Cancer Pain Management - WHO Ladder and Beyond

Quick Answer

How common is cancer pain?

Cancer pain affects 30-50% of patients during treatment and 70-90% of patients with advanced disease. It is the most feared symptom of cancer and significantly impacts quality of life, function, and psychological wellbeing. [1,2]

Types of cancer pain:

WHO Analgesic Ladder (1986, updated 2019):

Step 1 - Mild pain (NRS 1-3):

• Non-opioids: Paracetamol 1 g QID, NSAIDs (if no contraindications)
• Adjuvants: Consider early for neuropathic component

Step 2 - Moderate pain (NRS 4-6):

• Weak opioids: Tramadol 50-100 mg QID, Codeine 30-60 mg QID
• Continue Step 1 agents (multimodal)
• OR low-dose strong opioids (morphine 5-10 mg Q4H)

Step 3 - Severe pain (NRS 7-10):

• Strong opioids: Morphine, oxycodone, fentanyl, methadone, buprenorphine
• No ceiling dose - titrate to pain relief or limiting side effects
• Continue non-opioids and adjuvants

Opioid titration principles:

1. Calculate total 24-hour opioid requirement
2. Increase by 30-50% for uncontrolled pain
3. Provide breakthrough dose: 10-20% of total daily dose (Q1-2H PRN)
4. Reassess every 24-48 hours

Spinal analgesia indications:

• Uncontrolled pain despite high-dose systemic opioids
• Intolerable opioid side effects (sedation, confusion, myoclonus)
• Visceral pain poorly responsive to systemic therapy
• Improved analgesia with reduced systemic side effects

Key principle: Cancer pain is treatable in >90% of patients using WHO guidelines. Early aggressive management, regular reassessment, and attention to breakthrough/incident pain are essential.

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Clinical Overview

Definition and Classification

Cancer Pain Definition: Pain caused by the cancer itself, cancer treatment (surgery, radiation, chemotherapy), or diagnostic procedures. May persist beyond treatment as chronic cancer-related pain.

Classification by Pathophysiology:

Classification by Temporal Pattern:

Epidemiology

Risk factors for severe pain:

• Bone metastases (most common cause)
• Advanced stage disease
• Pancreatic, head/neck, lung cancers (highest pain prevalence)
• Previous pain history
• Younger age
• Female gender
• Psychological comorbidity (depression, anxiety)

Etiology

Tumor-related pain (60-80%):

• Bone metastases (most common)
• Nerve compression/infiltration
• Visceral organ involvement
• Soft tissue infiltration
• Raised intracranial pressure

Treatment-related pain (15-25%):

• Post-surgical (thoracotomy, mastectomy, amputation)
• Post-radiation (fibrosis, mucositis, enteritis)
• Chemotherapy-induced (mucositis, neuropathy, aseptic necrosis)
• Hormone therapy (arthralgias)

Procedural pain (5%):

• Bone marrow biopsy, lumbar puncture, catheter insertion
• Diagnostic imaging, endoscopy

Non-cancer-related pain (10%):

• Pre-existing chronic pain conditions
• Age-related degenerative conditions

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Pain Assessment

Comprehensive Assessment

Essential elements:

Breakthrough pain assessment:

• Frequency (number of episodes/day)
• Severity (average peak intensity)
• Duration (minutes to hours)
• Relationship to background analgesia (end-of-dose vs. spontaneous)
• Triggers (movement, eating, coughing - incident pain)
• Current rescue medication efficacy

Special considerations:

• Cognitively impaired patients (use PAINAD, Abbey scales)
• Pediatric patients (Faces Pain Scale)
• Cultural/linguistic differences

Investigation

Imaging:

• MRI (spinal cord compression, nerve involvement, bone marrow infiltration)
• CT (bone metastases, visceral lesions)
• PET-CT (metabolic activity of lesions)
• Bone scan (osteoblastic metastases)

Neurophysiology:

• EMG/Nerve conduction studies (plexopathy, radiculopathy)
• Quantitative sensory testing (neuropathic component)

