What is the recommended order of knee injections, including corticosteroids (Non-Steroidal Anti-Inflammatory Drugs), hyaluronic acid, and platelet-rich plasma (PRP)?

Recommended Order of Knee Injections for Osteoarthritis

Intra-articular corticosteroid injections should be the first-line injectable therapy for knee osteoarthritis, with hyaluronic acid considered as a second-line option if corticosteroids provide inadequate relief, while platelet-rich plasma may be reserved for patients who fail both prior treatments. 1

First-Line Injectable: Corticosteroid Injections

Corticosteroids are strongly recommended as the initial injectable therapy based on the highest quality evidence demonstrating short-term efficacy (1-3 months) for pain relief and functional improvement in knee OA. 1

• The 2019 ACR/Arthritis Foundation guidelines provide a strong recommendation for intra-articular glucocorticoid injections in knee OA, which is the highest level of recommendation among all injectable therapies. 1
• Corticosteroids are conditionally recommended over other forms of intra-articular injection, including hyaluronic acid preparations, as the evidence for efficacy of glucocorticoid injections is of considerably higher quality than that for other agents. 1
• Clinical benefit typically lasts 1-3 months, making corticosteroids ideal for acute symptom management. 1

Safety Considerations for Corticosteroids

• Limit injections to no more than 3-4 injections in the same joint per year, with a minimum interval of 6 weeks between injections to minimize potential cartilage damage risk. 1, 2
• Diabetic patients should monitor glucose levels closely for 1-3 days post-injection due to transient hyperglycemia risk. 1
• While concerns exist about cartilage loss with repeated injections, changes in cartilage thickness have not been associated with worsening pain or function in clinical studies. 1

Second-Line Injectable: Hyaluronic Acid

Hyaluronic acid should be considered only after inadequate response to corticosteroid injections, as the evidence quality is substantially lower and more inconsistent. 1

• The 2022 AAOS guidelines recommend against routine use of hyaluronic acid in knee OA due to inconsistent evidence across 17 high-quality and 11 moderate-quality studies, with a number needed to treat of 17 patients. 1
• However, hyaluronic acid may provide sustained or further pain reduction with repeated courses and demonstrates no serious adverse effects in systematic reviews. 1
• The subset of patients who benefit from hyaluronic acid remains unclear, making patient selection challenging. 1

Third-Line Injectable: Platelet-Rich Plasma

Platelet-rich plasma should be reserved for patients who have failed both corticosteroid and hyaluronic acid injections, as it has limited guideline support and inconsistent evidence. 1

• The 2022 AAOS guidelines found only 2 high-quality and 1 moderate-quality study supporting PRP, with notable inconsistency showing worse treatment response in patients with severe knee OA. 1
• Research suggests PRP may have superior long-term efficacy (6-12 months) compared to corticosteroids and hyaluronic acid in early-stage OA, but this is not reflected in major guideline recommendations. 3
• Combined PRP and hyaluronic acid therapy shows promise in research studies but lacks guideline-level evidence. 4
• Concerns exist regarding cost, safety profile, and lack of standardization in PRP preparation methods. 1

Clinical Algorithm for Sequential Injection Therapy

1. Start with corticosteroid injection for immediate symptom relief (effective 1-3 months). 1
2. Reassess at 3 months: If inadequate response or symptom recurrence, consider repeat corticosteroid (maximum 3-4 per year). 1
3. If corticosteroids fail or cannot be repeated due to frequency limits, trial hyaluronic acid series (typically 3 weekly injections). 1
4. If both fail, consider PRP in patients with mild-to-moderate OA (Kellgren-Lawrence grade II-III), avoiding use in severe OA. 1, 3

Important Caveats

• Avoid overuse of the injected joint for 24 hours following any injection, but immobilization is discouraged. 1
• Ultrasound guidance is not required for knee injections but may improve accuracy when available. 1
• All injectable therapies should be part of a comprehensive treatment plan including weight loss, physical therapy, and oral NSAIDs as appropriate. 1
• Injectable therapies provide symptomatic relief but do not modify disease progression or delay need for arthroplasty. 1