Cabergoline for levodopa-induced complications in Parkinson's disease

  • Review
  • Intervention

Authors

  • Carl E Clarke,

    Corresponding author
    1. College of Medical and Dental Sciences, School of Clinical and Experimental Medicine, Birmingham, West Midlands, UK
    • Carl E Clarke, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, West Midlands, B18 7QH, UK. c.e.clarke@bham.ac.uk.

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  • Katherine HO Deane

    1. University of East Anglia, Edith Cavell Building, Norwich, UK
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Abstract

Background

Long term levodopa therapy in Parkinson's disease is associated with the development of motor complications including abnormal involuntary movements 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 cabergoline therapy versus placebo in patients with Parkinson's disease, already established on levodopa and suffering from motor complications.

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 Limited.

Selection criteria

Randomised controlled trials of cabergoline 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

Cabergoline has been compared with placebo in two phase II (6 - 12 weeks) and one phase III randomised controlled trials (24 weeks). These were double-blind, parallel group, multicentre studies including 268 patients with Parkinson's disease and motor complications. The reduction of 1.14 hours (WMD; 95% CI -0.06, 2.33; p = 0.06) in off time in favour of cabergoline was not statistically significant. Inadequate data on dyskinesia was collected either on rating scales or as adverse event reporting to allow a conclusion to be drawn. A small but statistically significant advantage of cabergoline over placebo was seen in one study for UPDRS ADL (part II) score and UPDRS motor score. No such advantage was seen in one other study due to small numbers of patients and the comparatively low doses of cabergoline used. No significant differences in Schwab and England scale were seen in two studies. Levodopa dose reduction was significantly greater with cabergoline (WMD 149.6 mg/d; 95% CI 94.1, 205.1; p < 0.00001). There was a trend towards more dopaminergic adverse events with cabergoline but this did not reach statistical significance at the p < 0.01 level. However, there was a trend towards fewer withdrawals from cabergoline.

Authors' conclusions

In the management of the motor complications seen in Parkinson's disease, cabergoline can be used to reduce levodopa dose and modestly improve motor impairment and disability with an acceptable adverse event profile. These conclusions are based on, at best, medium term evidence.

Plain language summary

Cabergoline 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 (choreoathetosis), 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 when used as initial therapy. For this reason, dopamine agonists have for some years been added once these problems develop in the hope of improving them. Cabergoline 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.

Cabergoline has been compared with inactive placebo in two smaller and shorter (6 - 12 weeks) studies and one larger, medium term trial (24 weeks). These trials included 268 patients with Parkinson's disease and motor complications. The average reduction in the time patients spent in the immobile off state was 1.1 hours greater with cabergoline compared with placebo, although this was not statistically significant. Inadequate data on dyskinesia was collected to allow a conclusion to be drawn. A small but significant advantage of cabergoline over placebo was seen in one study for activities of daily living and physical functioning. No such advantage was seen in one other study due to small numbers of patients and the comparatively low doses of cabergoline used. Levodopa dose reduction was greater with cabergoline by 145 mg per day. There was a trend towards more side effects with cabergoline but towards fewer withdrawals from cabergoline treatment.

In the management of the motor complications seen in Parkinson's disease, cabergoline can be used to reduce levodopa dose and modestly improve motor function and activities of daily living with an acceptable side effect profile. This is based on, at best, medium term evidence. Further long term trials are required to compare the newer with the older dopamine agonists, particularly in terms of quality of life and cost.

Laički sažetak

Kabergolin za komplikacije izazvane levodopom kod Parkinsonove bolesti

U kasnijim fazama Parkinsonove bolesti javljaju se nuspojave zbog uporabe levodope u liječenju. Radi se o od nehotičnim pokretima istezanja (diskinezija), bolnim grčevima u nogama (distonija) i skraćenom odgovoru na svaku dozu (engl. end-of-dose deterioration) ili skraćivanje djelovanja doze (engl. wearing-off efect). Agonisti dopamina oponašaju levodopu u mozgu, ali oni ne uzrokuju ove dugoročne komplikacije liječenja kad se koriste u inicijalnoj terapiji. Iz tog razloga, agonisti dopamina se dodaju zadnjih godina kada se razviju spomenuti problemi u očekivanju da će dovesti do njihovog poboljšanja. Kabergolin je agonist dopamina licenciran za liječenje kasne Parkinsonove bolesti. U ovom Cochrane sustavnom pregledu literature ispitana su istraživanja nad ovim lijekom kako bi vidjeli koliko je učinkovit i koje nuspojave uzrokuje.

Kabergolin je uspoređen s neaktivnim placebom u dva manja i kraća (6 - 12 tjedana) istraživanja te u jednom većem, srednjeg trajanja (24 tjedana). U ova istraživanja uključeno je 268 bolesnika s Parkinsonovom bolesti i motoričkim komplikacijama. Prosječno smanjenje vremena koje bolesnici provedu u nepokretnom "off" stanju je 1,1 sati više sa kabergolinom u usporedbi sa placebom, iako to nije statistički značajno. Neadekvatni podaci prikupljeni o diskineziji ne omogućuju zaključak. Manja ali značajna prednost kabergolina u odnosu na placebo je vidljiva u jednom istraživanju aktivnosti svakodnevnog života i tjelesnog funkcioniranja. Takva prednost nije vidljiva prilikom jednog drugog istraživanja, zbog malog broja pacijenata i relativno niske doze korištenog kabergolina. Smanjenje doze levodope je bilo veće kad je korišten kabergolin, za 145 mg dnevno. Postoji trend većeg broja nuspojava tijekm terapije kabergolinom, ali i manjeg broja odustajanja od terapije kabergolinom.

U liječenju motoričkih komplikacija koje se viđaju kod Parkinsonove bolesti, kabergolin može koristiti za smanjenje levodopa doze i skromno poboljšanje motoričke funkcije i aktivnosti svakodnevnog života s prihvatljivim profilom nuspojava. To se temelji na, u najboljem slučaju, dokazima umjerene kvalitete. Daljnje dugoročne studije su potrebne za usporedbe novijih sa starijim vrstama agonista dopamina, posebno u smislu kvalitete života i troškova.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Diana Rubić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr