Action And Clinical Pharmacology: Morphine is an opioid analgesic which exerts an agonist effect at specific, saturable opioid receptors in the CNS and other tissues. In man, morphine produces a variety of effects including analgesia, constipation from decreased gastrointestinal motility, suppression of the cough reflex, respiratory depression from reduced responsiveness of the respiratory centre to CO2, nausea and vomiting via stimulation of the CTZ, changes in mood including euphoria and dysphoria, sedation, mental clouding, and alterations of the endocrine and autonomic nervous systems.
The psychological effects are of longer duration than that of analgesia. Morphine-induced analgesia is relatively selective in that other sensory modalities (touch, vision, hearing) are not affected. Moderate doses of morphine are effective in relieving clinical (pathological) pain and increasing pain threshold to tolerate pain. The capacity to perceive the sensation of pain may be relatively unaltered. The analgesic effects of morphine are due to its CNS action, i.e., limbic system, hypothalamus, and centrally induced endocrinological effect. At present, the exact mechanism by which opiates exert their effects remains unknown.
Pharmacokinetics: Morphine is readily absorbed from the gastrointestinal tract and after s.c. or i.m. injection. Due to first-pass metabolism in the liver, the effect of an oral dose is less than after parenteral administration. With repeated regular dosing, orally administered morphine is about one-third as potent as when given by i.m. injection. Morphine is primarily excreted in the urine as morphine-3-glucuronide. About 7 to 10% of a dose of morphine is excreted in the feces via the bile.
The morphine sulfate extended release capsules produce peak morphine levels at steady state in approximately 3 to 4 hours following administration. In human pharmacokinetic studies, they have been shown to have an extended release action, when compared to oral morphine sulfate syrup, as characterized by a flatter peak serum concentration curve which took longer to attain; the elimination half-life was significantly lengthened. Therapeutic levels are maintained over a period of 12 hours.
This product has not been compared to any slow-release morphine preparation on the Canadian market, and therefore is not interchangeable.
Indications And Clinical Uses: The symptomatic relief of severe pain.
Contra-Indications: Should not be given to patients with: hypersensitivity to opiate opioids; acute asthma or other obstructive airway disease and acute respiratory depression; cor pulmonale; cardiac arrhythmias; acute alcoholism; severe cirrhosis; delirium tremens; severe CNS depression, convulsive disorders; increased cerebrospinal or intracranial pressure; head injury or brain tumor (may cause marked exaggeration of cerebrospinal fluid pressure and mask the clinical course); suspected surgical abdomen; surgical anastomosis (opioids may cause increase in intraluminal pressure); after surgery of the biliary tract; surgical anastomosis; hypotension; concomitant MAO inhibitors (or within 14 days of such therapy). tag_WarningWarnings
Manufacturers’ Warnings In Clinical States: This product has not been compared to slow-release morphine preparation on the Canadian market, and therefore is not interchangeable.
Drug Dependence: As with other opioids, tolerance and physical dependence tend to develop upon repeated administration of morphine and there is potential for abuse of the drug and for development of strong psychological dependence. The morphine sulfate extended release capsules should therefore be prescribed and handled with the high degree of caution appropriate to the use of a drug with strong abuse potential. Drug abuse is not, however, a problem in patients with severe pain in which morphine is appropriately indicated. On the other hand, in the absence of a clear indication for a strong opioid analgesic, drug-seeking behavior must be suspected and resisted, particularly in patients with a history of, or propensity for drug abuse. Withdrawal symptoms may occur following abrupt discontinuation of morphine therapy or upon administration of an opioid antagonist. Therefore, patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer required for pain control.
Severe pain antagonizes the subjective and respiratory depressant actions of morphine. Should pain suddenly subside, these effects may rapidly become manifest. Patients who are scheduled for cordotomy or other interruption of pain transmission pathways should not receive the morphine sulfate extended release capsules within 24 hours of the procedure.
Pregnancy: Animal studies indicate that morphine may be teratogenic at high doses in mice and may cause an increased incidence of abortions and reduced birth weight in rabbits. In humans, it is not known whether morphine can cause fetal harm when administered during pregnancy or can affect reproductive capacity. The morphine sulfate extended release capsules should be given to pregnant patients only if clearly needed and when the anticipated benefits outweigh the risks to the fetus and the mother. Infants born to mothers who are physically dependent on opioids exhibit withdrawal symptoms, such as generalized tremors, hypertonicity, hyperalertness, sleeplessness, excessive crying, vomiting, diarrhea, yawning, and occasional fever.
Precautions: General: The respiratory depressant effects of morphine, and the capacity to elevate cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated intracranial pressure produced by trauma. Also, morphine may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients, morphine must be used with extreme caution and only if it is judged to be essential.
Morphine should be used with extreme caution in patients with chronic pulmonary disease; substantially decreased respiratory reserve, preexisting respiratory depression, hypoxia or hypercapnia. Such patients are often less sensitive to the stimulatory effects of carbon dioxide on the respiratory centre and the respiratory depressant effects of morphine may reduce respiratory drive to the point of apnea.
Morphine administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of such drugs as phenothiazines or certain anesthetics.
Morphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
Morphine may cause a decrease in systemic vascular resistance in patients with myocardial infarction. A transient fall in systemic arterial pressure may result, leading to severe hypotension. Administered in large doses, morphine may cause severe hypotension even in the supine patient.
Special Risk Groups: Morphine should be administered with caution, and in reduced dosages, to elderly or debilitated patients, to patients with severely reduced hepatic or renal function, and in patients with Addison’s disease, hypothyroidism, prostatic hypertrophy or urethral stricture, hypopituitarism, anemia, severe malnutrition, fulminant ulcerative colitis, untreated myxedema.
Labor/Delivery and Lactation: Morphine crosses the placental barrier and its administration during labor can produce respiratory depression in the neonate. Morphine has been detected in human breast milk. Caution should be exercised if morphine is administered to a nursing mother.
Occupational Hazards: Morphine may impair the mental and/or physical abilities needed for certain potentially hazardous activities such as driving a car or operating machinery. Patients should be cautioned accordingly.
Patients should also be cautioned about the combined effects of morphine with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics and alcohol.
Drug Interactions: Generally, the effects of morphine may be antagonized by acidifying agents and potentiated by alkalinizing agents.
Anticholinergics: The concomitant use of anticholinergics with opioids, including morphine, may result in an increased risk of severe constipation and urinary retention.
Opioid Antagonists: Concomitant use of opioid antagonists may result in reversal of analgesia, and may precipitate withdrawal symptoms in patients who are physically dependent on narcotics.
CNS Depressants: CNS depressants, such as other opioids, alcohol, anesthetics, antihistamines, barbiturates, beta-blockers, chloral hydrate, glutethimide, hypnotics, MAO inhibitors, phenothiazines, pyrazolidone, sedatives, skeletal muscle relaxants and tricyclic antidepressants may enhance the depressant effects of morphine. Concurrent use may result in potentiation of CNS depression and death may occur. If used concurrently with CNS depressants, dosage adjustment may be required.
Amphetamines: Amphetamines potentiate the analgesic effect of morphine.
Oral Anticoagulants: Morphine may increase the anticoagulant activity of coumarin and other anticoagulants.
Adverse Reactions: The major hazards associated with morphine, as with other opioid analgesics, are respiratory depression and, to a lesser degree, circulatory depression. Respiratory arrest, shock and cardiac arrest have occurred following oral or parenteral use of morphine.
Most Common Adverse Effects Requiring Medical Attention: The most frequently observed side effects of opioid analgesics such as morphine are sedation, nausea and vomiting, constipation and sweating.
