Morphine

Morphine is an Opioid receptor agonist belonging to the analgesic class.

Morphine is an opioid agonist used for the relief of moderate to severe acute and chronic pain.

Morphine is Well absorbed from the gastrointestinal tract (oral) and into the blood (SC/IM). Bioavailability is 17-33 % via oral route. Time taken to reach peak plasma concentration is 1 hour (Conventional Tablet); 3-4 hours (extended-release tablet); 20-60 minutes (supp); 50-90 minutes (SUBQ); 30-60 minutes (IM); 20 minutes (IV). The volume of distribution of morphine is 5.31L/kg. Morphine-6-glucuronide has a volume of distribution of 3.61L/kg. Morphine is 35% protein bound, the metabolite morphine-3-glucuronide is 10% protein bound, and morphine-6-glucuronide is 15% protein bound. Morphine is 90% metabolized by glucuronidation by UGT2B7 and sulfation at positions 3 and 6. Morphine can also be metabolized to codeine, normorphine, and morphine ethereal sulfate.

Morphine shows side effects like Drowsiness, stomach pain and cramps, dry mouth, headache, nervousness, mood changes, small pupils (black circles in the middle of the eyes, difficulty urinating or pain when urinating.

Morphine is available in the form of Oral tablet, Oral capsule, Oral solution, Injectable solution, and Rectal suppositories.

Morphine is available in India, US, UK, China, Japan, Canada, Singapore, Germany, Australia, France, Turkey, Spain and Hungary.

Morphine is an Analgesic belonging to the class Opioid receptor agonist.

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.

Time taken to reach peak plasma concentration is 1 hour (Conventional Tablet); 3-4 hours (extended-release tablet); 20-60 minutes (supp); 50-90 minutes (SUBQ); 30-60 minutes (IM); 20 minutes (IV).

The onset of action of Morphine is approximately 30 minutes (conventional tab); 5-10 minutes (IV).

The duration of action of Morphine is 3-5 hours (immediate-release); 8-24 hours (extended-release tab/cap); 3-7 hours (supp); Up to 24 hours (rectal).

Morphine is available in the form of Oral tablet, Oral capsule, Oral solution, Injectable solution, and Rectal suppositories.

Morphine is used to relieve moderate to severe pain. Morphine extended-release tablets and capsules are only used to relieve severe (around-the-clock) pain that cannot be controlled using other pain medications.

Morphine is an Opioid receptor agonist belonging to the analgesic class.

Morphine binds to opioid receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression.

Morphine is approved for use in the following clinical indications

• Acute coronary syndrome, refractory ischemic chest pain
• Acute pain in opioid-naive patients
• Acute pain in patients on chronic opioid therapy for pain
• Acute postoperative pain
• Acute vaso-occlusive pain in sickle cell disease
• Chronic pain, including chronic cancer pain
• Dyspnea in palliative care patients
• Neuraxial analgesia
• Pain and sedation; critically ill patients in the ICU

• Acute coronary syndrome, refractory ischemic chest pain

IV: 2 to 4 mg initially, followed by 2 to 8 mg every 5 to 15 minutes as needed or 1 to 5 mg initially, followed by 1 to 5 mg every 5 to 30 minutes as needed.

• Acute pain in opioid-naive patients

Oral Dose:

Initial: 10 mg every 4 hours as needed; if pain is not relieved, may increase dose as tolerated. May give up to 30 mg every 4 hours as needed for severe, acute pain in hospitalized patients at low risk for respiratory depression.

IV Dose:

Intermittent: Initial: 1 to 4 mg every 1 to 4 hours as needed; if pain is not relieved, may increase dose as tolerated. May give up to 10 mg every 4 hours as needed for severe, acute pain in hospitalized patients at low risk for respiratory depression. For some severe acute pain episodes (eg, trauma), may initially give more frequently (eg, every 5 to 15 minutes) if needed and titrate to pain relief; once pain relief is achieved, reduce frequency (eg, every 3 to 4 hours as needed).

IM Dose:

Opioid-naive patients: Initial: 5 to 10 mg every 3 to 4 hours as needed; if pain is not relieved, may increase dose as tolerated.

Rectal Dose: Opioid-naive patients: Initial: 10 mg every 4 hours scheduled or as needed; may increase or decrease the dose as tolerated following the same precautions as oral dosing up to 30 mg every 4 hours scheduled or as needed.

• Acute pain in patients on chronic opioid therapy for pain

Oral, IV, SUBQ: Usual dose: In conjunction with the scheduled long-acting opioid, administer 5% to 20% of the basal daily morphine milligram equivalents (MME) requirement given as needed using an IR formulation with subsequent dosage adjustments based upon response.

• Acute postoperative pain

IV Dose: 1 to 4 mg every 1 to 4 hours as needed; may give up to 10 mg every 2 to 4 hours as needed for severe, acute pain in patients at low risk for respiratory depression.

