Palliative Pain Management

1. Clinical Overview

Summary

Effective pain management is the cornerstone of palliative care, affecting 70-90% of patients with advanced cancer and requiring systematic, evidence-based approaches. [1,2] The principles are guided by the WHO Analgesic Ladder, which emphasises a stepwise approach encapsulated in the mantra: "By the mouth, by the clock, by the ladder, for the individual". [3] Morphine remains the gold standard strong opioid for moderate-to-severe cancer pain, though individualization based on patient factors (renal function, prior opioid exposure, comorbidities) is essential. [4,5]

Successful management requires not just prescribing opioids, but:

• Proactive side effect management (Constipation/Nausea)
• Adjuvant analgesia (for neuropathic/bone/visceral pain)
• Recognition and management of opioid toxicity
• Addressing total pain (physical, psychological, social, spiritual)
• Regular reassessment using validated pain scales

Pain in palliative care is multidimensional. Dame Cicely Saunders introduced the concept of "Total Pain", recognizing that physical pain is amplified by psychological distress, social isolation, and spiritual suffering. [6] Effective management requires holistic assessment and interdisciplinary collaboration.

Key Principles

The Four Pillars of WHO Analgesic Ladder

1. By the Mouth (Oral Route Preferred)

   • Non-invasive, preserves autonomy
   • Maintains steady plasma levels
   • Alternative routes when oral route compromised: subcutaneous, transdermal, rectal, sublingual [7]

2. By the Clock (Regular Dosing)

   • Prevents pain returning rather than chasing pain
   • Modified release formulations BD (e.g., MST, Zomorph)
   • PRN doses for breakthrough pain only (not primary analgesia)
   • Prevents "pain memory" and central sensitization [8]

3. By the Ladder (Stepwise Escalation)

   • Step 1: Non-opioid ± Adjuvant
   • Step 2: Weak opioid + Non-opioid ± Adjuvant
   • Step 3: Strong opioid + Non-opioid ± Adjuvant
   • Modern approach: Consider skipping Step 2 in severe pain [9]

4. For the Individual (Personalized Care)

   • Tailor to pain mechanism, patient factors, comorbidities
   • Cultural and spiritual considerations
   • Patient preferences and goals of care

Clinical Pearls

The 1/6th Rule: The breakthrough dose (for "rescue" pain relief) should always be 1/6th of the total 24-hour regular opioid dose.

• Example: Patient on Zomorph 30mg BD (Total 60mg/24h).
• Breakthrough = 60mg ÷ 6 = 10mg Oramorph PRN (up to hourly).
• Rationale: Based on pharmacokinetic studies showing immediate-release morphine provides effective analgesia at this ratio. [10]

Renal Failure Danger: Morphine is metabolised to Morphine-6-Glucuronide (M6G), a potent active metabolite that is renally excreted. In renal impairment (eGFR less than 30), M6G accumulates causing neurotoxicity (myoclonus, agitation, hallucinations, seizures, coma). [11,12]

• Safe alternatives: Fentanyl, Alfentanil, Buprenorphine (hepatically metabolized to inactive metabolites).
• Avoid: Morphine, Codeine, Dihydrocodeine, Tramadol in severe renal impairment.

Laxatives Are Non-Negotiable: Prescribing a strong opioid without a laxative is clinical negligence. Opioid-induced constipation:

• Occurs in 90-95% of patients [13]
• Does NOT develop tolerance (unlike nausea)
• Can cause bowel obstruction, perforation if untreated
• Start immediately: Senna (stimulant) + Macrogol (osmotic) or Docusate (stool softener)
• Consider peripherally-acting mu-opioid receptor antagonists (PAMORA) like Naloxegol for refractory cases [14]

Opioid Rotation Saves Lives: If pain is poorly controlled despite dose escalation OR toxicity develops, switch to a different opioid. Incomplete cross-tolerance means you can reduce the equivalent dose by 25-50%, maintaining analgesia while reducing side effects. [15]

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2. Pathophysiology of Pain in Advanced Disease

Pain Mechanisms

Understanding pain mechanisms guides treatment selection:

1. Nociceptive Pain

Somatic (well-localized, aching):

• Bone metastases (most common in palliative care)
• Soft tissue invasion
• Post-surgical pain
• Treatment: Opioids ± NSAIDs, radiotherapy for bone pain

Visceral (diffuse, cramping, referred):

• Liver capsule distension
• Bowel obstruction
• Pancreatic cancer
• Treatment: Opioids ± steroids (for capsule pain), antispasmodics

2. Neuropathic Pain

• Nerve compression/infiltration by tumor
• Chemotherapy-induced peripheral neuropathy (CIPN)
• Post-herpetic neuralgia
• Phantom limb pain
• Characteristics: Burning, shooting, electric shock, allodynia, hyperalgesia
• Treatment: Adjuvants (gabapentinoids, tricyclics, SNRIs) ± opioids [16]

3. Mixed Pain

• Most cancer pain involves multiple mechanisms
• Requires combination therapy targeting different pathways

Molecular Mechanisms

Peripheral Sensitization:

• Tumor-induced inflammation releases prostaglandins, bradykinin, substance P
• Lowers nociceptor threshold
• Targeted by: NSAIDs (COX inhibition), steroids

Central Sensitization:

• Prolonged C-fiber activation causes spinal cord hyperexcitability
• NMDA receptor activation
• Wind-up phenomenon
• Targeted by: Ketamine (NMDA antagonist), Methadone (NMDA antagonism + mu-agonism)

Descending Inhibition:

• Opioids enhance descending pain inhibition from periaqueductal gray
• Mu, kappa, delta receptor activation
• Problem: Tolerance develops, requiring dose escalation

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3. The WHO Analgesic Ladder

Step 1: Non-Opioid ± Adjuvant

Paracetamol: 1g QDS (max 4g/24h)

• Mechanism: COX inhibition in CNS
• Hepatotoxic > 4g/day or in liver disease
• Reduce dose in frailty (less than 50kg): 500mg QDS

NSAIDs:

• Ibuprofen: 400mg TDS (lower GI risk)
• Naproxen: 500mg BD (longer half-life, better compliance)
• Diclofenac: 50mg TDS (higher cardiovascular risk)
• Indications: Bone pain, inflammatory pain, soft tissue pain
• Mechanism: COX-1/COX-2 inhibition reduces prostaglandin synthesis
• Contraindications: Active peptic ulcer, severe renal impairment, heart failure
• Gastroprotection: PPI (Omeprazole 20mg OD) if age > 65 or risk factors [17]

COX-2 Selective (Celecoxib):

• Lower GI bleeding risk
• Similar cardiovascular risk to traditional NSAIDs
• Useful if NSAID needed but GI intolerance

Step 2: Weak Opioid + Non-Opioid ± Adjuvant

Codeine: 30-60mg QDS (max 240mg/24h)

• Pro-drug: requires CYP2D6 metabolism to morphine
• 10% of Caucasians are poor metabolizers (no effect)
• 1-2% are ultra-rapid metabolizers (toxicity risk)
• Constipation inevitable
• Conversion: Oral Codeine 60mg ≈ Oral Morphine 6mg

Tramadol: 50-100mg QDS (max 400mg/24h)

• Dual mechanism: Weak mu-agonist + SNRI (Serotonin/Noradrenaline reuptake inhibition)
• Advantages: Lower constipation than pure opioids, useful in neuropathic pain
• Risks:
  • Lowers seizure threshold (avoid in epilepsy)
  • Serotonin syndrome if combined with SSRIs/MAOIs
  • CYP2D6 dependent (variable response)
• Conversion: Oral Tramadol 100mg ≈ Oral Morphine 10mg

Dihydrocodeine: 30mg QDS (alternative to Codeine)

Modern Evidence: The 2019 WHO guidelines suggest considering direct step to strong opioids in moderate-severe pain, bypassing Step 2, due to:

• Ceiling effect of weak opioids
• Similar side effect profile to strong opioids
• Delays in achieving adequate analgesia [9]

Step 3: Strong Opioid + Non-Opioid ± Adjuvant

Morphine: Gold standard

• Immediate Release (IR): Oramorph, Sevredol
  • "Onset: 20-30 minutes"
  • "Duration: 4 hours"
  • Use for titration and breakthrough
• Modified Release (MR): MST, Zomorph
  • "Duration: 12 hours (BD dosing)"
  • Steady state achieved in 24-48 hours
• Metabolism: Hepatic glucuronidation to M3G (inactive) and M6G (active, analgesic, renally excreted)

Oxycodone: Second-line (if morphine intolerance)

• Advantages:
  • Less nausea, hallucinations than morphine
  • Better in renal impairment (though still caution)
  • Better oral bioavailability (~60% vs morphine ~30%)
• Metabolism: CYP2D6 to oxymorphone (minor active metabolite)
• Conversion: Oral Morphine 10mg ≈ Oral Oxycodone 5-7mg (ratio 1.5-2:1)
• Forms: OxyNorm (IR), OxyContin (MR)

Fentanyl: Third-line (patches for stable pain)

• Advantages:
  • Transdermal delivery (compliance, dysphagia)
  • "Lipophilic: crosses BBB rapidly"
  • No active metabolites (safe in renal failure)
  • Less constipation than morphine
• Disadvantages:
  • Slow onset/offset (12-24h to steady state)
  • Requires subcutaneous fat (poor absorption in cachexia)
  • Heat increases absorption (fever, hot bath → toxicity risk)
  • Expensive
• Conversion: See Section 6

Alfentanil: Specialist use (subcutaneous infusions)

• Ultra-short acting fentanyl analogue
• Indication: Renal failure, opioid rotation, CSCI
• Advantage: Rapid titration, predictable in renal impairment
• Conversion: Complex, requires specialist palliative care input

Buprenorphine: Partial mu-agonist

• Advantages:
  • Ceiling effect for respiratory depression (safer)
  • Hepatic metabolism (renal failure safe)
  • Transdermal patches available
• Disadvantages:
  • "Partial agonist: can precipitate withdrawal if switching from full agonist"
  • Difficult to reverse with naloxone (high receptor affinity)
  • Not suitable for severe pain (ceiling effect for analgesia ~3mg/day)

Methadone: Specialist only

• Advantages:
  • NMDA receptor antagonist (neuropathic pain, opioid-induced hyperalgesia)
  • Long, unpredictable half-life (24-36h, up to 150h)
  • Cheap
• Disadvantages:
  • Complex pharmacokinetics (accumulation risk)
  • QT prolongation (Torsades de Pointes risk)
  • Requires specialist palliative care/pain team
  • Difficult conversions (non-linear, ratio changes with morphine dose)

Diamorphine (Heroin): UK use only

• Advantage: High solubility (ideal for subcutaneous/intramuscular injection in small volumes)
• Use: Subcutaneous infusions when oral route lost
• Conversion: Oral Morphine ÷ 3 = SC Diamorphine

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4. Initiating and Titrating Morphine

Opioid-Naive Patient with Moderate-Severe Pain

Immediate Release Morphine Titration:

1. Start Low:

   • Oramorph 5mg every 4 hours (10mg if severe pain or robust patient)
   • Plus PRN dose: Same dose (5mg) for breakthrough pain, minimum 1-hour intervals

2. Assess Response at 24-48 Hours:

   • Count total morphine used (regular + PRN)
   • Example: 5mg x 6 doses = 30mg regular, plus 15mg PRN = 45mg total in 24h

3. Convert to Modified Release:

   • Total daily dose ÷ 2 = BD dose
   • Example: 45mg ÷ 2 = 22.5mg BD → Round to MST 30mg BD
   • Calculate new PRN: 60mg ÷ 6 = 10mg Oramorph PRN

4. Titrate Every 3-7 Days:

   • If > 3 breakthrough doses in 24h, increase regular dose
   • Increase by 30-50% each time
   • Reassess regularly

Patient Currently on Step 2 (Weak Opioid)

Stop Weak Opioid and Calculate Morphine Equivalent:

Example: Patient on Codeine 60mg QDS (total 240mg/24h)

• Codeine 240mg ÷ 10 = Morphine 24mg equivalent
• Start MST 15mg BD (conservative, total 30mg) + Oramorph 5mg PRN
• Alternative: Start IR morphine and titrate as above

Important: Remove weak opioid to avoid confusion and duplication. Don't combine codeine and morphine.

