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Morphine is a natural product that is the prototype for the class of natural and synthetic opioid analgesics. Opioids produce a wide spectrum of pharmacologic effects including analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal motility, altered circulatory dynamics, histamine release and physical dependence.

Morphine produces both its therapeutic and its adverse effects by interaction with one or more classes of specific opioid receptors located throughout the body. Morphine acts as a pure agonist, binding with and activating opioid receptors at sites in the peri-aqueductal and peri-ventricular grey matter, the ventro-medial medulla and the spinal cord to produce analgesia.

Effects on the 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 brainstem respiratory centers. The mechanism of respiratory depression involves a reduction in the responsiveness of the brainstem 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, and little tolerance develops to this effect. 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 in the setting of KADIAN® overdose (See OVERDOSE)

Effects on the 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 the sphincter of Oddi.

Effects on the Cardiovascular System

Morphine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Release of histamine may be induced by morphine and can contribute to opioid-induced hypotension. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating.

Pharmacodynamics

Plasma Level-Analgesia Relationships

In any particular patient, both analgesic effects and plasma morphine concentrations are related to the morphine dose.

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 basis of clinical evaluation of the patient and the balance between therapeutic and adverse effects.

For any fixed dose and dosing interval, KADIAN (morphine sulfate extended-release) ® will have, at steady-state, a lower Cmax and a higher Cmin than conventional morphine.

Pharmacokinetics

KADIAN® capsules contain polymer coated extended-release pellets of morphine sulfate that release morphine significantly more slowly than from conventional oral preparations. KADIAN (morphine sulfate extended-release) ® activity is primarily due to morphine. One metabolite, morphine-6-glucuronide, has been shown to have analgesic activity, but does not readily cross the blood-brain barrier.

Following oral administration of morphine, the extent of absorption is essentially the same for immediate or extended-release formulations, although the time to peak blood level (Tmax) will be longer and the Cmax will be lower for formulations that delay the release of morphine in the gastrointestinal tract.

Elimination of morphine is primarily via hepatic metabolism to glucuronide metabolites (55 to 65%) which are then renally excreted. The terminal half-life of morphine is 2 to 4 hours, however, a longer term half-life of about 15 hours has been reported in studies where blood has been sampled up to 48 hours.

The single-dose pharmacokinetics of KADIAN (morphine sulfate extended-release) ® are linear over the dosage range of 30 to 100 mg. The single dose and multiple dose pharmacokinetic parameters of KADIAN (morphine sulfate extended-release) ® in normal volunteers are summarized in Table 1.

Table 1: Mean pharmacokinetic parameters (% coefficient variation) resulting from a fasting single dose study in normal volunteers and a multiple dose study in patients with cancer pain.

Absorption

Following the administration of oral morphine solution, approximately 50% of the morphine absorbed reaches the systemic circulation within 30 minutes. However, following the administration of an equal amount of KADIAN (morphine sulfate extended-release) ® to healthy volunteers, this occurs, on average, after 8 hours. As with most forms of oral morphine, because of pre-systemic elimination, only about 20 to 40% of the administered dose reaches the systemic circulation.

Food Effects: While concurrent administration of food slows the rate of absorption of KADIAN (morphine sulfate extended-release) ®, the extent of absorption is not affected and KADIAN (morphine sulfate extended-release) ® can be administered without regard to meals.

Steady State: When KADIAN (morphine sulfate extended-release) ® is given on a fixed dosing regimen to patients with chronic pain due to malignancy, steady state is achieved in about two days. At steady state, KADIAN (morphine sulfate extended-release) ® will have a significantly lower Cmax and a higher Cmin than equivalent doses of oral morphine solution and some other extended-release preparations (see Graph 1).

Graph 1 (Study # MOB-1/90): Mean steady state plasma morphine concentrations for KADIAN (morphine sulfate extended-release) ® (twice a day), extended-release morphine tablet (twice a day) and oral morphine solution (every 4 hours); plasma concentrations are normalized to 100 mg every 24 hours, (n=24).

