Morphine

Registered South African indications:

• Relief of severe pain

Registered South African contraindications

Oral (srt)

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Acute hepatic disease
• Phaeochromocytoma
• Respiratory depression
• Obstructive airways disease
• Acute alcoholism
• Head injuries
• Conditions of raised intracranial pressure
• After operation of the biliary tract
• Acute bronchial asthma
• Heart failure secondary to chronic lung disease
• Paralytic ileus
• Delayed gastric emptying
• Comatose patients
• Pre-operative use
• For the first 24 hours post-operatively
• Paediatric use
• Coadministration with alcohol
• Coadministration with monoamine oxidase inhibitors or within 14 days of their use

Oral (sol)

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Lactation
• Ileus
• Acute abdomen
• Head injury or raised intracranial pressure with a decrease in the level of consciousness, unless ventilation is performed
• Patients with compromised airways

Contraindications registered in other jurisdictions

Oral (srt)

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Acute hepatic disease
• Respiratory depression
  - With hypoxia and/or hypercapnia
  - Acute
• Obstructive airways disease
  - Severe chronic obstructive pulmonary disease
• Bronchial asthma
• Heart failure secondary to chronic lung disease
• Excessive bronchial secretions
• Head injuries
• Conditions of raised intracranial pressure
• Acute alcoholism
• Ulcerative colitis
• Paralytic ileus
• Acute abdomen
• Delayed gastric emptying
• Pre-operative use
• For the first 24 hours post-operatively
• Coadministration with monoamine oxidase inhibitors or within 14 days of their use

South African recommendations

• Renal impairment
• Hepatic impairment
• Elderly
• Debilitated patients
• Asthma (srt)
• Decreased respiratory reserve
  - Cor pulmonale (srt)
  - Kyphoscoliosis (srt)
  - Emphysema (srt)
  - Severe obesity (srt)
• Pre-existing sleep apnoea (srt)
• History of alcohol and drug abuse (srt)
• Hypothyroidism
• Adrenocortical insufficiency
• Prostatic hypertrophy
• Myasthenia gravis
• Hypotension with hypovolaemia (srt)
• Shock
• Inflammatory or obstructive bowel disorders
• Seizure disorders (srt)
• Opioid dependency (srt)
• Pancreatitis (srt)
• Diseases of the biliary tract (srt)
• History of epilepsy (srt)
• Constipation (srt)
• Sickle cell disease (srt)
  (See additional prescribing points)
• Prolonged use (srt)
• Abrupt withdrawal (srt)
• Galactose intolerance (srt)
• Lapp lactase deficiency (srt)
• Glucose-galactose malabsorption (srt)
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Moderate to severe renal impairment (eGFR<49ml/min/1.73m²) (srt)
• Moderate to severe hepatic impairment (srt)
• Elderly
• Children
• Impaired respiratory function (srt)
• Reduced respiratory reserve
  - Severe cor pulmonale (srt)
  - Sleep apnoea
• Delirium tremens (srt)
• Seizure disorders (srt)
• Hypotension​​
  - With hypovolaemia (srt)
• Hypothyroidism
• Adrenocortical insufficiency
• Prostatic hypertrophy
• Urethral disease (srt)
• Shock
• Inflammatory or obstructive bowel disorders
• Constipation (srt)
• Biliary disorders
• Current or past history of substance misuse disorder
• Current or past history of alcohol abuse
• Prolonged use
• Abrupt withdrawal
• Risk of tolerance
• Risk of physical dependence
• Risk of psychological dependence
• Sickle cell disease
• Myasthenia gravis (srt)
• Opioid dependent patients (srt)
• Pancreatitis (srt)
• History of epilepsy (srt)
• Possibility of paralytic ileus occurring (srt)
• Undergoing additional pain relieving procedures (srt)
  - Cordotomy (srt)
  - Surgery (srt)
  - Plexus blockade (srt)
• Risk of opioid misuse (srt)
• Coadministration with central nervous system depressants
• Galactose intolerance (srt)
• Lapp lactase deficiency (srt)
• Glucose-galactose malabsorption (srt)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: srt, pdr, sol

Dosages below include:

• South African Standard Treatment Guidelines indications and dosages
• South African registered indications and dosages

South African Standard Treatment Guidelines indications and dosages

For the different morphine salts and extemporaneously prepared morphine oral solution, see additional prescribing points

