Journal of Neurology

, Volume 253, Issue 12, pp 1633–1639 | Cite as

End-of-dose deterioration in non ergolinic dopamine agonist monotherapy of Parkinson’s disease

  • Astrid Thomas
  • Laura Bonanni
  • Angelo Di Iorio
  • Sara Varanese
  • Francesca Anzellotti
  • Anna D’Andreagiovanni
  • Fabrizio Stocchi
  • Marco Onofrj


The study was designed to investigate the possible occurrence of “wearing-off” (WO) during dopamine agonist (DA) monotherapy. Sixty patients with “de novo” idiopathic PD were randomised into one of two DA monotherapy branches to receive oral ropinirole at 15 mg per day, or pramipexole at 2.1 mg per day. DA doses could be increased in the following two years but levodopa could not be added until the study ended. WO was assessed by self-evaluation charts confirmed by a blinded observation of a 30% or greater deterioration in the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score. Proc Mixed and Kaplan-Meier curves evaluated treatment variables as a function of time. T-tests were used to compare post-hoc variables reclassified according to WO occurrence. Thirty patients received ropinirole, and 30 pramipexole monotherapy. Eighteen patients (30%) experienced “wearing-off” 15–21 months after beginning monotherapy. No differences were observed between treatments. WO phenomena was observed 3.4 ± 0.3 hours after intake of the morning or afternoon dose and consisted of UPDRS score worsening by 11.1 ± 2.1 points (69–111% more than “on” score). Statistical evaluation gave evidence of differences between patients who experienced WO and those who did not: UPDRS motor scores obtained at admission to the study were higher (by 3.4 ± 0.2 points, p = 0.01 t-test) and DA doses at 6–12 months were higher in fluctuating patients. UPDRS motor scores deteriorated, however. similarly and there were no differences, in UPDRS scores recorded in ON conditions, between fluctuating and non-fluctuating patients at the end of the study. Our findings provide evidence of WO phenomena in patients with early PD receiving non-ergolinic DA monotherapy.


Parkinson’s disease wearing-off non ergonilic dopaminoagonists monotherapy 


  1. 1.
    Bonuccelli U (2003) Comparing dopamine agonists in Parkinson’s disease. Curr Opin Neurol 16(Suppl 1):S13–9PubMedCrossRefGoogle Scholar
  2. 2.
    Chase TN, Konitsiotis S, Oh JD (2001) Striatal molecular mechanisms and motor dysfunction in Parkinson’s Disease. Adv Neurol 86:335–60Google Scholar
  3. 3.
    Cristina S, Zangalia R, Mancini F, Martignoni E, Nappi G, Pacchetti C (2003) High-dose ropinirole in advanced Parkinson’s disease with severe dyskinesias. Clin Neuropharmacol 26:146–50PubMedCrossRefGoogle Scholar
  4. 4.
    de la Fuente-Fernández R , Schulzer M, Mak E, Calne DB, Stoessl AJ (2004) Presynaptic mechanisms of motor fluctuations in Parkinson’s disease: a probabilistic model. Brain 4:888–99CrossRefGoogle Scholar
  5. 5.
    Deleu D, Northway MG, Hanssens Y (2002) Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson’s disease. Clin Pharmacokinet 41:261–309PubMedCrossRefGoogle Scholar
  6. 6.
    Deutsche Gesellschaft fűr Neurologie:Leitlinien-Parkinson-Syndrome; Therapieeinleitung
  7. 7.
    Fahn S, Elton R, Members of UPDRS Development Committee (1987) In: Fahn S, Marsden CD, Calne DB, Goldstein M (eds). Recent Developments in Parkinson’s Disease, Vol 2. Macmillan Health Care Information, Florham Park NJ, pp 153–64Google Scholar
  8. 8.
    Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, Olanow CW, Tanner C, Marek K, Parkinson Study Group (2004) Levodopa and the progression of Parkinson’s disease. N Engl J Med 351:2498–508PubMedCrossRefGoogle Scholar
  9. 9.
    Fukuyama H, Kawamura J, Akiguchi I, Kimura J, Imai T (1996) Bromocriptine therapy in early stage Parkinson’s Disease. Eur Neurol 52:324–8Google Scholar
  10. 10.
    Goetz CG, Janko K, Blasucci L, Jaglin JA (2003) Impact of placebo assignment in clinical trials of Parkinson’s Disease. Mov Disord 18:1146–9PubMedCrossRefGoogle Scholar
  11. 11.
    Goetz CG, Poewe W, Rascol O, Sampaio C (2005) Evidence-based medical review update: Pharmacological and surgical treatments of Parkinson’s disease: 2001 to 2004. Mov Disord 20:523–39PubMedCrossRefGoogle Scholar
  12. 12.
    Hely MA, Morris JG, Rail D, Reid WG, O’Sullivan DJ, Williamson PM, Genge S, Broe GA (1989) The Sydney Multicentre Study of Parkinson’s disease: a report on the first 3 years. J Neurol Neurosurg Psychiatry 52:324–8PubMedGoogle Scholar
  13. 13.
    Hoehn MM, Yahr MD (1967) Parkinsonism: onset, progression, and mortality. Neurology 17:427–42PubMedCrossRefGoogle Scholar
  14. 14.
    Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinic-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–4PubMedCrossRefGoogle Scholar
  15. 15.
    Inzelberg R, Schechtman E, Nisipeanu P (2003) Cabergoline, pramipexole and ropinirole used as monotherapy in early Parkinson’s disease: an evidence-based comparison. Drugs Aging 20:847–55PubMedCrossRefGoogle Scholar
  16. 16.
    Jankovic J (2005) Motor fluctuations and dyskinesias in Parkinson’s disease: Clinical manifestations. Mov Disord 20(Suppl 11):S11–6PubMedCrossRefGoogle Scholar
  17. 17.
    Jenner P (2002) Pharmacology of dopamineagonists in the treatment of Parkinson’s Disease. Neurology 58:S1–S8PubMedGoogle Scholar
  18. 18.
    Jenner P (2003) The MPTP-treated primate as a model of motor complications. Neurology 61(suppl3):S4–S11PubMedGoogle Scholar
  19. 19.
    Kaye CM, Nicholls B (2000) Clinical pharmacokinetics of ropinirole. Clin Pharmacokinet 39:243–54PubMedCrossRefGoogle Scholar
  20. 20.
    Korczyn AD, Thalamas C, Adler CH (2002) Dosing with ropinirole in a clinical setting. Acta Neurol Scand 106:200–4PubMedCrossRefGoogle Scholar
  21. 21.
    Lees AJ (2001) Ten-years follow-up of three different initial treatments in de-novo PD. A randomized trial. Neurology 57:1687–1694PubMedGoogle Scholar
  22. 22.
    Mazzella L, Yahr MD, Marinelli L, Huang N, Moshier E, Di Rocco A (2005) Dyskinesias predict the onset of motor response fluctuations in patients with Parkinson’s disease on l-dopa monotherapy. Parkinsonism Relat Disord 11:151–5PubMedCrossRefGoogle Scholar
  23. 23.
    Moher D, Schulze KF, Altman D for the CONSORT group (2001) The CONSORT Statement: Revised recommendations for improving the quality of reports of parallel-group randomised trials. JAMA 285:1987–91PubMedCrossRefGoogle Scholar
