Clinical pharmacology of levodopa-induced dyskinesia

Levodopa-induced dyskinesia (LID) is a major impediment to the successful therapy of Parkinson's disease. The development of LID is facilitated by dopaminergic denervation but may not require denervation. Repeated levodopa dosing is necessary to induce dyskinesia, implying the development of sensitization to levodopa. There is inconclusive evidence on whether repeated dosing lowers the threshold (shifts the levodopa-dyskinesia response curve to the left), increases the severity of dyskinesia (increases the maximum effect that is initially zero) or induces more complex changes in the dose-response curve. Once a patient develops LID, the severity of LID is not dose responsive, but the duration of dyskinesia is. Clinically, it is very difficult to separate the antiparkinsonian and dyskinetic effects of levodopa. Whether this separation is possible with more selective agonists with antiparkinsonian effects that are equipotent to levodopa is unknown. The fact that selective stimulation of the pallidum does not separate antiparkinsonian and dyskinetic actions implies that they are closely related anatomically and physiologically.