Dopamine agonists in the treatment of early Parkinson's disease: A meta-analysis

https://doi.org/10.1016/j.parkreldis.2008.07.004Get rights and content

Abstract

Our objective was to perform a meta-analysis of randomized controlled trials of dopamine agonists (DA) as monotherapy as well as adjunctive therapy for the early treatment of Parkinson's disease (PD). A systematic literature search was conducted through April 2007. Both efficacy and safety endpoints were evaluated. DA monotherapy showed superior efficacy but more frequent adverse events compared to placebo. In addition, DA demonstrated inferior efficacy to levodopa, but was associated with fewer motor complications. However, DAs were associated with a greater incidence of nuisance side effects, such as hallucinations, somnolence and dizziness. The use of DA is an effective treatment option for the treatment of early PD and appears especially useful among PD patients with wearing-off phenomenon or dyskinesias on levodopa; however it may result in more adverse events and higher withdrawal rates.

Introduction

Parkinson's disease (PD) is a progressive movement disorder characterized by symptoms of tremor, rigidity and bradykinesia. It is the second most prevalent neurodegenerative disease affecting approximately 1 million Americans [1]. PD is relatively uncommon in patients aged less than 40 years, but increases steadily thereafter. It has been estimated to affect about 1% of patients greater than 60 years of age, with an average onset around 62 years [1]. PD is caused by a progressive loss of dopaminergic neurons in the basal ganglia region of the brain. Dopamine activity is lost within the nigrostriatal tracts, with compensatory increases in acetylcholine activity [2], [3].

Dopaminergic drugs (levodopa, dopamine agonists) may be recommended as initial agents of choice in patients with early PD, although differentiation of drugs and classes is not specifically made [4], [5]. Levodopa has traditionally been considered the most effective agent for the treatment of PD. Although clinical and pathologic studies have failed to prove that levodopa slows disease progression, a significant reduction in symptoms has been seen [6]. However, the development of disabling motor complications (e.g. wearing-off, dyskinesia) can impact its long-term use. Dopamine agonists (DA), including ergot and non-ergot agents, have generally been considered less effective than levodopa, but are recommended as alternative first line agents in early disease [4], [5]. They do, however, offer the advantage of fewer motor complications, including dyskinesias and wearing-off, and more convenient dosing schemes as compared with levodopa.

Numerous clinical trials have evaluated the efficacy of DA versus placebo, versus levodopa, and in combination with levodopa. We performed a meta-analysis of randomized controlled trials evaluating the efficacy and safety of DA both in comparison and in combination with levodopa in patients with early PD.

Section snippets

Data sources

A systematic literature search of MEDLINE, EMBASE, CINAHL, Web of Science, and the Cochrane Database (2007, issue 2) was conducted for the years 1990 through April 2007. A search strategy using the Medical Subject Headings (MeSH) and text keywords dopamine agonist, bromocriptine, pergolide, cabergoline, lisuride, α-dihydroergocryptine, pramipexole, ropinirole, rotigotine, in combination with Parkinson's, Parkinson's disease, and PD was used. In addition, a manual search of references from

Study identification and selection

Our search yielded 678 potential literature citations (Fig. 1). Of those, 617 were excluded through a review of abstracts leaving 61 articles for full publication review. Twenty-five of these were excluded because they were either not randomized, controlled trials or did not report the desired outcome data. Thus, 25 (n = 5185) trials were found to conform to our inclusion criteria (Table 1) [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29],

Discussion

This meta-analysis of 25 randomized clinical trials in patients with early PD provides substantiation for the use of DA as potential first line agents in these patients, which is in accordance with current guidelines [4], [5]. It also clarifies uncertainties, including efficacy and side effect profiles, about the role these drugs have as monotherapy in comparison to levodopa for initial therapy which is in agreement with prior systematic reviews [37].

Our meta-analysis demonstrates that patients

Conclusions

In patients with early PD, use of DA is an effective treatment option for reducing PD symptoms. DA use results in fewer motor complications, including wearing-off phenomenon or dyskinesias compared to levodopa, but is associated with a higher incidence of withdrawal from therapy as well as common adverse events. There may also be an advantage of combining DAs and levodopa versus employing a higher dose of levodopa alone in early PD, which may result in less wearing-off and fewer motor

Conflict of interest

WLB, CMW, JK, JA, CIC have no conflicts to report. AAP is an employee of Boehringer Ingelheim. DS is on the speakers bureau for Boehringer Ingelheim and owns stock in Pfizer, Elan, and Johnson and Johnson.

Acknowledgements

The present study was financially supported by Boehringer Ingelheim Pharmaceuticals.

Authors contributions: WLB and CIC were responsible for formulating the research question; WLB, JA and CIC conducted the literature search; WLB, CMW, JA, and CIC were responsible for the data analyses, and interpreting the data and results; WLB, DS, CMW, JK, JA, AAP, and CIC were responsible for writing the manuscript.

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