Skip to main content
SpringerLink
Log in

Recent Clinical Advances in Pharmacotherapy for Levodopa-Induced Dyskinesia

  • Current Opinion
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Onset of involuntary movement patterns of the face, body and limbs are known as dyskinesia. They mostly appear in association with long-term levodopa (l-dopa) therapy in patients with Parkinson’s disease. Consequences include patient distress, caregiver embarrassment and reduced quality of life. A severe intensity of this motor complication may result in troublesome disability; however, patients typically prefer motor behaviour with slight, non-troublesome dyskinesia to ‘OFF’ states. Pharmacotherapy of dyskinesia is complex. Continuous nigrostriatal postsynaptic dopaminergic receptor stimulation may delay onset of l-dopa-associated dyskinesia, while non-physiological, ‘pulsatile’ receptor stimulation facilitates appearance of dyskinesia. In the past, there have been many clinical trial failures with compounds that were effective in animal models of dyskinesia. Only the N-methyl-d-aspartate antagonist amantadine has shown moderate antidyskinetic effects in small well-designed clinical studies. Amantadine is an old antiviral compound, which moderately improves impaired motor behaviour. Recently, there has been a resurgence of its use due to the US Food and Drug Administration approval of an extended-release (ER) amantadine formulation for treatment of l-dopa-induced dyskinesia. This pharmacokinetic innovation improved dyskinesia and ‘OFF’ states in pivotal trials, with a once-daily oral application in the evening. Amantadine ER provides higher and more continuous amantadine plasma bioavailability than conventional immediate-release formulations, which require administration up to three times daily.

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

Similar content being viewed by others

References

  1. de Rijk MC, Launer LJ, Berger K, Breteler MM, Dartigues JF, Baldereschi M, et al. Prevalence of Parkinson’s disease in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology. 2000;54(11 Suppl 5):S21–3.

    PubMed  Google Scholar 

  2. Bach JP, Riedel O, Klotsche J, Spottke A, Dodel R, Wittchen HU. Impact of complications and comorbidities on treatment costs and health-related quality of life of patients with Parkinson’s disease. J Neurol Sci. 2012;314(1–2):41–7.

    Article  PubMed  Google Scholar 

  3. Berg D, Godau J, Seppi K, Behnke S, Liepelt-Scarfone I, Lerche S, et al. The PRIPS study: screening battery for subjects at risk for Parkinson’s disease. Eur J Neurol. 2013;20(1):102–8.

    Article  CAS  PubMed  Google Scholar 

  4. Przuntek H, Müller T, Riederer P. Diagnostic staging of Parkinson’s disease: conceptual aspects. J Neural Transm (Vienna). 2004;111(2):201–16.

    Article  CAS  Google Scholar 

  5. Müller T, Öhm G, Eilert K, Möhr K, Rotter S, Haas T, et al. Benefit on motor and non-motor behavior in a specialized unit for Parkinson’s disease. J Neural Transm (Vienna). 2017;124(6):715–20.

    Article  Google Scholar 

  6. Contin M, Riva R, Martinelli P, Albani F, Baruzzi A. Effect of age on the pharmacokinetics of oral levodopa in patients with Parkinson’s disease. Eur J Clin Pharmacol. 1991;41(5):463–6.

    Article  CAS  PubMed  Google Scholar 

  7. Boraud T, Bezard E, Bioulac B, Gross CE. Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alterations of pallidal neurones in the MPTP-treated monkey. Brain. 2001;124:546–57.

    Article  CAS  PubMed  Google Scholar 

  8. Bezard E, Brotchie JM, Gross CE. Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci. 2001;2(8):577–88.

    Article  CAS  PubMed  Google Scholar 

  9. Stocchi F, Olanow CW. Continuous dopaminergic stimulation in early and advanced Parkinson’s disease. Neurology. 2004;62(1 Suppl 1):S56–63.

    Article  CAS  PubMed  Google Scholar 

  10. Widnell K. Pathophysiology of motor fluctuations in Parkinson’s disease. Mov Disord. 2005;20(Suppl 11):S17–22.

    Article  PubMed  Google Scholar 

  11. Witjas T, Kaphan E, Azulay JP, Blin O, Ceccaldi M, Pouget J, et al. Nonmotor fluctuations in Parkinson’s disease: frequent and disabling. Neurology. 2002;59(3):408–13.

