Double-Blind Crossover Clinical and Pharmacokinetic Comparison of Oral Morphine Syrup and Sustained Release Morphine Sulfate Capsules in Patients with Cancer-Related Pain

Abstract

A total of 35 patients with advanced cancer and severe pain not controllable by step 2 analgesics (according to WHO criteria) were included in this double-blind study. No patients were receiving concomitant oncological treatment. During a stabilisation period, all patients received sufficient morphine sulfate 5 mg/ml syrup every 4 hours to achieve a satisfactory level of pain relief (60 to 300 mg/day). The patients were then randomised to receive the same dosage of morphine sulfate 5 mg/ml syrup every 4 hours or sustained release (SR) morphine sulfate (as 30 or 60mg capsules) every 12 hours for 6 days, according to a double-blind crossover design. Analgesic efficacy was assessed daily with a visual analogue scale and a 5-point verbal rating scale. At the end of each treatment period, morphine plasma concentrations at steady-state were measured by high performance liquid chromatography. There were no differences between the 2 formulations in terms of subjective analgesic efficacy (measured at 10am, 2pm, 6pm and 10pm) among 20 evaluable patients. Overall, the incidence of opiate-related adverse events was similar with both formulations, and no unexpected adverse events were reported. Mean (± SD) pharmacokinetic parameters assessed in 25 patients were as follows: the maximum plasma concentration was 49.5 ± 28.4 µg/L for morphine syrup vs 48.1 ± 30.7 for the SR capsules [90% confidence interval (CI) 86.8 to 114.0%]; and the area under the concentration-time curve from zero to 12 hours (AUC12h) was 308.4 ± 203.8 µg/L·h for the syrup vs 323 ± 201.7 for the capsules (90% CI 99.1 to 124.5%). There was a linear relationship between the daily dose of morphine and AUC12h. The results of this study suggest that equal dosages of morphine as SR capsules (containing 30 or 60mg morphine) given 12-hourly and morphine 5 mg/ml syrup given 4-hourly are bioequivalent. Furthermore, the 2 formulations are equally effective and well tolerated in the treatment of severe pain in patients with cancer.