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Amantadine Revisited: A Contender for Initial Treatment in Parkinson’s Disease?

Abstract

The best practice for the initiation of symptomatic motor treatment for Parkinson’s disease is an ongoing topic of debate. Fueled by interpretation of the results of the LEAP and MED Parkinson’s disease studies, many practitioners opt for early initiation of levodopa formulations, avoiding dopamine agonists to circumvent potential deleterious side effects, namely impulse control disorder. Compared with levodopa, monoamine oxidase inhibitors may lack necessary potency. Ignored in this academic debate is another therapeutic option for patients with Parkinson’s disease requiring treatment initiation: amantadine. Amantadine was first reported effective in the treatment of Parkinson’s disease in 1969 and several studies were published in the 1970s supporting its efficacy. Currently, amantadine is mainly utilized as an add-on therapy to mitigate levodopa-related dyskinesia and, more recently, new long-acting amantadine formulations have been developed, with new indications to treat motor fluctuations. Amantadine has not been reported to cause dyskinesia and is rarely implicated in impulse control disorder.

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References

  1. 1.

    de Bie RMA, Clarke CE, Espay AJ, Fox SH, Lang AE. Initiation of pharmacological therapy in Parkinson’s disease: when, why, and how. Lancet Neurol. 2020;19:452–61.

    Article  Google Scholar 

  2. 2.

    Fox SH, Katzenschlager R, Lim SY, Barton B, de Bie RMA, Seppi K, Coelho M, Sampaio C, Movement Disorder Society Evidence-Based Medicine Committee. International Parkinson and Movement Disorder Society evidence-based medicine review: update on treatments for the motor symptoms of Parkinson’s disease. Move Disord. 2018;33:1248–66.

    CAS  Article  Google Scholar 

  3. 3.

    Hubsher G, Haider M, Okun MS. Amantadine: the journey from fighting flu to treating Parkinson disease. Neurology. 2012;78:1096–9.

    CAS  Article  Google Scholar 

  4. 4.

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

    CAS  Article  Google Scholar 

  5. 5.

    Fahn S, Isgreen WP. Long-term evaluation of amantadine and levodopa combination in parkinsonism by double-blind crossover analyses. Neurology. 1975;25:695–700.

    CAS  Article  Google Scholar 

  6. 6.

    Aoki F, Sitar D. Clinical pharmacokinetics of amantadine hydrochloride. Clin Pharmacokinet. 1988;14:35–51.

    CAS  Article  Google Scholar 

  7. 7.

    Farnebo LO, Fuxe K, Goldstein M, Hamberger B, Ungerstedt U. Dopamine and noradrenaline releasing action of amantadine in the central and peripheral nervous system: a possible mode of action in Parkinson’s disease. Eur J Pharmacol. 1971;16:27–38.

    CAS  Article  Google Scholar 

  8. 8.

    Mizoguchi K, Yokoo H, Yoshida M, et al. Amantadine increases the extracellular dopamine levels in the striatum by re-uptake inhibition and by N-methyl-D-aspartate antagonism. Brain Res. 1994;662:255–8.

    CAS  Article  Google Scholar 

  9. 9.

    Volonté MA, Moresco RM, Messa C, et al. A PET study with [11-C]raclopride in Parkinson’s disease: preliminary results on the effect of amantadine on the dopaminergic system. Neurol Sci. 2001;22:107–8.

    Article  Google Scholar 

  10. 10.

    Takahashi T, Yamashita H, Zhang YX, Nakamura S. Inhibitory effect of MK-801 on amantadine-induced dopamine release in the rat striatum. Brain Res Bull. 1996;41:363–7. https://doi.org/10.1016/s0361-9230(96)00211-0.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Gocovri (prescribers information). gocovrihcp.com. Accessed 16 Feb 2021.

  12. 12.

    Butzer JF, Silver DE, Sans AL. Amantadine in Parkinson’s disease: a double-blind, placebo-controlled, crossover study with long-term follow-up. Neurology. 1975;25:603–6.

    CAS  Article  Google Scholar 

  13. 13.

    Parkes JD, Baxter RC, Marsden CD, Rees JE. Comparative trial of benzhexol, amantadine, and levodopa in the treatment of Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1974;37:422–6.

    CAS  Article  Google Scholar 

  14. 14.

    Cox B, Danta G, Schnieden H, Yuill GM. Interactions of L-dopa and amantadine in patients with Parkinsonism. J Neurol Neurosurg Psychiatry. 1973;36:354–61.

    CAS  Article  Google Scholar 

  15. 15.

    Mawdsley C, Williams IR, Pullar IA, Davidson DL, Kinlock NE. Treatment of parkinsonism by amantadine and levodopa. Clin Pharmacol Ther. 1972;13:575–83.

    CAS  Article  Google Scholar 

  16. 16.

    Fieschi C, Nardini M, Casacchia M, Tedone ME. Amantadine versus L-2 dopa and amantadine plus L-dopa. Lancet. 1970;2:154–5.

    CAS  Article  Google Scholar 

  17. 17.

    Parkes JD, Baxter RC, Curzon G, et al. Treatment of Parkinson’s disease with amantadine and levodopa: a one-year study. Lancet. 1971;1:1083–6.

    CAS  Article  Google Scholar 

  18. 18.

    Vale S, Espejel MA. Amantadine for dyskinesia tarda. N Engl J Med. 1971;284:673.

    CAS  PubMed  Google Scholar 

  19. 19.

    Crane G. More on amantadine for dyskinesia. N Engl J Med. 1971;285:1150–1.

    CAS  PubMed  Google Scholar 

  20. 20.

    Verhagen Metman L, Del Dotto P, van den Munckhof P, et al. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology. 1998;50:1323–6.

    CAS  Article  Google Scholar 

  21. 21.

    Verhagen Metman LV, 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;56:1383–6.

    Article  Google Scholar 

  22. 22.

    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;23:82–5.

    CAS  Article  Google Scholar 

  23. 23.

    Luginger E, Wenning GK, Bosch S, Poewe W. Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson’s disease. Mov Disord. 2000;15:873–8.

    CAS  Article  Google Scholar 

  24. 24.

    Sawada H, Oeda T, Kuno S, Nomoto M, Yamamoto K, Yamamoto M, et al. Amantadine Study Group. Amantadine for dyskinesias in Parkinson’s disease: a randomized controlled trial. PLoS ONE. 2010;5:e15298. https://doi.org/10.1371/journal.pone.0015298.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Elmer L, Juncos J, Singer C, Truong D, Criswell S, Parashos S, Felt L, et al. Pooled analyses of phase III studies of ADS-5102 (Amantadine) extended-release capsules for dyskinesia in Parkinson’s disease. CNS Drugs. 2018;32:387–98.

    CAS  Article  Google Scholar 

  26. 26.

    Osmolex (prescribers information) label. fda.gov. Accessed 16 Feb 2021.

  27. 27.

    Symmetrel (prescribers information) label. fda.gov. Accessed 16 Feb 2021.

  28. 28.

    deVries T, Dentiste A, Handiwala L, Jacobs D. Bioavailability and pharmacokinetics of once-daily amantadine extended-release tablets in healthy volunteers: results from three randomized, crossover, open-label, phase 1 studies. Neurol Ther. 2019;8:449–60.

    Article  Google Scholar 

  29. 29.

    Blanchard DL. Amantadine caused corneal edema. Cornea. 1990;9:181.

    CAS  Article  Google Scholar 

  30. 30.

    Weintraub D, Sohr M, Potenza MN, Siderowf AD, Stacy M, Voon V, et al. Amantadine use associated with impulse control disorders in Parkinson disease in cross-sectional study. Ann Neurol. 2010;68:963–8.

    Article  Google Scholar 

  31. 31.

    Garcia-Ruiz PJ, Martinez Castrillo JC, Alonso-Canovas A, Herranz Barcenas A, Vela L, Sanchez Alonso P, et al. Impulse control disorder in patients with Parkinson’s disease under dopamine agonist therapy: a multicentre study. J Neurol Neurosurg Psychiatry. 2014;85:840–4. https://doi.org/10.1136/jnnp-2013-306787.

    Article  PubMed  Google Scholar 

  32. 32.

    Weintraub D. Impulse control disorders in Parkinson’s disease: prevalence and possible risk factors. Parkinsonism Relat Disord. 2009;3:S110–3. https://doi.org/10.1016/S1353-8020(09)70794-1.

    Article  Google Scholar 

  33. 33.

    Redenšek S, Jenko Bizjan B, Trošt M, Dolžan V. Clinical and clinical-pharmacogenetic models for prediction of the most common psychiatric complications due to dopaminergic treatment in Parkinson’s disease. Int J Neuropsychopharmacol. 2020;23:496–504. https://doi.org/10.1093/ijnp/pyaa028.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord. 2001;16:448–58.

    CAS  Article  Google Scholar 

  35. 35.

    Quinn N, Critchley P, Marsden CD. Young onset Parkinson’s disease. Mov Disord. 1987;2:73–91. https://doi.org/10.1002/mds.870020201.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Ku S, Glass GA. Age of Parkinson’s disease onset as a predictor for the development of dyskinesia. Mov Disord. 2010;25:1177–82.

    Article  Google Scholar 

  37. 37.

    Brüggemann N, Klein C. Parkin type of early-onset Parkinson disease. 2001 Apr 17 [updated 2020 Apr 23]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle (WA): University of Washington; 1993-2021. https://www.ncbi.nlm.nih.gov/books/NBK1478/. Accessed 16 Feb 2021.

  38. 38.

    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;74:941–9. https://doi.org/10.1001/jamaneurol.2017.0943.

    Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    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;32:1701–9. https://doi.org/10.1002/mds.27131.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Perez-Lloret S, Rey M, Fabre N, Ory F, Spampinato U, Brefel-Courbon C, et al. Prevalence and pharmacological factors associated with impulse-control disorder symptoms in patients with Parkinson disease. Clin Neuropharmacol. 2012;35:261–5. https://doi.org/10.1097/WNF.0b013e31826e6e6d.

    Article  PubMed  Google Scholar 

  41. 41.

    Thomas A, Bonanni L, Gambi F, Di Iorio A, Onofrj M. Pathological gambling in Parkinson disease is reduced by amantadine. Ann Neurol. 2010;68:400–4. https://doi.org/10.1002/ana.22029.

    Article  PubMed  Google Scholar 

  42. 42.

    Sharma VD, Lyons KE, Pahwa R. Amantadine extended-release capsules for levodopa-induced dyskinesia in patients with Parkinson’s disease. Ther Clin Risk Manag. 2018;14:665–73. https://doi.org/10.2147/TCRM.S144481.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Constantinescu R. Update on the use of pramipexole in the treatment of Parkinson’s disease. Neuropsychiatr Dis Treat. 2008;4:337–52. https://doi.org/10.2147/ndt.s2325.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Requip (prescribers information). https://www.accessdata.fda.gov/. Accessed 16 Jul 2021.

  45. 45.

    Pollack AE, Turgeon SM, Fink JS. Apomorphine priming alters the response of striatal outflow pathways to D2 agonist stimulation in 6-hydroxydopamine-lesioned rats. Neuroscience. 1997;79:79–93. https://doi.org/10.1016/s0306-4522(96)00681-1.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Rasagiline (prescribers information). https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/201971Orig1s000lbl.pdf. Accessed 16 Jul 2021.

  47. 47.

    Xadago (prescribers information). https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207145lbl.pdf. Accessed 16 Feb 2021.

  48. 48.

    Nourianz (prescribers information). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022075Orig1s000ClinPharmR.pdf. Accessed 16 Jul 2021.

  49. 49.

    Barbosa P, Lees AJ, Magee C, Djamshidian A, Warner TT. A retrospective evaluation of the frequency of impulsive compulsive behaviors in Parkinson’s disease patients treated with continuous waking day apomorphine pumps. Mov Disord Clin Pract. 2016;4:323–8. https://doi.org/10.1002/mdc3.12416.

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Grassi G, Albani G, Terenzi F, et al. New pharmacological and neuromodulation approaches for impulsive-compulsive behaviors in Parkinson’s disease. Neurol Sci. 2021;42:2673–82. https://doi.org/10.1007/s10072-021-05237-8.

    Article  PubMed  Google Scholar 

  51. 51.

    Warren N, O’Gorman C, Lehn A, Siskind D. Dopamine dysregulation syndrome in Parkinson’s disease: a systematic review of published cases. J Neurol Neurosurg Psychiatry. 2017;88:1060–4. https://doi.org/10.1136/jnnp-2017-315985.

    Article  PubMed  Google Scholar 

  52. 52.

    Ramirez-Zamora A, Gee L, Boyd J, Biller J. Treatment of impulse control disorders in Parkinson’s disease: practical considerations and future directions. Expert Rev Neurother. 2016;16:389–99. https://doi.org/10.1586/14737175.2016.115810.3.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    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;351:2498–508.

    CAS  Article  Google Scholar 

  54. 54.

    Verschuur CVM, Suwijn SR, Boel JA, Post B, Bloem BR, van Hilten JJ, et al. Randomized delayed-start trial of levodopa in Parkinson’s disease. N Engl J Med. 2019;380:315–24. https://doi.org/10.1056/NEJMoa1809983.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    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;5:183–90. https://doi.org/10.1002/mdc3.12595.

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Hauser RA, Walsh RR, Pahwa R, Chernick D, Formella AE. Amantadine ER (Gocovri®) significantly increases ON time without any dyskinesia: pooled analyses from pivotal trials in Parkinson’s disease. Front Neurol. 2021;12:645706.

    Article  Google Scholar 

  57. 57.

    Tanner CM, Pahwa R, Hauser RA, et al. EASE LID 2: a 2-year open-label trial of Gocovri (amantadine) extended release for dyskinesia in Parkinson’s disease. J Parkinsons Dis. 2020;10:543–58.

    Article  Google Scholar 

  58. 58.

    Agbo F, Isaacson SH, Gil R, et al. Pharmacokinetics and comparative bioavailability of apomorphine sublingual film and subcutaneous apomorphine formulations in patients with parkinson’s disease and “OFF” episodes: results of a randomized, three-way crossover, open-label study. Neurol Ther. 2021. https://doi.org/10.1007/s40120-021-00251-6.

    Article  PubMed  Google Scholar 

  59. 59.

    Thijssen E, den Heijer J, Puibert D, Lei M, Hasegawa D, Keum K, Mochel K, Roset P, van Brummelen E, Naranda T, Groeneveld G (2021) Randomized, placebo-controlled study investigating the safety, pharmacokinetics and efficacy of inhaled apomorphine in Parkinson’s disease patients [abstract]. Mov Disord. 2020;35(suppl 1). https://www.mdsabstracts.org/abstract/randomized-placebo-controlled-study-investigating-the-safetypharmacokinetics-and-efficacy-of-inhaled-apomorphine-in-parkinsons-disease-patients/. Accessed 25 Sept 2021.

  60. 60.

    Shpiner DS, Bette S, Di Luca DG, Margolesky J. CVT-301 for the treatment of Parkinson’s disease. Expert Rev Neurother. 2019;19(7):603–11. https://doi.org/10.1080/14737175.2019.1621748.

    CAS  Article  PubMed  Google Scholar 

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Correspondence to Jason Margolesky.

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Sarah Marmol has no conflicts of interest to declare. Matthew Feldman has no conflicts of interest to declare. Carlos Singer has received grants from Pharma2B, Sunovion, Adamas, Revance, and Amneal, and honoraria from Abbvie and Mitsubishi. Jason Margolesky has no conflicts of interest to declare.

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SM performed the literature review, contributed significantly to the revised manuscript, and was co first author with MF. MF performed the literature review, contributed significantly to the revised manuscript, and was co first author with SM. CS conceptualized, designed, and provided revision to the manuscript. JM conceptualized, designed, and drafted the manuscript and performed the literature review. All authors approve the final version of the manuscript for submission and publication, and agree to be accountable for the work presented.

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Marmol, S., Feldman, M., Singer, C. et al. Amantadine Revisited: A Contender for Initial Treatment in Parkinson’s Disease?. CNS Drugs 35, 1141–1152 (2021). https://doi.org/10.1007/s40263-021-00862-5

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