• Click here for the Pain Chapter (Standard Treatment Guidelines And Essential Medicines List For South Africa, Hospital Level, Adults, 2019 Edition)
• Click here for the Sedation Chapter (Standard Treatment Guidelines And Essential Medicines List For South Africa, Hospital Level, Adults, 2019 Edition)
• Click here for the Anaesthesiology and Intensive Care Chapter (Standard Treatment Guidelines And Essential Medicines List For South Africa, Hospital Level, Adults, 2019 Edition)
• Click here for the Medicines Used in Palliative Care Chapter (Standard Treatment Guidelines And Essential Medicines List For South Africa, Hospital Level, Adults, 2019 Edition)

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South African registered indications and dosages

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with morphine

Intractable pain not controlled with non-narcotic analgesics (including intractable pain due to cancer) - severe

• Oral (srt): Initial: 10-20mg, 12hrly; Maintenance: 10-100mg, 12hrly alone or in combination, with an increase in dosage required due to increase in pain or tolerance to agent

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The dosage of morphine sulphate SR tablets is dependent upon the severity of pain and the patient’s previous history of analgesic therapy

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When substituting morphine sulphate SR tablets for parenteral morphine, patients should be given a sufficiently increased dosage to compensate for the reduction in analgesic effects associated with orally administered morphine

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Morphine sulphate SR tablets is a sustained release formulation. The tablets should be swallowed whole and must not chewed, crushed, or dissolved due to the risk of rapid release and absorption of a potentially fatal dose of morphine 

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Relief of severe pain

• Oral (sol): Initial: 10-60mg, as a single dose; Repeat every 4-6hrs in case of decreasing effect; Recommended single dose range: 0.2-0.3mg/kg body weight; Treatment duration: At the discretion of medical practitioner and should not be given longer than absolutely necessary; Max: Should not exceed more than 4-6 fold of single dose/24hrs

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The dosage of morphine 20mg/ml must be adapted to the severity of pain and to the individual sensitivity of the patient

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The dose is removed from the 20ml bottle by counting the drops (1 drop = 1.25mg morphine sulphate)
Single dose: 0.5-3ml (i.e. 8-48 drops) = 10-60mg morphine sulphate
Total daily dose: Up to 18ml (i.e. 288 drops) = 360mg morphine sulphate

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If higher daily doses are required, other suitable active ingredient strengths may be used alternatively or in combination with the oral drops solution

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Method of administration: The oral drops solution is administered with a sufficient quantity of liquid. The medication can be taken independently of meals

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If prolonged analgesic treatment with the oral drops solution appears necessary based on the nature and severity of the disease, careful and regular monitoring within short time intervals should be installed (if required by means of temporary suspension of the medication) to evaluate if and to what extent the therapeutic necessity persists. If needed, more suitable pharmaceutical forms should be applied instead. In case of chronic pain conditions, a fixed dosage regimen is preferred

Paed. forms avail. in SA and covered in this monograph: pdr, sol

Paed. dosages below include:

• South African Standard Treatment Guidelines indications and dosages
• South African registered indications and dosages

South African Standard Treatment Guidelines indications and dosages

For the different morphine salts and extemporaneously prepared morphine oral solution, see additional prescribing points

• Click here for the Pain Control Chapter (Standard Treatment Guidelines And Essential Medicines List For South Africa, Hospital Level, Paediatrics, 2023 Edition)
• Click here for the Anaesthetics Chapter (Standard Treatment Guidelines And Essential Medicines List For South Africa, Hospital Level, Paediatrics, 2023 Edition)
• Click here for the Palliative Care Chapter (Standard Treatment Guidelines And Essential Medicines List For South Africa, Hospital Level, Paediatrics, 2023 Edition)

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South African registered indications and dosages

The use of morphine sulphate prolonged release tablets is contraindicated for paediatric use

The use of morphine sulphate 20mg/ml oral solution is not recommended for use in children

Pregnancy

South African recommendations

• Contraindicated
• Morphine sulphate solution and prolonged release tablets are contraindicated during pregnancy
• Infants born to mothers taking morphine sulphate may suffer withdrawal reactions
• Due to its mutagenic properties, morphine should be given to males with procreative potential and to females with childbearing potential only if effective contraceptive measures are guaranteed (sol)

Recommendations in other jurisdictions

• Contraindicated (srt)
• Morphine sulphate prolonged release tablets are not recommended during pregnancy and labour
• Regular use of morphine sulphate solution and prolonged release tablets in pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate
• If opioid use is required for a prolonged period in pregnant women, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
• Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available

