To compare the respiratory depressant and analgesic effects of nalbuphine and morphine, six healthy male subjects were given the drugs as single 0.15-mg/kg doses, and as four successive doses of 0.15 mg/kg. Respiratory depression was monitored by ventilatory and mouth occlusion pressure responses during CO2 rebreathing, while analgesia to experimental pain was tested with the submaximal effort tourniquet ischemia test. When given as single 0.15 mg/kg doses, both drugs significantly increases the threshold and tolerance for experimental pain. The analgesic effect was similar for both drugs at this dosage, as was depression of the ventilatory and occlusion pressure responses to CO2. Morphine administered in multiple doses progressively increased pain tolerance from 30 +/- 13% above control with the first dose of 0.15 mg/kg to 107 +/- 13% above control after the fourth dose (cumulative total 0.60 mg/kg). Nalbuphine produced a 40 +/- 12% increase in pain tolerance with an initial dose of 0.15 mg/kg, but additional increments of nalbuphine did not result in significantly greater analgesia. The increasing morphine dosage was associated with progressive rightward displacements and ultimately decreases in the slope of the CO2 response curves. Nalbuphine produced an initial rightward displacement of the CO2 response curves similar to morphine, but continued administration of the drug did not result in further displacement or changes in slope. These findings demonstrate that nalbuphine, in contrast to morphine, exhibits a ceiling effect for respiratory depression which is paralleled by its limited analgesic effect on experimental pain.