Problems with long-term levodopa therapy for Parkinson's disease.

The introduction of levodopa 25 years ago revolutionized the management of Parkinson's disease. However, it soon became apparent that the drug offered only symptomatic relief and did not affect the underlying pathology. Moreover, chronic use of the drug was associated with a range of adverse effects. Current therapeutic strategies seek to delay long-term complications of treatment for as long as possible. However, once they appear, most adverse effects are amenable to some form of management. A number of therapeutic strategies are available for treatment of Parkinson's disease. The final choice of therapy depends on the individual circumstances and requirements of the patient and should balance tolerance for adverse effects with the amount of symptomatic relief required. Patients receiving long-term levodopa therapy must contend with some adverse effects. After 5 years the majority of these patients suffer fluctuations, dyskinesias, toxicity, or loss of efficacy. Fluctuations can be reduced by changing the drug regimen to a combination therapy of Sinemet and Sinemet controlled-release (CR), or by the addition of deprenyl or a dopamine agonist. Variations in gastric emptying and absorption of levodopa and dietary factors become important. Dyskinesias in long-term levodopa therapy are poorly understood and difficult to manage, although dopamine agonists can be of some use. As the disease progresses, new disabilities appear that are less responsive to levodopa, and its efficacy can appear to diminish, with increased doses often leading to toxicity.