• Acute vaso-occlusive pain in sickle cell disease

IV Dose: Initial: 0.1 to 0.15 mg/kg (maximum initial dose: 10 mg) given once within 30 minutes of presentation, reassess pain within 20 minutes; if continued severe pain, may repeat with doses of 0.02 to 0.05 mg/kg every 20 to 30 minutes to achieve pain relief.

• Chronic pain, including chronic cancer pain

IV Dose: Initial: 2 to 5 mg every 2 to 4 hours as needed.

SUBQ Dose: Initial: 2 to 5 mg every 3 to 4 hours as needed.

• Dyspnea in palliative care patients

Oral, sublingual Dose: Immediate release (may use 100 mg/5 mL [20 mg/mL] solution): Initial: 2 mg every 2 hours as needed or 5 mg every 4 hours with 2.5 mg every 2 hours as needed or on an “offer, may refuse” basis (most patients will not need every dose).

SUBQ Dose: Initial: 2 mg every 2 hours as needed or on an “offer, may refuse” basis (most patients will not need every dose)

• Neuraxial analgesia

Single dose (using 0.5 or 1 mg/mL preservative-free solution): Opioid-naive patients: Usual range: 2.5 to 3.75 mg (may depend upon patient comorbidities).

Continuous infusion (using 0.5 or 1 mg/mL preservative-free solution): Opioid-naive patients: 0.2 to 0.4 mg/hour. May be given alone or usually in combination with local anesthetics (eg, bupivacaine, ropivacaine); when combined with a local anesthetic, analgesic effect is increased due to synergy.

Continuous microinfusion (using a device intended for continuous microinfusion): Initial: 3 to 7.5 mg over 24 hours.

• Pain and sedation; critically ill patients in the ICU

IV Dose:

Loading dose: 2 to 10 mg, followed by maintenance dosing.

Morphine is available in various strengths as 5 mg ,10mg, 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 20 mg, 40 mg, 45 mg, 50 mg, 75 mg, 80 mg, 90 mg, 120 mg, 10 mg/5 mL; 20 mg/5 mL; 10 mg/0.5 mL; 20 mg/mL; 100 mg/5 mL, 0.5 mg/mL; 1 mg/mL; 2 mg/mL; 4 mg/mL; 5 mg/mL; 8 mg/mL; 10 mg/mL.

Morphine is available in the form of Oral tablet, Oral capsule, Oral solution, Injectable solution, and Rectal suppositories.

• Dosage Adjustment in Kidney Patient

CrCl ≥60 mL/minute: No dosage adjustment necessary.

CrCl 30 to <60 mL/minute: Consider use of an alternative opioid analgesic. If necessary, administer 50% to 75% of usual initial dose; may also consider extending dose interval. Titrate cautiously to response.

CrCl 15 to <30 mL/minute: Avoid use. If necessary, administer 25% to 50% of usual initial dose; may also consider extending dose interval. Titrate cautiously to response.

CrCl <15 mL/minute: Avoid use.

Morphine is contraindicated in patients with

• Morphine sulfate is contraindicated in patients with known hypersensitivity to morphine.
• Morphine sulfate is contraindicated in patients with respiratory depression in the absence of resuscitative equipment.
• Morphine sulfate is contraindicated in patients with acute or severe bronchial asthma or hypercarbia.
• Morphine sulfate is contraindicated in any patient who has or is suspected of having paralytic ileus.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Some dosage forms may be contraindicated in patients with severe CNS depression.
• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), circulatory shock, or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock. Some dosage forms may be contraindicated in patients with cardiac arrhythmias or heart failure due to chronic lung disease.
• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists (codeine, hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis.
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction or acute pancreatitis; opioids may cause constriction of sphincter of Oddi.
• Cardiovascular conditions: Morphine may cause constipation, which may be problematic in patients with unstable angina and patients post–myocardial infarction.
• CNS depression/coma: Avoid use in patients with impaired consciousness or coma, as these patients are susceptible to intracranial effects of CO₂ retention.
• Delirium tremens: Use with caution in patients with delirium tremens. Some dosage forms may be contraindicated in patients with delirium tremens.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur. Some dosage forms may be contraindicated in patients with increased intracranial or cerebrospinal pressure, head injuries, or brain tumor.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment.
• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to potential increased risk for opioid use disorder and overdose; more frequent monitoring is recommended.
• Obesity: Use with caution in patients who are morbidly obese.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
• Psychosis: Use with caution in patients with toxic psychosis.
• Renal impairment: Use with caution in patients with renal impairment.
• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or preexisting respiratory depression, particularly when initiating therapy and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• Sleep-related disorders: Use with caution in patients with sleep-related disorders, including sleep apnea, due to increased risk for respiratory and CNS depression. Monitor carefully and titrate dosage cautiously in patients with mild sleep-disordered breathing. Avoid opioids in patients with moderate to severe sleep-disordered breathing.
• Seizure disorders: Use with caution in patients with seizure disorders; may cause or exacerbate preexisting seizures. Some dosage forms may be contraindicated in patients with seizure disorder.
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
• Benzodiazepines or other CNS depressants: Some dosage forms may be contraindicated in patients with acute alcoholism.

