Skip to main content

Advertisement

SpringerLink
Log in

The clinical spectrum of levodopa-induced motor complications

  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

After more than 40 years of clinical use, levodopa (LD) still remains the gold standard for symptomatic efficacy in Parkinson’s disease (PD). However, long-term treatment with LD is often complicated by the development of various types of motor response oscillations as well as drug-induced dyskinesias. These treatment-related motor complications evolve in approximately one-third of patients after only 2 years of LD exposure and, once established, they are difficult to treat and significantly contribute to overall disability and disease burden. Although first described soon after the introduction of LD, the pathophysiology of motor complications is still not completely understood. In fact, it is most likely that non-physiological pulsatile stimulation of dopamine receptors, which is followed by various downstream alterations, plays a key role in the development of LD-induced motor response oscillations and dyskinesias. This review outlines the various types of motor complications and will also address underlying mechanisms, treatment options, as well as impact on clinical disability and quality of life (QoL).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Alexander G, Crutcher M (1990) Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 13:266–271

    Article  CAS  PubMed  Google Scholar 

  2. Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F (2005) Impact of the motor complications of Parkinson’s disease on the quality of life. Mov Disord 20:224–230

    Article  PubMed  Google Scholar 

  3. Clarke C, Davies P (2000) Systematic review of acute levodopa and apomorphine challenge tests in the diagnosis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 69:590–594

    Article  CAS  PubMed  Google Scholar 

  4. Colosimo C, Martínez-Martín P, Fabbrini G, Hauser R, Merello M, Miyasaki J, Poewe W, Sampaio C, Rascol O, Stebbins G, Schrag A, Goetz C (2010) Task force report on scales to assess dyskinesia in Parkinson’s disease: critique and recommendations. Mov Disord 25:1131–1142

    Article  PubMed  Google Scholar 

  5. Contin M, Riva R, Martinelli P, Cortelli P, Albani F, Baruzzi A (1999) Concentration-effect relationship of levodopa-benserazide dispersible formulation versus standard form in the treatment of complicated motor response fluctuation in Parkinson’s disease. Clin Neuropharmacol 22:351–355

    CAS  PubMed  Google Scholar 

  6. Damiano A, McGrath M, Willian M, Snyder C, LeWitt P, Reyes P, Richter R, Means E (2000) Evaluation of a measurement strategy for Parkinson’s disease: assessing patient health-related quality of life. Qual Life Res 9:87–100

    Article  CAS  PubMed  Google Scholar 

  7. De Rijk M, Launer L, Berger K, Breteler M, Dartigues J, Baldereschi M, Fratiglioni L, Lobo A, Martinez-Lage J, Trenkwalder C, Hofman A (2000) Prevalence of Parkinson’s disease in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54(Suppl 5):21–23

    Google Scholar 

  8. Djaldetti R, Baron J, Ziv I, Melamed E (1996) Gastric emptying in Parkinson’s disease: patients with and without response fluctuations. Neurology 46:1051–1054

    CAS  PubMed  Google Scholar 

  9. Djaldetti R, Inzelberg R, Giladi N, Korczyn A, Peretz-Aharon Y, Rabey M, Herishano Y, Honigman S, Badarny S, Melamed E (2002) Oral solution of levodopa ethylester for treatment of response fluctuations in patients with advanced Parkinson’s disease. Mov Disord 17:297–302

    Article  PubMed  Google Scholar 

  10. Dodel R, Berger K, Oertel W (2001) Health-related quality of life and healthcare utilisation in patients with Parkinson’s disease. Pharmacoeconomics 19:1013–1038

    Article  CAS  PubMed  Google Scholar 

  11. Encarnacion E, Hauser R (2008) Levodopa-induced dyskinesias in Parkinson’s disease: etiology, impact on quality of life, and treatments. Eur Neurol 60:57–66

    Article  CAS  PubMed  Google Scholar 

  12. Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, Olanow C, Tanner C, Marek K, Group PS (2004) Levodopa and the progression of Parkinson’s disease. N Engl J Med 351:2498–2508

