In palliative patients, is midazolam or methotrimeprazine better for anxiety and agitation?

Midazolam is Superior to Methotrimeprazine for Anxiety and Agitation in Palliative Patients

Midazolam is the preferred agent for managing anxiety and agitation in palliative patients due to its rapid onset of action, multiple administration routes, and proven efficacy in palliative sedation. 1, 2

Comparison of Medications

Midazolam

• Pharmacology: Water-soluble, short-acting benzodiazepine with rapid CNS penetration
• Advantages:
  • Rapid onset of action
  • Multiple administration routes (IV, SC)
  • Can be co-administered with morphine or haloperidol
  • Considered one of the four essential drugs for quality care in dying patients 3
• Dosing: Starting dose 0.5-1 mg/h continuous infusion or 1-5 mg PRN; usual effective dose 1-20 mg/h 1

Methotrimeprazine (Levomepromazine)

• Pharmacology: Antipsychotic phenothiazine
• Advantages:
  • Antipsychotic effect for delirium
  • Some analgesic effect
  • Multiple administration routes (oral, IV, SC, IM)
• Dosing: Starting dose 12.5-25 mg; usual effective dose 12.5-25 mg every 8h with PRN dosing 1

Decision Algorithm for Medication Selection

1. For primary anxiety/agitation without delirium:

   • First choice: Midazolam (0.5-1 mg/h or 1-5 mg PRN)
   • Faster onset and shorter duration allows for better titration
   • More effective for rapid control of symptoms 4

2. For agitation with delirium:

   • First choice: Antipsychotic (methotrimeprazine 12.5-25 mg)
   • Consider adding midazolam if symptoms persist
   • Combination therapy often more effective than monotherapy 4

3. For terminal restlessness:

   • First choice: Midazolam continuous infusion
   • Escalate dose as needed for symptom control
   • Consider adding methotrimeprazine if delirium is present 2

Evidence Supporting Midazolam

The ESMO Clinical Practice Guidelines specifically recommend midazolam as the first-line agent for palliative sedation, noting its rapid onset and effectiveness 1. A comparative study demonstrated that protocols including midazolam controlled agitation more effectively (84% vs 64% with single agent) and more rapidly (15 minutes vs 60 minutes) than protocols without it 4.

Important Considerations

• Dosage adjustments: Reduce doses in elderly patients, those with renal/hepatic impairment, or patients on concurrent opioids 1, 5
• Monitoring: For non-imminently dying patients, monitor sedation level and vital signs; for imminently dying patients, focus only on comfort parameters 1
• Route selection: Subcutaneous or intravenous routes preferred in terminal stages 2
• Breakthrough dosing: Always provide for breakthrough medication 2

Potential Pitfalls

• Misdiagnosing delirium as anxiety can worsen symptoms if treated with benzodiazepines alone 2
• Inadequate dosing is common; terminal restlessness often requires higher doses than standard practice 2
• Abrupt discontinuation can cause rebound agitation 2
• Respiratory depression can occur, particularly with high doses or in patients with pulmonary insufficiency 6

While methotrimeprazine has advantages for patients with delirium or psychotic symptoms, midazolam's pharmacokinetic profile, rapid onset, and proven efficacy make it the superior choice for managing anxiety and agitation in most palliative care patients.