What is the World Health Organization analgesic step‑ladder for pain management and what are the recommended drug choices and dosing for each step?

WHO Analgesic Step Ladder for Pain Management

The WHO analgesic ladder is a three-step sequential approach that progresses from non-opioids (Step 1) to weak opioids (Step 2) to strong opioids (Step 3) based on pain intensity, with paracetamol/NSAIDs and adjuvants available at all steps. 1

The Three-Step Framework

Step 1: Mild Pain (NRS <3 or ≤4)

Drug Choices:

• Paracetamol (acetaminophen) as first-line 1
• NSAIDs (e.g., ibuprofen, diclofenac) as alternatives or additions 1
• Either agent can be used alone or in combination 1

Key Dosing:

• Paracetamol: up to 4g daily 2
• Ibuprofen: 1200mg daily for OTC use 2
• Diclofenac: typically 3-5 days maximum for acute pain, not exceeding 7 days without reassessment 3

Critical Monitoring:

• Long-term NSAID use requires periodic monitoring for gastrointestinal bleeding, platelet dysfunction, renal failure, and cardiovascular thrombotic events 1
• COX-2 inhibitors do not protect against renal failure despite reduced GI risk 1

Step 2: Mild-Moderate Pain (NRS 3-6)

Drug Choices:

• Codeine + paracetamol or NSAID 1
• Tramadol (1-1.5 mg/kg every 6 hours) + paracetamol or NSAID 1
• Dihydrocodeine + paracetamol or NSAID 1

Major Controversy - Step 2 May Be Obsolete:

• 53% of patients on Step 2 weak opioids require escalation to strong opioids within 6 days (median) due to inadequate analgesia 4
• Meta-analyses show no significant difference in effectiveness between non-opioids alone versus combinations with weak opioids 1
• The ESMO guidelines note that some authors suggest eliminating Step 2 entirely, replacing weak opioids with low-dose oral morphine 1
• Step 2 has a "ceiling effect" where doses above a threshold increase side effects without improving analgesia 1
• A 2022 randomized trial found no significant difference in time to pain control between the two-step approach (skipping weak opioids) versus the traditional three-step approach 4

Duration Limitations:

• Step 2 effectiveness typically limited to 30-40 days before requiring escalation 1

Step 3: Moderate-Severe Pain (NRS >6 or ≥7)

Drug Choices:

• Morphine (immediate-release or sustained-release) as the gold standard 1, 5
• Alternative strong opioids: fentanyl, oxycodone, hydromorphone, methadone 1
• Continue paracetamol/NSAIDs as adjuncts unless contraindicated 1

Morphine Dosing Protocols:

For Opioid-Naive Patients:

• Oral immediate-release morphine: 5mg every 4 hours scheduled, plus 5mg every hour as needed for breakthrough pain 5
• IV rapid titration (for severe pain): 1.5mg IV every 10 minutes until relief or adverse effects, median effective dose 4.5mg (range 1.5-34.5mg) 5

Efficacy Data:

• IV titration achieves 84% satisfactory relief at 1 hour versus 25% with oral morphine 5
• By 12 hours: 97% relief with IV versus 76% with oral 5

Rescue Dosing:

• Rescue dose = 10-15% of total daily opioid dose 5
• If >4 rescue doses needed per day, increase basal long-acting opioid dose 5

Universal Principles Across All Steps

Route of Administration

Oral route is first-line unless contraindicated by: 1

• Severe vomiting
• Bowel obstruction
• Severe dysphagia
• Severe confusion
• Need for rapid dose escalation
• Intolerable oral opioid side effects

Dosing Schedule

"By the clock" - scheduled around-the-clock (ATC) dosing, NOT "as needed" 1

• Prevents pain rather than chasing it 1
• Takes into account drug half-life, bioavailability, and duration of action 1

Breakthrough Pain Management

Always prescribe rescue medication proactively for breakthrough cancer pain (BTcP) 1

• BTcP episodes: moderate-severe intensity, rapid onset (minutes), short duration (median 30 minutes) 1
• Rescue doses guide daily titration of regular doses 1

Mandatory Side Effect Management

From first opioid dose: 5

• Prophylactic stimulant laxatives (opioid-induced constipation occurs in nearly all patients)
• Antiemetics available, especially first few days

Critical Contraindications and Cautions

Morphine: Avoid in significant renal insufficiency (eGFR <30 mL/min); use fentanyl or buprenorphine instead 5

NSAIDs: Exercise extreme caution in: 3

• Elderly patients (increased acute kidney injury and GI complications risk)
• Patients at bleeding risk
• Those on aspirin for cardiovascular protection (ibuprofen must be taken ≥30 minutes after or ≥8 hours before aspirin) 2

Fentanyl patches: Never use for rapid titration 5

Common Pitfalls to Avoid

1. Starting NSAIDs before trying paracetamol alone for arthritic pain contradicts evidence-based guidelines 2

2. Prolonging Step 2 weak opioids when pain remains uncontrolled - 92% eventually require escalation to strong opioids due to inefficacy 6

3. Forgetting prophylactic laxatives with opioid initiation leads to preventable constipation 5

4. Using "as needed" scheduling for chronic pain instead of ATC dosing results in inadequate pain control 1

5. Delaying strong opioids due to opioidophobia when pain severity (NRS ≥7) clearly indicates Step 3 5

Evidence Quality Note

The WHO ladder, while widely accepted since 1986, has methodological limitations in its validation studies including small sample sizes, retrospective analyses, high dropout rates, and lack of robust controlled trials 1, 7. However, it remains the international reference standard endorsed by ESMO and other major organizations 1. The most significant evolution is growing evidence supporting a two-step approach that bypasses weak opioids entirely 4.