Action And Clinical Pharmacology: Morphine is a narcotic analgesic which acts as an agonist at stereospecific and saturable opioid receptors in the CNS and other tissues.
In man, morphine produces a variety of effects including analgesia, sedation, changes in mood including euphoria and dysphoria, mental clouding, respiratory depression from reduced responsiveness of the brain stem respiratory centres to CO2, suppression of the cough reflex, constipation from decreased gastrointestinal activity, nausea and vomiting via stimulation of the chemoreceptor trigger zone (CTZ), alterations of the endocrine and autonomic nervous system.
Morphine is readily absorbed from the gastrointestinal tract following oral administration. Approximately 40% of the administered dose reaches the central compartment because of presystemic elimination (i.e., metabolism in the gut wall and liver). With repeated regular dosing, oral morphine is about one third as potent as when given by i.m. injection.
Virtually all morphine is converted to glucuronide metabolites, particularly morphine-3-glucuronide. 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.
At steady-state, Oramorph SR tablets produce peak morphine levels approximately 4 to 5 hours post-dose and therapeutic levels tend to persist for a 12 hour period. Steady-state is achieved after about 1 day on a fixed dosing regimen.
Indications And Clinical Uses: For the relief of moderate to severe chronic pain in patients who require prolonged dosing with an oral narcotic preparation.
Contra-Indications: Should not be given to patients with: hypersensitivity to opiate narcotics; respiratory depression; acute bronchial asthma or other chronic, obstructive pulmonary diseases or chronic 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; biliary tract surgery; concomitantly with MAO inhibitors (or within 14 days of such therapy).
Manufacturers’ Warnings In Clinical States: Drug Dependence and Abuse: As with other narcotics, morphine may cause physical dependence and tolerance following repeated administration, and there is potential for the development of strong psychological dependence and drug abuse. Morphine should therefore be prescribed and handled with a 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 where morphine is appropriately indicated. On the other hand, in the absence of a clear indication for a strong narcotic analgesic, drug-seeking behavior must be suspected and resisted, particularly in individuals with a history of, or propensity for, drug abuse.
Withdrawal Syndrome: A moderate to severe abstinence syndrome may occur in patients who abruptly discontinue morphine therapy or it may be precipitated through the administration of drugs with narcotic antagonist activity, e.g., naloxone or mixed agonist/antagonist analgesics (pentazocine, etc.). Patients on prolonged therapy who no longer require morphine for pain control should be withdrawn gradually from the drug.
Morphine should be used with caution and in reduced dosage during the concomitant use of other CNS depressants including sedatives or hypnotics, general anesthetics, phenothiazines and other tranquilizers, tricyclic antidepressants and alcohol as these may produce additive depressant effects. Respiratory depression, hypotension and profound sedation or coma may occur. Opioid analgesics, including morphine, may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
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 within 24 hours of the procedure.
Pregnancy: Studies of morphine in animals to evaluate the drug’s effect on reproduction have not been conducted.
There are no well-controlled studies in pregnant women and it is not known whether morphine can cause fetal harm when administered during pregnancy. Morphine should be given to pregnant patients only if clearly needed and if the anticipated benefits outweigh the risks to the fetus (see Precautions).
Precautions: General: As with any potent opioid, it is critical to adjust the dosing regimen for each patient individually, taking into account the patients prior analgesic treatment experience.
Respiratory depression is the major hazard of all morphine preparations and they should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of morphine may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.
The respiratory depressant effects of morphine with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. Morphine produces effects which may obscure neurologic signs of further increases in pressure in patients with head injuries. In such patients, morphine must be used with extreme caution and only if it is judged essential. Morphine may aggravate pre-existing convulsions in patients with convulsive disorders.
Morphine, like all opioid analgesics, may cause severe hypotension in individuals whose ability to maintain their blood pressure has already been compromised by a depleted blood volume, or a concurrent administration of drugs such as phenothiazines or general anesthetics. It should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.
The administration of morphine may obscure the diagnosis or clinical course in patients with acute abdominal conditions. 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.
Drug Interactions: In general, 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. MAO inhibitors (including procarbazine hydrochloride), pyrazolidone antihistamines, beta-blockers and alcohol may also enhance the depressant effect of morphine.
Agonist/antagonist opioid analgesics (i.e., pentazocine, nalbuphine, butorphanol or buprenorphine) should not be administered to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic. In these patients, mixed agonist-antagonists may reduce the analgesic effect or may precipitate withdrawal symptoms.
