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Drug Insight: continuous dopaminergic stimulation in the treatment of Parkinson's disease

Nature Clinical Practice Neurology volume 2, pages 382–392 (2006)Cite this article

Abstract

Continuous dopaminergic stimulation is a therapeutic strategy for the management of Parkinson's disease, which proposes that dopaminergic agents that provide continuous stimulation of striatal dopamine receptors will delay or prevent the onset of levodopa-related motor complications. Dopaminergic neurons in the basal ganglia normally fire in a random but continuous manner, so that striatal dopamine concentrations are maintained at a relatively constant level. In the dopamine-depleted state, however, intermittent oral doses of levodopa induce discontinuous stimulation of striatal dopamine receptors. This pulsatile stimulation leads to molecular and physiologic changes in basal ganglia neurons and the development of motor complications. These effects are reduced or avoided when dopaminergic therapies are delivered in a more continuous and physiologic manner. Studies in primate models and patients with Parkinson's disease have shown that continuous or long-acting dopaminergic agents are associated with a decreased risk of motor complications compared with short-acting dopamine agonists or levodopa formulations. Continuous dopaminergic stimulation can be achieved with a continuous infusion, but infusion therapies are cumbersome and not likely to be acceptable to patients with early disease. The current challenge is to develop a long-acting oral formulation of levodopa that provides comparable anti-parkinsonian benefits without motor complications.

Key Points

  • Levodopa remains the 'gold standard' for Parkinson's disease (PD) therapy, although chronic use of this drug is associated with the development of motor complications

  • Levodopa-induced motor complications can be divided into two main subgroups: motor fluctuations and dyskinesias

  • Continuous dopaminergic stimulation in patients with PD is associated with a reduced risk of motor complications compared with short-acting agents that induce discontinuous or pulsatile stimulation

  • Continuous dopaminergic stimulation might be achieved by continuous intestinal infusion of levodopa, or by modifying the pharmacokinetic profile of the drug by administering it in combination with a catechol-O-methyltransferase inhibitor

  • Long-acting dopamine agonists reduce the risk of motor complications, but they are not as effective as levodopa for treating PD, and levodopa supplementation is eventually needed in patients treated with these drugs

  • The challenge is to develop a long-acting formulation of levodopa that provides anti-parkinsonian benefits while avoiding motor complications

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Figure 1: Chronic levodopa response: narrowing of the therapeutic window.
Figure 2: Continuous firing of substantia nigra pars compacta neurons and constant striatal dopamine concentrations in the normal state.
Figure 3: Effect of intraintestinal levodopa infusion on motor complications in Parkinson's disease.
Figure 4: Comparison of pharmacokinetic profiles of levodopa–carbidopa administered at 3-hour intervals with and without the catechol-O-methyltransferase inhibitor entacapone.81

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Authors and Affiliations

  1. Professor and Chairman of the Department of Neurology and Professor of Neuroscience at the Mount Sinai School of Medicine, New York, NY, USA

    C Warren Olanow

  2. consultant and professor of neurology at the University of Navarra, Pamplona, Spain

    José A Obeso

  3. Professor of Neurology at IRCCS Neuromed School of Physiotherapy, Faculty of Medicine, University of Rome La Sapienza, and at the Neurological School of the University G d'Annunzio School of Medicine, Chieti, Italy

    Fabrizio Stocchi

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  1. C Warren Olanow
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  2. José A Obeso
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Correspondence to C Warren Olanow.

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Competing interests

CW Olanow has served as a consultant for Boehringer Ingleheim, Novartis/Orion, Schwarz, Solvay, Teva and Valeant. He has no stock in any of these companies. JA Obeso declared associations with Boeringher Ingleheim, GlaxoSmithKline, Newron, Novartis/Orion, Pfizer, Teva and Vernalis. F Stocchi serves as a consultant for Novartis, Newron, Teva and Vernalis, and has received honoraria from Boehringer, GlaxoSmithKline, Orion and Pfizer. JA Obeso is on the scientific board of GlaxoSmithKline and Novartis, and and has received honoraria for lecturing in meetings sponsored by Boeringher, GlaxoSmithKline, Novartis/Orion and Schwarz.

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Olanow, C., Obeso, J. & Stocchi, F. Drug Insight: continuous dopaminergic stimulation in the treatment of Parkinson's disease. Nat Rev Neurol 2, 382–392 (2006). https://doi.org/10.1038/ncpneuro0222

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