Pramipexole + Levodopa in Parkinson's Disease: Is the Whole Greater than the Sum of its Parts?

Abstract & Commentary

By Melissa J. Nirenberg, MD, PhD, Assistant Professor, Neurology and Neuroscience, Weill Cornell Medical College. Dr. Nirenberg reports that she has participated in consulting for Biovail.

Synopsis: Pramipexole has more than a simple additive benefit in augmenting the motor benefits of levodopa, but also increases the duration and severity of dyskinesias.

Source: Brodsky MA, et al. Effects of a dopamine agonist on the pharmacodynamics of levodopa in Parkinson disease. Arch Neurol 2010;67:27-32.

Levodopa and dopamine agonists (DAS) are commonly used treatments for Parkinson's disease (PD). Although DAs tend to have more side effects than levodopa, they are often favored as initial therapy because this strategy delays the onset of motor complications such as wearing off and dyskinesias. Later in the disease, DAs are frequently used as an adjunct to levodopa, to increase "on" times and reduce end-of-dose "wearing-off." While the benefits of combined DA/levodopa therapy are well established, it is unclear whether this is simply an additive benefit, or if there are also pharmacodynamic interactions between these drugs.

The goal of the current study was to examine the effects of pramipexole, a DA, on the motor response to levodopa in PD. The authors used a double-blind, randomized, placebo-controlled, crossover design to evaluate subjects with PD who were experiencing dyskinesias and motor fluctuations as a complication of long-term levodopa therapy. Each of the 13 study subjects was treated with pramipexole (3 mg/day) or placebo for a four-week period, and then with two-hour intravenous levodopa infusions on each of two consecutive days (after overnight discontinuation of oral levodopa). Blinded neurological assessments were performed concomitant with each levodopa infusion. Subjects were then switched to the other oral agent (placebo or pramipexole) for another four weeks, after which the same levodopa infusions and examinations were repeated. The primary outcome measure was finger-tapping speed, a marker for bradykinesia. Secondary outcome measures included quantitative analyses of dyskinesias and walking speed. All measures were compared at baseline (before levodopa infusion) versus during levodopa infusion, to adjust for the direct benefits of pramipexole on motor function.

Of the 13 study subjects, 10 completed the study and were included in the analysis; three dropped out (two because they were unable to tolerate DA taper during attempted crossover to placebo). Among those 10 subjects, pramipexole with levodopa treatment increased the mean finger-tapping speed beyond the change in baseline, more than doubled the area under the curve for finger-tapping speed, increased the mean peak finger-tapping speed, and improved mean walking speed. In addition, pramipexole prolonged the duration of response after levodopa infusion, and shortened the time to "on." Unfortunately, pramipexole therapy was also associated with increased mean baseline and peak dyskinesia scores. Based on these findings, the authors conclude that pramipexole "augmented the motor response to levodopa beyond a simple additive effect and increased the severity of levodopa-induced dyskinesia."

Commentary

Some PD medications—including inhibitors of monoamine oxidase B and catechol-O-methyltransferase—work partially or exclusively by increasing the availability of levodopa / dopamine in the brain. Accordingly, when added to levodopa therapy, these drugs reduce end-of-dose wearing off but can increase dyskinesias and other side effects. In contrast, DAs might potentially work independently of levodopa, through direct stimulation of postsynaptic dopamine receptors. Thus, while DAs are known to boost the clinical effects of levodopa, this may represent a simple additive effect of the two drugs.

In this study, the authors show that pramipexole enhances the motor benefits of levodopa beyond a simple additive effect, suggesting that DAs may affect the pharmacodynamics of levodopa. Study strengths include the randomized, double-blind, placebo-controlled design. Limitations include the small sample size, relatively high dropout rate, and use of intravenous levodopa infusions (since pramipexole may have different pharmacodynamic interactions with intravenous levodopa than with the oral levodopa that is used in clinical practice). All study subjects had PD with motor complications and were recruited from a single academic referral center, such that the findings may not be applicable to other patient populations.