Efficacy and Safety of Safinamide as an Adjunct to Levodopa for Motor Fluctuations in Parkinson's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Motor fluctuations often occur with long-term levodopa treatment in Parkinson's disease (PD). Safinamide is a drug that inhibits monoamine oxidase B (MAO-B) and modulates glutamate. It is used together with levodopa. A summary of the latest evidence is needed to assess its effectiveness and safety.

Objective: To assess the effectiveness and safety of safinamide as an additional therapy to levodopa for motor fluctuations in PD.

Methods: A systematic review and meta-analysis followed PRISMA guidelines. A thorough literature search was done from the beginning until January 2026 across PubMed, Scopus, the Cochrane Central Register of Controlled Trials, and Google Scholar. We included randomized controlled trials (RCTs) that compared safinamide (100 mg/day) to placebo as an addition to levodopa in adults with PD and motor fluctuations. The primary effectiveness outcomes were the change in daily OFF-time (in hours) and the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) score. The main safety outcome was the occurrence of dyskinesia. We assessed the risk of bias using the Cochrane RoB 2 tool. Data were combined using random-effects models, with results shown as mean difference (MD) or risk ratio (RR) with 95% confidence intervals (CIs). We evaluated the certainty of evidence using GRADE. The protocol was registered with PROSPERO (CRD420261298124).

Results: Three RCTs (N = 1127 participants) were included. Safinamide 100 mg significantly reduced daily OFF-time compared to placebo, with an MD of -1.21 h (95% CI: -1.60 to -0.82; I ² = 39%; moderate certainty). It also significantly improved motor function, as shown by the UPDRS-III MD of -3.13 points (95% CI: -4.89 to -1.37; I ² = 72%; low certainty). However, safinamide increased the risk of dyskinesia, with a RR of 3.01 (95% CI: 1.92 to 4.70; I ² = 0%; moderate certainty). In a secondary analysis of the Hattori trial's 50 mg arm (n = 131), safinamide 50 mg reduced OFF-time by -1.25 h (95% CI: -1.92 to -0.58) and improved the UPDRS-III by -4.06 points (95% CI: -5.54 to -2.59). This effect was smaller for OFF-time compared to the 100-mg dose, suggesting a potential dose-response relationship that warrants further investigation.

Conclusion: Safinamide 100 mg per day appears to be a helpful addition to levodopa for reducing OFF-time and improving motor function in PD patients with motor fluctuations. However, this benefit comes with a higher risk of dyskinesia, so careful patient selection and monitoring are important. The 50-mg dose shows similar but less pronounced effects, supporting 100 mg as the preferred dose. Further research is needed to confirm these findings.