Time-varying treatment effect modification of oral analgesic effectiveness by depressive symptoms in knee osteoarthritis: an application of structural nested mean models in a prospective cohort

Background: Depressive symptoms are common in knee osteoarthritis (OA), exacerbate knee pain severity and may influence outcomes of oral analgesic treatments. The aim was to assess whether oral analgesic effectiveness in knee OA varies by fluctuations in depressive symptoms. Methods: The sample included Osteoarthritis Initiative (OAI) participants not treated with oral analgesics at enrolment (n ¼ 1477), with radiographic disease at the first follow-up visit (defined as the index date). Oral analgesic treatment and depressive symptoms, assessed with the Center for Epidemiological Studies Depression [(CES-D) score ≥16] Scale, were measured over three annual visits. Knee pain severity was measured at visits adjacent to treatment and modifier using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale (rescaled range ¼ 0–100). Structural nested mean models (SNMMs) estimated causal mean differences in knee pain severity comparing treatment versus no treatment. Results: The average causal effects of treated versus not treated for observations without depressive symptoms showed negligible differences in knee pain severity. However, causal mean differences in knee pain severity comparing treatment versus no treatment among observations with depressive symptoms increased over time from −0.10 [95% confidence interval (CI): −9.94, 9.74] to −16.67 (95% CI: −26.33, −7.01). Accordingly, the difference in average causal effects regarding oral analgesic treatment for knee pain severity between person-time with and without depressive symptoms was largest (−16.53; 95% CI: −26.75, −6.31) at the last time point. Cumulative treatment for 2 or 3 years did not yield larger causal mean differences. Conclusions: Knee OA patients with persistent depressive symptoms and chronic pain may derive more analgesic treatment benefit than those without depressive symptoms and less pain.