Abstract
Fluctuations in response to levodopa in patients in the advanced stages of idiopathic Parkinson’s disease occur frequently and are a difficult problem to treat. Patients who are treated with levodopa have an additional 10% risk of experiencing response fluctuations with each year of treatment: 50% of patients have this problem after 5 years of receiving levodopa therapy and almost 100% of patients after 10 years.
The mechanisms by which response fluctuations occur are only partially understood and can be divided into three main types: (i) presynaptic neuronal degeneration leading to a lack of buffering of released levodopa, which is mainly related to wearing-off phenomena; (ii) postsynaptic changes in dopamine receptor sensitivity and number, partially caused by the presynaptic changes, which are clinically related to at-random response fluctuations; and (iii) pharmacokinetic and pharmacodynamic influences of exogenously administered dopaminergic agents.
Several oral and parenteral treatment strategies are recommended to manage response fluctuations, such as optimisation of dopamine receptor agonist therapy in combination with a reduction of the levodopa load; use of slow-release levodopa formulations; use of catechol-O-methyltransferase inhibitors; an increase of levodopa dose frequency; use of high-dose amantadine; and intermittent or continuous use of apomorphine and/or levodopa. Continuous stimulation of dopamine receptors with dopaminergic agents is one of the crucial basic steps in the treatment of patients at an advanced stage of Parkinson’s disease, and the preferential use of dopamine receptor agonists has proven to be successful in the prevention and treatment of response fluctuations.
Similar content being viewed by others
Notes
Use of tradenames is for product identification only and does not imply endorsement.
References
Morrish PK, Sawle GV, Brooks DJ. The rate of progression of Parkinson’s disease: a longitudinal [18F]DOPA PET study. In: Battistin L, Scarlato G, Caraceni T, et al., editors. Advances in neurology. Vol. 69. Philadelphia (PA): Lippincott-Raven Publishers, 1996: 427–31
Leenders KL. Pathophysiology of movement disorders studied using PET. J Neural Transm Suppl 1997; 50: 39–46
Hughes AJ, Daniel SE, Kilford L, et al. Accuracy of the clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55: 181–4
Marsden CD, Parkes JD. Success and problems of long-term levodopa therapy in Parkinson’s disease. Lancet 1977; I: 345–9
Block G, Liss C, Reines S, et al. Comparison of immediate-release and controlled-release carbidopa/levodopa in PD: a multicenter 5-year study. Eur Neurol 1997; 37: 23–7
Golbe LI. Young-onset Parkinson’s disease: a clinical review. Neurology 1991; 41: 168–73
Schrag A, Quinn N. Dyskinesias and motor fluctuations in Parkinson’s disease: a community based study. Brain 2000; 123: 2297–305
Fahn S. Fluctuations of disability in Parkinson’s disease: pathophysiological aspects. In: Marsden CD, Fahn S, editors. Movement disorders. London: Butterworth Scientific, 1982: 123–45
Nutt JG, Holford NH. The response to levodopa in Parkinson’s disease: imposing pharmacological law and order. Ann Neurol 1996; 39: 561–73
Melamed E, Bitton V, Zelig O. Delayed onset of response to single doses of L-dopa therapy. Clin Neuropharmacol 1986; 9: 182–8
Melamed E, Bitton V, Zelig O. Episodic unresponsiveness to single doses of L-dopa in parkinsonian fluctuators. Neurology 1986; 36: 100–3
Marsden CD, Parkes JD, Quinn N. Fluctuations of disability in Parkinson’s disease: clinical aspects. In: Marsden CD, Fahn S, editors. Movement disorders. London: Butterworth Scientific, 1982: 96–122
Lees AJ, Shaw KM, Stern GM. Off-period dystonia and on-period choreoathetosis in levodopa-treated Parkinson’s disease [letter]. Lancet 1977; II: 1034
Muenter MD, Sharpless NS, Tyce GM, et al. Patterns of dystonia in response to L-dopa therapy for Parkinson’s disease. Mayo Clin Proc 1977; 52: 163–74
Melamed E. Early-morning dystonia: a late side effect of long-term levodopa therapy in Parkinson’s disease. Arch Neurol 1979; 36: 308–10
Nausieda PA, Weiner WJ, Klawans HL. Dystonic foot response of parkinsonism. Arch Neurol 1980; 37: 132–6
Curtis L, Lees AJ, Stern GM, et al. Effect of L-dopa on course of Parkinson’s disease. Lancet 1984; II: 211–2
Poewe WH, Lees AJ, Stern GM. Dystonia in Parkinson’s disease: clinical and pharmacological features. Ann Neurol 1988; 23: 73–8
Nutt JG, Woodward WR, Carter JH, et al. Influence of fluctuations of plasma large neutral amino acids with normal diets on the clinical response to levodopa. J Neurol Neurosurg Psychiatry 1989; 52: 481–7
Baruzzi A, Cantin M, Riva R. Influence of meal ingestion time on pharmacokinetics of orally-administered levodopa in parkinsonian patients. Clin Neuropharmacol 1987; 10: 527–37
Carter JH, Nutt JH, Woodward WR. Amount and distribution of dietary protein affects clinical response to levodopa in Parkinson’s disease. Neurology 1990; 39: 401–4
Kurth MC, Tetrad LW, Irwin I, et al. Oral levodopa/carbidopa solution versus tablets in Parkinson’s patients with severe fluctuations: a pilot study. Neurology 1993; 43: 1036–9
Fabbrini G, Juncos J, Mouradian MM, et al. Levodopa pharmacokinetic mechanisms and motor fluctuations in Parkinson’s disease. Ann Neurol 1987; 21: 370–6
Fabbrini G, Mouradian MM, Juncos JL, et al. Motor fluctuations in Parkinson’s disease: central pathophysiological mechanisms. Pt I. Ann Neurol 1988; 24: 366–71
Mouradian MM, Juncos JL, Fabbrini G, et al. Motor fluctuations in Parkinson’s disease: central and pathophysiological mechanisms. Pt II. Ann Neurol 1988; 24: 372–8
Leenders KL, Palmer AJ, Quinn N, et al. Brain dopamine metabolism in patients with Parkinson’s disease measured with PET. J Neurol Neurosurg Psychiatry 1986; 49: 853–60
Bravi D, Mouradian MM, Roberts JW, et al. Wearing-off fluctuations in Parkinson’s disease: contribution of postsynaptic mechanisms. Ann Neurol 1994; 36: 27–31
Kostic V, Przedborski S, Flaster E, et al. Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson’s disease. Neurology 1991; 41: 202–5
Horstink MWIM, Zijlmans JCM, Pasman JW, et al. Which risk factors predict the levodopa response in fluctuating Parkinson’s disease. Ann Neurol 1990; 27: 537–43
De Jong GJ, Meerwaldt JD, Schmitz PIM. Factors that influence the occurrence of response variations in Parkinson’s disease. Ann Neurol 1987; 22: 4–7
Roos RAC, Vredevoogd CB, Van der Velde EA. Response fluctuations in Parkinson’s disease. Neurology 1990; 40: 1344–6
Montastrac JL, Rascol O, Senard JM, et al. A randomised controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkinson’s disease: a five year follow-up. J Neurol Neurosurg Psychiatry 1994; 57: 1034–8
Vermeulen RJ, Drukarch B, Sahadat MCR, et al. The selective dopamine D1 receptor agonist SKF 81297, stimulates motor behavior of MPTP-lesioned monkeys. Eur J Pharmacol 1993; 235: 143–7
Vermeulen RJ, Drukarch B, Sahadat MCR, et al. The dopamine D1 agonist SKF 81297 and the dopamine D2 agonist LY 171555 act synergistically to stimulate motor behavior of l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonian rhesus monkeys. Mov Disorder 1994; 9: 664–72
Grondin R, Bédard PJ, Britton DR, et al. Potential therapeutic use of the selective dopamine D1 receptor agonist, A-86929: an acute study in parkinsonian levodopa-primed monkeys. Neurology 1997; 49: 412–26
Goetz CG, Koller WC, Poewe W, et al. Management of Parkinson’s disease: an evidence-based review. Levodopa. Mov Disord 2002; 17Suppl. 4: S23–37
Goetz CG, Koller WC, Poewe W, et al. Management of Parkinson’s disease: an evidence-based review. DA agonists — non-ergot derivatives: apomorphine. Mov Disord 2002; 17Suppl. 4: S83–9
Lledo A. Dopamine agonists: the treatment for Parkinson’s disease in the XXI century? Parkinsonism Relat Disord 2001; 7: 51–8
Bedard PJ, Di Paolo T, Falardeau P, et al. Chronic treatment with L-dopa, but not bromocriptine, induces dyskinesia in MPTP-parkinsonian monkeys. Brain Res 1986; 379: 294–9
Pearce RK, Banerji T, Jenner P, et al. De novo administration of ropinirole and bromocriptine induces less dyskinesia than L-dopa in the MPTP-treated marmoset. Mov Disord 1998; 13: 234–41
Obeso JA, Rodriguez-Oroz MC, Rodriguez M, et al. Pathophysiology of the basal ganglia in Parkinson’s disease. Trends Neurosci 2000; 23Suppl. 10: S8–S19
Marsden CD. Parkinson’s disease. J Neurol Neurosurg Psychiatry 1994; 57: 672–81
Wolters EC, Tissingh G, Bergmans PLM, et al. Dopamine agonists in Parkinson’s disease. Neurology 1995; 45Suppl. 3: S28–34
Uitti RJ, Ahlskog JE. Comparative review of dopamine receptor agonists in Parkinson’s disease. CNS Drugs 1996; 5(5): 369–88
Stocchi F, Nordera G, Marsden CD. Strategies for treating patients with Parkinson’s disease with disastrous fluctuations and dyskinesias. Clin Neuropharmacol 1997; 20(2): 95–115
Olanow CW, Watts RL, Koller WC. An algorithm for the management of Parkinson’s disease (2001): treatment guidelines. Neurology 2001; 56Suppl. 5: S1–S88
Kulisevsky J, Lopez-Villegas D, Garcia-Sanchez C, et al. A six-month study of pergolide and L-dopa in de novo Parkinson’s disease patients. Clin Neuropharmacol 1998; 21: 358–62
Watts RL. The role of dopamine agonists in early Parkinson’s disease. Neurology 1997; 49(1 Suppl. 1): S34–48
Clarke CE. Dopamine agonist therapy in advanced Parkinson’s disease. Neurology Rev Int 1998; 2: 1–5
Boas J, Worm-Petersen J, Dupont J, et al. The levodopa dose-sparing capacity of pergolide compared to that of bromocriptine in an open-label, cross-over study. Eur J Neurol 1996; 3: 44–9
Olanow CW, Fahn S, Muenter M, et al. A multicenter double-blind placebo-controlled trial of pergolide as an adjunct to Sinemet in Parkinson’s disease. Mov Disord 1994; 9(1): 40–7
LeWitt PA, Ward CD, Larsen TA, et al. Comparison of pergolide and bromocriptine therapy in parkinsonism. Neurology 1983; 33(8): 1009–14
Pezzoli G, Martignoni E, Pacchetti C, et al. Pergolide compared with bromocriptine in Parkinson’s disease: a multicenter, crossover, controlled study. Mov Disord 1994; 9(4): 431–6
Comparisons of therapeutic effects of levodopa, levodopa and selegiline, and bromocriptine in patients with early, mild Parkinson’s disease: three year interim report: Parkinson’s Disease Research Group in the United Kingdom. BMJ 1993; 307(6902): 469–72
Hely MA, Morris JG, Reid WG, et al. The Sydney Multicentre Study of Parkinson’s disease: a randomised, prospective five year study comparing low dose bromocriptine with low dose levodopa-carbidopa. J Neurol Neurosurg Psychiatry 1994; 57(8): 903–10
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: 1484–91
Barone P, Bravi D, Bermejo-Pareja F, et al. Pergolide monotherapy in the treatment of early PD: a randomized, controlled study: Pergolide Monotherapy Study Group. Neurology 1999: 53: 573–9
Parkinson Study Group G. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. JAMA 2000; 284: 1931–8
Rinne UK, Bracco F, Chouza C, et al. Early treatment of Parkinson’s disease with cabergoline delays the onset of motor complications: results of a double-blind levodopa controlled trial. Drugs 1998; 55Suppl. 1: S23–30
Poewe WH, Lees AJ, Stern GM. Treatment of motor fluctuations in Parkinson’s disease with an oral sustained-release preparation of L-dopa: clinical and pharmacokinetic observations. Clin Neuropharmacol 1986; 9: 430–9
Coleman RJ. Current drug therapy for Parkinson’s disease. Drugs Aging 1992; 2(2): 112–24
Goetz CG, Koller WC, Poewe W, et al. Management of Parkinson’s disease: an evidence-based review. MAO-B inhibitors for the treatment of Parkinson’s disease. Mov Disord 2002; 17Suppl. 4: S38–44
Kurth MC, Adler CH, Hilaire MS, et al. Tolcapone improves motor function and reduces levodopa requirement in patients with Parkinson’s disease experiencing motor fluctuations. Neurology 1997; 48: 81–7
Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Ann Neurol 1997; 42: 747–55
Rinne UK, Larsen JP, Siden A, et al. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Neurology 1998; 51: 1309–14
Ruottinen HM, Rinne UK. Entacapone prolongs levodopa response in a one month double blind study in parkinsonian patients with levodopa related fluctuations. J Neurol Neurosurg Psychiatry 1996; 60: 36–40
Nutt JG. Effects of COMT inhibition on the pharmacokinetics of L-dopa. Adv Neurol 1996; 69: 493–6
Lyytinen J, Kaakkola S, Ahtila S, et al. Simultaneous MAO-B and COMT inhibition in L-dopa treated patients with Parkinson’s disease. Mov Disord 1997; 12: 497–505
Lees AJ. Dopamine agonists in Parkinson’s disease: a look at apomorphine. Fundam Clin Pharmacol 1993; 7: 121–8
Colosimo C, Merello M, Albanese A. Clinical usefulness of apomorphine in movement disorders. Clin Neuropharmacol 1994; 17: 243–59
van Laar T, Jansen ENH, Essink AWG, et al. Intranasal apomorphine in parkinsonian on-off fluctuations. Arch Neurol 1992; 49: 482–4
Dewey RB, Maraganore DM, Ahlskog JE. A double-blind placebo-controlled study of intranasal apomorphine spray as a rescue agent for off-states in Parkinson’s disease. Mov Disord 1998; 13: 782–7
Merello M, Pikielny R, Cammarota A, et al. Comparison of subcutaneous apomorphine versus dispersible Madopar latency and effect duration in Parkinson’s disease patients: a double-blind single-dose study. Clin Neuropharmacol 1997; 20: 165–7
Nutt JG, Carter JH, Lea ES, et al. Motor fluctuations during continuous levodopa infusions in patients with Parkinson’s disease. Mov Disord 1997; 12: 285–92
Melamed E, Zoldan J, Galili-Mosberg R, et al. Current management of motor fluctuations in patients with advanced Parkinson’s disease treated chronically with levodopa. J Neural Transm Suppl 1999; 56: 173–83
Djaldetti R, Melamed E. Levodopa ethylester: a novel rescue therapy for response fluctuations in Parkinson’s disease. Ann Neurol 1996; 39: 401–4
Gancher GT, Nutt JG, Woodward WR. Time course of tolerance to apomorphine in Parkinsonism. Clin Pharmacol Ther 1992; 52: 504–10
Neef C, van Laar T. Pharmacokinetic-pharmacodynamic relationships of apomorphine in patients with Parkinson’s disease. Clin Pharmacokinet 1999; 37: 257–71
Stocchi F, Farina C, Nordera G, et al. Implantable venous access system for apomorphine infusion in complicated Parkinson’s disease [letter]. Mov Disord 1999; 14: 358
Verhagen Metman L, Van den Munckhof P, Klaassen AAG, et al. Effects of supra-threshold levodopa doses on dyskinesias in advanced Parkinson’s disease. Neurology 1997; 49: 711–3
Papa SM, Chase TN. Levodopa-induced dyskinesias improved by a glutamate antagonist in Parkinsonian monkeys. Ann Neurol 1996; 39: 574–57
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
Metman LV, Del Dotto P, LePoole K, et al. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol 1999; 56: 1383–6
Uitti Rj, Rajput AH, Ahlskog JE, et al. Amantadine treatment is an independent predictor of survival in Parkinson’s disease. Neurology 1996; 46: 1551–6
Bennett JP, Elke R, Landow RN, et al. Suppression of dyskinesias in advanced Parkinson’s disease. Neurology 1993; 43: 1551–5
Trosch RM, Friedman JH, Lannon MC, et al. Clozapine use in Parkinson’s disease: a retrospective analysis of a large multicentered clinical experience. Mov Disord 1998; 13: 377–82
Durif F, Vidailhet M, Assal F, et al. Low-dose clozapine improves dyskinesias in Parkinson’s disease. Neurology 1997; 48: 658–62
Deuschl G, Krack P, Volkmann J. Deep brain stimulation for movement disorders. Mov Disord 2002; 7Suppl. 3: S1–211
Chase TN. The significance of continuous dopaminergic stimulation in the treatment of Parkinson’s disease. Drugs 1998; 55Suppl. 1: 1–9
Acknowledgements
The author has not received any funding for the preparation of this manuscript. There are no conflicts of interest that could be relevant to the contents of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
van Laar, T. Levodopa-Induced Response Fluctuations in Patients with Parkinson’s Disease. CNS Drugs 17, 475–489 (2003). https://doi.org/10.2165/00023210-200317070-00002
Published:
Issue Date:
DOI: https://doi.org/10.2165/00023210-200317070-00002