Laboratory:

• Renal function (opioid clearance)
• Hepatic function (drug metabolism)
• Calcium (bone metastases, hypercalcemia)
• Inflammatory markers

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Pharmacological Management

WHO Analgesic Ladder

Step 1: Non-opioids ± adjuvants (Mild pain, NRS 1-3):

Paracetamol:

• Dose: 1 g QID (max 4 g/day; 2 g/day if liver impairment)
• Mechanism: Central COX inhibition, endocannabinoid system, descending serotonergic pathways
• Safe, well-tolerated, minimal drug interactions
• Continue at all steps (synergistic with opioids)

NSAIDs:

• Ibuprofen 400-800 mg TID, Diclofenac 50 mg TID, Naproxen 250-500 mg BD
• Mechanism: COX-1/2 inhibition, reduce prostaglandin synthesis
• Efficacy: Particularly effective for bone pain, inflammatory pain
• Cautions: GI bleeding, renal impairment, cardiovascular risk, bone marrow suppression (thrombocytopenia)
• Celecoxib (COX-2 selective): Less GI toxicity, similar cardiovascular risk

Adjuvants at all steps:

• Consider early if neuropathic component present
• See adjuvant section below

Step 2: Weak opioids ± non-opioids ± adjuvants (Moderate pain, NRS 4-6):

Tramadol:

• Dose: 50-100 mg QID (max 400 mg/day; 300 mg if >75 years)
• Mechanism: Weak μ-opioid agonist + SNRI (inhibits 5-HT and NE reuptake)
• Advantages: Lower abuse potential, ceiling effect (safer), less respiratory depression
• Side effects: Nausea, dizziness, seizures (lowers threshold), serotonin syndrome (with MAOIs/SSRIs)
• Evidence: Effective for moderate cancer pain

Codeine:

• Dose: 30-60 mg Q4H (max 240 mg/day)
• Prodrug: Metabolized to morphine by CYP2D6 (10% of dose)
• Caution: Poor metabolizers (no analgesia) and ultra-rapid metabolizers (toxicity)
• Generally step 2 only; move to step 3 if inadequate

Alternative approach: Skip Step 2 and use low-dose strong opioids

• Morphine 5-10 mg Q4H (or equivalent)
• Faster titration possible
• Supported by current evidence

Step 3: Strong opioids ± non-opioids ± adjuvants (Severe pain, NRS 7-10):

Morphine (Gold Standard):

• Immediate-release (IR): 5-10 mg Q4H PRN for opioid-naïve; titrate based on response
• Sustained-release (SR): Calculate 24-hour requirement; give as BD or TDD dosing
• Breakthrough dose: 1/10th to 1/6th of total daily dose Q1-2H PRN
• Titration: Increase by 30-50% every 24-48 hours until adequate analgesia or limiting side effects
• No ceiling dose - average daily dose 100-300 mg, but may require >1000 mg/day
• Metabolites: M3G (neurotoxic - myoclonus, seizures), M6G (analgesic, respiratory depression)
• Caution in renal impairment: M3G/M6G accumulate; reduce dose or switch to different opioid

Oxycodone:

• Dose: IR 5-10 mg Q4-6H; SR 10 mg BD (opioid-naïve)
• 1.5-2× potency of morphine
• Similar side effect profile
• May cause less nausea than morphine
• Good alternative if morphine intolerance

Fentanyl:

• Transdermal patch: 12-25 mcg/hr (opioid-naïve); equianalgesic to morphine (use conversion tables)
• Benefits: Convenient, no first-pass metabolism, less constipation
• Cautions: Delayed onset (12-24 hours to steady state), delayed offset (12-24 hours after removal), heat increases absorption, cachectic patients poor absorption
• Breakthrough: Use immediate-release opioid (not fentanyl - too slow)
• Oral transmucosal fentanyl citrate (OTFC): For breakthrough pain; rapid onset (5-10 min)

Methadone:

