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Pramipexole for levodopa-induced complications in Parkinson's disease

  • Review
  • Intervention

Authors


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.

摘要

背景

以pramipexole治療巴金森氏病中由levodopa所導致的併發症

長期使用levodopa治療巴金森氏病跟一些動作方面的併發症相關,包括不正常的不自主運動(異動症dyskinesia)和每一次投藥之後的有效時間縮短(wearing off phenomenon)。有人認為多巴胺的受體刺激劑可以在維持或改善動作障礙的情形下,減少不能動的停止(off)期,也減少levodopa的需要量,並只稍微增加多巴胺相關的副作用。

目標

比較輔助的pramipexole和無活性的安慰劑在治療已經在吃levodopa的巴金森氏病人的有效性和安全性。

搜尋策略

電子搜尋MEDLINE, EMBASE and the Cochrane Controlled Trials Register等資料庫,手動搜尋the Cochrane Movement Disorders Group's strategy 中神經科的文獻,也檢視了所找到試驗的參考文獻表和其他評論。聯絡了Upjohn和Boehringer Ingelheim藥廠。

選擇標準

在被診斷為原發性巴金森氏病並有服用levodopa長期副作用的病人身上,比較pramipexole 和安慰劑的隨機分配試驗。

資料收集與分析

數據由作者們獨立地取出,差異則由討論解決。所使用的結果測量指標包括巴金森氏病評分量表、levodopa的劑量、停止(off)期的時間,以及中途退出及產生副作用的頻率。

主要結論

有4個隨機試驗,比較了在669個晚期巴金森氏病病人之中,pramipexole和安慰劑的效用。其中兩個第3期研究是中長期的(維持期為時24週),兩個第2期研究是短期的(維持期為時4週)。服用pramipexole的病人比起安慰劑的停止期明顯時間減少(weighted mean difference 1.8hours;1.2, 2.3 95% CI)。這4個研究中,異動症評分量表的分數沒有顯著差異,但是異動症這個副作用較常在服用pramipexole的病人中出現。在2個研究中,UPDRS complication score (part IV)這個對併發症打分數的量尺有顯著的進步,但在其他的研究中則沒有。在所有研究中,使用pramipexole病人的 UPDRS ADL score都有顯著的進步。四個研究之中,有三個研究在動作期(on state)的UPDRS motor score有顯著的進步。在三個研究中,Levodopa的劑量能夠減少,而統合分析顯示pramipexole的好處有顯著意義(weighted mean difference 115 mg; 87,143 95% CI)。在pramipexole造成的dopamine相關的副作用方面,只有幻覺相關的副作用的頻率達到了統計上的顯著意義。Pramipexole組中,中途退出的頻率則顯著地比較少。

作者結論

Pramipexole可以用來減少停止期(off time)、減少動作障礙及失能、減少需要的levodopa劑量,但會增加異動症的副作用。這個結論是來自短期和中長期的試驗(最長24週)。未來需要試驗來直接比較新的和舊的多巴胺受體刺激劑。

翻譯人

本摘要由新光醫院葉旭霖翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

在巴金森氏病較晚期時,會因使用levodopa而產生副作用。這些副作用包含了不自主的扭動(異動症dyskinesia)、腿部的疼痛痙?、及每次服藥的有效時間逐漸縮短(稱為endof dose deterioration 或 wearingoff effect。多巴胺受體刺激劑在腦部的作用和levodopa類似,但不會造成長期的副作用,因此多巴胺受體刺激劑在過去幾年中,只要病人產生levodopa的副作用就會被處方使用,希望能改善這些副作用。Pramipexole是一個最近在英國得到執照的多巴胺受體刺激劑,用來治療晚期的巴金森氏病在這篇評論中,我們會檢視用這個藥的研究,以了解這個藥多有效及它會造成的副作用。四個試驗比較了pramipexole和安慰劑在共669個晚期巴金森氏病人的療效。其中兩個研期是中長期的(24週),2個研究是短期的(4週)。Pramipexole和安慰劑相比顯著地縮短了不能動的off期,平均縮短了1.8個小時。在異動症的評分量尺方面,pramipexole和安慰劑在任何一個試驗中都沒有差異,但pramipexole比較常被報告有異動症的副作用。在2個研究中,the Unified Parkinson's Disease Rating Scale (UPDRS)併發症指數有明顯的改善,但在其他研究中則沒有。在所有的研究中,UPDRS日常活動指數都得到了顯著的進步。在4個採用UPDRS動作指標的研究中,有3個有顯著的進步。在3個研究中,Levodopa的劑量得以因為pramipexole而減少,而統合分析也顯示服用pramipexole有好處。服用pramipexole的病人中,似乎比較多人有噁心、嘔吐、頭暈的副作用,有幻覺的人數則確定比較多。Pramipexole組中,中途退出的病人顯著地比較少。總結來說,pramipexole可以減少停止期、使動作障礙和失能進步、減少levodopa的劑量,但會增加異動症的副作用。這些結果是根據短期和中長期的研究(最長為時24週)。我們需要更多試驗來比較新的和舊的多巴胺受體刺激劑。

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.