Current management of motor fluctuations in patients with advanced Parkinson’s disease treated chronically with levodopa

  • Eldad Melamed
  • J. Zoldan
  • R. Galili-Mosberg
  • I. Ziv
  • R. Djaldetti
Part of the Journal of Neural Transmission. Supplementa book series (NEURAL SUPPL, volume 56)


Motor fluctuations after long-term administration of levodopa may be due to central pharmacodynamic mechanisms such as reduced striatal synthesis and storage of dopamine from exogenous levodopa and subsensitization of postsynaptic dopaminergic receptors. Peripheral pharmacokinetic mechanisms may be equally important, particularly in motor fluctuations of the “delayed on” (increased time latencies from dose intake to start-up of clinical benefit) and “no-on” (complete failure of a levodopa dose to exert an “on” response) types. Levodopa itself has a very poor solubility. In addition, there is delayed gastric emptying in many advanced patients. Therefore, an oral dose of levodopa may remain in the stomach for long periods of time before it passes into the duodenum where there is immediate absorption. Consequently, in order to overcome response fluctuations caused by impaired pharmacokinetic mechanisms and to improve its absorption, we recommend that levodopa be taken in multiple small doses, on an empty stomach, preferably crushed and mixed with a lot of liquid. Protein intake should be minimized. Prokinetic drugs such as prepulsid (Cisaprid) could be used to facilitate gastric motility and levodopa transit time. Administration of crushed levodopa through nasoduodenal or gastrojejunostomy tubes may be helpful in certain circumstances. Bypassing the stomach with subcutaneous injections of apomorphine may provide dramatic rescue from difficult “off” situations. Oral and s.c. administration of novel, extremely soluble prodrugs of levodopa, e.g., levodopa ethylester, may offer a new approach to overcome difficulties in levodopa absorption. Addition of dopamine agonists, MAO-B inhibitors, COMT inhibitors and controlled release levodopa preparations may be helpful in prolonging the duration of efficacy of each single levodopa dose.

Levodopa, administered orally, usually combined with peripheral dopa decarboxylase inhibitors, continues to be the most widely-used and most effective pharmacological treatment for Parkinson’s disease (Melamed, 1987). Undoubtedly, the outstanding therapeutic success of levodopa represents a dramatic and revolutionary breakthrough in medicine, in general, and in neurology, in particular. Although, since the introduction of levodopa, there have been many additional pharmacological and even surgical anti- parkinsonian strategies, it still stands out as a mandatory axis of treatment in the majority of patients (Steigler and Quinn, 1992). Indeed, levodopa therapy improves, sometimes markedly, the motor signs and symptoms of the illness, the functional capacity and quality of life and perhaps also life expectancy of the afflicted patients. It is therefore unfortunate that after an initial problem-free period of successful, smooth and stable clinical benefit from levodopa that lasts about two to five years, the responsiveness of many patients worsens with the emergence of a variety of complications (Marsden et al., 1982; Hardie et al., 1984). These adverse reactions include dyskinesias and dystonias, psychotic problems and, particularly, the troublesome motor fluctuations (Marsden and Parkes, 1977; Marsden, 1994). The latter phenomenon may be particularly complex, limiting and disabling. It is believed that most patients on long-term levodopa therapy will, sooner or later, develop response fluctuations of varying types and severity (Riley and Lang, 1993). Because of the serious impact of these phenomena on the quality of life and function of the patients, many efforts are now being undertaken to identify the responsible mechanisms and to devise preventive and therapeutic measures.


