New Zealand - English - Medsafe (Medicines Safety Authority)
NEW ZEALAND DATA SHEET
1. PRODUCT NAME
Morphine Sulfate Injection BP, 5 mg/mL, solution for injection
Morphine Sulfate Injection BP, 10 mg/mL, solution for injection
Morphine Sulfate Injection BP, 15 mg/mL, solution for injection
Morphine Sulfate Injection BP, 30 mg/mL, solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each mL of DBL Morphine Sulfate Injection BP contains 5, 10, 15, or 30mg of morphine sulfate
pentahydrate. All four strengths are isotonic preparations.
For the full list of excipients, see
3. PHARMACEUTICAL FORM
Solution for injection: clear colourless to slightly yellow, sterile solution.
The pH of these solutions ranges from 3.2 to 4.0.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Morphine sulfate is indicated for the relief of moderate to severe pain not responsive to non-
opioid analgesics. It may also be used as a pre-operative medication and as an analgesic adjunct
in general anaesthesia.
4.2 Dose and method of administration
Note: Opioid antagonists and facilities for administration of oxygen and control of respiration
should be available during, and immediately following parenteral administration.
Subcutaneous, Intramuscular and Slow Intravenous Administration
Morphine sulfate is usually administered by intramuscular or subcutaneous injection,
in the range of 5 to 20 mg, depending on the cause of pain and the patient response. Doses may
be repeated every 4 to 6 hours.
Morphine sulfate may also be given intravenously when a rapid onset of action is desired. The
dose is usually in the range of 2.5 to 15 mg diluted in 4 to 5 mL of Water for Injections given
slowly over 4 to 5 minutes.
Morphine sulfate is given by intramuscular or subcutaneous injection in doses of 0.1
to 0.2 mg/kg bodyweight to a maximum of 15 mg. Injection may be repeated every 4 to 6 hours.
When a rapid onset of action is desirable, in a closely monitored environment, morphine may
be titrated intravenously with caution, in a dose of 0.05 to 0.1 mg/kg, incrementally over 5 to
15 minutes. Repeat intravenous dosing is unsubstantiated as a method of analgesia in children.
Morphine sulfate is not usually given pre-operatively in children under 1 year, and it should be
given with extreme care to neonates. It should not be given to premature infants (see
Continuous Intravenous Infusion
The dosage of morphine should be titrated according to the patient’s analgesic requirements
and previous opiate experience. For the management of acute pain via intravenous infusion,
most adults with no previous history of opioid intake can be continued on 0.5 to 2.0 mg/hour
after adequate analgesia has been established.
In children, an infusion dose of 0.01 to 0.05 mg/kg/hour morphine to a maximum intravenous
dose of 4 mg/hour is recommended.
It is recommended that an opioid antagonist and equipment for artificial ventilation be available.
Patient-Controlled Analgesia (PCA)
Patient-controlled analgesia allows patients to assess their own level of pain and consequently
titrate the amount of morphine they require for adequate pain control against sedation and other
The dosages and time intervals are preset into a microprocessor-controlled infusion pump.
When the patient experiences pain, a button is depressed by the patient and a dose of morphine
is administered intravenously. If the patient should depress the button before the preset time
interval (lockout interval) has elapsed, no extra drug is administered. For adults, demand doses
of 0.5 to a maximum of 1.5 mg morphine have been given via PCA using a lockout interval of
6 to 10 minutes. Along with the self-administered dose of morphine, some syringe pumps also
deliver a background continuous infusion of morphine at a basal rate. If a background infusion
is adopted, a dose of 1 mg/hour morphine is often used in adults. Some PCA pumps allow a
maximum dosage over a defined period to be preset in order to avoid patient overdosage.
There is limited clinical experience of the use of patient-controlled analgesia in children.
However, a demand dose of 0.01 to 0.025 mg/kg morphine has been used successfully in
children and adolescents between the ages of 7 to 19 years with a lockout interval of 6 to 10
minutes. If a background infusion is employed, an infusion dose of 0.015 mg/kg/hour morphine
may be used in children.
