Examining the Relationships Among Treatment, Pain, and Physical Function in Patients with Osteoarthritis: A Mediation-Modeling Approach.

OBJECTIVES: To better understand the relationships among treatment, pain, and physical function (PF).

METHODS: Data were collected from 2 published randomized trials of osteoarthritis patients received tanezumab or placebo. PF was measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) PF domain. Pain (WOMAC Pain domain) was a mediator of the effect of treatment on PF. A set of mediation models were investigated. Variables were treatment (tanezumab vs. placebo), WOMAC pain domain, and WOMAC PF domain. Cross-sectional mediation models were assessed separately at different weeks. Longitudinal mediation models used data from all weeks simultaneously. Results could identify a steady-state period.

RESULTS: The cross-sectional and longitudinal mediation models showed stable indirect effect of treatment through pain on PF across time, indicating that a pseudo steady-state model was appropriate. Therefore, the longitudinal steady-state mediation models were used with all available data assuming relationships among variables in the model being the same at all time points; results showed that the indirect effect of the treatment on PF was 77.8% in Study 1 (NCT02697773) and 74.1% in Study 2 (NCT02709486), both P<0.0001, while the direct effect was 22.2% for Study 1 (P=0.0003) and 25.9% for Study 2 (P=0.0019).

DISCUSSION: At least 75% of the treatment effect of tanezumab on physical functioning can be explained by the improvements in pain. However, tanezumab had an additional effect on physical functioning (~25%), which was independent of improvements in pain. Such independent effects are of considerable interest and require further research to determine their mechanisms.