailoring to achieve matching plasma opioid concentration-time curves after epidural (e.p.) and intravenous (i.v.) alfentanil administration. Each subject participated in 1 pretest and 2 test sessions. Our pain model was cutaneous electrical stimulation of the finger and toe, adjusted to produce a baseline pain report of 5 (strong pain on a 0–5 scale). On test day 1, subjects received e.p. alfentanil (750 μg) and an i.v. saline infusion. Serial measurements of analgesia, end tidal CO 2 , pupil size, subjective side effects, and plasma alfentanil concentrations were conducted before and at various time intervals over a 4-h period after alfentanil administration. On test day 2, subjects received e.p. saline and a pharmacokinetically tailored i.v. infusion (using individual pharmacokinetics determined on the pretest day) designed to achieve a plasma concentration-time profile identical to that observed on the epidural day. The same battery of effect measurements was administered as on the 1st test day. Plasma alfentanil was measured to verify the accuracy of the tailored infusion. Plasma alfentanil concentration profiles were nearly identical on both test days. Peak plasma alfentanil concentrations were near the reported minimum effective analgesic concentration (MEAC). Overall, analgesia was slightly greater with e.p. administration. Onset of pain relief was rapid, and duration was approximately 1.5 h with e.p. and 1 h with i.v. alfentanil. There were no differences in pupil size, ETCO 2 , or subjective side effects between e.p. versus i.v. administration. We concluded that a 750 μg dose of e.p. alfentanil produces plasma drug concentrations within the analgesic range and that systemic redistribution from the epidural space appears to account for most, but not all, of the analgesia. Side effects appear to be due to systemic absorption of the opioid. There may be little clinical benefit to e.p. administration at doses which result in plasma alfentanil concentrations near the MEAC.