Strong Opioid Analgesics

Strong opioid analgesics are full mu-receptor agonists with no analgesic ceiling, used for severe acute pain, cancer pain, palliative care and anaesthesia. Effective use depends on dose titration, parenteral and oral conversion, prevention of constipation and rapid recognition of respiratory depression.

Mechanism. Full mu agonism reduces nociceptive transmission in the dorsal horn, thalamus and cortex and activates descending inhibition. Dose-dependent respiratory depression arises from reduced brainstem sensitivity to carbon dioxide.

Pharmacokinetics. Morphine: oral bioavailability 20 to 30%, half-life 2 to 4 hours, glucuronide metabolites renally cleared. Oxycodone: bioavailability 60 to 80%, CYP3A4 and 2D6. Fentanyl: onset within 2 minutes intravenously, duration 30 to 60 minutes, redistributes, and context-sensitive half-life lengthens with infusion. Methadone: half-life 15 to 60 hours, highly variable.

Morphine.

• Oral immediate-release: 5 to 10 mg every 4 hours (2.5 to 5 mg if frail, elderly or renal impairment).
• Subcutaneous or intramuscular: 2.5 to 10 mg every 4 hours.
• Intravenous bolus titration: 1 to 2 mg every 5 minutes until pain relief.
• Patient-controlled analgesia: 1 mg bolus, 5 to 6 minute lockout, without background infusion in opioid-naive patients.
• Modified-release: only after daily need is known; give half of the daily requirement as each 12-hourly dose.
• Breakthrough: one tenth to one sixth of the 24-hour dose.

Oxycodone. 5 mg orally every 4 to 6 hours; breakthrough one tenth to one sixth of daily dose; fewer neuroexcitatory metabolites but still accumulates in renal failure.

Hydromorphone. 1 to 2 mg orally every 4 to 6 hours; 0.2 to 0.5 mg intravenously titrated; a useful alternative in renal impairment with reduced doses.

Fentanyl. 25 to 50 micrograms intravenously, titrated; intranasal in children 1.5 micrograms/kg; transdermal patches (12 to 100 micrograms/hour, changed every 72 hours) only for stable, opioid-tolerant patients taking at least 60 mg oral morphine equivalent daily for 1 week or more.

Methadone and pethidine. Methadone is specialist only because of accumulation and QT prolongation. Pethidine is avoided because norpethidine causes seizures and serotonin syndrome.

Diamorphine and tapentadol. Diamorphine is used in some regions and is highly soluble for subcutaneous infusion; tapentadol 50 mg orally every 4 to 6 hours, maximum 600 mg daily, with noradrenergic effects.

• First-line. Severe acute pain: titrated intravenous morphine or fentanyl. Cancer pain: oral morphine.
• Alternative. Oxycodone or hydromorphone for intolerance; subcutaneous infusion for patients unable to swallow.
• Specialist. Methadone, intrathecal or epidural opioids, patient-controlled analgesia, transdermal fentanyl.
• Emergency. Intravenous morphine 2 mg boluses in major trauma and acute coronary syndrome, with antiemetic and monitored.

Renal impairment. At eGFR under 30 mL/min avoid morphine; prefer fentanyl, hydromorphone or buprenorphine at reduced doses, or oxycodone with caution.

Rotation and conversion. Use equivalence tables, then reduce by 25 to 50%.

Opioid-induced constipation. Prescribe a stimulant laxative (senna 15 to 30 mg at night) with an osmotic laxative from the first dose.

Contraindications. Respiratory depression without ventilatory support; paralytic ileus; head injury with raised intracranial pressure without airway control; acute severe asthma; hypersensitivity; pethidine with monoamine oxidase inhibitors; transdermal fentanyl in opioid-naive patients and acute pain.

Serious adverse effects. Respiratory depression (boxed-warning-level, with benzodiazepines and gabapentinoids); sedation; hypotension; histamine release (morphine); chest-wall rigidity with rapid fentanyl; neurotoxicity and myoclonus with morphine and pethidine in renal failure; constipation; delirium; addiction.

Major interactions. Benzodiazepines, alcohol, gabapentinoids (respiratory depression); CYP3A4 inhibitors such as clarithromycin and ritonavir raise fentanyl, oxycodone and methadone; rifampicin lowers methadone and oxycodone; serotonergic drugs with fentanyl, methadone and pethidine; QT-prolonging drugs with methadone.

Common prescribing errors.

• High starting dose in opioid-naive patients.
• Confusing morphine and hydromorphone doses (a fivefold or greater difference).
• Mixing mg and micrograms.
• Fentanyl patch in opioid-naive patients.
• Heat applied to patches.
• No breakthrough or laxative.

Special groups.

• Pregnancy: single doses in labour cause neonatal respiratory depression; chronic use causes neonatal withdrawal.
• Breastfeeding: morphine at low doses acceptable.
• Children: morphine 0.05 to 0.1 mg/kg intravenously titrated, 0.2 to 0.3 mg/kg orally.
• Older adults and frail: halve starting doses.
• Kidney and liver: avoid morphine in renal failure; reduce doses in hepatic impairment.
• East Africa: oral morphine solution is the usual first strong opioid where available; supply and prescriber authorisation vary by country and facility and should not delay cancer pain relief.

Monitoring. Sedation score, respiratory rate and saturation every 5 to 15 minutes during intravenous titration, then hourly for 2 hours, then every 4 hours; pain scores; bowel chart; renal function.

Referral and escalation. Respiratory rate under 8 breaths/minute or sedation unrousable: naloxone, oxygen, senior help. Specialist palliative or pain input when needing rapid escalation, rotation, neuropathic features or suspected opioid use disorder.

Comparison with alternative classes. Strong opioids are the only agents that reliably treat severe pain, but carry the highest risk of respiratory depression and dependence.