References for this Review were identified through searches of PubMed (from 1966 to June, 2009) and the Cochrane Library (1948 to June, 2009) with the search terms “apomorphine”, “bromocriptine”, “cabergoline”, “dihydroergocryptine”, “dopamine agonist”, “dyskinesia”, “fibrosis”, “impulse control disorders”, “motor complications”, “(o)edema”, “pergolide”, “piribedil”, “pramipexole”, “ropinirole”, “rotigotine”, “sleep”, “somnolence”, and “cardiac valvulopathy”. Only peer-reviewed papers
ReviewA reassessment of risks and benefits of dopamine agonists in Parkinson's disease
Introduction
The use of oral dopamine agonists for the treatment of Parkinson's disease dates back to the 1970s when the ergolinic drug bromocriptine was first introduced. The first generation of dopamine agonists were all ergot derivatives and their pharmacological profile differed from that of levodopa in several ways. For example, ergot derivatives had a longer half-life than levodopa and had a differential affinity primarily to D1-like and D2-like dopamine receptors. Although more than 50 years have passed since the non-ergot agonist apomorphine was first reported to exert strong antiparkinsonian effects,1, 2 most of the currently used non-ergot dopamine agonists have entered the clinic more recently and include pramipexole, ropinirole, rotigotine, and piribedil (table 1).
The symptomatic efficacy of dopamine agonists to treat Parkinson's disease is firmly established and several studies have also shown that early use of these drugs as initial monotherapy is associated with a reduced long-term incidence of motor complications (ie, motor fluctuations and dyskinesia) compared with levodopa.3, 4, 5, 6, 7 Although this evidence has led to dopamine agonists being classified as first-line options for initial monotherapy in early Parkinson's disease in many national and international guidelines,8, 9 there have also been recent concerns about the safety profile of these drugs in the longer term. These concerns are related to the risk of developing impulse control disorders, peripheral oedema, daytime somnolence, and heart valve fibrosis. The recognition of the risk of cardiac fibrotic valvulopathies with pergolide and cabergoline10 has caused regulatory authorities in many countries to restrict the use of these drugs to second-line options with specialised cardiac safety monitoring.
In this Review, we first outline the benefits of using dopamine agonists in the management of Parkinson's disease. We then discuss recent evidence on each of the potential risks, outline the consequences for the management of Parkinson's disease, and provide recommendations for clinical neurologists on how to individualise treatment decisions based on considerations of their risks versus benefits.
Section snippets
Early monotherapy
On the basis of a consistent body of evidence from randomised controlled trials, the dopamine agonists dihydroergocryptine, pergolide, pramipexole, and ropinirole11, 12, 13, 14, 15, 16, 17, 18 have all been shown to be effective as monotherapy in early Parkinson's disease.8 The evidence for efficacy was less strong for bromocriptine, cabergoline, and lisuride as there have not been randomised trials of these compounds in early Parkinson's disease.19, 20, 21, 22 In recent placebo-controlled
Risks associated with dopamine agonist use in Parkinson's disease
The acute side-effects of dopamine agonists are similar to those observed with levodopa and include nausea, vomiting, and postural hypotension. These adverse events tend to occur with the initiation of treatment and tend to abate as tolerance to the drug develops.60 Discontinuation rates associated with adverse events did not differ between different dopamine agonists and levodopa in randomised double-blind trials.19, 61 However, compared with levodopa, dopamine agonists are associated with a
Risks versus benefits of dopamine agonists in clinical practice
As a class, dopamine agonists have been successfully used for many years as an adjunct therapy to levodopa in patients who develop motor complications, and have an important role as initial monotherapy, particularly in younger patients. Over the past decade, the driving force for the increased prominence of dopamine agonist monotherapy has been its documented benefits in reducing the risk of dyskinesias compared with levodopa.3, 5 As motor complications are often difficult to manage, contribute
Conclusions
The choice of drug when initiating therapy in early Parkinson's disease depends on several factors, including level of disability, age, comorbidities, and cognitive status, as well as the different risk profiles of the available drugs. Most commonly, initial drug therapy is with dopaminergic drugs, although amantadine or anticholinergic drugs might still be considered to be appropriate in a few cases. None of the available drugs has yet been proven to delay the progression of disability
Search strategy and selection criteria
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