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 clinical trials of osteoarthritis patients who received tanezumab or a 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 a stable indirect effect of treatment through the 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, whereas 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 (similar to 25%) that, was independent of improvements in pain. Such independent effects are of considerable interest and require further research to determine their mechanisms.

Automated summary

Through analyzing data from two published clinical trials, it was found that pain acted as a mediator between treatment and physical function, and at least 75% of the treatment effect can be explained by the improvement in pain.