Journal of Neural Transmission

, Volume 125, Issue 8, pp 1131–1135 | Cite as

Apomorphine and levodopa infusion for motor fluctuations and dyskinesia in advanced Parkinson disease

  • Angelo AntoniniEmail author
  • Bianca Nitu
Neurology and Preclinical Neurological Studies - Review Article


Development of motor fluctuations and dyskinesia characterizes the transition from early to advanced Parkinson disease stage. Current therapeutic strategies to manage motor complications aim at increasing the number of levodopa administrations and extending its benefit by the association of enzyme blockers and dopamine agonists. However, as disease progresses, mobility becomes progressively dependent on levodopa absorption and its plasma bioavailability, resulting in loss of independence, worse quality of life and increased caregiver burden. If patients continue to experience off-time with functional impact on activities of daily living after best medication adjustments, implementation of infusion with apomorphine or levodopa, and surgical therapies should be considered. Presence of troublesome dyskinesia would also favor the choice of an advanced treatment. Compared with pulsatile oral therapy, both apomorphine and levodopa infusion determine more continuous striatal dopamine receptors stimulation than oral levodopa resulting in significant reduction of off-time and dyskinesia, particularly peak-dose, although not in their complete resolution. This observation proves that abnormal synaptic plasticity and connectivity changes cannot be reversed once they are established. Early implementation of these therapeutic strategies ideally would target patients as soon as motor complications begin rather than at late stage of advanced Parkinson’s disease (PD) before dyskinesia have manifested. Preliminary evidence from early deep brain stimulation in patients with short disease duration and modest motor complications suggests that this approach can positively impact quality of life. It is conceivable that changing our PD treatment algorithm and implementing device-aided therapies at the beginning of the advanced phase before dyskinesia has established, will provide more stable motor conditions and longer functional autonomy.


Apomorphine Levodopa infusion gel Duodopa Dyskinesia Motor complications Wearing-off 


Compliance with ethical standards

Conflict of interest

Authors declare no competing interest.


  1. Antonini A, Tolosa E (2009) Apomorphine and levodopa infusion therapies for advanced Parkinson’s disease: selection criteria and patient management. Expert Rev Neurother 9:859–867CrossRefPubMedGoogle Scholar
  2. Antonini A, Chaudhuri KR, Martinez-Martin P, Odin P (2010) Oral and infusion levodopa-based strategies for managing motor complications in patients with Parkinson’s disease. CNS Drugs 24:119–129CrossRefPubMedGoogle Scholar
  3. Antonini A, Isaias IU, Rodolfi G et al (2011) A 5-year prospective assessment of advanced Parkinson disease patients treated with subcutaneous apomorphine infusion or deep brain stimulation. J Neurol 258:579–585CrossRefPubMedGoogle Scholar
  4. Antonini A, Odin P, Lopiano L et al (2013) Effect and safety of duodenal levodopa infusion in advanced Parkinson’s disease: a retrospective multicenter outcome assessment in patient routine care. J Neural Transm 120:1553–1558CrossRefPubMedGoogle Scholar
  5. Antonini A, Fung VS, Boyd JT et al (2016) Effect of levodopa-carbidopa intestinal gel on dyskinesia in advanced Parkinson’s disease patients. Mov Disord 31:530–537CrossRefPubMedPubMedCentralGoogle Scholar
  6. Antonini A, Poewe W, Chaudhuri KR, GLORIA Study Co-investigators et al (2017) Levodopa-carbidopa intestinal gel in advanced Parkinson’s: final results of the GLORIA registry. Parkinsonism Relat Disord 45:13–20CrossRefPubMedGoogle Scholar
  7. Antonini A, Moro E, Godeiro C, Reichmann H (2018a) Medical and surgical management of advanced Parkinson’s disease. Mov Disord. CrossRefPubMedGoogle Scholar
  8. Antonini A, Robieson WZ, Bergmann L, Yegin A, Poewe W (2018b) Age/disease duration influence on activities of daily living and quality of life after levodopa-carbidopa intestinal gel in Parkinson’s disease. Neurodegener Dis Manag 8:161–170CrossRefPubMedGoogle Scholar
  9. Bellucci A, Antonini A, Pizzi M, Spano P (2017) The end is the beginning: Parkinson’s disease in the light of brain imaging. Front Aging Neurosci 9:330. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bezard E (2013) Experimental reappraisal of continuous dopaminergic stimulation against l-dopa-induced dyskinesia. Mov Disord 28:1021–1022CrossRefPubMedGoogle Scholar
  11. Bjornestad A, Forsaa EB, Pedersen KF, Tysnes OB, Larsen JP, Alves G (2016) Risk and course of major complications in a population-based incident Parkinson’s disease cohort. Park Relat Disord 22:48–53CrossRefGoogle Scholar
  12. Borgemeester RW, Drent M, van Laar T (2016) Motor and non-motor outcomes of continuous apomorphine infusion in 125 Parkinson’s disease patients. Park Relat Disord 23:17–22CrossRefGoogle Scholar
  13. Cabrera LY, Goudreau J, Sidiropoulos C (2018) Critical appraisal of the recent US FDA approval for earlier DBS intervention. Neurology. CrossRefPubMedGoogle Scholar
  14. Calabresi P, Di Filippo M, Ghiglieri V, Tambasco N, Picconi B (2010) Levodopa-induced dyskinesias in patients with Parkinson’s disease: filling the bench-to-bedside gap. Lancet Neurol 9(11):1106–1117CrossRefPubMedGoogle Scholar
  15. Carta M, Bezard E (2011) Contribution of pre-synaptic mechanisms to l-DOPA-induced dyskinesia. Neuroscience 198:245–251CrossRefPubMedGoogle Scholar
  16. Cenci MA, Crossman AR (2018) Animal models of l-dopa-induced dyskinesia in Parkinson’s disease. Mov Disord. PubMedCrossRefGoogle Scholar
  17. Coelho M, Ferreira JJ (2012) Late-stage Parkinson disease. Nat Rev Neurol 8:435–442CrossRefPubMedGoogle Scholar
  18. Dafsari HS, Reker P, Silverdale M et al (2017) Subthalamic stimulation improves quality of life of patients aged 61 years or older with short duration of Parkinson’s disease. Neuromodulation. PubMedCrossRefGoogle Scholar
  19. Drapier S, Eusebio A, Degos B et al (2016) Quality of life in Parkinson’s disease improved by apomorphine pump: the OPTIPUMP cohort study. J Neurol 263:1111–1119CrossRefPubMedGoogle Scholar
  20. Elkurd MT, Bahroo LB, Pahwa R (2018) The role of extended-release amantadine for the treatment of dyskinesia in Parkinson’s disease patients. Neurodegener Dis ManagGoogle Scholar
  21. Fabbri M, Coelho M, Guedes LC et al (2017) Response of non-motor symptoms to levodopa in late-stage Parkinson’s disease: results of a levodopa challenge test. Parkinsonism Relat Disord 39:37–43CrossRefPubMedGoogle Scholar
  22. Fahn S, Oakes D, Shdoulson I et al (2004) Levodopa and the progression of Parkinson’s disease. N Engl J Med 351:2498–2508CrossRefPubMedGoogle Scholar
  23. Fox SH, Katzenschlager R, Lim SY et al (2011) The movement disorder society evidence-based medicine review update: treatments for the motor symptoms of Parkinson’s disease. Mov Disord 26(Suppl 3):S2–S41CrossRefPubMedGoogle Scholar
  24. Hadj Tahar A, Gregoire L, Bangassoro E, Bedard PJ (2000) Sustained cabergoline treatment reverses levodopa-induced dyskinesias in parkinsonian monkeys. Clin Neuropharmacol 23:195–202CrossRefPubMedGoogle Scholar
  25. Jenner P, Katzenschlager R (2016a) Apomorphine—pharmacological properties and clinical trials in Parkinson’s disease. Parkinsonism Relat Disord 33(Suppl 1):S13–S21CrossRefPubMedGoogle Scholar
  26. Jenner P, Katzenschlager R (2016b) Apomorphine—pharmacological properties and clinical trials in Parkinson’s disease. Park Relat Disord 33(Suppl 1):S13–S21CrossRefGoogle Scholar
  27. Katzenschlager R, Hughes A, Evans A et al (2005) Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson’s disease: a prospective study using single-dose challenges. Mov Disord 20:151–157CrossRefPubMedGoogle Scholar
  28. Katzenschlager R, Poewe W, Rascol O et al (2018) Double-blind, randomised, placebo-controlled, phase III study (Toledo) to evaluate the efficacy of apomorphine subcutaneous infusion in reducing ‘off’ time in Parkinson’s disease patients with motor fluctuations not well controlled on optimised medical treatment. Lancet Neurol (in press) Google Scholar
  29. Lang AE, Rodriguez RL, Boyd JT et al (2016) Integrated safety of levodopa-carbidopa intestinal gel from prospective clinical trials. Mov Disord 31:538–546CrossRefPubMedGoogle Scholar
  30. Maratos EC, Jackson MJ, Pearce RK, Cannizzaro C, Jenner P (2003) Both short- and long-acting D-1/D-2 dopamine agonists induce less dyskinesia than l-DOPA in the MPTP-lesioned common marmoset (Marmoset/Callithrix jacchus). Exp Neurol 179:90–102CrossRefPubMedGoogle Scholar
  31. Martinez-Martin P, Reddy P, Katzenschlager R et al (2015) EuroInf: a multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson’s disease. Mov Disord 30:510–516CrossRefPubMedGoogle Scholar
  32. Odin P, Ray Chaudhuri K, Slevin JT, National Steering Committees et al (2015) 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 21:1133–1144CrossRefPubMedGoogle Scholar
  33. Olanow CW, Kieburtz K, Odin P et al (2014) Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol 13:141–149CrossRefPubMedGoogle Scholar
  34. Pilleri M, Antonini A (2015) Therapeutic strategies to prevent and manage dyskinesias in Parkinson’s disease. Expert Opin Drug Saf 14:281–294CrossRefPubMedGoogle Scholar
  35. Porras G, De Deurwaerdere P, Li Q, Marti M, Morgenstern R, Sohr R, Bezard E, Morari M, Meissner WG (2014) l-Dopa-induced dyskinesia: beyond an excessive dopamine tone in the striatum. Sci Rep 4:3730CrossRefPubMedPubMedCentralGoogle Scholar
  36. Schuepbach WM, Rau J, Knudsen K et al (2013) Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med 368:610–622CrossRefPubMedGoogle Scholar
  37. Sensi M, Cossu G, Mancini F et al (2017) Which patients discontinue? Issues on Levodopa/carbidopa intestinal gel treatment: Italian multicentre survey of 905 patients with long-term follow-up. Parkinsonism Relat Disord 38:90–92CrossRefPubMedGoogle Scholar
  38. Sesar Á, Fernández-Pajarín G, Ares B, Rivas MT, Castro A (2017) Continuous subcutaneous apomorphine infusion in advanced Parkinson’s disease: 10-year experience with 230 patients. J Neurol 264:946–954CrossRefPubMedGoogle Scholar
  39. Sharma JC, Ross IN, Rascol O, Brooks D (2008) Relationship between weight, levodopa and dyskinesia: the significance of levodopa dose per kilogram body weight. Eur J Neurol 15:493–496CrossRefPubMedGoogle Scholar
  40. Stocchi F, Ruggieri S, Vacca L, Olanow CW (2002) Prospective randomized trial of lisuride infusion versus oral levodopa in patients with Parkinson’s disease. Brain 125:2058–2066CrossRefPubMedGoogle Scholar
  41. Timpka J, Fox T, Fox K, Honig H, Odin P, Martinez-Martin P, Antonini A, Chaudhuri KR (2016) Improvement of dyskinesias with l-dopa infusion in advanced Parkinson’s disease. Acta Neurol Scand 133:451–458CrossRefPubMedGoogle Scholar
  42. Timpka J, Nitu B, Datieva V, Odin P, Antonini A (2017) Device-aided treatment strategies in advanced Parkinson’s disease. Int Rev Neurobiol 132:453–474CrossRefPubMedGoogle Scholar
  43. Vizcarra JA, Situ-Kcomt M, Artusi CA et al (2018) Subthalamic deep brain stimulation and levodopa in Parkinson’s disease: a meta-analysis of combined effects. J Neurol. PubMedCrossRefGoogle Scholar
  44. Wirdefeldt K, Odin P, Nyholm D (2016) Levodopa-carbidopa intestinal gel in patients with Parkinson’s disease: a systematic review. CNS Drugs 30:381–404CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeuroscienceUniversity of PaduaPaduaItaly
  2. 2.Colentina Clinical HospitalBucharestRomania

Personalised recommendations