Remifentanil is a newly synthesized 4-anilidopiperidine with an ester side chain susceptible to esterase metabolism. We evaluated the safety, analgesic efficacy, and pharmacokinetics of remifentanil in 48 male volunteers. Volunteers were randomized to receive increasing doses of remifentanil, alfentanil, or placebo. Analgesic efficacy was evaluated by increasing tolerance to a spring-loaded rod measured at the tibia and sternum at multiple time points. Respiratory depression was measured by changes in arterial blood gas tensions and peripheral hemoglobin oxygen saturation. Hemodynamics were continuously monitored by means of an intra-arterial catheter. Both remifentanil and alfentanil produced a dose-dependent increase in analgesia and respiratory depression. Remifentanil was 20 to 30 times more potent (milligram to milligram) than alfentanil when assessed by either analgesic efficacy or respiratory measures. The pharmacokinetics of remifentanil were best described by a biexponential decay curve. Remifentanil had a small volume of distribution of 0.39 (SD, ±0.25) L/kg (alfentanil, 0.52 ± 2 L/kg), with a rapid distribution phase of 0.94 (SD, ±0. 57) min and an extremely short elimination half-life of 9.5 (SD, ±4) min compared with an elimination half-life of alfentanil of 58 (SD, ±7.6) min. The t1/2 ke0 (half-time for equilibration between plasma and the effect compartment) of remifentanil for analgesia was calculated as 1.3 min. Thus, remifentanil appears to have a pharmacologic profile similar to other potent μ agonists, but with exceptionally short-lasting pharmacokinetics, which is likely to make it a very useful opioid for clinical practice.