Professional Documents
Culture Documents
Neurologists have several choices of drugs that have been shown to be effective for the treatment of the symptoms of Lancet Neurol 2009; 8: 929–37
Parkinson’s disease. Among the first options are the dopamine agonists, which are commonly used both as an early Published Online
monotherapy and as an adjunct therapy to levodopa. However, before starting any treatment, the overall benefit-to- August 25, 2009
DOI:10.1016/S1474-
risk ratio to individual patients must be considered. For the dopamine agonists, the available evidence on their
4422(09)70225-X
symptomatic efficacy, effect on long-term levodopa-related motor complications, putative effect on progression of
Parkinson Institute, Istituti
disease, and adverse event profile must be taken into account. Recently, the ocurrence of adverse events such as leg Clinici di Perfezionamento,
oedema, daytime somnolence, impulse control disorders, and fibrosis have increasingly been recognised. The risks of Milan, Italy (A Antonini MD);
these potentially serious adverse events must therefore be taken into account and treatment decisions should be Neurology Service, Hospital
Clinic, University of Barcelona
based on considerations of risks versus benefits for individual patients.
and Centro de Investigación
Biomedica en Red sobre
Introduction Benefits of dopamine agonists in the medical Enfermedades
The use of oral dopamine agonists for the treatment of management of Parkinson’s disease Neurodegenerativas
(CIBERNED), Barcelona, Spain
Parkinson’s disease dates back to the 1970s when the Early monotherapy
(E Tolosa MD); Department of
ergolinic drug bromocriptine was first introduced. The On the basis of a consistent body of evidence from Neurology, Juntendo
first generation of dopamine agonists were all ergot randomised controlled trials, the dopamine agonists University School of Medicine,
derivatives and their pharmacological profile differed dihydroergocryptine, pergolide, pramipexole, and Tokyo, Japan (Y Mizuno MD);
Department of Neurology,
from that of levodopa in several ways. For example, ergot ropinirole11–18 have all been shown to be effective as
Kagawa Prefectural Central
derivatives had a longer half-life than levodopa and had a monotherapy in early Parkinson’s disease.8 The evidence Hospital, Kagawa, Japan
differential affinity primarily to D1-like and D2-like for efficacy was less strong for bromocriptine, cabergoline, (M Yamamoto MD); and
dopamine receptors. Although more than 50 years have and lisuride as there have not been randomised trials of Department of Neurology,
Medical University of
passed since the non-ergot agonist apomorphine was first these compounds in early Parkinson’s disease.19–22 In Innsbruck, Austria
reported to exert strong antiparkinsonian effects,1,2 most recent placebo-controlled trials, rotigotine23,24 and (W H Poewe MD)
of the currently used non-ergot dopamine agonists have piribedil25 have been shown to be efficacious in early Correspondence to:
entered the clinic more recently and include pramipexole, disease. Of note, cabergoline,7 pergolide,6 pramipexole,4,5 Werner H Poewe, Department of
ropinirole, rotigotine, and piribedil (table 1). and ropinirole3 have also been tested against levodopa in Neurology, Medical University of
Innsbruck, Anichstrasse 35,
The symptomatic efficacy of dopamine agonists to treat large randomised trials. The results from these trials
A-6020 Innsbruck, Austria
Parkinson’s disease is firmly established and several have all shown a significantly reduced risk of motor werner.poewe@i-med.ac.at
studies have also shown that early use of these drugs as complications compared with levodopa, in particular
initial monotherapy is associated with a reduced long-term dyskinesias, over double-blind follow-up periods of up to
incidence of motor complications (ie, motor fluctuations 5 years. However, the effect on symptoms as assessed
and dyskinesia) compared with levodopa.3–7 Although this with the unified Parkinson’s disease rating scale (UPDRS)
evidence has led to dopamine agonists being classified as was consistently greater for levodopa (table 2).
first-line options for initial monotherapy in early
Parkinson’s disease in many national and international Continuous dopaminergic stimulation and reduced risk
guidelines,8,9 there have also been recent concerns about of motor complications
the safety profile of these drugs in the longer term. These The exact reason why initial monotherapy with a
concerns are related to the risk of developing impulse dopamine agonist is associated with a reduced risk for
control disorders, peripheral oedema, daytime somnolence, motor complications, in particular dyskinesias, compared
and heart valve fibrosis. The recognition of the risk of with levodopa is not fully understood. The most popular
cardiac fibrotic valvulopathies with pergolide and hypothesis is that therapies with long half-lives provide
cabergoline10 has caused regulatory authorities in many more continuous stimulation of brain dopaminergic
countries to restrict the use of these drugs to second-line receptors and that such continuous stimulation is key to
options with specialised cardiac safety monitoring. the reduced risk of motor complications with longer-acting
In this Review, we first outline the benefits of using drugs compared with short-acting drugs, such as
dopamine agonists in the management of Parkinson’s levodopa. Short-acting drugs induce discontinuous or
disease. We then discuss recent evidence on each of the pulsatile stimulation, which is associated with altered
potential risks, outline the consequences for the gene expression and firing patterns in basal ganglia
management of Parkinson’s disease, and provide output neurons, particularly of the direct pathway, that
recommendations for clinical neurologists on how to cause development of levodopa-induced dyskinesias.26–28
individualise treatment decisions based on considerations This concept is supported by data from several preclinical
of their risks versus benefits. studies in primates treated with MPTP (1-methyl-4-
imaging (single photon emission computed associated with their “on-demand” delivery (ie,
tomography)45 as the primary outcome measure. Both apomorphine rescue injections) or continuous delivery
studies showed that treatment with the dopamine (ie, rotigotine patch, apomorphine infusions). When
agonist was associated with a significant decrease in the patients with advanced Parkinson’s disease who are
rate of decline of the imaging biomarker compared with treated with levodopa receive an agonist to reduce “off”
that seen for levodopa. However, as neither study episodes, dyskinesia can emerge or, if already present,
included a placebo group, they cannot conclusively can worsen. This risk can usually be controlled by
indicate whether the results reflect “protection” reducing the pre-existing total daily dose of levodopa.58,59
provided by the agonist or “toxicity” caused by levodopa.
The study results could also have been due to differences Risks associated with dopamine agonist use in
in the pharmacological effect of these drugs on the Parkinson’s disease
biomarker rather than on cell survival or function.46 The acute side-effects of dopamine agonists are similar
However, data from a recent study (INSPECT; to those observed with levodopa and include nausea,
Investigating Effects of Short-Term Treatment With vomiting, and postural hypotension. These adverse
Pramipexole or Levodopa on ¹²³I-β-CIT and SPECT events tend to occur with the initiation of treatment and
Imaging in Early Parkinson’s) indicated that short-term tend to abate as tolerance to the drug develops.60
pramipexole therapy did not modify dopamine Discontinuation rates associated with adverse events did
transporter binding measured with β-CIT SPECT.47 not differ between different dopamine agonists and
Nevertheless, this neuroimaging biomarker might be levodopa in randomised double-blind trials.19,61 However,
insufficiently sensitive to detect the effect of an compared with levodopa, dopamine agonists are
intervention on disease progression in the long associated with a higher rate of some dopaminergic
term.42,46,48,49 side-effects, including hallucinations, somnolence, and
More recently, delayed-start designs for trials assessing sudden-onset sleep, as well as impulse control disorders
disease-modifying versus symptomatic effects have been (figure).62 Additionally, certain adverse reactions,
used to investigate disease modification in Parkinson’s including peripheral oedema and fibrotic reactions,
disease.50,51 In a trial with a delayed-start design, patients seem to be specifically associated with the use of
are randomised to receive the study drug or placebo for a dopamine agonists and are not seen with other
fixed time interval (eg, 9 months), after which patients in dopaminergic therapies. Peripheral oedema can be
the placebo group are switched to the study drug and induced by all types of dopamine agonists, and possibly
followed for another fixed time interval. Whereas levodopa, whereas fibrosis seems mainly to be caused by
differences between the two groups at the end of the ergot derivatives.
placebo-controlled phase can be explained by both
symptomatic and/or disease-modifying effects, a Peripheral oedema
difference that is sustained until the end of the second Oedema is a poorly understood complication of agonist
phase, when patients in both groups are receiving the therapy in Parkinson’s disease. This adverse event has
same drug, is assumed to indicate a true disease-modifying probably been under-reported for a long time and can
effect. A recent trial of this design showed benefits of occur with both ergot and non-ergot therapy. A post-hoc
early versus delayed treatment with the monoamine analysis of the CALM-PD trial recently found the 4-year
oxidase B inhibitor rasagiline in a large cohort of patients incidence of leg oedema to be 45% in patients who were
with early Parkinson’s disease;51,52 furthermore, a trial initially randomised to pramipexole.63 Although this
combining a delayed-start design with dopamine percentage is higher than previous estimates,3,4 the
transporter binding visualised on SPECT imaging as a authors note that oedema seemed to emerge after at
surrogate marker for disease progression is underway to least 2 years of therapy. Thus, earlier studies, which
assess the disease-modifying effects of pramipexole (the tended to be of shorter duration, are likely to have
PROUD study; Assessment of Potential ImPact of missed this complication. Leg oedema also occurs as a
PRamipexole On Underlying Disease).53 complication of ergot-derived dopamine agonists,64 or
even levodopa, which suggests a class effect. This
Adjunct therapy in advanced Parkinson’s disease hypothesis would seem plausible as dopamine is an
Several dopamine agonists extend “on” time and reduce important regulator of the sympathetic nervous system,
“off” time disability when used as an adjunct therapy in aldosterone secretion, and ATP-mediated sodium and
patients treated with levodopa who have motor potassium channels.
fluctuations. Such efficacy probably reflects the longer
half-life of drugs such as pergolide, pramipexole, and Daytime sleepiness and sleep attacks
ropinirole, for which class I evidence from randomised Depending on the trial design and criteria used, excessive
placebo-controlled trials in Parkinson’s disease is daytime sleepiness was found in 16–51% of patients with
available. The efficacy of apomorphine injections or Parkinson’s disease (in studies that included more than
infusions54,55 or transdermal rotigotine56,57 is mainly 90 individuals; table 3). Sudden-onset sleep as a side-effect
26% of patients treated with pergolide and cabergoline, an important role as initial monotherapy, particularly in
10% of patients treated with non-ergot agonists, and 10% younger patients. Over the past decade, the driving force
of control patients. Severe valvulopathy was observed in for the increased prominence of dopamine agonist
less than 1% of patients in both cross-sectional and monotherapy has been its documented benefits in
observational studies. Overall, the severity of reducing the risk of dyskinesias compared with
ergot-induced vavulopathies tends to correlate with levodopa.3,5 As motor complications are often difficult to
cumulative doses.101,105 On the basis of such findings, the manage, contribute substantially to overall disability
European Medicines Agency has added new warnings and cost of illness,107 and contribute to poor quality of
and contraindications to the product information of life in Parkinson’s disease,108 this benefit is considered
cabergoline and pergolide to reduce the risk of fibrosis. by many to outweigh both the inferior symptomatic
In addition to treatment of Parkinson’s disease, efficacy and the specific risks associated with dopamine
dopamine agonists are also first-line therapies for restless agonist therapy compared with levodopa. However,
legs syndrome. The smaller doses of cabergoline or excessive daytime sleepiness, sudden-onset sleep, and
pergolide used in patients with this syndrome, compared impulse control disorders can have serious consequences
with dose levels used in patients with Parkinson’s disease, both for the patient and their social relations. The need
might explain the absence of reports of cardiac for a balanced and individualised process by which to
valvulopathy in such patients. Neither cabergoline nor define the best initial monotherapy strategy for any
pergolide are approved for use in restless legs syndrome, given patient is also indicated by the results of the
and the non-ergot pramipexole and ropinirole are the pramipexole CALM-PD extension study.39 After 6 years,
only dopamine agonists currently licensed for this when about 90% of patients in both groups of the
indication, making it unlikely that cardiac valvulopathy original cohort were on levodopa, the outcome for
will become a serious drug-induced complication in overall impairment in activities of daily living was
restless legs syndrome. similar in the initial pramipexole and levodopa groups.
The mechanisms underlying cardiac valvulopathy The same was true for mean scores on quality of life
induced by cabergoline or pergolide are likely to involve scales and also for motor function as assessed by the
agonism of these two drugs at the 5-HT2B receptor UPDRS. However, motor complications, including
subtype, which is expressed on heart valve leaflets.106 wearing off, “on-off” effects, and dyskinesias, were more
This action might induce fibroblast mitogenesis, thereby common when patients were treated initially with
inducing thickening, retraction, and stiffening of valves levodopa than with pramipexole, although disabling
and causing incomplete leaflet coaptation and valvular dyskinesias were uncommon in both groups. Epworth
regurgitation. The extent to which fibrotic valvular sleepiness scale scores were higher with initial
changes are reversible after discontinuation, and pramipexole treatment, indicating more sleepiness in
whether switching to a non-ergot agonist prevents the inital pramipexole group than in the initial levodopa
further progression, is being studied. Preliminary group.
evidence from a prospective 2-year follow-up study of
21 patients who had developed moderate to severe Number of patients EDS screening EDS in patients EDS in controls
(controls) criteria or tool with PD (%) (%)
valvulopathy during ergot therapy and were switched to
non-ergot agonists showed regression of valve regurg- van Hilten et al65 90 (71) Questionnaire 44·4 31·0
itation in 13 patients. In 46 patients in the same study Tandberg et al66 245 (100) Questionnaire 15·5 1·0
who had continued therapy on cabergoline and pergolide, Ondo et al67 303 (··) ESS >10 50·2 ··
there was an 8% per year incidence of new cases of Hobson et al68 638 (··) ESS ≥7 51·0 ··
moderate to severe regurgitation in any heart valve Tan et al69 201 (214) ESS ≥10 19·9 9·8
(Antonini A, unpublished). Although the observation of Brodsky et al70 101 (100) ESS ≥10 40·6 19·0
regression of valve regurgitation in more than half of the Högl et al71 99 (44) ESS ≥10 33·0 11·0
patients who replaced ergot with non-ergot agonists is Paus et al72 177* (··) ESS ≥10 75·0 ··
encouraging, persistence of abnormalities in a large Marinus et al73 143 (104) ESS >10 27·0 3·0
proportion of the patients is worrisome. This persistence Kumar et al74 149 (115) ESS ≥8 21·0 3·0
could be due to flow turbulence induced by the valve Monaca et al75 222 (··) ESS >10 43·2 ··
dysfunction, which might contribute to worsening Ferreira et al76 176 (174) ESS ≥15 33·5 16·1
fibrosis even when the drug causing the complications Verbaan et al77 419 (150) SCOPA-DS ≥5 43·0 10·0
is withdrawn. Ghorayeb et al78 1625 (··) ESS ≥10 29·0 ··
Studies with more than 90 individuals were selected. ··=data not available. EDS=excessive daytime sleepiness.
Risks versus benefits of dopamine agonists in ESS=Epworth sleepiness score. PD=Parkinson’s disease. SCOPA-DS=scales for outcomes in PD-daytime sleepiness.
clinical practice *2952 patients were screened by telephone interview and 177 were identified to have EDS; after assessment, there
As a class, dopamine agonists have been successfully were 133 (75%) with an ESS of ≥10.
used for many years as an adjunct therapy to levodopa
Table 3: Frequency of EDS in individuals with Parkinson’s disease and controls
in patients who develop motor complications, and have
4 Parkinson Study Group. Pramipexole vs levodopa as initial 26 Olanow CW, Obeso JA, Stocchi F. Continuous dopamine-receptor
treatment for Parkinson disease: a randomized controlled trial. treatment of Parkinson’s disease: scientific rationale and clinical
JAMA 2000; 284: 1931–38. implications. Lancet Neurol 2006; 5: 677–87.
5 Holloway RG, Shoulson I, Fahn S, et al. Pramipexole vs levodopa as 27 Olanow CW, Obeso JA, Stocchi F. Drug insight: continuous
initial treatment for Parkinson disease: a 4-year randomized dopaminergic stimulation in the treatment of Parkinson’s disease.
controlled trial. Arch Neurol 2004; 61: 1044–53. Nat Clin Pract Neurol 2006; 2: 382–92.
6 Oertel WH, Wolters E, Sampaio C, et al. Pergolide versus levodopa 28 Cenci MA. Dopamine dysregulation of movement control in
monotherapy in early Parkinson’s disease patients: the PELMOPET L-DOPA-induced dyskinesia. Trends Neurosci 2007; 30: 236–43.
study. Mov Disord 2005; 21: 343–53. 29 Bedard PJ, Di Paolo T, Falardeau P, Boucher R. Chronic treatment
7 Bracco F, Battaglia A, Chouza C, et al. The long-acting dopamine with L-DOPA, but not bromocriptine induces dyskinesia in
receptor agonist cabergoline in early Parkinson’s disease: final MPTP-parkinsonian monkeys. Correlation with [3H]spiperone
results of a 5-year, double-blind, levodopa-controlled study. binding. Brain Res 1986; 379: 294–99.
CNS Drugs 2004; 18: 733–46. 30 Maratos EC, Jackson MJ, Pearce RK, Jenner P. Antiparkinsonian
8 Horstink M, Tolosa E, Bonuccelli U, et al. Review of the activity and dyskinesia risk of ropinirole and L-DOPA combination
therapeutic management of Parkinson’s disease. Report of a joint therapy in drug naive MPTP-lesioned common marmosets
task force of the European Federation of Neurological Societies (Callithrix jacchus). Mov Disord 2001; 16: 631–41.
and the Movement Disorder Society-European Section. Part I: 31 Smith LA, Tel BC, Jackson MJ, et al. Repeated administration of
early (uncomplicated) Parkinson’s disease. Eur J Neurol 2006; piribedil induces less dyskinesia than L-dopa in MPTP-treated
13: 1170–85. common marmosets: a behavioural and biochemical investigation.
9 Miyasaki JM, Martin W, Suchowersky O, Weiner WJ, Lang AE. Mov Disord 2002; 17: 887–901.
Practice parameter: initiation of treatment for Parkinson’s disease: 32 Maratos EC, Jackson MJ, Pearce RK, Cannizzaro C, Jenner P. Both
an evidence-based review. Report of the Quality Standards short- and long-acting D-1/D-2 dopamine agonists induce less
Subcommittee of the American Academy of Neurology. Neurology dyskinesia than L-DOPA in the MPTP-lesioned common marmoset
2002; 58: 11–17. (Callithrix jacchus). Exp Neurol 2003; 179: 90–102.
10 Horvath J, Fross RD, Kleiner-Fisman G, et al. Severe multivalvular 33 Katzenschlager R, Hughes A, Evans A, et al. Continuous
heart disease: a new complication of the ergot derivative dopamine subcutaneous apomorphine therapy improves dyskinesias in
agonists. Mov Disord 2004; 19: 656–62. Parkinson‘s disease: a prospective study using single-dose
11 Bergamasco B, Frattola L, Muratorio A, Piccoli F, Mailland F, challenges. Mov Disord 2005; 20: 151–57.
Parnetti L. Alpha-dihydroergocryptine in the treatment of de novo 34 Stocchi F, Ruggieri S, Vacca L, Olanow CW. Prospective
parkinsonian patients: results of a multicentre, randomized, randomized trial of lisuride infusion versus oral levodopa in
double-blind, placebo-controlled study. Acta Neurol Scand 2000; patients with Parkinson’s disease. Brain 2002; 125: 2058–66.
101: 372–80. 35 Stocchi F, Vacca L, Ruggieri S, Olanow CW. Intermittent vs
12 Barone P, Bravi D, Bermejo-Pareja F, et al; for the Pergolide continuous levodopa administration in patients with advanced
Monotherapy Study Group. Pergolide monotherapy in the Parkinson disease: a clinical and pharmacokinetic study.
treatment of early PD: a randomized, controlled study. Neurology Arch Neurol 2005; 62: 905–10.
1999; 53: 573–79. 36 Antonini A, Isaias IU, Canesi M, et al. Duodenal levodopa infusion
13 Shannon KM, Bennett JP Jr, Friedman JH; for the Pramipexole for advanced Parkinson’s disease: 12-month treatment outcome.
Study Group. Efficacy of pramipexole, a novel dopamine agonist, as Mov Disord 2007; 22: 1145–49.
monotherapy in mild to moderate Parkinson‘s disease. Neurology 37 Koller WC, Hutton JT, Tolosa E, Capilldeo R; for the Carbidopa/
1997; 49: 724–28. Levodopa Study Group. Immediate-release and controlled-release
14 Adler CH, Sethi DK, Hauser RA, et al. Ropinirole for the treatment carbidopa/levodopa in PD: a 5-year randomized multicenter study.
of early Parkinson’s disease. Neurology 1997; 49: 393–99. Neurology 1999; 53: 1012–19.
15 DA agonists—non-ergot derivatives. Ropinirole: management of 38 PDtrials. Primary objective of STRIDE-PD study was not achieved.
Parkinson’s disease. Mov Disord 2002; 17 (suppl 4): S98–102. http://www.pdtrials.org/en/clinical_research_news/release/
16 DA agonists—non-ergot derivatives. Pramipexole: management of pr_1236180097 (accessed Aug 17, 2009).
Parkinson’s disease. Mov Disord 2002; 17 (suppl 4): S93–97. 39 Parkinson Study Group CALM Cohort Investigators. Long-term
17 DA agonists—non-ergot derivatives. Piribedil: management of effect of initiating pramipexole vs levodopa in early Parkinson
Parkinson’s disease. Mov Disord 2002; 17 (suppl 4): S90–92. disease. Arch Neurol 2009; 66: 563–70.
18 DA agonists—ergot derivatives. Pergolide: management of 40 Hauser RA, Rascol O, Korczyn AD, et al. Ten-year follow-up of
Parkinson’s disease. Mov Disord 2002; 17 (suppl 4): S79–82. Parkinson’s disease patients randomized to initial therapy with
19 Goetz CG, Poewe W, Rascol O, Sampaio C. Evidence-based medical ropinirole or levodopa. Mov Disord 2007; 22: 2409–17.
review update: pharmacological and surgical treatments of 41 Katzenschlager R, Head J, Schrag A, Ben-Shlomo Y, Evans A,
Parkinson’s disease: 2001 to 2004. Mov Disord 2005; 20: 523–39. Lees AJ. Fourteen-year final report of the randomized PDRG-UK
20 Montastruc JL, Rascol O, Senard JM, Rascol O. A randomised trial comparing three initial treatments in PD. Neurology 2008;
controlled study comparing bromocriptine to which levodopa 71: 474–80.
was later added, with levodopa alone in previously untreated 42 European Medicines Agency. Guideline on clinical investigation of
patients with Parkinson’s disease: a five year follow up. medicinal products in the treatment of Parkinson’s disease
J Neurol Neurosurg Psychiatry 1994; 57: 1034–38. (CHMP/563/95 Rev.1). July, 2008. http://www.emea.europa.eu/
21 Rinne UK, Bracco F, Chouza C, et al; for the PKDS009 Study pdfs/human/ewp/056395en.pdf (accessed Aug 7, 2009).
Group. Early treatment of Parkinson’s disease with cabergoline 43 Olanow CW. Can we achieve neuroprotection with currently
delays the onset of motor complications. Results of a double-blind available anti-parkinsonian interventions? Neurology 2009;
levodopa controlled trial. Drugs 1998; 55 (suppl 1): 23–30. 72: S59–64.
22 Rinne UK. Lisuride, a dopamine agonist in the treatment of early 44 Whone AL, Remy P, Davis MR, et al. The REAL-PET study: Slower
Parkinson’s disease. Neurology 1989; 39: 336–39. progression in early Parkinson’s disease treated with ropinirole
23 Jankovic J, Watts RL, Martin W, Boroojerdi B. Transdermal compared with levodopa. Neurology 2002; 58 (suppl 3): A82.
rotigotine: double-blind, placebo-controlled trial in Parkinson 45 Dopamine transporter brain imaging to assess the effects of
disease. Arch Neurol 2007; 64: 676–82. pramipexole vs levodopa on Parkinson disease progression.
24 Watts RL, Jankovic J, Waters C, Rajput A, Boroojerdi B, Rao J. JAMA 2002; 287: 1653–61.
Randomized, blind, controlled trial of transdermal rotigotine in 46 Ahlskog JE. Slowing Parkinson’s disease progression: recent
early Parkinson disease. Neurology 2007; 68: 272–76. dopamine agonist trials. Neurology 2003; 60: 381–89.
25 Rascol O, Dubois B, Caldas AC, Senn S, Del Signore S, Lees A. 47 Jennings D, Tabamo R, Seibyl J, Marek K. InSPECT: investigating
Early piribedil monotherapy of Parkinson’s disease: a planned the effect of short-term treatment with pramipexole or levodopa on
seven-month report of the REGAIN study. Mov Disord 2006; 123b-CIT and SPECT imaging. Mov Disord 2007; 22 (suppl 16):
21: 2110–15. S143 (abstract).
48 Ravina B, Eidelberg D, Ahlskog JE, et al. The role of radiotracer 71 Högl B, Seppi K, Brandauer E, et al. Increased daytime sleepiness
imaging in Parkinson disease. Neurology 2005; 64: 208–15. in Parkinson‘s disease: a questionnaire survey. Mov Disord 2003;
49 Marek K, Jennings D, Tamagnan G, Seibyl J. Biomarkers for 18: 319–23.
Parkinson’s disease: tools to assess Parkinson’s disease onset and 72 Paus S, Brecht HM, Koster J, Seeger G, Klockgether T, Wullner U.
progression. Ann Neurol 2008; 64 (suppl 2): S111–21. Sleep attacks, daytime sleepiness, and dopamine agonists in
50 Parkinson Study Group. A controlled, randomized, delayed-start Parkinson’s disease. Mov Disord 2003; 18: 659–67.
study of rasagiline in early Parkinson disease. Arch Neurol 2004; 73 Marinus J, Visser M, van Hilten JJ, Lammers GJ, Stiggelbout AM.
61: 561–66. Assessment of sleep and sleepiness in Parkinson disease. Sleep
51 Olanow CW, Hauser RA, Jankovic J, et al. A randomized, 2003; 26: 1049–54.
double-blind, placebo-controlled, delayed start study to assess 74 Kumar S, Bhatia M, Behari M. Excessive daytime sleepiness in
rasagiline as a disease modifying therapy in Parkinson’s disease Parkinson’s disease as assessed by Epworth Sleepiness Scale (ESS).
(the ADAGIO study): rationale, design, and baseline characteristics. Sleep Med 2003; 4: 339–42.
Mov Disord 2008; 23: 2194–201. 75 Monaca C, Duhamel A, Jacquesson JM, et al. Vigilance troubles in
52 Olanow CW, Rascol O. Early rasagiline treatment slows UPDRS Parkinson’s disease: a subjective and objective polysomnographic
decline in the ADAGIO delayed start study. Ann Neurol 2008; study. Sleep Med 2006; 7: 448–53.
64 (suppl 12): S68 (abstract). 76 Ferreira JJ, Desboeuf K, Galitzky M, et al. Sleep disruption, daytime
53 Schapira A, Hsu HH, Scrine MF, Gordon KL, Marek K. PROUD: somnolence and ’sleep attacks’ in Parkinson’s disease: a clinical
The impact of early vs delayed treatment with pramipexole on survey in PD patients and age-matched healthy volunteers.
new onset Parkinson’s disease. Mov Disord 2008; 23 (suppl 1): Eur J Neurol 2006; 13: 209–14.
S194 (abstract). 77 Verbaan D, Marinus J, Visser M, van Rooden SM, Stiggelbout AM,
54 Poewe W, Kleedorfer B, Wagner M, Bosch S, Schelosky L. van Hilten JJ. Patient-reported autonomic symptoms in Parkinson
Continuous subcutaneous apomorphine infusions for fluctuating disease. Neurology 2007; 69: 333–41.
Parkinson’s disease. Long-term follow-up in 18 patients. 78 Ghorayeb I, Loundou A, Auquier P, Dauvilliers Y, Bioulac B,
Adv Neurol 1993; 60: 656–59. Tison F. A nationwide survey of excessive daytime sleepiness in
55 Dewey RB Jr, Hutton JT, LeWitt PA, Factor SA. A randomized, Parkinson’s disease in France. Mov Disord 2007; 22: 1567–72.
double-blind, placebo-controlled trial of subcutaneously injected 79 Frucht S, Rogers JD, Greene PE, Gordon MF, Fahn S. Falling asleep
apomorphine for parkinsonian off-state events. Arch Neurol 2001; at the wheel: motor vehicle mishaps in persons taking pramipexole
58: 1385–92. and ropinirole. Neurology 1999; 52: 1908–10.
56 LeWitt PA, Lyons KE, Pahwa R. Advanced Parkinson disease treated 80 Seppi K, Hogl B, Diem A, Peralta C, Wenning GK, Poewe W.
with rotigotine transdermal system: PREFER study. Neurology 2007; Levodopa-induced sleepiness in the Parkinson variant of multiple
68: 1262–67. system atrophy. Mov Disord 2006; 21: 1281–83.
57 Poewe WH, Rascol O, Quinn N, et al. Efficacy of pramipexole and 81 Voon V, Fox SH. Medication-related impulse control and repetitive
transdermal rotigotine in advanced Parkinson’s disease: a behaviors in Parkinson disease. Arch Neurol 2007; 64: 1089–96.
double-blind, double-dummy, randomised controlled trial. 82 Weintraub D, Siderowf AD, Potenza MN, et al. Association of
Lancet Neurol 2007; 6: 513–20. dopamine agonist use with impulse control disorders in Parkinson
58 Facca A, Sanchez-Ramos J. High-dose pergolide monotherapy in disease. Arch Neurol 2006; 63: 969–73.
the treatment of severe levodopa-induced dyskinesias. Mov Disord 83 Voon V, Hassan K, Zurowski M, et al. Prevalence of repetitive and
1996; 11: 327–29. reward-seeking behaviors in Parkinson disease. Neurology 2006;
59 Cristina S, Zangaglia R, Mancini F, Martignoni E, Nappi G, 67: 1254–57.
Pacchetti C. High-dose ropinirole in advanced Parkinson’s disease 84 Isaias IU, Siri C, Cilia R, De Gaspari D, Pezzoli G, Antonini A. The
with severe dyskinesias. Clin Neuropharmacol 2003; 26: 146–50. relationship between impulsivity and impulse control disorders in
60 Yamamoto M, Schapira AH. Dopamine agonists in Parkinson’s Parkinson’s disease. Mov Disord 2008; 23: 411–15.
disease. Expert Rev Neurother 2008; 8: 671–77. 85 Voon V, Hassan K, Zurowski M, et al. Prospective prevalence of
61 Rascol O, Goetz C, Koller W, Poewe W, Sampaio C. Treatment pathologic gambling and medication association in Parkinson
interventions for Parkinson’s disease: an evidence based disease. Neurology 2006; 66: 1750–52.
assessment. Lancet 2002; 359: 1589–98. 86 Weintraub D. Dopamine and impulse control disorders in
62 Stowe RL, Ives NJ, Clarke C, et al. Dopamine agonist therapy in Parkinson’s disease. Ann Neurol 2008; 64 (suppl 2): S93–100.
early Parkinson’s disease. Cochrane Database Syst Rev 2008; 87 Cilia R, Siri C, Marotta G, et al. Functional abnormalities
2: CD006564. underlying pathological gambling in Parkinson disease.
63 Biglan KM, Holloway RG Jr, McDermott MP, Richard IH. Risk Arch Neurol 2008; 65: 1604–11.
factors for somnolence, edema, and hallucinations in early 88 Shaunak S, Wilkins A, Pilling JB, Dick DJ. Pericardial,
Parkinson disease. Neurology 2007; 69: 187–95. retroperitoneal, and pleural fibrosis induced by pergolide.
64 Blackard WG. Edema--an infrequently recognized complication of J Neurol Neurosurg Psychiatry 1999; 66: 79–81.
bromocriptine and other ergot dopaminergic drugs. Am J Med 1993; 89 Bowler JV, Ormerod IE, Legg NJ. Retroperitoneal fibrosis and
94: 445. bromocriptine. Lancet 1986; 2: 466.
65 van Hilten JJ, Weggeman M, van der Velde EA, Kerkhof GA, 90 Demonet JF, Rostin M, Dueymes JM, Ioualalen A, Montastruc JL,
van Dijk JG, Roos RA. Sleep, excessive daytime sleepiness and Rascol A. Retroperitoneal fibrosis and treatment of Parkinson’s
fatigue in Parkinson’s disease. J Neural Transm Park Dis Dement Sect disease with high doses of bromocriptine. Clin Neuropharmacol
1993; 5: 235–44. 1986; 9: 200–01.
66 Tandberg E, Larsen JP, Karlsen K. Excessive daytime sleepiness and 91 Wiggins J, Skinner C. Bromocriptine induced pleuropulmonary
sleep benefit in Parkinson’s disease: a community-based study. fibrosis. Thorax 1986; 41: 328–30.
Mov Disord 1999; 14: 922–27.
92 Ward CD, Thompson J, Humby MD. Pleuropulmonary and
67 Ondo WG, Dat Vuong K, Khan H, Atassi F, Kwak C, Jankovic J. retroperitoneal fibrosis associated with bromocriptine treatment.
Daytime sleepiness and other sleep disorders in Parkinson’s J Neurol Neurosurg Psychiatry 1987; 50: 1706–07.
disease. Neurology 2001; 57: 1392–96.
93 Kains JP, Hardy JC, Chevalier C, Collier A. Retroperitoneal fibrosis
68 Hobson DE, Lang AE, Martin WR, Razmy A, Rivest J, Fleming J. in two patients with Parkinson’s disease treated with bromocriptine.
Excessive daytime sleepiness and sudden-onset sleep in Parkinson Acta Clin Belg 1990; 45: 306–10.
disease: a survey by the Canadian Movement Disorders Group.
94 Todman DH, Oliver WA, Edwards RL. Pleuropulmonary fibrosis
JAMA 2002; 287: 455–63.
due to bromocriptine treatment for Parkinson’s disease.
69 Tan EK, Lum SY, Fook-Chong SM, et al. Evaluation of somnolence Clin Exp Neurol 1990; 27: 79–82.
in Parkinson’s disease: comparison with age- and sex-matched
95 Hely MA, Morris JG, Lawrence S, Jeremy R, Genge S. Retroperitoneal
controls. Neurology 2002; 58: 465–68.
fibrosis, skin and pleuropulmonary changes associated with
70 Brodsky MA, Godbold J, Roth T, Olanow CW. Sleepiness in bromocriptine therapy. Aust N Z J Med 1991; 21: 82–84.
Parkinson’s disease: a controlled study. Mov Disord 2003; 18: 668–72.
96 Agarwal P, Fahn S, Frucht SJ. Diagnosis and management of 103 Antonini A, Poewe W. Fibrotic heart-valve reactions to
pergolide-induced fibrosis. Mov Disord 2004; 19: 699–704. dopamine-agonist treatment in Parkinson’s disease.
97 Townsend M, MacIver DH. Constrictive pericarditis and Lancet Neurol 2007; 6: 826–29.
pleuropulmonary fibrosis secondary to cabergoline treatment for 104 Simonis G, Fuhrmann JT, Strasser RH. Meta-analysis of heart valve
Parkinson’s disease. Heart 2004; 90: e47. abnormalities in Parkinson’s disease patients treated with
98 Tintner R, Manian P, Gauthier P, Jankovic J. Pleuropulmonary dopamine agonists. Mov Disord 2007; 22: 1936–42.
fibrosis after long-term treatment with the dopamine agonist 105 Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G.
pergolide for Parkinson Disease. Arch Neurol 2005; 62: 1290–95. Valvular heart disease and the use of dopamine agonists for
99 Pritchett AM, Morrison JF, Edwards WD, Schaff HV, Connolly HM, Parkinson’s disease. N Engl J Med 2007; 356: 39–46.
Espinosa RE. Valvular heart disease in patients taking pergolide. 106 Roth BL. Drugs and valvular heart disease. N Engl J Med 2007;
Mayo Clin Proc 2002; 77: 1280–86. 356: 6–9.
100 Van Camp G, Flamez A, Cosyns B, Goldstein J, Perdaens C, 107 Spottke AE, Reuter M, Machat O, et al. Cost of illness and its
Schoors D. Heart valvular disease in patients with Parkinson’s predictors for Parkinson‘s disease in Germany.
disease treated with high-dose pergolide. Neurology 2003; Pharmacoeconomics 2005; 23: 817–36.
61: 859–61. 108 Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F. Impact of
101 Van Camp G, Flamez A, Cosyns B, et al. Treatment of Parkinson’s the motor complications of Parkinson’s disease on the quality of
disease with pergolide and relation to restrictive valvular heart life. Mov Disord 2005; 20: 224–30.
disease. Lancet 2004; 363: 1179–83. 109 University of South Florida. Patients starting Parkinson’s drug
102 Bleumink GS, van der Molen-Eijgenraam M, Strijbos JH, rasagaline earlier do better. http://hscweb3.hsc.usf.edu/health/
Sanwikarja S, van Puijenbroek EP, Stricker BH. now/?p=3564 (accessed Aug 18, 2009).
Pergolide-induced pleuropulmonary fibrosis.
Clin Neuropharmacol 2002; 25: 290–93.