Dopamine Agonist Motor Fluctuation Levodopa Dose COMT Inhibitor Response Fluctuation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Baruzzi A, Cantin M, Riva R (1987) Influence of meal ingestion time on pharmacokinetics of orally-administered levodopa in parkinsonian patients. Clin Neuropharmacol 10: 527–537PubMedCrossRefGoogle Scholar
  2. Carter JH, Nutt JH, Woodward WR (1909) amount and distribution of dietary protein affects clinical response to levodopa in Parkinson’s disease. Neurology 39: 552–556CrossRefGoogle Scholar
  3. Djaldetti R, Melamed E (1996) Levodopa ethylester: A novel rescue therapy for response fluctuations in Parkinson’s disease. Ann Neurol 39: 401–404CrossRefGoogle Scholar
  4. Djaldetti R, Koren M, Ziv I, Achiron A, Melamed E (1995) Effect of Cisapride on response fluctuations in Parkinson’s disease. Mov Disord 10: 81–84PubMedCrossRefGoogle Scholar
  5. Djaldetti R, Ziv I, Melamed E (1996a) Impaired absorption of oral levodopa: A major cause for response fluctuations in Parkinson’s disease. Isr J Med Sci 32: 1224–1227PubMedGoogle Scholar
  6. Djaldetti R, Baron J, Ziv I, Melamed E (1996b) Gastric emptying in Parkinson’s disease: Patients with and without response fluctuations. Neurology 46: 1051–1054PubMedCrossRefGoogle Scholar
  7. Fabrini G, Mouradian MM, Juncos JL, Schlegel J, Mohr E, Chase TN (1988) Motor fluctuations in Parkinson’s disease: Central pathophysiological mechanisms, Part I. Ann Neurol 24: 366–371CrossRefGoogle Scholar
  8. Fahn S (1977) Episodic failure of absorption of levodopa: a factor in the control of clinical fluctuations in the treatment of parkinsonism. Neurology 27: 390–392CrossRefGoogle Scholar
  9. Goetz GG, Diedrich NJ (1992) Dopaminergic agonists for the treatment of Parkinson’s disease. Neurol Clin 10: 527–540PubMedGoogle Scholar
  10. Golbe LI, Lieberman AN, Muenter MD, Ahlskog JE, Gopinathan G (1988) Deprenyl in the treatment of symptom fluctuations in advanced Parkinson’s disease. Clin Neuropharmacol 11: 45–55PubMedCrossRefGoogle Scholar
  11. Hardie RJ, Lees AJ, Stern GM (1984) On-off fluctuations in Parkinson’s disease: A clinical and neuropharmacological study. Brain 107: 487–506PubMedCrossRefGoogle Scholar
  12. Hefti F, Melamed E (1980) L-dopa’s mechanism of action in Parkinson’s disease. Trends Neurosci 3: 229–231Google Scholar
  13. Jenner P (1995) The rational for use of dopamine agonists in Parkinson’s disease. Neurology 45 [Suppl 3]: S6–S12PubMedCrossRefGoogle Scholar
  14. Kaakkola S, Teravainen H, Ahtila S, Rita H, Gordin A (1994) Effect of entecapone, a COMT inhibitor, on clinical disability and levodopa metabolism in parkinsonian patients. Neurology 44: 77–80PubMedCrossRefGoogle Scholar
  15. Kurth MC, Tetrud LW, Irwin I, Lyness WH, Langston JW (1993) Oral levodopa/ carbidopa solution versus tablets in Parkinson’s patients with severe fluctuations — a pilot study. Neurology 43: 1036–1039PubMedCrossRefGoogle Scholar
  16. Kurth MC, Adler CH, Saint-Hillaire M (1997) Tolcapone improves motor function and reduces levodopa requirement in patients with Parkinson’s disease experiencing motor fluctuations: a multicenter double-blind randomized placebo-controlled trial. Neurology 48: 81–87PubMedCrossRefGoogle Scholar
  17. Lesser RP, Fahn S, Snider SR, Cote L (1979) Analysis of the clinical problems in parkinsonism and the complications of long-term levodopa therapy. Neurology 29: 1253–1266PubMedCrossRefGoogle Scholar
  18. Marsden CD (1994) Parkinson’s disease. J Neurol Neurosurg Psychiatry 57: 672–681PubMedCrossRefGoogle Scholar
  19. Marsden CD, Parkes JD (1977) Success and problems of long-term levodopa therapy in Parkinson’s disease. Lancet 1: 345–349PubMedCrossRefGoogle Scholar
  20. Marsden CD, Parkes JD, Quinn NP (1982) Fluctuations of disability in Parkinson’s disease — clinical aspects. In: Marsden CD, Fahn S (eds) Movement disorders. Butterworth, London, pp 96–122Google Scholar