- Sedation: Most patients experience initial drowsiness partly for pharmacokinetic reasons and partly because patients often recuperate from prolonged fatigue after the relief of persistent pain. Drowsiness usually clears in 3 to 5 days and is usually not a reason for concern providing that it is not excessive, or associated with unsteadiness or confusional symptoms. If excessive sedation persists the reason for it must be sought. Some of these are: concomitant sedative medications, hepatic or renal failure, exacerbated respiratory failure, higher doses than tolerated in an older patient, or the patient is actually more severely ill than realized. If it is necessary to reduce the dose, it can be carefully increased again after 3 or 4 days if it is obvious that the pain is not being well controlled. Dizziness and unsteadiness may be caused by postural hypotension particularly in elderly or debilitated patients. It can be alleviated if the patient lies down. Because of the slower clearance in patients over 50 years of age, an appropriate dose in this age group may be as low as half or less the usual in the younger age group.
- Nausea and Vomiting: Nausea and vomiting occur frequently after single doses of opioids or as an early unwanted effect of regular opioid therapy. When instituting prolonged therapy for chronic pain the routine prescription of antiemetic should be considered. Patients taking the equivalent of a single dose of 20 mg or more of morphine every 4 hours (60 mg of morphine sulfate extended release capsules every 12 hours) usually require an antiemetic during early therapy. Small doses of prochlorperazine or haloperidol are the most frequently prescribed antiemetics. Nausea and vomiting tend to lessen in a week or so but may persist due to opioid-induced gastric stasis. In such patients, metoclopramide is often useful.
- Constipation: Practically all patients become constipated while taking opioids on a persistent basis. In some instances, particularly the elderly or bedridden, patients may become impacted. It is essential to caution the patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged opioid therapy. Softeners, laxatives and other appropriate measures should be used as required.
- CNS: euphoria, dysphoria, weakness, insomnia, dizziness, headache, agitation, tremor, uncoordinated muscle movements, visual disturbances, confusional symptoms and occasionally hallucinations.
- Gastrointestinal: dry mouth, anorexia, constipation, cramps, taste alterations and biliary tract spasm.
- Genitourinary: urinary retention or hesitance, reduced libido or potency.
- Cardiovascular: supraventricular tachycardia, postural hypotension, palpitations, faintness and syncope.
- Endocrine: A syndrome of inappropriate antidiuretic hormone secretion characterized by hyponatremia secondary to decreased free-water excretion may be prominent (monitoring of electrolytes may be necessary).
- Allergic: pruritus, urticaria, other skin rashes and edema.
Withdrawal (Abstinence) Syndrome: Physical dependence with or without psychological dependence tend to occur on chronic administration. An abstinence syndrome may be precipitated when opioid administration is discontinued or opioid antagonists administered. The following withdrawal symptoms may be observed after opioids are discontinued: body aches, diarrhea, gooseflesh, loss of appetite, nervousness or restlessness, runny nose, sneezing, tremors or shivering, stomach cramps, nausea, trouble with sleeping, unusual increase in sweating and yawning, weakness, tachycardia and unexplained fever. With appropriate medical use of opioids and gradual withdrawal from the drug, these symptoms are usually mild.
Symptoms And Treatment Of Overdose: Symptoms: Serious morphine overdosage is characterized by 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, and sometimes hypotension and bradycardia. Severe overdosage may result in apnea, circulatory collapse, cardiac arrest and death. Convulsions may occur in young children. tag_Treatment
Treatment: Primary attention should be given to the establishment of adequate respiratory exchange through provision of a patent airway and controlled or assisted ventilation. The opioid antagonist naloxone is a specific antidote against respiratory depression due to overdosage or as a result of unusual sensitivity to morphine. An appropriate dose of this antagonist should therefore be administered, preferably by the i.v. route. The usual initial i.v. adult dose of naloxone is 0.4 mg or higher. Concomitant efforts at respiratory resuscitation should be carried out. Since the duration of action of morphine, particularly extended release formulations, may exceed that of the antagonist, the patient should be under continued surveillance and doses of the antagonist should be repeated as needed to maintain adequate respiration.
