MSL Oral Solution

MSL Sulphate is indicated for the prolonged relief of severe & intractable pain, and for the relief of post-operative pain.

Morphine is a phenanthrene derivative which acts mainly on the CNS and smooth muscles. It binds to opiate receptors in the CNS altering pain perception and response. Analgesia, euphoria and dependence are thought to be due to its action at the mu-1 receptors while resp depression and inhibition of intestinal movements are due to action at the mu-2 receptors. Spinal analgesia is mediated by morphine agonist action at the K receptor.

15 mg retard tablet:

Adults: A patient presenting with severe pain, uncontrolled by weaker opioids (e.g. dihydrocodeine) should normally be started on 30 mg 12 hourly. Patients previously on normal release oral morphine should be given the same total daily dose as Morphine Sulphate 15 mg tablets but in divided doses at 12-hourly intervals. Increasing severity of pain will require an increased dosage of the tablets. Higher doses should be made, where possible in 30-50% increments as required. The correct dosage for any individual patient is that which is sufficient to control pain with no, or tolerable, side effects for a full 12 hours. Patients receiving Morphine Sulphate 15 mg tablets in place of parenteral morphine should be given a sufficiently increased dosage to compensate for any reduction in analgesic effects associated with oral administration. Usually such increased requirement is of the order of 100%. In such patients individual dose adjustments are required. Children: For children with severe cancer pain, a starting dose in the range of 0.2 to 0.8 mg morphine per kg bodyweight 12 hourly is recommended. Post-operative pain: Morphine Sulphate 15 mg tablets are not recommended in the first 24 hours post-operatively or until normal bowel function has returned; thereafter it is suggested that the following dosage schedule be observed at the physician’s discretion: (a) Morphine Sulphate 30 mg tablets 12 hourly to patients over 70 kg, (c) Elderly- a reduction in dosage may be advisable in the elderly, (d) Children- not recommended. Supplemental parenteral morphine may be given if required but with careful attention to the total dosages of morphine, and bearing in mind the prolonged effects of morphine in this prolonged release formulation.

10 mg tablet:

Adults and children over 12 years: The dosage of Morphine 10 mg tablet is dependent on the severity of pain and the patient’s previous history of analgesic requirements. One Morphine 10 mg tablet to be taken every four hours or as directed by a physician. Increasing severity of pain or tolerance to morphine will require increased dosage of Morphine 10 mg tablet to achieve the desired relief. Patients receiving morphine orally in place of parenteral morphine should be given a sufficiently increased dosage to compensate for any reduction in analgesic effects associated with oral administration. Usually such increased requirement is of the order of 100%. In such patients individual dose adjustments are required. Elderly: A reduction in adult dosage may be advisable. Children 3-12 years of age: 3-5 years- 5 mg, 4-hourly; 6-12 years- 5-10 mg, 4-hourly.

Oral Solution:

• Adults: Usual dose 10-20 mg (5-10 ml) every 4 hours.
• Children 13 to 18 years: Maximum single dose 5-20 mg (2.5-10 ml) every 4 hours
• Children 6-12 years: Maximum dose 5-10 mg (2.5-5 ml) every 4 hours.
• Children 1-5 years: Maximum dose 5 mg (2.5 ml) every 4 hours.
• Children under 1 year: Not recommended.

Dosage can be increased under medical supervision according to the severity of the pain and the patient’s previous history of analgesic requirements. Reductions in dosage may be appropriate in the elderly, patients with moderate-severe renal or hepatic impairment, or where sedation is undesirable.

Morphine Sulfate is readily absorbed from the gastrointestinal tract following oral administration. However, when Oral Solution (5 mg/5 ml) is used in place of parenteral morphine, a 50% to 100% increase in dosage is usually required in order to achieve the same level of analgesia

MSL should be used with caution in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anaesthetics, phenothiazines, other tranquilisers, muscle relaxants, antihypertensives and alcohol. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual doses of morphine. Mixed agonist/antagonist opioid analgesics (e.g. buprenorphine, nalbuphine, pentazocine) should not be administered to a patient who has received a course of therapy with a pure opioid agonist analgesic. Medicinal products that block the action of acetylcholine, for example antihistamines, anti-parkinsons and anti-emetics, may interact with morphine to potentiate the anticholinergic adverse effects. Cimetidine inhibits the metabolism of morphine. Monoamine oxidase inhibitors are known to interact with narcotic analgesics producing CNS excitation or depression with hyper- or hypotensive crisis. MSL should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy. Plasma concentrations of morphine may be reduced by rifampicin. Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine, ritonavir induces the hepatic enzymes responsible for the glucuronidation of morphine, and may possibly decrease plasma concentrations of morphine.

