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.
Morphine is readily absorbed when given orally, rectally or by 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, oral morphine is about 1/3 as potent as when given by i.m. injection and rectal sustained-release suppositories have approximately 40% the potency of s.c. morphine. The rectal dose of the sustained-release suppositories is approximately equivalent to the oral dose of the sustained-release tablets after repeated dosing. Morphine is primarily excreted in the urine as morphine-3-glucuronide. Formation of glucuronidated metabolites is less following rectal administration compared to oral administration. About 7 to 10% of a dose of morphine is excreted in the feces via the bile.
When administered every 12 hours, the sustained-release tablets provide equivalent analgesia to morphine oral solution given 4-hourly. In most cases, administration on a 12-hourly schedule produces equivalent pain control to 8-hourly administration. The sustained-release suppositories given 12-hourly provide equivalent pain control to the sustained-release tablets given orally at the same dose and frequency, or to morphine administered s.c. at a dose approximately 40% of the daily rectal dose.
Absorption of the sustained-release tablets is equivalent to that of immediate-release tablet or liquid formulations and is not significantly affected by administration with food. At steady-state, the sustained-release tablets produce peak morphine levels approximately 4 to 5 hours post-dose and therapeutic levels persist for a 12-hourly period. Comparison of the sustained-release suppositories and tablets indicate attainment of peak concentrations at 4.1 and 4.3 hours post-dose respectively. The extent of absorption of sustained-release suppositories at steady-state is equivalent to that of the sustained-release tablets and approximately 40% of that of s.c. morphine.
The relationship between mean plasma concentration and dose has been shown to be linear over a dosage range of 60 to 600 mg/day in the case of the sustained-release tablets and 60 to 1 200 mg/day in the case of the sustained-release suppositories.
Indications And Clinical Uses: For the relief of severe pain requiring the prolonged use of an opioid analgesic preparation.
Contra-Indications: Should not be given to patients with: hypersensitivity to opioid analgesics; acute asthma or other obstructive airway disease and acute respiratory depression; cor pulmonale; cardiac arrhythmias; acute alcoholism; delirium tremens; severe CNS depression; convulsive disorders; increased cerebrospinal or intracranial pressure; head injury; brain tumor; suspected surgical abdomen; concomitant MAO inhibitors (or within 14 days of such therapy).
Manufacturers’ Warnings In Clinical States: 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 sustained-release tablets 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 a problem in patients with severe pain in which morphine is appropriately indicated. However, in the absence of a clear indication for a strong opioid analgesic, drug-seeking behavior must be suspected and resisted, particularly in individuals 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.
CNS Depression: Morphine should be used only with caution and in reduced dosage during concomitant administration of other opioid analgesics, general anesthetics, phenothiazines and other tranquilizers, sedative-hypnotics, tricyclic antidepressants and other CNS depressants (including alcohol). Respiratory depression, hypotension and profound sedation or coma may result.
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 morphine sulfate sustained release tablets within 24 hours of the procedure.
Pregnancy: Animal studies with morphine and other opioids have indicated the possibility of teratogenic effect. In humans, it is not known whether morphine can cause fetal harm when administered during pregnancy or can affect reproductive capacity. The sustained-release morphine should be given to pregnant patients only if clearly needed and when the anticipated benefits outweigh the risks to the fetus.
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 essential.
Morphine should be used with extreme caution in patients with substantially decreased respiratory reserve, pre-existing 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.
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.
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 alkalizing agents.
The analgesic effect of morphine is potentiated by amphetamines, chlorpromazine and methocarbamol. CNS depressants, such as other opioids, anesthetics, sedatives, hypnotics, barbiturates, phenothiazines, chloral hydrate and glutethimide may enhance the depressant effects of morphine. Monoamine oxidase inhibitors (including procarbazine), pyrazolidone antihistamines, beta-blockers and alcohol may also enhance the depressant effect of morphine.
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, vomiting, constipation, lightheadedness, dizziness and sweating.
