Pharmacokinetics and Metabolism
Morphine sulfate extended-release tablets are an extended-release tablet containing morphine sulfate. Following oral administration of a given dose of morphine, the amount ultimately absorbed is essentially the same whether the source is morphine sulfate extended-release tablets or a conventional formulation. Morphine is released from this product somewhat more slowly than from conventional oral preparations. Because of pre-systemic elimination (i.e., metabolism in the gut wall and liver) only about 40% of the administered dose reaches the central compartment.
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.
Although a small fraction (less than 5%) of morphine is demethylated, for all practical purposes, virtually all morphine is converted to glucuronide metabolites; among these, morphine-3-glucuronide is present in the highest plasma concentration following oral administration.
The glucuronide system has a very high capacity and is not easily saturated even in disease. Therefore, rate of delivery of morphine to the gut and liver should not influence the total and, probably, the relative quantities of the various metabolites formed. Moreover, even if rate affected the relative amounts of each metabolite formed, it should be unimportant clinically because morphine’s metabolites are ordinarily inactive.
The following pharmacokinetic parameters show considerable inter-subject variation but are representative of average values reported in the literature. The volume of distribution (Vd) for morphine is 4 liters per kilogram, and its terminal elimination half-life is normally 2 to 4 hours.
Following the administration of conventional 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 morphine sulfate extended-release tablets to normal volunteers, however, this extent of absorption occurs, on average, after 1.5 hours.
The possible effect of food upon the systemic bioavailability of morphine sulfate extended-release tablets has not been systematically evaluated for all strengths. Data from at least one study suggests that concurrent administration of morphine sulfate extended-release tablets with a fatty meal may cause a slight decrease in peak plasma concentration.
Variation in the physical/mechanical properties of a formulation of an oral morphine drug product can affect both its absolute bioavailability and its absorption rate constant (ka). The formulation employed in morphine sulfate extended-release tablets has not been shown to affect morphine’s oral bioavailability, but does decrease its apparent ka. Other basic pharmacokinetic parameters (e.g., volume of distribution [Vd], elimination rate constant [ke], clearance [Cl]) are unchanged as they are fundamental properties of morphine in the organism. However, in chronic use, the possibility that shifts in metabolite to parent drug ratios may occur cannot be excluded.
When immediate-release oral morphine or extended-release morphine sulfate 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.
The effects described below are common to all morphine-containing products.
Central Nervous System
The principal actions of therapeutic value of morphine are analgesia and sedation (i.e., sleepiness and anxiolysis).
The precise mechanism of the analgesic action is unknown. However, specific CNS opiate receptors and endogenous compounds with morphine-like activity have been identified throughout the brain and spinal cord and are likely to play a role in the expression of analgesic effects.
Morphine produces respiratory depression by direct action on brain stem respiratory centers. The mechanism of respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension, and to electrical stimulation.
Morphine depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen with worsening hypoxia.
Gastrointestinal Tract and Other Smooth Muscle
Gastric, biliary and pancreatic secretions are decreased by morphine. Morphine causes a reduction in motility associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm. The end result is constipation. Morphine can cause a marked increase in biliary tract pressure as a result of spasm of sphincter of Oddi.
Morphine produces peripheral vasodilation which may result in orthostatic hypotension. Release of histamine can occur and may contribute to opioid-induced hypotension. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating.
Plasma Level- Analgesia Relationships
In any particular patient, both analgesic effects and plasma morphine concentrations are related to the morphine dose. In non-tolerant individuals, plasma morphine concentration-efficacy relationships have been demonstrated and suggest that opiate receptors occupy effector compartments, leading to a lag-time, or hysteresis, between rapid changes in plasma morphine concentrations and the effects of such changes. The most direct and predictable concentration-effect relationships can, therefore, be expected at distribution equilibrium and/or steady state conditions. In general, the minimum effective analgesic concentration in the plasma of non-tolerant patients ranges from approximately 5 to 20 ng/mL.
While plasma morphine-efficacy relationships can be demonstrated in non-tolerant individuals, they are influenced by a wide variety of factors and are not generally useful as a guide to the clinical use of morphine. The effective dose in opioid-tolerant patients may be 10-50 times as great (or greater) than the appropriate dose for opioid-naive individuals. Dosages of morphine should be chosen and must be titrated on the bases of clinical evaluation of the patient and the balance between therapeutic and adverse effects.
For any fixed dose and dosing interval, morphine sulfate extended-release tablets will have at steady state, a lower Cmax and a higher Cmin than conventional morphine. This is a potential advantage; a reduced fluctuation in morphine concentration during the dosing interval should keep morphine blood levels more centered within the theoretical "therapeutic window." (Fluctuation for a dosing interval is defined as [Cmax-Cmin]/ [Css average].) On the other hand, the degree of fluctuation in serum morphine concentration might conceivably affect other phenomena. For example, reduced fluctuations in blood morphine concentrations might influence the rate of tolerance induction.
The elimination of morphine occurs primarily as renal excretion of 3-morphine glucuronide. A small amount of the glucuronide conjugate is excreted in the bile, and there is some minor enterohepatic recycling. Because morphine is primarily metabolized to inactive metabolites, the effects of renal disease on morphine’s elimination are not likely to be pronounced. However, as with any drug, caution should be taken to guard against unanticipated accumulation if renal and/or hepatic function is seriously impaired.