26.3 Palliative Care & End-of-Life Symptom Control

Palliative medicine and terminal symptom management are essential components of the MRCP(UK) examination. Candidates must master the pharmacological principles of strong opioid titration, equianalgesic dose conversions, prescribing safety in renal failure, continuous subcutaneous infusions (syringe drivers), and targeted therapy for end-of-life symptoms.

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1. Cancer Pain & The WHO Analgesic Ladder

The World Health Organization (WHO) three-step analgesic ladder provides the framework for systematic cancer pain pharmacotherapy:

• Step 1 (Mild Pain): Non-opioid analgesics: Paracetamol (1 g QDS) ± Non-Steroidal Anti-Inflammatory Drugs (NSAIDs, e.g. ibuprofen 400 mg TDS or naproxen 500 mg BD with a proton pump inhibitor).
• Step 2 (Moderate Pain): Weak opioids: Codeine phosphate (30–60 mg QDS), dihydrocodeine (30 mg QDS), or tramadol (50–100 mg QDS) ± non-opioids.
• Step 3 (Severe Pain): Strong opioids: Morphine, oxycodone, fentanyl, alfentanil, buprenorphine, or methadone ± non-opioids.
• Adjuvant Analgesics (At Any Step):
  • Neuropathic Pain: Gabapentin, pregabalin, duloxetine, or amitriptyline.
  • Metastatic Bone Pain: NSAIDs, bisphosphonates (zoledronic acid), denosumab, and single-fraction external beam radiotherapy.
  • Visceral Capsular Distension / Raised ICP: Corticosteroids (dexamethasone 4–16 mg daily).

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2. Strong Opioid Titration & Conversion Rules

Oral Morphine: Gold-Standard Step 3 Analgesic

• Initiation in Opioid-Naïve Patients: Begin with immediate-release oral morphine solution (Oramorph) 5 mg to 10 mg every 4 hours as required, or a low-dose modified-release oral morphine (e.g. MST Continus or Zomorph 10 mg to 20 mg twice daily).
• Breakthrough / PRN Pain Rule: The rescue dose for acute breakthrough pain is strictly one-sixth (1/6th) of the total 24-hour regular background oral morphine dose, prescribed every 2 to 4 hours as required. For example, if a patient takes 60 mg modified-release morphine twice daily (total 120 mg/24h), the breakthrough dose is $120 \div 6 = 20\text{ mg}$ immediate-release morphine.
• Dose Titration: If breakthrough doses are required frequently (≥ 2–3 times per day), calculate the total morphine consumed over the preceding 24 hours (regular plus rescue doses) and increase the regular modified-release dose by 30% to 50%.

Opioid Equianalgesic Conversion Ratios

Transdermal Fentanyl & Buprenorphine Patches

• Indications: Strictly indicated for stable, chronic pain in patients who are already opioid-tolerant. They are strictly contraindicated in acute, unstable, rapidly fluctuating pain due to slow onset and prolonged elimination half-life.
• Pharmacokinetics: Highly lipophilic synthetic opioids that form a subcutaneous tissue reservoir. Following initial application, therapeutic serum concentrations take 12 to 24 hours to establish; conversely, after patch removal, drug continues to be absorbed from the dermal depot with an elimination half-life of 17 to 24 hours.
• Replacement Frequency: Fentanyl matrix patches are replaced every 72 hours (3 days). Buprenorphine patches are replaced every 7 days (or 3–4 days depending on formulation).
• Cautions: Systemic heat (pyrexia, heat pads, warm baths) markedly increases dermal blood flow and drug release, risking fatal opioid toxicity. Severe cachexia impairs cutaneous depot formation.

