The Concept of ‘Continuous Dopaminergic Stimulation’
PD is a progressive neurodegenerative disorder with prominent motor features. The cardinal motor signs – bradykinesia, rigidity and tremor – are treated effectively by dopaminergic therapies. Levodopa is the most potent dopaminergic drug for PD and all patients suffering from PD will eventually require levodopa therapy. However, with continued treatment and as the disease progresses the response to oral levodopa becomes unstable and motor fluctuations emerge, including off-periods (when medication effects wear off) and dyskinesia (dystonic or choreatic movements). In this stage the pharmacokinetic properties of levodopa, with its short half-life of 90–120 minutes, gain increasing importance for the duration of the motor response. Many peripheral factors have an additional impact on plasma levels of levodopa: abnormal gastric acidity, reduced gut motility and dietary amino acids competing with levodopa uptake via the duodenal amino acid transporter may lead to irregular fluctuations of plasma levels despite regular oral intake of the drug. As the number of striatal dopaminergic terminals decreases to <20% with disease progression, their buffering and transforming capacity is lost. Levodopa is increasingly metabolised by nondopaminergic cells (e.g. serotoninergic neurons), which do not provide a regulated release and do not possess the re-uptake facilities of dopaminergic cells. As a consequence, large fluctuations in the extracellular striatal concentration of dopamine parallel the fluctuations in levodopa plasma levels. The striatal medium spiny neurons, which are normally exposed to a relatively stable synaptic release of dopamine, become ‘sensitised’ by these erratic inputs and alter their firing pattern, which causes downstream abnormalities in the neuronal activity of the basal ganglia. Motor off-states are characterised by abnormal increases in the neuronal firing of the STN, which drives the inhibitory output nuclei of the basal ganglia, internal globus pallidus and substantia nigra pars reticulata. The increased gamma-aminobutyric acid (GABA)-ergic output of these nuclei inhibits thalamocortical and brainstem motor pathways and causes akinesia. Opposite changes in firing rate and additional abnormalities in the patterning of neuronal activity are observed during dyskinetic on-states.

CDS by means of subcutaneous or intravenous infusion of lisuride, apomorpine or levodopa has been shown to dramatically improve motor fluctuations, even in severely affected patients. Moreover, experimental studies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)– primate model of parkinsonism and clinical trials have demonstrated that the early use of dopamine agonists with a medium to long half-life can delay the onset of dyskinesia or hypokinetic fluctuations compared with levodopa monotherapy. The downside may be a less pronounced improvement of motor symptoms, which becomes increasingly apparent when the disease progresses beyond Hoehn and Yahr stage II. Nevertheless, providing a more continuous central dopaminergic stimulation either by using dopamine agonists or by stabilising peripheral levodopa plasma levels through the addition of catecholamine-O-methyl (COMT) or monaminoxidase (MAO) inhibitors is now a central issue in the early and late treatment of PD, and governs evidence-based treatment guidelines. Recently, new dopamine agonist formulations have become available for clinical practice, such as the transdermal patch application of rotigotine¹ or the controlled-release version of ropinirole,² with pharmacokinetic properties that are close to ideal in providing constant drug levels. However, despite the theoretical framework of CDS, no clinical trial has so far proved the superiority of these new dopamine agonist formulations over older formulations in terms of reducing or delaying fluctuating treatment responses.