Maximum tolerated dose of nalmefene in patients receiving epidural fentanyl and dilute bupivacaine for postoperative analgesia.

Background: This study investigated the ability of the modified continual reassessment method (MCRM) to determine the maximum tolerated dose of the opioid antagonist nalmefene, which does not reverse analgesia in an acceptable number of postoperative patients receiving epidural fentanyl in 0.075% bupivacaine. Methods: In the postanesthetic care unit, patients received a single intravenous dose of 0.25, 0.50, 0.75, or 1.00 μg/kg nalmefene. Reversal of analgesia was defined as an increase in pain score of two or more integers above baseline on a visual analog scale from 0 through 10 after nalmefene administration. Patients were treated in cohorts of one, starting with the lowest dose. The maximum tolerated dose of nalmefene was defined as that dose, among the four studied, with a final mean probability of reversal of anesthesia (P ROA ) closest to 0.20 (i.e., a 20% chance of causing reversal). The modified continual reassessment method is an iterative Bayesian statistical procedure that, in this study, selected the dose for each successive cohort as that having a mean P ROA closest to the preselected target P ROA of 0.20. Results: The modified continual reassessment method repeatedly updated the P ROA of each dose level as successive patients were observed for presence or absence of ROA. After 25 patients, the maximum tolerated dose of nalmefene was selected as 0.50 μg/kg (final mean P ROA = 0.18). The 1.00-μg/kg dose was never tried because its projected P ROA was far above 0.20. Conclusions: The modified continual reassessment method facilitated determination of the maximum tolerated dose ofnalmefene. Operating characteristics of the modified continual reassessment method suggest it may be an effective statistical tool for dose-finding in trials of selected analgesic or anesthetic agents.