Opioid Prescribing in Renal Impairment (eGFR < 30 mL/min)

Renal clearance of opioids and their active metabolites is a critical source of MRCP examination questions:

• Morphine: Metabolized in the liver by glucuronidation into Morphine-3-Glucuronide (M3G) and Morphine-6-Glucuronide (M6G). M6G is a potent mu-opioid agonist responsible for analgesia and central narcosis; M3G has low opioid affinity but acts as an antagonist and causes central neurotoxicity. In renal impairment (eGFR < 30 mL/min), both metabolites accumulate dramatically, producing severe somnolence, profound respiratory depression, cognitive failure, hallucinations, myoclonus, and hyperalgesia. Avoid morphine in severe renal failure.
• Oxycodone: Metabolized to noroxycodone and oxymorphone. While less toxic than morphine metabolites, they undergo renal elimination and can accumulate. Use with extreme caution and lengthened dosing intervals in mild-to-moderate renal impairment (eGFR 30–50 mL/min).
• Drugs of Choice in Severe Renal Impairment (eGFR < 30 mL/min / Dialysis):
  • Fentanyl: Rapidly metabolized by hepatic CYP3A4 to inactive norfentanyl; negligible renal excretion of active drug. Safe in severe renal impairment.
  • Alfentanil: Ideal for continuous subcutaneous syringe drivers in renal failure due to rapid hepatic metabolism and inactive metabolites.
  • Buprenorphine: Metabolized hepatically and excreted primarily via the biliary/faecal route; unaffected by renal clearance.

Universal Co-Prescriptions with Strong Opioids

• Constipation: Opioids bind mu-receptors in the myenteric plexus, suppressing peristalsis and intestinal secretions. Unlike nausea or sedation, tolerance to constipation never develops. A regular bowel regimen combining a stimulant laxative and an osmotic/softening agent (e.g. senna plus docusate, or macrogol) is mandatory from day one.
• Nausea: Occurs in up to 30% of patients during opioid initiation via stimulation of the chemoreceptor trigger zone (CTZ). Tolerance typically develops within 5 to 7 days. Co-prescribe a low-dose D2-antagonist (e.g. haloperidol 0.5–1.5 mg daily or metoclopramide 10 mg TDS) as required.

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3. Syringe Drivers & Continuous Subcutaneous Infusions (CSCI)

An ambulatory syringe driver (e.g. McKinley T34 / CME BodyGuard) delivers medications by continuous subcutaneous infusion over a 24-hour period.

• Indications for CSCI Initiation:
  1. Persistent nausea, intractable vomiting, or severe gastrointestinal malabsorption;
  2. Severe dysphagia (head and neck cancers, motor neuron disease, stroke);
  3. Mechanical or functional malignant bowel obstruction;
  4. Profound asthenia, altered consciousness, or comatose state in the terminal dying phase.
• Technical Considerations: Diluted in water for injections or 0.9% sodium chloride. Typical infusion sites include the anterior chest wall, upper anterior arm, abdomen, or upper outer thigh (avoiding oedematous, irradiated, or broken skin).

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4. End-of-Life Symptom Management

                      Palliative Symptom Management Pathways
                                         |
     +-------------------+---------------+-------------------+-------------------+
     |                   |                                   |                   |
Nausea & Vomiting    Dyspnoea                            Secretions           Delirium / Agitation
- Chemical:          - Fan therapy (trigeminal)          - Repositioning      - Identify causes
  Haloperidol        - Low-dose morphine SC                (lateral)            (urinary retention)
- Stasis:            - Midazolam (panic/anxiety)         - Hyoscine           - Mild: Haloperidol
  Metoclopramide     - Oxygen only if                      butylbromide       - Severe: Midazolam
- Bowel Obstruction:   SpO2 < 90%                          or Glycopyrronium  - Refractory:
  Buscopan, Octreotide                                   - Avoid deep suction   Levomepromazine

