CLINICAL PHARMACOLOGY
METABOLISM AND PHARMACOKINETICS
MSIR Oral Solution Concentrate and MSIR Tablets containing morphine sulfate are for oral administration and are conventional immediate-release products. Only about 40% of the administered dose reaches the central compartment because of pre-systemic elimination (i.e., metabolism in the gut wall and liver).
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 intersubject 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 approximately 2 to 4 hours. Following the administration of conventional oral morphine products, approximately 50% of the morphine that will reach the central compartment intact reaches it within 30 minutes.
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 basic pharmacokinetic parameters (e.g., volume of distribution [Vd], elimination rate constant [ke], clearance [Cl]) 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 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.
While there is no predictable relationship between morphine blood levels and analgesic response, effective analgesia will not occur below some minimum blood level in a given patient. The minimum effective blood level for analgesia will vary among patients, especially among patients who have been previously treated with potent mu (µ) agonist opioids. Similarly, there is no predictable relationship between blood morphine concentration and untoward clinical responses; again, however, higher concentrations are more likely to be toxic than lower ones.
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.
The elimination half-life of morphine is reported to vary between 2 and 4 hours. Thus, steady-state is probably achieved on most regimens within a day. 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.
Individual differences in the metabolism of morphine suggest that MSIR Oral Solution, Concentrate and MSIR Tablets be dosed conservatively according to the dosing initiation and titration recommendations in the DOSAGE AND ADMINISTRATION section.
PHARMACODYNAMICS
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 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 narcotic 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. In addition, 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 the sphincter of Oddi.
CARDIOVASCULAR SYSTEM
Morphine produces peripheral vasodilation which may result in orthostatic hypotension. Release of histamine can occur and may contribute to narcotic-induced hypotension. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, and sweating.
|
