What medications are used to treat knee pain, particularly for conditions like osteoarthritis?

Medication for Knee Pain

Start with acetaminophen (paracetamol) up to 4000 mg daily as first-line pharmacological treatment for knee pain, particularly osteoarthritis, and escalate to topical NSAIDs if inadequate response after 2-4 weeks. 1, 2

First-Line Pharmacological Treatment

Acetaminophen (paracetamol) is the oral analgesic to try first and, if successful, is the preferred long-term oral analgesic. 1

• Acetaminophen demonstrates clear superiority over placebo with a number needed to treat of 3 for pain improvement 3
• Maximum dose is 4000 mg daily, which provides similar efficacy to ibuprofen in both analgesic (1200 mg) and anti-inflammatory (2400 mg) doses for short-term treatment 4, 5
• Acetaminophen has a superior safety profile compared to NSAIDs, with significantly lower risk of gastrointestinal complications 4, 3

Second-Line: Topical NSAIDs

If acetaminophen provides inadequate relief after 2-4 weeks, topical diclofenac should be the next step before considering oral NSAIDs. 2

• Topical diclofenac has a positive effect size of 0.91 compared to placebo for knee osteoarthritis pain 2
• Topical NSAIDs cause markedly fewer gastrointestinal adverse events compared to oral NSAIDs, with main side effects being local application site reactions 2
• This is particularly important for patients age ≥60 years, history of peptic ulcer disease, or concurrent use of corticosteroids or anticoagulants 2

Third-Line: Oral NSAIDs

Oral NSAIDs (such as naproxen or ibuprofen) should be considered only in patients unresponsive to acetaminophen and topical NSAIDs, particularly those with effusion. 1

• NSAIDs are modestly superior to acetaminophen for pain reduction but show similar efficacy for functional improvement 3
• Naproxen sodium (440-660 mg daily) and ibuprofen (1200 mg daily) effectively relieve pain in mild to moderate knee OA, with naproxen showing particular benefit for night pain 6
• Use the lowest possible dose for the shortest possible time due to significant gastrointestinal, renal, and cardiovascular toxicity risks 7, 4
• NSAIDs should never be used right before or after coronary artery bypass graft surgery 7
• Regular monitoring of renal function, blood pressure, and gastrointestinal symptoms is necessary 2

Acute Exacerbations

Intra-articular corticosteroid injections are indicated for acute exacerbations of knee pain, especially if accompanied by effusion. 1, 2

• Provides short-term pain relief effective for 1-3 weeks with effect size of 1.27 compared to placebo 2
• Most beneficial when there is visible inflammation or joint effusion 1

Alternative Second-Line Options

• Duloxetine can be considered for patients with inadequate response to first-line treatments 8
• Intra-articular hyaluronic acid may provide longer-lasting symptom improvement than corticosteroids, though evidence is mixed and cost-effectiveness is not well established 1, 8, 2

What to Avoid

Strongly avoid opioids (including tramadol) for knee pain due to limited efficacy and significant adverse effects including toxicity and dependence risk. 8

• The American Academy of Orthopaedic Surgeons strongly recommends against oral narcotics for knee pain 8
• The VA/DoD guidelines suggest against initiating opioids for osteoarthritis-related knee pain 8

Essential Non-Pharmacological Adjuncts

Optimal management requires combining medications with non-pharmacological treatments—these are not optional add-ons but essential components. 1, 2

• Land-based exercise (aerobic and/or resistance training) is recommended and provides additional benefit even when patients are on analgesics 1, 8
• Weight reduction for overweight patients 1, 8
• Physical therapy as part of comprehensive management 8
• Quadriceps strengthening exercises are particularly important 1

Common Pitfalls

• Do not combine acetaminophen with NSAIDs and aspirin routinely—aspirin increases naproxen excretion and combination therapy increases adverse event frequency without clear additional benefit 7
• Do not assume all knee pain requires anti-inflammatory doses—many patients respond adequately to pure analgesics like acetaminophen, avoiding unnecessary NSAID toxicity 4, 5
• Do not use NSAIDs chronically without monitoring—assess for gastrointestinal symptoms, renal function changes, and cardiovascular risk factors regularly 2, 7