Pilot study of duloxetine plus aerobic exercise for pain and depressive symptoms in knee osteoarthritis

Abstract Objective Pain and depressive symptoms are common in knee osteoarthritis (KOA), and their co-occurrence creates bidirectional effects that complicate treatment, as intervening on one does not necessarily improve the other. This single-group pilot study evaluated the feasibility of a 12-week supervised hybrid aerobic exercise program plus duloxetine targeting pain, depressive symptoms, and physical function. Methods Between May 2023 and March 2025, participants with symptomatic KOA and mild-to-severe depressive symptoms were recruited from the University of Maryland Medical System, the VA Maryland Health Care System, and the Baltimore metropolitan area. The intervention combined a hybrid walking program (two home-based and one supervised session per week) with duloxetine, initiated at 30 mg and titrated to 60 mg. Clinical outcomes were collected at baseline and 12 weeks and included structured assessments and physical performance tests. Results The recruitment target was 20 participants; 34 enrolled, 21 initiated treatment, and 17 completed the protocol. Knee Injury and Osteoarthritis Outcome Score pain scores increased by 14.2 points (95% CI: 6.5, 21.9), indicating less pain, while Hamilton Depression Rating Scale scores decreased by 5.5 points (95% CI: −9.0, −2.0), implying a reduction in depressive symptoms. Physical function improved as measured by changes in six-minute walk test (130 ft; 95% CI: 56.7, 204.1), 20-meter gait speed (0.08 m/s; 95% CI: 0.004, 0.154), and chair stands (1.8 repetitions; 95% CI: 0.7, 2.8). Conclusion This study demonstrates feasibility and preliminary efficacy signals for an exercise–pharmacologic protocol and underscores the need for larger randomized clinical trials. Clinical Trial Registration https://clinicaltrials.gov/, NCT04111627