    Article  PubMed  Google Scholar 

  12. Melamed E, Hefti F, Wurtman RJ. Nonaminergic striatal neurons convert exogenous l-dopa to dopamine in parkinsonism. Ann Neurol. 1980;8(6):558–63.

    Article  CAS  PubMed  Google Scholar 

  13. Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol. 2000;47(4 Suppl 1):S2–9.

    CAS  PubMed  Google Scholar 

  14. Müller T, Möhr JD. Long-term management of Parkinson’s disease using levodopa combinations. Expert Opin Pharmacother. 2018;19(9):1003–11.

    Article  PubMed  CAS  Google Scholar 

  15. Stocchi F, Vacca L, Ruggieri S, Olanow CW. Intermittent vs continuous levodopa administration in patients with advanced Parkinson disease: a clinical and pharmacokinetic study. Arch Neurol. 2005;62(6):905–10.

    Article  PubMed  Google Scholar 

  16. Bravi D, Mouradian MM, Roberts JW, Davis TL, Sohn YH, Chase TN. Wearing-off fluctuations in Parkinson’s disease: contribution of postsynaptic mechanisms. Ann Neurol. 1994;36(1):27–31.

    Article  CAS  PubMed  Google Scholar 

  17. Fabbrini G, Brotchie JM, Grandas F, Nomoto M, Goetz CG. Levodopa-induced dyskinesias. Mov Disord. 2007;22(10):1379–89.

    Article  PubMed  Google Scholar 

  18. Cerri S, Siani F, Blandini F. Investigational drugs in phase I and phase II for levodopa-induced dyskinesias. Expert Opin Investig Drugs. 2017;26(7):777–91.

    Article  CAS  PubMed  Google Scholar 

  19. Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med. 2004;351(24):2498–508.

    Article  CAS  PubMed  Google Scholar 

  20. Stocchi F, Rascol O, Kieburtz K, Poewe W, Jankovic J, Tolosa E, et al. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol. 2010;68(1):18–27.

    Article  CAS  PubMed  Google Scholar 

  21. Verschuur CVM, Suwijn SR, Boel JA, Post B, Bloem BR, van Hilten JJ, LEAP Study Group, et al. Randomized delayed-start trial of levodopa in Parkinson’s disease. N Engl J Med. 2019;380(4):315–24.

    Article  CAS  PubMed  Google Scholar 

  22. Luquin MR, Scipioni O, Vaamonde J, Gershanik O, Obeso JA. Levodopa-induced dyskinesias in Parkinson’s disease: clinical and pharmacological classification. Mov Disord. 1992;7(2):117–24.

    Article  CAS  PubMed  Google Scholar 

  23. Marconi R, Lefebvre-Caparros D, Bonnet AM, Vidailhet M, Dubois B, Agid Y. Levodopa-induced dyskinesias in Parkinson’s disease phenomenology and pathophysiology. Mov Disord. 1994;9(1):2–12.

    Article  CAS  PubMed  Google Scholar 

  24. Adler CH. Relevance of motor complications in Parkinson’s disease. Neurology. 2002;58(4 Suppl 1):S51–6.

    Article  PubMed  Google Scholar 

  25. Jankovic J. Motor fluctuations and dyskinesias in Parkinson’s disease: clinical manifestations. Mov Disord. 2005;20(Suppl 11):S11–6.

    Article  PubMed  Google Scholar 

  26. Rice JE, Antic R, Thompson PD. Disordered respiration as a levodopa-induced dyskinesia in Parkinson’s disease. Mov Disord. 2002;17(3):524–7.

    Article  CAS  PubMed  Google Scholar 

  27. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  28. Krack P, Pollak P, Limousin P, Hoffmann D, Xie J, Benazzouz A, et al. Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson’s disease. Brain. 1998;121(Pt 3):451–7.

    Article  PubMed  Google Scholar 

  29. Vitek JL. Deep brain stimulation for Parkinson’s disease. A critical re-evaluation of STN versus GPi DBS. Stereotact Funct Neurosurg. 2002;78(3–4):119–31.

    Article  PubMed  Google Scholar 

  30. Vitek JL, Bakay RA, Freeman A, Evatt M, Green J, McDonald W, et al. Randomized trial of pallidotomy versus medical therapy for Parkinson’s disease. Ann Neurol. 2003;53(5):558–69.

