Skip to main content
SpringerLink
Log in

Adjunctive Therapies in Parkinson’s Disease: How to Choose the Best Treatment Strategy Approach

  • Therapy in Practice
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

End-of-dose motor fluctuations are regarded as one of the core troublesome symptoms by patients with Parkinson’s disease (PD). Treatment of levodopa (l-dopa)-induced motor fluctuations is still an unmet medical need. l-dopa is the gold standard in the treatment of motor PD symptoms; notwithstanding, a wide range of adjunct therapies are currently available for the treatment of end-of-dose motor fluctuations. Additionally, device-aided therapies, such as deep brain stimulation, l-dopa-carbidopa intestinal gel infusion, and on-demand injection or continuous apomorphine infusion, may be considered when oral treatments are not sufficient to control motor fluctuations. In spite of the several evidence-based reviews and guidelines available, there is no agreement on which add-on therapy should be started first or its optimal timing. Equally challenging is the choice and timing between device-aided therapies. Herein, we propose a general overview of oral and device-aided treatments for PD patients with end-of-dose motor fluctuations, offering two possible algorithms that can guide clinicians during the therapeutic decision process.

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
Fig. 3

Similar content being viewed by others

References

  1. Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007;68(5):384–6.

    Article  CAS  Google Scholar 

  2. Aquino CC, Fox SH. Clinical spectrum of levodopa-induced complications. Mov Disord. 2015;30(1):80–9.

    Article  CAS  Google Scholar 

  3. Olanow CW, Stern MB, Sethi K. The scientific and clinical basis for the treatment of Parkinson disease (2009). Neurology. 2009;72(21 Suppl 4):S1–136.

    Article  Google Scholar 

  4. Warren Olanow C, Kieburtz K, Rascol O, Poewe W, Schapira AH, Emre M, et al. Factors predictive of the development of Levodopa-induced dyskinesia and wearing-off in Parkinson’s disease. Mov Disord. 2013;28(8):1064–71.

    Article  CAS  Google Scholar 

  5. Stocchi F. The levodopa wearing-off phenomenon in Parkinson’s disease: pharmacokinetic considerations. Expert Opin Pharmacother. 2006;7(10):1399–407.

    Article  CAS  Google Scholar 

  6. Politis M, Wu K, Molloy S, G Bain P, Chaudhuri KR, Piccini P. Parkinson’s disease symptoms: the patient’s perspective. Mov Disord. 2010;25(11):1646–51.

    Article  Google Scholar 

  7. Lieberman A. Wearing-off of levodopa of greatest concern for PD patients. Eur J Neurol. 2014;Suppl 2:190.

    Google Scholar 

  8. Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F. Impact of the motor complications of Parkinson’s disease on the quality of life. Mov Disord. 2005;20(2):224–30.

    Article  Google Scholar 

  9. Nutt JG. Pharmacokinetics and pharmacodynamics of levodopa. Mov Disord. 2008;23(Suppl 3):S580–4.

    Article  Google Scholar 

  10. Fox SH, Katzenschlager R, Lim SY, Barton B, de Bie RMA, Seppi K, et al. International Parkinson and movement disorder society evidence-based medicine review: update on treatments for the motor symptoms of Parkinson’s disease. Mov Disord. 2018;33(8):1248–66.

    Article  CAS  Google Scholar 

  11. Martinez-Fernandez R, Schmitt E, Martinez-Martin P, Krack P. The hidden sister of motor fluctuations in Parkinson’s disease: a review on nonmotor fluctuations. Mov Disord. 2016;31(8):1080–94.

    Article  CAS  Google Scholar 

  12. 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  Google Scholar 

  13. Antonini A, Moro E, Godeiro C, Reichmann H. Medical and surgical management of advanced Parkinson’s disease. Mov Disord. 2018;33(6):900–8.

    Article  Google Scholar 

  14. Ferreira JJ, Katzenschlager R, Bloem BR, Bonuccelli U, Burn D, Deuschl G, et al. Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson’s disease. Eur J Neurol. 2013;20(1):5–15.

    Article  CAS  Google Scholar 

  15. 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  Google Scholar 

  16. Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G. Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. N Engl J Med. 2007;356(1):39–46.

    Article  CAS  Google Scholar 

  17. Henriksen T. Clinical insights into use of apomorphine in Parkinson’s disease: tools for clinicians. Neurodegener Dis Manag. 2014;4(3):271–82.

    Article  Google Scholar 

  18. Isaacson S, Lew M, Ondo W, Hubble J, Clinch T, Pagan F. Apomorphine subcutaneous injection for the management of morning akinesia in parkinson’s disease. Mov Disord Clin Pract. 2017;4(1):78–83.

    Article  Google Scholar 

  19. Borkar N, Mu H, Holm R. Challenges and trends in apomorphine drug delivery systems for the treatment of Parkinson’s disease. Asian J Pharm Sci. 2017. https://doi.org/10.1016/j.ajps.2017.11.004.

    Article  Google Scholar 

  20. Hauser RA, Olanow CW, Dzyngel B, Bilbault T, Shill H, Isaacson S, et al. Sublingual apomorphine (APL-130277) for the acute conversion of OFF to ON in Parkinson’s disease. Mov Disord. 2016;31(9):1366–72.

    Article  CAS  Google Scholar 

  21. Ramot Y, Nyska A, Adar L, et al. ND0701, A novel formulation of apomorphine for subcutaneous infusion, in comparison to a commercial apomorphine formulation: 28-day pharmacokinetic study in minipigs and a phase I study in healthy volunteers to assess the safety, tolerability, pharmacokinetics and relative bioavailability. CNS Drugs. 2018;32(5):443–54.

    Article  CAS  Google Scholar 

  22. Borgohain R, Szasz J, Stanzione P, Meshram C, Bhatt M, Chirilineau D, et al. Randomized trial of safinamide add-on to levodopa in Parkinson’s disease with motor fluctuations. Mov Disord. 2014;29(2):229–37.

    Article  CAS  Google Scholar 

  23. Onofrj M, Bonanni L, Thomas A. An expert opinion on safinamide in Parkinson’s disease. Expert Opin Investig Drugs. 2008;17(7):1115–25.

    Article  CAS  Google Scholar 

  24. Murata M, Hasegawa K, Kanazawa I, Fukasaka J, Kochi K, Shimazu R. Zonisamide improves wearing-off in Parkinson’s disease: a randomized, double-blind study. Mov Disord. 2015;30(10):1343–50.

    Article  CAS  Google Scholar 

  25. Bonifati V, Meco G. New, selective catechol-O-methyltransferase inhibitors as therapeutic agents in Parkinson’s disease. Pharmacol Ther. 1999;81(1):1–36.

    Article  CAS  Google Scholar 

  26. Russ H, Muller T, Woitalla D, Rahbar A, Hahn J, Kuhn W. Detection of tolcapone in the cerebrospinal fluid of parkinsonian subjects. Naunyn-Schmiedeberg’s Arch Pharmacol. 1999;360(6):719–20.

    Article  CAS  Google Scholar 

  27. Ferreira JJ, Lees A, Rocha JF, Poewe W, Rascol O, Soares-da-Silva P. Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial. Lancet Neurol. 2015;15(2):154–65.

    Article  Google Scholar 

  28. Trenkwalder C, Chaudhuri KR, Garcia Ruiz PJ, LeWitt P, Katzenschlager R, Sixel-Doring F, et al. Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson’s disease—clinical practice recommendations. Parkinson Relat Disord. 2015;21(9):1023–30.

    Article  Google Scholar 

  29. Timpka J, Nitu B, Datieva V, Odin P, Antonini A. Device-aided treatment strategies in advanced Parkinson’s disease. Int Rev Neurobiol. 2017;132:453–74.

    Article  Google Scholar 

  30. Okun MS. Deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2012;367(16):1529–38.

    Article  CAS  Google Scholar 

  31. Alomar S, King NK, Tam J, Bari AA, Hamani C, Lozano AM. Speech and language adverse effects after thalamotomy and deep brain stimulation in patients with movement disorders: a meta-analysis. Mov Disord. 2017;32(1):53–63.

    Article  Google Scholar 

  32. 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  Google Scholar 

  33. Esselink RA, de Bie RM, de Haan RJ, Steur EN, Beute GN, Portman AT, et al. Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in Parkinson’s disease: one year follow-up of a randomised observer-blind multi centre trial. Acta Neurochir. 2006;148(12):1247–55 (discussion 55).

    Article  CAS  Google Scholar 

  34. Mestre TA, Sidiropoulos C, Hamani C, Poon YY, Lozano AM, Lang AE, et al. Long-term double-blinded unilateral pedunculopontine area stimulation in Parkinson’s disease. Mov Disord. 2016;31(10):1570–4.

    Article  Google Scholar 

  35. Stowe R, Ives N, Clarke CE, Deane K, Wheatley K, Gray R, et al. Evaluation of the efficacy and safety of adjuvant treatment to levodopa therapy in Parkinson s disease patients with motor complications. Cochrane Database Syst Rev. 2010;7:CD007166.

    Google Scholar 

  36. Cattaneo C, Sardina M, Bonizzoni E. Safinamide as add-on therapy to levodopa in mid- to late-stage Parkinson’s disease fluctuating patients: post hoc analyses of studies 016 and SETTLE. J Parkinson’s Dis. 2016;6(1):165–73.

    Article  CAS  Google Scholar 

  37. Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, et al. 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. 2014;13(2):141–9.

    Article  CAS  Google Scholar 

  38. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Botzel K, et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2006;355(9):896–908.

    Article  CAS  Google Scholar 

  39. Odekerken VJ, Boel JA, Schmand BA, de Haan RJ, Figee M, van den Munckhof P, et al. GPi vs STN deep brain stimulation for Parkinson disease: three-year follow-up. Neurology. 2016;86(8):755–61.

    Article  CAS  Google Scholar 

  40. Antonini A, Tolosa E, Mizuno Y, Yamamoto M, Poewe WH. A reassessment of risks and benefits of dopamine agonists in Parkinson’s disease. Lancet Neurol. 2009;8(10):929–37.

    Article  CAS  Google Scholar 

  41. Eggert K, Oertel WH, Lees AJ. Safety and efficacy of tolcapone in the long-term use in Parkinson disease: an observational study. Clin Neuropharmacol. 2014;37(1):1–5.

    Article  CAS  Google Scholar 

  42. Hamani C, Richter E, Schwalb JM, Lozano AM. Bilateral subthalamic nucleus stimulation for Parkinson’s disease: a systematic review of the clinical literature. Neurosurgery. 2008;62(Suppl 2):863–74.

    PubMed  Google Scholar 

  43. Pahwa R, Wilkinson SB, Overman J, Lyons KE. Bilateral subthalamic stimulation in patients with Parkinson disease: long-term follow up. J Neurosurg. 2003;99(1):71–7.

    Article  Google Scholar 

  44. Lang AE, Rodriguez RL, Boyd JT, Chouinard S, Zadikoff C, Espay AJ, et al. Integrated safety of levodopa–carbidopa intestinal gel from prospective clinical trials. Mov Disord. 2016;31(4):538–46.

    Article  CAS  Google Scholar 

  45. Mancini F, Comi C, Oggioni GD, Pacchetti C, Calandrella D, Coletti Moja M, et al. Prevalence and features of peripheral neuropathy in Parkinson’s disease patients under different therapeutic regimens. Parkinson Relat Disord. 2014;20(1):27–31.

    Article  CAS  Google Scholar 

  46. Martinez-Martin P, Reddy P, Katzenschlager R, Antonini A, Todorova A, Odin P, et al. EuroInf: a multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson’s disease. Mov Disord. 2015;30(4):510–6.

    Article  CAS  Google Scholar 

  47. Antonini A, Isaias IU, Rodolfi G, Landi A, Natuzzi F, Siri C, et al. A 5-year prospective assessment of advanced Parkinson disease patients treated with subcutaneous apomorphine infusion or deep brain stimulation. J Neurol. 2011;258(4):579–85.

    Article  CAS  Google Scholar 

  48. Volkmann J, Albanese A, Antonini A, Chaudhuri KR, Clarke CE, de Bie RM, et al. Selecting deep brain stimulation or infusion therapies in advanced Parkinson’s disease: an evidence-based review. J Neurol. 2013;260(11):2701–14.

    Article  Google Scholar 

  49. Catalan MJ, Antonini A, Calopa M, Bajenaru O, de Fabregues O, Minguez-Castellanos A, et al. Can suitable candidates for levodopa/carbidopa intestinal gel therapy be identified using current evidence? eNeurologicalSci. 2017;8:44–53.

    Article  Google Scholar 

  50. Antonini A, Stoessl AJ, Kleinman LS, Skalicky AM, Marshall TS, Sail KR, et al. Developing consensus among movement disorder specialists on clinical indicators for identification and management of advanced Parkinson’s disease: a multi-country Delphi-panel approach. Curr Med Res Opin. 2018. https://doi.org/10.1080/03007995.2018.1502165.

    Article  PubMed  Google Scholar 

  51. Defer GL, Widner H, Marie RM, Remy P, Levivier M. Core assessment program for surgical interventional therapies in Parkinson’s disease (CAPSIT-PD). Mov Disord. 1999;14(4):572–84.

    Article  CAS  Google Scholar 

  52. Liu Y, Li W, Tan C, Liu X, Wang X, Gui Y, et al. Meta-analysis comparing deep brain stimulation of the globus pallidus and subthalamic nucleus to treat advanced Parkinson disease. J Neurosurg. 2014;121(3):709–18.

    Article  Google Scholar 

  53. Follett KA, Torres-Russotto D. Deep brain stimulation of globus pallidus interna, subthalamic nucleus, and pedunculopontine nucleus for Parkinson’s disease: which target? Parkinson Relat Disord. 2012;18(Suppl 1):S165–7.

    Article  Google Scholar 

  54. Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P, et al. Pallidal versus subthalamic deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2010;362(22):2077–91.

    Article  CAS  Google Scholar 

  55. Antonini A, Nitu B. Apomorphine and levodopa infusion for motor fluctuations and dyskinesia in advanced Parkinson disease. J Neural Transm (Vienna). 2018. https://doi.org/10.1007/s00702-018-1906-0.

    Article  Google Scholar 

  56. Schuepbach WM, Rau J, Knudsen K, Volkmann J, Krack P, Timmermann L, et al. Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med. 2013;368(7):610–22.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Anne-Marie Williams for editorial assistance (English language editing and referencing).

Author information

Authors and Affiliations

  1. Instituto de Medicina Molecular, Lisbon, Portugal

    Margherita Fabbri & Joaquim J. Ferreira

  2. Department of Neuroscience “Rita Levi Montalcini”, University of Turin, Turin, Italy

    Margherita Fabbri

  3. Laboratorio de Farmacologia Clínica e Terapêutica, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal

    Mario M. Rosa & Joaquim J. Ferreira

  4. Department of Neurosciences, Serviço de Neurologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal

    Mario M. Rosa

  5. CNS, Campus Neurológico Sénior, Torres Vedras, Portugal

    Joaquim J. Ferreira

Authors
  1. Margherita Fabbri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mario M. Rosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joaquim J. Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joaquim J. Ferreira.

Ethics declarations

Funding

No specific funding was received for this work.

Conflict of interest

Dr. Margherita Fabbri reports grants from AbbVie. Prof. Mario Miguel Rosa reports no conflict of interests and no additional disclosures. Prof. Joaquim J. Ferreira reports consultancies for Ipsen, GlaxoSmithKline, Novartis, Teva, Lundbeck, Solvay, Abbott, BIAL, Merck-Serono and Merz. He has also received grants from GlaxoSmithKline, Grunenthal, Teva and Fundação MSD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fabbri, M., Rosa, M.M. & Ferreira, J.J. Adjunctive Therapies in Parkinson’s Disease: How to Choose the Best Treatment Strategy Approach. Drugs Aging 35, 1041–1054 (2018). https://doi.org/10.1007/s40266-018-0599-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40266-018-0599-2

Search

Navigation