MCR

/ Rafa

Initial Dose and Titration: In opioid-naive patients, for ease of titration, it is recommended that the initial daily dosage of morphine be established using morphine immediate-release tablets (MIR) using a 4-hourly schedule. The total daily dose should then be divided into two and administered as MCR tablets 12-hourly. Because of the difficulty of titrating MCR, opioid-naive patients who are started directly on MCR therapy should initially receive a conservative dose of 10-20 mg, 12-hourly, in order to avoid overdose. The majority of patients will then require an upward titration. Most patients are controlled on 30-100 mg of MCR 12-hourly. However, smaller doses such as 10 mg 12-hourly may be adequate in some patients, while higher doses may be needed in others. As there is no upper limit to the amount of morphine that may be given in intractable oncologic pain, the quantity administered should be that which produces adequate analgesia. During the course of treatment the patient may experience breakthrough pain due to an increase in the level of pain or the development of tolerance to the drug. If this breakthrough pain occurs often, an increase in the dosage may be required. If other measures to relieve pain (e.g., nerve blocks) are employed, the morphine dosage should be reduced to an appropriate level.
Children: For children with severe cancer pain, a starting dose in the range of 0.2 to 0.8 mg morphine per kg body weight 12 hourly is recommended. Doses should then be titrated as for adults. Since the controlled release tablets must be swallowed whole, and not broken, chewed, dissolved or crushed, only children who are able to swallow the tables in whole, can use MCR tables.
For full details see prescribing information.

Relief of protracted pain post-operative, oncology.

Respiratory depression, head injury, known or suspected paralytic ileus, ‘acute abdomen’, delayed gastric emptying, obstructive airways disease, acute or severe bronchial asthma hypersensitivity to any of the tablet constituents, acute hepatic disease, concurrent administration of monoamine oxidase inhibitors or within two weeks of discontinuation of their use.
Children under three years of age. Since the controlled release tablets must be swallowed whole, and not broken, chewed, dissolved or crushed, only children who are able to swallow the tables in whole, can use MCR tables.
Not recommended for pre-operative use or for the first 24 hours post-operatively.
See prescribing information for full details.

The diagnosis or clinical course of acute abdominal conditions may be obscured by opioids. Exercise caution in elderly and debilitated patients and in patients sensitive to CNS depressants, including those with cardiovascular disease, myxedema, acute alcoholism, delirium tremens, cerebral arteriosclerosis, fever, kyphoscoliosis, Addison’s disease, adrenocortical insufficiency, prostatic hypertrophy or urethral stricture, toxic psychosis, severe CNS depression, coma, gallbladder dysfunction, inflammatory bowel disorders, opiate dependent patients or a history of drug abuse. As with all narcotics a reduction in dosage may be advisable in the elderly, in hypothyroidism and in patients with significantly impaired renal or hepatic function. Renal and hepatic dysfunction may cause a prolonged duration of action and a cumulative effect. Seizures may become aggravated, or may occur in individuals without a history of convulsive disorders, if dosage is substantially increased because of tolerance. The cough reflex is suppressed. Exercise caution when using opioid analgesics post-operatively and in patients with pulmonary disease. Morphine should be used with caution in patients about to undergo surgery of the biliary tract since it may cause spasm of the sphincter of Oddi. Similarly, morphine should be used with caution in patients with acute pancreatitis secondary to biliary tract disease. Use with caution in patients with atrial flutter and other supraventricular tachycardias. Vagolytic action may increase the ventricular response rate. This drug may produce drowsiness or dizziness. Therefore, patients should be warned that their ability to perform potentially-hazardous tasks requiring mental alertness or physical coordination, such as driving a vehicle or operating machinery, may be impaired. Concomitant use of alcohol and MCR tablets may increase the undesirable effects of MCR tablets; concomitant use should be avoided. It is not always possible to ensure bio-equivalence between different brands of prolonged release morphine products. Therefore, if patients (once titrated to an effective dose) need to be changed from MCR preparations to other slow, sustained or prolonged release morphine or other potent narcotic analgesic preparations, the physician needs to take into account the need for retitration and clinical assessment.
Use in Children : Morphine should be administered with caution and in carefully determined dosages to small children since they may be relatively sensitive to opiates. Since the controlled release tablets must be swallowed whole, and not broken, chewed, dissolved or crushed, only children who are able to swallow the tables in whole, can use MCR tables. The administration of broken, chewed or crushed tablets may lead to a rapid release and absorption of a potentially fatal dose of morphine. Accidental consumption of MCR tablets, especially in children, can result in a fatal overdose of morphine.
For full details see prescribing information.

