Signals of increased risk of serotonin syndrome associated with drug interaction with tramadol in spontaneous adverse event reporting database

초록

Background: Tramadol, a potent analgesic agent is commonly used in various pain conditions. Widespread use of tramadol may trigger coincidence of a potential adverse event serotonin syndrome due to drug interaction with other drugs with serotonergic effect. Objectives: To assess signal of increased risk of serotonin syndrome associated with combined use of tramadol and drugs with anticholinergic burden including antidepressants and antihistamines, compared with tramadol only, in a spontaneous adverse event reporting database. Methods: We applied case‐non‐case approach using all reports that includes tramadol in Korean Adverse Event Reporting System Database from 2012 to 2016. Serotonin syndrome cases were defined as reports with “serotonin syndrome” as the adverse event, and reports with neuromuscular, neurovegetative, mental, and digestive symptoms using WHO‐ART terminology. Non‐cases were all other reports. Among antidepressants and antihistamines, drugs with higher anticholinergic effect were defined as study drugs. Odds ratios (ORs) and their 95% confidence intervals (CIs) associated with combined use of antidepressants or antihistamines with tramadol were calculated using logistic regression model adjusting for age, sex, source, and year of reporting, use of antimigraine, antiemetic agents, and use of other study drugs. Results: Among individual case reports involving tramadol, 4345 were identified as cases, and 55 680 were non‐cases. Compared with tramadol‐only group, the adjusted ORs of combined use of antidepressant was 1.36 (95% CI, 1.05‐1.76) for serotonin receptor inhibitors, and 0.79 (95% CI, 0.59‐1.07) for tricyclic antidepressants. Compared with tramadol‐only group, the adjusted ORs of combined use of antihistamines was 1.76 (95% CI, 1.47‐2.10) for first generation, and 1.56 (95% CI, 1.22‐1.98) for second generation agents. Conclusions: A tendency of increased number of spontaneous reporting with serotonin syndrome associated with combined use of antidepressants or antihistamines with tramadol were observed. When tramadol users have to use antidepressants or antihistamines with high anticholinergic burden in combination, careful monitoring is needed.