Pharmacokinetics and clinical efficacy of oral morphine solution and controlled-release morphine tablets in cancer patients

Abstract

Twenty‐three adult patients with chronic pain due to cancer completed a double‐blind, randomized, two‐phase crossover trial comparing plasma morphine concentrations and analgesic efficacy of oral morphine sulfate solution (MSS) and controlled‐release morphine sulfate tablets (MS Contin [MSC], Purdue Frederick, Inc., Toronto, Ontario, Canada). MS Contin was given every 12 hours to all patients except those whose daily morphine dose could not be equally divided into two 12‐hour doses with the tablet strengths available. MSS was given every 4 hours. Patients received both of the test drugs for at least 5 days, and, on the final day of each phase, peripheral venous blood samples for morphine analysis were obtained. Eighteen patients received MSC every 12 hours, and five received it every 8 hours. The same total daily morphine dose was given in both phases. In the 18 patients who received MSC every 12 hours, the daily morphine dose was 183.9 ± 140.0 mg (mean ± SD). In this group, the mean area under the curve (AUC) with MSC was 443.6 ± 348.4 ng/ml/hour, compared with 406.8 ± 259.7 ng/ml/hour for MSS (P > 0.20). Mean maximum morphine concentrations (C_max) for MSC and MSS were 67.9 ± 42.1 and 58.8 ± 30.3 ng/ml, respectively (P > 0.05). Mean minimum morphine concentrations (C_min) were 17.0 ± 17.7 and 18.3 ± 15.0, respectively (P > 0.30). There was a significant difference (P < 0.001) between the two drugs in time required to reach maximum morphine concentration (T_msx). Mean T_max after MSC occurred at 3.6 ± 2.3 hours. After MSS, it occurred at 1.3 ± 0.4 hours. In the five patients who received MSC every 8 hours, the findings paralleled those in the principal group, with no significant differences between MSC and MSS in C_max or C_min. and a highly significant difference between the two in T_max. However, in this small group of patients, the AUC with MSC was significantly (P = 0.04) greater than that with MSS. All patients had very good pain control throughout the study and both formulations were well tolerated. There were no significant differences between MSC and MSS in pain scores or side effects. Under the conditions of this study there was no clinically significant difference in bioavailability between MSC and oral MSS. When given on a 12‐hourly basis in individually titrated doses, the MSC provided therapeutic plasma morphine concentrations throughout the dosing interval.