The most serious adverse reactions include respiratory depression and apnea. Less frequently, circulatory depression, respiratory arrest, shock and cardiac arrest may occur. The most frequent adverse reactions are constipation, lightheadedness, dizziness, sedation, nausea, vomiting and sweating. Patients experiencing these adverse reactions should receive lower doses of the drug and/or symptomatic treatment of the With chronic therapy nausea and vomiting are unusual with MCR tablets but should they occur the tablets can be readily combined with an anti-emetic if required. Constipation may be treated with appropriate laxatives. The following adverse reactions have also been reported:
Central Nervous System: Euphoria, dysphoria, delirium, insomnia, somnolence, agitation, anxiety, fear, hallucinations, disorientation, confusion, drowsiness, lethargy, impairment of mental and physical performance, coma, mood changes, weakness, headache, visual disturbances, tremor, drug dependence (physical & psychological), miosis, uncoordinated muscle movements, myoclonus, seizure, increased intracranial pressure, paresthesia, vertigo and muscle rigidity.
Respiratory: Thoracic and mediastinal disorders Bronchospasm, cough decreased, pulmonary oedema, and respiratory depression.
Immune system disorders: Allergic reaction, anaphylactic reaction, anaphylactoid reaction and laryngospasm.
Gastrointestinal: Dry mouth, anorexia, constipation, abdominal pain, gastrointestinal disorders, ileus, dyspepsia, laryngospasm, diarrhea, cramps and taste alterations. Patients with chronic ulcerative colitis may experience increased colonic motility. Toxic dilatation has been reported in patients with acute ulcerative colitis. Concomitant administration of anthraquinone laxatives may counteract opioid-induced constipation.
Hepatobiliary disorders: increased hepatic enzymes, exacerbation of pancreatitis, biliary tract spasm and pain.
Cardiovascular: Facial flushing, peripheral circulatory collapse, tachycardia, bradycardia, arrhythmia, palpitations, chest wall rigidity, hypertension, hypotension, faintness, chills and syncope.
Genitourinary: Urethral spasm and spasm of vesical sphincters, urinary retention or hesitancy, oliguria, antidiuretic effect, reduced libido or potency, erectile dysfunction, amenorrhea.
Dermatologic: Pruritus, urticaria, other skin rashes, diaphoresis, edema, and rarely hemorrhagic urticaria.
Other: Thinking disturbances, asthenia, malaise, drug tolerance, drug withdrawal syndrome, peripheral oedema.
For full details see prescribing information.

