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Motor fluctuations and dyskinesia in Parkinson disease

Daniel Tarsy, MD
Section Editor
Howard I Hurtig, MD
Deputy Editor
John F Dashe, MD, PhD


Motor fluctuations and dyskinesia are important complications of levodopa therapy that affect many patients with advancing Parkinson disease (PD). This topic review will discuss the medical management of patients with PD who are experiencing motor fluctuations. Other clinical aspects of PD are discussed separately. (See "Etiology and pathogenesis of Parkinson disease" and "Clinical manifestations of Parkinson disease" and "Diagnosis and differential diagnosis of Parkinson disease" and "Pharmacologic treatment of Parkinson disease" and "Management of nonmotor symptoms in Parkinson disease" and "Palliative approach to Parkinson disease and parkinsonian disorders".)

Device-assisted and surgical treatments are additional therapeutic options that improve motor function in selected patients with advanced typical PD and motor fluctuations, whose condition cannot be further improved by medical therapy. These treatments (deep brain stimulation, continuous levodopa/carbidopa intestinal gel infusion, and continuous subcutaneous apomorphine infusion) are reviewed separately. (See "Device-assisted and surgical treatments for Parkinson disease".)


Patients with PD typically experience a smooth and even response to the early stages of levodopa treatment. As the disease advances, however, the effect of levodopa begins to wear off several hours after some or even all doses, leaving patients aware that the duration of action of a dose of levodopa is not being sustained. As many as 50 percent of patients on levodopa for several years will experience motor fluctuations and dyskinesia [1].

Motor fluctuations — Motor fluctuations are alterations between periods of being "on," during which the patient experiences a positive response to medication, and being "off," during which the patient experiences a reemergence of the Parkinson symptoms suppressed during the "on" state. The reason motor fluctuations occur is not entirely clear, but current thinking holds that motor fluctuations evolve as PD progresses because progressive degeneration of the nigro-striatal dopaminergic pathway reduces the ability of nerve terminals to store and release dopamine physiologically. As a result of this loss of storage capacity, the response to exogenous levodopa defaults to a more pulsatile or bolus impact on postsynaptic dopamine receptors (the short duration response) in keeping with levodopa's short (90 minute) half-life and its rapid cycling pharmacokinetics. Plasma levels of levodopa may fluctuate because of the additional problem of erratic intestinal absorption related to slowed intestinal motility and other factors.

There are several types of motor fluctuations, including the following:

