Levodopa/dopamine replacement strategies in Parkinson's disease--future directions.

After 40 years, levodopa remains the most effective therapy for the treatment of PD. However, long-term therapy is complicated by motor fluctuations and dyskinesia that can represent a source of significant disability for some patients. Other medical therapies that are currently available for the treatment of PD primarily represent an attempt to prevent or treat motor complications. Surgical therapies improve motor complications in appropriate candidates, but do not provide antiparkinsonian benefits that are superior to levodopa, and are themselves associated with potentially serious side effects. Increasing information suggests that levodopa-induced motor complications relate to pulsatile, nonphysiologic dopamine replacement. A therapeutic strategy that could deliver levodopa/dopamine to the brain in a more continuous and physiologic manner might be expected to provide all of the benefits of standard levodopa with reduced motor complications. Such a levodopa formulation might replace all current dopaminergic antiparkinsonian medications and avoid the need for surgery in most PD patients. However, problems of continuous dopaminergic stimulation must be addressed and avoided, and the issue of nondopaminergic features remains to be addressed.