Breastfeeding

South African recommendations 

• Contraindicated 
• Morphine sulphate solution and prolonged release tablets are contraindicated during breastfeeding
• Infants born to mothers taking morphine sulphate prolonged release tablets may suffer withdrawal reactions (srt)
• Since clinically relevant concentrations can be reached in infants, mothers taking morphine sulphate solution should not breastfeed their infants (sol)

Recommendations in other jurisdictions

• Contraindicated (srt) 
• Administration to breastfeeding women is not recommended as morphine is secreted in breast milk and may cause respiratory depression in the infant

Fertility

South African recommendations

• Animal studies have shown that morphine may reduce fertility
• Reduced fertility has been shown in male rats administered repeat doses of morphine subcutaneously. A study reported in the literature in female rats treated i.p. with up to 15mg/kg/day of morphine before mating, up to 30mg/kg/day over pregnancy and up to 40mg/kg/day postpartum showed reduced fertility of the mothers and an increase in stillborns, and in the live offspring reduced growth, morphine withdrawal symptoms, and suppression of sperm production (srt)
• In male rats, reduced fertility and chromosomal damage in gametes have been reported. Furthermore, in several animal species morphine had an effect on the sexual performance of males and on the fertility of females (sol)

Recommendations in other jurisdictions

Oral (srt)

• Effects of morphine exposure on sexual maturation of male rats, their reproductive capacity and the development of their progeny have been examined. Results indicated that exposure during adolescence led to pronounced inhibition of several indices of sexual maturation (e.g., hormone levels, reduced gonad weights), smaller litters and selective gender specific effects on endocrine function in the offspring
• Animal studies have shown that morphine may reduce fertility
• A disruption in ovulation and amenorrhoea can occur in women given morphine

South African recommendations

• Caution; dose adjustment recommended
  Morphine sulphate must be used with caution, or in reduced doses, in patients with impaired renal function
  *No specific dose adjustment has been provided by the manufacturer

Recommendations in other jurisdictions

Oral (srt)

• eGFR≥50ml/min/1.73m²: No dose adjustment recommended 
• eGFR 10-49ml/min/1.73m²: Caution; dose adjustment recommended 
  Administer 25-50% of the original (posology) dose. Monitor renal function
• eGFR<10ml/min/1.73m²: Caution; not recommended
  It is preferable that extended-release formulations be avoided in those with altered renal function
  Severe and prolonged respiratory depression may occur in patients with renal impairment given morphine; this is attributed to the accumulation of the active metabolite morphine-6-glucuronide. Therefore, morphine sulphate prolonged release tablets should not be administered to patients with moderate or severe renal impairment

South African recommendations

• Caution; dose adjustment recommended 
  Morphine sulphate must be used with caution, or in reduced doses, in patients with impaired hepatic function
  Morphine sulphate should be dosed with special caution (sol)
  *No specific dose adjustment has been provided by the manufacturer

Recommendations in other jurisdictions

Oral (srt)

• Mild (Child-Pugh class A): No dose adjustment recommended 
• Moderate (Child-Pugh class B): Caution, no dose adjustment recommended 
  Closely monitor hepatic function parameters. Terminate therapy if signs of toxicity are observed
• Severe (Child-Pugh class C): Caution; not recommended 
  As with other opioid analgesic containing preparations, morphine sulphate slow release tablets should not be administered to patients with severe hepatic impairment as it may precipitate coma
• Acute hepatic disease: Contraindicated 

South African recommendations

• Caution; dose adjustment recommended 
  The dosage should be reduced in the elderly and debilitated patient
  Elderly patients (usually 75 years and older) and patients with poor overall physical condition may be more sensitive to morphine. Therefore, the adjustment of dose must be done more carefully and/or the dosage intervals must be extended. As appropriate, lower dosage strengths must be given instead (sol)
  *No specific dose adjustment has been provided by the manufacturer

Recommendations in other jurisdictions

• Caution; dose adjustment recommended 
  As with all narcotics, a reduction in dosage may be advisable in the elderly
  It is recommended to start cautiously with lower doses; titrating slowly while carefully observing for signs of toxicity. Use is not recommended in elderly patients with hepatic and/or renal impairments
  *No specific dose adjustment has been provided by the manufacturer

