Pramipexole for levodopa-induced complications in Parkinson's disease

To compare the efficacy and safety of adjuvant pramipexole therapy versus inactive placebo in patients with Parkinson's disease, already established on levodopa.

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.

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 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.

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.

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.