• Dose: Start 5-10 mg Q8-12H (opioid-naïve)
• Unique properties: NMDA receptor antagonist (reverses tolerance), inhibits serotonin/NE reuptake
• Indications: Neuropathic pain, opioid rotation to reduce side effects, high-dose morphine alternatives
• Cautions: Long half-life (8-120 hours), unpredictable pharmacokinetics, QT prolongation (torsades risk), multiple drug interactions (CYP3A4, CYP2B6, CYP2C19)
• Requires expertise: Start low, go slow, ECG monitoring

Buprenorphine:

• Low dose: 0.2-0.4 mg SL (analgesic)
• High dose: 2-24 mg SL/SL (opioid substitution)
• Properties: Partial μ-agonist, κ-antagonist, high receptor affinity (long duration), ceiling effect on respiratory depression (safer)
• Routes: Sublingual, transdermal patch, buccal film
• Benefits: Safer in renal impairment, less euphoria (lower abuse potential), mild withdrawal if stopped
• Cautions: Precipitates withdrawal if given to patient on full agonist; wait 12-24 hours after last morphine dose

Hydromorphone:

• Dose: IR 2-4 mg Q3-4H; SR 8 mg Q24H (extended-release)
• 5× potency of morphine
• Less nausea, pruritus than morphine
• Good alternative if morphine side effects problematic

Alfentanil:

• Rapid onset (1-2 min), short duration (15-30 min)
• Used subcutaneously for breakthrough pain, palliative care
• Less histamine release than morphine

Opioid Rotation

Indications:

• Inadequate analgesia despite dose escalation
• Intolerable side effects (sedation, myoclonus, nausea, confusion)
• Route change required (oral to transdermal)
• Renal/hepatic dysfunction affecting metabolism

Principles:

• Calculate total daily morphine equivalent dose (MED)
• Reduce by 25-50% when switching (incomplete cross-tolerance)
• Titrate new opioid as needed
• Monitor for 48-72 hours

Equianalgesic conversion table:

Example conversion:

• Patient on morphine 60 mg Q4H (360 mg/24hr)
• Converting to oxycodone: 360 mg / 1.5 = 240 mg/24hr oxycodone
• Reduce by 25-50%: Start 180 mg/24hr oxycodone (90 mg SR BD)
• Provide breakthrough dose: 15-20 mg IR oxycodone PRN

Adjuvant Analgesics

For neuropathic component:

For bone pain:

For visceral pain:

• Antispasmodics (hyoscine butylbromide for colic)
• Corticosteroids (liver capsular stretch, bowel obstruction)
• PPIs/H2 blockers (GI mucosal pain)

For muscle spasm:

• Benzodiazepines (diazepam, clonazepam)
• Baclofen
• Tizanidine

Management of Opioid Side Effects

Constipation (most common):

• Prevention essential - start prophylactic laxatives with opioids
• Stimulant + softener: Senna + docusate (1-2 tablets BD-TDS)
• Osmotic: Macrogol (Movicol), lactulose
• Rectal: Glycerin suppositories, phosphate enemas if refractory
• Peripheral opioid antagonist: Methylnaltrexone (subcutaneous, for refractory cases; does not cross BBB - preserves analgesia)

Nausea:

• Usually resolves after 5-7 days
• Prophylaxis: Haloperidol 0.5-1.5 mg nocte or metoclopramide 10 mg TDS
• If persistent: Switch opioid or add antiemetic regularly

Sedation/Cognitive impairment:

• Usually transient (3-5 days with titration)
• Reduce dose, add psychostimulant (methylphenidate 5-10 mg morning)
• Check for other causes (dehydration, hypercalcemia, brain metastases)
• Consider opioid rotation

Pruritus:

• Antihistamines (often ineffective)
• Opioid rotation (fentanyl > oxycodone > morphine for pruritus)
• Low-dose naloxone infusion (rarely)

Respiratory depression:

• Rare in cancer patients with chronic dosing (tolerance develops)
• More common with acute titration, opioid-naïve patients
• Management: Reduce dose, physical stimulation, naloxone 0.04-0.4 mg IV (titrate to avoid withdrawal/pain)

Myoclonus/Seizures:

• Usually with high-dose morphine or renal impairment (M3G accumulation)
• Benzodiazepines (clonazepam 0.5-2 mg nocte)
• Opioid rotation (fentanyl, methadone less neurotoxic)

Hyperalgesia/Allodynia:

• Opioid-induced hyperalgesia vs. disease progression
• Try opioid rotation, add NMDA antagonist (methadone, ketamine), reduce dose if possible

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Breakthrough Pain

Definition and Types

Definition: "A transient increase in pain intensity over and above baseline pain, occurring despite stable background analgesia."

Types:

Epidemiology:

• Occurs in 40-80% of cancer patients on opioid therapy
• Average 3-4 episodes per day
• Duration: 15-30 minutes typical
• Often undertreated

Management

Oral immediate-release opioids:

• Dose: 10-20% of total daily opioid dose
• Frequency: Q1-2H PRN (usually 4-6 doses/day provided)
• Onset: 20-30 minutes; Peak: 60-90 minutes
• Problem: Slow onset for rapid breakthrough pain

Rapid-onset fentanyl preparations:

• Oral transmucosal fentanyl citrate (OTFC - Actiq): Onset 5-10 min, duration 1-2 hours
• Fentanyl buccal tablet (FBT - Fentora): Onset 5-10 min
• Sublingual fentanyl (Abstral, Subsys): Onset 5-10 min
• Intranasal fentanyl (Instanyl, PecFent): Onset 5-10 min
• Nasal spray fentanyl (Lazanda): Onset 5-10 min

Dosing:

• Not based on background opioid dose
• Individual titration required
• Start with lowest dose; titrate to effective dose over episodes

Indications for rapid-onset fentanyl:

• Rapid onset breakthrough pain (<5 min to peak)
• Severe intensity
• Multiple daily episodes
• Poor response to oral rescue opioids

Pre-emptive dosing for incident pain:

• Give rescue dose 30 minutes before predictable activity
• Example: Give immediate-release opioid before physiotherapy, dressing changes, movement

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Interventional Pain Management

Indications for Spinal (Epidural/Intrathecal) Analgesia

Absolute indications:

• Uncontrolled pain despite escalating systemic opioids
• Intolerable systemic opioid side effects preventing dose escalation

Relative indications:

• Visceral pain (abdomen, pelvis) - responds well to intrathecal morphine
• Single-level neuropathic pain (nerve root compression)
• Bone pain from pelvic/perineal tumors
• Prolonged survival expected (months to years)

Spinal Analgesia Techniques

Epidural analgesia:

• Catheter placed in epidural space
• Can be temporary (percutaneous) or permanent (tunneled with port/subcutaneous reservoir)
• Advantages: Easier placement, lower infection risk than intrathecal
• Disadvantages: Higher dose requirement (10× intrathecal), systemic absorption

Intrathecal analgesia:

• Catheter placed in intrathecal space (CSF)
• Drug delivered directly to spinal cord receptors
• Advantages: Lower doses, fewer systemic side effects, better analgesia for spinal targets
• Disadvantages: Higher infection risk (meningitis), technical complexity

Intrathecal Drug Delivery Systems

Externalized systems:

• Percutaneous catheter with external pump
• For short-term use (days to weeks) or trial
• Higher infection risk

Implanted systems:

• Catheter: Tunneled from spinal space to abdominal pocket
• Pump: Programmable (SynchroMed) or fixed-rate (Codman)
• Programmable: Can adjust dose, bolus, complex regimens; MRI conditional
• Power source: Battery lasts 3-7 years; requires replacement

Drugs used intrathecally:

Polyanalgesic consensus algorithm:

• Step 1: Morphine or hydromorphone alone
• Step 2: Add bupivacaine
• Step 3: Add clonidine
• Step 4: Add ziconotide (replace opioid or combine)
• Step 5: Rotations, combinations based on patient response

