Safety of COMT-inhibitors in parkinson's disease: a phase-IV comparative study on adverse events of Tolcapone, Entacapone and Opicapone.

Catechol-O-methyltransferase (COMT) inhibitors-Tolcapone, Entacapone, and Opicapone-are adjunct therapies for advanced Parkinson's disease (PD), improving motor control. Their distinct safety profiles may influence clinical decisions and patient adherence. This study provides a comprehensive descriptive analysis of adverse events (AEs) reported for these drugs and a comparative safety assessment based on post-marketing AE reports and drug sales data from 2018 to 2023. A retrospective analysis was conducted using data from the FDA Adverse Event Reporting System (FAERS). AEs were categorized by severity and compared across COMT-inhibitors. Drug utilization trends were evaluated through retail and hospital sales data, expressed as standard units and market share. AE incidence was normalized for drug exposure using the median number of pills per day. Statistical comparisons were performed using Fisher's exact test to assess differences in AE rates. Entacapone was sold 100 times more than Opicapone and 1000 times more than Tolcapone. When normalized for drug exposure, total AEs were significantly lower for Entacapone than Opicapone (OR = 0.0435, p < 0.001) and Tolcapone (OR = 0.1397, p < 0.001). Tolcapone also exhibited a significantly lower AE risk than Opicapone (OR = 0.3119, p < 0.001). Similarly, Entacapone had significantly fewer serious AEs than Opicapone (OR = 0.0732, p < 0.001) and Tolcapone (OR = 0.0872, p < 0.001), indicating a more favorable safety profile. This is the first study directly comparing the safety profiles of COMT-inhibitors head-to-head. Entacapone appears to be the safest long-term COMT-inhibitor, with the lowest risk of both serious and non-serious AEs. A long-term, prospective clinical trial is warranted to overcome retrospective limitations and confirm these findings.