Nausea & Vomiting: Mechanism-Based Prescribing

• Chemical / Metabolic (Opioids, Hypercalcaemia, Uraemia, Chemotherapy): Mediated via dopamine D2 and 5-HT3 receptors in the Chemoreceptor Trigger Zone (CTZ) in the area postrema. First-line: Haloperidol (1.5–3 mg/24h CSCI or 0.5–1.5 mg nocte) or levomepromazine (6.25–12.5 mg/24h CSCI).
• Gastric Stasis / Autonomic Neuropathy (Hepatomegaly, Ascites, Opioids): Mediated via gastric mechanoreceptors. First-line: Prokinetic agents—Metoclopramide (30–60 mg/24h CSCI or 10 mg TDS) or domperidone (blocks peripheral D2 receptors, enhancing gastric motility).
• Malignant Bowel Obstruction (MBO): Occurs in advanced ovarian, colorectal, and gastric malignancies.
  • CRITICAL CONTRAINDICATION: In established mechanical obstruction, prokinetic agents (metoclopramide) are strictly contraindicated because stimulating peristalsis against a closed obstruction causes agonizing colicky pain, bowel ischaemia, and risk of catastrophic bowel perforation.
  • MBO Regimen: Antispasmodic/antisecretory: Hyoscine butylbromide (Buscopan 60–120 mg/24h CSCI); Antiemetic: Cyclizine (150 mg/24h CSCI) or haloperidol; Antisecretory: Octreotide (somatostatin analogue, 300–600 mcg/24h CSCI), which profoundly suppresses gastric, pancreatic, and biliary secretions; plus dexamethasone (8–16 mg SC) to reduce peritumoral oedema.
• Raised Intracranial Pressure / Vestibular Nausea: Mediated via histamine H1 and muscarinic receptors. First-line: Cyclizine (150 mg/24h CSCI or 50 mg TDS) plus dexamethasone (8–16 mg daily).

Palliative Breathlessness (Dyspnoea)

• Non-Pharmacological (First-Line): Directing a cool stream of air from a handheld electric fan across the lower face stimulates mechano-receptors in the trigeminal nerve (V2/V3 sensory distribution), which modulate respiratory centres in the brainstem, reducing the subjective perception of breathlessness. Positioning upright and open windows are complementary.
• Pharmacological Therapy:
  • Low-Dose Opioids: Subcutaneous morphine 1.25 mg to 2.5 mg PRN (or oral morphine 2.5–5 mg PRN; or adding 10–20% to baseline 24-hour syringe driver). Low-dose opioids reduce central ventilatory drive, blunt excessive hypercapnic perception, and alleviate anxiety without causing respiratory depression.
  • Benzodiazepines: Subcutaneous midazolam 2.5 mg PRN (or sublingual lorazepam 0.5 mg) for associated acute anxiety or panic.
  • Supplemental Oxygen: Indicated only if the patient is demonstrably hypoxaemic (SpO₂ < 90%); in non-hypoxaemic patients, oxygen provides no superior benefit over a fan and causes nasal mucosal crusting.

Terminal Respiratory Secretions ("Death Rattle")

• Pathophysiology: Inability of the semi-conscious or comatose patient to swallow or cough up normal salivary and bronchial secretions, resulting in turbulent, oscillating secretions in the hypopharynx during respiration.
• Communication: Reassure the family that the sound does not indicate distress, choking, or suffocation to the dying patient.
• Nursing Measures: Reposition into a lateral semi-prone position to encourage gravitational drainage; gentle oral toileting. Avoid aggressive deep suctioning, which induces gagging, coughing, and mucosal bleeding.
• Antimuscarinic Pharmacotherapy: Must be administered early; antimuscarinics inhibit new fluid production but do not clear pre-existing pooled fluid.
  • Hyoscine butylbromide (Buscopan 20 mg SC PRN or 60–120 mg/24h CSCI): Quarternary ammonium compound; does not cross the blood-brain barrier, thereby avoiding central sedation or paradoxical agitation.
  • Glycopyrronium bromide (200–400 mcg SC PRN or 600–1,200 mcg/24h CSCI): Also does not cross the blood-brain barrier; highly effective antisecretory agent.
  • Hyoscine hydrobromide crosses the blood-brain barrier and causes central sedation and delirium; therefore, it is generally less favoured.

Terminal Agitation & Restlessness

• Screen for Reversible Triggers: Acute urinary retention (palpate bladder, perform bladder scan, insert urethral catheter), severe faecal impaction (perform gentle rectal exam), uncontrolled pain, acute hypoxaemia, or drug-induced akathisia.
• Pharmacotherapy:
  • Midazolam (2.5–5 mg SC PRN or 10–30 mg/24h CSCI): First-line anxiolytic and sedative for terminal anxiety and distress.
  • Haloperidol (1.5–3 mg SC PRN or 3–5 mg/24h CSCI): Preferred for delirium with psychotic symptoms, paranoia, or hallucinations.
  • Levomepromazine (12.5–25 mg SC PRN or 25–50 mg/24h CSCI): Broad-spectrum sedative neuroleptic for refractory terminal agitation.