Morphine

How to prescribe/use (adult perioperative)

IV titration for acute pain: give small boluses and reassess frequently
- Typical: 1–2 mg IV every 2–3 min (or 0.02–0.05 mg/kg in increments) until comfortable; then observe for sedation/respiratory depression
- Aim for analgesia with minimal sedation; document sedation score and RR
PCA morphine (common adult settings; local policy varies)
- Demand dose often 1 mg; lockout 5 min; no background infusion in opioid-naïve adults
- Use antiemetic strategy and regular non-opioid analgesics to reduce opioid requirement
Neuraxial (intrathecal/epidural) morphine: long-acting hydrophilic opioid—requires extended monitoring
- Intrathecal: typical 100–200 micrograms (obstetric often 100 micrograms); epidural: 2–5 mg (institution-dependent)
- Risk of delayed respiratory depression (often 6–12 h; can be up to 24 h); ensure protocolised obs and naloxone availability
Renal impairment: avoid or reduce dose and extend interval; consider alternatives (e.g., fentanyl) due to active metabolites
- Morphine-6-glucuronide accumulates → prolonged opioid effect/respiratory depression; morphine-3-glucuronide → neuroexcitation
Hepatic impairment: reduced clearance and increased bioavailability; start low, go slow
- Reduced first-pass metabolism increases effect of oral dosing; monitor sedation closely

Monitoring and safety

Minimum monitoring after parenteral/neuraxial morphine: RR, sedation score, SpO2 (and ideally capnography in high-risk), pain score, nausea/itching
- High-risk: OSA, elderly/frail, renal failure, obesity, concomitant sedatives, neuraxial morphine
Treat opioid-induced respiratory depression: stimulate, airway support, oxygen/ventilation; titrated naloxone if needed
- Give small IV boluses (e.g., 40–100 micrograms) to restore ventilation while preserving analgesia; consider infusion if recurrent due to longer opioid duration

Class and receptor pharmacology

Phenanthrene opioid; prototype strong opioid analgesic
Receptor actions: primarily μ (μ1 analgesia, μ2 respiratory depression/constipation), also κ and δ to lesser extent
Mechanism: Gi/o-coupled receptors → ↓ adenylyl cyclase, ↓ presynaptic Ca2+ influx, ↑ postsynaptic K+ efflux → reduced neurotransmitter release (e.g., substance P) and neuronal hyperpolarisation
Physiological effects: analgesia (spinal/supraspinal), sedation, euphoria/dysphoria, respiratory depression, cough suppression, miosis, reduced GI motility, biliary spasm, histamine release

Pharmacokinetics (PK)

Physicochemical: relatively hydrophilic compared with fentanyl; slower CNS equilibration; more rostral spread in CSF when neuraxial
Absorption: oral bioavailability low–moderate due to significant first-pass metabolism (variable between individuals)
Distribution: moderate protein binding; crosses placenta; Vd moderate–large
Metabolism: hepatic glucuronidation (UGT2B7) to active M6G and neuroexcitatory M3G; minor N-demethylation
Elimination: renal excretion of metabolites; accumulation in renal failure; half-life ~2–3 h (longer in elderly/renal impairment)
Context: duration of analgesia typically 3–4 h after IV/IM; neuraxial duration much longer (up to 24 h)

Pharmacodynamics (PD) and dose–response

Analgesic potency: reference opioid; fentanyl ~100× more potent (approx), oxycodone ~1.5× oral potency vs oral morphine (approx; varies)
Ceiling effect: none for analgesia/respiratory depression (full agonist at μ)
Respiratory depression: reduced brainstem CO2 responsiveness; worsened by sleep, sedatives, OSA, neuraxial morphine, renal failure
Cardiovascular: usually stable; histamine release can cause vasodilation, hypotension, flushing; bradycardia via vagal tone
GI/GU: nausea/vomiting (CTZ/vestibular), constipation (reduced peristalsis), urinary retention (esp neuraxial), biliary colic (sphincter of Oddi spasm)
CNS: sedation, pruritus (esp neuraxial; central mechanism), miosis; at high doses or with M3G accumulation → myoclonus, agitation, delirium

Indications (anaesthesia/ICU/pain)

Moderate–severe acute pain: perioperative, trauma, burns; adjunct in balanced anaesthesia (less common now than fentanyl/remifentanil for intra-op)
Neuraxial opioid for postoperative analgesia (e.g., major abdominal, caesarean section) where long duration desirable
Palliative care: chronic cancer pain (oral modified release and immediate release for breakthrough)
Acute pulmonary oedema (historical/selected use): anxiolysis/venodilation; use cautiously due to respiratory depression and evidence base

