Objective: To evaluate the efficacy and safety of oral amantadine (AMA) compared to placebo in the treatment of dyskinesia (DYS) and motor fluctuations (MF) in Parkinson’s disease (PD) through a systematic review and meta-analysis of randomized controlled trials (RCTs).

Background: AMA immediate-release (IR) has proved to be efficacious in levodopa-induced DYS; nevertheless, in terms of MF, the evidence base was inconclusive [1]. Furthermore, oral AMA is currently divided into three formulations based on different pharmacokinetics, including IR, delayed-release/extended-release (DR/ER), and immediate-release/extended-release (IR/ER), and the data on these formulations is limited.

Method: We systematically searched the relevant studies from the MEDLINE and Scopus databases from inception to February 2024. The Risk of Bias 2 tool (RoB2) was used to assess the quality of studies [2]. Various dyskinesia rating scales (Pooled DRS) and UPDRS part 4 subscore or MDS-UPDRS part 4 (Pooled UPDRS) depicted the DYS outcome, “OFF” time depicted the MF outcome, and adverse events (AEs) depicted the safety outcome. Continuous data for DYS from each study were combined using standardized mean difference (SMD, Cohen’s d) by random-effects model, DerSimonian-Laird model; for MF, using mean difference (MD) by fixed-effects, inverse-variance model. Dichotomous data for AEs were combined using odds ratio (OR) by fixed-effects, Mantel-Haenszel model. Subgroup analysis for each formulation of AMA was planned.

Results: Fourteen RCTs from thirteen published articles were included. For DYS, change scores of Pooled DRS and Pooled UPDRS were significantly improved (Pooled DRS, SMD = -1.32, 95% CI [-1.78, -0.86]; Pooled UPDRS, SMD = -0.95, 95% CI [-1.33, -0.58]), and for each formulation in subgroup analysis. For MF, “OFF” time was significantly reduced (MD = -0.66, 95% CI [-0.93, -0.40]), and for two formulations in subgroup analysis (IR, MD = -0.75, 95% CI [-1.41, -0.10]; DR/ER, -0.96, 95% CI [-1.35, -0.57]). AEs were significantly found in AMA (OR = 3.30, 95% CI [2.29, 4.74]), including dry mouth, hallucination, peripheral edema, dizziness, and constipation.

Conclusion: AMA was efficacious in treating DYS, with some minor adverse events. In addition, both AMA IR and DR/ER were efficacious in treating MF. This was the first meta-analysis, to our knowledge, that demonstrated the efficacy of AMA IR in MF.

References: 1. Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson’s disease [published correction appears in Mov Disord. 2018 Dec;33(12):1992]. Mov Disord. 2018;33(8):1248-1266. doi:10.1002/mds.27372
2. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. Published 2019 Aug 28. doi:10.1136/bmj.l4898

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MDS Abstracts - https://www.mdsabstracts.org/abstract/efficacy-and-safety-of-amantadine-in-parkinsons-disease-with-dyskinesia-and-motor-fluctuations-a-systematic-review-and-meta-analysis/