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. 2025 Jun 15;7(1):e001115.
doi: 10.1136/bmjno-2025-001115. eCollection 2025.

Efficacy and safety of oral amantadine in Parkinson's disease with dyskinesia and motor fluctuations: a systematic review and meta-analysis of randomised controlled trials

Surachet Rujirussawarawong  1 , Saharat Aungsumart  1 , Chayut Kasemsuk  1 , Natlada Limotai  1
Affiliations

Efficacy and safety of oral amantadine in Parkinson's disease with dyskinesia and motor fluctuations: a systematic review and meta-analysis of randomised controlled trials

Surachet Rujirussawarawong et al. BMJ Neurol Open. .

Abstract

Background: Oral amantadine is available in three formulations with distinct pharmacokinetics: immediate-release (IR), delayed-release/extended-release (DR/ER) and immediate-release/extended-release (IR/ER). While all formulations alleviate levodopa-induced dyskinesia, only DR/ER has shown efficacy for motor fluctuations. This meta-analysis evaluates the impact of amantadine formulations on motor complications in Parkinson's disease (PD).

Methods: A systematic search of PubMed and Scopus (inception to February 2024) identified randomised controlled trials (RCTs) evaluating dyskinesia using various Dyskinesia Rating Scales (DRS) and Unified Parkinson's Disease Rating Scale (UPDRS) or Movement Disorder Society (MDS)-UPDRS part 4 subscores ((MDS-)UPDRS IV), motor fluctuations using 'OFF' time and safety through adverse events. Subgroup analysis assessed formulation-specific effects. The I² statistic determined the use of fixed-effects or random-effects models for efficacy outcomes. Dyskinesia was analysed using standardised mean difference (SMD), motor fluctuations with mean difference (MD) and adverse events with ORs via a fixed-effects Mantel-Haenszel model.

Results: Fourteen RCTs (13 articles) were included. Amantadine significantly reduced dyskinesia (DRS: SMD=-1.32, 95% CI (-1.78 to -0.86); (MDS-)UPDRS IV: SMD=-0.95, 95% CI (-1.33 to -0.58)), with similar effects across formulations. 'OFF' time decreased significantly (MD=-0.66, 95% CI (-0.93 to -0.40)), notably with IR (MD=-0.75, 95% CI (-1.41 to -0.10)) and DR/ER (MD=-0.96, 95% CI (-1.35 to -0.57)), but not IR/ER (MD=-0.23, 95% CI (-0.68 to 0.22)). Adverse events (OR=3.30, 95% CI (2.29 to 4.74)) included dry mouth, hallucinations, peripheral oedema, dizziness and constipation.

Conclusions: All amantadine formulations alleviated dyskinesia. Additionally, DR/ER improved motor fluctuations, while IR demonstrated benefits, although the evidence is limited by short study durations.

Prospero registration number: CRD42024513081.

Keywords: META-ANALYSIS; MOVEMENT DISORDERS; NEUROPHARMACOLOGY; PARKINSON'S DISEASE.

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Conflict of interest statement

No, there are no competing interests.

Figures

Figure 1
Figure 1. PRISMA 2020 flow diagram illustrating the study selection process. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Figure 2
Figure 2. Traffic light plots presenting domain-level judgements for each study using V.2 of the Cochrane Risk of Bias Tool (RoB 2).
Figure 3
Figure 3. Forest plot using the random-effects model presenting the change scores of the DRS for oral amantadine compared with placebo as well as for each formulation in the subgroup analysis. DR/ER, delayed-release/extended-release; DRS, Dyskinesia Rating Scale; IR, immediate-release; IR/ER, immediate-release/extended-release.
Figure 4
Figure 4. Forest plot using the random-effects model presenting the change scores of the (MDS-)UPDRS IV for oral amantadine compared with placebo, as well as for each formulation in the subgroup analysis. DR/ER, delayed-release/extended-release; IR, immediate-release; (MDS-)UPDRS IV, Unified Parkinson’s Disease Rating Scale (UPDRS) or Movement Disorder Society (MDS)-UPDRS part 4 subscores.
Figure 5
Figure 5. Forest plot using the fixed-effects model presenting the ‘OFF’ time for oral amantadine compared with placebo, as well as for each formulation in the subgroup analysis. DR/ER, delayed-release/extended-release; IR, immediate-release; IR/ER, immediate-release/extended-release.
Figure 6
Figure 6. Forest plot presenting the number of patients with adverse events for oral amantadine compared with placebo.
See this image and copyright information in PMC

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