Morphine may increase the anticoagulant activity of coumarin and other anticoagulants.
Special Risk Groups: Morphine should be administered with caution and in reduced dosages in the following populations: the elderly or debilitated and those with severe impairment of hepatic, pulmonary or renal function; myxoedema or hypothyroidism; adrenocortical insufficiency (e.g., Addison’s Disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; kyphoscoliosis, or inability to swallow.
Labor and Delivery: Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation which tends to shorten labor.
Morphine crosses the placental barrier and its administration during labor can produce respiratory depression in the neonate.
Neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression. A specific narcotic antagonist, naloxone, should be available for reversal of narcotic-induced respiratory depression in the neonate.
Lactation: Low levels of morphine have been detected in human milk. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of morphine is stopped. Caution should therefore be exercised if morphine is administered to a nursing mother.
Children: The safety and effectiveness of morphine have not been evaluated in children.
Occupational Hazards: Driving and Operating Dangerous Machinery: 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.
Adverse Reactions: The adverse reactions caused by morphine are essentially those observed with other opioid analgesics. The major hazards associated with morphine, as with other narcotic 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 Reactions Requiring Medical Attention: The most frequently observed side effects of narcotic 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 dose in the younger age group.
Nausea and Vomiting: Nausea and vomiting occur frequently after single doses of narcotics 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 a single dose of 20 mg or more of morphine (60 mg every 12 hours of Oramorph SR) 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 narcotic-induced gastric stasis. In such patients, metoclopramide is often useful.
Constipation: Practically all patients become constipated while taking narcotics 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 narcotic therapy. Softeners, laxatives and other appropriate measures should be used as required.
Less frequently observed side effects include: CNS: weakness, headache, agitation, tremor, uncoordinated muscle movements, seizure, alterations of mood (nervousness, apprehension, depression, floating feeling), dreams, muscle rigidity, transient hallucinations and disorientation, visual disturbances, insomnia and increased intracranial pressure.
Gastrointestinal: dry mouth, constipation, biliary tract spasm, laryngospasm, anorexia, diarrhea, cramps, and taste alterations.
Cardiovascular: supraventricular tachycardia, bradycardia, palpitations, faintness, syncope, postural hypotension and hypertension.
Genitourinary: urinary retention or hesitancy, reduced libido or potency.
Dermatologic: pruritus, urticaria, other skin rashes, edema and diaphoresis.
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).
Other: paresthesia, muscle tremor, blurred vision, nystagmus, diplopia and miosis.
Withdrawal (Abstinence) Syndrome: Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug or withdrawal symptoms may be precipitated through the administration of narcotic antagonist drugs. The abstinence syndrome is characterized by some or all of the following; restlessness, lacrimation, rhinorrhea, yawning, perspiration, gooseflesh, restless sleep and mydriasis during the first 24 hours. These symptoms often increase in severity and over the next 72 hours may be accompanied by increasing irritability, anxiety, weakness, twitching and spasms of muscles; kicking movements; severe backache, abdominal and leg pains; abdominal and muscle cramps, hot and cold flashes, insomnia, nausea, anorexia, vomiting, intestinal spasm, diarrhea, coryza and repetitive sneezing; increase in body temperature, blood pressure, respiratory rate and heart rate. Because of excessive loss of fluids through sweating, vomiting and diarrhea, there is usually marked weight loss, dehydration, ketosis, and disturbances in acid-base balance. Cardiovascular collapse can occur. Without treatment most observable symptoms disappear in 5 to 14 days; however, there appears to be a phase of secondary or chronic abstinence which may last for 2 to 6 months characterized by insomnia, irritability and muscular aches. If treatment of physical dependence of patients on morphine is necessary, the patient may be detoxified by gradual reduction of the dosage. Gastrointestinal disturbances or dehydration should be treated accordingly.
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, skeletal muscle flaccidity, 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 narcotic 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 extended release formulations, may excced 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 narcotics, the administration of the usual dose of narcotic 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 narcotic antagonists in such individuals should be avoided if possible. If a narcotic 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: As with any potent opioid product, the administration and dosing of morphine should be individualized for each patient taking into account the following: the properties of morphine; the nature and severity of the pain or pains experienced; the general condition and medical status of the patient; daily dose and potency of opioids or other medication given previously or concurrently and the degree of opioid tolerance, if any.
As with other strong narcotic 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 narcotics 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.
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.