  21. Melamed E (1987) L-dopa. In: Adelman G (ed) Encyclopedia of neuroscience. Birkhauser-Boston, Cambridge, pp 553–554Google Scholar
  22. Melamed E, Bitton V (1986) Delayed onset of responses to individual doses of levodopa in parkinsonian fluctuators on long-term L-dopa therapy. Clin Neuropharmacol 9: 182–186PubMedCrossRefGoogle Scholar
  23. Melamed E, Bitton V, Zelig O (1986) Episodic unresponsiveness to single doses of L-dopa in parkinsonian fluctuators. Neurology 36: 1001–1003CrossRefGoogle Scholar
  24. Montastruc JL, Rascol O, Senard JM (1993) Current status of dopamine agonists in Parkinson’s disease management. Drugs 46: 384–393PubMedCrossRefGoogle Scholar
  25. Mouradian MM, Juncos JL, Fabrini G, Schlegel J, Bartko JJ, Chase TN (1988) Motor fluctuations in Parkinson’s disease: Central pathophysiological mechanisms. Part II. Ann Neurol 24: 372–378PubMedCrossRefGoogle Scholar
  26. Muenter MD, Tyce GM (1971) L-dopa therapy of Parkinson’s disease: Plasma L-dopa concentrations therapeutic response and side effects. Mayo Clin Proc 46: 231–239PubMedGoogle Scholar
  27. Nutt JG (1987) On-off phenomenon: relation to levodopa pharmacokinetics and pharmacodynamics. Ann Neurol 22: 535–540PubMedCrossRefGoogle Scholar
  28. Nutt JG (1990) Levodopa-induced dyskinesia: Review, observations and speculations. Neurology 40: 340–345PubMedCrossRefGoogle Scholar
  29. Pincus JH, Barry K (1987) Protein redistribution diet restores motor function in patients with dopa-resistant “off” periods. Neurology 38: 481–483CrossRefGoogle Scholar
  30. Poewe WH, Lees AJ, Stern GM (1986) Treatment of motor fluctuations in Parkinson’s disease with an oral sustained-release preparation of L-dopa: clinical and pharmaco-kinetic observations. Clin Neuropharmacol 9: 430–439PubMedCrossRefGoogle Scholar
  31. Rajput AM, Martin W, Saint-Hillaire MH, Dorflinger E, Pedder S (1997) Tolcapone improves motor function in parkinsonian patients with the “wearing off” phenomenon: a double-blind, placebo-controlled multicenter study. Neurology 49: 1066–1071PubMedCrossRefGoogle Scholar
  32. Riley DE, Lang AE (1993) The spectrum of levodopa-related fluctuations in Parkinson’s disease. Neurology 43: 1459–1464PubMedCrossRefGoogle Scholar
  33. Roberts JW, Cora-Locatelli G, Bravi D, Amantea MA, Mouradian MM, Chase TN (1994) Catechol-0-methyltransferase inhibitor tolcapone prolongs levodopa/ carbidopa action in parkinsonian patients. Neurology 44: 2685–2688Google Scholar
  34. Steiger NJ, Quinn NP (1992) Levodopa-based therapy. In: Koller WC (ed) Handbook of Parkinson’s disease. Marcel Dekker, New York, pp 391–410Google Scholar
  35. Stern MB (1997) Contemporary approaches to the pharmacotherapeutic management of Parkinson’s disease: An overview. Neurology 49 [Suppl 1]: S2–S9PubMedCrossRefGoogle Scholar
  36. Stibe CMH, Lees AJ, Kempster PA, Stern GM (1988) Subcutaneous apomorphine in parkinsonian on-off oscillations. Lancet 1: 403–406PubMedCrossRefGoogle Scholar
  37. Stocchi F, Nordera G, Marsden CD (1997) Strategies for treating patients with advanced Parkinson’s disease with disastrous fluctuations and dyskinesias. Clin Neuropharmacol 20: 95–115PubMedCrossRefGoogle Scholar
  38. Waters CH (1997) Managing the late complications of Parkinson’s disease. Neurology 49 [Suppl 1] S49–S57PubMedCrossRefGoogle Scholar
  39. Wooten GF (1988) Progress in understanding the pathophysiology of treatment-related fluctuations in Parkinson’s disease. Ann Neurol 24: 363–365PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 1999

Authors and Affiliations

  • Eldad Melamed
    • 1
    • 2
  • J. Zoldan
    • 1
    • 2
  • R. Galili-Mosberg
    • 1
    • 2
  • I. Ziv
    • 1
    • 2
  • R. Djaldetti
    • 1
    • 2
  1. 1.Department of NeurologyRabin Medical Center, Beilinson CampusPetah TikvaIsrael
  2. 2.Sackler School of MedicineTel-Aviv UniversityIsrael

Personalised recommendations