Long-term tramadol use increases the risk of depression in patients with musculoskeletal pain: A retrospective cohort study

J Affect Disord. 2026 Mar 30:121715. doi: 10.1016/j.jad.2026.121715. Online ahead of print.

ABSTRACT

BACKGROUND: Tramadol is commonly prescribed for musculoskeletal pain and has pharmacological properties suggesting potential antidepressant effects, but its long-term impact on mental health in real-world settings remains unclear. This study aimed to explore the association between the duration of tramadol use and the risk of depression.

METHODS: This retrospective cohort study used the National Health Insurance Service-Health Screening Cohort database in South Korea (2002-2019). Patients diagnosed with musculoskeletal pain between 2003 and 2007 were identified. Tramadol users and nonusers were matched 1:1 within the same sex using propensity scores. Tramadol users were categorized based on 5-year cumulative days of tramadol prescription: 1-29 days, 30-89 days, and ≥ 90 days. The outcome was incident depression, identified based on both diagnostic codes and prescription records. Adjusted hazard ratios were estimated using Cox proportional hazards regression, and dose-response relationship was further assessed using restricted cubic splines.

RESULTS: Among 48,066 matched patients (24,033 tramadol users, 24,033 nonusers), the risk of depression increased with longer duration of tramadol use. Compared to nonusers, the adjusted hazard ratios for depression risk were 1.19 (95% CI: 1.13-1.25) for 1-29 days, 1.26 (95% CI: 1.15-1.38) for 30-89 days, and 1.37 (95% CI: 1.23-1.53) for ≥90 days (P for trend <0.001). A dose-dependent relationship was also observed.

CONCLUSION: Long-term tramadol use may be associated with an increased risk of depression in patients with musculoskeletal pain. These findings underscore the need for careful consideration of tramadol's potential mental health effects in clinical practice.

PMID:41921874 | DOI:10.1016/j.jad.2026.121715