For essential information on the important details of the management of cancer pain, the reader may wish to consult the following resources:
Cancer Pain: A Monograph on the management of cancer pain. Health and Welfare Canada.
Twycross, R.G. and Lack, S.A. Symptom control in far advanced cancer: Pain relief.
The following dosing recommendations, therefore, can only be considered suggested approaches to what is actually a series of clinical decisions in the management of the pain of an individual patient.
Conversion from Conventional Oral Morphine to Oramorph SR: Patients currently receiving an immediate release oral morphine product (every 4 to 6 hours) may be transferred to Oramorph SR at the same total daily morphine dosage equally divided into two 12 hourly Oramorph SR doses.
For initial conversion, the 30 mg tablet strength is recommended for patients with a daily morphine requirement of 120 mg or less.
Conversion from Parenteral Morphine or Other Opioids (Parenteral or Oral) to Oramorph SR: For patients who are receiving an alternate narcotic, the “oral morphine sulfate equivalent” of the analgesic presently being used should be determined (see Table I).
On the basis of standard equivalence tables, a 1:2 or 1:3 ratio of parenteral to oral morphine equivalence is suggested. The total daily oral morphine dosage should then be equally divided into two 12 hourly Oramorph SR doses.
Estimates of the relative potency of opioids are only approximate and are influenced by route of administration, individual patient differences, and possibly, by an individual’s medical condition. Consequently, it is difficult to recommend any fixed rule for converting a patient to Oramorph SR directly. In patients whose daily morphine requirements are expected to be less than or equal to 120 mg/day, the 30 mg tablet strength is recommended for the initial titration period. Once a stable dose regimen is reached, the patient can be converted to the 60 mg or 100 mg tablet strength, as appropriate.
Use of Oramorph SR as the First Opioid Analgesic: There has been no systematic evaluation of Oramorph SR as an initial opioid analgesic in the management of pain. Because it may be more difficult to titrate a patient using extended release morphine, it is ordinarily advisable to begin treatment using an immediate-release formulation.
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 may be justified in some patients to cover periods of physical activity.
Adjustment in dose should not be attempted by breaking or crushing the tablets. Therefore, in patients with low daily morphine requirements, precise titration may be difficult because the smallest available tablet of Oramorph SR contains 30 mg of morphine. The usual recommended dose (every 12 hours) increments are 15, 30, 45, 60, 90, 120, 150, 180, 200 mg. Above the 200 mg/dose (400 mg/day) increments should be by 30 to 60 mg/dose. Because of the extended release properties of Oramorph SR, dosage adjustments should generally be separated by 48 hours.
Oramorph SR tablets 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, Oramorph SR may be administered every 8 hours. More frequent (than every 8 hours) administration of Oramorph SR is not recommended. Alternatively, a supplemental dose of a short-acting analgesic may be given.
In adjusting dose requirements, it is recommended that the dosing interval never be extended beyond 12 hours because the administration of very large single doses may lead to acute overdose.
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 symptoms of confusion, and that 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 of the narcotic analgesic may become feasible due to a change in the patient’s condition or improved mental state.
Narcotic 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 is usually not narcotic-responsive.
Availability And Storage: 30 mg: Each off-white compressed biconvex extended release tablet with “30” debossed on one side and product identification “54/090” debossed on the other side, contains: morphine sulfate 30 mg. Nonmedicinal ingredients: colloidal silicon dioxide, hydroxypropyl methylcellulose, lactose and stearic acid. Unit dose, cards of 25; cartons of 4. Opaque plastic bottles of 50.
60 mg: Each off-white compressed biconvex extended release tablet with “60” debossed on one side and product identification “54/933” debossed on the other side, contains: morphine sulfate 60 mg. Nonmedicinal ingredients: colloidal silicon dioxide, hydroxypropyl methylcellulose, lactose and stearic acid. Unit dose, cards of 25; cartons of 4. Opaque plastic bottles of 100.
100 mg: Each off-white compressed biconvex extended release tablet with “100” debossed on one side and product identification “54/862” debossed on the other side, contains: morphine sulfate 100 mg. Nonmedicinal ingredients: colloidal silicon dioxide, hydroxypropyl methylcellulose, lactose and stearic acid. Unit dose, cards of 25; cartons of 4. Opaque plastic bottles of 100.
The tablets should be swallowed intact, not chewed or crushed. Store at 15 to 30°C. Protect from moisture.
ORAMORPH SR Boehringer Ingelheim Morphine Sulfate Narcotic Analgesic