    Article  PubMed  Google Scholar 

  31. Figee M, de Koning P, Klaassen S, Vulink N, Mantione M, van den Munckhof P, et al. Deep brain stimulation induces striatal dopamine release in obsessive-compulsive disorder. Biol Psychiatry. 2014;75(8):647–52.

    Article  CAS  PubMed  Google Scholar 

  32. Harati A, Muller T. Neuropsychological effects of deep brain stimulation for Parkinson’s disease. Surg Neurol Int. 2013;4(Suppl 6):S443–7.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Katzenschlager R, Poewe W, Rascol O, Trenkwalder C, Deuschl G, Chaudhuri KR, et al. Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018;17(9):749–59.

    Article  CAS  PubMed  Google Scholar 

  34. Klostermann F, Jugel C, Bomelburg M, Marzinzik F, Ebersbach G, Müller T. Severe gastrointestinal complications in patients with levodopa/carbidopa intestinal gel infusion. Mov Disord. 2012;27(13):1704–5.

    Article  PubMed  Google Scholar 

  35. Nyholm D, Jansson R, Willows T, Remahl IN. Long-term 24-hour duodenal infusion of levodopa: outcome and dose requirements. Neurology. 2005;65(9):1506–7.

    Article  PubMed  Google Scholar 

  36. Stocchi F, Vacca L, De Pandis MF, Barbato L, Valente M, Ruggieri S. Subcutaneous continuous apomorphine infusion in fluctuating patients with Parkinson’s disease: long-term results. Neurol Sci. 2001;22(1):93–4.

    Article  CAS  PubMed  Google Scholar 

  37. Verhagen Metman L, Del Dotto P, LePoole K, Konitsiotis S, Fang J, Chase TN. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol. 1999;56(11):1383–6.

    Article  Google Scholar 

  38. Verhagen ML, Del Dotto P, van den Munckhof P, Fang J, Mouradian MM, Chase TN. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology. 1998;50(5):1323–6.

    Article  Google Scholar 

  39. Davies WL, Grunert RR, Haff RF, McGahen JW, Neumayer EM, Paulshock M, et al. Antiviral activity of 1-adamantanamine (amantadine). Science. 1964;144(3620):862–3.

    Article  CAS  PubMed  Google Scholar 

  40. Schwab RS, England AC Jr, Poskanzer DC, Young RR. Amantadine in the treatment of Parkinson’s disease. JAMA. 1969;208(7):1168–70.

    Article  CAS  PubMed  Google Scholar 

  41. Schwab RS, England AC Jr. Amantadine HCL (Symmetrel) and its relation to levo-dopa in the treatment of Parkinson’s disease. Trans Am Neurol Assoc. 1969;94:85–90.

    CAS  PubMed  Google Scholar 

  42. Muhlack S, Musch P, Konietzka S, Woitalla D, Przuntek H, Muller T. Impact of oral fast release amantadine on movement performance in patients with Parkinson’s disease. Pharmaceutics. 2010;2(3):313–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Müller T, Kuhn W, Quack G, Przuntek H. Intravenous application of amantadine and antiparkinsonian efficacy in Parkinsonian patients. J Neural Transm Suppl. 1995;46:407–13.

    PubMed  Google Scholar 

  44. Müller T, Kuhn W, Schulte T, Przuntek H. Intravenous amantadine sulphate application improves the performance of complex but not simple motor tasks in patients with Parkinson’s disease. Neurosci Lett. 2003;339(1):25–8.

    Article  PubMed  Google Scholar 

  45. Bailey EV, Stone TW. The mechanism of action of amantadine in Parkinsonism: a review. Arch Int Pharmacodyn Ther. 1975;216(2):246–62.

    CAS  PubMed  Google Scholar 

  46. Chase TN, Bibbiani F, Oh JD. Striatal glutamatergic mechanisms and extrapyramidal movement disorders. Neurotoxicol Res. 2003;5(1–2):139–46.

    Article  Google Scholar 

  47. Nastuk WL, Su P, Doubilet P. Anticholinergic and membrane activities of amantadine in neuromuscular transmission. Nature. 1976;264(5581):76–9.

