Ropinirole for levodopa-induced complications in Parkinson's disease
Editorial Group: Cochrane Movement Disorders Group
Published Online: 22 JAN 2001
Assessed as up-to-date: 12 NOV 2000
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
How to Cite
Clarke CE, Deane K. Ropinirole for levodopa-induced complications in Parkinson's disease. Cochrane Database of Systematic Reviews 2001, Issue 1. Art. No.: CD001516. DOI: 10.1002/14651858.CD001516.
- Publication Status: Edited (no change to conclusions)
- Published Online: 22 JAN 2001
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.
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.
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.
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.
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.
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.
Plain language summary
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.
電子搜索了包括MEDLINE, EMBASE和Cochrane Controlled Trials Register.手工檢索神經學文獻是Cochrane Movement Disorders Group的方法之一. 並且檢驗了已確認的研究的參考文獻及其他回顧分析報告。也連絡了Smith Kline Beecham。
評估ropinirole相對應於安慰劑使用, 於臨床上診斷為原發性(idiopathic)巴金森氏病, 並合併長期左旋多巴治療併發症患者之隨機對照試驗。
有三項總共包含263位病人的雙盲、平行分組的隨機對照試驗。其中兩項第二階段(phase II)研究相對規模較小，追蹤期間短(12週)，並且使用相對低劑量的ropinirole (平均3.3和3.5毫克/ 天)每日分兩次服用。基於臨床的異質性和統計異質性，這兩項試驗的結果並沒有被納入綜合分析中。本回顧分析的結論是基於一單一的第三階段(phase III)研究，其追蹤中等期間(26週)，並使用目前於英國獲准的最大劑量，每日分3次服用。鑑於在Leiberman 98的研究中，因為最初不均衡的試驗端，評估停電時間的變化相當困難，所以無法對ropinirole是否對停電(off)時間有任何效果下任何肯定的結論。然而，在不良反應方面，接受ropinirole的病人明顯增加了異動症的發生(Leiberman 98; odds ratio 2.90; 1.36, 6.19 95% CI; 表8)。在這項研究中，測量運動障礙和失能的方法太差，因此所得到的訊息不完整。在Leiberman 98研究中，ropinirole的使用比起安慰劑，可以顯著減少左旋多巴的劑量98(weighted mean difference 180 mg/d; 106, 25395% CI;;表2)。除了ropinirole會增加異動症以外，其他的副作用在ropinirole及安慰劑都沒有明顯差異。在Leiberman 98中，ropinirole組具有較少退出試驗的趨勢，但沒有達到統計學意義。
此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。
在較晚期的巴金森氏病，左旋多巴治療會產生一些副作用。這些包括不自主運動(異動症)、腿部痙攣疼痛(肌張力不全，dystonia)、和對單一劑量反應的縮短，即所謂“劑量末惡化(endofdose deterioration)”或“減弱效應(wearingoff effect)”。 多巴胺受體促進劑藥物模仿多巴胺在大腦中作用，但它們不會導致這些長期多巴胺治療的併發症。因此，這些年來，當這些問題出現時，多巴胺受體促進劑常常被使用，希望能夠改善症狀。Ropinirole 是一新的多巴胺促進劑，最近獲准在英國治療早期及晚期的巴金森氏病。在這次檢回顧分析，我們檢驗了關於這種藥物的臨床試驗，看看其療效如何及其會造成甚麼副作用。有三項包含263位病人試驗比較了repinirole及非活性的安慰劑在較晚期的巴金森病患者的效果。其中兩項研究相對規模較小，並進行了短期追蹤(12週)，並且使用相對低劑量的ropinirole (最大8及10毫克/ 天)每日分兩次服用。基於這些原因，這項試驗的結果並沒有被納入統計分析中。另一研究是追蹤了中等期間(26週)，並使用目前於英國獲准的最大劑量的ropinirole(24毫克/天)，每日分3次服用。本回顧分析的結論就是基於這項單一的試驗，因此檢視必須額外小心。結果發現在ropinirole和安慰劑間，於病患發生停電(off)的時間上並沒有顯著差異。不過這可能是因為本試驗的病患數太少。身體運動困難、和日常活動困難(如洗澡、購物等)的評估在這些試驗做得太差，因此只能得到不完整的資訊。Ropinirole比起安慰劑，可以減少左旋多巴劑量180毫克/天。然而，接受Ropinirole的病人異動症也會增加(是安慰劑的2.9倍)。其它的副作用及退出試驗率則無明顯差異。Ropinirole可以減少左旋多巴劑量但會增加異動症。停電時間在此單一試驗中並沒有明確的減少。ropinirole和安慰劑的副作用類似。這些結論適用於最多26個星期的短期和中期的治療。並且需要更長期的試驗以評估患者生活品質、花費，並且也需要比較新與舊的多巴促進劑效果。