Sedation: Some degree of sedation is experienced by most patients upon initiation of therapy. This may be at least 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 confusion. 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 dose 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 narcotic therapy. When instituting prolonged therapy for chronic pain the routine prescription of an antiemetic should be considered. Patients taking the equivalent of 20 mg or more of oral morphine every 4 hours (60 mg every 12 hours of MS Contin) 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 patients, particularly the elderly or bedridden, fecal impaction may result. It is essential to caution the patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged narcotic therapy. Stool softeners, stimulant laxatives and other appropriate measures should be used as required.
Other adverse reactions include: Cardiovascular: supra-ventricular tachycardia, postural hypotension, palpitations, faintness and syncope.
CNS: euphoria, dysphoria, weakness, insomnia, dizziness, confusion 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.
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.
Treatment: Primary attention should be given to the establishment of adequate respiratory exchange through the provision of a patent airway and controlled or assisted ventilation. The opioid antagonist naloxone HCl is a specific antidote against respiratory depression due to overdosage or as a result of unusual sensitivity to morphine. An appropriate dose of one of the antagonists 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 sustained 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. 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 a sustained release formulation has been taken.
Dosage And Administration: 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, nondrug measures and psychosocial support.
References on the important details of cancer pain management may be obtained from the manufacturer.
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 orally or rectally every 12 hours.
The suppository may be used in situations where the patient cannot tolerate oral dosing. Up to 2 suppositories of the same or varying strengths may be used at one time, to achieve the required dose for 12-hourly administration.
Suppository administration is achieved by finger length insertion into the rectum, with the patient in a reclining position. Where appropriate, patients should be encouraged to attempt a bowel movement prior to insertion of the suppository. When a bowel movement occurs after insertion of a suppository, loss of a portion of the dose is possible. In such cases, the dose of the suppositories should not be repeated until the next scheduled administration. In the intervening period, breakthrough pain should be managed with appropriate rescue analgesics.
Patients over the age of 50 tend to require much lower doses of morphine than in 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 formulations may be transferred to MS Contin at the same total daily morphine dosage, equally divided into two 12-hourly MS Contin doses.
For patients who are receiving an alternate opioid, the “oral morphine sulfate 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 sulfate dosage that should provide equivalent analgesia. This total daily oral morphine dosage should then be equally divided into two 12-hourly MS Contin doses. Some patients may require a lower dose on initial conversion, followed by further titration during chronic dosing, to maintain optimal analgesia.
Dose Titration: 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 at certain times may be justified in some patients to cover periods of physical activity.
Because of the sustained release properties of MS Contin, 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 for the tablets are 15, 30, 45, 60, 90, 120, 150, 180 and 200 mg. The usual recommended dose (q12h) increments for the suppositories are 30, 60, 90, 120, 160 and 200 mg. Above the 200 mg/dose (400 mg/day) increments should be by 30 to 60 mg/dose.
MS Contin is 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 pain-exhausted patient. The dose, therefore, should be maintained for at least 3 days before reduction, provided the sedation is not excessive or associated with unsteadiness and confusion, 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 narcotic dose should be made. Smaller doses or complete discontinuation may become feasible due to a change in the patient’s condition or improved mental state.
The tablets should be swallowed intact, not chewed or crushed. The 200 mg tablet (only) is scored and may be broken in half. The half tablet should also be swallowed intact.
Opioid analgesics may only be partially effective in relieving 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 opioid analgesics, but it may be necessary to refer such patients at an early time for other forms of pain therapy.
Availability And Storage: Suppositories: 30 mg: Each sustained-release suppository contains: morphine sulfate 30 mg. Nonmedicinal ingredients: calcium phosphate, glycerol tricocoate and sodium alginate. Alcohol-, gluten-, lactose-, sulfite- and tartrazine-free. Strips of 6; cartons of 4 strips.