An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Oxygen, i.v. fluids, vasopressors and other supportive measures should be used as indicated.
Note: In an individual physically dependent on opioids, the administration of the usual dose of opioid antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of antagonist administered. The use of opioid antagonists in such individuals should be avoided if possible. If an opioid antagonist must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care by using dosage titration, commencing with 10 to 20% of the usual recommended initial dose.
Evacuation of gastric contents may be useful in removing unabsorbed drug, particularly when an extended release formulation has been taken.
Dosage And Administration: This product has not been compared to any slow-release morphine preparation on the Canadian market, and therefore is not interchangeable.
Administration and dosing of morphine should be individualized bearing in mind the properties of the drug. In addition, the nature and severity of the pain or pains experienced, and the total condition of the patient must be taken into account. Of special importance is other medication given previously or concurrently.
As with other strong opioid analgesics, use of morphine for the management of persistent pain should be preceded by a thorough assessment of the patient and diagnosis of the specific pain or pains and their causes. Use of opioids for the relief of chronic pain, including cancer pain, all important as it may be, should be only one part of a comprehensive approach to pain control including other treatment modalities or drug therapy, non-drug measures and psychosocial support.
For essential information on the important details of the management of cancer pain, the reader may wish to consult the following resource: Cancer Pain: A Monograph on the Management of Cancer Pain. Health and Welfare Canada.
Initial Adult Dose: Individual dosing requirements vary considerably based on each patient’s age, weight, severity of pain, and medical and analgesic history.
The most frequent initial dose is 30 mg every 12 hours.
The capsules may be opened, and the microgranules given mixed with soft food, liquids or by gastric tube or gastrotomy to dysphagic (e.g. E.N.T. cancer) patients who can benefit from the analgesia obtained from an extended release preparation.
Patients over the age of 50 tend to require much lower doses of morphine than the younger age group. In elderly and debilitated patients and those with impaired respiratory function or significantly decreased renal function, the initial dose should be one-half the usual recommended dose.
Patients currently receiving other oral morphine immediate release formulations may be transferred to M-Eslon capsules at the same total daily morphine dosage, equally divided into two 12-hourly M-Eslon doses.
For patients who are receiving an alternate opioid, the “oral morphine equivalent” of the analgesic presently being used should be determined. Having determined the total daily dosage of the present analgesic, Table I can be used to calculate the approximate daily oral morphine dosage that should provide equivalent analgesia. This total daily oral morphine dosage should then be equally divided in two 12 hourly M-Eslon doses.
Dose titration is the key to success with morphine therapy. Proper optimization of doses scaled to the relief of the individual’s pain should aim at the regular administration of the lowest dose of morphine which will maintain the patient free of pain at all times. Dose adjustments should be based on the patient’s clinical response. Higher doses may be justified in some patients to cover periods of physical activity.
Because of the extended release properties of M-Eslon capsules, dosage adjustments should generally be separated by 48 hours. If dose increments turn out to be required, they should be proportionately greater at the lower dose level (in terms of percentage of previous dose), than when adjusting a higher dose. The usual recommended dose (every 12 hours) increments are 30, 60, 90, 120, 150, 180, 200 mg. Above the 200 mg/dose (400 mg/day) increments should be by 30 to 60 mg/dose.
Morphine sulfate extended release capsules are designed to allow 12-hourly dosing. If “breakthrough” pain repeatedly occurs at the end of a dose interval, it is generally an indication for a dosage increase, not more frequent administration. However, where judged necessary for optimization of drug effects, the product may be administered every 8 hours. More frequent (than every 8 hours) administration is not recommended.
