CNS Drugs

, Volume 32, Issue 10, pp 971–979 | Cite as

Does Late Levodopa Administration Delay the Development of Dyskinesia in Patients with De Novo Parkinson’s Disease?

  • Seok Jong Chung
  • Han Soo Yoo
  • Hye Sun Lee
  • Hyo Eun Jeong
  • Soo-Jong Kim
  • Jungsu S. Oh
  • Jae Seung Kim
  • Young H. Sohn
  • Phil Hyu LeeEmail author
Original Research Article



It remains controversial whether late levodopa administration is a reasonable approach to reducing the risk of levodopa-induced dyskinesia in Parkinson’s disease.


This study aimed to investigate the effects of levodopa sparing on the development of levodopa-induced dyskinesia.


We retrospectively reviewed medical records for patients with de novo Parkinson’s disease who visited the Yonsei Parkinson Center between April 2009 and June 2015 and received at least 2 years of treatment. Among 657 patients with drug-naïve Parkinson’s disease who met the study criteria, 90 were initially treated with dopamine agonists (levodopa-sparing group; levodopa supplementation after 2.15 years). Another 90 patients who were initially treated with levodopa (levodopa group) were matched to the 90 patients for age, sex, follow-up duration, Parkinson’s disease duration, Unified Parkinson’s Disease Rating Scale Part III scores, and baseline dopamine transporter availability in the posterior putamen. The effects of levodopa sparing on dyskinesia development were assessed with Kaplan–Meier estimates and a stratified Cox regression model adjusted for age of onset, sex, dopamine transporter availability, and daily levodopa dose per weight.


The levodopa-sparing group had a comparable age of onset (54.80 ± 7.36 years) to the levodopa group (56.53 ± 6.16 years). The Kaplan–Meier analysis revealed that the risk of levodopa-induced dyskinesia after treatment initiation was similar between the groups. Once the levodopa-sparing group started levodopa supplementation, they had a higher risk of developing levodopa-induced dyskinesia. However, a stratified Cox regression model indicated that hazard ratios for levodopa sparing to levodopa-induced dyskinesia development were 0.138 (95% confidence interval 0.024–0.785) after treatment initiation and 0.438 (95% confidence interval 0.105–1.832) after levodopa initiation.


Late levodopa administration was associated with a low risk of dyskinesia after adjusting for confounding effects and may be a reasonable strategy for prolonging the levodopa-induced dyskinesia-free period in Parkinson’s disease.


Compliance with Ethical Standards


This research was supported by a Grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health and Welfare, Republic of Korea (Grant No. HI16C1118), and the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (Grant No. NRF-2018R1D1A1B07048959).

Conflict of interest

Seok Jong Chung, Han Soo Yoo, Hye Sun Lee, Hyo Eun Jeong, Soo-Jong Kim, Jungsu S. Oh, Jae Seung Kim, Young H. Sohn, and Phil Hyu Lee have no conflicts of interest directly relevant to the content of this article.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent to participate

For this type of study, formal consent is not required.

Supplementary material

40263_2018_549_MOESM1_ESM.pdf (167 kb)
Supplementary material 1 (PDF 167 kb)


