First-Line Pain Reliever for Osteoarthritis
Acetaminophen (paracetamol) up to 4,000 mg/day is the recommended first-line oral analgesic for osteoarthritis, based on its superior safety profile compared to NSAIDs, despite having modestly lower efficacy. 1
Rationale for Acetaminophen as First-Line
The EULAR and NICE guidelines consistently recommend acetaminophen as initial therapy because it provides a favorable balance between benefit and harm 1. While acetaminophen demonstrates modest efficacy with an effect size of 0.21 (95% CI 0.02 to 0.41) and a number needed to treat of 2, it avoids the serious morbidity associated with NSAIDs 1, 2.
Safety Advantages Over NSAIDs
- Gastrointestinal safety: Acetaminophen shows no increased GI symptoms compared to placebo in meta-analyses, whereas NSAIDs carry significant risk of bleeding, perforation, and obstruction 1
- Cardiovascular safety: No reports of cardiovascular harm exist for acetaminophen, while COX-2 inhibitors (rofecoxib, valdecoxib, celecoxib) and traditional NSAIDs demonstrate CV toxicity 1
- Renal safety: Evidence for renal toxicity from therapeutic doses is sparse 1
- Hepatic safety: At recommended therapeutic doses, hepatotoxicity is not a clinical concern (overdose situations excluded) 1
Critical Dosing Consideration
Use the full 4,000 mg/day dose before declaring treatment failure - underdosing is a common pitfall that leads to premature escalation to NSAIDs 3. Regular dosing may be more effective than as-needed administration 1.
Topical NSAIDs as Alternative First-Line (Specific Joints)
For knee and hand osteoarthritis specifically, topical NSAIDs can be considered alongside or before oral acetaminophen 1. Topical NSAIDs are particularly preferred for patients ≥75 years old due to superior safety profile with comparable local efficacy 3, 4.
When to Escalate Beyond First-Line
If acetaminophen at full dose (4,000 mg/day) provides insufficient pain relief after 2-4 weeks, escalate to oral NSAIDs at the lowest effective dose for the shortest duration 1.
NSAID Selection and Protection Strategy
When NSAIDs become necessary:
- Use lowest effective dose for shortest duration and reassess periodically 1, 3
- For patients with GI risk factors: Use COX-2 selective inhibitor OR non-selective NSAID plus proton pump inhibitor 1, 3
- For patients with cardiovascular risk: Coxibs are contraindicated; use non-selective NSAIDs with extreme caution 1
- For patients on low-dose aspirin: Consider other analgesics before adding NSAIDs due to compounded GI risk 1
Important Caveats
Recent high-quality evidence challenges acetaminophen's efficacy: A 2019 Cochrane review found acetaminophen provided only 3% absolute improvement in pain (minimal clinically important difference is 9%), raising questions about clinical significance 5. However, given the absence of increased adverse events and the substantial risks of NSAIDs in the elderly osteoarthritis population, acetaminophen remains the safer initial choice for real-world practice 5.
The strength of recommendation for acetaminophen (87/100 on visual analog scale, 92% expert agreement) reflects this risk-benefit calculation prioritizing patient safety and mortality prevention over maximal pain relief 1.
Non-Pharmacological Core Treatments (Concurrent with Analgesics)
These should be initiated simultaneously with any analgesic, not sequentially: