Maximizing the benefit:risk ratio of levodopa therapy in Parkinson's disease

For over 30 years, levodopa has been the gold standard for managing the symptoms of Parkinson's disease. Treatment with levodopa has resulted in a marked decrease in disease-associated mortality and morbidity. However, one of its drawbacks is that many patients experience a shorter duration of response and increased motor fluctuations with disease progression and long-term levodopa therapy. These increased motor fluctuations, including dyskinesias, may be the consequence of oxidative stress or inability to store and regulate intrasynaptic dopamine concentrations with disease progression. Clinical investigations have demonstrated that continuous dopaminergic stimulation may widen the therapeutic window for levodopa and improve motor fluctuations. Strategies for providing continuous dopaminergic replacement include administration of levodopa by continuous infusion, controlled-release levodopa, long-acting dopamine agonists, and inhibitors of levodopa metabolism. The catechol-O-methyltransferase inhibitors that block a compensatory metabolic pathway for levodopa and prolong its duration may improve the consistency of the dopaminergic response.