  1. 1.
    Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30(12):1591–601. Scholar
  2. 2.
    Jenner P. Preventing and controlling dyskinesia in Parkinson’s disease: a view of current knowledge and future opportunities. Mov Disord. 2008;23(Suppl. 3):S585–98. Scholar
  3. 3.
    Sharma JC, Bachmann CG, Linazasoro G. Classifying risk factors for dyskinesia in Parkinson’s disease. Parkinsonism Relat Disord. 2010;16(8):490–7. Scholar
  4. 4.
    Chase TN. Levodopa therapy: consequences of the nonphysiologic replacement of dopamine. Neurology. 1998;50(5 Suppl. 5):S17–25.CrossRefPubMedGoogle Scholar
  5. 5.
    Bezard E, Brotchie JM, Gross CE. Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci. 2001;2(8):577–88. Scholar
  6. 6.
    Cenci MA, Lundblad M. Post- versus presynaptic plasticity in l-DOPA-induced dyskinesia. J Neurochem. 2006;99(2):381–92. Scholar
  7. 7.
    Barone P. Clinical strategies to prevent and delay motor complications. Neurology. 2003;61(6 Suppl. 3):S12–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Rinne UK, Bracco F, Chouza C, Dupont E, Gershanik O, Marti Masso JF, et al. Early treatment of Parkinson’s disease with cabergoline delays the onset of motor complications: results of a double-blind levodopa controlled trial. The PKDS009 Study Group. Drugs. 1998;55(Suppl. 1):23–30.CrossRefPubMedGoogle Scholar
  9. 9.
    Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. 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;342(20):1484–91. Scholar
  10. 10.
    Lees AJ, Katzenschlager R, Head J, Ben-Shlomo Y. Ten-year follow-up of three different initial treatments in de-novo PD: a randomized trial. Neurology. 2001;57(9):1687–94.CrossRefPubMedGoogle Scholar
  11. 11.
    Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. Parkinson Study Group. JAMA. 2000;284(15):1931–8.CrossRefGoogle Scholar
  12. 12.
    Oertel WH, Wolters E, Sampaio C, Gimenez-Roldan S, Bergamasco B, Dujardin M, et al. Pergolide versus levodopa monotherapy in early Parkinson’s disease patients: the PELMOPET study. Mov Disord. 2006;21(3):343–53. Scholar
  13. 13.
    Gray R, Ives N, Rick C, Patel S, Gray A, Jenkinson C, et al. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet. 2014;384(9949):1196–205. Scholar
  14. 14.
    Rascol O, Goetz C, Koller W, Poewe W, Sampaio C. Treatment interventions for Parkinson’s disease: an evidence based assessment. Lancet. 2002;359(9317):1589–98. Scholar
  15. 15.
    Hauser RA, Rascol O, Korczyn AD, Jon Stoessl A, Watts RL, Poewe W, et al. Ten-year follow-up of Parkinson’s disease patients randomized to initial therapy with ropinirole or levodopa. Mov Disord. 2007;22(16):2409–17. Scholar
  16. 16.
    Hong JY, Oh JS, Lee I, Sunwoo MK, Ham JH, Lee JE, et al. Presynaptic dopamine depletion predicts levodopa-induced dyskinesia in de novo Parkinson disease. Neurology. 2014;82(18):1597–604. Scholar
  17. 17.
    Cilia R, Akpalu A, Sarfo FS, Cham M, Amboni M, Cereda E, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(Pt 10):2731–42. Scholar
  18. 18.
    Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55(3):181–4.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Warren Olanow C, Kieburtz K, Rascol O, Poewe W, Schapira AH, Emre M, et al. Factors predictive of the development of levodopa-induced dyskinesia and wearing-off in Parkinson’s disease. Mov Disord. 2013;28(8):1064–71. Scholar
  20. 20.
    Chung SJ, Yoo HS, Moon H, Oh JS, Kim JS, Park YH, et al. Early-onset drug-induced parkinsonism after exposure to offenders implies nigrostriatal dopaminergic dysfunction. J Neurol Neurosurg Psychiatry. 2018;89(2):169–74. Scholar
  21. 21.
    Oh JS, Oh M, Chung SJ, Kim JS. Cerebellum-specific 18F-FDG PET analysis for the detection of subregional glucose metabolism changes in spinocerebellar ataxia. Neuroreport. 2014;25(15):1198–202. Scholar
  22. 22.
    Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27(9):1533–9. Scholar
  23. 23.
    Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE, et al. Development of dyskinesias in a 5-year trial of ropinirole and l-dopa. Mov Disord. 2006;21(11):1844–50. Scholar
  24. 24.
    Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord. 2010;25(15):2649–53. Scholar
  25. 25.
    Holloway RG, Shoulson I, Fahn S, Kieburtz K, Lang A, Marek K, et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol. 2004;61(7):1044–53. Scholar
  26. 26.
    Parkinson Study Group CALM Cohort Investigators. Long-term effect of initiating pramipexole vs levodopa in early Parkinson disease. Arch Neurol. 2009;66(5):563–70. Scholar
  27. 27.
    Constantinescu R, Romer M, McDermott MP, Kamp C, Kieburtz K. Impact of pramipexole on the onset of levodopa-related dyskinesias. Mov Disord. 2007;22(9):1317–9. Scholar
  28. 28.
    Talati R, Reinhart K, Baker W, White CM, Coleman CI. Pharmacologic treatment of advanced Parkinson’s disease: a meta-analysis of COMT inhibitors and MAO-B inhibitors. Parkinsonism Relat Disord. 2009;15(7):500–5. Scholar
  29. 29.
    Elmer LW, Bertoni JM. The increasing role of monoamine oxidase type B inhibitors in Parkinson’s disease therapy. Expert Opin Pharmacother. 2008;9(16):2759–72. Scholar
  30. 30.
    Yahalom G, Cohen OS, Warmann-Alaluf N, Shabat C, Strauss H, Elincx-Benizri S, et al. The impact of early versus late levodopa administration. J Neural Transm (Vienna). 2017;124(4):471–6. Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Seok Jong Chung
    • 1
  • Han Soo Yoo
    • 1
  • Hye Sun Lee
    • 2
  • Hyo Eun Jeong
    • 3
  • Soo-Jong Kim
    • 4
  • Jungsu S. Oh
    • 4
  • Jae Seung Kim
    • 4
  • Young H. Sohn
    • 1
  • Phil Hyu Lee
    • 1
    • 5
    Email author
  1. 1.Department of NeurologyYonsei University College of MedicineSeoulSouth Korea
  2. 2.Department of BiostatisticsYonsei University College of MedicineSeoulSouth Korea
  3. 3.Department of Family MedicineYonsei University College of MedicineSeoulSouth Korea
  4. 4.Department of Nuclear Medicine, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulSouth Korea
  5. 5.Severance Biomedical Science InstituteYonsei University College of MedicineSeoulSouth Korea

Personalised recommendations