Abstract
Background
The long-term use of levodopa in Parkinson’s disease is associated with the development of motor complications including abnormal involuntary movements (dyskinesia) and a shortening response to each dose (wearing off phenomenon). It is thought that dopamine agonists can reduce the duration of immobile off periods and the need for levodopa therapy whilst maintaining or improving motor impairments and only minimally increasing dopaminergic adverse events.
Objectives
To compare the efficacy and safety of adjuvant pramipexole therapy versus inactive placebo in patients with Parkinson’s disease, already established on levodopa.
Search methods
Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group’s strategy. Examination of the reference lists of identified studies and other reviews. Contact with Pharmacia Upjohn and Boehringer Ingelheim.
Selection criteria
Randomised controlled trials of pramipexole versus placebo in patients with a clinical diagnosis of idiopathic Parkinson’s disease and long-term complications of levodopa therapy.
Data collection and analysis
Data was abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson’s disease rating scales, levodopa dosage, ‘off’ time measurements and the frequency of drop outs and adverse events.
Main results
Four randomised controlled trials have compared pramipexole with placebo in 669 patients with later Parkinson’s disease. Two phase III studies were medium term (24 weeks maintenance period) and 2 phase II studies were short term (4 weeks maintenance period). The reduction in off time was significantly greater with pramipexole compared with placebo (weighted mean difference 1.8 hours; 1.2, 2.3 95% CI). No significant changes were noted in a dyskinesia rating scale in any of the 4 studies, but dyskinesia as an adverse event was reported more frequently with pramipexole. A significant improvement occurred in UPDRS complication score (part IV) in 2 studies but not in the remaining trials. Statistically significant improvements in UPDRS ADL score occurred with pramipexole in all studies. Significant improvements in UPDRS motor scores in the on state were reported in 3 of the 4 studies. Levodopa dose reduction was allowed in 3 studies and meta-analysis shows a significant difference in favour of pramipexole (weighted mean difference 115 mg; 87, 143 95% CI). Trends toward a higher incidence of dopaminergic adverse events with pramipexole only reached statistical significance regarding hallucinations. There were significantly fewer withdrawals from pramipexole.
Authors’ conclusions
Pramipexole can be used to reduce off time, improve motor impairments and disability and reduce levodopa dose at the expense of increased dyskinetic adverse events. This conclusion is based on short and medium term trials (up to 24 weeks). Further trials are required to directly compare the newer with the older dopamine agonists.
Plain language summary
In the later stages of Parkinson’s disease, side effects occur because of the use of levodopa in its treatment. These consist of involuntary writhing movements (dyskinesia), painful cramps in the legs and a shortened response to each dose referred to as ‘end-of-dose deterioration’ or the ‘wearing-off effect’. Dopamine agonist drugs act by mimicking levodopa in the brain, but they do not cause these long-term treatment complications. For this reason, dopamine agonists have for some years been added once these problems develop in the hope of improving them. Pramipexole is a new dopamine agonist recently licensed in the UK for the treatment of later Parkinson’s disease. In this review, we will examine the trials performed with this drug to see how effective it is and what side effects it causes.
Four trials have compared pramipexole with placebo in 669 patients with later Parkinson’s disease. Two studies were medium term (24 weeks) and 2 studies were short term (4 weeks). Pramipexole significantly reduced the time patients spent in the immobile off state compared with placebo by an average of 1.8 hours. No changes occurred in a dyskinesia rating scale in any of the studies, but dyskinesia recorded as a side effect was reported more frequently with pramipexole. A significant improvement occurred in the Unified Parkinson’s Disease Rating Scale (UPDRS) complication score in 2 studies but not in the remaining trials. Significant improvements in UPDRS activities of daily living score occurred with pramipexole in all studies. Significant improvements in UPDRS motor scores in the mobile on state were reported in 3 of the 4 studies. Levodopa dose reduction was allowed in 3 studies and meta-analysis showed a significant difference in favour of pramipexole. There was a suggestion of more side effects such as nausea, vomiting and dizziness with pramipexole and a definite increase in hallucinations in those given pramipexole. There were significantly fewer withdrawals from pramipexole.
In conclusion, pramipexole can be used to reduce off time, improve motor impairments and disability and reduce levodopa dose at the expense of increased dyskinetic side effects. This is based on short and medium term trials (up to 24 weeks). Further trials are required to directly compare the newer with the older dopamine agonists.
