Palliative and prophylactic benefits of continuously administered dopaminomimetics in Parkinson's disease

Abstract

Motor response complications that ultimately affect most parkinsonian patients appear related to altered dopaminergic mechanisms at both the presynaptic and postsynaptic levels. "Wearing-off" phenomena reflect a shortened duration of the antiparkinsonian action of levodopa, caused initially by the reduced capacity of the degenerating nigrostriatal system to store dopamine. Later, secondary changes in postsynaptic structures contribute substantially to these complications as well as to the changes in levodopa dose-antiparkinsonian response relation and the threshold for levodopa-induced dyskinesias that underlie "on-off" fluctuations and "peak-dose" dyskinesias. In parkinsonian rats, levodopa treatment not only fails to normalize striatal systems modified by the loss of dopaminergic afferents, but actually tends to exacerbate these alterations. Moreover, the vulnerability of these downstream systems to levodopa-induced change appears closely related to the severity of dopamine terminal loss and the intermittence of levodopa administration. In parkinsonian patients, switching from a standard intermittent levodopa regimen to a continuously infused dopaminomimetic alleviates motor fluctuations and widens the therapeutic window for levodopa. Taken together, currently available data support the view that continuous dopaminomimetic therapy has both immediate and delayed palliative value for advanced parkinsonian patients and potentially could confer prophylactic benefit to those at earlier stages of their disorder.