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Literature review current through: Nov 2017. | This topic last updated: Oct 31, 2017.
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  1. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines. Neurology 2001; 56:S1.
  2. Quinn N. Drug treatment of Parkinson's disease. BMJ 1995; 310:575.
  3. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001; 16:448.
  4. Van Gerpen JA, Kumar N, Bower JH, et al. Levodopa-associated dyskinesia risk among Parkinson disease patients in Olmsted County, Minnesota, 1976-1990. Arch Neurol 2006; 63:205.
  5. Fox SH, Lang AE. Levodopa-related motor complications--phenomenology. Mov Disord 2008; 23 Suppl 3:S509.
  6. Hauser RA, Deckers F, Lehert P. Parkinson's disease home diary: further validation and implications for clinical trials. Mov Disord 2004; 19:1409.
  7. Odin P, Ray Chaudhuri K, Slevin JT, et al. Collective physician perspectives on non-oral medication approaches for the management of clinically relevant unresolved issues in Parkinson's disease: Consensus from an international survey and discussion program. Parkinsonism Relat Disord 2015; 21:1133.
  8. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA 2014; 311:1670.
  9. Nyholm D, Stepien V. Levodopa fractionation in Parkinson's disease. J Parkinsons Dis 2014; 4:89.
  10. Nutt JG, Chung KA, Holford NH. Dyskinesia and the antiparkinsonian response always temporally coincide: a retrospective study. Neurology 2010; 74:1191.
  11. Hauser RA, Hsu A, Kell S, et al. Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial. Lancet Neurol 2013; 12:346.
  12. Stocchi F, Hsu A, Khanna S, et al. Comparison of IPX066 with carbidopa-levodopa plus entacapone in advanced PD patients. Parkinsonism Relat Disord 2014; 20:1335.
  13. Ahlskog JE, Muenter MD, McManis PG, et al. Controlled-release Sinemet (CR-4): a double-blind crossover study in patients with fluctuating Parkinson's disease. Mayo Clin Proc 1988; 63:876.
  14. Jankovic J, Schwartz K, Vander Linden C. Comparison of Sinemet CR4 and standard Sinemet: double blind and long-term open trial in parkinsonian patients with fluctuations. Mov Disord 1989; 4:303.
  15. Hutton JT, Morris JL, Román GC, et al. Treatment of chronic Parkinson's disease with controlled-release carbidopa/levodopa. Arch Neurol 1988; 45:861.
  16. Lieberman A, Gopinathan G, Miller E, et al. Randomized double-blind cross-over study of Sinemet-controlled release (CR4 50/200) versus Sinemet 25/100 in Parkinson's disease. Eur Neurol 1990; 30:75.
  17. Pahwa R, Factor SA, Lyons KE, et al. Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006; 66:983.
  18. Pappert EJ, Buhrfiend C, Lipton JW, et al. Levodopa stability in solution: time course, environmental effects, and practical recommendations for clinical use. Mov Disord 1996; 11:24.
  19. Olanow CW, Fahn S, Muenter M, et al. A multicenter double-blind placebo-controlled trial of pergolide as an adjunct to Sinemet in Parkinson's disease. Mov Disord 1994; 9:40.
  20. Rascol O, Lees AJ, Senard JM, et al. Ropinirole in the treatment of levodopa-induced motor fluctuations in patients with Parkinson's disease. Clin Neuropharmacol 1996; 19:234.
  21. Lieberman A, Ranhosky A, Korts D. Clinical evaluation of pramipexole in advanced Parkinson's disease: results of a double-blind, placebo-controlled, parallel-group study. Neurology 1997; 49:162.
  22. Lieberman A, Olanow CW, Sethi K, et al. A multicenter trial of ropinirole as adjunct treatment for Parkinson's disease. Ropinirole Study Group. Neurology 1998; 51:1057.
  23. Pahwa R, Stacy MA, Factor SA, et al. Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease. Neurology 2007; 68:1108.
  24. LeWitt PA, Lyons KE, Pahwa R, SP 650 Study Group. Advanced Parkinson disease treated with rotigotine transdermal system: PREFER Study. Neurology 2007; 68:1262.
  25. Schapira AH, Barone P, Hauser RA, et al. Extended-release pramipexole in advanced Parkinson disease: a randomized controlled trial. Neurology 2011; 77:767.