Avoid alcohol. Concomitant use may lead to profound sedation, respiratory depression, coma, and death.

Lactation studies have not been conducted with Morphine Sulfate Tablets and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production.

Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome. There are no available data with Morphine Sulfate Tablets in pregnant women to inform a drug associated risk for major birth defects and miscarriage.

• Common

Itching, Urinary retention (epidural/intrathecal or oral), Vomiting, Constipation, Headache, Sleepiness, Abdominal pain, Weakness or lack of energy, Backache, Depression, Diarrhea, Shortness of breath, Fever, Insomnia, Loss of appetite, Nausea, Numbness and tingling, Swelling of extremities, Rash, Sweating, Dry mouth, Respiratory depression, Anxiety, Dizziness, Abnormal liver function test results, Amblyopia, Hiccups, Dizziness upon standing, Lightheadedness/fainting.

• Rare

Cardiac arrest, Circulatory depression, Constricted pupils, Feeling unwell (malaise), Ileus, Jerky muscle movements, Lightheadedness, Severe allergic reaction (anaphylaxis, rare), Shock, Spinning sensation (vertigo), Thinking disturbances.

• Benzodiazepines and Other Central Nervous System (CNS) Depressants

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

• Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

• Monoamine Oxidase Inhibitors (MAOIs)

MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

May reduce the analgesic effect of Morphine Sulfate Tablets and/or precipitate withdrawal symptoms.

• Muscle Relaxants

Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

• Cimetidine

The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report.

• Diuretics

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone

• Anticholinergic Drugs

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

• P-Glycoprotein (P-gp) Inhibitors

The concomitant use of P-gp inhibitors can increase the exposure to morphine by two-fold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

The common side effects of Morphine include the following

• Common side effects

Drowsiness, stomach pain and cramps, dry mouth, headache, nervousness, mood changes, small pupils (black circles in the middle of the eyes, difficulty urinating or pain when urinating.

• Rare side effects

Blue or purple colour to the skin, changes in heartbeat, agitation, hallucinations (seeing things or hearing voices that do not exist), fever, sweating, confusion, fast heartbeat, shivering, severe muscle stiffness or twitching, loss of coordination, nausea, vomiting, or diarrhea, nausea, vomiting, loss of appetite, weakness, or dizziness, inability to get or keep an erection, irregular menstruation, decreased sexual desire, seizures, extreme drowsiness, fainting, chest pain, fever, hives, rash, itching, swelling of the eyes, face, mouth, lips or throat, hoarseness, difficulty breathing or swallowing.

• Pregnancy

Pregnancy Category C

Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome. There are no available data with Morphine Sulfate Tablets in pregnant women to inform a drug associated risk for major birth defects and miscarriage.

• Nursing Mothers

Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-toplasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with Morphine Sulfate Tablets and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production.

• Pediatric Use

The safety and effectiveness of Morphine Sulfate Injection in pediatric patients below the age of 18 have not been established.

• Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general, use caution when selecting a dose for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Symptoms: Respiratory depression, pinpoint pupils, hypoxia, hypothermia, severe dizziness, severe drowsiness, hypotension, bradycardia, circulatory failure pulmonary oedema, severe nervousness or restlessness, hallucinations, convulsion (especially in infants and children); skeletal muscle flaccidity, cold and clammy skin.

Management: Ensure adequate airway, ventilation, and oxygenation. Administration of opioid antagonist e.g. naloxone may be given as an antidote.

• Pharmacodynamic

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.

• Pharmacokinetics

Absorption

Morphine is Well absorbed from the gastrointestinal tract (oral) and into the blood (SC/IM). Bioavailability is 17-33 % via oral route. Time taken to reach peak plasma concentration is 1 hour (conventional tab); 3-4 hours (extended-release tab); 20-60 minutes (supp); 50-90 minutes (SUBQ); 30-60 minutes (IM); 20 minutes (IV).

Distribution

The volume of distribution of morphine is 5.31L/kg. Morphine-6-glucuronide has a volume of distribution of 3.61L/kg. Morphine is 35% protein bound, the metabolite morphine-3-glucuronide is 10% protein bound, and morphine-6-glucuronide is 15% protein bound.

Metabolism and Excretion

Morphine is 90% metabolized by glucuronidation by UGT2B7 and sulfation at positions 3 and 6. Morphine can also be metabolized to codeine, normorphine, and morphine ethereal sulfate.

• https://www.drugs.com/morphine.html#dosage
• https://go.drugbank.com/drugs/DB00295
• https://www.mims.com/india/drug/info/morphine?type=full&mtype=generic
• https://medlineplus.gov/druginfo/meds/a682133.html#:~:text=Morphine is used to relieve,use of other pain medications.
• https://www.rxlist.com/morphine/generic-drug.htm#what_are_side_effects_associated_with_using_morphine
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022207s010lbl.pdf
• https://www.uptodate.com/contents/morphine-drug-information#F8776768