  24. 24.
    Oertel WH, Wolters E, Sampaio C, Gimenez-Roldan S, Bergamasco B, Dujardin M, Grosset DG, Arnold G, Leenders KL, Hundemer HP, Lledo A, Wood A, Frewer P, Schwarz J (2006) Pergolide versus levodopa monotherapy in early Parkinson’s disease patients: The PELMOPET study. Mov Disord 21:343–53PubMedCrossRefGoogle Scholar
  25. 25.
    Onofrj M, Thomas A, Iacono D, Di Iorio A, Bonanni L (2001) Switch-over from Tolcapone to Entacapone in severe Parkinson’s Disease patients. Eur Neurol 46:11–6PubMedCrossRefGoogle Scholar
  26. 26.
    Parkinson Study Group (2000) A randomized controlled trial comparing pramipexole with levodopa in early Parkinson’s disease: design and methods of the CALM-PD Study. Clin Neuropharmacol 23:34–44CrossRefGoogle Scholar
  27. 27.
    Parkinson Study Group (2002) Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 287:1653–1661CrossRefGoogle Scholar
  28. 28.
    Quinn NP (1998) Classification of fluctuations in patients with Parkinson’s Disease. Neurology 51(suppl 2):S25–S29PubMedGoogle Scholar
  29. 29.
    Rascol O, Brooks DJ, Brunt ER, Korczyn AD, Poewe WH, Stocchi F (1998) Ropinirole in the treatment of early Parkinson’s disease: a 6-month interim report of a 5-year levodopa-controlled study. 056 Study Group. Mov Disord 13:39–45PubMedCrossRefGoogle Scholar
  30. 30.
    Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE (2000) A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 342(20):1484–91PubMedCrossRefGoogle Scholar
  31. 31.
    Shannon KM, Bennett JP, Friedman JH (1997) Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson’s disease. The Pramipexole Study Group. Neurology 49(3):724–8PubMedGoogle Scholar
  32. 32.
    Shulman LM, Minager A, Rabinstein A, Weiner WJ (2000) The use of dopamine agonists in very elderly patients with Parkinson’s disease. Mov Disord 15(4):664–8PubMedCrossRefGoogle Scholar
  33. 33.
    Smala AM, Spottke EA, Machat O, Siebert U, Meyer D, Kohne-Volland R, Reuther M, DuChane J, Oertel WH, Berger KB, Dodel RC (2003) Cabergoline versus levodopa monotherapy: a decision analysis. Mov Disord 18(8):898–905PubMedCrossRefGoogle Scholar
  34. 34.
    Stocchi F, Vacca L, Berardelli A, De Pandis F, Ruggieri S (2001) Long-duration effect and the postsynaptic compartment: study using a dopamine agonist with a short half-life. Mov Disord 16(2):301–5PubMedCrossRefGoogle Scholar
  35. 35.
    Stocchi F, Vacca L, Berardelli A, Onofrj M, Manfredi M, Ruggieri S (2003) Dual dopamine agonist treatment in Parkinson’s disease. J Neurol 250(7):822–826PubMedCrossRefGoogle Scholar
  36. 36.
    Tan EK, Jankovic J (2001) Choosing dopamine agonists in Parkinson’s disease. Clin Neuropharmacol 24:247–53PubMedCrossRefGoogle Scholar
  37. 37.
    Thomas A, Iacono D, Luciano AL, Armellino K, Di Iorio A, Onofrj M (2004) Duration of amantadine benefit on dyskinesia of severe Parkinson’s disease. J Neurol Neurosurg Psychiatry 75:141–3PubMedGoogle Scholar
  38. 38.
    Whone AL, Watts RL, Stoessel AJ, Davis M, Reske S, Nahmias C, Lang AE, Rascol O, Ribeiro MJ, Remy P, Poewe WH, Hauser RA, Brooks DJ (2003) REAL-PET Study Group. Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol 54:93–101PubMedCrossRefGoogle Scholar
  39. 39.
    World Medical Association (1997) Declaration of Helsinki. Recommendations Guiding Physicians in Biomedical Research involving human subjects. JAMA 277:925–6CrossRefGoogle Scholar

Copyright information

© Steinkopff Verlag Darmstadt 2006

Authors and Affiliations

  • Astrid Thomas
    • 1
    • 3
  • Laura Bonanni
    • 1
    • 3
  • Angelo Di Iorio
    • 3
  • Sara Varanese
    • 1
    • 3
  • Francesca Anzellotti
    • 1
    • 3
  • Anna D’Andreagiovanni
    • 1
    • 3
  • Fabrizio Stocchi
    • 4
  • Marco Onofrj
    • 1
    • 2
    • 3
  1. 1.Neurophysiopathology, Movement Disorders Center, Dept. of Oncology and NeuroscienceUniversity “G.D’Annunzio” Chieti-PescaraPescaraItaly
  2. 2.Neurophysiopathology, Movement Disorders CenterPescaraItaly
  3. 3.Aging Research Center, Ce.S.I.“Gabriele D’Annunzio” University FoundationChieti-PescaraItaly
  4. 4.San Raffaele PisanaRoma

Personalised recommendations