Dose Escalation Principles

• No arbitrary ceiling: Dose according to pain, not fear
• Typical dose range: 30-300mg/24h oral morphine equivalent
• Some patients need > 1000mg/24h: Suggests opioid-resistant pain (consider adjuvants, interventional techniques)
• Fear of addiction is unfounded: Physical dependence ≠ addiction. Psychological addiction rare in cancer pain. [18]
• Fear of respiratory depression: Not clinically significant when titrated appropriately. Pain is an antidote to respiratory depression. [19]

Special Populations

Elderly/Frail:

• Start at 50% usual dose
• Slower titration
• More susceptible to delirium, falls

Renal Impairment (eGFR less than 30):

• Avoid morphine (M6G accumulation)
• Use Fentanyl, Alfentanil, or Buprenorphine
• Oxycodone: Use with caution, reduce dose by 50%

Hepatic Impairment:

• Increased sensitivity, delayed clearance
• Start low, titrate slowly
• Avoid Tramadol, Codeine (pro-drug activation unpredictable)

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5. Conversion Ratios (Opioid Rotation)

Standard Equianalgesic Conversions

Opioid Rotation Strategy

When to Consider Rotation:

1. Inadequate analgesia despite dose escalation
2. Intolerable side effects (nausea, sedation, hallucinations)
3. Opioid-induced neurotoxicity (myoclonus, hyperalgesia)
4. Change in renal function
5. Route change required (e.g., dysphagia)

How to Rotate:

1. Calculate equianalgesic dose of new opioid
2. Reduce by 25-50% (due to incomplete cross-tolerance)
3. Provide breakthrough doses of new opioid
4. Titrate as needed

Example:

• Patient on Morphine 120mg/24h with persistent nausea
• Switch to Oxycodone: 120mg ÷ 1.5 = 80mg equivalent
• Reduce by 25%: 80mg × 0.75 = 60mg Oxycodone per 24h
• Prescribe: OxyContin 30mg BD + OxyNorm 10mg PRN (60mg ÷ 6 = 10mg)

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6. Fentanyl Patches

Indications

• Stable pain (not for rapid titration)
• Poor compliance / Swallowing difficulties
• Renal failure (eGFR less than 30)
• Patient preference (non-oral route)

Available Strengths

• 12 mcg/hr, 25 mcg/hr, 50 mcg/hr, 75 mcg/hr, 100 mcg/hr
• Duration: 72 hours (change every 3 days)

Conversion from Oral Morphine

Conservative Approach (BNF):

Rule of Thumb:

• 12 mcg/hr ≈ 30-45mg Oral Morphine/24h
• 25 mcg/hr ≈ 60-90mg Oral Morphine/24h
• 50 mcg/hr ≈ 120-180mg Oral Morphine/24h

Practical Application

Switching from Oral Morphine to Fentanyl Patch:

1. Apply patch
2. Continue oral morphine at same dose for 12 hours (patch takes 12-24h to reach steady state)
3. After 12h, stop regular morphine, keep PRN
4. Provide oral morphine PRN for breakthrough (calculate as 1/6th of original morphine dose)
5. Reassess at 72h (first patch change)

Switching from Fentanyl Patch to Oral Morphine:

1. Remove patch
2. Start oral morphine 12 hours after removal (fentanyl continues to release from subcutaneous depot)
3. Calculate morphine dose from conversion table

Important Cautions

Heat Increases Absorption:

• Fever, electric blankets, hot baths, saunas increase absorption by 30-50%
• Risk of toxicity
• Monitor closely, provide naloxone education to carers

Cachexia/Low Body Fat:

• Requires subcutaneous fat for absorption
• Poor absorption in very thin patients (less than 40kg, BMI less than 16)
• Consider alternative (alfentanil CSCI)

Skin Reactions:

• Rotate patch sites
• Avoid irritated skin
• Adhesion problems: use Tegaderm overlay

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7. Adjuvant Analgesia

Adjuvants target specific pain mechanisms not fully responsive to opioids alone.

Bone Pain (Most Common in Metastatic Cancer)

Mechanism: Osteoclast activation, periosteal stretch, inflammatory mediators, nerve compression

1. NSAIDs (First-line):

• Inhibit prostaglandin synthesis (drives osteoclast activity)
• Naproxen 500mg BD or Ibuprofen 400mg TDS
• Add PPI if risk factors
• Evidence: RCTs show 30-50% pain reduction [20]

2. Bisphosphonates:

• Inhibit osteoclast-mediated bone resorption
• Zoledronic Acid 4mg IV (single dose, repeat monthly if needed)
• Pamidronate 90mg IV
• Evidence: NNT = 11 for pain reduction in bone metastases [21]
• Bonus: Reduces skeletal-related events (fractures, hypercalcemia, cord compression)

3. Denosumab (RANK-ligand inhibitor):

• Alternative to bisphosphonates
• 120mg SC monthly
• Superior to zoledronic acid for preventing skeletal-related events
• Risk: Osteonecrosis of jaw (dental check before starting)

4. Radiotherapy (Most Effective):

• Single fraction (8Gy) to metastatic lesion
• 60-80% achieve pain relief within 2-4 weeks [22]
• Indications: Localized bone pain, impending fracture
• Wide-field radiotherapy (hemi-body) for multiple sites

5. Steroids:

• Dexamethasone 4-8mg OD
• Reduces peri-tumoral edema, inflammation
• Short-term use (side effects accumulate)

6. Surgical Stabilization:

• Impending pathological fracture (Mirel's score ≥8)
• Weight-bearing bones (femur, spine)

Neuropathic Pain

Characteristics: Burning, shooting, electric shock, numbness, allodynia, hyperalgesia

Mechanisms: Nerve compression, chemotherapy-induced neuropathy, post-herpetic neuralgia, phantom limb

1. Gabapentinoids (First-line):

• Gabapentin: Start 300mg ON, titrate to 300mg TDS, max 3600mg/day
• Pregabalin: Start 75mg BD, titrate to 300mg BD (faster titration, better bioavailability)
• Mechanism: Bind alpha-2-delta calcium channels, reduce neurotransmitter release
• Evidence: NNT = 6-7 for 50% pain relief [23]
• Side effects: Sedation, dizziness, weight gain
• Renal dose adjustment required

2. Tricyclic Antidepressants:

• Amitriptyline: Start 10mg ON, titrate to 25-75mg ON
• Mechanism: Noradrenaline/Serotonin reuptake inhibition, sodium channel blockade
• Evidence: NNT = 3-4 (better than gabapentinoids but more side effects) [24]
• Contraindications: Cardiac conduction defects, glaucoma, urinary retention
• Side effects: Dry mouth, constipation, drowsiness, postural hypotension

3. SNRIs:

• Duloxetine: 60mg OD (especially for chemotherapy-induced neuropathy)
• Evidence: Effective in diabetic neuropathy, CIPN [25]
• Better tolerated than amitriptyline

4. Steroids (Nerve Compression):

• Dexamethasone 8-16mg OD
• Reduces peri-tumoral edema
• Rapid onset (hours-days)
• Essential in spinal cord compression (see Emergency Scenarios)

5. Ketamine (Specialist Use):

• NMDA antagonist
• Used in refractory neuropathic pain, opioid-induced hyperalgesia
• Routes: Oral, SC infusion, IV
• Requires specialist palliative care/pain team
• Side effects: Dissociation, hallucinations, bladder toxicity (long-term)

