Motor and nonmotor complications in Parkinson's disease: an argument for continuous drug delivery?

Abstract

The complications of long-term levodopa therapy for Parkinson's disease (PD) include motor fluctuations, dyskinesias, and also nonmotor fluctuations-at least equally common, but less well appreciated-in autonomic, cognitive/psychiatric, and sensory symptoms. In seeking the pathophysiologic mechanisms, the leading hypothesis is that in the parkinsonian brain, intermittent, nonphysiological stimulation of striatal dopamine receptors destabilizes an already unstable system. Accordingly, a major goal of PD treatment in recent years has been the attainment of continuous dopaminergic stimulation (CDS)-or, less theoretically (and more clinically verifiable), continuous drug delivery (CDD). Improvements in the steadiness of the plasma profiles of various dopaminergic therapies may be a signal of progress. However, improvements in plasma profile do not necessarily translate into CDS, or even into CDD to the brain. Still, it is reassuring that clinical studies of approaches to CDD have generally been positive. Head-to-head comparative trials have often failed to uncover evidence favoring such approaches over an intermittent therapy. Nevertheless, the findings among recipients of subcutaneous apomorphine infusion or intrajejunal levodopa/carbidopa intestinal gel suggest that nonmotor PD symptoms or complications may improve in tandem with motor improvement. In vivo receptor binding studies may help to determine the degree of CDS that a dopaminergic therapy can confer. This may be a necessary first step toward establishing whether CDS is, in fact, an important determinant of clinical efficacy. Certainly, the complexities of optimal PD management, and the rationale for an underlying strategy such as CDS or CDD, have not yet been thoroughly elucidated.

Fig. 1

Plasma levels of immediate-release oral levodopa with versus without entacapone in a PD patient receiving treatment (arrowheads) every 2 h (data adapted from Nutt 1996)

Fig. 2

Plasma levels (a) and motor-function (tapping total) profiles (b) for slow- versus immediate-release oral levodopa/carbidopa in 18 PD patients with motor fluctuations (data adapted from Pahwa et al. 1997). LC-CR (slow) controlled-release levodopa/carbidopa, LC-IR immediate-release levodopa/carbidopa

Fig. 3

Plasma levels for PR (a)/ER (b) versus IR formulations of oral dopamine agonists: Ropinirole (a) in 20 patients with early PD (data adapted from Tompson and Vearer 2007), and pramipexole (b) in 14 healthy volunteers (data adapted from Jenner et al. 2009). ER extended-release, IR immediate-release, PR prolonged-release. ^aOnly the last two doses are graphed for pramipexole IR

Fig. 4

Plasma apomorphine levels (left y-axis scale) and simultaneous clinical-state scores (right y-axis scale) for each of four recipients of continuous subcutaneous apomorphine infusion. Arrowheads on x-axis mark bolus doses. Clinical state was a global objective/subjective rating in half-point increments, including ratings of −1 for fully “OFF”, 0 for threshold of “ON”, +1 for fully “ON”, and +1.5 for dyskinesia or subjectively overdosed (e.g., light-headed, confused) (data adapted from Manson et al. 2001)

Fig. 5

Plasma levodopa levels for sustained- (slow-) release oral levodopa/carbidopa (a) versus continuous intraduodenal infusion of LCIG (b) in each of 12 patients with advanced PD. In each graph, the solid black curve with solid black circles for its data points displays the mean for all curves (data adapted from Nyholm et al. 2003)

Fig. 6

Variability in the plasma level of various formulations of dopaminergic therapies. Coefficient of variation (CV) (a)—the standard deviation in plasma level, expressed as a percentage of group geometric mean plasma level—for oral immediate-release levodopa/carbidopa/entacapone versus levodopa/carbidopa (LCE vs. LC), oral slow- versus immediate-release levodopa/carbidopa (LC-CR vs. LC), and intraduodenal levodopa/carbidopa intestinal gel versus oral slow-release levodopa/carbidopa (LCIG vs. LC-CR). Peak-to-trough fluctuation (PTF) (b)—C _max − C _min, expressed as a percentage of group geometric mean plasma level—for oral slow- versus immediate-release ropinirole (RPR-XL vs. RPR-IR), oral slow- versus immediate-release pramipexole (PPX-ER vs. PPX-IR), and transdermal rotigotine (RTG). CR controlled-release, ER and XL extended-release