    Article  CAS  PubMed  Google Scholar 

  13. Forno L (1996) Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 55:259–272

    Article  CAS  PubMed  Google Scholar 

  14. Gerfen C, Engber T, Mahan L et al (1990) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250:1429–1432

    Article  CAS  PubMed  Google Scholar 

  15. Goetz C (1999) Rating scales for dyskinesias in Parkinson’s disease. Mov Disord 14(Suppl 1):48–53

    PubMed  Google Scholar 

  16. Goetz C, Poewe W, Rascol O et al (2004) Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 19:1020–1028

    Article  PubMed  Google Scholar 

  17. PS 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 23:34–44

    Article  Google Scholar 

  18. Hauser R, Friedlander J, Zesiewicz T, Adler C, Seeberger L, O’Brien C, Molho E, Factor S (2000) A home diary to assess functional status in patients with Parkinson’s disease with motor fluctuations and dyskinesia. Clin Neuropharmacol 23:75–81

    Article  CAS  PubMed  Google Scholar 

  19. Hauser R, McDermott M, Messing S (2006) Factors associated with the development of motor fluctuations and dyskinesias in Parkinson disease. Arch Neurol 63:1756–1760

    Article  PubMed  Google Scholar 

  20. Herrero M, Augood S, Hirsch E et al (1995) Effects of L-dopa on preproenkephalin and preprotachykinin gene expression in the MPTP-treated monkey striatum. Neuroscience 68:1189–1198

    Article  CAS  PubMed  Google Scholar 

  21. Hoehn M (1992) The natural history of Parkinson’s disease in the pre-levodopa and post-levodopa eras. Neurol Clin 10:311–339

    Google Scholar 

  22. Holloway R, Shoulson I, Fahn S, Kieburtz K, Lang A, Marek K, McDermott M, Seibyl J, Weiner W, Musch B, Kamp C, Welsh M, Shinaman A, Pahwa R, Barclay L, Hubble J, LeWitt P, Miyasaki J, Suchowersky O, Stacy M, Russell D, Ford B, Hammerstad J, Riley D, Standaert D, Wooten F, Factor S, Jankovic J, Atassi F, Kurlan R, Panisset M, Rajput A, Rodnitzky R, Shults C, Petsinger G, Waters C, Pfeiffer R, Biglan K, Borchert L, Montgomery A, Sutherland L, Weeks C, DeAngelis M, Sime E, Wood S, Pantella C, Harrigan M, Fussell B, Dillon S, Alexander-Brown B, Rainey P, Tennis M, Rost-Ruffner E, Brown D, Evans S, Berry D, Hall J, Shirley T, Dobson J, Fontaine D, Pfeiffer B, Brocht A, Bennett S, Daigneault S, Hodgeman K, O’Connell C, Ross T, Richard K, Watts A, Group PS (2004) Pramipexole vs. levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 61:1044–1053

    Article  PubMed  Google Scholar 

  23. http://www.clinicaltrial.gov/ct2/show/NCT01071395 (2010) Validation of dyskinesia rating scales. In: clinicaltrials.gov (ed)

  24. Hung S, Adeli G, Arenovich T, Fox S, Lang A (2007) Patient perception of dyskinesias in Parkinson’s disease. Neurology 68:A232

    Article  Google Scholar 

  25. Jolkkonen J, Jenner P, Marsden C (1995) l-Dopa reverses altered gene expression of substance P but not enkephalin in the caudate-putamen of common marmosets treated with MPTP. Brain Res Mol Brain Res 32:297–307

    Article  CAS  PubMed  Google Scholar 

  26. Jost W (2010) Gastrointestinal dysfunction in Parkinson’s disease. J Neurol Sci 289:69–73

    Article  CAS  PubMed  Google Scholar 

  27. Karlsen K, Tandberg E, Arsland D, Larsen J (2000) Health related quality of life in Parkinson’s disease: a prospective longitudinal study. J Neurol Neurosurg Psychiatry 69:584–589

    Article  CAS  PubMed  Google Scholar 

  28. Kish S, Shannak K, Hornykiewicz O (1988) Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease. Pathophysiologic and clinical implications. N Engl J Med 318:876–880

    Article  CAS  PubMed  Google Scholar 

  29. Kostic V, Przedborski S, Flaster E, Sternic N (1991) Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson’s disease. Neurology 41:202–205

    CAS  PubMed  Google Scholar 

  30. Krygowska-Wajs A, Lorens K, Thor P, Szczudlik A, Konturek S (2000) Gastric electromechanical dysfunction in Parkinson’s disease. Funct Neurol 15:41–46

    CAS  PubMed  Google Scholar 

  31. Künzle H (1975) Bilateral projections from precentral motor cortex to the putamen and other parts of the basal ganglia. An autoradiographic study in Macaca fascicularis. Brain Res 88:195–209

    Article  PubMed  Google Scholar 

  32. Leenders K, Poewe W, Palmer A, Brenton D, Frackowiak R (1986) Inhibition of L-[18F]fluorodopa uptake into human brain by amino acids demonstrated by positron emission tomography. Ann Neurol 20:258–262

    Article  CAS  PubMed  Google Scholar 

  33. Lees A (1987) A sustained-release formulation of l-dopa (Madopar HBS) in the treatment of nocturnal and early-morning disabilities in Parkinson’s disease. Eur Neurol 27:126–134

    Article  PubMed  Google Scholar 

  34. Lees A, Katzenschlager R, head J, Ben-Shlomo Y (2001) Ten year follow-up of three different initial treatments in de-novo PD: a randomized trial. Neurology 57:1687–1694

    CAS  PubMed  Google Scholar 

  35. Luquin M, Scipioni O, Vaamonde J, Gershanik O, Obeso J (1992) Levodopa-induced dyskinesias in Parkinson’s disease: clinical and pharmacological classification. Mov Disord 7:117–124

    Article  CAS  PubMed  Google Scholar 

  36. Marconi R, Lefebvre-Caparros D, Bonnet A, Vidailhet M, Dubois B, Agid Y (1994) Levodopa-induced dyskinesias in Parkinson’s disease phenomenology and pathophysiology. Mov Disord 9:2–12

    Article  CAS  PubMed  Google Scholar 

  37. Marsden C (1994) Parkinson’s disease. J Neurol Neurosurg Psychiatry 57:672–681

    Article  CAS  PubMed  Google Scholar 

  38. Melamed E (1979) Early-morning dystonia. A late side effect of long-term levodopa therapy in Parkinson’s disease. Arch Neurol 36:308–310

    CAS  PubMed  Google Scholar 

  39. Muenter M, Sharpless N, Tyce G, Darley F (1977) Patterns of dystonia (“I-D-I” and “D-I-D-”) in response to l-dopa therapy for Parkinson’s disease. Mayo Clin Proc 52:163–174

    CAS  PubMed  Google Scholar 

  40. Nutt J (1990) Levodopa-induced dyskinesia: review, observations, and speculations. Neurology 40:340–345

    CAS  PubMed  Google Scholar 

  41. Nutt J, Fellman J (1984) Pharmacokinetics of levodopa. Clin Neuropharmacol 7:35–49

    Article  CAS  PubMed  Google Scholar 

  42. Nutt J, Woodward W (1986) Levodopa pharmacokinetics and pharmacodynamics in fluctuating Parkinsonian patients. Neurology 36:739–744

    CAS  PubMed  Google Scholar 

  43. Nutt J, Wooten G (2005) Clinical practice. Diagnosis and initial management of Parkinson’s disease. N Engl J Med 353:1021–1027

    Article  CAS  PubMed  Google Scholar 

  44. Oertel W, Wolters E, Sampaio C, Gimenez-Roldan S, Bergamasco B, Dujardin M, Grosset D, Arnold G, Leenders K, Hundemer H, Lledó A, Wood A, Frewer P, Schwarz J (2006) Pergolide versus levodopa monotherapy in early Parkinson’s disease patients: The PELMOPET Study. Mov Disord 21:343–353