The demand dosage and lockout interval should be determined according to the patient’s
analgesic requirements. Patients receiving a background infusion of morphine should generally
receive a smaller demand dose relative to equivalent patients utilising a demand dose only.
Techniques such as PCA with background continuous infusion are associated with a higher rate
of adverse effects and require close monitoring.
General Information for Cancer Pain
When morphine is administered by continuous intravenous or subcutaneous infusion for relief
of severe, chronic pain associated with cancer, the dosage of morphine must be individualised
according to the response and tolerance of the patient. In some patients with exceptionally
severe, chronic pain it may be necessary to exceed the usual dosage. Reduced dosage is
indicated in poor-risk patients, in very young or very old patients, and in patients receiving other
Orally administered morphine should be used in preference to parenteral morphine whenever
adequate pain control can be achieved by this route. However, oral morphine is often
inadequate or impractical in the terminally ill patient.
Patients being converted from oral morphine to either intramuscular (IM), intravenous (IV) or
subcutaneous (SC) morphine require dosage reduction (about one-sixth), since about 60% of
oral morphine is metabolised in first-pass metabolism (i.e. 1 mg of either IM, SC or IV
morphine for every 6 mg of oral morphine). The dose should then be titrated according to the
patient’s clinical response.
For cancer pain, DBL Morphine Sulfate Injection BP should be given regularly around the
clock, in most instances every 4 hours. The basis of pain control with DBL Morphine Sulfate
Injection BP should be regular scheduling rather than on an ‘as required’ or PRN narcotic order.
Patients requiring high doses of morphine usually need to be awakened for medication during
the night to prevent morning pain.
Morphine Dosage Increase
Dosage increases for intravenous, subcutaneous or intramuscular administration of morphine
should not be made more frequently than every 24 hours, since it will take approximately 4 to
5 morphine half-lives to attain a new steady state concentration in a patient with normal liver
and kidney function.
Following all dosage increases, the patient must be monitored closely for side-effects, the most
common being sedation, nausea, vomiting, constipation and hypotension.
Morphine sulfate is contraindicated in the following situations:
patients with known hypersensitivity to morphine or other opioids
with acute or severe bronchial asthma or other obstructive airways disease
respiratory insufficiency or depression, especially in the presence of cyanosis and/or
excessive bronchial secretion
other conditions where respiratory reserve is depleted, such as severe emphysema, chronic
bronchitis or kyphoscoliosis
severe CNS depression
diabetic acidosis where there is a danger of coma
severe liver disease or incipient hepatic encephalopathy
following biliary tract surgery or surgical anastomosis
suspected surgical abdomen
in patients who are taking or who have taken MAO inhibitors within the previous fourteen
heart failure secondary to pulmonary disease
acute alcoholism or delirium tremens
raised intracranial or cerebrospinal pressure and in convulsive states such as status
epilepticus, tetanus or strychnine poisoning (see
Morphine is contraindicated in premature infants or during labour for delivery of premature
The administration of morphine via patient-controlled analgesia to children less than six years
of age and adults with poor cognitive function is contraindicated.
The continuous intravenous infusion of morphine in patients with hepatic or renal disease is
4.4 Special warnings and precautions for use
Therapy should only be initiated by a specialist with experience in chronic pain management
and in accordance with guidelines approved by the New Zealand Medical Association.
Large doses and/or rapid administration of morphine may produce rapid onset of respiratory
depression including central sleep apnoea (CSA) and sleep-related hypoxemia, bradycardia, or
even cardiac arrest.
Morphine delays gastric emptying, which may be expected to increase the risks of aspiration,
either associated with morphine induced CNS depression or coma, or during or after general
Profound sedation, respiratory depression, coma, and death may result from the concomitant
use of morphine with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine
medicines with antihistamine-sedating actions such as antipsychotics, other opioids, alcohol).