When given once-daily (every 24 hours) to 24 patients with malignancy, KADIAN (morphine sulfate extended-release) ® had a similar Cmax and higher Cmin at steady state in clinical usage, when compared to twice-daily (every 12 hours) extended-release morphine tablets, given at an equivalent total daily dosage (see Graph 2 and Table 1). Drug-disease interactions are frequently seen in the older and more gravely ill patients, and may result in both altered absorption and reduced clearance as compared to normal volunteers (see Geriatric, Hepatic Failure, andRenal Insufficiency sections)

Graph 2 (Study # MOR-9/92): Dose normalized mean steady state plasma morphine concentrations for KADIAN (morphine sulfate extended-release) ® (once a day), and an equivalent dose of a 12-hour, extended-release morphine tablet given twice a day. Plasma concentrations are normalized to 100 mg every 24 hours, (n=24).

Distribution

Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. The volume of distribution of morphine is approximately 3 to 4 L/kg. Morphine is 30 to 35% reversibly bound to plasma proteins. Although the primary site of action of morphine is in the CNS, only small quantities pass the blood-brain barrier. Morphine also crosses the placental membranes (see PRECAUTIONS - Pregnancy) and has been found in breast milk (see PRECAUTIONS - Nursing Mothers)

Metabolism

The major pathway of the detoxification of morphine is conjugation, either with D-glucuronic acid in the liver to produce glucuronides or with sulfuric acid to give morphine-3-etheral sulfate. Although a small fraction (less than 5%) of morphine is demethylated, for all practical purposes, virtually all morphine is converted to glucuronide metabolites including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5 to 15%). Studies in healthy subjects and cancer patients have shown that the glucuronide metabolite to morphine mean molar ratios (based on AUC) are similar after both single doses and at steady state for KADIAN®, 12-hour extended-release morphine sulfate tablets and morphine sulfate solution.

M3G has no significant analgesic activity. M6G has been shown to have opioid agonist and analgesic activity in humans.

Excretion

Approximately 10% of morphine dose is excreted unchanged in the urine. Most of the dose is excreted in the urine as M3G and M6G. A small amount of the glucuronide metabolites is excreted in the bile and there is some minor enterohepatic cycling. Seven to 10% of administered morphine is excreted in the feces.

The mean adult plasma clearance is about 20-30 mL/minute/kg. The effective terminal half-life of morphine after IV administration is reported to be approximately 2.0 hours. Longer plasma sampling in some studies suggests a longer terminal half-life of morphine of about 15 hours.

Special Populations

Geriatric: The elderly may have increased sensitivity to morphine and may achieve higher and more variable serum levels than younger patients. In adults, the duration of analgesia increases progressively with age, though the degree of analgesia remains unchanged. KADIAN (morphine sulfate extended-release) ® pharmacokinetics have not been investigated in elderly patients ( > 65 years) although such patients were included in the clinical studies.

Nursing Mothers: Morphine is excreted in the maternal milk, and the milk to plasma morphine AUC ratio is about 2.5:1. The amount of morphine received by the infant depends on the maternal plasma concentration, amount of milk ingested by the infant, and the extent of first pass metabolism.

Pediatric: Infants under 1 month of age have a prolonged elimination half-life and decreased clearance relative to older infants and pediatric patients. The clearance of morphine and its elimination half-life begin to approach adult values by the second month of life. Pediatric patients old enough to take capsules should have pharmacokinetic parameters similar to adults, dosed on a per kilogram basis (see PRECAUTIONS - Pediatric Use).

Gender: No meaningful differences between male and female patients were demonstrated in the analysis of the pharmacokinetic data from clinical studies.

Race: Pharmacokinetic differences due to race may exist. Chinese subjects given intravenous morphine in one study had a higher clearance when compared to caucasian subjects (1852 + 116 mL/min versus 1495 + 80 mL/min).

Hepatic Failure: The pharmacokinetics of morphine were found to be significantly altered in individuals with alcoholic cirrhosis. The clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine plasma AUC ratios also decreased in these patients indicating a decrease in metabolic activity.

Renal Insufficiency: The pharmacokinetics of morphine are altered in renal failure patients. AUC is increased and clearance is decreased. The metabolites, M3G and M6G accumulate several fold in renal failure patients compared with healthy subjects.

Drug-Drug Interactions: The known drug interactions involving morphine are pharmacodynamic, not pharmacokinetic (see PRECAUTIONS - DRUG INTERACTIONS).

Last reviewed on RxList: 1/11/2008
This monograph has been modified to include the generic and brand name in many instances.