Examination of overall treatment effect and the proportion attributable to contextual effect in osteoarthritis: meta-analysis of randomised controlled trials

Objective: To examine the overall treatment effect and the proportion attributable to contextual effect (PCE) in randomised controlled trials (RCTs) of diverse treatments for osteoarthritis (OA).

Methods: We searched MEDLINE, EMBASE, CENTRAL, Science Citation Index, AMED, CINAHL through October 2014, supplemented with manual search of reference lists, published meta-analyses and systematic reviews. Included were RCTs in OA comparing placebo with representative complementary, pharmacological, non-pharmacological and surgical treatments. The primary outcome was pain. Secondary outcomes were function and stiffness. The overall treatment effect was defined as the improvement from baseline in the treatment group. The contextual effect was defined as that of the placebo group. The PCE was calculated by dividing the contextual effect over the overall treatment effect. The effect size (ES) of overall treatment effect and the PCE were pooled using random-effects model. Subgroup analysis and meta-regression were conducted to examine determinants of the PCE.

Results: In total, 215 trials (41,392 participants) were included. The overall treatment effect for pain-reduction ranged from the smallest with lavage (ES=0.46, 95%CI: 0.24, 0.68) to the largest with topical NSAIDs (ES=1.37, 95%CI 1.19, 1.55). On average, 75% (PCE=0.75, 95%CI 0.72, 0.79) of pain reduction was attributable to contextual effect. It varied by treatment from 47% (PCE=0.47, 95%CI: 0.32, 0.70) for intra-articular corticosteroid to 91% (PCE=0.91, 95%CI: 0.60, 1.37) for joint lavage. Similar results were observed for function and stiffness. Treatment delivered by needle/injection and other means but oral medication, longer duration of treatment, larger sample size (≥100 per arm) and public funding source were associated with increased PCE for pain-reduction.

Conclusions: The majority (75%) of the overall treatment effect in OA RCTs is attributable to contextual effects, rather than the specific effect of treatments. Reporting overall treatment effect and PCE, in addition to traditional ES over placebo, permits a more balanced, clinically meaningful interpretation of RCT results. This would help dispel the frequent discordance between conclusions from RCT evidence and clinical experience - the “efficacy paradox”.