Because of these risks, reserve concomitant prescribing of these drugs for use in patients for
whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and
benzodiazepines increases the risk of medicine-related mortality compared to use of opioid
analgesics alone. Because of similar pharmacological properties, it is reasonable to expect
similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly
with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of
concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose
of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and
titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a
benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic,
and titrate based on clinical response. Follow patients closely for signs and symptoms of
respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when
morphine is used with benzodiazepines or other CNS depressants (including alcohol and illicit
drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant
use of the benzodiazepine or other CNS depressant have been determined. Screen patients for
risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk
for overdose and death associated with the use of additional CNS depressants including alcohol
and illicit drugs (see
). If respiratory depression of any form occurs, consider
decreasing the opioid dosage using best practices for opioid taper.
Drug Dependence and Tolerance
Morphine can produce drug dependence and therefore has the potential for being abused.
Psychological dependence, physical dependence, and tolerance may develop upon repeated
administration of morphine. However it should be noted that clinically significant respiratory
depression, addiction, rapid tolerance and euphoria rarely develop when doses of morphine are
carefully titrated against the pain in patients with terminal disease and severe pain.
Drug dependence does not develop if morphine is administered regularly at individually
optimised doses to the cancer patient with moderate to severe pain. While a certain degree of
physical dependence occurs, a psychological dependence does not occur. If a cancer patient no
longer requires an opioid for pain control, a gradual reduction in dose will prevent any
discontinuance. Clinically significant tolerance to morphine is unusual in the cancer patient
being treated for severe pain. In most cases, a plateauing of dose requirements is seen, as a
need to increase morphine dose means an increase in pain and not tolerance.
Withdrawal of morphine should be undertaken gradually, as abrupt withdrawal in patients who
are physically dependent may precipitate an acute withdrawal syndrome, including convulsions.
Use with Other CNS Depressants
Morphine should be used with caution and in reduced dosage in patients who are concurrently
receiving other opioid analgesics, general anaesthetics, phenothiazines, other tranquillisers,
sedative hypnotics, tricyclic antidepressants, and other CNS depressants (including alcohol).
Respiratory depression, hypotension and profound sedation or coma may result.
The respiratory depressant effects of morphine and its capacity to elevate cerebrospinal fluid
pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions,
or a pre-existing increase in intracranial pressure. Furthermore, opioids produce adverse
reactions, including confusion, miosis and vomiting, which may obscure the clinical course of
patients with head injuries. Morphine should only be used in such patients with extreme
caution, and only if it is judged to be essential.
Respiratory depression is the chief hazard of all morphine preparations. Respiratory depression
occurs most frequently in elderly and debilitated patients, and in those suffering from conditions
significantly decrease pulmonary ventilation. Morphine should be used with extreme caution
in patients having a substantially decreased respiratory reserve, and patients with pre-existing
respiratory depression, hypoxia or hypercapnia. In such patients, even the usual therapeutic
doses of morphine may decrease respiratory drive while simultaneously increasing airways
resistance to the point of apnoea (see
The development of serotonin syndrome (SS), which is potentially life-threatening, has been
reported with opioid use, including with morphine. These reports generally occurred when
morphine was used concomitantly with serotonergic drugs (see Section 4.5 Interactions with
Other Medicines). Signs of SS may include clonus, agitation, diaphoresis, tremor, hyperreflexia,
hypertonia and temperature elevation.
Cases of adrenal insufficiency have been reported with opioid use. Presentation of adrenal
insufficiency may include non-specific symptoms and signs including nausea, vomiting,
anorexia, fatigue, weakness, dizziness, and low blood pressure.
The administration of morphine may result in severe hypotension in the post-operative patient
or any individual whose ability to maintain blood pressure has been compromised by a depleted
blood volume, shock, or the administration of such drugs as the phenothiazines or certain
Morphine may produce orthostatic hypotension in ambulatory patients.
