Hemodynamic Edema-related Safety Signals of Single-ingredient and Combination Tramadol Products: A Disproportionality Analysis of the Korea Adverse Event Reporting System

Tramadol is widely prescribed to manage moderate to severe pain and is available as single-ingredient and tramadol/ acetaminophen combination products. This study investigated hemodynamic edema-related safety signals associated with tramadol and compared reporting patterns between single-ingredient and combination products using Korea Institute of Drug Safety & Risk Management-Korea Adverse Event Reporting System Database (KAERS DB) (2510A0002). A disproportionality analysis was conducted using KAERS DB submitted between 2021 and 2025. Hemodynamic edema-related adverse events (AEs) were identified using the Standardized Medical Dictionary for Regulatory Activities Query for “haemodynamic oedema, effusions and fluid overload.” Safety signals were evaluated using the proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC). A positive signal was defined as an AE reported at least three times with PRR ≥2, ROR ≥2, and lower limit of 95% confidence interval for the IC >0. Among 53,955 reports involving single-ingredient tramadol products, 371 (0.69%) involved hemodynamic edema-related AEs, compared with 1,332 (3.16%) of 42,099 reports involving combination products. Combination products showed a broader range of safety signals than single-ingredient products. Lymphedema was the only signal detected for single-ingredient tramadol, whereas combination products generated signals for lymphedema, peripheral edema, swelling, pleural effusion, and pericardial effusion. Combination tramadol products demonstrated a broader spectrum of hemodynamic edema-related safety signals than single-ingredient products. These findings highlight the need for greater clinical awareness of tramadol-associated edema and further investigation of its underlying mechanisms.