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Morphine, a pure 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 include drowsiness, changes in mood, respiratory depression, decreased gastrointestinal motility, nausea, vomiting and alterations of the endocrine and autonomic nervous system.

Effects on the Central Nervous System (CNS)

The principal therapeutic action of morphine is analgesia. Other therapeutic effects of morphine include anxiolysis, euphoria and feelings of relaxation. Although the precise mechanism of the analgesic action is unknown, 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 and perception of analgesic effects. In common with other opi-oids, morphine causes respiratory depression, in part by a direct effect on the brainstem respiratory centers. Morphine and related opioids depress 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; however, when asphyxia is present during opioid overdose, marked mydriasis occurs.

Effects on the Gastrointestinal Tract and on Other Smooth Muscle

Gastric, biliary and pancreatic secretions are decreased by morphine. Morphine causes a reduction in motility and is 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 may be constipation. Morphine can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi. Morphine may also cause spasm of the sphincter of the urinary bladder.

Effects on the Cardiovascular System

In therapeutic doses, morphine does not usually exert major effects on the cardiovascular system. Morphine produces peripheral vasodilation which may result in orthostatic hypotension and fainting. Release of histamine can occur, which may play a role in opioid-induced hypotension. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating.

Pharmacodynamics

Morphine concentrations are not predictive of analgesic response, especially in patients previously treated with opioids. The minimum effective concentration varies widely and is influenced by a variety of factors, including the extent of previous opioid use, age, and general medical condition. Effective doses in tolerant patients may be significantly higher than in opioid-naïve patients.

In all patients, the dose of morphine should be titrated on the basis of clinical evaluation of the patient and to achieve a balance between therapeutic and adverse effects.

Pharmacokinetics

AVINZA (morphine sulfate) consists of two components, an immediate release component that rapidly achieves plateau morphine plasma concentrations and an extended release component that maintains plasma concentrations throughout the 24-hour dosing interval. The amount of morphine absorbed from AVINZA (morphine sulfate) following oral administration is similar to that absorbed from other oral morphine formulations.

The oral bioavailability of morphine is less than 40% and shows large inter-individual variability due to extensive pre-systemic metabolism.

Absorption

Following single-dose oral administration of a 60 mg dose of AVINZA (morphine sulfate) under fasting conditions, morphine concentrations of approximately 3 to 6 ng/ml were achieved within 30 minutes after dosing and maintained for the 24-hour dosing interval. The pharmacokinet-ics of AVINZA (morphine sulfate) were shown to be dose-proportional over a single oral dose range of 30 to 120 mg in healthy volunteers and a multiple oral dose range of at least 30 to 180 mg in patients with chronic moderate to severe pain.

Food Effects

When a 60 mg dose of AVINZA (morphine sulfate) was administered immediately following a high fat meal, peak morphine concentrations and AUC values were similar to those observed when the dose of AVINZA (morphine sulfate) was administered in a fasting state, although achievement of initial concentrations was delayed by approximately 1 hour under fed conditions. Therefore, AVINZA (morphine sulfate) can be administered without regard to food. When the contents of AVINZA (morphine sulfate) were administered by sprinkling on applesauce, the rate and extent of morphine absorption were found to be bioequivalent to the same dose when administered as an intact capsule.

Steady State

When dosed once-daily, AVINZA (morphine sulfate) steady-state pharmacokinetics are characterized by a plateau-like plasma concentration profile. Steady-state plasma concentrations of morphine are achieved 2 to 3 days after initiation of once-daily administration of AVINZA (morphine sulfate) .

AVINZA (morphine sulfate) 60 mg Capsules (once-daily) and 10 mg morphine oral solution (6 times daily) were equally bioavailable.

Graph 1: Mean Steady-State Plasma Morphine Concentrations Following Once – Daily Administration of AVINZA (morphine sulfate) Capsules or 6-Times Daily Administration of Morphine Solution

A once-daily dose of AVINZA (morphine sulfate) provided similar Cmax, Cmin, and AUC values and peak-trough fluctuations (% FL, Cmax-Cmin/Cav) compared to 6-times daily administration of the same total daily dose of morphine oral solution (Table 1).

Table 1 Pharmacokinetic Data Mean

Distribution

Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. Although the primary site of action is the CNS, only small quantities cross the blood-brain barrier. Morphine also crosses the placental membranes and has been found in breast milk. The volume of distribution of morphine is approximately 1 to 6 L/kg, and morphine is 20 to 35% reversibly bound to plasma proteins.