6. Topical Agents:

• Capsaicin cream: Substance P depletion (burning initially, then numbness)
• Lidocaine patches: Local anesthetic effect

Visceral Pain

Liver Capsule Pain (distension from hepatomegaly/metastases):

• Dexamethasone 8mg OD: Reduces capsular swelling
• NSAIDs
• Opioids (often less effective alone)

Bowel Obstruction:

• Hyoscine Butylbromide 60-120mg/24h CSCI: Antispasmodic
• Octreotide 300-600mcg/24h CSCI: Reduces GI secretions
• Dexamethasone: Reduces peri-tumoral edema (may relieve partial obstruction)
• Avoid pro-kinetics if complete obstruction

Pancreatic Pain:

• Often severe, opioid-resistant
• Coeliac plexus block: Neurolytic injection (CT/EUS-guided)
• Steroids, high-dose opioids, ketamine

Incident Pain (Movement-Related)

Definition: Pain on movement (e.g., weight-bearing, coughing) but minimal at rest

Challenges: Short-acting PRN opioids too slow (30min onset vs brief pain episode)

Strategies:

• Pre-emptive dosing: Take PRN 30 minutes before planned activity
• Faster-acting opioids:
  • "Fentanyl lozenges (Actiq): Onset 10-15 minutes"
  • "Intranasal fentanyl: Onset 5-10 minutes"
• Non-pharmacological: Physiotherapy, supports, bracing
• Interventional: Nerve blocks, vertebroplasty (spinal metastases)

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8. Opioid-Induced Side Effects

Constipation (90-95% of Patients)

Mechanism: Mu-receptor activation in GI tract reduces peristalsis, increases absorption of water

Prevention (Mandatory):

1. Stimulant Laxative:
   • Senna 15-30mg ON (increase to BD if needed)
   • Bisacodyl 10mg ON
2. Osmotic Laxative:
   • Macrogol (Movicol) 1-3 sachets daily
   • Lactulose 15-30ml BD (can cause bloating)
3. Stool Softener:
   • Docusate 200mg BD

Refractory Constipation:

• Naloxegol (PAMORA - Peripherally Acting Mu-Opioid Receptor Antagonist):
  • 25mg OD
  • Reverses constipation without affecting analgesia
  • "Evidence: NNT = 5 for spontaneous bowel movement [14]"
  • Expensive, specialist initiation
• Methylnaltrexone SC injection (alternative PAMORA)

Red Flags:

• No bowel movement for 3 days → Escalate laxatives, consider enema/suppositories
• Abdominal pain, distension, vomiting → Exclude obstruction (AXR)

Nausea and Vomiting (30-40% of Patients)

Mechanisms: Chemoreceptor trigger zone (CTZ) stimulation, gastroparesis, vestibular

Management:

1. First Week (usually transient):
   • Metoclopramide 10mg TDS (pro-kinetic + D2 antagonist)
     • Avoid in bowel obstruction
   • Haloperidol 1.5mg ON or BD (D2 antagonist, less sedating)
2. Persistent Nausea:
   • Levomepromazine 6.25mg ON/BD (broad-spectrum antiemetic)
   • Ondansetron 4-8mg BD (if other causes, e.g., chemotherapy)
3. Consider Opioid Rotation if intractable

Important: Nausea usually settles after 5-7 days (tolerance develops). Constipation does NOT.

Sedation and Drowsiness

Common in First Week:

• Tolerance develops (central mu-receptor desensitization)
• Reassure patient, avoid driving/operating machinery
• Usually resolves by day 5-7

Persistent Sedation:

• Check for opioid toxicity (myoclonus, confusion)
• Exclude other causes (hypercalcemia, brain metastases, medications)
• Consider opioid rotation (switch to oxycodone, less sedating)
• Reduce dose if pain well-controlled

Psychostimulants (Specialist Use):

• Methylphenidate 5-10mg morning: Counteracts sedation
• Limited evidence, used in selected patients

Opioid-Induced Neurotoxicity

Presentation:

• Myoclonus (muscle jerks, especially at night)
• Hallucinations (visual, tactile)
• Confusion, delirium
• Hyperalgesia (paradoxical increase in pain)
• Seizures (rare)

Risk Factors:

• High opioid doses (> 300mg morphine equivalent)
• Renal impairment (M6G accumulation)
• Dehydration
• Concurrent medications (gabapentinoids, benzodiazepines)

Management:

1. Hydration (IV fluids if needed)
2. Opioid Rotation: Switch to alternative opioid (e.g., morphine → oxycodone, reduce by 25-50%)
3. Benzodiazepines for Myoclonus:
   • Clonazepam 0.5mg ON
   • Midazolam SC if severe
4. Treat Delirium: Haloperidol 0.5-1mg
5. Withhold Dose: If severe toxicity, omit next dose, restart at lower dose once improving

Respiratory Depression

Reality: Rare when opioids appropriately titrated for pain. Pain is an antagonist to respiratory depression. [19]

Risk Factors:

• Opioid-naive patient given excessive first dose
• Rapid IV bolus
• Concurrent sedatives (benzodiazepines, gabapentinoids)
• Sleep apnea, COPD

Recognition:

• Respiratory Rate less than 8 breaths/min
• Unrousable
• Cyanosis, pinpoint pupils

Management:

1. Mild (RR 8-10, rousable):
   • Stop opioid
   • Oxygen if hypoxic
   • Observe closely
2. Severe (RR less than 8, unrousable):
   • Naloxone:
     • Caution: Full reversal causes acute withdrawal and excruciating pain
     • Dilute: 400mcg in 10ml saline (40mcg/ml)
     • Give 0.5-1ml (20-40mcg) IV every 2 minutes until RR > 10
     • Goal: Reverse respiratory depression, NOT complete opioid reversal
     • Duration: 30-60 minutes (shorter than morphine) → Re-sedation risk, repeat dosing may be needed
   • Airway support: Bag-valve-mask if needed
3. Restart Opioid: Once stable, reduce dose by 50% and re-titrate

Pruritus (Itching)

Mechanism: Central mu-receptor activation, histamine release (morphine > oxycodone/fentanyl)

Management:

• Antihistamines: Chlorphenamine 4mg TDS
• Switch to Oxycodone (less histamine release)
• Ondansetron 4mg (5-HT3 antagonist, evidence in opioid-induced pruritus)

Opioid-Induced Hyperalgesia (OIH)

Definition: Paradoxical increase in pain sensitivity despite increasing opioid dose

Mechanism: NMDA receptor activation, descending facilitation, glial cell activation

Clues:

• Pain worsens despite dose escalation
• Change in pain character (more diffuse, less localized)
• Allodynia, hyperalgesia

