Elsevier

The Lancet Neurology

Volume 8, Issue 10, October 2009, Pages 929-937
The Lancet Neurology

Review
A reassessment of risks and benefits of dopamine agonists in Parkinson's disease

https://doi.org/10.1016/S1474-4422(09)70225-XGet rights and content

Summary

Neurologists have several choices of drugs that have been shown to be effective for the treatment of the symptoms of Parkinson's disease. Among the first options are the dopamine agonists, which are commonly used both as an early monotherapy and as an adjunct therapy to levodopa. However, before starting any treatment, the overall benefit-to-risk ratio to individual patients must be considered. For the dopamine agonists, the available evidence on their symptomatic efficacy, effect on long-term levodopa-related motor complications, putative effect on progression of disease, and adverse event profile must be taken into account. Recently, the ocurrence of adverse events such as leg oedema, daytime somnolence, impulse control disorders, and fibrosis have increasingly been recognised. The risks of these potentially serious adverse events must therefore be taken into account and treatment decisions should be based on considerations of risks versus benefits for individual patients.

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

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

References (109)

  • AM Pritchett et al.

    Valvular heart disease in patients taking pergolide

    Mayo Clin Proc

    (2002)
  • A Struppler et al.

    Studies of mechanism of action of apomorphine on Parkinson's tremor

    Z Klein Med

    (1953)
  • RS Schwab et al.

    Apomorphine in Parkinson's disease

    Trans Am Neurol Assoc

    (1951)
  • O Rascol et al.

    A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa

    N Engl J Med

    (2000)
  • Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial

    JAMA

    (2000)
  • RG Holloway et al.

    Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial

    Arch Neurol

    (2004)
  • WH Oertel et al.

    Pergolide versus levodopa monotherapy in early Parkinson's disease patients: the PELMOPET study

    Mov Disord

    (2005)
  • F Bracco et al.

    The long-acting dopamine receptor agonist cabergoline in early Parkinson's disease: final results of a 5-year, double-blind, levodopa-controlled study

    CNS Drugs

    (2004)
  • M Horstink et al.

    Review of the therapeutic management of Parkinson's disease. Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder Society-European Section. Part I: early (uncomplicated) Parkinson's disease

    Eur J Neurol

    (2006)
  • JM Miyasaki et al.

    Practice parameter: initiation of treatment for Parkinson's disease: an evidence-based review. Report of the Quality Standards Subcommittee of the American Academy of Neurology

    Neurology

    (2002)
  • J Horvath et al.

    Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists

    Mov Disord

    (2004)
  • B Bergamasco et al.

    Alpha-dihydroergocryptine in the treatment of de novo parkinsonian patients: results of a multicentre, randomized, double-blind, placebo-controlled study

    Acta Neurol Scand

    (2000)
  • P Barone et al.

    Pergolide monotherapy in the treatment of early PD: a randomized, controlled study

    Neurology

    (1999)
  • KM Shannon et al.

    Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson's disease

    Neurology

    (1997)
  • CH Adler et al.

    Ropinirole for the treatment of early Parkinson's disease

    Neurology

    (1997)
  • Ropinirole: management of Parkinson's disease

    Mov Disord

    (2002)
  • Pramipexole: management of Parkinson's disease

    Mov Disord

    (2002)
  • Piribedil: management of Parkinson's disease

    Mov Disord

    (2002)
  • Pergolide: management of Parkinson's disease

    Mov Disord

    (2002)
  • CG Goetz et al.

    Evidence-based medical review update: pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004

    Mov Disord

    (2005)
  • JL Montastruc et al.

    A randomised controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkinson's disease: a five year follow up

    J Neurol Neurosurg Psychiatry

    (1994)
  • UK Rinne et al.

    Early treatment of Parkinson's disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial

    Drugs

    (1998)
  • UK Rinne

    Lisuride, a dopamine agonist in the treatment of early Parkinson's disease

    Neurology

    (1989)
  • J Jankovic et al.

    Transdermal rotigotine: double-blind, placebo-controlled trial in Parkinson disease

    Arch Neurol

    (2007)
  • RL Watts et al.

    Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease

    Neurology

    (2007)
  • O Rascol et al.

    Early piribedil monotherapy of Parkinson's disease: a planned seven-month report of the REGAIN study

    Mov Disord

    (2006)
  • CW Olanow et al.

    Drug insight: continuous dopaminergic stimulation in the treatment of Parkinson's disease

    Nat Clin Pract Neurol

    (2006)
  • EC Maratos et al.

    Antiparkinsonian activity and dyskinesia risk of ropinirole and L-DOPA combination therapy in drug naive MPTP-lesioned common marmosets (Callithrix jacchus)

    Mov Disord

    (2001)
  • LA Smith et al.

    Repeated administration of piribedil induces less dyskinesia than L-dopa in MPTP-treated common marmosets: a behavioural and biochemical investigation

    Mov Disord

    (2002)
  • R Katzenschlager et al.

    Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson's disease: a prospective study using single-dose challenges

    Mov Disord

    (2005)
  • F Stocchi et al.

    Prospective randomized trial of lisuride infusion versus oral levodopa in patients with Parkinson's disease

    Brain

    (2002)
  • F Stocchi et al.

    Intermittent vs continuous levodopa administration in patients with advanced Parkinson disease: a clinical and pharmacokinetic study

    Arch Neurol

    (2005)
  • A Antonini et al.

    Duodenal levodopa infusion for advanced Parkinson's disease: 12-month treatment outcome

    Mov Disord

    (2007)
  • WC Koller et al.

    Immediate-release and controlled-release carbidopa/levodopa in PD: a 5-year randomized multicenter study

    Neurology

    (1999)
  • Primary objective of STRIDE-PD study was not achieved

  • Long-term effect of initiating pramipexole vs levodopa in early Parkinson disease

    Arch Neurol

    (2009)
  • RA Hauser et al.

    Ten-year follow-up of Parkinson's disease patients randomized to initial therapy with ropinirole or levodopa

    Mov Disord

    (2007)
  • R Katzenschlager et al.

    Fourteen-year final report of the randomized PDRG-UK trial comparing three initial treatments in PD

    Neurology

    (2008)
  • Guideline on clinical investigation of medicinal products in the treatment of Parkinson's disease (CHMP/563/95 Rev.1)

  • CW Olanow

    Can we achieve neuroprotection with currently available anti-parkinsonian interventions?

    Neurology

    (2009)
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