Introduction
Morphine, the main alkaloid of opium, was first obtained from poppy seeds in 1805. It is a potent analgesic, though its use is limited due to tolerance, withdrawal, and the risk of abuse. Morphine is still routinely used today, though there are a number of semi-synthetic opioids of varying strength such as codeine, fentanyl, methadone, hydrocodone, hydromorphone, meperidine, and oxycodone.
Morphine was granted FDA approval in 1941.
Uses
Morphine is an opioid agonist used for the relief of moderate to severe acute and chronic pain.
Morphine is used for the management of chronic, moderate to severe pain.
Opiods, including morphine, are effective for the short term management of pain. Patients taking opioids long term may need to be monitored for the development of physical dependence, addiction disorder, and drug abuse.
Associated Conditions
Pharmacodynamics
Morphine binding to opioid receptors blocks transmission of nociceptive signals, signals pain-modulating neurons in the spinal cord, and inhibits primary afferent nociceptors to the dorsal horn sensory projection cells.
Morphine has a time to onset of 6-30 minutes. Excess consumption of morphine and other opioids can lead to changes in synaptic neuroplasticity, including changes in neuron density, changes at postsynaptic sites, and changes at dendritic terminals.
Intravenous morphine's analgesic effect is sex dependent. The EC50 in men is 76ng/mL and in women is 22ng/mL.
Morphine-6-glucuronide is 22 times less potent than morphine in eliciting pupil constriction.
Mechanism of Action
Morphine-6-glucuronide is responsible for approximately 85% of the response observed by morphine administration. Morphine and its metabolites act as agonists of the mu and kappa opioid receptors. The mu-opioid receptor is integral to morphine's effects on the ventral tegmental area of the brain. Morphine's activation of the reward pathway is mediated by agonism of the delta-opioid receptor in the nucleus accumbens, while modification of the respiratory system and addiction disorder are mediated by agonism of the mu-opioid receptor.
Absorption
Morphine is absorbed in the alkaline environments of the upper intestine and rectal mucosa. The bioavailability of morphine is 80-100%. There is significant first-pass metabolism, therefore oral doses are 6 times larger than parenteral doses to achieve the same effect. Morphine reaches steady-state concentrations after 24-48 hours. Parenteral morphine has a Tmax of 15 minutes and oral morphine has a Tmax of 90 minutes, with a Cmax of 283nmol/L. The AUC of morphine is 225-290nmol*h/L.
Volume of Distribution
The volume of distribution of morphine is 5.31L/kg. Morphine-6-glucuronide has a volume of distribution of 3.61L/kg.
Protein Binding
Morphine is 35% protein bound, the metabolite morphine-3-glucuronide is 10% protein bound, and morphine-6-glucuronide is 15% protein bound.
Route of Elimination
70-80% of an administered dose is excreted within 48 hours. Morphine is predominantly eliminated in the urine with 2-10% of a dose recovered as the unchanged parent drug. 7-10% of a dose of morphine is eliminated in the feces.
Half Life
Morphine has a half life of 2-3 hours.
Clearance
The apparent clearance of intravenous or subcutaneous morphine is 1600 mL/min.
Toxicity
The LD50 is 0.78µg/mL in males and 0.98µg/mL in females.
Patients experiencing an overdose present with respiratory depression, somnolence, skeletal muscle flaccidity, cold and clammy skin, miosis, and mydriasis. Symptoms of overdose can progress to pulmonary edema, bradycardia, hypotension, cardiac arrest, and death. Treat overdose with symptomatic and supportive treatment which may include the use of oxygen, vasopressors, and naloxone.
Food Interactions
- Avoid alcohol. Concomitant use may lead to profound sedation, respiratory depression, coma, and death.
- Take with or without food. There is no significant different in the AUC or Cmax of oral extended release tablets when taken with or without food.
Dosage
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.
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