Central Nervous System Disorders

• Confusion
• Insomnia
• Agitation
• Dizziness
• Drowsiness 
• Headache
• Involuntary muscle contractions
• Somnolence
• Euphoria
• Hallucinations
• Altered mood
• Drug dependence
  - Psychological dependence (addiction)
  - Physical dependence
  (See additional prescribing points)
• Dysphoria
• Thinking disturbances
• Seizures
• Hyperalgesia
• Hypertonia
• Paraesthesia
• Syncope
• Restlessness
• Allodynia
• Sleep apnoea syndrome (srt)
• Sleep-related breathing disorders (srt)
  - Central sleep apnoea (srt)
  - Sleep-related hypoxaemia (srt)
• Fatigue
• Myoclonus
• Medicine tolerance
• Medicine withdrawal syndrome
• Neonatal medicine withdrawal syndrome
• Anxiety

Cardiovascular Disorders

• Palpitations
• Bradycardia
• Tachycardia
• Facial flushing
• Hypotension
• Circulatory failure
• Hypertension

Respiratory Disorders

• Respiratory depression
• Bronchospasm (potentially fatal outcomes)
• Decreased cough
• Pulmonary oedema (potentially fatal outcomes)

Gastrointestinal Disorders

• Constipation
• Nausea and vomiting
• Abdominal pain
• Anorexia
• Dry mouth
• Dyspepsia
• Taste perversion
• Ileus
• Narcotic bowel syndrome

Hepatobiliary Disorders

• Exacerbation of pancreatitis
• Biliary pain
• Increased hepatic enzymes

Genitourinary Disorders

• Difficulty in micturition (srt)
• Uretric spasm (srt)
• Urinary retention
• Abnormal ejaculation (srt)
• Amenorrhea
• Decreased libido
• Erectile dysfunction
• Dysuria

Endocrine and Metabolic Disorders

• Hypothermia
• Increased serum prolactin (srt)
• Decreased plasma cortisol (srt)
• Decreased plasma testosterone (srt)
• Reversible adrenal insufficiency (srt)
  (See additional prescribing points)

Musculoskeletal Disorders

• Muscle rigidity (sol)
• Muscle cramps (sol)
• Muscle contractions (sol)

Skin and Subcutaneous Tissue Disorders

• Hyperhidrosis
• Rash
• Dry skin (srt)
• Pruritis
• Urticaria

Immune, Blood and Lymphatic System Disorders

• Allergic reaction (srt)
• Anaphylactic reaction
• Anaphylactoid reaction
• Hypersensitivity
• Peripheral oedema

Sensory Disorders

• Eye pain (srt)
• Miosis
• Visual disturbance
• Blurred vision (sol)
• Nystagmus (sol)
• Vertigo

• Monoamine oxidase inhibitors
• Selegiline
• Moclobemide
• Linezolid
• Central nervous system depressants
  (See additional prescribing points)
• Concomitant opioids
• Anaesthetics
• Hypnotics
• Sedatives
• Benzodiazepines
• Tricyclic antidepressants
• Antipsychotics
• Gabapentin
• Phenothiazines
• Neuromuscular blocking agents
• Mixed agonist/antagonist opioid analgesics
• Buprenorphine
• Nalbuphine
• Pentazocine
• Histamine 2 receptor antagonists
• Sedating antihistamines
• Cimetidine
• Antibacterial agents
• Rifampicin
• Ritonavir
• Metoclopramide
• Domperidone
• Antiarrhythmics
• Mexiletine
• Anxiolytics
• Antidiarrhoeal and antiperistaltic agents
• Loperamide
• Kaolin
• Antimuscarinics
• Atropine
• ciprofloxacin
• Oral P2Y12 inhibitors

Other interactions

• Alcohol

• Respiratory function
• Blood pressure
• Oxygenation
• Level of consciousness
• Urine drug testing

Additional observations

• Signs and symptoms
  - Hypogonadism
  - Hypoadrenalism
  - Misuse, abuse, and addiction
• Mental status
• Pain control

Morphine salts available in South Africa

Morphine Sulphate	Morphine Hydrochloride	Morphine Tartrate
Slow release tablet; Injection; Solution	Powder (Discontinued)	Combination preparation, see Morphine/ Cyclizine

Morphine oral solution

• Morphine oral solution forms part of medicines compounded, or prepared “extemporaneously”, which are unlicensed medicines and not subject to Medicines Regulatory Authority oversight. Thus, assumptions cannot be made regarding quality and stability of these compounded products relative to licensed medicines
• For more information, please refer to extemporaneous preparations: STG, Adult, 2019 
• There is a lack of robust data on extemporaneous formulations for neonates and infants with available excipients and formulations in South Africa
• It is thus recommended for this group of patients; a diluted morphine intravenous formulation be used orally (in consultation with specialists in units and your pharmacy department)
• For example, add 1ml of 10mg/ml IV solution to 9ml normal saline (preservative-free), to make 1mg/ml concentration (to be stored in fridge for no longer than 7 days)