Morphine sulphate should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy.
Administration of a mixed agonist/antagonist opioid analgesic (e.g., pentazocine, buprenorphine) to a patient receiving therapy with a pure agonist opioid such as morphine may reduce the analgesic effect, or precipitate withdrawal. Use with caution and in reduced dosage in patients concurrently receiving other opioid analgesics, general anesthetics, antihistamines, phenothiazines, barbiturates, other tranquilizers, sedative-hypnotics, tricyclic antidepressants and other CNS depressants including alcohol (concomitant use of alcohol and MCR tablets should be avoided), anticholinergics or neuromuscular blocking agents, muscle relaxants, antihypertensives and gabapentin . Respiratory depression, hypotension, profound sedation, coma, severe constipation, or urinary retention may result. Medicinal products that block the action of acetylcholine, for example antihistamines, anti-parkinsons and anti-emetics, may interact with morphine sulphate to potentiate anticholinergic adverse events. The depressant effects of morphine may be enhanced by chloral hydrate, glutethimide, beta-adrenergic blockers (propranolol) and furazolidone. Plasma concentrations of morphine sulphate may be reduced by rifampicin. Cimetidine inhibits the metabolism of morphine sulphate. Case reports have described CNS toxicity (confusion, disorientation, respiratory depression, apnea, seizures) following concurrent administration of cimetidine and opioid analgesics, though no clear-cut cause and effect relationship has been established. The analgesic effect of morphine is potentiated by chlorpromazine and methocarbamol. Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine sulphate, ritonavir induces the hepatic enzymes responsible for the glucuronidation of morphine sulphate, and may possibly decrease plasma concentrations of morphine sulphate.Diagnostic Interference Because opioids may increase biliary tract pressure with resultant increases in plasma amylase or lipase, measurements of their levels may be unreliable for 24 hours following administration.
For full details see prescribing information.

Safety of use in pregnancy has not been established. The placental transfer of opioids is rapid. Maternal addiction following illicit use, resulting in withdrawal symptoms in the neonate, is well documented. Withdrawal symptoms include irritability, excessive crying, yawning, sneezing, increased respiratory rate, tremors, hyperreflexia, fever, vomiting, increased stools and diarrhea. These symptoms usually appear during the first days of life.
Use in Labor: Opioids cross the placental barrier and may cause respiratory depression and psycho-physiologic effects in the neonate. Resuscitation may be required; naloxone should be readily available. Morphine is contraindicated during labor for delivery of a premature infant.
Lactation: MCR is not recommended for use in nursing mothers.

Manifestations: Morphine overdose is initially characterized by sedation, confusion and delirium. If such symptoms become apparent, MCR should be withdrawn and the patient monitored. Later manifestations of serious morphine overdose include respiratory depression (reduced respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, flaccidity of skeletal muscle, cold or clammy skin, pin-point pupils and sometimes hypotension and bradycardia. Severe overdose may result in apnea, circulatory collapse, cardiac arrest and death. Rhabdomyolysis progressing to renal failure has been reported in opioid overdose.
Crushing and taking the contents of a controlled release dosage form may lead to the release of morphine in an immediate fashion; this might result in a fatal overdose.
Treatment: Primary attention should be given to establishing adequate respiratory exchange through the provision of a patent airway and institution of assisted or controlled ventilation. If depressed respiration is associated with muscular rigidity, an i.v. neuromuscular blocking agent may be required. Because of the risk of systemic withdrawal, an opioid antagonist-preferably naloxone should only be administered for symptomatic respiratory or cardiovascular depression. Since the duration of action of MCR exceeds that of naloxone, administration of the antagonist should be repeated to maintain adequate respiration and the patient should be kept under observation. In the case of massive overdose, administer naloxone 0.8 mg intravenously. Repeat at 2-3 minute intervals as necessary, or by an infusion of 2 mg in 500 ml of normal saline or 5% dextrose (0.004 mg/ml). The infusion should be run at a rate related to the previous bolus doses administered and should be in accordance with the patient’s response. However, because the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. MCR tablets will continue to release and add to the morphine load for up to 12 hours after administration and the management of morphine overdose should be modified accordingly. For less severe overdose, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required. In individuals who are physically dependent upon morphine, the administration of the usual dose of naloxone will precipitate an acute withdrawal syndrome. The severity of the syndrome is dependent on the degree of physical dependence and the dose of naloxone given. If at all possible, avoid the use of an antagonist in such individuals. However, if absolutely necessary, administer the naloxone with extreme caution, using only 10-20% of the usual initial dose given. Employ supportive measures as indicated. Evacuate the stomach by emesis or gastric lavage if treatment can be instituted within 12 hours following ingestion. Observe the patient for a rise in temperature or pulmonary complications that may require antibiotic therapy.