Metabolism

The major pathway of morphine detoxification is conjugation, either with D-glucuronic acid to produce glucuronides or with sulfuric acid to produce morphine-3-etheral sulfate. While a small fraction (less than 5%) of morphine is demethylated, virtually all morphine is converted by hepatic metabolism to the 3- and 6-glucuronide metabolites (M3G and M6G; about 50% and 15%, respectively). M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.

Excretion

Most of a dose of morphine is excreted in urine as M3G and M6G, with elimination of morphine occurring primarily as renal excretion of M3G. Approximately 10% of the dose is excreted unchanged in urine. A small amount of the glucuronide conjugates are excreted in bile, with minor enterohepatic recycling. Seven to 10% of administered morphine is excreted in the feces.

The mean adult plasma clearance is approximately 20 to 30 ml/min/kg. The effective terminal half-life of morphine after IV administration is reported to be approximately 2 hours. In some studies involving longer periods of plasma sampling, a longer terminal half-life of morphine of about 15 hours was reported.

In Vitro AVINZA (morphine sulfate) -Alcohol Interaction

In vitro studies performed by the FDA demonstrated that when AVINZA (morphine sulfate) 30 mg was mixed with 900 mL of buffer solutions containing ethanol (20% and 40%), the dose of morphine that was released was alcohol concentration-dependent, leading to a more rapid release of morphine. While the relevance of in vitro lab tests regarding AVINZA (morphine sulfate) to the clinical setting remains to be determined, this acceleration of release may correlate with in vivo rapid release of the total morphine dose, which could result in the absorption of a potentially fatal dose of morphine.

Special Populations

Geriatric

Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. AVINZA (morphine sulfate) pharmacokinetics have not been studied specifically in elderly patients.

Nursing Mothers

Low levels of morphine sulfate have been detected in maternal milk. The milk: plasma morphine AUC ratio is about 2.5:1. The amount of morphine delivered to the infant depends on the plasma concentration of the mother, the amount of milk ingested by the infant, and the extent of first-pass metabolism.

Pediatric

The pharmacokinetics of AVINZA (morphine sulfate) have not been studied in pediatric patients below the age of 18.The range of dose strengths available may not be appropriate for treatment of very young pediatric patients. Sprinkling on applesauce is NOT a suitable alternative for these patients.

Gender

A gender analysis of pharmacokinetic data from healthy subjects taking AVINZA (morphine sulfate) indicated that morphine concentrations were similar in males and females.

Race

There may be some pharmacokinetic differences associated with race. In one published study, Chinese subjects given intravenous morphine had a higher clearance when compared to Caucasian subjects (1852 +/- 116 ml/min compared to 1495 +/- 80 ml/min).

Hepatic Failure

Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. 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 subjects, indicating diminished metabolic activity.

Renal Insufficiency

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 patients with renal failure as compared to patients with normal renal function.

Drug-Drug Interactions

Known drug-drug interactions involving morphine are pharma-codynamic, not pharmacokinetic. (see PRECAUTIONS: DRUG INTERACTIONS)

Clinical Studies

AVINZA (morphine sulfate) was studied in over 140 healthy volunteers and 560 patients with chronic, moderate to severe pain who participated in 6 pharmacokinetic studies, 4 clinical studies and 3 studies which provided both pharmacokinetic and clinical data. The patient population included those who were either receiving chronic opioid therapy or had a prior sub-optimal response to acetaminophen and/or NSAID therapy, as well as patients who previously received intermittent opioid analgesic therapy. In the controlled clinical studies, patients were followed from 7 days to up to 4 weeks, and in the open label studies, patients were followed for up to 6 to 12 months.

AVINZA (morphine sulfate) was studied in a double-blind, placebo-controlled, fixed-dose, parallel group trial in 295 patients with moderate to severe pain due to osteoarthritis. These patients had either a prior sub-optimal response to acetaminophen, NSAID therapy, or previously received intermittent opioid analgesic therapy. Thirty-milligrams AVINZA (morphine sulfate) capsules administered once-daily, either in the morning or the evening, were more effective than placebo in reducing pain.

Table 2 : Change from Baseline in WOMAC OA Index Pain VAS Subscale Score

This study was not designed to assess the effects of AVINZA (morphine sulfate) on the course of the osteoarthritis.

Last reviewed on RxList: 2/26/2009
This monograph has been modified to include the generic and brand name in many instances.