OBJECTIVES: Knee osteoarthritis (KOA) is the most common form of arthritis. The placebo effect is a well-known phenomenon with substantial impact on subjectively measured outcomes. The aim of this review was to describe the existing evidence on the challenges, hypotheses, and potential solutions to mitigate the intra-articular (IA) placebo effect in clinical trials investigating the effect of IA therapies in reducing pain in KOA.

METHODS: A targeted literature review was conducted using Embase, MEDLINE®, and Cochrane CENTRAL (inception - December 16, 2019). Eligible studies included those in which the effect of IA-placebo had been described in KOA patients.

RESULTS: Twenty-three studies were included for qualitative evidence synthesis following screening of 2,320 studies. Challenges with the placebo effect included as follows: Diminishing/masking of the effect of active treatments; Longevity of placebo effects (6 to 12 months); Over-inflation of active treatment efficacy in single-arm trials; and Unknown placebo mechanism of action. Hypotheses for the cause of the placebo effect were: Biological effects (genetics, dilution of inflammatory markers, neurobiological mechanisms); Patient expectations (confidence in physician, personality, perception of treatment as innovative); Confounders (comedications, arthrocentesis, physiotherapy, occupational therapy, assistive ambulatory devices, appropriate footwear, patient education, and weight loss); Environmental effects (study setting and geography, provider type, patient-physician relationship); Cultural effects (perception of participating into a clinical trial) and Clinician expectations (confidence in treatment). Proposed solutions for the placebo effect were: Awareness and acknowledgement when making decisions about an active treatment’s efficacy; Use of alternative controls (no treatment, sham injection); Use of placebo as a therapy; and Further research on mechanism of action.

CONCLUSIONS: Several explanations and mitigation strategies for the IA-placebo effect have been proposed. Further elucidation and suggestions for how to adjust for the IA-placebo effect may help guide the strategic development of future clinical trials in KOA.