Because of possible vagolytic action that may produce a significant increase in the ventricular
response rate, morphine should be used with caution in patients with atrial flutter and other
Acute Abdominal Condition
The administration of morphine or other opioids may obscure the diagnosis or clinical course
in patients with acute abdominal conditions. Morphine should be used with caution in patients
with inflammatory or obstructive bowel disorders, or with ulcerative colitis, and should only be
used when necessary in patients with acute pancreatitis.
Morphine may aggravate pre-existing convulsions in patients with convulsive disorders. If
dosage is escalated substantially above recommended levels because of tolerance development,
convulsions may occur in individuals without a history of convulsive disorders.
Other Special Risk Patients
Morphine should be given with caution, and in reduced dosages, to certain patients, such as the
stricture. Caution should also be observed if morphine is administered to patients with toxic
psychosis or myasthenia gravis. Morphine should be used with extreme caution in patients with
disorders characterised by hypoxia, since even usual therapeutic doses of opioids may decrease
respiratory drive to the point of apnoea while simultaneously increasing airway resistance.
Renal or Hepatic Disease
Morphine may have a prolonged duration and cumulative effect in patients with kidney or liver
dysfunction. In these patients, analgesia may last for 6, 8 or even up to 24 hours following a
standard dose. Continuous infusions are contraindicated in these patients (see
Caution should be observed when morphine is administered to patients with impaired renal
function, as the pharmacologically active metabolite, morphine-6-glucuronide, may accumulate
in these patients. This may lead to CNS and respiratory depression.
In patients with shock, impaired perfusion may prevent complete absorption following
subcutaneous or intramuscular injection of morphine. Repeated administration may result in
overdosage due to an excessive amount of morphine suddenly being absorbed when circulation
Safety and efficacy of morphine in neonates have not been established. However, neonates
have an enhanced susceptibility to the respiratory depressant effects of morphine. Morphine
should not be administered to premature infants (see
4.4 – Other Special Risk Patients
Renal or Hepatic Disease
Morphine should be administered with caution and in reduced dosages to elderly or debilitated
pharmacodynamics of morphine are more variable in geriatric patients than in younger adults.
Therefore, initial dosage should be selected carefully based on clinical assessment of response
to test doses and consideration of the patient’s age and ability to clear the drug.
Effect on Laboratory Tests
Morphine delays gastric emptying, thereby invalidating test results in gastric emptying studies.
Morphine may constrict the sphincter of Oddi and increase biliary tract pressure, preventing
delivery of Tc
disofenin to the small bowel. These actions result in delayed visualisation,
and thus resemble obstruction of the common bile duct.
4.5 Interaction with other medicines and other forms of interaction
Acidifying agents generally increase the clearance of morphine, thus antagonising its effects,
while alkalising agents decrease clearance and so potentiate the effects of morphine.
Morphine should be used with great caution and in reduced dosage in
patients concurrently receiving other central nervous system depressants including other
opioids, sedatives, hypnotics, general anaesthetics, phenothiazines, other tranquillisers and
alcohol because of the risk of respiratory depression, hypotension and profound sedation or
coma. When such combined therapy is contemplated, the dose of one or both agents should be
Benzodiazepines and other Central Nervous System (CNS) Depressants
increases the risk of respiratory depression, profound sedation, coma,
Reserve concomitant prescribing of these drugs for use in patients for
whom alternative treatment options are inadequate. Limit dosages
and durations to the minimum required. Follow patients closely for
signs of respiratory depression and sedation (see
antihistamine-sedating actions such as antipsychotics, other opioids,
Significant impairment of motor function has also been noted following concomitant morphine
administration and alcohol ingestion.
Concurrent administration with tricyclic antidepressants or beta-blockers may enhance the CNS
depressant effects of morphine.
Diazepam, when used following high doses of morphine, exacerbates the hypotensive effects
produced by morphine, and is associated with reduced plasma catecholamine levels.
