Risk of cardiovascular events according to the tricyclic antidepressant dosage in patients with chronic pain: a retrospective cohort study

Abstract

Purpose We aimed to examine the risk of cardiovascular adverse events by tricyclic antidepressant (TCA) dosage among patients with chronic pain. Methods A retrospective cohort study was conducted using a nationwide sample cohort. Among patients aged ≥ 18 years with a chronic pain diagnosis and no history of cardiovascular events, we extracted users and non-users of TCAs through 1:1 propensity score matching. TCA users were categorized into three groups according to the mean defined daily dose (DDD): very low doses (< 0.15 DDD), low doses (0.15–0.34 DDD), and traditional doses (≥ 0.34 DDD). A 6-month follow-up was conducted with an intention-to-treat approach. We examined the hazard ratio of cardiovascular adverse events using Cox proportional hazards analysis. Results In total, 16,660 matched patients were followed up (8330 TCA users and 8330 non-users). TCA use did not significantly increase cardiovascular adverse events (hazard ratio [HR] 1.12, 95% confidence interval [CI] 0.94–1.33). Low-dose (0.15–0.34 DDD) TCAs (HR 1.37, 95% CI 1.08–1.74), particularly low-dose (0.15–0.34 DDD) nortriptyline (HR 2.11, 95% CI 1.44–3.08), was associated with an increased risk of cardiovascular adverse events. Administration of TCAs at the traditional dose (≥ 0.34 DDD) increased the risk of ischemic stroke (HR 2.08, 95% CI 1.11–3.88). Conclusion Close monitoring of patients on long-term, low-dose use of TCAs should be conducted to avoid an increase in the cumulative dose, which increases the risk of cardiovascular adverse events.