What is the recommended dosage and management of morphine for palliative care in patients with co-morbidities, including impaired renal (kidney) function or hepatic (liver) impairment?

Morphine in Palliative Care: Dosage and Management with Co-morbidities

In patients with renal impairment (eGFR <30 mL/min), fentanyl or buprenorphine via transdermal route or intravenously are the safest opioids of choice rather than morphine, which requires significant dose reduction and careful monitoring if used. 1

Mechanism of Action

Morphine produces analgesia by:

• Binding to μ-opioid receptors in the central nervous system
• Reducing neurotransmitter release presynaptically
• Hyperpolarizing dorsal horn neurons postsynaptically, preventing rostral transmission of pain signals 2

Pharmacokinetics in Normal Function

• Absorption: Oral bioavailability 30-40%
• Distribution: Hydrophilic with moderate volume of distribution
• Metabolism: Primarily hepatic via glucuronidation (UGT2B7), producing active metabolite morphine-6-glucuronide
• Elimination: Primarily renal excretion of metabolites
• Half-life: 2-4 hours for immediate release formulations 1

Standard Dosing in Palliative Care

1. Initial Titration:

   • Start with immediate-release morphine 2.5-5 mg orally every 4 hours for opioid-naïve elderly patients 3
   • Titrate by 25-50% every 24 hours based on pain control and side effects 3
   • Use the same dose for breakthrough pain as the regular 4-hourly dose 1

2. Maintenance:

   • Convert to controlled-release formulation once stable dosing established
   • For 12-hourly controlled release morphine, use one-third of the regular dose as breakthrough dose 1
   • Double dose at bedtime for patients on 4-hourly regimen to avoid nighttime awakening 1

Dosage Adjustments for Co-morbidities

Renal Impairment

• Mild-Moderate Impairment:

  • Reduce dose by 25-50%
  • Extend dosing interval
  • Monitor closely for signs of toxicity 4

• Severe Impairment (eGFR <30 mL/min):

  • Avoid morphine if possible - consider fentanyl or buprenorphine instead 1
  • If morphine must be used:
    • Reduce dose by 50-75%
    • Extend dosing interval to 6-8 hours
    • Monitor for signs of toxicity from accumulation of morphine-6-glucuronide 5

Hepatic Impairment

• Mild-Moderate Impairment:

  • Start with lower than usual dosage
  • Titrate slowly while monitoring for respiratory depression and sedation 4

• Severe Impairment:

  • Reduce initial dose by 50%
  • Extend dosing interval
  • Titrate very cautiously 4

Elderly Patients

• Start at lower doses (2.5-5 mg oral morphine every 4 hours)
• Titrate more slowly (25% increases every 24-48 hours)
• Monitor closely for CNS effects (confusion, drowsiness)
• Be aware of increased sensitivity due to decreased renal function 3

Alternative Routes of Administration

When oral route is not feasible:

1. Subcutaneous:

   • Relative potency ratio of oral to subcutaneous morphine is 1:2 1
   • Can be given as bolus injections every 4 hours or continuous infusion

2. Rectal:

   • Bioavailability same as oral route
   • Potency ratio of oral to rectal is 1:1 1

3. Intravenous:

   • Relative potency ratio of oral to IV morphine is 1:3 1
   • Preferred for severe pain requiring urgent relief

Management of Side Effects

1. Constipation:

   • Always prescribe prophylactic laxatives 1, 3
   • Not subject to tolerance development

2. Nausea/Vomiting:

   • Prescribe metoclopramide or antidopaminergic drugs prophylactically for first few days 1, 3
   • Usually resolves within 3-5 days

3. Sedation/Confusion:

   • Usually transient during initiation or dose increases
   • If persistent, consider dose reduction or opioid rotation

4. Respiratory Depression:

   • Rare in opioid-tolerant patients with appropriate dose titration
   • Higher risk in elderly, those with respiratory disease, or renal impairment

Breakthrough Pain Management

• For patients on immediate-release morphine: use the same dose as regular 4-hourly dose
• For patients on controlled-release morphine: use one-third of the 12-hourly dose 1
• For predictable breakthrough pain: administer at least 20 minutes before pain trigger 1

Common Pitfalls and Caveats

1. Failure to adjust dose in renal impairment:

   • Morphine metabolites accumulate in renal failure, leading to toxicity
   • Consider alternative opioids like fentanyl or buprenorphine in severe renal impairment 5

2. Inadequate breakthrough dosing:

   • Using too small a rescue dose leads to poor pain control
   • The full dose is more likely to be effective 1

3. Neglecting prophylactic measures:

   • Always prescribe laxatives to prevent constipation
   • Consider prophylactic antiemetics for the first few days 3

4. Fear of high doses when needed:

   • High-dose morphine can be safely administered when titrated appropriately
   • No evidence that properly titrated morphine shortens life 6

5. Inappropriate dosing frequency:

   • Immediate-release morphine should not be given more frequently than every 4 hours
   • Controlled-release morphine should not be given more frequently than every 12 hours (except in select cases) 1