Avoidance of dyskinesia: preclinical evidence for continuous dopaminergic stimulation

Current concepts suggest that avoidance of pulsatile stimulation of dopamine receptors in Parkinson's disease (PD) can prevent the onset of dyskinesia. In MPTP-treated primates, repeated administration of levodopa or other short-acting dopamine agonist drugs leads to the onset of marked involuntary movements. In contrast, treatment with long-acting dopamine agonists leads to a much lower level of dyskinesia. Similar results have been obtained in PD patients, although the introduction of levodopa is a requirement in virtually all patients and this leads to further increases in motor complications. The concept of continuous dopaminergic stimulation should also apply to levodopa, such that reduced dyskinesia would be expected if it could be administered in a manner that avoids pulsatile receptor stimulation. In MPTP monkeys, administration of multiple small doses of levodopa in conjunction with the peripheral COMT inhibitor entacapone removes much of the pulsatility of motor function seen with standard levodopa treatment regimens and, at the same time, results in a lower incidence and intensity of dyskinesia. Furthermore, the addition of multiple small doses of levodopa plus entacapone to dopamine agonist treatment also avoids dyskinesia induction in MPTP-treated primates. These results suggest that administering of levodopa with entacapone as either initial or supplemental therapy for PD patients might reduce the risk for motor complications. Clinical trials to assess this hypothesis and determine if the results in MPTP monkeys can be duplicated in PD patients are warranted.