Management:

• Opioid Rotation (preferably to methadone with NMDA antagonism)
• Ketamine infusions
• Dose Reduction (counterintuitive but effective)

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9. Breakthrough Pain Management

Definition

Breakthrough Pain: Transient exacerbation of pain occurring despite adequate background analgesia. [26]

Types:

1. Incident Pain: Predictable, related to activity (movement, coughing, dressing changes)
2. Spontaneous Pain: Unpredictable, no obvious trigger
3. End-of-Dose Failure: Pain before next scheduled dose (inadequate background analgesia)

Characteristics

• Onset: Rapid (often less than 5 minutes)
• Duration: Short (typically 15-60 minutes)
• Frequency: Variable (1-10+ episodes per day)

Management Principles

1. Assess Background Analgesia:

• If > 4 breakthrough doses per 24h → Increase regular opioid dose
• Calculate total opioid use (regular + PRN) and adjust regular dose accordingly

2. Optimize PRN Dosing:

• Dose: 1/6th of total 24h opioid dose
• Timing: Can be repeated hourly (4-hourly if modified release)
• Route: Match speed of pain onset
  • "Oral IR morphine: Onset 20-30min (suitable for slower-onset breakthrough pain)"
  • "Fentanyl products: Faster onset"

3. Rapid-Onset Opioids for Incident Pain:

Important: These products are NOT simply scaled-down versions of background fentanyl. They require separate titration starting from lowest dose (regardless of background opioid).

4. Pre-emptive Analgesia:

• For predictable incident pain (e.g., dressing changes, physiotherapy)
• Give PRN dose 30 minutes before planned activity

Algorithm for Uncontrolled Breakthrough Pain

> 4 Breakthrough Doses in 24h
           ↓
  Calculate Total Opioid Use
  (Regular + All PRN doses)
           ↓
    Increase Regular Dose by 30-50%
           ↓
  Recalculate PRN (1/6th of new total)
           ↓
      Reassess in 24-48h

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10. Special Situations

Renal Impairment (eGFR less than 30)

Problem: Morphine-6-Glucuronide (M6G) accumulation → Neurotoxicity

Safe Opioids (No Dose Adjustment):

• Fentanyl (transdermal patches or SC infusion)
• Alfentanil (SC infusion)
• Buprenorphine (patches)

Use with Caution (Reduce Dose by 50%, Monitor Closely):

• Oxycodone: Minor renal excretion, but safer than morphine

AVOID:

• Morphine
• Codeine (metabolized to morphine)
• Tramadol
• Dihydrocodeine

Hepatic Impairment

Problem: Reduced metabolism, increased bioavailability, accumulation

Approach:

• Start at 50% usual dose
• Extend dosing intervals
• Monitor for sedation, confusion
• Avoid Tramadol, Codeine (unpredictable pro-drug activation)

Safest Options:

• Oxycodone (some hepatic impairment data)
• Fentanyl (predictable even in liver disease)

Elderly and Frail

Considerations:

• Reduced clearance, increased sensitivity
• Polypharmacy (drug interactions)
• Falls risk (sedation, postural hypotension)
• Cognitive impairment (delirium risk)

Approach:

• "Start low, go slow": 50% usual starting dose
• Simplify regimen (BD modified release better than QDS)
• Regular cognitive assessment
• Careful laxative regimen (falls from rushing to toilet)

Cachexia and Low Body Weight

Fentanyl Patches:

• Require subcutaneous fat for absorption
• Poor absorption if BMI less than 16, weight less than 40kg
• Consider alternative: Alfentanil CSCI

Dose Adjustment:

• Consider reducing dose if less than 50kg (especially paracetamol: 500mg QDS max)

Pediatric Palliative Care

Principles: Similar to adults but weight-based dosing

Morphine Dosing:

• Starting dose: 200-400 mcg/kg/dose every 4h (oral)
• SC/IV: 100-200 mcg/kg/dose every 4h
• Titrate according to response
• No arbitrary maximum dose

Challenges:

• Pain assessment in non-verbal children (use FLACC scale)
• Parental anxiety about opioids
• Limited formulations (liquid morphine preferred)

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11. Non-Pharmacological Interventions

Radiotherapy

External Beam Radiotherapy (EBRT):

• Bone Metastases: Single 8Gy fraction, 60-80% pain relief [22]
• Neuropathic Pain (nerve compression): 20Gy in 5 fractions
• Hemi-body Radiotherapy: Multiple bone metastases
• Onset: 1-4 weeks

Radionuclide Therapy:

• Strontium-89, Radium-223 (for widespread bone metastases)
• Bone-seeking isotopes
• Useful in prostate cancer with diffuse bone involvement

Interventional Pain Management

Nerve Blocks:

• Coeliac Plexus Block: Pancreatic cancer pain (50-90% response) [27]
• Paravertebral Block: Chest wall pain
• Intercostal Blocks: Rib metastases, post-thoracotomy pain
• Neurolytic Blocks: Phenol/alcohol for permanent denervation

Intrathecal Drug Delivery:

• Implantable pumps delivering morphine/local anesthetic into CSF
• Indications: Severe pain, inadequate analgesia with systemic opioids, intolerable side effects
• 1/300th of oral morphine dose provides equivalent analgesia
• Specialist pain team/neurosurgery

Vertebroplasty/Kyphoplasty:

• Cement injection into collapsed vertebrae
• Indications: Pathological vertebral compression fractures
• Rapid pain relief (24-48h)
• Evidence mixed (better for acute fractures less than 6 weeks)

Cordotomy:

• Surgical/radiofrequency ablation of spinothalamic tract
• Indications: Unilateral severe pain (mesothelioma, Pancoast tumor)
• Highly effective but risk of complications (motor weakness, breathing issues if bilateral)

Physical and Psychological Therapies

Physiotherapy:

• Passive movements, positioning
• Reduce contractures, maintain function
• TENS (Transcutaneous Electrical Nerve Stimulation)

Occupational Therapy:

• Aids and adaptations
• Energy conservation techniques
• Maintain independence

Psychological Support:

• Cognitive Behavioral Therapy (CBT): Coping strategies
• Mindfulness, relaxation techniques
• Address anxiety and depression (lower pain threshold)

Complementary Therapies:

• Acupuncture: Mixed evidence, may help in selected patients
• Massage: Comfort, human touch, reduces anxiety
• Music therapy, aromatherapy

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12. Difficult Pain Scenarios

Total Opioid-Resistant Pain

Definition: Pain persisting despite morphine equivalent > 300mg/24h

Mechanisms: Often neuropathic, ischemic, or psychological component

Approach:

1. Reassess Pain:
   • Mechanism (nociceptive vs neuropathic vs mixed)
   • Total pain (psychological, social, spiritual distress)
2. Maximize Adjuvants:
   • Gabapentinoids, tricyclics, steroids, NSAIDs
3. Opioid Rotation:
   • Switch to methadone (NMDA antagonism)
4. Add Ketamine (NMDA antagonist):
   • SC infusion 100-500mg/24h
   • Requires specialist team
5. Interventional Techniques:
   • Nerve blocks, intrathecal pumps, cordotomy
6. Holistic Assessment:
   • Psychologist, chaplain, social work
   • Address existential distress ("Why is this happening to me?")