Concurrent administration of morphine may increase the hypotensive
effects of antihypertensive agents or other drugs with hypotensive effects.
Morphine may enhance the neuromuscular blocking action of skeletal
muscle relaxants and produce an increased degree of respiratory depression.
agonist/antagonist opioid analgesics (e.g., pentazocine and 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/antagonist analgesics may reduce the
analgesic effect or may precipitate withdrawal symptoms.
Monoamine Oxidase Inhibitors (MAOIs):
MAOIs intensify the effects of morphine and other
opioid drugs which can cause anxiety, confusion, and significant depression of respiration,
sometimes leading to coma. Morphine should not be given to patients taking MAOIs or within
14 days of stopping such treatment. It is unknown whether there is an interaction between the
new selective MAOIs (e.g., moclobemide and selegiline) and morphine. Therefore, caution is
advised with such drug combinations.
Cimetidine and Other H2 Receptor Antagonists:
There is a report of confusion and severe
A potentially lethal interaction between cimetidine and morphine, in which the patient exhibited
apnoea, a significantly reduced respiratory rate and suffered a grand mal seizure, has been
reported. Administration of naloxone increased the respiratory rate; however, confusion,
disorientation, generalised twitching and periods of apnoea persisted for 80 hours. Confusion
has also been associated with concomitant use of ranitidine and morphine.
Morphine reduces the efficacy of diuretics by inducing the release of antidiuretic
hormone. Morphine may also lead to acute retention of urine by causing spasm of the sphincter
of the bladder, particularly in men with prostatism.
The analgesic effect of morphine is potentiated by chlorpromazine.
Dexamphetamine and other amphetamines may enhance the analgesic effects
and decrease the sedation and lack of alertness caused by morphine.
Morphine may potentiate the anticoagulant activity of coumarin anticoagulant
Morphine may antagonise the effects of metoclopramide on gastrointestinal
motility. Intravenous metoclopramide antagonises the effects of morphine on gastric emptying.
Morphine may alter the metabolism of zidovudine, by competitively inhibiting
glucuronidation or directly inhibiting hepatic
microsomal metabolism. Zidovudine and
morphine should therefore not be administered concurrently, because the toxicity of either or
both of these drugs may be increased.
Ritonavir may increase the activity of glucuronyl transferases and co-administration
with morphine may result in decreased morphine serum levels and possible loss of analgesic
Morphine delays gastric emptying, so may affect the absorption of orally
administered drugs. For example, morphine delays the absorption of paracetamol and
Concurrent administration of morphine and anticholinergic agents or
other drugs with anticholinergic activity may increase the risk of severe constipation; this may
lead to paralytic ileus and/or urinary retention.
Concurrent administration of morphine and antidiarrhoeal agents with
antiperistaltic actions may increase the risk of severe constipation and CNS depression.
Naloxone antagonises the analgesic, CNS and respiratory depressive
effects of morphine, and may precipitate withdrawal in patients who are physically dependent
Naltrexone blocks the therapeutic effects of opioids, so should be discontinued several days
prior to elective surgery if administration prior to, during, or following surgery is unavoidable.
Administration of naltrexone to a patient who is physically dependent on morphine will
precipitate withdrawal symptoms.
Clinical Impact: The co-administration of oral P2Y
inhibitors and morphine can decrease the
absorption and peak concentration of oral P2Y
inhibitors and delay the onset of the antiplatelet
Intervention: Consider the use of a parenteral antiplatelet agent in the setting of acute coronary
syndrome requiring co-administration of morphine.
Examples of P2Y
inhibitors include but are not limited to: clopidogrel, prasugrel, ticagrelor.
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter
system has resulted in serotonin syndrome. Drugs that affect the serotonergic neurotransmitter
system include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine
antagonists, and monoamine oxidase inhibitors (MAOIs).