Hypersensitivity. Morphine Sulphate is contra-indicated in respiratory depression, head injury, obstructive airways disease, paralytic ileus, acute abdominal pain, delayed gastric emptying, known morphine sensitivity, acute hepatic disease, concurrent administration of mono-amine oxidase inhibitors or within two weeks of discontinuation of their use. Not recommended during pregnancy. Not recommended for children below 3 years of age.

In normal doses, the commonest side effects of morphine are nausea, vomiting, constipation and drowsiness. With chronic therapy, nausea and vomiting are unusual with morphine Sulphate tablets but should they occur the tablets can be readily combined with an anti-emetic if required. Constipation may be treated with appropriate laxatives. Psychiatric disorders: Common- confusion, insomnia. Nervous system disorders: Common- Dizziness, headache, involuntary muscle, contractions, somnolence. Gastrointestinal disorders: Very Common – Constipation, nausea; Common- abdominal pain, anorexia, dry mouth, vomiting. Skin and subcutaneous tissue disorders: Common- Hyperhidrosis, Rash. General disorders: Asthenic conditions, pruritus.

Morphine Sulphate is not recommended during pregnancy and labour due to the risk of neonatal respiratory depression. Administration to nursing mothers is not recommended as morphine is excreted in breast milk. Withdrawal symptoms may be observed in the new born of mothers undergoing chronic treatment.

The major risk of opioid excess is respiratory depression. As with all narcotics a reduction in dosage may be advisable in the elderly, in hypothyroidism, in renal and chronic hepatic disease. Use with caution in patients with impaired respiratory function, severe bronchial asthma, convulsive disorders, acute alcoholism, delirium tremens, raised intracranial pressure, hypotension with hypovolaemia, severe cor pulmonale, opioid dependent patients, patients with a history of substance abuse, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy, adrenocortical insufficiency. MSL Sulphate tablets should not be used where there is a possibility of paralytic ileus occurring. If paralytic ileus be suspected or occur during use, MSL Sulphate tablets should be discontinued immediately. MSL may lower the seizure threshold in patients with a history of epilepsy. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. Prolonged use of MSL 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. Hyperalgesia that will not respond to a further dose increase of morphine Sulphate may very rarely occur in particular in high doses. A morphine Sulphate dose reduction or change in opioid may be required. MSL has an abuse profile similar to other strong agonist opioids. MSL may be sought and abused by people with latent or manifest addiction disorders. There is potential for development of psychological dependence (addiction) to opioid analgesics, including morphine. The drug should be used with particular care in patients with a history of alcohol and drug abuse. Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events, which may be fatal.

Signs of morphine toxicity and overdose are pin-point pupils, skeletal muscle flaccidity, bradycardia, respiratory depression, hypotension, somnolence and central nervous system depression which can progress to stupor or coma. Circulatory failure and deepening coma may occur in more severe cases. Overdose can result in death. Rhabdomyolysis progressing to renal failure has been reported in opioid overdose. Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation. Oral activated charcoal (50g for adults, 1g/kg for children) may be considered if a substantial amount has been ingested within one hour, provided the airway can be protected. The pure opioid antagonists are specific antidotes against the effects of opioid overdose. Other supportive measures should be employed as needed. In the case of massive overdose, administer naloxone 0.8 mg intravenously. Repeat at 2-3 minute intervals as necessary, or by an infusion of 2 mg in 500 ml of normal saline or 5% dextrose (0.004 mg/ml). The infusion should be run at a rate related to the previous bolus doses administered and should be in accordance with the patient’s response. However, because the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. For less severe overdose, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required. Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose. 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.

Opioid analgesics

Store in a cool and dry place, protected from light.