Intra-articular placebo effect in the treatment of knee osteoarthritis: a survey of the current clinical evidence. (January 2022)

• Record Type: Journal Article
• Authors: Fazeli, Mir Sohail; McIntyre, Louis; Huang, Yili; Chevalier, Xavier
• Is Part Of: Therapeutic advances in musculoskeletal disease. Volume 14(2022)
• Publication Date: 2022-01
• Subjects: knee -- osteoarthritis -- pain -- placebo effect -- randomized controlled trial -- review; Musculoskeletal system -- Diseases -- Periodicals; Musculoskeletal Diseases -- Periodicals; 616.7
• DOI: 10.1177/1759720X211066689
• Languages: English
• ISSNs: 1759-720X

Abstract

Knee osteoarthritis (KOA) is a debilitating disease characterized by chronic pain, stiffness, and decreased mobility. Intra-articular injectable therapies show good clinical efficacy in improving symptoms; however, these therapies and their comparators (intra-articular saline) have been associated with a large underlying placebo effect. We aimed to describe the existing evidence on the challenges, hypotheses, and potential solutions to mitigate the intra-articular placebo effect in clinical trials in KOA. A targeted literature review was conducted by searching Embase, MEDLINE®, and CENTRAL using predefined study selection criteria. All eligible studies identified were extracted for relevant data, and results were narratively summarized. Forty-three studies were included following screening. Challenges associated with the intra-articular placebo effect included its ability to mask the comparative efficacy of active treatments in trials ( n = 7 studies), long-lasting effects (up to 6 months; n = 3), and substantial variation of placebo effect sizes across populations ( n = 3). Hypotheses for the mechanism of the placebo effect included aspiration of synovial fluid during administration ( n = 6) and dilution of inflammatory mediators ( n = 2). Factors affecting the placebo effect size were more invasive routes of administration (e.g., injection versus oral; n = 4) and patient expectations ( n = 2). Proposed solutions included the suggestion for readers to weigh the relevance of clinical trial evidence against the presence of large underlying placebo effects ( n = 9), discontinuation of intra-articular saline as an appropriate placebo ( n = 5), and inclusion of 'no treatment' or sham injection as a control ( n = 4). The intra-articular placebo effect is a well-documented occurrence in KOA clinical trials, and it is suggested that it be accounted for when designing randomized controlled trials. Awareness and understanding of the intra-articular placebo effect in KOA are required for fair interpretation of clinical trial evidence.