Dopamine agonist therapy in early Parkinson's disease

Stowe R, Ives N, Clarke CE, van Hilten JJ, Ferreira J, Hawker RJ, Shah L, Wheatley K, Gray R

Published Online:

January 21, 2009

This 'umbrella' meta-analysis assesses dopamine agonists as a drug class in early Parkinson's disease. Twenty-nine eligible trials, involving 5247 participants, were identified. It confirms reports from individual trials that motor complications are reduced with dopamine agonists compared to levodopa, but also demonstrates that other important side-effects are increased and symptom control is poorer with agonists. Unfortunately, the balance of risks and benefits remains unclear highlighting the need for further studies assessing patient-rated overall quality of life and economic measures as their primary outcomes.

Abstract (click to read)

Background:

Dopamine agonists are being used increasingly as first line treatment for Parkinson's disease, but there remains uncertainty about their clinical and cost-effectiveness relative to levodopa.

Objectives:

This meta-analysis aims to quantify more reliably the benefits and risks of dopamine agonists compared to placebo or levodopa in early Parkinson's disease.

Search strategy:

We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, PubMed, LILACS and Web of Science, plus major journals in the field, abstract books, conference proceedings and reference lists of retrieved publications.

Selection criteria:

Randomised trials comparing an orally administered dopamine agonist (with or without levodopa) versus placebo or levodopa or both placebo and levodopa in participants with early Parkinson's disease.

Data collection and analysis:

Two authors independently extracted data on clinician-rated disability, motor complications, other side-effects, treatment concordance, levodopa dose and mortality.

Main results:

Twenty-nine eligible trials, involving 5247 participants, were identified. Participants randomised to a dopamine agonist were less likely to develop dyskinesia (odds ratio (OR) 0.51, 95% confidence interval (CI) 0.43 to 0.59; P < 0.00001), dystonia (OR 0.64, 95% CI 0.51 to 0.81; P = 0.0002) and motor fluctuations (OR 0.75, 95% CI 0.63 to 0.90; P = 0.002) than levodopa-treated participants. However, various 'non-motor' side-effects, including oedema (OR 3.68, 95% CI 2.62 to 5.18; P < 0.00001), somnolence (OR 1.49, 95% CI 1.12 to 2.00; P = 0.007), constipation (OR 1.59, 95% CI 1.11 to 2.28; P = 0.01), dizziness (OR 1.45, 95% CI 1.09 to 1.92; P = 0.01), hallucinations (OR 1.69, 95% CI 1.13 to 2.52; P = 0.01) and nausea (OR 1.32, 95% CI 1.05 to 1.66; P = 0.02) were all increased in agonist-treated participants (compared with levodopa-treated participants). Agonist-treated participants were also significantly more likely to discontinue treatment due to adverse events (OR 2.49, 95% CI 2.08 to 2.98; P < 0.00001). Finally symptomatic control of Parkinson's disease was better with levodopa than with agonists, but data were reported too inconsistently and incompletely to meta-analyse.

Authors' conclusions:

This meta-analysis confirms that motor complications are reduced with dopamine agonists compared to levodopa, but also establishes that other important side-effects are increased and symptom control is poorer with agonists. Larger, long-term comparative trials assessing patient-rated quality of life are needed to assess more reliably the balance of benefits and risks of dopamine agonists compared to levodopa.

This record should be cited as:

Stowe R, Ives N, Clarke CE, van Hilten JJ, Ferreira J, Hawker RJ, Shah L, Wheatley K, Gray R. Dopamine agonist therapy in early Parkinson's disease. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD006564. DOI: 10.1002/14651858.CD006564.pub2

Assessed as up to date:

January 7, 2008

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Primary Review Group:

Movement Disorders Group

PEARLS - Practical Evidence About Real Life Situations (click to read)

Clinical question:

Compared to placebo or levodopa, how effective and safe are dopamine agonists (DAs) in early Parkinson’s disease (PD)?

Bottom line:

Compared to placebo or levodopa, DAs reduce motor complications (dystonia, dyskinesia and motor fluctuations) in patients with early PD1. However, symptom control is poorer with DAs, and ‘non-motor’ side-effects are increased (oedema, somnolence, constipation, dizziness, hallucinations, nausea and headaches). Patients on a DA were more than twice as likely to discontinue treatment prematurely due to adverse effects than control patients, suggesting that the ‘non-motor’ side-effects were of sufficient severity to have a meaningful impact on patient’s quality of life and were perhaps at least as clinically important as the motor complications.

Caveat:

Unfortunately the balance of risks and benefits remains unclear, as only one trial included overall quality of life and cost-effectiveness as outcome measures. Larger, long-term comparative trials assessing patient-rated quality of life are needed to assess more reliably the balance of benefits and risks of DAs compared to levodopa. It is also important that cost-effectiveness is assessed, as there is a need for better evidence on the cost-effectiveness of the considerably more expensive DAs.

Context:

Parkinson's disease is a progressive disorder affecting over six million people worldwide, making it the most common neurodegenerative disease after Alzheimer's disease2. In the absence of curative therapy, treatment is directed towards alleviating the characteristic symptoms of PD such as bradykinesia, tremor, rigidity and postural instability3. Levodopa combined with a peripheral dopa-decarboxylase inhibitor provides effective symptomatic control. However, long-term levodopa use is associated with the development of motor complications such as involuntary movements (dyskinesia) and motor fluctuations ('wearing-off' phenomenon and unpredictable 'on-off' fluctuations). Since levodopa was introduced in the 1960s, two other drug classes have also become widely used4. These are dopamine agonists and monoamine oxidase type B inhibitors (MAOBIs) and are used either alone (as first-line treatment) or in combination with levodopa, in an attempt to control symptoms or delay the onset of motor complications or both in early PD.

Cochrane Systematic Review:

1. Stowe RL et al. Dopamine agonist therapy in early Parkinson’s disease. Cochrane Reviews 2008, Issue 2. Art. No.: CD006564. DOI: 10.1002/14651858.CD006564.pub2. This review contains 29 trials involving 5,247 participants. 2. Schapira AH. BMJ 1999 ;318 :311-314. 3. Clarke CE. Neurology, Neurosurgery and Psychiatry. 2002 ;72 :122-127. 4. Quinn NP. Baillieres Clinical Neurology 1997 ;6 :1-13.

Authored by:

Brian R McAvoy

Cochrane Primary Health Care Field

Health topics:

Neurology > Movement disorders > Parkinson's disease

Cochrane Summaries^beta

Independent high-quality evidence for health care decision making

Dopamine agonist therapy in early Parkinson's disease

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