Subcutaneous Levodopa in Parkinson's Disease: A Systematic Review and Meta-Analysis

Background: Many Parkinson's disease patients receiving oral levodopa/carbidopa experience a troublesome wearing off effect. Higher doses to mitigate OFF-time are limited by adverse effects occurring at peak dopamine levels, particularly dyskinesia. A novel strategy to reduce OFF-time without increasing peak dopamine levels is the continuous subcutaneous infusion of levodopa/carbidopa, or their prodrug equivalents foslevodopa/foscarbidopa. Objectives: Assess whether subcutaneous infusion therapies safely reduce OFF-time and improve quality of life scores compared to oral levodopa/carbidopa. Methods: We searched MEDLINE, Embase, CENTRAL and ICTRP up to 28th October 2024 for clinical trials comparing subcutaneous infusions of levodopa or foslevodopa to oral levodopa in Parkinson's disease. Results: Screening of 1114 records identified seven studies in which 725 patients received subcutaneous infusion regimens of levodopa/carbidopa (ND0612) (407 patients) or foslevodopa/foscarbidopa (318 patients). Moderate quality evidence indicated subcutaneous infusion reduced the daily duration of OFF-time by 1.98 h (p = 0.0004). Moderate quality evidence indicated improvements in health-related quality of life score PDQ-39 (p = 0.0003) and sleep score PDSS-2 (p = 0.02), but an increase in the rate of treatment-emergent adverse events, mostly related to the infusion site (p = 0.04). Conclusions: Subcutaneous infusion therapies produce a clinically and statistically significant reduction in the duration of OFF-time experienced by patients with Parkinson's disease, compared to oral levodopa/carbidopa. Patient experience is improved by a statistically, but not clinically, significant degree. There are increased adverse events, mostly related to the infusion site. Overall, subcutaneous infusion regimens could provide a meaningful alternative for Parkinson's disease patients who experience severe motor fluctuations with existing levodopa formulations.