Steady-State Pharmacokinetics of Controlled Release Oral Morphine Sulphate in Healthy Subjects

Abstract

The pharmacokinetics of oral morphine sulphate as controlled release tablets ('MS-Contin') and solution were compared at steady-state. Plasma morphine concentrations were determined over 24 hours following the last dose of each drug when given in a randomised, crossover fashion to healthy subjects. Radioimmunoassay was used, which was sensitive yet provided good specificity relative to high-performance liquid chromatography. Controlled release tablets had 86% the bioavailability of the solution. Although each dose of controlled release tablets was double that of the solution, their peak plasma concentrations were the same. Time to maximum concentration was 3 times longer for controlled release tablets with an absorption half-life twice that of the solution. Elimination of both drugs was similar and biphasic with the minor terminal portion at 10 times the half-life of the major early process. These data explain the analgesic duration of 12 hours observed in clinical studies and the lack of accumulation with morphine compared with methadone.

The bioavailability and pharmacokinetics of morphine after intravenous, oral and buccal administration in healthy volunteers.

“…One study has reported a bioavailability of 100% for oral solution in patients (McQuay et al, 1983) but the assay method employed is now recognised to cross-react extensively with metabolites giving a falsely elevated result (Aherne & Littleton, 1985). The absolute bioavailability for morphine of controlled release morphine sulphate (MST Continus) was not significantly different from that after oral aqueous solution, in keeping with a number of studies (Hanks et al, 1981;Savarese et al, 1986;Homesley et al, 1986;Sloan et al, 1987;Khojasteh et al, 1987;Poulain etal., 1988) which have shown the relative bioavailability of MST compared with aqueous solution to be between 85 and 94%. The figure (for absolute bioavailability) of 22% is similar to that reported by Vater and his colleagues (1984), who investigated the intravenous pharmacokinetics of morphine in a group of healthy volunteers, and in a subsequent study compared these data with plasma concentrations after MST administered to the same subjects.…”

Controlled‐release oxycodone compared with controlled‐release morphine in the treatment of cancer pain: A randomized, double‐blind, parallel‐group study

“…Trough (C&J and approximate peak (C,,) plasma opioid concentrations were determined from blood samples taken at 0 and 3 h (Savarese et al, 1986;Thirlwell et al, 1989;Reder et al, 1996) after the last dose, respectively. Peak-totrough fluctuation in plasma concentrations was calculated using the scaled difference, (C,,-C,,)/C,, where C, is the average of the Oand 3-h concentration values.…”

“…Steady-state is reached in approximately 1 day with both formulations (Savarese et al, 1986;Reder et al, 1996), allowing dose titration every 1 to 2 days if necessary. Dose titration was accomplished with equal facility with both oral CR formulations.…”

Controlled-release morphine tablets in patients with chronic cancer pain

“…In cancer patients as well as other populations, the plasma concentration curve obtained with CR morphine in the Contin system mimics that of the IR product in several critical ways: values for area under the curve 0 -12 , maximum clearance, and minimum clearance are comparable. 20,30 Because the therapeutic profile of IR morphine is satisfactory in terms of the balance of efficacy and side effects, there was no reason to develop the CR product to change the degree of fluctuation of the curve. In fact, there is some evidence that any attempts to achieve a smoother curve may promote the development of tolerance.…”