Outcomes and Complications

Outcomes:

• 50% achieve good pain relief

• Reduced systemic opioid side effects
• Improved function and quality of life
• Cost-effective if survival >3-6 months

Complications:

• Infection (meningitis, epidural abscess, pump pocket)<1-3%
• Catheter issues (dislodgement, kinking, fracture) 10-20%
• Granuloma formation (intrathecal morphine/hydromorphone) - rare but serious
• Post-dural puncture headache
• CSF leak
• Device malfunction
• Endocrine effects (hypogonadism, adrenal suppression - with high-dose intrathecal opioids)

Contraindications:

• Active infection
• Coagulopathy
• Severe spinal deformity
• Uncontrolled psychiatric illness
• Inability to follow up
• Limited life expectancy (<1 month) - consider simpler interventions

Other Interventional Techniques

Nerve blocks:

• Diagnostic (prognostic) or therapeutic
• Neurolytic blocks for visceral pain (celiac plexus, superior hypogastric plexus, ganglion impar)
• Celiac plexus block: Excellent for upper abdominal/visceral pain (pancreatic, gastric, hepatic)
• Duration: Weeks to months with neurolysis (alcohol, phenol)

Vertebroplasty/Kyphoplasty:

• For painful vertebral compression fractures
• Cement injection stabilizes fracture
• Rapid pain relief in 70-90%
• Contraindications: Retropulsion of bone fragment, cord compression, coagulopathy

Radiation therapy:

• Effective for bone pain (60-80% response rate)
• Single fraction (8 Gy) vs. multiple fractions - similar efficacy for pain control
• Prevents pathological fractures, spinal cord compression
• Pathological fracture risk reduced by 50%

Radiofrequency ablation:

• For painful bone metastases (osteoid osteoma, metastatic lesions)
• Percutaneous probe applies heat to destroy tumor tissue

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Indigenous Health Considerations

Aboriginal and Torres Strait Islander Populations:

Disparities:

• Higher cancer mortality rates (gap in cancer outcomes)
• Later stage at diagnosis
• Lower access to palliative care services
• Geographic barriers to comprehensive cancer care
• Historical medical mistrust affecting opioid use discussions

Cultural considerations:

• Discussion of opioid use may raise concerns about addiction
• Family decision-making important - may delay decisions
• Traditional healers and bush medicine may be preferred initially
• "Sorry Business" and cultural obligations may affect care seeking

Management approaches:

• Early palliative care referral
• Culturally safe pain assessment
• Use of Aboriginal Health Workers/Liaison Officers
• Telehealth for specialist palliative care in remote areas
• Clear communication about pain management goals
• Home-based palliative care with community support where possible

Māori Populations:

Similar disparities in cancer outcomes and access to palliative care.

Whānau involvement:

• Family integral to pain management decisions
• Need for culturally appropriate communication about prognosis and symptom management
• Integration of rongoa Māori (traditional healing) alongside Western medicine
• Addressing systemic barriers to opioid access

Key principle: Cancer pain management in Indigenous populations requires culturally safe approaches, attention to access barriers, and recognition of the role of family and traditional healing practices.

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ANZCA Exam Focus

High-Yield Topics

Written Examination:

• WHO analgesic ladder (steps, drugs, dosing)
• Opioid pharmacology (morphine metabolism, equianalgesic doses, side effects)
• Opioid rotation calculations and principles
• Breakthrough pain management (rapid-onset fentanyl)
• Intrathecal drug delivery indications and complications

Viva Voce:

• Opioid titration in cancer pain
• Management of opioid side effects
• Spinal cord compression scenario
• Case: Renal impairment with cancer pain (opioid choice)
• Breakthrough pain assessment and management

Common Exam Scenarios

Scenario 1: Opioid Rotation

• Patient on morphine SR 100 mg BD (200 mg/24hr)
• Uncontrolled pain, severe nausea, pruritus
• Converting to fentanyl patch

Key points:

• Calculate equianalgesic dose
• Apply 25-50% reduction for cross-tolerance
• Choose appropriate patch strength
• Continue breakthrough IR morphine initially
• Educate about delayed onset/offset

Scenario 2: Renal Impairment

• Patient with GFR 25 mL/min
• Metastatic cancer, severe pain
• Currently on morphine, developing confusion/myoclonus

Key points:

• Morphine metabolites (M3G, M6G) accumulate in renal failure
• Switch to opioid without active metabolites (fentanyl, methadone, buprenorphine)
• Reduce starting dose
• More frequent monitoring

Scenario 3: Spinal Cord Compression

• Back pain with neurological symptoms
• Known metastatic breast cancer

Key points:

• Emergency (irreversible paralysis if delayed)
• High-dose dexamethasone (16 mg then 4 mg QID)
• Urgent MRI
• Radiation therapy or surgical decompression
• Analgesia (opioids ± NSAIDs ± neuropathic agents)

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Assessment Content

SAQ 1: Opioid Titration and Breakthrough Pain (20 marks)

Question:

A 68-year-old man with metastatic lung cancer has severe back pain from vertebral metastases (NRS 8/10). He is opioid-naïve. His renal function is normal (eGFR 75 mL/min).

a) Describe your initial opioid management, including drug choice, starting dose, titration strategy, and breakthrough dosing. (8 marks)

b) After 48 hours, he is taking morphine 10 mg Q4H (60 mg/24hr) with acceptable pain control (NRS 3/10 at rest, 7/10 with movement) but reports 3-4 episodes daily of severe pain lasting 15-20 minutes with movement. How would you adjust his regimen? (6 marks)

c) One week later, his pain is well-controlled at rest, but he develops severe constipation unresponsive to laxatives, and his creatinine rises to 180 μmol/L (eGFR 28 mL/min). He also has intermittent confusion. Outline your management. (6 marks)

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Model Answer:

a) Initial opioid management (8 marks):

Example titration:

• Day 1: Morphine 5-10 mg Q4H PRN; receives 40 mg total
• Day 2: Convert to morphine SR 20 mg BD (or 30 mg BD if pain severe) + IR morphine 5 mg Q1H PRN
• Reassess daily; titrate up by 30-50% if pain uncontrolled

b) Breakthrough pain management (6 marks):

Assessment:

• Background pain controlled (NRS 3/10)
• Incident pain with movement (NRS 7/10)
• 3-4 episodes daily, lasting 15-20 minutes
• Current breakthrough dosing likely inadequate

Management:

c) Renal impairment and opioid toxicity management (6 marks):

Diagnosis:

• Opioid toxicity secondary to renal impairment
• Morphine metabolites (M3G, M6G) accumulate in renal failure
• M3G causes neurotoxicity (confusion, myoclonus, seizures)
• M6G causes respiratory depression, sedation

Management:

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References

1. Portenoy RK, Lesage P. Management of cancer pain. Lancet. 1999;353(9165):1695-1700. PMID: 10334111

2. van den Beuken-van Everdingen MHJ, Hochstenbach LMJ, Joosten EAJ, et al. Update on Prevalence of Pain in Patients With Cancer: Systematic Review and Meta-Analysis. J Pain Symptom Manage. 2016;51(6):1070-1090. PMID: 27112310

3. Goudas LC, Bloch R, Gialeli-Goudas M, et al. The epidemiology of cancer pain. Cancer Invest. 2005;23(2):182-190. PMID: 15898069

4. World Health Organization. Cancer Pain Relief: With a Guide to Opioid Availability. 2nd ed. Geneva: WHO; 1996. PMID: N/A

5. Eisenberg E, McNicol ED, Carr DB. Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin. Drugs. 2006;66(18):2269-2278. PMID: 17176142

6. Foley KM. The treatment of cancer pain. N Engl J Med. 1985;313(2):84-95. PMID: 4007362

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