Spinal Cord Compression (Oncological Emergency)

Presentation:

• New/worsening back pain (95%)
• Lower limb weakness (75%)
• Sensory level
• Sphincter dysfunction (late, poor prognostic sign)

Immediate Management:

1. Dexamethasone 16mg IV/PO STAT, then 8mg BD
2. MRI whole spine (within 24h)
3. Neurosurgery/Oncology referral (urgent)
4. Analgesia: High-dose opioids for pain
5. Treatment:
   • Radiotherapy: 20Gy in 5 fractions (if not surgical candidate)
   • Surgical decompression: If single level, good prognosis, radiosensitive tumor

Prognosis: Ambulatory at presentation = 80% remain ambulatory. Paraplegic at presentation = less than 5% regain walking. [28]

Key: Early recognition and treatment critical. Delay causes irreversible paralysis.

Pathological Fracture

Risk Assessment: Mirel's Score

• Site (upper limb, lower limb, peritrochanteric)
• Pain (mild, moderate, functional)
• Lesion type (blastic, mixed, lytic)
• Size (less than 1/3, 1/3-2/3, > 2/3 cortex)
• Score ≥8: High fracture risk → Prophylactic fixation

Management:

• Acute fracture: Surgical fixation if prognosis > 6 weeks
• Impending fracture: Prophylactic internal fixation
• Analgesia: High-dose opioids, nerve blocks

Neuropathic Pain Refractory to First-Line Agents

Escalation:

1. Maximize gabapentin (3600mg/day) or pregabalin (600mg/day)
2. Add amitriptyline (up to 75mg ON)
3. Switch to duloxetine 60-120mg OD
4. Ketamine infusions (specialist)
5. Methadone (NMDA antagonism)
6. Interventional: Nerve blocks, spinal cord stimulation (if prognosis > 3 months)

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13. Palliative Sedation

Definition

Deliberate reduction in consciousness to relieve refractory symptoms at end of life when all other interventions have failed.

NOT euthanasia: Intent is symptom relief, not hastening death. Death occurs from underlying disease.

Indications (Refractory Symptoms)

• Severe pain unresponsive to maximal therapy
• Dyspnea despite opioids, oxygen, bronchodilators
• Agitated delirium
• Severe vomiting/bleeding
• Existential/psychological distress (rare, requires careful ethics review)

Refractory = Symptom cannot be controlled despite aggressive efforts without unacceptable side effects or sedation.

Types

1. Respite Sedation (Temporary):

• Short period (e.g., 24-48h) to allow rest
• Sedation reversed to reassess

2. Continuous Palliative Sedation:

• Maintained until death
• Usually in last hours-days of life

Medications

Midazolam (First-line):

• Start: 2.5-5mg SC bolus, then 10-30mg/24h CSCI
• Titrate to achieve desired sedation level (Ramsay 4-5: asleep, minimal response)
• No ceiling dose

Levomepromazine:

• 12.5-50mg/24h CSCI
• Sedating, broad-spectrum antiemetic

Phenobarbital:

• 600-1200mg/24h CSCI
• Refractory sedation

Ethical Framework

1. Patient/family consent (if patient lacks capacity, family + MDT decision)
2. All reversible causes addressed (hypercalcemia, opioid toxicity)
3. Multidisciplinary team agreement
4. Clear documentation: Indication, rationale, discussions, plan
5. Proportionality: Sedation level proportionate to symptom severity
6. Regular review: Reassess daily

Double Effect Principle: Accepting risk of hastening death as unintended consequence of symptom relief is ethically acceptable if intent is purely symptom control.

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14. Communication and Ethical Considerations

Addressing Patient Fears

"Will I become addicted?"

• Physical dependence ≠ addiction
• Addiction: Psychological craving, drug-seeking behavior, use despite harm
• Cancer pain patients: Addiction rate less than 1% [18]
• Reassure: We titrate to pain, can wean if pain improves

"Will morphine hasten my death?"

• Evidence: Appropriate opioid use does NOT shorten survival [29]
• Pain causes tachycardia, hypertension, stress response → More harmful than opioids
• Goal: Comfort, quality of life

"Is this the end? Are you giving up?"

• Morphine often perceived as "end-of-life drug"
• Explain: Morphine is a tool for severe pain at any stage
• Some patients live years on opioids
• Reassure: We adjust as needed, this is not giving up

Cultural and Spiritual Considerations

Opioid Stigma:

• Some cultures view opioids as morally wrong
• Others fear loss of mental clarity preventing spiritual preparation for death
• Approach: Respect beliefs, explore alternatives, involve family/spiritual leaders

Pain as Redemptive Suffering:

• Some patients (particularly Catholic tradition) view suffering as spiritually meaningful
• Approach: Validate belief, explore nuanced options (moderate analgesia allowing alertness)

Family Dynamics:

• Family may disagree with patient preferences
• Approach: Mediate, emphasize patient autonomy (if capacity), align goals

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15. Emergency Scenarios in Palliative Pain Management

Opioid Overdose

Recognition:

• Respiratory rate less than 8
• Pinpoint pupils
• Unrousable
• Bradycardia, hypotension

Management:

1. Airway: Position, suction, jaw thrust
2. Breathing: Bag-valve-mask if RR less than 6 or apneic
3. Naloxone:
   • Dilute 400mcg in 10ml saline (40mcg/ml)
   • Give 0.5-1ml (20-40mcg) IV every 2min until RR > 10
   • Avoid full reversal (pain crisis)
4. Monitor: Re-sedation risk (naloxone shorter half-life than morphine)
5. Admit: HDU/ICU if severe

Acute Severe Pain (Pain Crisis)

Causes: Pathological fracture, visceral perforation, bleeding into tumor

Management:

1. Assess: History, examination, imaging if needed
2. Analgesia:
   • IV/SC Morphine: 2.5-5mg bolus, repeat every 10min until pain controlled (no ceiling)
   • Ketamine: 10-25mg IV bolus (specialist)
3. Treat Cause: Surgical fixation, radiotherapy, embolization
4. Admit: Inpatient hospice/palliative care unit

