Sustained relief of chronic pain. Pharmacokinetics of sustained release morphine

Abstract

There are a number of modified release formulations of morphine with recommended dosage intervals of either 12 or 24 hours, including tablets (MS Contin, Oramorph SR), capsules (Kapanol, Skenan), suspension and suppositories. Orally administered solid dosage forms are most popular but significant differences exist in the resultant pharmacokinetics and bioequivalence status of morphine after both single doses and at steady state. Following single doses, the plasma morphine concentrations showed pronounced differences in the 0- to 12-hour period with a 4- to 5-fold difference in the mean peak concentration (Cmax) for morphine and the time to Cmax (tmax) The area under the concentration-time curve (AUC) from 0 to 24 hours for the 4 formulations show greater similarity. None of the formulations were shown to be bioequivalent according to US Food and Drug Administration (FDA) criteria. At steady state, fluctuations in plasma morphine concentrations throughout a 12-hour dosage interval were greatest for MS Contin and least for Kapanol. In fact, the relatively small fluctuations in plasma morphine concentrations following Kapanol administration suggested the same formulation could successfully be used with a 24-hour dosage interval. The pharmacokinetic parameters of morphine following Kapanol once daily were similar to MS Contin (12 hours) with the obvious exception of the longer tmax. There is also another once daily oral morphine preparation (MXL) which has been shown to be bioequivalent to Kapanol under fasting conditions only in a single dose study in volunteers. Food has been shown to have an effect on the pharmacokinetics of morphine following doses of immediate release solution and the modified release preparations. However, bioequivalence is generally maintained between the fed and fasting states for most preparations. MS Contin tablets have been administered rectally, but morphine pharmacokinetic parameters show greater variability compared with oral administration and the 2 routes are not bioequivalent. The results suggest a slower rate but greater extent of morphine adsorption. Somewhat similar results were obtained when Kapanol granules are administered rectally. The morphine pharmacokinetics following administration of a specifically formulated controlled release suppository showed less variability (rectal bioavailability was 42%). The pronounced differences in morphine pharmacokinetics between the various formulations are not translated into measurable differences in the pharmacodynamic effects of pain relief and adverse effects. The lack of bioequivalence between some of the formulations suggests that care should be exercised if physicians change modified release formulations as dosage adjustments may be necessary in some patients.