Groundbreaking study reveals most effective adjunctive drug for Parkinson's disease

In a recent study published in npj Parkinson's Disease, a group of researchers concisely compared the efficacy, tolerability, and safety of various anti-Parkinson's drugs used with levodopa, utilizing a network meta-analysis (NMA) approach.

Study: Comparative efficacy and safety of adjunctive drugs to levodopa for fluctuating Parkinson’s disease – network meta-analysis. Image Credit: Barabasa/


Motor symptoms mark Parkinson's disease (PD) due to the loss of dopaminergic neurons. Although levodopa is the treatment cornerstone, long-term use leads to complications like motor fluctuations and dyskinesia, necessitating adjunctive anti-PD drugs (e.g., Dopamine Agonists (DAs), Monoamine Oxidase B Inhibitors (MAOBIs), Catechol-O-Methyltransferase Inhibitors (COMTIs), Adenosine A2A Receptor Antagonists (A2ARA)).

These drugs mitigate off-time but carry unique adverse event (AE) risks. Further research is needed because, despite the proven efficacy of various anti-PD drugs in reducing off-time, each has specific adverse event risks, and direct comparisons between them are scarce.

Existing NMAs often exclude newly available drugs or certain drug forms and stages of PD, and they typically use Unified Parkinson's Disease Rating Scale (UPDRS) scores rather than off-time reduction, which is more relevant for patients with advanced PD experiencing motor fluctuations.

About the study 

The present research strictly adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-NMA guidelines, with its protocol recorded at the International Prospective Register of Systematic Reviews (PROSPERO).

An extensive search was executed across PubMed, Embase, and Cochrane Library, focusing on studies published until July 2021, which employed specific keywords related to Parkinson's disease and various treatment drugs.

Two independent reviewers meticulously screened titles and abstracts, advancing relevant articles for comprehensive review, with any conflicts settled through a third opinion.

The scope was narrowed to randomized controlled trials published in English, involving Parkinson's patients experiencing motor fluctuations and comparing placebo with selected Parkinson's drugs or among the drugs themselves.

These studies needed to analyze specific outcomes and adhere to approved drug dosages in certain regions. Exclusions were made for non-original, repetitive data or summaries. Beyond traditionally published studies, the research also incorporated six reports from Japan's Pharmaceuticals and Medical Devices Agency, contributing additional valuable data.

Two independent researchers performed data extraction, focusing on various efficacy, tolerability, and safety outcomes. Additional data points were also compiled, such as author details, sample size, demographics, and medication specifics. Each study's quality was rigorously assessed, categorizing them based on their risk of bias.

Statistical analysis was done within a frequentist framework, utilizing specific software tools. The results, articulated as standard mean differences or odds ratios with 95% confidence intervals, underwent comprehensive analysis, including ranking through Surface Under the Cumulative Ranking Curve (SUCRA) values.

The research also thoroughly examined any inconsistencies or heterogeneities within the collected data, underpinning the study's thoroughness and credibility.

Study results 

The initial literature search in the study under discussion produced 2,692 records, narrowing to 1,637 after duplicates were removed. Upon further scrutiny, only 48 studies met the inclusion criteria for the NMA.

These studies and six reports from Japanese common technical documents comprised the 54 studies analyzed, encompassing 12 different PD drugs. However, the tolerability and safety outcome NMA included 11 drugs due to insufficient data on the ropinirole transdermal patch.

Compared with a placebo, the NMA outcomes revealed significant improvement in daily off-time with all drugs except for pramipexole ER. Ropinirole transdermal patch had the highest ranking for improvement in daily off-time, followed by pramipexole, ropinirole ER, and safinamide.

Regarding discontinuation due to all causes, pramipexole, and ropinirole showed a significantly lower risk than placebo, with ropinirole ranking the highest in this outcome, followed by pramipexole, safinamide, and ropinirole ER.

For discontinuation due to AEs, no drug was associated with a lower risk than placebo. However, pramipexole ranked highest, followed by safinamide, ropinirole, and rotigotine transdermal patch. Similar results were observed for the incidence of AEs, with safinamide ranking highest, followed by pramipexole ER, selegiline, and rotigotine transdermal patch.

In the context of specific AEs, none of the 11 drugs were linked with a lower risk of dyskinesia compared to placebo. Still, selegiline ranked highest, followed by rasagiline, istradefylline, and entacapone.

Similarly, no drug showed a lower risk of hallucination than placebo, but entacapone ranked highest in this outcome. For the incidence of orthostatic hypotension (OH), the rotigotine transdermal patch was associated with a lower risk than the placebo and ranked the highest, followed by safinamide, pramipexole, and selegiline.

The inconsistency assessment within the study revealed no global inconsistency of treatment effect for any of the outcomes, indicating a reliable comparison across the different metrics and treatments.

However, one notable exception was found in the network for discontinuation due to all causes, where an inconsistency emerged between the direct and indirect comparison of placebo and entacapone.

This extensive analysis underscores the complexity of treatment effects among various anti-PD drugs. It highlights the necessity of considering individual patient profiles, drug efficacy, tolerability, and safety profiles when making clinical decisions for PD patients.

The detailed ranking and analysis provided by this NMA offer valuable insights for healthcare providers in tailoring the most appropriate treatment plans.

Journal reference:
  • Sako, W., Kogo, Y., Koebis, M. et al. (2023) Comparative efficacy and safety of adjunctive drugs to levodopa for fluctuating Parkinson’s disease – network meta-analysis. npj Parkinsons Dis. 9, 143. doi: 

Posted in: Medical Science News | Medical Research News | Medical Condition News | Pharmaceutical News

Tags: Adenosine, Dopamine, Dopaminergic, Drugs, Dyskinesia, Efficacy, Hallucination, Healthcare, Hypotension, Levodopa, Medical Devices, Neurons, Orthostatic Hypotension, Parkinson's Disease, Pharmaceuticals, Placebo, Pramipexole, Receptor, Research, Ropinirole, Rotigotine, Selegiline, Software

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Written by

Vijay Kumar Malesu

Vijay holds a Ph.D. in Biotechnology and possesses a deep passion for microbiology. His academic journey has allowed him to delve deeper into understanding the intricate world of microorganisms. Through his research and studies, he has gained expertise in various aspects of microbiology, which includes microbial genetics, microbial physiology, and microbial ecology. Vijay has six years of scientific research experience at renowned research institutes such as the Indian Council for Agricultural Research and KIIT University. He has worked on diverse projects in microbiology, biopolymers, and drug delivery. His contributions to these areas have provided him with a comprehensive understanding of the subject matter and the ability to tackle complex research challenges.