Risk of Hyponatremia after Tramadol/Acetaminophen Single-Pill Combination Therapy: A Real-World Study Based on the OMOP–CDM Database

BACKGROUND AND OBJECTIVE: Tramadol has been reported to cause hyponatremia but the evidence is conflicting. The risk of hyponatremia resulting from combination oral tramadol/acetaminophen (TA) therapy is thus unknown. This study examined whether, compared with acetaminophen (AA), TA use is associated with an increased risk of hyponatremia. METHODS: Hospital data compatible with the Observational Medical Outcomes Partnership–Common Data Model (OMOP–CDM; version 5.3) for 30,999 patients taking TA or AA from 2011 through 2020 were analyzed. New-onset hyponatremia was defined as a serum sodium level < 135 mEq/L within 10 days after drug initiation. The incidence rate ratio was calculated based on crude and 1:1 propensity-score-matched models. Subgroup analyses compared patients taking TA extended-release (TA–ER) and TA immediate-release (TA–IR) formulations. RESULTS: Among the 30,999 patients, 12,122 (39.1%) were aged > 65 years and 16,654 (53.7%) were male. Hyponatremia within 10 days developed in 1613 (8.4%) of the 19,149 patients in the TA group; the incidence rate was higher than in the AA group (4.2%; 493 out of 11,850 cases). In the propensity-score-matched model, the incidence rate of hyponatremia in the TA group was 6.8 per 1000 person-days (PD), which was 1.57-fold (1.31, 1.89) higher than that in the AA group (4.3 per 1000 PD). In both the crude and propensity-score-matched models, the incidence rate of hyponatremia was significantly higher in the TA–ER than TA–IR subgroup. CONCLUSION: In this real-world study, hyponatremia was more frequently observed in the TA than AA group, and in the TA–ER than TA–IR subgroup. Therefore, it is imperative to prescribe tramadol cautiously and closely monitor electrolyte levels. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40268-023-00436-4.