  26. LeWitt PA, Ward CD, Larsen TA, et al. Comparison of pergolide and bromocriptine therapy in parkinsonism. Neurology 1983; 33:1009.
  27. Guttman M. Double-blind comparison of pramipexole and bromocriptine treatment with placebo in advanced Parkinson's disease. International Pramipexole-Bromocriptine Study Group. Neurology 1997; 49:1060.
  28. Pezzoli G, Martignoni E, Pacchetti C, et al. Pergolide compared with bromocriptine in Parkinson's disease: a multicenter, crossover, controlled study. Mov Disord 1994; 9:431.
  29. Korczyn AD, Brooks DJ, Brunt ER, et al. Ropinirole versus bromocriptine in the treatment of early Parkinson's disease: a 6-month interim report of a 3-year study. 053 Study Group. Mov Disord 1998; 13:46.
  30. Clarke CE, Deane KD. Cabergoline versus bromocriptine for levodopa-induced complications in Parkinson's disease. Cochrane Database Syst Rev 2001; :CD001519.
  31. Poewe WH, Rascol O, Quinn N, et al. Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson's disease: a double-blind, double-dummy, randomised controlled trial. Lancet Neurol 2007; 6:513.
  32. Frankel JP, Lees AJ, Kempster PA, Stern GM. Subcutaneous apomorphine in the treatment of Parkinson's disease. J Neurol Neurosurg Psychiatry 1990; 53:96.
  33. Dewey RB Jr, Hutton JT, LeWitt PA, Factor SA. A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events. Arch Neurol 2001; 58:1385.
  34. Deleu D, Hanssens Y, Northway MG. Subcutaneous apomorphine : an evidence-based review of its use in Parkinson's disease. Drugs Aging 2004; 21:687.
  35. Watkins P. COMT inhibitors and liver toxicity. Neurology 2000; 55:S51.
  36. Rascol O, Brooks DJ, Melamed E, et al. 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 2005; 365:947.
  37. Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005; 62:241.
  38. Schapira AH, Fox SH, Hauser RA, et al. Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. JAMA Neurol 2017; 74:216.
  39. Borgohain R, Szasz J, Stanzione P, et al. Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson's disease. Mov Disord 2014; 29:1273.
  40. Borgohain R, Szasz J, Stanzione P, et al. Randomized trial of safinamide add-on to levodopa in Parkinson's disease with motor fluctuations. Mov Disord 2014; 29:229.
  41. Golbe LI, Lieberman AN, Muenter MD, et al. Deprenyl in the treatment of symptom fluctuations in advanced Parkinson's disease. Clin Neuropharmacol 1988; 11:45.
  42. Waters CH, Sethi KD, Hauser RA, et al. Zydis selegiline reduces off time in Parkinson's disease patients with motor fluctuations: a 3-month, randomized, placebo-controlled study. Mov Disord 2004; 19:426.
  43. Pierantozzi M, Pietroiusti A, Galante A, et al. Helicobacter pylori-induced reduction of acute levodopa absorption in Parkinson's disease patients. Ann Neurol 2001; 50:686.
  44. Pierantozzi M, Pietroiusti A, Brusa L, et al. Helicobacter pylori eradication and l-dopa absorption in patients with PD and motor fluctuations. Neurology 2006; 66:1824.
  45. Rees K, Stowe R, Patel S, et al. Helicobacter pylori eradication for Parkinson's disease. Cochrane Database Syst Rev 2011; :CD008453.
  46. Nutt JG, Woodward WR, Hammerstad JP, et al. The "on-off" phenomenon in Parkinson's disease. Relation to levodopa absorption and transport. N Engl J Med 1984; 310:483.
  47. Karstaedt PJ, Pincus JH. Protein redistribution diet remains effective in patients with fluctuating parkinsonism. Arch Neurol 1992; 49:149.
  48. Riley D, Lang AE. Practical application of a low-protein diet for Parkinson's disease. Neurology 1988; 38:1026.
  49. Cereda E, Barichella M, Pedrolli C, Pezzoli G. Low-protein and protein-redistribution diets for Parkinson's disease patients with motor fluctuations: a systematic review. Mov Disord 2010; 25:2021.
  50. Nonnekes J, Snijders AH, Nutt JG, et al. Freezing of gait: a practical approach to management. Lancet Neurol 2015; 14:768.
  51. Donovan S, Lim C, Diaz N, et al. Laserlight cues for gait freezing in Parkinson's disease: an open-label study. Parkinsonism Relat Disord 2011; 17:240.
  52. Espay AJ, Dwivedi AK, Payne M, et al. Methylphenidate for gait impairment in Parkinson disease: a randomized clinical trial. Neurology 2011; 76:1256.
  53. Moreau C, Delval A, Defebvre L, et al. Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial. Lancet Neurol 2012; 11:589.
  54. Moro E, Hamani C, Poon YY, et al. Unilateral pedunculopontine stimulation improves falls in Parkinson's disease. Brain 2010; 133:215.
  55. Ferraye MU, Debû B, Fraix V, et al. Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease. Brain 2010; 133:205.
  56. Thevathasan W, Cole MH, Graepel CL, et al. A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation. Brain 2012; 135:1446.
  57. Merims D, Djaldetti R, Melamed E. Waiting for ON: a major problem in patients with Parkinson disease and ON/OFF motor fluctuations. Clin Neuropharmacol 2003; 26:196.
  58. Soykan I, Sarosiek I, Shifflett J, et al. Effect of chronic oral domperidone therapy on gastrointestinal symptoms and gastric emptying in patients with Parkinson's disease. Mov Disord 1997; 12:952.
  59. Jost WH. Gastrointestinal motility problems in patients with Parkinson's disease. Effects of antiparkinsonian treatment and guidelines for management. Drugs Aging 1997; 10:249.
  60. Doggrell SA, Hancox JC. Cardiac safety concerns for domperidone, an antiemetic and prokinetic, and galactogogue medicine. Expert Opin Drug Saf 2014; 13:131.
  61. Leelakanok N, Holcombe A, Schweizer ML. Domperidone and Risk of Ventricular Arrhythmia and Cardiac Death: A Systematic Review and Meta-analysis. Clin Drug Investig 2016; 36:97.
  62. Trenkwalder C, Chaudhuri KR, García Ruiz PJ, et al. Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson's disease--Clinical practice recommendations. Parkinsonism Relat Disord 2015; 21:1023.
  63. Onofrj M, Thomas A. Acute akinesia in Parkinson disease. Neurology 2005; 64:1162.
  64. Hung SW, Adeli GM, Arenovich T, et al. Patient perception of dyskinesia in Parkinson's disease. J Neurol Neurosurg Psychiatry 2010; 81:1112.
  65. Luginger E, Wenning GK, Bösch S, Poewe W. Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson's disease. Mov Disord 2000; 15:873.
  66. Snow BJ, Macdonald L, Mcauley D, Wallis W. The effect of amantadine on levodopa-induced dyskinesias in Parkinson's disease: a double-blind, placebo-controlled study. Clin Neuropharmacol 2000; 23:82.
  67. Thomas A, Iacono D, Luciano AL, et al. Duration of amantadine benefit on dyskinesia of severe Parkinson's disease. J Neurol Neurosurg Psychiatry 2004; 75:141.
  68. Metman LV, Del Dotto P, LePoole K, et al. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol 1999; 56:1383.
  69. Wolf E, Seppi K, Katzenschlager R, et al. Long-term antidyskinetic efficacy of amantadine in Parkinson's disease. Mov Disord 2010; 25:1357.
  70. Pahwa R, Tanner CM, Hauser RA, 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; 74:941.
  71. Wagle Shukla A. Extended-Release Amantadine-A Smart Pill for Treatment of Levodopa-Induced Dyskinesia but Does the Evidence Justify the Cost? JAMA Neurol 2017; 74:904.
  72. Durif F, Vidailhet M, Assal F, et al. Low-dose clozapine improves dyskinesias in Parkinson's disease. Neurology 1997; 48:658.
  73. Bennett JP Jr, Landow ER, Schuh LA. Suppression of dyskinesias in advanced Parkinson's disease. II. Increasing daily clozapine doses suppress dyskinesias and improve parkinsonism symptoms. Neurology 1993; 43:1551.
  74. Durif F, Debilly B, Galitzky M, et al. Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled study. Neurology 2004; 62:381.
  75. Fox SH, Katzenschlager R, Lim SY, et al. The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the motor symptoms of Parkinson's disease. Mov Disord 2011; 26 Suppl 3:S2.
  76. Williams DR, Evans AH, Fung VSC, et al. Practical approaches to commencing device-assisted therapies for Parkinson disease in Australia. Intern Med J 2017; 47:1107.