Contraindications and cautions

Absolute/strong: hypersensitivity; acute severe respiratory depression without ventilatory support
Caution: OSA, obesity, elderly, head injury/raised ICP (CO2 retention → cerebral vasodilation), severe asthma/COPD, hypotension, hypovolaemia
Renal failure: avoid or major dose reduction; monitor for prolonged sedation, myoclonus, delirium
Biliary disease/pancreatitis: may worsen pain due to sphincter of Oddi spasm (class effect; clinical relevance variable)
Concomitant CNS depressants (benzodiazepines, gabapentinoids, alcohol) increase risk of sedation and respiratory depression

Adverse effects and management

Respiratory depression: reduce/stop opioid, support airway/ventilation; titrated naloxone; consider infusion due to shorter naloxone half-life
Nausea/vomiting: antiemetics (ondansetron, cyclizine, droperidol per policy), hydration, reduce opioid dose with multimodal analgesia
Pruritus (esp neuraxial): low-dose naloxone infusion, nalbuphine, antihistamines often less effective if central mechanism
Constipation: stimulant + softener (e.g., senna + docusate) and/or macrogols; consider peripherally acting μ-antagonists in refractory cases
Urinary retention: monitor bladder; catheterise if needed; more common with neuraxial opioids
Histamine-mediated hypotension/bronchospasm: slow administration, fluids/vasopressors; consider alternative opioid if problematic

Drug interactions

Additive CNS/respiratory depression with benzodiazepines, propofol, volatile agents, gabapentinoids, sedating antihistamines, alcohol
MAOIs/serotonergic drugs: morphine has minimal serotonergic activity compared with some opioids (e.g., tramadol, meperidine), but caution with polypharmacy and altered mental state
Mixed agonist–antagonists (e.g., nalbuphine, buprenorphine) can reduce morphine effect or precipitate withdrawal in dependent patients

Special situations

Pregnancy/labour: crosses placenta; neonatal respiratory depression possible; neuraxial morphine commonly used post-caesarean with monitoring
Breastfeeding: generally compatible in usual doses but monitor infant for sedation/poor feeding; avoid high doses and prolonged use
Opioid tolerance/dependence: higher doses required; avoid abrupt cessation; consider multimodal and regional techniques; plan for withdrawal risk
Acute pain in chronic opioid users: continue baseline opioid, add short-acting opioid for acute pain, and use non-opioid adjuncts; consider ketamine, clonidine/dexmedetomidine, regional

Describe the pharmacology of morphine.

Structure your answer: class/receptors → mechanism → PK → PD effects → metabolism/metabolites → key cautions.

Class: strong opioid; phenanthrene; predominantly μ-receptor agonist
Mechanism: Gi/o-coupled μ receptor → ↓cAMP, ↓presynaptic Ca2+ entry, ↑postsynaptic K+ efflux → reduced nociceptive transmission
PK: relatively hydrophilic; slower CNS onset than fentanyl; oral bioavailability reduced by first-pass; hepatic glucuronidation; renal excretion of metabolites
Metabolites: M6G active (analgesia/resp depression); M3G neuroexcitatory (myoclonus, agitation); both accumulate in renal failure
PD: analgesia, sedation, respiratory depression, miosis, nausea/vomiting, constipation, pruritus, urinary retention; histamine release → hypotension

Why is morphine problematic in renal failure? What would you use instead?

Examiners want metabolites + clinical consequences + safer alternatives.

Morphine is glucuronidated to M6G (active) and M3G (neuroexcitatory); both are renally excreted and accumulate when GFR is low
Consequences: prolonged sedation and respiratory depression (M6G), confusion/delirium and myoclonus (M3G)
Management: avoid or reduce dose markedly and extend interval; close monitoring; treat toxicity with ventilatory support and titrated naloxone
Alternatives in severe renal impairment: fentanyl/alfentanil (no active renally cleared metabolites), remifentanil (esterases), consider oxycodone with caution; seek pain/renal guidance

Compare morphine with fentanyl (PK/PD and clinical implications).

A common FRCA comparison: lipid solubility, onset/duration, histamine, neuraxial spread, metabolism.

