Drugs & Aging

, Volume 22, Issue 9, pp 731–740 | Cite as

Alternatives to Levodopa in the Initial Treatment of Early Parkinson’s Disease

  • Andrew LeesEmail author
Review Article


Parkinson’s disease (PD) is primarily a disease of elderly patients. This article reviews current knowledge and recent developments relating to drugs that can be used as alternatives to levodopa as initial treatment of PD.

Synthetic orally acting dopamine agonists have found increasing favour as an option for early PD in relatively young patients. This strategy is based on evidence that this approach may delay the onset of motor fluctuations, at least during the first 5 years of treatment. Subcutaneous apomorphine infusions may attenuate motor fluctuations in late-stage disease, and transdermal rotigotine, a dopamine agonist in development, has also been shown to be efficacious. The greater proclivity for dopamine agonists to cause psychotoxicity has, however, limited their routine use in the elderly.

Selective monoamine oxidase type B (MAO-B) inhibitors, used as monotherapy, delay the need for the introduction of levodopa by about 9 months. These agents appear to be less efficacious than dopamine agonists but are better tolerated. Concern has been expressed about the potential of the MAO-B inhibitor selegiline (deprenyl) to induce cardiovascular adverse effects (orthostatic hypotension), either directly or through its amphetamine catabolites. Rasagiline is a new MAO-B inhibitor that is not broken down to amphetamine derivatives and is indicated as both monotherapy in early PD and as adjunctive therapy in PD patients with motor fluctuations.

Two older classes of agents have undergone a resurgence of interest in recent years. Amantadine, which enhances dopaminergic transmission and has antiglutamate activity, is occasionally used as monotherapy but has recently been widely used as an antidyskinetic agent in late-stage PD. Anticholinergic drugs, such as benztropine (benzatropine) and orphenadrine also provide control of symptoms when used as monotherapy, but their psychotoxic, cognitive and autonomic adverse events make them inappropriate for the treatment of the elderly.

Effective therapy in PD should prevent disease progression and abolish motor and cognitive handicap. Currently, none of the existing drugs meets all these needs.


Levodopa Dopamine Agonist Amantadine Selegiline Pramipexole 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Dr Lees has sat on the Data Safety Monitoring Board for rasagiline trials for Teva, and he has received honoraria from GlaxoSmithKline Alliance, Orion, Roche, Novartis, Boehringer-Ingelheim.


  1. 1.
    McDonald WM, Richard IH, DeLong MR. Prevalence, etiology, and treatment of depression in Parkinson’s disease. Biol Psychiatry 2003; 54: 363–75PubMedCrossRefGoogle Scholar
  2. 2.
    Abbott RD, Ross GW, White LR, et al. Environmental, lifestyle, and physical precursors of clinical Parkinson’s disease: recent findings from the Honolulu-Asia Aging Study. J Neurol 2003; 250Suppl. 3: III30–9PubMedGoogle Scholar
  3. 3.
    Guttman M, Kish SJ, Furukawa Y. Current concepts in the diagnosis and management of Parkinson’s disease [published erratum appears in CMAJ 2003; 168: 544]. CMAJ 2003; 168: 293–301PubMedGoogle Scholar
  4. 4.
    Strickland D, Bertoni JM. Parkinson’s prevalence estimated by a state registry. Mov Disord 2004; 19: 318–23PubMedCrossRefGoogle Scholar
  5. 5.
    Le WD, Jankovic J. Are dopamine receptor agonists neuroprotective in Parkinson’s disease? Drugs Aging 2001; 18: 389–96PubMedCrossRefGoogle Scholar
  6. 6.
    Olanow CW. The scientific basis for the current treatment of Parkinson’s disease. Annu Rev Med 2004; 55: 41–60PubMedCrossRefGoogle Scholar
  7. 7.
    Rascol O, Payoux P, Ory F, et al. Limitations of current Parkinson’s disease therapy. Ann Neurol 2003; 53Suppl. 3: S3–12PubMedCrossRefGoogle Scholar
  8. 8.
    LeWitt PA, Nyholm D. New developments in levodopa therapy. Neurology 2004; 62: S9–16PubMedCrossRefGoogle Scholar
  9. 9.
    Olanow CW, Jankovic J. Neuroprotective therapy in Parkinson’s disease and motor complications: a search for a pathogenesis-targeted, disease-modifying strategy. Mov Disord 2005; 20Suppl. 11: S3–10PubMedCrossRefGoogle Scholar
  10. 10.
    Deleu D, Northway MG, Hanssens Y. Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson’s disease. Clin Pharmacokinet 2002; 41: 261–309PubMedCrossRefGoogle Scholar
  11. 11.
    Movement Disorders Society Evidence-Based Review. Management of Parkinson’s disease: an evidence-based review. Mov Disord 2002; 17: S1–S166Google Scholar
  12. 12.
    Chase TN. Levodopa therapy: consequences of the nonphysiologic replacement of dopamine. Neurology 1998; 50: S17–25PubMedCrossRefGoogle Scholar
  13. 13.
    Pfeiffer RF. Potential of transdermal drug delivery in Parkinson’s disease. Drugs Aging 2002; 19: 561–70PubMedCrossRefGoogle Scholar
  14. 14.
    Holloway RG, Shoulson I, Fahn S, et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial [published erratum appears in Arch Neurol. 2005; 62: 430]. Arch Neurol 2004; 61: 1044–53PubMedCrossRefGoogle Scholar
  15. 15.
    Romrell J, Fernandez HH, Okun MS. Rationale for current therapies in Parkinson’s disease. Expert Opin Pharmacother 2003; 4: 1747–61PubMedCrossRefGoogle Scholar
  16. 16.
    Rascol O, Goetz C, Koller W, et al. Treatment interventions for Parkinson’s disease: an evidence based assessment. Lancet 2002; 359: 1589–98PubMedCrossRefGoogle Scholar
  17. 17.
    Chan DK. The art of treating Parkinson disease in the older patient. Aust Fam Physician 2003; 32: 927–31PubMedGoogle Scholar
  18. 18.
    MacMahon DG. The initial drug treatment of older patients with Parkinson’s disease: consider an agonist, but don’t demonise dopa. Age Ageing 2003; 32: 244–5PubMedCrossRefGoogle Scholar
  19. 19.
    Hristova AH, Koller WC. Early Parkinson’s disease: what is the best approach to treatment. Drugs Aging 2000; 17: 165–81PubMedCrossRefGoogle Scholar
  20. 20.
    Inzelberg R, Schechtman E, Nisipeanu P. Cabergoline, pramipexole and ropinirole used as monotherapy in early Parkinson’s disease: an evidence-based comparison. Drugs Aging 2003; 20: 847–55PubMedCrossRefGoogle Scholar
  21. 21.
    Navan P, Findley LJ, Jeffs JA, et al. Randomized, double-blind, 3-month parallel study of the effects of pramipexole, pergolide, and placebo on Parkinsonian tremor. Mov Disord 2003; 18: 1324–31PubMedCrossRefGoogle Scholar
  22. 22.
    Manson AJ, Turner K, Lees AJ. Apomorphine monotherapy in the treatment of refractory motor complications of Parkinson’s disease: long-term follow-up study of 64 patients. Mov Disord 2002; 17: 1235–41PubMedCrossRefGoogle Scholar
  23. 23.
    Watts RL, Wendt J, Nausieda PL, et al. Efficacy, safety, and tolerability of the rotigotine transdermal patch in patients with early-stage, idiopathic Parkinson’s disease: a multicenter, multinational, randomized, double-blind, placebo-controlled trial [abstract]. Mov Disord 2004; 19: 258Google Scholar
  24. 24.
    Bhatia K, Brooks DJ, Burn DJ, et al. Updated guidelines for the management of Parkinson’s disease. Hosp Med 2001; 62: 456–70PubMedGoogle Scholar
  25. 25.
    Agarwal P, Fahn S, Frucht SJ. Diagnosis and management of pergolide-induced fibrosis. Mov Disord 2004; 19: 699–704PubMedCrossRefGoogle Scholar
  26. 26.
    Van Camp G, Flamez A, Cosyns B, et al. Treatment of Parkinson’s disease with pergolide and relation to restrictive valvular heart disease. Lancet 2004; 363: 1179–83PubMedCrossRefGoogle Scholar
  27. 27.
    Rascol O, Pathak A, Bagheri H, et al. New concerns about old drugs: valvular heart disease on ergot derivative dopamine agonists as an exemplary situation of pharmacovigilance. Mov Disord 2004; 19: 611–3PubMedCrossRefGoogle Scholar
  28. 28.
    Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson’s disease with ropinirole versus levodopa: the REAL-PET study. Ann Neurol 2003; 54: 93–101PubMedCrossRefGoogle Scholar
  29. 29.
    Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. JAMA 2000; 284: 1931–8CrossRefGoogle Scholar
  30. 30.
    Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002; 287: 1653–61CrossRefGoogle Scholar
  31. 31.
    Lees AJ, Katzenschlager R, Head J, et al. Ten-year follow-up of three different initial treatments in de-novo PD: a randomized trial. Neurology 2001; 57: 1687–94PubMedCrossRefGoogle Scholar
  32. 32.
    Yamada M, Yasuhara H. Clinical pharmacology of MAO inhibitors: safety and future. Neurotoxicology 2004; 25: 215–21PubMedCrossRefGoogle Scholar
  33. 33.
    Stocchi F, Olanow CW. Neuroprotection in Parkinson’s disease: clinical trials. Ann Neurol 2003; 53Suppl. 3: S87–97PubMedCrossRefGoogle Scholar
  34. 34.
    Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1989; 321: 1364–71CrossRefGoogle Scholar
  35. 35.
    Myllyla VV, Sotaniemi KA, Vuorinen JA, et al. Selegiline as initial treatment in de novo parkinsonian patients. Neurology 1992; 42: 339–43PubMedCrossRefGoogle Scholar
  36. 36.
    Palhagen S, Heinonen EH, Hagglund J, et al. Selegiline delays the onset of disability in de novo parkinsonian patients: Swedish Parkinson Study Group. Neurology 1998; 51: 520–5PubMedCrossRefGoogle Scholar
  37. 37.
    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: 426–32PubMedCrossRefGoogle Scholar
  38. 38.
    Montastruc JL, Chaumerliac C, Desboeuf K, et al. Adverse drug reactions to selegiline: a review of the French pharmacovigilance database. Clin Neuropharmacol 2000; 23: 271–5PubMedCrossRefGoogle Scholar
  39. 39.
    Churchyard A, Mathias CJ, Boonkongchuen P, et al. Autonomic effects of selegiline: possible cardiovascular toxicity in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997; 63: 228–34PubMedCrossRefGoogle Scholar
  40. 40.
    Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP patients requiring levodopa: Parkinson Study Group. Ann Neurol 1996; 39: 37–45Google Scholar
  41. 41.
    Lees AJ. Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early, mild Parkinson’s disease: Parkinson’s Disease Research Group of the United Kingdom. BMJ 1995; 311: 1602–7PubMedCrossRefGoogle Scholar
  42. 42.
    Ives N, Stowe R, Marro J, et al. Monoamine oxidase type B inhibitors in early Parkinson’s disease: meta-analysis of 17 randomised trials involving 3525 patients. BMJ 2004; 329: 593–6PubMedCrossRefGoogle Scholar
  43. 43.
    Ben-Shlomo Y, Bhatia K. Using monoamine oxidase type B inhibitors in Parkinson’s disease. BMJ 2004; 329: 581–2PubMedCrossRefGoogle Scholar
  44. 44.
    Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson’s disease (2001): treatment guidelines. Neurology 2001; 56: S1–S88PubMedCrossRefGoogle Scholar
  45. 45.
    Clarke A, Johnson ES, Mallard N, et al. A new low-dose formulation of selegiline: clinical efficacy, patient preference and selectivity for MAO-B inhibition. J Neural Transm 2003; 110: 1257–71PubMedCrossRefGoogle Scholar
  46. 46.
    Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004; 61: 561–6CrossRefGoogle Scholar
  47. 47.
    Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol 2002; 59: 1937–43CrossRefGoogle Scholar
  48. 48.
    Parkinson Study Group, Stern M. A controlled trial of rasagiline in Parkinson’s disease patients with levodopa-related motor fluctuations (PRESTO Study) [abstract]. Ann Neurol 2003; 54: S27Google Scholar
  49. 49.
    Rascol O, Brooks D, Melamed E, et al. A comparative randomised study of rasagiline versus placebo or entacapone as adjunct to levodopa in Parkinson’s disease patients with motor fluctuations (the LARGO Study) [abstract]. Neurology 2004; 62: 346Google Scholar
  50. 50.
    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: 241–8CrossRefGoogle Scholar
  51. 51.
    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: 947–54PubMedCrossRefGoogle Scholar
  52. 52.
    Am OB, Amit T, Youdim MB. Contrasting neuroprotective and neurotoxic actions of respective metabolites of anti-Parkinson drugs rasagiline and selegiline. Neurosci Lett 2004; 355: 169–72PubMedCrossRefGoogle Scholar
  53. 53.
    Maruyama W, Takahashi T, Youdim M, et al. The anti-Parkinson drug, rasagiline, prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells. J Neural Transm 2002; 109: 467–81PubMedCrossRefGoogle Scholar
  54. 54.
    Effect of lazabemide on the progression of disability in early Parkinson’s disease: the Parkinson Study Group. Ann Neurol 1996; 40: 99–107Google Scholar
  55. 55.
    Safinamide: FCE 26743, NW 1015, PNU 151774, PNU 151774E. Drugs R D 2004; 5: 355–8Google Scholar
  56. 56.
    Klivenyi P, Ferrante RJ, Gardian G, et al. Increased survival and neuroprotective effects of BN82451 in a transgenic mouse model of Huntington’s disease [published erratum appears in J Neurochem 2003; 87: 272]. J Neurochem 2003; 86: 267–72PubMedCrossRefGoogle Scholar
  57. 57.
    Lees AJ. Drugs for Parkinson’s disease. J Neurol Neurosurg Psychiatry 2002; 73: 607–10PubMedCrossRefGoogle Scholar
  58. 58.
    Uitti RJ, Rajput AH, Ahlskog JE, et al. Amantadine treatment is an independent predictor of improved survival in Parkinson’s disease. Neurology 1996; 46: 1551–6PubMedCrossRefGoogle Scholar
  59. 59.
    Katzenschlager R, Sampaio C, Costa J, et al. Anticholinergics for symptomatic management of Parkinson’s disease. Cochrane Database Syst Rev 2003; (2): CD003735Google Scholar
  60. 60.
    Emre M. Dementia in Parkinson’s disease: cause and treatment. Curr Opin Neurol 2004; 17: 399–404PubMedCrossRefGoogle Scholar
  61. 61.
    Hughes AJ, Daniel SE, Blankson S, et al. A clinicopathologic study of 100 cases of Parkinson’s disease. Arch Neurol 1993; 50: 140–8PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Reta Lila Weston Institute of Neurological SciencesUniversity College LondonLondonUK

Personalised recommendations