Ropinirole for levodopa-induced complications in Parkinson's disease

In the later stages of Parkinson's disease, side effects occur because of the use of levodopa treatment. These consist of involuntary writhing movements (dyskinesia), painful cramps in the legs (dystonia) 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. Ropinirole is a new dopamine agonist recently licensed in the UK for the treatment of early and 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.

Three trials have compared ropinirole with an inactive placebo in 263 patients in the later stages of Parkinson's disease. Two studies were relatively small, were conducted over the short term (12 weeks), and used relatively low doses of ropinirole (maximum allowed 8 and 10 mg/d) in a twice daily administration regime. For these reasons, the results of these trials have not been included in a statistical overview. The other study was medium term (26 weeks) and used ropinirole doses in line with the current UK licensed maximum (24 mg/d) in a three times a day regime. The conclusions of this review are based on this single trial and thus should be viewed with some caution.

No clear difference in the time patients spent in the immobile off state was found between ropinirole and placebo. However, this was probably due to there being too few patients in the trial. Measurements of physical difficulties and problems with activities of daily living (such as bathing, shopping, etc.) were poor in these studies with incomplete information available. Levodopa dose reduction was greater with ropinirole than placebo by 180 mg/d. However, dyskinesia was increased in those who received ropinirole (2.9 times more common with ropinirole than placebo). No other differences in side effects or withdrawals from treatment were found.

Ropinirole reduces levodopa dose but at the expense of increased dyskinetic side effects. No clear effect on off time reduction was found in this single trial. Side effects were similar with ropinirole and placebo. These conclusions apply to short and medium term treatment, up to 26 weeks. Further longer term trials are required, with measurements of quality of life and costs, and also studies to compare the newer with the older dopamine agonists.

Authors' conclusions: 

Ropinirole therapy can reduce levodopa dose but at the expense of increased dyskinetic adverse events. No clear effect on off time reduction was found but this may have been due to the under-powering of the single evaluable trial. Inadequate data on motor impairments and disability was collected to assess these outcomes. These conclusions apply to short and medium term treatment, up to 26 weeks. Further longer term trials are required, with measurements of effectiveness, and also studies to compare the newer with the older dopamine agonists.

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Background: 

Long-term levodopa therapy for Parkinson's disease is complicated by the development of motor fluctuations and abnormal involuntary movements. One approach is to add a dopamine agonist at this stage of the disease to reduce the time the patient spends immobile or off and to reduce the dose of levodopa in the hope of reducing such problems in the future.

Objectives: 

To compare the efficacy and safety of adjuvant ropinirole therapy versus placebo in patients with Parkinson's disease already established on levodopa therapy and suffering from motor complications.

Search strategy: 

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 SmithKline Beecham.

Selection criteria: 

Randomised controlled trials of ropinirole 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 withdrawals and adverse events.

Main results: 

Three double-blind, parallel group, randomised, controlled trials have been conducted on 263 patients. The two phase II studies were relatively small, were conducted over the short term (12 weeks), and used relatively low doses of ropinirole (mean administered doses 3.3 and 3.5 mg/d) in a twice daily regime. In view of this clinical heterogeneity and some statistical heterogeneity, the results of these trials have not been included in a meta-analysis. The conclusions of this review are based on the evidence from a single phase III study which was medium term (26 weeks) and used ropinirole doses in line with the current UK licensed maximum in a thrice daily regime.

In view of difficulties in assessing changes in off time in Leiberman 98, caused by the initial imbalance between the arms of the trial, it is unsafe to draw any firm conclusion about the effect of ropinirole on off time. However, as an adverse event, dyskinesia was significantly increased in those who received ropinirole (Leiberman 98; odds ratio 2.90; 1.36, 6.19 95% CI; Table 8). Measurements of motor impairments and disability were poor in this study with incomplete information available. Levodopa dose could be reduced in Leiberman 98 with a significantly larger reduction on ropinirole than on placebo (weighted mean difference 180 mg/d; 106, 253 95% CI; Table 2). No significant differences in the frequency of adverse event reports were noted between ropinirole and placebo apart from the increase in dyskinesia with ropinirole. There was a trend towards fewer withdrawals from ropinirole in Leiberman 98 but this did not reach statistical significance.

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