60 mg: Each sustained-release suppository contains: morphine sulfate 60 mg. Nonmedicinal ingredients: calcium phosphate, glycerol tricocoate and sodium alginate. Alcohol-, gluten-, lactose-, sulfite- and tartrazine-free. Strips of 6; cartons of 4 strips.
100 mg: Each sustained-release suppository contains: morphine sulfate 100 mg. Nonmedicinal ingredients: calcium phosphate, glycerol, tricocoate and sodium alginate. Alcohol-, gluten-, lactose-, sulfite- and tartrazine-free. Strips of 6; cartons of 4 strips.
200 mg: Each sustained-release suppository contains: morphine sulfate 200 mg. Nonmedicinal ingredients: calcium phosphate, glycerol tricocoate and sodium alginate. Alcohol-, gluten-, lactose-, sulfite- and tartrazine-free. Strips of 6; cartons of 4 strips.
Tablets: 15 mg: Each green, round, sustained-release, film-coated, bi-convex tablet, imprinted with PF on one side and 15 mg on the other, contains: morphine sulfate 15 mg. Nonmedicinal ingredients: cetostearyl alcohol, D&C Yellow #10 aluminum lake, FD&C Blue #1 aluminum lake, hydroxyethyl cellulose, lactose, magnesium stearate, methylcellulose, polyethylene glycol, talc and titanium dioxide. Alcohol-, gluten-, sulfite- and tartrazine-free. Plastic, opaque bottles of 50; blister packs of 25.
30 mg: Each violet, round, sustained-release, film-coated, bi-convex tablet, imprinted with PF on one side and 30 mg on the other, contains: morphine sulfate 30 mg. Nonmedicinal ingredients: cetostearyl alcohol, D&C Red #7 calcium lake, FD&C Blue #1 aluminum lake, hydroxyethyl cellulose, hydroxylpropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, talc and titanium dioxide. Alcohol-, gluten-, sulfite- and tartrazine-free. Plastic, opaque bottles of 50; blister packs of 25.
60 mg: Each orange, round, sustained-release, film-coated, bi-convex tablet, imprinted with PF on one side and 60 mg on the other, contains: morphine sulfate 60 mg. Nonmedicinal ingredients: cetostearyl alcohol, D&C Yellow #10 aluminum lake, FD&C Red #3 aluminum lake, FD&C Yellow #6 aluminum lake, hydroxyethyl cellulose, hydroxylpropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, talc and titanium dioxide. Alcohol-, gluten-, sulfite- and tartrazine-free. Plastic, opaque bottles of 50; blister packs of 25.
100 mg: Each grey, round, sustained-release, film-coated, bi-convex tablet, imprinted with PF on one side and 100 mg on the other, contains: morphine sulfate 100 mg. Nonmedicinal ingredients: cetostearyl alcohol, FD&C Blue #2 aluminum lake, iron oxide, hydroxyethyl cellulose, hydroxylpropyl methylcellulose, magnesium stearate, polyethylene glycol, talc and titanium dioxide. Alcohol-, gluten-, lactose-, sulfite- and tartrazine-free. Plastic, opaque bottles of 50; blister packs of 25.
200 mg: Each red, scored, caplet-shaped, sustained-release, film-coated, bi-convex tablet, imprinted with PF on one side and 200 mg on the other, contains: morphine sulfate 200 mg. Nonmedicinal ingredients: cetostearyl alcohol, FD&C Blue #2,, FD&C Red #3, FD&C Yellow #6 aluminum lake, hydroxyethyl cellulose, hydroxylpropyl methylcellulose, magnesium stearate, polyethylene glycol, talc and titanium dioxide. May be broken in half. Alcohol-, gluten-, lactose-, sulfite- and tartrazine-free. Plastic, opaque bottles of 50; blister packs of 25.
Store tablets and suppositories 15 to 30 °C. The suppositories may also be refrigerated.
MS CONTIN® Purdue Frederick Morphine Sulfate Opioid Analgesic