4.6 Fertility, pregnancy and lactation
Effects on Fertility
Prolonged use of opioids may result in impairment of reproductive function, including fertility
and sexual dysfunction in both sexes, and irregular menses in women.
Use in Pregnancy - Category C
Morphine has been associated with foetal CNS defects in rodent studies. It is not known
whether morphine can cause foetal harm in humans when administered during pregnancy.
Pregnant patients should only be given morphine when the benefits clearly outweigh potential
risks to the foetus.
Long term use of morphine during pregnancy may result in a neonatal opioid withdrawal state.
Babies born to mothers who are physically dependent on morphine may also be physically
dependent on the drug.
Use in Labour/Delivery
Morphine is not recommended for use in women during and immediately before labour. The
effects of opioid analgesics are unpredictable. They may prolong labour by temporarily
reducing the strength, duration and frequency of uterine contractions, or conversely they may
tend to shorten labour by increasing the rate of cervical dilatation.
Morphine crosses the placenta, and can produce respiratory depression in the neonate if it is
administered during labour. Infants born to mothers receiving opioid analgesics during labour
should be observed closely for signs of respiratory depression. In such infants, a specific opioid
Use in Lactation
Morphine is excreted in human milk and breast-feeding is not recommended while a patient is
receiving morphine. Withdrawal symptoms have been observed in breast-fed infants when
maternal administration of morphine sulfate is stopped.
4.7 Effects on ability to drive and use machines
Occupational hazards: Morphine may impair the mental and/or physical abilities required for
the performance of potentially hazardous tasks, such as driving a car or operating machinery.
Morphine in combination with other opioid analgesics, phenothiazines, sedative-hypnotics and
alcohol have additive depressant effects. Patients should be cautioned accordingly.
4.8 Undesirable effects
The adverse reactions caused by morphine are essentially the same as those observed with other
opioid analgesics. They include the following major hazards: respiratory depression, apnoea
and to a lesser degree circulatory depression, respiratory arrest, shock and cardiac arrest.
Most Common Adverse Effects:
Constipation, light-headedness, dizziness, sedation, nausea,
vomiting, sweating, dysphoria and euphoria.
Most patients receiving morphine will experience initial drowsiness. This usually
disappears in three to five days and is not a cause for concern unless it is excessive, or
accompanied with unsteadiness or confusion. Excessive or persistent sedation should be
investigated. Factors to be considered should include: concurrent sedative medications, the
presence of hepatic or renal insufficiency, exacerbated respiratory failure, tolerance to the dose
used, especially in older patients, disease severity and the patient’s general condition. If the
dose of morphine has been reduced and pain is not adequately controlled, the dose may be
carefully increased again after a few days.
Dizziness and unsteadiness may be associated with morphine-induced postural hypotension
particularly in elderly or debilitated patients. The dosage should be adjusted according to
individual needs but, because of reduced clearance, dosage may be lower in patients over 50
years of age.
Nausea and Vomiting:
Nausea and vomiting are common after single doses of morphine or as
an early undesirable effect of regular opioid therapy. The prescription of a suitable antiemetic
should be considered. The frequency of nausea and vomiting usually decreases within a week
or so but may persist due to opioid-induced gastric stasis. Metoclopramide is often useful in
Virtually all patients suffer from constipation while taking opioids on a chronic
basis. Some patients, particularly elderly, debilitated or bedridden patients, may become
impacted. Patients must be cautioned accordingly and laxatives, softeners and other appropriate
treatments should be initiated at the beginning of opioid therapy.
Other Adverse Reactions Include:
Flushing of the face, chills, tachycardia, bradycardia, palpitations, faintness,
syncope, hypotension and hypertension.
Central Nervous System:
Euphoria, dysphoria, weakness, headache, restlessness, anxiety,
agitation, tremor, uncoordinated muscle movements, insomnia, dizziness, vertigo, delirium,
confusional symptoms, occasionally hallucinations, allodynia and hyperalgesia.
alterations and biliary tract cramps and biliary spasm.
