A-3665, a new short-acting opioid: A comparison with alfentanil

A-3665 is a new short-acting synthetic opioid of the piperidine class. We conducted a double-blind, escalating dose comparison of A-3665 to alfentanil and placebo. Analgesic efficacy was assessed after the administration of A- 3665 in increasing intravenous doses (0.25, 0.5, 1, 2, 4, 8, 16, 32, and 64 μg/kg) to nine groups of volunteers. At the lower doses (0.25, 0.5, 1, and 2 μg/kg), five volunteers were in each group; four received A-3665 and one received placebo in a double-blind manner. There were nine volunteers in each of the next three groups; four received A-3665 (4, 8, or 16 μg/kg), four received alfentanil (4, 8, or 16 μg/kg), and one received placebo. At the 32 μg/kg and 64 μg/kg dose levels, five subjects each were to be enrolled (four to receive A-3665 and one to receive placebo); however, the study was terminated after two subjects in the 64 μg/kg group had significant respiratory depression. Both drugs caused potent analgesia, compared with placebo, with peak effect occurring 3 min after injection. There was no significant difference in analgesic potency of A-3665 and alfentanil as measured by tolerance to tibial pressure at 3 min. At the dose of 16 μg/kg, both drugs significantly increased pain tolerance to tibial pressure compared with placebo at 3 min, but alfentanil continued to display significant analgesic effect versus placebo and versus A-3665 at 6, 11, and 15 min after injection. A-3665 caused significant respiratory depression at doses of 32 μg/kg and 64 μg/kg, but alfentanil did not induce significant respiratory depression at the doses tested. A-3665 is a potent opioid analgesic that can be administered safely to humans. Over the dosage range tested, it appears equipotent to alfentanil but has a significantly shorter duration of action. It may also cause more respiratory depression and have a greater incidence of pruritus.