Post-operative use of morphine sulphate slow release tablets

• Morphine sulphate slow release tablets should be used with caution post-operatively (as with all morphine preparations) but especially following abdominal surgery
• Gastric motility should have returned and be maintained

Adrenal insufficiency

• Opioid analgesics may cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy
• Symptoms of adrenal insufficiency may include e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure
• Should not be used where there is a possibility of paralytic ileus occurring
• Should paralytic ileus be suspected to occur during use, treatment should be discontinued immediately
• Extreme caution should be exercised when administering morphine to patients with phaeochromocytoma, since aggravated hypertension has been reported in association with diamorphine
• As with all morphine sulphate preparations, patients about to undergo additional pain relieving procedures (e.g. cordotomy, surgery, plexus blockade) should not receive morphine sulphate slow release tablets for 24 hours prior to the intervention
• If further treatment with morphine sulphate slow release tablets is indicated then the dosage should be adjusted to the new post-operative requirement
• The major risk of opioid excess is respiratory depression

Potential for abuse (srt)

• For all patients, prolonged use of morphine sulphate slow release tablets may lead to medicine dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression). Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse
• A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions
• Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced
• Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient
• Overuse or misuse may result in overdose and/or death
• It is important that patients only use medicines that are prescribed and do not give this medicine to anyone else
• Patients should be closely monitored for signs of misuse, abuse or addiction. The clinical need for analgesic treatment should be reviewed regularly

Drug abuse, dependence and withdrawal (abstinence) syndrome

• Morphine has an abuse potential similar to other strong agonist opioids, and should be used with special caution in patients with a history of alcohol or drug abuse
• Use of opioid analgesics may be associated with the development of physical and/or psychological dependence or tolerance
• The risk increases with the time the agent is used, and with higher doses
• Symptoms can be minimised with adjustments of dose or dosage form, and gradual withdrawal of morphine
• Hyperalgesia that does not respond to a further dose increase of morphine may occur in particular in high doses
• A morphine dose reduction or change in opioid may be required
• An unexplained increase in abdominal pain associated with disturbed intestinal motility, symptoms of constipation, bloating, abdominal distension and increased gastroesophageal reflux during treatment with morphine sulphate, may indicate the development of opioid-induced bowel dysfunction or narcotic bowel syndrome
• In such situations consider the use of alternative analgesics and a morphine detoxification
• The patient may develop tolerance to morphine with chronic use and require progressively higher doses of morphine sulphate slow release tablets to maintain pain control
• Prolonged use may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy
• When a patient no longer requires therapy with morphine, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal
• The opioid medicine withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations
• Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate
• If women take this medicine during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome

Coadministration with central nervous system depressants

• Coadministration of morphine sulphate and sedative medicines such as benzodiazepines or related agents may result in sedation, respiratory depression, coma and death
• Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible
• If a decision is made to prescribe morphine sulphate concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible
• The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms

Acute chest syndrome (ACS) in patients with sickle cell disease (SCD)

• Due to a possible association between ACS and morphine use in SCD patients treated with morphine during a vaso-occlusive crisis, close monitoring for ACS symptoms is warranted

Morphine acts as an agonist at opiate receptors in the CNS, particularly mu and to a lesser extent kappa receptors. Mu receptors are thought to mediate supraspinal analgesia, respiratory depression and euphoria, and kappa receptors, spinal analgesia, miosis and sedation.

Slow release tablet 10mg

• MST continus 10mg Tablet (Mundipharma) originator
• SRM Rhotard 10 (Akacia)

Slow release tablet 30mg

• MST continus 30mg Tablet (Mundipharma) originator
• SRM Rhotard 30 (Akacia)

Slow release tablet 60mg

• MST continus 60mg Tablet (Mundipharma) originator
• SRM Rhotard 60 (Akacia)

Slow release tablet 100mg

• MST continus 100mg Tablet (Mundipharma) originator
• SRM Rhotard 100 (Akacia)

Powder 5g

• Morphine Hydrochloride S/7 (Allied Drug Company) Discontinued: 22/11/2022