Hypercalcemia (Common Cause of Pain Exacerbation)

Presentation: Confusion, thirst, polyuria, constipation, bone pain

Investigations: Corrected Calcium > 2.6 mmol/L

Management:

1. IV Fluids: 0.9% Saline 1L over 4-6h (rehydrate)
2. Bisphosphonate: Zoledronic Acid 4mg IV (onset 2-4 days)
3. Monitor: Renal function, electrolytes
4. Analgesia: Pain often improves with calcium correction

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16. Transitioning Routes: When Oral Route Lost

Common Reasons

• Dysphagia (head/neck cancer, esophageal obstruction)
• Severe nausea/vomiting
• Reduced consciousness
• Intestinal obstruction
• Patient preference

Alternative Routes

Subcutaneous (Preferred):

• Advantages: Simple, can be managed at home, suitable for CSCI (Continuous Subcutaneous Infusion)
• Disadvantages: Requires site changes every 3-7 days, limited volume (less than 2ml/h)
• Opioids: Morphine, Diamorphine (UK - highly soluble), Alfentanil, Oxycodone
• Conversion: Oral Morphine ÷ 2 = SC Morphine

Transdermal:

• Fentanyl patches (see Section 6)
• Buprenorphine patches
• Slow onset/offset, requires stable pain

Rectal:

• Morphine suppositories (same dose as oral)
• Useful if short-term loss of oral route
• Cultural acceptability varies

Intravenous:

• Hospital setting, central/peripheral access
• Same dose as subcutaneous
• Avoid if possible (infection risk, limits mobility)

Sublingual/Buccal:

• Fentanyl lozenges, sublingual tablets
• Faster onset than oral
• Useful for breakthrough pain

Setting Up a Syringe Driver (CSCI)

Indications:

• Unable to take oral medication
• Poor compliance
• Frequent vomiting

McKinley T34 / Graseby MS26 (Common UK devices):

Example Prescription:

• Patient on Oral Morphine 60mg/24h (MST 30mg BD)
• Switch to SC Diamorphine: 60mg ÷ 3 = 20mg/24h
• Add Levomepromazine 6.25mg (antiemetic)
• Add Hyoscine Butylbromide 60mg (antisecretory)
• Make up to 10ml with Water for Injection
• Set syringe driver to deliver over 24 hours

Monitoring:

• Check site daily (redness, swelling, pain → Change site)
• Reassess symptoms every 24h
• Provide PRN SC doses (1/6th of 24h dose) for breakthrough

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17. Examination Focus

Common OSCE/Viva Scenarios

Scenario 1: Prescribing Morphine

• "Patient with metastatic lung cancer, currently on Paracetamol 1g QDS and Codeine 60mg QDS. Pain score 7/10. Prescribe strong opioid."

Answer:

1. Stop Codeine (avoid duplication)
2. Calculate morphine equivalent: Codeine 240mg/24h ÷ 10 = 24mg morphine equivalent
3. Start MST 15mg BD (conservative) or Oramorph 5mg 4-hourly
4. Provide Oramorph 5mg PRN (hourly if needed)
5. Prescribe Senna 15mg ON + Macrogol 1 sachet OD (laxatives)
6. Prescribe Metoclopramide 10mg TDS PRN (antiemetic)
7. Review in 24-48h, titrate according to response

Scenario 2: Calculating Breakthrough Dose

• "Patient on MST 60mg BD. What is the PRN dose?"

Answer:

• Total 24h dose = 120mg
• Breakthrough = 120mg ÷ 6 = 20mg Oramorph PRN (hourly if needed)

Scenario 3: Renal Impairment

• "Patient with eGFR 18, metastatic renal cancer, severe bone pain. Current morphine 90mg/24h causing confusion and myoclonus. Manage."

Answer:

1. Recognize opioid neurotoxicity (M6G accumulation in renal failure)
2. Rehydrate (IV fluids)
3. Opioid Rotation to renal-safe opioid:
   • Fentanyl patch: Morphine 90mg ≈ 25mcg/h patch
   • Apply patch, continue morphine for 12h, then stop regular morphine
   • Provide Oramorph PRN for breakthrough (reduced dose)
4. Alternatively: Alfentanil CSCI (requires specialist input, conversion complex)
5. Treat myoclonus: Clonazepam 0.5mg ON

Scenario 4: Bone Pain

• "Patient with prostate cancer, multiple bone metastases, pain despite MST 120mg BD. Adjuvants?"

Answer:

1. NSAIDs: Naproxen 500mg BD + PPI (if no contraindications)
2. Bisphosphonate: Zoledronic Acid 4mg IV (or Denosumab 120mg SC)
3. Radiotherapy: Single 8Gy fraction to most painful site
4. Steroids: Dexamethasone 4mg OD (short-term, reduces peri-tumoral edema)
5. Continue titrating opioid

Scenario 5: Spinal Cord Compression

• "Patient with breast cancer presents with thoracic back pain for 2 weeks, now bilateral leg weakness and difficulty passing urine. Manage."

Answer:

1. Recognize Spinal Cord Compression (oncological emergency)
2. Immediate:
   • Dexamethasone 16mg IV/PO STAT, then 8mg BD
   • Analgesia: Oramorph 10mg IV/SC
   • Catheterize if urinary retention
3. Investigations:
   • MRI whole spine (urgent, within 24h)
4. Referral:
   • Neurosurgery (if single level, good prognosis, radioresistant tumor)
   • Oncology (radiotherapy 20Gy in 5 fractions if not surgical candidate)
5. Prognosis: Ambulatory at presentation = Good chance of remaining ambulatory. Paraplegic = Poor prognosis for recovery.

Viva Questions and Model Answers

Q: What is the mechanism of morphine? A: Morphine is a full mu-opioid receptor agonist. It binds to mu, kappa, and delta receptors in the CNS and periphery. Mu-receptor activation:

• Analgesia: Enhances descending inhibition from periaqueductal gray, inhibits ascending pain pathways
• Respiratory depression: Reduces medullary respiratory center sensitivity to CO2
• Constipation: Mu-receptors in GI tract reduce peristalsis, increase water absorption
• Euphoria/Sedation: Limbic system effects
• Metabolized via hepatic glucuronidation to M3G (inactive) and M6G (active, analgesic, renally excreted).

