Ropinirole for levodopa-induced complications in Parkinson's disease. 2001

C E Clarke, and K H Deane

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. OBJECTIVE 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. 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 SmithKline Beecham. METHODS 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. METHODS 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. 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. 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.

UI MeSH Term Description Entries
D007211 Indoles Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
D007980 Levodopa The naturally occurring form of DIHYDROXYPHENYLALANINE and the immediate precursor of DOPAMINE. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to DOPAMINE. It is used for the treatment of PARKINSONIAN DISORDERS and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. L-Dopa,3-Hydroxy-L-tyrosine,Dopaflex,Dopar,L-3,4-Dihydroxyphenylalanine,Larodopa,Levopa,3 Hydroxy L tyrosine,L 3,4 Dihydroxyphenylalanine,L Dopa
D010300 Parkinson Disease A progressive, degenerative neurologic disease characterized by a TREMOR that is maximal at rest, retropulsion (i.e. a tendency to fall backwards), rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression. Pathologic features include loss of melanin containing neurons in the substantia nigra and other pigmented nuclei of the brainstem. LEWY BODIES are present in the substantia nigra and locus coeruleus but may also be found in a related condition (LEWY BODY DISEASE, DIFFUSE) characterized by dementia in combination with varying degrees of parkinsonism. (Adams et al., Principles of Neurology, 6th ed, p1059, pp1067-75) Idiopathic Parkinson Disease,Lewy Body Parkinson Disease,Paralysis Agitans,Primary Parkinsonism,Idiopathic Parkinson's Disease,Lewy Body Parkinson's Disease,Parkinson Disease, Idiopathic,Parkinson's Disease,Parkinson's Disease, Idiopathic,Parkinson's Disease, Lewy Body,Parkinsonism, Primary
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000978 Antiparkinson Agents Agents used in the treatment of Parkinson's disease. The most commonly used drugs act on the dopaminergic system in the striatum and basal ganglia or are centrally acting muscarinic antagonists. Antiparkinson Drugs,Antiparkinsonian Agents,Antiparkinsonians,Agents, Antiparkinson,Agents, Antiparkinsonian,Drugs, Antiparkinson
D016032 Randomized Controlled Trials as Topic Works about clinical trials that involve at least one test treatment and one control treatment, concurrent enrollment and follow-up of the test- and control-treated groups, and in which the treatments to be administered are selected by a random process, such as the use of a random-numbers table. Clinical Trials, Randomized,Controlled Clinical Trials, Randomized,Trials, Randomized Clinical
D017322 Clinical Trials, Phase II as Topic Works about studies that are usually controlled to assess the effectiveness and dosage (if appropriate) of diagnostic, therapeutic, or prophylactic drugs, devices, or techniques. These studies are performed on several hundred volunteers, including a limited number of patients with the target disease or disorder, and last about two years. This concept includes phase II studies conducted in both the U.S. and in other countries. Drug Evaluation, FDA Phase 2 as Topic,Drug Evaluation, FDA Phase II as Topic,Evaluation Studies, FDA Phase 2 as Topic,Evaluation Studies, FDA Phase II as Topic
D017326 Clinical Trials, Phase III as Topic Works about comparative studies to verify the effectiveness of diagnostic, therapeutic, or prophylactic drugs, devices, or techniques determined in phase II studies. During these trials, patients are monitored closely by physicians to identify any adverse reactions from long-term use. These studies are performed on groups of patients large enough to identify clinically significant responses and usually last about three years. This concept includes phase III studies conducted in both the U.S. and in other countries. Clinical Trials, Phase 3 as Topic,Drug Evaluation, FDA Phase 3 as Topic,Drug Evaluation, FDA Phase III as Topic,Evaluation Studies, FDA Phase 3 as Topic,Evaluation Studies, FDA Phase III as Topic
D018491 Dopamine Agonists Drugs that bind to and activate dopamine receptors. Dopamine Receptor Agonists,Dopaminergic Agonists,Agonists, Dopamine Receptor,Agonists, Dopaminergic,Dopamine Agonist,Dopamine Receptor Agonist,Dopaminergic Agonist,Receptor Agonists, Dopamine,Agonist, Dopamine,Agonist, Dopamine Receptor,Agonist, Dopaminergic,Agonists, Dopamine,Receptor Agonist, Dopamine
D020820 Dyskinesias Abnormal involuntary movements which primarily affect the extremities, trunk, or jaw that occur as a manifestation of an underlying disease process. Conditions which feature recurrent or persistent episodes of dyskinesia as a primary manifestation of disease may be referred to as dyskinesia syndromes (see MOVEMENT DISORDERS). Dyskinesias are also a relatively common manifestation of BASAL GANGLIA DISEASES. Asterixis,Ballismus,Hemiballismus,Involuntary Movements,Lingual-Facial-Buccal Dyskinesia,Orofacial Dyskinesia,Abnormal Movements,Hemiballism,Linguofacial Dyskinesia,Oral Dyskinesia,Oral-Facial Dyskinesia,Tardive Oral Dyskinesia,Abnormal Movement,Dyskinesia,Dyskinesia, Lingual-Facial-Buccal,Dyskinesia, Linguofacial,Dyskinesia, Oral,Dyskinesia, Oral-Facial,Dyskinesia, Orofacial,Dyskinesias, Lingual-Facial-Buccal,Dyskinesias, Linguofacial,Dyskinesias, Oral,Dyskinesias, Oral-Facial,Dyskinesias, Orofacial,Involuntary Movement,Lingual Facial Buccal Dyskinesia,Lingual-Facial-Buccal Dyskinesias,Linguofacial Dyskinesias,Movement, Abnormal,Movement, Involuntary,Movements, Abnormal,Movements, Involuntary,Oral Dyskinesias,Oral Facial Dyskinesia,Oral-Facial Dyskinesias,Orofacial Dyskinesias,Tardive Oral Dyskinesias

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