    Article  PubMed  Google Scholar 

  45. Olanow C, Agid Y, Mizuno Y, Albanese A, Bonuccelli U, Bonucelli U, Damier P, De Yebenes J, Gershanik O, Guttman M, Grandas F, Hallett M, Hornykiewicz O, Jenner P, Katzenschlager R, Langston W, LeWitt P, Melamed E, Mena M, Michel P, Mytilineou C, Obeso J, Poewe W, Quinn N, Raisman-Vozari R, Rajput A, Rascol O, Sampaio C, Stocchi F (2004) Levodopa in the treatment of Parkinson’s disease: current controversies. Mov Disord 19:997–1005

    Article  PubMed  Google Scholar 

  46. Pacchetti C, Albani G, Martignoni E, Godi L, Alfonsi E, Nappi G (1995) “Off” painful dystonia in Parkinson’s disease treated with botulinum toxin. Mov Disord 10:333–336

    Article  CAS  PubMed  Google Scholar 

  47. Paci C, Thomas A, Onofrj M (2001) Amantadine for dyskinesia in patients affected by severe Parkinson’s disease. Neurol Sci 22:75–76

    Article  CAS  PubMed  Google Scholar 

  48. Pierantozzi M, Pietroiusti A, Brusa L, Galati S, Stefani A, Lunardi G, Fedele E, Sancesario G, Bernardi G, Bergamaschi A, Magrini A, Stanzione P, Galante A (2006) Helicobacter pylori eradication and l-dopa absorption in patients with PD and motor fluctuations. Neurology 66:1824–1829

    Article  CAS  PubMed  Google Scholar 

  49. Poewe W, Lees A, Stern G (1988) Dystonia in Parkinson’s disease: clinical and pharmacological features. Ann Neurol 23:73–78

    Article  CAS  PubMed  Google Scholar 

  50. Poewe W, Lees A, Stern G (1986) Low-dose l-dopa therapy in Parkinson’s disease: a 6-year follow-up study. Neurology 36:1528–1530

    CAS  PubMed  Google Scholar 

  51. Quinn N, Critchley P, Marsden C (1987) Young onset Parkinson’s disease. Mov Disord 2:73–91

    Article  CAS  PubMed  Google Scholar 

  52. Rajput A (1992) Frequency and cause of Parkinson’s disease. Can J Neurol Sci 19(Suppl 1):103–107

    CAS  PubMed  Google Scholar 

  53. Rajput A (2001) Levodopa prolongs life expectancy and is non-toxic to substantia nigra. Parkinsonism Relat Disord 8:95–100

    Article  CAS  PubMed  Google Scholar 

  54. Rascol O, Brooks D, Korczyn A, De Deyne P, Clarke C, Lang A (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 342:1484–1491

    Article  CAS  PubMed  Google Scholar 

  55. Rascol O, Brooks D, Melamed E, Oertel W, Poewe W, Stocchi F, Tolosa E, group Ls (2005) Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 365:947–954 Mar 12–18

    Article  CAS  PubMed  Google Scholar 

  56. Rinne U, Bracco F, Chouza C, Dupont E, Gershanik O, Marti Masso J, Montastruc J, Marsden C (1998) 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 55(Suppl 1):23–30

    Article  CAS  PubMed  Google Scholar 

  57. Schrag A, Ben-Shlomo Y, Brown R, Marsden C, Quinn N (1998) Young-onset Parkinson’s disease revisited—clinical features, natural history, and mortality. Mov Disord 13:885–894

    Article  CAS  PubMed  Google Scholar 

  58. Schrag A, Quinn N (2000) Dyskinesias and motor fluctuations in Parkinson’s disease. A community-based study. Brain 123(Pt 11):2297–2305

