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Crossover Trials in Clinical Analgesic Assays: Studies of Buprenorphine and Morphine

Analgesic studies of buprenorphine, a thebaine derivative and potent partial narcotic agonist, were carried out in patients with cancer who had postoperative or chronic pain. Intramuscular buprenorphine was compared with intramuscular morphine in a series of sequentially related, twin crossover assays and was found to be about 25 times as potent as morphine. Side effects were essentially morphinelike. In a second assay, the acceptability and analgesic activity of sublingual buprenorphine was studied in a 6‐dose, balanced, incomplete block assay, a modification of the twin crossover design employed in the all‐intramuscular trial. Sublingual buprenorphine was found to be about 15 times as potent as intramuscular morphine and was well accepted by our patients. The 4‐dose twin crossover trial in which doses are adjusted sequentially is more flexible in that a wide range of doses may be studied, but it lacks the ability of the 6‐dose design to provide estimates of the curvature of the dose‐response slopes of the study drugs. When first‐dose‐only data were analyzed as parallel group assays, the main difference in results compared with the crossover studies was a decrease in efficiency and sensitivity.