Drugs and drug delivery in PD: optimizing control of symptoms with pramipexole prolonged‐release

Abstract

Intermittent or pulsatile dopamine-receptor stimulation is postulated to induce plastic changes in motor systems that are responsible for the development of motor fluctuations and dyskinesia, complicating long-term levodopa therapy of Parkinson's disease (PD). Continuous dopamine stimulation (CDS) is a concept that refers to the hypothesis that more continuous dopamine-receptor stimulation will reduce the risk of motor complications, particularly dyskinesias, and may also treat established dyskinesias. In line with this hypothesis, the intermittent administration of dopaminergic agents with short half-lives induce motor complications in animal models, whilst the continuous administration of the same compounds via mini-pumps substantially reduces such symptoms. Continuous drug delivery (CDD) strategies are therefore explored in clinical trials to prevent or manage motor complications. The early use of a dopamine agonist reduces the risk of motor fluctuations compared with levodopa. Conversely, the early combination of the catechol-O-methyltransferase inhibitor entacapone with levodopa has failed to demonstrate a comparable advantage. Outcomes of uncontrolled long-term studies of PD patients with motor complications treated for several months with subcutaneous continuous infusion of apomorphine or intraduodenal levodopa are compatible with CDS. New once-daily prolonged-release formulations of dopamine agonists have demonstrated antiparkinsonian efficacy in randomized trials conducted in early as well as advanced patients with PD. Once-daily administration is convenient and may improve compliance. Other theoretical advantages in terms of efficacy or tolerability deserve further exploration.