Tolerability and safety of ropinirole versus other dopamine agonists and levodopa in the treatment of Parkinson's disease: meta-analysis of randomized controlled trials.
BACKGROUND
Dopamine agonists have a well established role in the treatment of Parkinson's disease. The choice of a particular dopamine agonist requires assessing the benefit-risk balance of each available medication.


OBJECTIVE
The present study evaluated the tolerability and safety of ropinirole against those of other dopamine agonists (bromocriptine, cabergoline, pramipexole, rotigotine, pergolide) and placebo in monotherapy and adjuvant therapy with levodopa in the treatment of Parkinson's disease, as reported in the peer reviewed medical literature.


METHODS
A systematic review of the medical literature was carried out for relevant English language articles in the MEDLINE database and Cochrane Library from January 1975 to November 2008. The searches were limited to either double-blind clinical trials or randomized clinical trials that included both patients with early Parkinson's disease receiving dopamine agonist monotherapy, and patients at a later stage on combined treatment with levodopa. The Cochrane Collaboration guidelines were followed and the following data were extracted from each study: identifier (title and bibliographical reference), classification of the quality of the evidence (Jadad criteria), type and design of the study, number of patients, patient demographics (average age, sex), Parkinson's disease stage (Hoehn and Yahr Scale), treatment (monotherapy or adjuvant to levodopa), drugs used (including dosage and duration), study objective (safety or tolerability), method of evaluation of results, randomization and blinding, and description of all the adverse events in all treatment groups. A meta-analysis was performed, calculating relative risks (RRs) and confidence intervals for the 12 most relevant adverse events. On the basis of incidence and clinical importance criteria, the final selection of 12 adverse events was made by consensus between the investigators.


RESULTS
Forty randomized clinical trials were included. Direct comparison of ropinirole with bromocriptine showed a lower RR of constipation for ropinirole (0.55 [95% CI 0.35, 0.89]), while the direct comparison with levodopa showed a lower RR of dyskinesia for ropinirole (0.25 [95% CI 0.09, 0.71]); no significant differences for either dyskinesia or constipation were found when a direct comparison of ropinirole and rotigotine was made. For nausea, ropinirole, pergolide and rotigotine versus placebo all demonstrated similar RRs (2.25 [95% CI 1.85, 2.74]; 2.28 [95% CI 1.54, 3.37]; and 2.08 [95% CI 1.30, 3.34], respectively). On indirect comparison of ropinirole with pramipexole, ropinirole showed a higher RR for nausea (2.25 [95% CI 1.85, 2.74] vs 1.48 [95% CI 1.24, 1.76]), dizziness (1.87 [95% CI 1.48, 2.37] vs 1.20 [95% CI 1.01, 1.43]), somnolence (2.45 [95% CI 1.30, 4.61] vs 1.68 [95% CI 1.25, 2.25]), and dyskinesia (2.71 [95% CI 1.74, 4.21] vs 2.27 [95% CI 1.58, 3.27]). Pramipexole (3.36 [95% CI 2.41, 4.68], pergolide (4.80 [95% CI 2.24, 10.29]), ropinirole (2.84 [95% CI 1.34, 5.99]), and rotigotine (4.02 [95% CI 1.23, 13.11]) all had a higher RR of hallucinations compared with placebo. Pramipexole also showed a higher RR of confusion (2.64 [95% CI 1.18, 5.91]) and constipation (2.23 [95% CI 1.53, 3.25]) compared with placebo.


CONCLUSIONS
In all the included studies, dopamine agonists, including ropinirole, exhibited a higher incidence of adverse events than placebo. Ropinirole showed an adverse event profile similar to other dopamine agonists. Consideration of the clinical characteristics of each patient and the differences in the incidence of adverse events related to each dopamine agonist, may help to optimize the dopamine agonist therapy.
Kulisevsky
Jaime
J
Unit of Movement Disorders, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Pagonabarraga
Javier
J
D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use; D018491:Dopamine Agonists / Q000009:adverse effects / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic
D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D007211:Indoles; C046649:ropinirole; D007980:Levodopa