The authors studied the respiratory and analgesic effects of nalbuphine (0.21 mg/kg, intravenous), naloxone (0.014 mg/kg, intravenous), and placebo (normal saline) when given after morphine (0.21 mg/kg, intravenous) in a double-blind, randomized fashion. Resting end-tidal CO2 (PETCO2), ventilatory and occlusion pressure responses to CO2 rebreathing, and pain threshold were measured in 12 healthy adult volunteers before, 5 min, and 30 min after morphine. Nalbuphine, naloxone, or saline were administered 55 min after morphine, and the above measurements were repeated 5 min later (60 min after morphine) as well as 90, 120, 180, and 240 min after morphine. Whereas naloxone reversed respiratory depression as measured by all three respiratory parameters, nalbuphine either further depressed (resting PETCO2) or did not affect (ventilatory and occlusion pressure responses to CO2 rebreathing) respiratory drive. Morphine produced a significant elevation of the pain threshold. Significant decreases in the pain threshold were seen only after naloxone. Saline and nalbuphine did not significantly alter the pain threshold. The data indicate that nalbuphine may not reliably antagonize moderate doses of morphine.