Adjustment or Reduction of Dosage: During the first 2 or 3 days of effective pain relief, the patient may exhibit drowsiness or sleep for prolonged periods. This can be misinterpreted as the effect of excessive analgesic dosing rather than the first sign of relief in a patient exhausted by pain. The dose, therefore, should be maintained for at least 3 days before reduction, provided the sedation is not excessive or associated with unsteadiness and confusional symptoms, and respiratory activity and other vital signs are adequate. If excessive sedation persists, the reason(s) for such an effect must be sought. Some of these are: concomitant sedative medications, hepatic or renal failure, exacerbated respiratory failure, higher doses than tolerated by an older patient, or the patient is actually more severely ill than realized. If it is necessary to reduce the dose, it can be carefully increased again after 3 or 4 days if it is obvious that the pain is not being well controlled.
Following successful relief of severe pain, periodic attempts to reduce the opioid dose should be made. Smaller doses or complete discontinuation of the opioid analgesic may become feasible due to a change in the patient’s condition or improved mental state.
Opioid agents do not relieve effectively dysesthetic pain, post-herpetic neuralgia, stabbing pains, activity-related pain, and some forms of headache. This is not to say that patients with advanced cancer suffering from some of these forms of pain should not be given an adequate trial of opiate analgesics, but it may be necessary to refer such patients at an early time for other forms of pain therapy. Pain without nociception does not respond to opioids.
Availability And Storage: 10 mg: Each #4 hard gelatin capsule, printed with the logo
“M-ESLON” and “10” in black, opaque white cap and body, contains: morphine sulfate 10 mg in the form of extended release microgranules. Nonmedicinal ingredients: dibutyl sebacate, ethylcellulose, gelatin, polyethylene glycol, starch, sucrose, talc and titanium dioxide. Tartrazine-free.
15 mg: Each #4 hard gelatin capsule, printed with the logo
“M-ESLON” and “15” in black, opaque yellow cap and transparent natural body, contains: morphine sulfate 15 mg in the form of extended release microgranules. Nonmedicinal ingredients: dibutyl sebacate, ethylcellulose, FD&C No. 10, gelatin, polyethylene glycol, starch, sucrose, talc and titanium dioxide. Tartrazine-free.
30 mg: Each #4 hard gelatin capsule, printed with the logo
“M-ESLON” and “30” in black, opaque pink cap and transparent natural body contains: morphine sulfate 30 mg in the form of extended release microgranules. Nonmedicinal ingredients: dibutyl sebacate, ethylcellulose, FD&C Red No. 3, gelatin, polyethylene glycol, starch, sucrose, talc and titanium dioxide. Tartrazine-free.
60 mg: Each #3 hard gelatin capsule, printed with the logo
“M-ESLON” and “60” in black, opaque orange cap and transparent natural body, contains: morphine sulfate 60 mg in the form of extended release microgranules. Nonmedicinal ingredients: dibutyl sebacate, ethylcellulose, FD&C Yellow No. 6, gelatin, polyethylene glycol, starch, sucrose, talc and titanium dioxide. Tartrazine-free.
100 mg: Each #2 hard gelatin capsule, printed with the logo
“M-ESLON” and “100” in black, opaque white cap and transparent natural body, contains: morphine sulfate 100 mg in the form of extended release microgranules. Nonmedicinal ingredients: dibutyl sebacate, ethylcellulose, gelatin, polyethylene glycol, starch, sucrose, talc and titanium dioxide. Tartrazine-free.
200 mg: Each #0 hard gelatin capsule, printed with the logo
“M-ESLON” and “200” in black, transparent natural cap and body, contains: morphine sulfate 200 mg in the form of extended release microgranules. Nonmedicinal ingredients: dibutyl sebacate, ethylcellulose, gelatin, polyethylene glycol, starch, sucrose and talc. Tartrazine-free.
Cartons containing blister packs of 20. White, opaque polypropylene bottles of 50 with tamper-evident polyethylene caps. Store at room temperature and protect from excessive heat.
M-ESLON® Rh´ne-Poulenc Rorer Morphine Sulfate Opioid Analgesic
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