    Article  PubMed  Google Scholar 

  59. Snow B, Macdonald L, Mcauley D, Wallis W (2000) The effect of amantadine on levodopa-induced dyskinesias in Parkinson’s disease: a double-blind, placebo-controlled study. Clin Neuropharmacol 23:82–85

    Article  CAS  PubMed  Google Scholar 

  60. Soykan I, Lin Z, Bennett J, McCallum R (1999) Gastric myoelectrical activity in patients with Parkinson’s disease: evidence of a primary gastric abnormality. Dig Dis Sci 44:927–931

    Article  CAS  PubMed  Google Scholar 

  61. Stacy M, Bowron A, Guttman M, Hauser R, Hughes K, Larsen J, LeWitt P, Oertel W, Quinn N, Sethi K, Stocchi F (2005) Identification of motor and nonmotor wearing-off in Parkinson’s disease: comparison of a patient questionnaire versus a clinician assessment. Mov Disord 20:726–733

    Article  PubMed  Google Scholar 

  62. Stocchi F, Rascol O, Kieburtz K, Poewe W, Jankovic J, Tolosa E, Barone P, Lang A, Olanow C (2010) Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol 68:18–27

    Article  CAS  PubMed  Google Scholar 

  63. Tanner C, Goldman S (1996) Epidemiology of Parkinson’s disease. Neurol Clin 14:317–335

    Article  CAS  PubMed  Google Scholar 

  64. Verhagen Metman L, Del Dotto P, van den Munckhof P, Fang J, Mouradian M, Chase T (1998) Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology 50:1323–1326

    CAS  PubMed  Google Scholar 

  65. Whone A, Watts R, Stoessl A, Davis M, Reske S, Nahmias C, Lang A, Rascol O, Ribeiro M, Remy P, Poewe W, Hauser R, Brooks D, Group R-PS (2003) Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET Study. Ann Neurol 54:93–101

    Article  CAS  PubMed  Google Scholar 

  66. Witjas T, Kaphan E, Azulay J, Blin O, Ceccaldi M, Pouget J, Poncet M, Chérif A (2002) Nonmotor fluctuations in Parkinson’s disease: frequent and disabling. Neurology 59:408–413

    PubMed  Google Scholar 

  67. Wolf E, Seppi K, Katzenschlager R, Hochschorner G, Ransmayr G, Schwingenschuh P, Ott E, Kloiber I, Haubenberger D, Auff E, Poewe W (2010) Long-term antidyskinetic efficacy of amantadine in Parkinson’s disease. Mov Disord 25(10):1357–1363

    Google Scholar 

  68. Zeng B, Pearce R, MacKenzie G, Jenner P (2000) Alterations in preproenkephalin and adenosine-2a receptor mRNA, but not preprotachykinin mRNA correlate with occurrence of dyskinesia in normal monkeys chronically treated with l-dopa. Eur J Neurosci 12:1096–1104

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

Klaus Seppi has received honoraria for speaking and consulting from Novartis, Boehringer Ingelheim, Lundbeck, Schwarz Pharma, UCB Pharma, and GlaxoSmithKline. Werner Poewe served as a consultant for Boehringer Ingelheim, Esai Ltd., Novartis, Sovay, and Teva. He was in the advisory panel for Boehringer Ingelheim, Esai Ltd., Genzyme, Novartis, Schering Plough, Sovay, Teva, and Valeant. He received research support from Boehringer Ingelheim and Astra Zeneca. He serves as a review editor for the Journal of Neurology and as a member of the editorial advisory board for the European Journal of Neurology. E. Hametner has no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Neurology, Innsbruck Medical University, Anichstraße 35, 6020, Innsbruck, Austria

    E. Hametner, K. Seppi & W. Poewe

Authors
  1. E. Hametner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Seppi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W. Poewe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W. Poewe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hametner, E., Seppi, K. & Poewe, W. The clinical spectrum of levodopa-induced motor complications. J Neurol 257 (Suppl 2), 268–275 (2010). https://doi.org/10.1007/s00415-010-5719-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-010-5719-9

Keywords

Search

Navigation