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When Should Levodopa Therapy be Initiated in Patients with Parkinson’s Disease?

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Abstract

Levodopa is available in three forms: immediate-release, orally disintegrating and sustained-release tablets. Levodopa is metabolised in the gastrointestinal tract, kidney and liver by aromatic acid dopa decarboxylase using pyridoxine as a cofactor. Approximately 70–80% of the dose is eliminated in the urine. Central conversion of levodopa to dopamine likely occurs at surviving dopaminergic terminals and at serotonergic and adrenergic nerve terminals that contain decarboxylase. Dopamine is metabolised by catechol-O-methyltransferase and monoamine oxidase. The major metabolites of dopamine are homovanillic acid and dihydroxyphenylacetic acid.

Levodopa remains the most efficacious pharmacological treatment for the symptoms of Parkinson’s disease (PD). Results of current levodopa trials suggest that treatment with levodopa at the onset of disease provides superior motor and functional control compared with dopamine receptor agonists. Moreover, levodopa is generally better tolerated with a lower incidence of gastrointestinal and neuropsychiatric adverse effects. The debate over the role of levodopa in the treatment of PD is fuelled by the results of in vitro studies that show generation of free radicals by levodopa and its toxic effects on cell cultures. Levodopa has also consistently been shown to produce motor fluctuations (in particular dyskinesias) sooner than has been observed in PD patients, especially younger patients, given dopamine agonists initially. However, the cumulative body of knowledge thus far does not show definitive evidence that levodopa is neurotoxic to parkinsonian patients.

In older PD patients with lesser risk of motor fluctuations, levodopa may be used initially, and perhaps solely, in demented PD patients and those at higher risk of developing neuropsychiatric adverse effects. In young parkinsonian patients with mild motor dysfunction, use of levodopa may be delayed or the dosage minimised. However, because of levodopa’s superior efficacy, when a rapid and sustained symptomatic improvement is required because of significant motor disability, levodopa may be used as the first-line agent regardless of age.

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  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Ehringer H, Hornykiewicz O. Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system [in German]. Klin Wochenschr 1960; 38: 1236–9

    Article  PubMed  CAS  Google Scholar 

  2. Birkmayer W, Hornykiewicz O. The L-3,4-dioxyphenylalanine (DOPA)-effect in Parkinson-akinesia [in German]. Wien Klin Wochenschr 1961; 73: 787–8

    PubMed  CAS  Google Scholar 

  3. Barbeau A, Sourkes T, Murphy G. Les catecholamines dans la maladie de Parkinson. In: DeAjuriaguerra J, editor. Monoamines et systeme nerveux central. Paris: Masson, 1962: 925–7

    Google Scholar 

  4. Cotzias GC. L-Dopa for Parkinsonism [letter]. N Engl J Med 1968; 278(11): 630

    PubMed  CAS  Google Scholar 

  5. Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino acids and modification of parkinsonism. N Engl J Med 1967 Feb 16; 276(7): 374–9

    Article  PubMed  CAS  Google Scholar 

  6. Tolosa E, Marti MJ, Valldeoriola F, et al. History of levodopa and dopamine agonists in Parkinson’s disease treatment. Neurology 1998; 50 (6 Suppl. 6): S2–10; discussion S44-18

    Article  PubMed  CAS  Google Scholar 

  7. Cotzias GC, Papavasiliou PS, Gellene R. Modification of Parkinsonism: chronic treatment with L-dopa. N Engl J Med 1969; 2807): 337–45

    Article  PubMed  CAS  Google Scholar 

  8. Markham CH, Treciokas LJ, Diamond SG. Parkinson’s disease and levodopa: a five-year follow-up and review. West J Med 1974; 121(3): 188–206

    PubMed  CAS  Google Scholar 

  9. Nyholm D, Aquilonius SM. Levodopa infusion therapy in Parkinson disease: state of the art in 2004. Clin Neuropharmacol 2004; 27(5): 245–56