Urinary retention or hesitancy, ureteric spasm, reduced libido or potency,
amenorrhoea, erectile dysfunction and hypogonadism.
A syndrome of inappropriate antidiuretic hormone secretion characterised by
electrolytes may be necessary). Morphine stimulates prolactin release, and may also cause
Blurred vision, nystagmus, diplopia and miosis.
Pruritis, urticaria, other skin rashes including contact dermatitis, and oedema.
Allergic reactions may be due to histamine release, and may be more frequent in asthmatic
patients. Anaphylactic reactions following intravenous injection have been reported rarely.
subcutaneous injection, particularly when repeated.
Physical dependence and tolerance may develop with long term use
Withdrawal (Abstinence) Syndrome:
Chronic use of opioid analgesics may be associated with
the development of physical dependence, with or without psychological dependence. An
abstinence syndrome may be precipitated when opioid administration is suddenly discontinued
or opioid antagonists administered.
Withdrawal symptoms that may be observed after discontinuation of opioid use include; body
aches, diarrhoea, piloerection, anorexia, nervousness or restlessness, rhinorrhoea, sneezing,
tremors or shivering, abdominal colic, nausea, sleep disturbance, unusual increase in sweating
and yawning, weakness, tachycardia and unexplained fever. With appropriate dose adjustments
and gradual withdrawal these symptoms are usually mild.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows
continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are
asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.
Overdosage with morphine is characterised by respiratory depression (a decrease in respiratory
progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes
bradycardia and hypotension. In severe overdosage, apnoea, circulatory collapse, cardiac arrest
and death may occur.
Immediate attention should be given to the re-establishment of adequate respiratory exchange
through provision of a patient airway and institution of assisted or controlled ventilation.
In patients physically dependent on opioids, respiratory support is the first line of treatment. In
these patients, the use of naloxone is potentially dangerous.
Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed
The opioid antagonist, naloxone, is a specific antidote against respiratory depression which may
result from overdosage or unusual sensitivity to opioids. The recommended adult dose of
naloxone for the treatment of severe opiate induced respiratory depression is 0.4 to 2 mg
intravenously every 2 to 3 minutes as necessary, simultaneously with assisted respiration.
For children, the initial dose recommended is 0.01 mg/kg naloxone. A response should be seen
after 2 to 3 doses. Note the duration of action of naloxone is usually shorter than that of
morphine and thus the patient should be carefully observed for signs of CNS depression
If the response to naloxone is suboptimal or not sustained, additional naloxone may be
administered as needed, or given by continuous intravenous infusion to maintain alertness and
respiratory function. There is no information available about the cumulative dose of naloxone
that may be safely administered.
Naloxone should not be administered in the absence of clinically significant respiratory or
circulatory depression secondary to morphine overdosage.
Naloxone should be administered cautiously to persons who are known or suspected to be
physically dependent on morphine. In such cases, an abrupt or complete reversal of opioid
effects may precipitate an acute withdrawal syndrome. The severity of the withdrawal
syndrome produced will depend on the degree of physical dependence and the dose of the
antagonist administered. If it is necessary to treat serious respiratory depression in the
physically dependent patient, the antagonist should be administered with extreme care and by
titration with smaller than usual doses of the antagonist.
Morphine toxicity may be a result of overdosage but because of the large inter-individual
variation in sensitivity to opioids, it is difficult to assess the exact dose of any opioid that is
toxic or lethal. The toxic effects of morphine tend to be overshadowed by the presence of pain
or tolerance. Patients having chronic morphine therapy have been known to take in excess of
3,000 mg/day with no apparent toxic effects being present.
For advice on the management of overdose please contact the National Poisons Centre on 0800
POISON (0800 764766).
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Morphine is the principal alkaloid of opium. Morphine acts as an agonist, binding to receptors
in the brain, spinal cord and other tissues. These sites have been classified as
concentration in the limbic system.