    Article  CAS  PubMed  Google Scholar 

  48. Aoki FY, Sitar DS. Clinical pharmacokinetics of amantadine hydrochloride. Clin Pharmacokinet. 1988;14(1):35–51.

    Article  CAS  PubMed  Google Scholar 

  49. Elmer LW, Juncos JL, Singer C, Truong DD, Criswell SR, Parashos S, et al. Pooled analyses of phase III studies of ADS-5102 (amantadine) extended-release capsules for dyskinesia in Parkinson’s disease. CNS Drugs. 2018;32(4):387–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hauser RA, Pahwa R, Wargin WA, Souza-Prien CJ, McClure N, Johnson R, et al. Pharmacokinetics of ADS-5102 (amantadine) extended release capsules administered once daily at bedtime for the treatment of dyskinesia. Clin Pharmacokinet. 2019;58(1):77–88.

    Article  CAS  PubMed  Google Scholar 

  51. Thomas A, Iacono D, Luciano AL, Armellino K, Di Iorio A, Onofrj M. Duration of amantadine benefit on dyskinesia of severe Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2004;75:141–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Ory-Magne F, Corvol JC, Azulay JP, Bonnet AM, Brefel-Courbon C, Damier P, et al. Withdrawing amantadine in dyskinetic patients with Parkinson disease: the AMANDYSK trial. Neurology. 2014;82(4):300–7.

    Article  CAS  PubMed  Google Scholar 

  53. Hauser RA, Pahwa R, Wargin WA, Souza-Prien CJ, McClure N, Johnson R, et al. Pharmacokinetics of ADS-5102 (amantadine) extended release capsules administered once daily at bedtime for the treatment of dyskinesia. Clin Pharmacokinet. 2019;58(1):77–88.

    Article  CAS  PubMed  Google Scholar 

  54. Isaacson SH, Fahn S, Pahwa R, Tanner CM, Espay AJ, Trenkwalder C, et al. Parkinson’s patients with dyskinesia switched from immediate release amantadine to open-label ADS-5102. Mov Disord Clin Pract. 2018;5(2):183–90.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Oertel W, Eggert K, Pahwa R, Tanner CM, Hauser RA, Trenkwalder C, et al. Randomized, placebo-controlled trial of ADS-5102 (Amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia in Parkinson’s Disease (EASE LID 3). Mov Disord. 2017;32(12):1701–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hauser RA, Pahwa R, Tanner CM, Oertel W, Isaacson SH, Johnson R, et al. ADS-5102 (Amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia in Parkinson’s Disease (EASE LID 2 Study): interim results of an open-label safety study. J Parkinsons Dis. 2017;7(3):511–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pahwa R, Tanner CM, Hauser RA, Sethi K, Isaacson S, Truong D, et al. Amantadine extended release for levodopa-induced dyskinesia in Parkinson’s disease (EASED study). Mov Disord. 2015;30(6):788–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pahwa R, Tanner CM, Hauser RA, Isaacson SH, Nausieda PA, Truong DD, et al. ADS-5102 (Amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia in Parkinson Disease (EASE LID study): a randomized clinical trial. JAMA Neurol. 2017;74(8):941–9.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Pahwa R, Isaacson S, Jimenez-Shaheed J, Malaty IA, Deik A, Johnson R, et al. Impact of dyskinesia on activities of daily living in Parkinson’s disease: results from pooled phase 3 ADS-5102 clinical trials. Parkinsonism Relat Disord. 2019;60(3):118–25.

    Article  PubMed  Google Scholar 

  60. Wolf E, Seppi K, Katzenschlager R, Hochschorner G, Ransmayr G, Schwingenschuh P, et al. Long-term antidyskinetic efficacy of amantadine in Parkinson’s disease. Mov Disord. 2010;25(10):1357–63.

    Article  PubMed  Google Scholar 

  61. Miller P, Soundy A. The pharmacological and non-pharmacological interventions for the management of fatigue related multiple sclerosis. J Neurol Sci. 2017;381:41–54.

    Article  CAS  PubMed  Google Scholar 

  62. Tur C. Fatigue management in multiple sclerosis. Curr Treat Options Neurol. 2016;18(6):26.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Gramish JA, Kopp BJ, Patanwala AE. Effect of amantadine on agitation in critically ill patients with traumatic brain injury. Clin Neuropharmacol. 2017;40(5):212–6.

    Article  CAS  PubMed  Google Scholar 

  64. Müller HF, Dastoor DP, Klingner A, Cole M, Boillat J. Amantadine in senile dementia: electroencephalographic and clinical effects. J Am Geriatr Soc. 1979;27(1):9–16.

