Does Delaying Levodopa Prevent Motor Complications in Parkinson's Disease? A Meta-Analysis

Abstract

Background: There has been a long debate whether delaying treatment with levodopa prevents motor complications in Parkinson's disease (PD).

Objectives: We performed a meta-analysis on randomized clinical trials (RCTs) that compared early- versus delayed-start treatment with levodopa in PD.

Methods: A systematic review was conducted in PubMed, EMBASE, and Web of Science databases from inception to July 1, 2023. Only RCTs that compared early and delayed levodopa treatment in PD were included. Non-randomized comparisons from follow-up studies were included as well. Our primary outcomes were occurrence of overall motor complications, motor fluctuations, and dyskinesias.

Results: Seven studies with a total of 1149 patients (636 in the early-start group and 513 in the delayed-start) were included in our analysis. There was no difference between groups regarding motor complications (OR 1.39; 95% CI: 0.68-1.72; P = 0.37) or dyskinesias (OR 1.52; 95% CI: 0.90-2.57; P = 0.11). Motor fluctuations occurred less frequently in the early-start group (OR 0.70; 95% CI: 0.52-0.95; P = 0.02). Nonetheless, on subgroup analysis of dopamine agonists, rate of dyskinesias was smaller in the delayed-start group (OR 1.82; 95% CI: 1.08-3.07; P = 0.03).

Conclusions: Delaying treatment with levodopa does not seem to prevent levodopa-related motor complications in PD. Adjunct treatment with dopamine agonists may reduce the need for higher doses of levodopa and thus reduce the risk for dyskinesias but this practice is often associated with a higher frequency of adverse effects related to dopamine agonists.

Keywords: Parkinson's disease; dyskinesia; levodopa; meta‐analysis; motor fluctuations.

Figure 1

PRISMA flowchart.

Figure 2

Forest plot of the three primary outcomes. There were no significant differences between groups regarding overall motor complications and dyskinesias. However, motor fluctuations were less common in the early‐start levodopa group. The three outcomes had high heterogeneity. CALM‐PD, Comparison of the agonist pramipexole with levodopa on motor complications of Parkinson's disease; CI, confidence interval; LEAP, Levodopa in Early Parkinson's Disease; M‐H, Mantel–Haenszel test; PDRG‐UK, Parkinson's Disease Research Group of the United Kingdom.

Figure 3

Subgroup analysis of subjects initially treated with dopamine agonists. Delayed treatment with levodopa was significantly associated with a decrease in dyskinesias. CALM‐PD, Comparison of the agonist pramipexole with levodopa on motor complications of Parkinson's disease; CI, confidence interval; LEAP, Levodopa in Early Parkinson's Disease; M‐H, Mantel–Haenszel test; PDRG‐UK, Parkinson's Disease Research Group of the United Kingdom.