Lipid solubility: morphine less lipophilic → slower onset; fentanyl highly lipophilic → rapid onset
Duration: morphine longer clinical duration after bolus; fentanyl shorter after small bolus but can accumulate with infusion (context-sensitive half-time increases)
Histamine: morphine can cause histamine-mediated vasodilation/hypotension; fentanyl minimal histamine release
Neuraxial: morphine hydrophilic → wider CSF spread and delayed respiratory depression; fentanyl lipophilic → faster onset, more segmental, less delayed depression
Metabolism: morphine → M6G/M3G (renal issues); fentanyl hepatic metabolism to inactive metabolites

Explain opioid-induced respiratory depression and how you would manage it after morphine.

Focus on physiology, risk factors, and practical naloxone titration.

Mechanism: μ-receptor activation in brainstem reduces ventilatory response to CO2 and hypoxia; sedation worsens airway obstruction (especially OSA)
Recognise: rising sedation score precedes apnoea; low RR, shallow breathing, hypercapnia; miosis may be present
Immediate management: call for help; stimulate; airway manoeuvres; oxygen; support ventilation (bag-mask/NIV/intubation as required)
Naloxone: titrate IV boluses (e.g., 40–100 micrograms) to adequate ventilation; avoid large bolus that abolishes analgesia and precipitates acute withdrawal
Re-sedation: naloxone duration may be shorter than morphine/M6G; consider infusion and ongoing monitoring

What are the advantages and disadvantages of intrathecal morphine?

Key points: long duration, excellent analgesia, but delayed respiratory depression and pruritus.

Advantages: profound postoperative analgesia (often 12–24 h), opioid-sparing, improved mobilisation and respiratory mechanics when pain is well controlled
Disadvantages: pruritus, nausea/vomiting, urinary retention, and delayed respiratory depression due to rostral CSF spread
Risk factors for respiratory depression: higher dose, elderly, OSA, obesity, concomitant sedatives, magnesium, and systemic opioids
Monitoring: protocolised observations for at least 12–24 h (depending on local policy), with sedation score and RR; naloxone available

A patient has severe pain despite repeated morphine boluses. How do you approach this?

Demonstrate safe titration, reassessment, and differential diagnosis of uncontrolled pain.

Reassess: confirm pain source and exclude surgical complication (bleeding, compartment syndrome, ischaemia), neuropathic pain, bladder retention, tight cast/dressing
Assess opioid effect: sedation score, RR, SpO2/EtCO2; avoid chasing pain into respiratory depression
Optimise multimodal: paracetamol, NSAID (if appropriate), regional/neuraxial techniques, ketamine (opioid-tolerant), clonidine/dexmedetomidine where suitable
Consider opioid issues: tolerance, opioid-induced hyperalgesia (less typical with morphine than remifentanil but possible), wrong diagnosis, inadequate dosing interval
If escalating doses: senior review; consider alternative opioid (e.g., fentanyl) and monitored setting

Explain the causes of pruritus after neuraxial morphine and how you treat it.

Central mechanism and opioid antagonist/agonist-antagonist treatments are key.

Mechanism: mainly central (μ-receptor-mediated) rather than histamine; therefore antihistamines may sedate but often do not treat itch effectively
Treatment options: low-dose naloxone infusion (reduces itch with minimal analgesia loss), nalbuphine (κ-agonist/μ-antagonist), ondansetron sometimes used
Supportive: reassure, cool packs; avoid excessive sedating antihistamines in patients at risk of respiratory depression

List the main side effects of morphine and give a brief mechanism for each.

A classic viva list: respiratory, CVS, GI, CNS, GU, skin.

Respiratory depression: reduced brainstem CO2 sensitivity (μ2)
Nausea/vomiting: CTZ stimulation + vestibular sensitisation; delayed gastric emptying
Constipation: reduced peristalsis and increased sphincter tone (μ in gut)
Hypotension/flushing: histamine release and vasodilation; bradycardia via vagal tone
Pruritus: central μ effect (especially neuraxial)
Urinary retention: increased sphincter tone and reduced detrusor contractility (worse with neuraxial)
Miosis: parasympathetic stimulation of Edinger–Westphal nucleus

How would you convert oral morphine to IV morphine in the perioperative period?

State that ratios vary; show safe principles: reduce dose, titrate, and monitor.

Recognise variability: oral morphine bioavailability is variable; conversion ratios are approximate and depend on formulation and patient factors
Rule-of-thumb often used: IV morphine is roughly 2–3 times as potent as oral (i.e., oral:IV ≈ 2–3:1), but start conservatively and titrate to effect
Account for: age, renal/hepatic function, pain severity, opioid tolerance, and concurrent sedatives
Practical approach: continue baseline opioid where possible; if NBM convert to parenteral with dose reduction and close monitoring; consider PCA