    Article  PubMed  Google Scholar 

  65. Garssen MP, Schmitz PI, Merkies IS, Jacobs BC, van der Meche FG, van Doorn PA. Amantadine for treatment of fatigue in Guillain–Barre syndrome: a randomised, double blind, placebo controlled, crossover trial. J Neurol Neurosurg Psychiatry. 2006;77(1):61–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kraus MF, Smith GS, Butters M, Donnell AJ, Dixon E, Yilong C, et al. Effects of the dopaminergic agent and NMDA receptor antagonist amantadine on cognitive function, cerebral glucose metabolism and D2 receptor availability in chronic traumatic brain injury: a study using positron emission tomography (PET). Brain Inj. 2005;19(7):471–9.

    Article  CAS  PubMed  Google Scholar 

  67. Sailer M, Heinze HJ, Schoenfeld MA, Hauser U, Smid HG. Amantadine influences cognitive processing in patients with multiple sclerosis. Pharmacopsychiatry. 2000;33(1):28–37.

    Article  CAS  PubMed  Google Scholar 

  68. Malek N, Grosset DG. Medication adherence in patients with Parkinson’s disease. CNS Drugs. 2015;29(1):47–53.

    Article  CAS  PubMed  Google Scholar 

  69. Goetz CG, Laska E, Hicking C, Damier P, Muller T, Nutt J, et al. Placebo influences on dyskinesia in Parkinson’s disease. Mov Disord. 2008;23(5):700–7.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Bonifati V, Fabrizio E, Cipriani R, Vanacore N, Meco G. Buspirone in levodopa-induced dyskinesias. Clin Neuropharmacol. 1994;17(1):73–82.

    Article  CAS  PubMed  Google Scholar 

  71. Durif F, Debilly B, Galitzky M, Morand D, Viallet F, Borg M, et al. Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled study. Neurology. 2004;62(3):381–8.

    Article  CAS  PubMed  Google Scholar 

  72. Katzenschlager R, Manson AJ, Evans A, Watt H, Lees AJ. Low dose quetiapine for drug induced dyskinesias in Parkinson’s disease: a double blind cross over study. J Neurol Neurosurg Psychiatry. 2004;75(2):295–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kobylecki C, Burn DJ, Kass-Iliyya L, Kellett MW, Crossman AR, Silverdale MA. Randomized clinical trial of topiramate for levodopa-induced dyskinesia in Parkinson’s disease. Parkinsonism Relat Disord. 2014;20(4):452–5.

    Article  PubMed  Google Scholar 

  74. Meco G, Fabrizio E, Di RS, Alessandri A, Pratesi L. Mirtazapine in l-dopa-induced dyskinesias. Clin Neuropharmacol. 2003;26(4):179–81.

    Article  CAS  PubMed  Google Scholar 

  75. Schaeffer E, Pilotto A, Berg D. Pharmacological strategies for the management of levodopa-induced dyskinesia in patients with Parkinson’s disease. CNS Drugs. 2014;28(12):1155–84.

    Article  CAS  PubMed  Google Scholar 

  76. Ramot Y, Nyska A, Maronpot RR, Shaltiel-Karyo R, Tsarfati Y, Manno RA, et al. Ninety-day local tolerability and toxicity study of ND0612, a novel formulation of levodopa/carbidopa, administered by subcutaneous continuous infusion in minipigs. Toxicol Pathol. 2017;45(6):764–73.

    Article  CAS  PubMed  Google Scholar 

  77. Westin J, Nyholm D, Palhagen S, Willows T, Groth T, Dougherty M, et al. A pharmacokinetic-pharmacodynamic model for duodenal levodopa infusion. Clin Neuropharmacol. 2011;34(2):61–5.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, St. Joseph Hospital Berlin-Weißensee, Gartenstr. 1, 13088, Berlin, Germany

    Thomas Müller & Jan-Dominique Möhr

Authors
  1. Thomas Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jan-Dominique Möhr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Müller.

Ethics declarations

Funding

No funding was received in relation to this article.

Conflict of interest

TM. and J.-D.M. have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the article. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Müller, T., Möhr, JD. Recent Clinical Advances in Pharmacotherapy for Levodopa-Induced Dyskinesia. Drugs 79, 1367–1374 (2019). https://doi.org/10.1007/s40265-019-01170-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-019-01170-5

Search

Navigation