Richard Sackler

A Bioequivalence Study of Oral Controlled‐Release Morphine Using Naltrexone Blockade

Twenty‐three normal volunteers who received morphine sulphate (MS Contin) with naltrexone completed this randomized, analytically blinded, two‐way crossover comparison of the bioavailability of one 200‐mg oral controlled‐release morphine sulfate tablet with two 100‐mg MSC tablets. Morphine effects were blocked by three 100‐mg doses of naltrexone. The first dose of naltrexone was given 24 hours before MSC dosing, followed by a second dose at the time of MSC dosing and a third dose 24 hours after MSC administration. Compared with two 100‐mg MSC tablets, the 200‐mg tablet was 96% bioavailable (90% confidence interval, 88.14–105.74%). The 90% confidence intervals for mean Cmax and AUC0–24 for one 200‐mg MSC tablet were within ±20% of the Cmax and AUC0–24 of two 100‐mg tablets, indicating the two dosage forms are bioequivalent. Single 200‐mg doses of MSC given with the naltrexone blockade were generally well tolerated, and adverse effects were similar to those reported for naltrexone alone and for lower doses of morphine without naltrexone. Naltrexone proved safe and effective in blocking the effects of controlled‐release morphine, permitting bioequivalence studies of a high dose of morphine in normal volunteers.