Q: Why is morphine dangerous in renal failure? A: Morphine-6-Glucuronide (M6G) is an active metabolite with potent analgesic and sedative properties. It is renally excreted. In renal impairment (eGFR less than 30), M6G accumulates, causing:

• Prolonged sedation
• Neurotoxicity (myoclonus, hallucinations, confusion, seizures)
• Respiratory depression Safe alternatives in renal failure: Fentanyl, Alfentanil, Buprenorphine (hepatically metabolized to inactive metabolites).

Q: Describe opioid rotation and its rationale. A: Opioid rotation is switching from one opioid to another when:

• Pain is poorly controlled despite dose escalation
• Intolerable side effects develop
• Pharmacokinetic factors change (e.g., renal impairment)

Rationale: Incomplete cross-tolerance. Different opioids have variable affinities for mu, kappa, delta receptors and different receptor subtypes. Switching allows:

• Dose reduction (typically 25-50% of equianalgesic dose)
• Maintained or improved analgesia
• Reduced side effects

Method: Calculate equianalgesic dose, reduce by 25-50%, titrate to effect.

Q: How do you manage opioid-induced constipation? A:

1. Prevention (mandatory):
   • Start laxatives simultaneously with opioid
   • Stimulant (Senna 15-30mg ON) + Osmotic (Macrogol 1-3 sachets/day)
2. Escalation:
   • Increase laxative doses
   • Add stool softener (Docusate 200mg BD)
3. Rescue:
   • Suppositories (Bisacodyl 10mg)
   • Enema (Phosphate enema)
4. Refractory:
   • Naloxegol (PAMORA) 25mg OD: Peripherally acting mu-opioid receptor antagonist, reverses constipation without affecting analgesia
5. Exclude obstruction if sudden worsening (AXR, examination)

Q: Explain the concept of Total Pain. A: Dame Cicely Saunders described Total Pain as the multidimensional nature of suffering in palliative care:

1. Physical: Tumor invasion, treatment side effects
2. Psychological: Fear, anxiety, depression, anger
3. Social: Loss of role, financial worries, family burden
4. Spiritual: Existential distress, loss of meaning, questioning faith

These dimensions interact: Psychological distress lowers pain threshold, making physical pain worse. Effective pain management requires addressing all dimensions through interdisciplinary team (doctors, nurses, psychologists, social workers, chaplains).

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18. Patient and Layperson Explanation

Will I become addicted?

No. Using morphine for cancer pain does not make you an addict. Addiction means you crave the drug psychologically and seek it for the "high," even when it harms you. This almost never happens when morphine is used for pain.

Your body will get used to the drug (tolerance), so we might need to increase the dose over time, but that's normal and not addiction. If your pain improves, we can reduce the dose safely.

Will the morphine hasten my death?

No. There is a common myth that morphine "finishes people off." This is not true. When used correctly for pain, morphine is very safe. Research shows that patients on morphine for pain live just as long (or longer) as those without good pain control.

Uncontrolled pain causes stress on your body (fast heart rate, high blood pressure), which is more harmful. Morphine allows you to rest, eat, and maintain strength.

Why do I need laxatives?

Morphine slows down your bowel, causing constipation in almost everyone. Unlike nausea (which usually gets better after a week), constipation does NOT improve on its own.

If you don't take laxatives, you will develop severe constipation, which can be more painful and distressing than the cancer itself. We prescribe laxatives at the same time as morphine to prevent this. Think of them as a pair—morphine and laxatives always go together.

What if the morphine makes me sleepy?

It's normal to feel a bit drowsy in the first few days of starting morphine. This usually settles within a week as your body adjusts. Avoid driving or operating machinery during this time.

If drowsiness persists or worsens, let us know. We can adjust the dose or switch to a different pain medication.

Can I still have a glass of wine?

Small amounts of alcohol (e.g., one glass of wine with dinner) are usually safe once you're stable on your morphine dose. Alcohol can add to drowsiness, so start slowly and see how you feel.

Avoid binge drinking, as combining alcohol with morphine increases the risk of dangerous sedation.

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19. Summary: Key Principles for Clinical Practice

1. WHO Ladder: Stepwise approach, but consider skipping Step 2 in severe pain
2. Morphine: Gold standard, start low (5mg IR), titrate to effect, no arbitrary ceiling
3. 1/6th Rule: Breakthrough dose = Total daily dose ÷ 6
4. Laxatives: Non-negotiable, start with opioid (Senna + Macrogol)
5. Renal Failure: Avoid morphine (M6G accumulation), use Fentanyl/Alfentanil/Buprenorphine
6. Adjuvants: Target pain mechanism (NSAIDs for bone, gabapentinoids for neuropathic)
7. Opioid Rotation: Switch opioid if poor control or toxicity, reduce by 25-50%
8. Breakthrough Pain: Rapid-onset opioids for incident pain, optimize background if > 4 PRN/day
9. Total Pain: Address physical, psychological, social, spiritual dimensions
10. Communication: Normalize opioids, address addiction fears, involve patient/family in decisions

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20. References

Primary Sources

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19. Clemens KE, et al. Is there a higher risk of respiratory depression in opioid-naive palliative care patients during symptomatic therapy of dyspnea with strong opioids?. J Palliat Med. 2008;11(2):204-216. doi:10.1089/jpm.2007.0151

20. Mercadante S, et al. Episodic (breakthrough) pain: consensus conference of an expert working group of the European Association for Palliative Care. Cancer. 2002;94(3):832-839. doi:10.1002/cncr.10249

21. Wong MH, et al. Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database Syst Rev. 2002;(2):CD002068. doi:10.1002/14651858.CD002068

22. Chow E, et al. Update of the international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases. Int J Radiat Oncol Biol Phys. 2012;82(5):1730-1737. doi:10.1016/j.ijrobp.2011.02.008

23. Moore RA, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2014;2014(4):CD007938. doi:10.1002/14651858.CD007938.pub3

24. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007;(4):CD005454. doi:10.1002/14651858.CD005454.pub2

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26. Davies AN, et al. Breakthrough cancer pain: an observational study of 1000 European oncology patients. J Pain Symptom Manage. 2013;46(5):619-628. doi:10.1016/j.jpainsymman.2012.12.009

27. Yan BM, Myers RP. Neurolytic celiac plexus block for pain control in unresectable pancreatic cancer. Am J Gastroenterol. 2007;102(2):430-438. doi:10.1111/j.1572-0241.2006.00972.x

28. Loblaw DA, et al. Systematic review of the diagnosis and management of malignant extradural spinal cord compression: the Cancer Care Ontario Practice Guidelines Initiative's Neuro-Oncology Disease Site Group. J Clin Oncol. 2005;23(9):2028-2037. doi:10.1200/JCO.2005.00.067

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Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances, local guidelines, and specialist input where appropriate. Always consult appropriate specialists for complex palliative care scenarios.