Levodopa therapy for Parkinson's disease: Challenges and future prospects

Levodopa therapy has been the gold standard for the treatment of Parkinson’s disease (PD) since its introduction 40 years ago. It has revolutionized symptomatic treatment by providing improvement in activities of daily living, quality of life, and longevity for millions of patients with Parkinson’s disease around the world, and can be considered one of the great miracles of modern medical therapy. No other therapy for PD developed to date provides antiparkinsonian benefits that are superior to what can be achieved with levodopa, and the drug remains the gold standard against which new therapies must be measured. However, levodopa treatment is not a panacea. Acute dopaninergic side effects such as nausea, vomiting, and orthostatic hypotension may occur at the onset of treatment. These have been largely overcome by the combination of levodopa with a peripheral decarboxylase inhibitor. Chronic levodopa treatment may be associated with side effects in the form of potentially disabling motor complications (motor fluctuations and dyskinesia). These can begin within months of starting levodopa, and are present in up to 90% of patients who have been treated with the drug for 10 years. Most other currently available anti-parkinsonian therapies primarily act by delaying the onset, or diminishing the severity, of these motor complications, but do not provide anti-parkinsonian benefits beyond those which otherwise could be obtained with levodopa alone. What is surprising is how little research has focused on the pathophysiologic basis of why levodopa causes these side effects. Few well-designed double-blind, placebo-controlled studies have examined the clinical and pharmacological properties of levodopa. The recent ELLDOPA study published in 2004 was the first double-blind study testing the effect of different doses of levodopa in comparison to placebo. It confirmed the clinical impression that higher levodopa doses were associated with increased short-term efficacy, but increased motor complications. No study has yet addressed the optimal method by which levodopa should be administered to optimize efficacy and minimize motor complications. That situation is beginning to change. Increasing information is now available about how dopamine functions in the normal basal ganglia, how the basal ganglia are disrupted in the dopamine depleted state, and how current methods of administering levodopa might lead to motor complications. This in turn has led to studies aimed at determining how to deliver levodopa to the brain in a more physiological manner in an attempt to obtain the benefits of the drug without complicating motor fluctuations and dyskinesia. This supplement incorporates peer-reviewed articles providing the current state of knowledge regarding the use of levodopa in PD. Dr. Stanley Fahn provides a compelling history of the development of levodopa. Individual papers address the phenomenology of motor complications, the issue of levodopa toxicity, and the limitations of levodopa therapy relative to the non-dopaminergic features of PD. State of the art papers review the anatomy of the dopamine system, the organization of the basal ganglia and the role of dopamine *Correspondence to: Dr. C. Warren Olanow, Department of Neurology, Mount Sinai School of Medicine, 1 Gustave Levy Place, Annenberg 1494, New York. E-mail: warren.olanow@mssm.edu Potential conflict of interest: Dr. Olanow has served as a consultant for Novartis, Teva, BI, Solvay, Ceregene, and Merck Second. Received 28 January 2008; Accepted 2 March 2008 Published online in Wiley InterScience (www.interscience.wiley. com). DOI: 10.1002/mds.22048