Morphine

Morphine is the prototype strong opioid agonist and the reference against which other opioid doses are expressed. It is the usual first-line strong opioid for severe acute, cancer and palliative pain, and for breathlessness in advanced disease. Its main hazards are respiratory depression, sedation, constipation and accumulation of an active metabolite in kidney impairment.

Class. Full mu-opioid receptor agonist (phenanthrene opioid).

Mechanism. Agonism at mu receptors in brain, spinal cord and gut reduces nociceptive transmission and perception of pain, and causes sedation, respiratory depression, miosis, nausea and reduced gastrointestinal motility.

Pharmacokinetics. Oral bioavailability is 20 to 40% because of first-pass metabolism. Immediate-release onset is 20 to 30 minutes orally, 5 to 10 minutes intravenously, with duration of 3 to 4 hours (12 hours for modified-release). Half-life about 2 to 3 hours. Brain entry is slow, so the peak effect after an intravenous dose lags by 10 to 20 minutes.

Metabolism. Hepatic glucuronidation to morphine-6-glucuronide (active, analgesic and respiratory depressant) and morphine-3-glucuronide (inactive for analgesia, may cause neuroexcitation). Both are renally cleared and accumulate in kidney impairment.

Indications are severe acute pain (trauma, postoperative, myocardial infarction), cancer and palliative pain, breathlessness in advanced disease, and pre-anaesthetic analgesia. Doses are titrated to effect; there is no fixed maximum dose, but every increase needs reassessment.

Opioid-naive adults, acute pain

• Oral immediate release: 5 to 10 mg every 4 hours (2.5 to 5 mg in older or frail patients).
• Intravenous titration: 1 to 2 mg every 5 minutes until pain is controlled, then 2 to 5 mg every 3 to 4 hours as needed. Reduce to 0.5 to 1 mg increments in older adults.
• Subcutaneous or intramuscular: 2.5 to 10 mg every 4 hours. Intramuscular absorption is unreliable and is not preferred.
• Patient-controlled analgesia: bolus 1 mg, lockout 5 to 10 minutes, background infusion not used in opioid-naive patients.

Cancer and palliative pain

• Start oral immediate-release morphine 2.5 to 10 mg every 4 hours. Titrate daily by 30 to 50% based on total use and response.
• After 2 to 3 days of stable requirement, convert to modified release: total 24-hour dose divided into two doses every 12 hours (10 to 30 mg every 12 hours as a usual start). Keep breakthrough dose at one sixth of the total 24-hour oral dose.
• Parenteral dose is one half to one third of the oral dose. Continuous subcutaneous infusion over 24 hours by syringe driver is used when swallowing fails.

Breathlessness. Oral 2.5 mg every 4 hours as needed or 5 to 10 mg modified release every 12 hours (opioid-naive start low).

Children

• Oral, 1 to 12 years: 0.2 to 0.5 mg/kg every 4 hours.
• Intravenous bolus: 0.05 to 0.1 mg/kg every 4 hours; infusion 10 to 30 micrograms/kg/hour.
• Neonates: intravenous 25 to 50 micrograms/kg every 6 hours, with respiratory monitoring.

Contraindications. Respiratory depression without ventilatory support; acute severe asthma; paralytic ileus or suspected acute surgical abdomen when examination would be obscured; raised intracranial pressure or head injury with altered consciousness (relative); monoamine oxidase inhibitor use within 14 days; known hypersensitivity; phaeochromocytoma (relative).

Boxed-warning-level risks. Addiction, abuse and misuse; life-threatening respiratory depression; accidental exposure (especially children); neonatal opioid withdrawal syndrome with prolonged use in pregnancy; profound sedation, respiratory depression and death with benzodiazepines and other central nervous system depressants.

Adverse effects. Common: nausea, vomiting, constipation, drowsiness, pruritus, urinary retention, dizziness. Serious: respiratory depression, hypotension, biliary spasm, myoclonus and seizures at high dose or with renal failure, delirium, hyperalgesia, and opioid use disorder.

Interactions. Benzodiazepines, other opioids, alcohol, sedating antihistamines, gabapentinoids and anaesthetics add sedation and respiratory depression. Monoamine oxidase inhibitors risk serotonin syndrome or hypertensive crisis. Rifampicin lowers morphine exposure. Naloxone and naltrexone antagonise effect. Anticholinergics worsen constipation and urinary retention.

Common prescribing errors. Confusing mg and mL of oral solutions of different strengths; using the oral dose for the parenteral route; starting too high in older adults or kidney impairment; omitting a laxative; unrecognised accumulation in renal failure; combining with an infusion without a sedation monitoring plan.

Special groups

• Pregnancy: use only when necessary at the lowest dose; neonatal respiratory depression if given near delivery; neonatal withdrawal after prolonged use.
• Breastfeeding: single doses are acceptable; avoid repeated or high doses and observe the infant for sedation.
• Older adults: start at one half to one third of the usual dose.
• Kidney impairment: avoid if eGFR is under 30 mL/min where possible; if used, reduce dose by 50 to 75% and extend the interval, or choose fentanyl or buprenorphine.
• Liver impairment: reduce the dose and extend the interval; avoid in severe disease.
• Regional: oral morphine solution is often the only strong opioid in supply, so confirm the local concentration (for example 10 mg/5 mL) before prescribing and write doses in mg and mL.

Formulations. Oral solution (10 mg/5 mL, 10 mg/mL and others), immediate-release tablets, modified-release tablets and capsules, injection (10 and 15 mg/mL), suppositories.

Administration. Intravenous doses are diluted to 1 mg/mL in 0.9% sodium chloride and given slowly over at least 5 minutes with titration. Modified-release tablets are swallowed whole. Doses may be taken with or without food.

Baseline. Respiratory rate and oxygen saturation, sedation score, renal function, hepatic function, concurrent sedatives, opioid exposure history and substance use history.

Monitoring. Pain score, respiratory rate, sedation score and oxygen saturation. After parenteral doses, check every 5 to 15 minutes initially, then hourly for the first hours; continuous capnography or pulse oximetry for patient-controlled analgesia or high-risk patients. Bowel function daily. Reassess dose with each change.

Therapeutic drug monitoring. Not used.

Dose reduction and stopping thresholds. Reduce or hold for respiratory rate under 10 breaths/minute, excessive sedation (drowsy and difficult to rouse), new myoclonus or delirium. After more than 1 week of regular use, reduce by 10 to 25% every few days to avoid withdrawal.

Referral and escalation. Respiratory rate under 8 breaths/minute, unrousable sedation or oxygen desaturation needs stopping the opioid, airway support, oxygen and naloxone. Pain needing repeated escalation, neuropathic pain, or toxicity at modest doses needs palliative care or pain team review.