OBJECTIVES: The pharmacokinetic characteristics of tapentadol, marketed as Nucynta, put patients at higher risk of developing serotonin syndrome when prescribed concomitantly with other serotonergic medications. This research aims to examine the potential risk of serotonin syndrome by quantifying the concurrent use of tapentadol and other serotonergic medications. METHODS: This was a retrospective cohort study. All patients with tapentadol claims were identified in the IMS Lifelink database from 2008 to 2014. The main outcome measure was the percentage of tapentadol patients with serotonergic medication usage overlap. This was compared to tramadol and oxycodone, opioids that have little or no association with serotonin syndrome. Statistical comparisons were performed using t-tests. RESULTS: There were 9882 unique tapentadol patients, of which 5819 patients had indications for a serotonergic medication. 424 (7.29%) patients indicated for tapentadol and a serotonergic medication experienced an overlap. There were 266,132 unique tramadol patients, of which 117,862 (44.3%) have had an indication for a serotonergic medication. 7,032 (5.97%) of patients indicated for tramadol and a serotonergic medication experienced an overlap. A t-test showed that there was a significant difference between the percentages with a p-value of 0.0009. There were 472,999 oxycodone patients, of which 179,549 had indications for serotonergic medication. 5139 (2.86%) patients experienced overlap. CONCLUSIONS: Patients indicated for tapentadol and a serotonergic medication are more likely to experience an overlap than patients indicated for tramadol and a serotonergic medication. Due to this concomitant use, Tapentadol patients may experience a higher risk of developing serotonin syndrome. These findings can be used to help regulators recommend label changes for tapentadol and guide healthcare providers in prescribing decision-making in patients with indications for opioids and serotonergic medication.