Morphine exerts its primary effects in the central nervous system and organs containing smooth
Morphine produces many effects, including analgesia, decreased gastrointestinal motility,
respiratory depression, drowsiness, changes in mood and alterations of the endocrine and
autonomic nervous systems.
Nausea and vomiting may occur through direct stimulation of the chemoreceptor trigger zone
Urinary retention may occur due to increased bladder sphincter tone.
5.2 Pharmacokinetic properties
Absorption of morphine sulfate after intramuscular and subcutaneous injection is fairly rapid
with peak analgesia occurring 30 to 60 minutes and 50 to 90 minutes after injection via the
respective routes. Peak analgesia occurs within 20 minutes after intravenous administration.
Morphine is distributed throughout the body, but particularly to parenchymatous tissue such as
kidney, lung, liver and spleen. Lower concentrations are found in skeletal muscle and brain
tissue. Morphine diffuses across the placenta and trace amounts are found in sweat and breast
milk. About 35% is protein bound, mainly to albumin.
Morphine is metabolised principally in the liver by conjugation with glucuronic acid. The
principal metabolites are morphine-3-glucuronide and morphine-6-glucuronide. Morphine-6-
glucuronide is pharmacologically active and has a half-life somewhat longer than morphine.
Elimination half-life from serum is approximately 1.5 to 2 hours in healthy subjects and 90%
of the dose is recovered in urine within 24 hours. Approximately 7 to 10% of the dose is
recovered in faeces, the majority after conjugation and excretion via bile.
Chinese subjects given intravenous morphine have a higher rate of clearance when compared
to white subjects (1852 + 116 mL/min versus 1495 + 80 mL/min) because of an increase in the
partial metabolic clearance by glucuronidation.
– Paediatric Use and
section 4.2 Dose and method of administration
In older patients, the volume of distribution is considerably smaller and initial concentrations
of morphine are correspondingly higher. See also
– Other Special Risk Patients and
– Renal or Hepatic Disease.
5.3 Preclinical safety data
The carcinogenic or mutagenic potential of morphine has not been established.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Water for injections
1N hydrochloric acid (for pH adjustment)
The solution does not contain any antioxidant or preservative.
A solution of thiopentone and morphine forms an inactive preparation.
6.3 Shelf life
The shelf life of unopened DBL Morphine Sulfate Injection BP ampoules is 24 months for the
5 mg/mL and 30 mg/mL presentations, and 30 months for the 10 mg/mL and 15 mg/mL
6.4 Special precautions for storage
Store at or below 25°C. Protect from light.
DBL Morphine Sulfate Injection BP should be used within 24 hours of opening, in order to
avoid the risk of microbial contamination.
As with all parenteral drug products, intravenous admixtures should be visually
inspected for clarity, particulate matter, precipitate and leakage prior to administration,
whenever solution and container permit. Solutions showing haziness, particulate matter,
precipitate or leakage should not be used. Development of a yellow colour in morphine
solutions does not indicate toxicity or loss of potency or efficacy.
6.5 Nature and contents of container
DBL Morphine Sulfate Injection BP ampoules are available as follows:
5 and 50
5 and 50
5 and 50
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Contains no antimicrobial agent. Product is for single use in one patient only. Discard any
No special requirements for disposal. Any unused medicinal product or waste material should
be disposed of in accordance with local requirements.
7. MEDICINE SCHEDULE
Class B1 Controlled Drug
Pfizer New Zealand Limited
PO Box 3998
Auckland, New Zealand
Toll Free Number: 0800 736 363
9. DATE OF FIRST APPROVAL
28 April 1983
10. DATE OF REVISION OF THE TEXT
15 November 2019
SUMMARY TABLE OF CHANGES
Summary of new information
Inclusion of central sleep apnoea (CSA) and sleep-related hypoxemia.
Inclusion of endocrine effects and serotonin syndrome including signs
Addition of interaction with P2Y12 inhibitors and serotonergic drugs.
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