When immediate-release oral morphine or MS CONTIN is given on a fixed dosing regimen, steady-state is achieved in about a day.

For a given dose and dosing interval, the AUC and average blood concentration of morphine at steady-state (Css) will be independent of the specific type of oral formulation administered so long as the formulations have the same absolute bioavailability. The absorption rate of a formulation will, however, affect the maximum (Cmax) and minimum (Cmin) blood levels and the times of their occurrence.

Absorption

Following the administration of immediate-release oral morphine products, approximately fifty percent of the morphine that will reach the central compartment intact reaches it within 30 minutes. Following the administration of an equal amount of MS CONTIN to normal volunteers, however, this extent of absorption occurs, on average, after 1.5 hours.

Food Effects

The possible effect of food upon the systemic bioavailability of MS CONTIN® has not been systematically evaluated for all strengths. One study, conducted with the 30 mg MS CONTIN Tablets, showed no significant differences in Cmax and AUC _(0-24h) values, whether the tablet was taken while fasting or with a high-fat breakfast.

Distribution

The volume of distribution (Vd) for morphine is approximately 4 liters per kilogram. Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen, and brain. Morphine also crosses the placental membranes and has been found in breast milk.

Metabolism

Although a small fraction (less than 5%) of morphine is demethylated, for all practical purposes, virtually all morphine is converted to the 3- and 6- (M3G and M6G) glucuronide metabolites. M3G is present in the highest plasma concentration following oral administration and possesses no significant analgesic activity. M6G, while possessing analgesic activity, is present in the plasma in low concentrations.

Excretion

The elimination of morphine occurs primarily as renal excretion of morphine-3- glucuronide and its terminal elimination half-life after intravenous administration is normally 2 to 4 hours. In some studies involving longer periods of plasma sampling, a longer terminal half- life of about 15 hours was reported. A small amount of the glucuronide conjugate is excreted in the bile, and there is some minor enterohepatic recycling. As with any drug, caution should be taken to guard against unanticipated accumulation if renal and/or hepatic function is seriously impaired.

Special Populations

Renal Impairment

Morphine pharmacokinetics are altered in patients with renal failure. Clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in these patients as compared to patients with normal renal function.

Drug-Drug Interactions

Known drug-drug interactions involving morphine are pharmacodynamic not pharmacokinetic.

Bookmark this page: