Treatment of levodopa-induced dyskinesia

Levodopa provides the most effective symptomatic treatment for Parkinson's disease (PD). Initiation of treatment of PD too early and/or very aggressive treatment with large doses of levodopa results in severe motor fluctuations and dyskinesias in 30% of patients with PD. Chronic levodopa treatment over a period of 9 years or more will invariably result in disabling motor fluctuations in 90% of PD patients. The motor fluctuations and associated dyskinesia are due to progressive dopamine denervation, an unregulated pattern of release of dopamine in the synapse, fluctuating levels of receptor sensitivity, and fluctuating levels of dopamine receptor stimulation. Once the dyskinesias are established, they are difficult to treat. The current medical therapy is a by-product of several explorative open-label trials, as well as a few blinded and double-label placebo-controlled clinical trials, of varying duration in a small number of patients. These studies suggest that amantadine, a glutamate antagonist, may be the most effective, easily available, and inexpensive medical treatment for levodopa-induced dyskinesia. Several other drugs, already approved for other medical ailments, also have been tried but not evaluated in large-scale clinical trials. None of these drugs is approved by the US Food and Drug Administration specifically for levodopa-induced dyskinesia. By far, the most effective treatment of levodopa-induced dyskinesia appears to be deep brain stimulation, with globus pallidus interna or the subthalamic nucleus as the two major targets of placement of electrodes.