BACKGROUND: Buprenorphine is used as an analgesic for postoperative and chronic pain. The usual sublingual dose is 0.2 to 0.8 mg, and the usual parenteral dose is 0.3 mg for acute postoperative pain. The pharmacokinetic and related pharmacodynamic properties of buprenorphine at these doses have not been characterized. OBJECTIVE: The aim of this study was to assess the pharmacokinetic properties of buprenorphine 0.002 mg/kg IV (0.15 mg/70 kg) and its antinociceptive and psychomotor effects. METHODS: Healthy male volunteers received 0.002 mg/kg buprenorphine IV in a randomized, double-blind, placebo-controlled, crossover design. Blood samples were collected at 0.5, 1, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, and 8 hours for the determination of plasma concentrations. Pharmacokinetic parameters were estimated by a compartmental model using specialized software. Antinociceptive and psychomotor effects were determined for 8 hours. Quantitative sensory testing with thermal and electrical (nociceptive flexion RIII reflex) stimulations was performed. The cold pressor test was used to assess pain tolerance to a tonic, intense pain stimulation. Psychomotor performance was assessed by the digit symbol substitution test (DSST). Participants also rated sedation on an 11-point numeric scale (0 = none to 10 = severe). A selective liquid chromatography-tandem mass spectrometry assay was developed for the determination of buprenorphine; the limit of quantification was 0.05 ng/mL using a 0.25-mL plasma aliquot. Participants were instructed to report adverse effects, which were recorded for type, time of onset, seriousness, and duration. RESULTS: The study enrolled 12 participants, all of whom were white. Mean (SD) age was 26 (3.5) years, and mean weight was 67 (9) kg. None of the participants had a history of opiate abuse. Buprenorphine significantly increased the objective (nociceptive flexion RIII reflex) and subjective pain thresholds for >4 hours and pain tolerance (cold pressor test) for 2 hours. The mean (SD) RIII reflex threshold and subjective threshold at baseline were 31.6 (9.5) mA and 45.5 (22.3) mA, respectively. The maximum increases (mean [SD]) were +14.1 (17.5) mA for the RIII reflex (P = 0.02) and +24.2 (21.7) mA for the subjective threshold (P = 0.02), corresponding to mean (SEM) percentages of 53.7% (20.2%) and 74.7% (20.4%) of the baseline values, respectively. The maximum increases were observed at 120 minutes for both measures. The effect of buprenorphine on pain tolerance peaked at 30 minutes. Mean (SEM) latency before withdrawal of the hand was 69 (10) seconds, corresponding to a mean increase of 63.8% (14.4%) from baseline (P = 0.003). Buprenorphine had a significant effect on the DSST. The mean maximum decrease in the total number of symbols drawn was -6 (14.5%; P = 0.005) at 1 hour. The participants reported high levels of sedation: at peak effect (120 minutes), mean scores increased from 2.9 to 6.4 (SEM 0.7) (P = 0.005). Levels returned to baseline values by the end of the session, unlike for the nociceptive tests. The onset of effects occurred during the distribution phase for all the measures, and their duration was observed across a wide range of concentrations during the elimination phase. The most likely explanation for this finding is the high affinity of buprenorphine at mu-opioid receptors, and possibly distribution to the brain. Buprenorphine t(l/2) was 2.75 hours. A secondary peak in concentration was observed at 90 minutes, suggesting enterohepatic circulation of buprenorphine. A 2-compartment model adequately described buprenorphine pharmacokinetics. CONCLUSIONS: A clinically relevant analgesic dose of 0.002 mg/kg (0.15 mg/70 kg) of buprenorphine had a significant effect on nociception and psychomotor performance in these healthy male volunteers. A 2-compartment model satisfactorily characterized buprenorphine pharmacokinetics, and we found evidence of enterohepatic circulation.