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Kadian

CLINICAL PHARMACOLOGY

Mechanism Of Action

Morphine sulfate, an opioid agonist, is relatively selective for the mu receptor, although it can interact with other opioid receptors at higher doses. In addition to analgesia, the widely diverse effects of morphine sulfate include analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal motility, altered circulatory dynamics, histamine release, physical dependence, and alterations of the endocrine and autonomic nervous systems.

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 full agonist, binding with and activating opioid receptors at sites in the peri-aqueductal and peri-ventricular grey matter, the ventromedial medulla and the spinal cord to produce analgesia.

Pharmacodynamics

Plasma Level-Analgesia Relationships

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 to 50 times as great (or greater) than the appropriate dose for opioid-na´ve 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.

CNS Depressant/Alcohol Interaction

Additive pharmacodynamic effects may be expected when KADIAN is used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

Effects on the Central Nervous System

The principal actions of therapeutic value of morphine are analgesia and sedation. 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.

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 morphine 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 or peripheral vasodilation may include pruritus, flushing, red eyes and sweating.

Effects on the Endocrine System

Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Pharmacokinetics

Absorption

KADIAN capsules contain polymer coated extended-release pellets of morphine sulfate that release morphine significantly more slowly than oral morphine solution. Following the administration of oral morphine solution, approximately 50% of the morphine absorbed reaches the systemic circulation within 30 minutes compared to 8 hours with an equal amount of KADIAN. Because of pre-systemic elimination, only about 20 to 40% of the administered dose reaches the systemic circulation.

Both dose-normalized Cmax and dose-normalized AUC0-48hr values of morphine after a single dose administration of KADIAN in healthy volunteers are less than those for morphine oral solution or an extended-release tablet formulation (Table 1).

When KADIAN was given twice daily to 24 patients with chronic pain due to malignancy, steady-state was achieved in about two days. At steady-state, KADIAN has a significantly lower Cmax and a higher Cmin than equivalent doses of oral morphine solution given every 4 hrs and an extended-release tablet given twice daily. When given once daily to 24 patients with malignancy, KADIAN had a similar Cmax and higher Cmin at steady-state when compared to an extended-release morphine tablets, given twice daily at an equivalent total daily dosage (see Table 1).

The single-dose pharmacokinetics of KADIAN are linear over the dosage range of 30 to 100 mg.

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.

Regimen/Dosage Form AUC#,+ (ng•h/mL) Cmax+ (ng/mL) Tmax (h) Cmin+ (ng/mL) Fluctuation*
Single Dose (n=24)
KADIAN Capsule 271.0 (19.4) 15.6 (24.4) 8.6 (41.1) na^ na
Extended-Release Tablet 304.3 (19.1) 30.5 (32.1) 2.5 (52.6) na na
Morphine Solution 362.4 (42.6) 64.4 (38.2) 0.9 (55.8) na na
Multiple Dose (n=24)
KADIAN Capsule Once Daily 500.9 (38.6) 37.3 (37.7) 10.3 (32.2) 9.9 (52.3) 3.0 (45.5)
Extended-Release Tablet Twice Daily 457.3 (40.2) 36.9 (42.0) 4.4 (53.0) 7.6 (60.3) 4.1 (51.5)
# For single dose AUC = AUC0-48h, for multiple dose AUC = AUC0-24h at steady-state
+ For single dose parameter normalized to 100 mg, for multiple dose parameter normalized to 100 mg per 24 hours
* Steady-state fluctuation in plasma concentrations = Cmax-Cmin/Cmin
^ Not applicable

Food effect: While concurrent administration of food slows the rate of absorption of KADIAN, the extent of absorption is not affected and KADIAN can be administered without regard to meals.

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 Use in Specific Populations] and has been found in breast milk [see Use in Specific Populations].

Metabolism

Major pathways of morphine metabolism include glucuronidation in the liver to produce metabolites including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5 to 15%) and sulfation in the liver to produce morphine-3-etheral sulfate. A small fraction (less than 5%) of morphine is demethylated. M3G has no significant contribution to the analgesic activity. Although M6G does not readily cross the blood-brain barrier, it has been shown to have opioid agonist and analgesic activity in humans.

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.

Excretion

Approximately 10% of a morphine dose is excreted unchanged in the urine. Most of the dose is excreted in the urine as M3G and M6G which are then renally excreted. 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 of morphine is about 20 to 30 mL/minute/kg. The effective terminal half-life of morphine after IV administration is reported to be approximately 2 hours. The terminal elimination half-life of morphine following a single dose of KADIAN administration is approximately 11 to 13 hours.

Specific Populations

Geriatric Patients: The pharmacokinetics of KADIAN have not been investigated in elderly patients ( > 65 years) although such patients were included in the clinical studies.

Pediatric Patients: The pharmacokinetics of KADIAN have not been evaluated in a pediatric population.

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

Race: 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 Impairment: 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. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.

Renal Impairment: The pharmacokinetics of morphine are altered in patients with renal failure. The AUC is increased and clearance is decreased. Metabolites, M3G and M6G accumulate several fold in patients with renal failure compared to healthy subjects. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted.

Last reviewed on RxList: 4/30/2014
This monograph has been modified to include the generic and brand name in many instances.

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