Abstract & Commentary
Source: Whone AL, et al. Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol. 2003;54:93-101.
The non-ergot dopamine agonists ropinirole and pramipexole effectively ameliorate the cardinal motor features of idiopathic Parkinson’s disease (PD). In vitro and in vivo studies of both drugs have shown possible neuroprotective benefit against the effects of oxidative stress. If true, these agents would be the first drugs with the ability to impact the natural history of this progressive neurodegenerative illness.
The current study used serial 18-flurodopa PET imaging to measure the reduction in nigrostriatal innervation of the putamen in PD patients. A total of 186 patients with clinically diagnosed early PD (symptom duration less than 2 years) were randomized in doubleblind fashion to receive either ropinirole or levodopa. The dose of ropinirole was gradually increased until therapeutic benefit was attained, to a maximum daily dose of 24 mg, and the dose of levodopa was increased to clinical efficacy to a maximum dose of 1000 mg per day. If symptoms were inadequately controlled, patients could receive open-label supplementary levodopa. PET scans were performed 4 weeks after either drug was begun and again 2 years later, with a 12-hour washout period prior to scanning.
Of 186 PD patients enrolled in the study, 21 were discovered to have normal baseline 18-flurodopa PET scans, suggesting that the clinical diagnosis of PD was incorrect; these patients were excluded from the analysis. Of 87 patients enrolled in the ropinirole arm, 15 required supplemental levodopa, while only 7 of 75 patients enrolled in the levodopa arm required supplementation. The mean reduction in putamen uptake was 13.4% for the ropinirole group and 20.3% for the levodopa group (P = .022). Clinical measures of rigidity and bradykinesia demonstrated that patients treated with levodopa enjoyed superior motor performance compared to those treated with ropinirole. Adverse events were more common in the ropinirole group, including nausea (43.7% vs 21.3%) and somnolence (37.9% vs 9.3%). Hallucinations (6 patients to 1) and confusion (5 patients to 1) were also more common with ropinirole.
Commentary
Whone and colleagues conclude that "this vivo 18-flurodopa PET study suggests that, relative to levodopa, ropinirole is associated with a slower loss of dopamine-terminal function in patients with early PD." Neurology Alert readers should be aware, however, that this does not represent the opinion of many members of the movement disorder community. Although a consortium of movement disorder experts performed the study, it was paid for and contracted by the manufacturer of ropinirole, GlaxoSmithKline.
The present study is hampered by problems that are too numerous to fully delineate in these pages. In brief, the design is flawed, in that the study allowed for flexible dosing of the drugs and for supplementation by levodopa, confounding any attempt to correlate dose and effect. The fact that 21 patients were enrolled in the study and only later found to have normal PET scans calls into question the reliability of the enrolling evaluations. Studies with pramipexole, a closely related dopamine receptor agonist, have demonstrated that treatment with agonists affects the expression of dopamine receptors as measured by SPECT. It is unknown whether treatment with either levodopa or ropinirole directly affects fluorodopa uptake on PET, and because all scans were performed during treatment with only a 12-hour washout, this important question prevents reliable conclusions from being drawn from the data.
What is clear from the study is that patients treated with levodopa enjoyed better motor performance with fewer side effects and fewer adverse events. Neurology Alert readers should view trials contracted by pharmaceutical companies with appropriate caution. — Steven Frucht, MD, Assistant Professor of Neurology, Movement Disorders Division, Columbia-Presbyterian Medical Center, Assistant Editor, Neurology Alert.
The non-ergot dopamine agonists ropinirole and pramipexole effectively ameliorate the cardinal motor features of idiopathic Parkinsons disease.
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