    Article  PubMed  CAS  Google Scholar 

  10. Product Information: Sinemet®, carbidopa/levodopa. Whitehouse Station (NJ): Merck and Co., 2002

  11. Bredberg E, Tedroff J, Aquilonius SM, et al. Pharmacokinetics and effects of levodopa in advanced Parkinson’s disease. Eur J Clin Pharmacol 1990; 39(4): 385–9

    Article  PubMed  CAS  Google Scholar 

  12. Okereke CS. Role of integrative pharmacokinetic and pharmacodynamic optimization strategy in the management of Parkinson’s disease patients experiencing motor fluctuations with levodopa. J Pharm Pharm Sci 2002; 5(2): 146–61

    PubMed  CAS  Google Scholar 

  13. Goldberg LI, Rajfer SI. Dopamine receptors: applications in clinical cardiology. Circulation 1985; 75: 245–8

    Article  Google Scholar 

  14. Pfeiffer R. Optimization of levodopa therapy. Neurology 1992; 42(Suppl. 1): 39–43

    PubMed  CAS  Google Scholar 

  15. Koller WC, Hubble JP. Levodopa therapy in Parkinson’s disease. Neurology 1990; 40 (10 Suppl. 3): 40–7

    PubMed  Google Scholar 

  16. Calne DB. Treatment of Parkinson’s disease. N Engl J Med 1993; 329(14): 1021–7

    Article  PubMed  CAS  Google Scholar 

  17. Capildeo R. Implications of the 5-year CR FIRST trial. Sinemet CR Five-Year International Response Fluctuation Study. Neurology 1998; 50 (6 Suppl. 6): S15–17; discussion S44-18

    Article  PubMed  CAS  Google Scholar 

  18. Kurth MC. Using liquid levodopa in the treatment of Parkinson’s disease: a practical guide. Drugs Aging 1997; 10(5): 332–40

    Article  PubMed  CAS  Google Scholar 

  19. Product Information: Parcopa™ orally disintegrating tablets, carbidopa-levodopa orally disintegrating tablets. Milwaukee (WI): Schwarz Pharma, 2003

  20. Yeh KC, August TF, Bush DF, et al. Pharmacokinetics and bioavailability of Sinemet CR: a summary of human studies. Neurology 1989; 39 (11 Suppl. 2): 25–38

    PubMed  CAS  Google Scholar 

  21. Mouradian MM, Heuser IJ, Baronti F, et al. Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson’s disease. Ann Neurol 1990; 27: 18–22

    Article  PubMed  CAS  Google Scholar 

  22. Stocchi F, Olanow C, Warren MD. Continuous dopaminergic stimulation in early and advanced Parkinson’s disease. Neurology 2004 Jan 13; 62(1) Suppl. 1: S56–63

    Article  PubMed  CAS  Google Scholar 

  23. Nyholm D, Nilsson Remahl A, Dizdar N, et al. Duodenal levodopa infusion monotherapy versus oral polypharmacy in advanced Parkinson disease. Neurology 2005; 64: 216–23

    Article  PubMed  CAS  Google Scholar 

  24. Nutt JG, Woodward WR, Beckner RM, et al. Effect of peripheral catechol-O-methyltransferase inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patient. Neurology 1994; 44(5): 913–9

    Article  PubMed  CAS  Google Scholar 

  25. Product Information: Comtan®, entacapone. East Hanover (NJ): Novartis Pharmaceutical Corporation, 2000

  26. Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Ann Neurol 1997; 42: 747–55

    Article  Google Scholar 

  27. Product Information: Stalevo™ (carbidopa, levodopa and entacapone) tablets. East Hanover (NJ): Novartis Pharmaceuticals Corporation, 2003

  28. Product Information: Comtan®, entacapone. East Hanover (NJ): Novartis Pharmaceutical Corporation, 2000

  29. Product Information: TASMAR® tablets, tolcapone tablets. Costa Mesa (CA): Valeant Pharmaceuticals, Inc., 2006

  30. Figa-Talamanca L, Gualandi C, Di Meo L, et al. Hyperthermia after discontinuance of levodopa and bromocriptine therapy: impaired dopamine receptors a possible cause. Neurology 1985; 35(2): 258–61

    Article  PubMed  CAS  Google Scholar 

  31. Friedman JH, Feinberg SS, Feldman RG. A neuroleptic malignant-like syndrome due to levodopa therapy withdrawal. JAMA 1985; 254(19): 2792–5

    Article  PubMed  CAS  Google Scholar 

  32. Sian J, Dexter DT, Lees AJ, et al. Glutathione-related enzymes in brain in Parkinson’s disease. Ann Neurol 1994; 36(3): 356–61

    Article  PubMed  CAS  Google Scholar 

  33. Jenner P. Oxidative stress in Parkinson’s disease. Ann Neurol 2003; 53Suppl. 3: S26–48

    Article  PubMed  CAS  Google Scholar 

  34. Fahn S, Cohen G. The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann Neurol 1992; 32(6): 804–12

    Article  PubMed  CAS  Google Scholar 

  35. Mena MA, Pardo B, Paino CL, et al. Levodopa toxicity in foetal rat midbrain neurones in culture: modulation by ascorbic acid. Neuroreport 1993; 4(4): 438–40

    Article  PubMed  CAS  Google Scholar 

  36. Mytilineou C, Han SK, Cohen G. Toxic and protective effects of L-dopa on mesencephalic cell cultures. J Neurochem 1993; 61(4): 1470–8

    Article  PubMed  CAS  Google Scholar 

  37. Tanaka M, Sotomatsu A, Kanai H, et al. Dopa and dopamine cause cultured neuronal death in the presence of iron. J Neurol Sci 1991; 101(2): 198–203

    Article  PubMed  CAS  Google Scholar 

  38. Steece-Collier K, Collier TJ, Sladek CD, et al. Chronic levodopa impairs morphological development of grafted embryonic dopamine neurons. Exp Neurol 1990; 110(2): 201–8

    Article  PubMed  CAS  Google Scholar 

  39. Agid Y. Levodopa: is toxicity a myth? Neurology 1998; 50(4): 858–63

    Article  PubMed  CAS  Google Scholar 

  40. Mytilineou C, Walker RH, Baptiste R, et al. Levodopa is toxic to dopamine neurons in an in vitro but not an in vivo model of oxidative stress. J Pharmacol Exp Ther 2003; 304(2): 792–800

    Article  PubMed  CAS  Google Scholar 

  41. Quinn N, Parkes D, Janota I, et al. Preservation of the substantia nigra and locus coeruleus in a patient receiving levodopa (2 kg) plus decarboxylase inhibitor over a four-year period. Mov Disord 1986; 1(1): 65–8

    Article  PubMed  CAS  Google Scholar 

  42. Rajput AH. Levodopa prolongs life expectancy and is non-toxic to substantia nigra. Parkinsonism Relat Disord 2001; 8(2): 95–100

    Article  PubMed  CAS  Google Scholar 

  43. Camp DM, Loeffler DA, LeWitt PA. L-DOPA does not enhance hydroxyl radical formation in the nigrostriatal dopamine system of rats with a unilateral 6-hydroxydopamine lesion. J Neurochem 2000; 74(3): 1229–40

    Article  PubMed  CAS  Google Scholar 

  44. Murer MG, Dziewczapolski G, Menalled LB, et al. Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions. Ann Neurol 1998; 43(5): 561–75

    Article  PubMed  CAS  Google Scholar 

  45. Datla KP, Blunt SB, Dexter DT. Chronic L-DOPA administration is not toxic to the remaining dopaminergic nigrostriatal neurons, but instead may promote their functional recovery, in rats with partial 6-OHDA or FeCl(3) nigrostriatal lesions. Mov Disord 2001; 16(3): 424–34

    Article  PubMed  CAS  Google Scholar 

  46. Han SK, Mytilineou C, Cohen G. L-DOPA up-regulates glutathione and protects mesencephalic cultures against oxidative stress. J Neurochem 1996; 66(2): 501–10

    Article  PubMed  CAS  Google Scholar 

  47. Mena MA, Davila V, Sulzer D. Neurotrophic effects of LDOPA in postnatal midbrain dopamine neuron/cortical astrocyte cocultures. J Neurochem 1997; 69(4): 1398–408

    Article  PubMed  CAS  Google Scholar 

  48. Blin J, Bonnet AM, Agid Y. Does levodopa aggravate Parkinson’s disease? Neurology 1988; 38(9): 1410–6

    Article  PubMed  CAS  Google Scholar 

  49. Scigliano G, Musicco M, Soliveri P, et al. Mortality associated with early and late levodopa therapy initiation in Parkinson’s disease. Neurology 1990; 40(2): 265–9

    Article  PubMed  CAS  Google Scholar 

  50. Lesser RP, Fahn S, Snider SR, et al. Analysis of the clinical problems in parkinsonism and the complications of long-term levodopa therapy. Neurology 1979; 29 (9 Pt 1): 1253–60

    Article  PubMed  CAS  Google Scholar 

  51. Uitti RJ, Ahlskog JE, Maraganore DM, et al. Levodopa therapy and survival in idiopathic Parkinson’s disease: Olmsted County project. Neurology 1993; 43(10): 1918–26

    Article  PubMed  CAS  Google Scholar 

  52. Markham CH, Diamond SG. Modification of Parkinson’s disease by long-term levodopa treatment. Arch Neurol 1986; 43(4): 405–7

    Article  PubMed  CAS  Google Scholar 

  53. Markham CH, Diamond SG. Long-term follow-up of early dopa treatment in Parkinson’s disease. Ann Neurol 1986; 19(4): 365–72

    Article  PubMed  CAS  Google Scholar 

  54. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002; 287(13): 1653–61

    Google Scholar 

  55. Holloway RG, Shoulson I, Fahn S, et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 2004; 61(7): 1044–53

    Article  PubMed  Google Scholar 

  56. 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(1): 93–101

    Article  PubMed  CAS  Google Scholar 

  57. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004; 351(24): 2498–508

    Article  PubMed  CAS  Google Scholar 

  58. Agid Y, Olanow CW, Mizuno Y. Levodopa: why the controversy? [letter]. Lancet 2002; 360(9332): 575

    Article  PubMed  CAS  Google Scholar 

  59. 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(9): 1687–94

    Article  PubMed  CAS  Google Scholar 

  60. Oertel WH, Wolters E, Sampaio C, et al. Pergolide versus levodopa monotherapy in early Parkinson’s disease patients: the PELMOPET study. Mov Disord 2006; 21(3): 343–53

    Article  PubMed  Google Scholar 

  61. Rascol O, Brooks DJ, Korczyn AD, et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa: 056 Study Group. N Engl J Med 2000; 342(20): 1484–91

    Article  PubMed  CAS  Google Scholar 

  62. Morrish PK. Real-PET and CONSORT. Ann Neurol 2003; 54(5): 692–3

    Article  PubMed  Google Scholar 

  63. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. JAMA 2000; 284(15): 1931–8

    Article  Google Scholar 

  64. Arnulf I, Bonnet AM, Damier P, et al. Hallucinations, REM sleep, and Parkinson’s disease: a medical hypothesis. Neurology 2000; 55(2): 281–8

    Article  PubMed  CAS  Google Scholar 

  65. Fischer P, Danielczyk W, Simanyi M, et al. Dopaminergic psychosis in advanced Parkinson’s disease. Adv Neurol 1990; 53: 391–7

    PubMed  CAS  Google Scholar 

  66. Giladi N, Treves TA, Paleacu D, et al. Risk factors for dementia, depression and psychosis in long-standing Parkinson’s disease. J Neural Transm 2000; 107(1): 59–71

    Article  PubMed  CAS  Google Scholar 

  67. Greene P, Cote L, Fahn S. Treatment of drug-induced psychosis in Parkinson’s disease with clozapine. Adv Neurol 1993; 60: 703–6

    PubMed  CAS  Google Scholar 

  68. Goetz CG, Stebbins GT. Risk factors for nursing home placement in advanced Parkinson’s disease. Neurology 1993; 43(11): 2227–9

    Article  PubMed  CAS  Google Scholar 

  69. Miyawaki E, Lyons K, Pahwa R, et al. Motor complications of chronic levodopa therapy in Parkinson’s disease. Clin Neuropharmacol 1997; 20(6): 523–30

    Article  PubMed  CAS  Google Scholar 

  70. Golbe LI. Young-onset Parkinson’s disease: a clinical review. Neurology 1991; 41 (2 Pt 1): 168–73

    Article  PubMed  CAS  Google Scholar 

  71. Grandas F, Galiano ML, Tabernero C. Risk factors for levodopa-induced dyskinesias in Parkinson’s disease. J Neurol 1999; 246(12): 1127–33

    Article  PubMed  CAS  Google Scholar 

  72. Kumar N, Van Gerpen JA, Bower JH, et al. Levodopa-dyskinesia incidence by age of Parkinson’s disease onset. Mov Disord 2005; 20(3): 342–4

    Article  PubMed  Google Scholar 

  73. Quinn N, Critchley P, Marsden CD. Young onset Parkinson’s disease. Mov Disord 1987; 2(2): 73–91

    Article  PubMed  CAS  Google Scholar 

  74. Schrag A, Ben-Shlomo Y, Brown R, et al. Young-onset Parkinson’s disease revisited: clinical features, natural history, and mortality. Mov Disord 1998; 13(6): 885–94

    Article  PubMed  CAS  Google Scholar 

  75. 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(2): 205–9

    Article  PubMed  Google Scholar 

  76. Saint-Hilaire MH, Feldman RG. The ‘on-off’ phenomenon in Parkinson’s disease. In: Joseph AB, Young RR, editors. Movement disorders in neurology and neuropsychiatry. Boston (MA): Blackwell Scientific Publications, 1999: 180–4

    Google Scholar 

  77. Chase TN, Oh JD. Striatal mechanisms and pathogenesis of parkinsonian signs and motor complications. Ann Neurol 2000; 47 (4 Suppl. 1): S122–30

    PubMed  CAS  Google Scholar 

  78. de la Fuente-Fernandez R, Lu JQ, Sossi V, et al. Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson’s disease: PET evidence of increased dopamine turnover. Ann Neurol 2001; 49(3): 298–303

    Article  PubMed  Google Scholar 

  79. Chase TN, Engber TM, Mouradian MM. Contribution of dopaminergic and glutamatergic mechanisms to the pathogenesis of motor response complications in Parkinson’s disease. Adv Neurol 1996; 69: 497–501

    PubMed  CAS  Google Scholar 

  80. Sage JI, Sonsalla PK, McHale DM, et al. Clinical experience with duodenal infusions of levodopa for the treatment of motor fluctuations in Parkinson’s disease. Adv Neurol 1990; 53: 383–6

    PubMed  CAS  Google Scholar 

  81. Hughes AJ, Bishop S, Kleedorfer B, et al. Subcutaneous apomorphine in Parkinson’s disease: response to chronic administration for up to five years. Mov Disord 1993; 8(2): 165–70

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

No sources of funding were used to assist in the preparation of this review.

Dr Fernandez has served as a consultant, speaker, member of an advisory board or conducted clinical research under contract for Amarin, AstraZeneca, Aventis, Boehringer Ingelheim, Boston Life Sciences, Biogen Idec, Cephalon, Elan, Forest Laboratories, GlaxoSmithKline, Huntington Study Group, Ipsen, Kyowa, Merck KgaA, Merz, MylanBertek, National Parkinson Foundation, Neurotrax, National Institutes of Health/National Institute of Neurological Disorders and Stroke, Novartis, Parkinson Study Group, Solstice, Teva, United Biosource Corporation, Valeant and Vernalis. The other authors have no potential conflicts of interest that are directly relevant to the content of this review.

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  1. Department of Neurology, University of Florida, 100 S. Newell Drive, P.O. Box 100236, Gainesville, Florida, 32608, USA

    Irene A. C. Halkias, Ihtsham Haq, Zhigao Huang &  Hubert H. Fernandez

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Halkias, I.A.C., Haq, I., Huang, Z. et al. When Should Levodopa Therapy be Initiated in Patients with Parkinson’s Disease?. Drugs Aging 24, 261–273 (2007). https://doi.org/10.2165/00002512-200724040-00001

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