Placebo Effect Sizes in Clinical Trials of Knee Osteoarthritis Using Intra-Articular Injections of Biologic Agents

Patients with knee osteoarthritis rely on symptomatic treatments, in which up to 75% of the pain reduction can be attributed to the placebo effect. This effect may vary based on treatment type (eg, biologics vs nonbiologic injection) and route of administration (eg, intra-articular vs topical vs oral). The placebo effect is an integral part of treatment effect size calculation; thus, network analyses comparing efficacies of different treatments may be inaccurate. The objective of this study was to test the hypothesis that placebo effects differ between treatment types and route of delivery.

A systematic literature search was conducted in August 2019. Randomized trials comparing pain outcomes of oral, topical, or intra-articular placebo interventions to active treatments were included. The outcome measure of interest was change in pain scores from baseline. Data were stratified by length of follow-up and treatment subcategory.

A total of 129 articles were included with 9,218 patients receiving placebo treatments. Reduction in pain from baseline occurred in 93% of the subcategory data points. Biologic intra-articular placebo injections had the greatest pain reduction at one month (mean ± SD visual analog scale -32.2 ± 24.6; mean ± SD Western Ontario and McMaster Universities Arthritis Index -16.3 ± 3.81). At one month and two months, placebo intra-articular injections had a greater pain reduction than oral placeboes (P ≤ 0.01).

The robust placebo effect is influenced by the active treatment category and changes over time. The variation in placebo response despite analogous placebo methodologies implies using network meta-analyses to compare treatments from different active treatment categories by evaluating the change from placebo is inaccurate.