Could you elaborate on the WHO analgesic ladder for managing pain in adult cancer patients, including drug choices and dosing?

WHO Analgesic Ladder for Cancer Pain Management

The WHO analgesic ladder provides a sequential three-step approach to cancer pain management, progressing from non-opioids (Step 1) to weak opioids (Step 2) to strong opioids (Step 3), though emerging evidence supports bypassing Step 2 and moving directly to low-dose strong opioids for moderate pain. 1

Core Principles of Administration

Analgesics must be administered on a regular, around-the-clock schedule—never "as needed" for baseline pain control. 1 The oral route should be the first choice whenever possible, only switching to parenteral routes when oral intake is impossible due to severe vomiting, bowel obstruction, dysphagia, confusion, or when rapid dose escalation is required. 1

• Rescue doses (10-20% of total daily opioid dose) must be prescribed proactively for breakthrough pain, available every 1-2 hours as needed. 2, 3
• If patients require ≥4 rescue doses in 24 hours, increase the scheduled baseline opioid dose accordingly. 3
• Treatment plans must be written, explained to patients, and re-evaluated regularly with anticipation of breakthrough pain and side effects. 1

Step 1: Mild Pain (Non-Opioid Analgesics)

For mild pain, start with paracetamol (acetaminophen) 1000 mg every 4-6 hours, with a maximum daily dose of 4 grams. 1, 4 Despite widespread use, a Cochrane systematic review highlights limited evidence supporting paracetamol's effectiveness for cancer pain. 1

NSAIDs as Adjuncts

• NSAIDs are particularly recommended for inflammatory pain and bone pain. 1
• However, there is no conclusive evidence supporting or refuting NSAIDs alone or combined with opioids for mild cancer pain, with only 26-51% of patients achieving adequate relief in limited studies. 1
• Critical safety monitoring is required: NSAIDs carry significant risks of gastrointestinal bleeding, platelet dysfunction, renal failure, and cardiovascular events (especially COX-2 inhibitors). 1
• Avoid NSAIDs with methotrexate, and use cautiously with nephrotoxic (cisplatin) or myelotoxic chemotherapy. 1

Step 2: Mild to Moderate Pain (Weak Opioids)

The traditional Step 2 uses weak opioids (codeine, tramadol, dihydrocodeine), but this step is increasingly controversial and may be eliminated in favor of low-dose strong opioids. 1

Tramadol Considerations

• Tramadol has widespread use but limited supporting data and can cause severe side effects including dizziness and nausea. 1
• Adequate comparative studies with other Step 2 drugs are lacking. 1

Emerging Evidence Against Step 2

• A 2022 randomized trial demonstrated that 53% of patients on weak opioids required escalation to strong opioids (median time 6 days), with no difference in time to pain control between starting with weak versus strong opioids. 5
• The two-step approach (bypassing weak opioids) resulted in less nausea and lower costs. 5
• Some experts recommend eliminating Step 2 entirely, replacing weak opioids with low-dose oral morphine. 1

Step 3: Moderate to Severe Pain (Strong Opioids)

For moderate to severe pain, initiate oral morphine immediately: 20-40 mg for opioid-naïve patients, or 5-10 mg IV/SC when urgent relief is needed or oral route unavailable. 2

Morphine Dosing and Titration

• Administer immediate-release (IR) morphine every 4 hours with rescue doses available up to hourly for breakthrough pain. 2
• The potency ratio is 1:2 to 1:3 for oral to IV/SC administration. 2
• For very severe pain, strong opioids can be prescribed as first-line therapy, bypassing Steps 1 and 2 entirely. 1, 2

Alternative Strong Opioids

• Oxycodone: 20 mg orally (1.5-2 times more potent than oral morphine). 2
• Hydromorphone: 8 mg orally (7.5 times more potent than oral morphine). 2
• For renal impairment (eGFR <30 mL/min): Use IV fentanyl or buprenorphine, as these are the safest options in advanced kidney disease. 2, 4

Multimodal Approach

Combine strong opioids with paracetamol 1000 mg every 4-6 hours and ibuprofen 400 mg every 4-6 hours (if no contraindications) for enhanced analgesia. 2

Essential Prophylaxis and Side Effect Management

Laxatives must be prescribed routinely for all patients on opioids to prevent constipation. 2 This is non-negotiable as constipation occurs in the vast majority of opioid-treated patients.

• Antiemetics (metoclopramide or antidopaminergics) should be provided for opioid-induced nausea/vomiting. 2
• Monitor for respiratory depression, sedation, and endocrine effects (hypogonadism with chronic use). 4
• In renal impairment, use all opioids cautiously at reduced doses. 2

Critical Pitfalls to Avoid

Never delay strong opioids for severe pain—the WHO ladder explicitly allows starting at Step 3 for very severe pain. 1, 2 Weak opioids (codeine, tramadol) are inadequate for severe pain and will only delay adequate relief. 2

• Never prescribe two sustained-release opioids together. 1
• Do not use transdermal fentanyl for rapid titration—it is only appropriate once pain is controlled with other opioids. 2
• Avoid withholding opioids due to concerns about psychiatric symptoms or addiction in cancer patients with legitimate pain. 3
• Never exceed paracetamol 4 g daily (3 g for chronic use, elderly, or liver disease) to avoid hepatotoxicity. 4

Integrated Approach Beyond Medications

Pain medications are only one component of comprehensive cancer pain management, which must incorporate: 1

• Primary antitumor treatments
• Interventional analgesic therapy (nerve blocks, neuromodulation, intrathecal drug delivery)
• Non-invasive techniques including psychological and rehabilitative interventions

This multimodal approach maximizes analgesia while minimizing adverse effects and addresses the multidimensional nature of cancer pain. 6, 7