Context: Levodopa is the gold-standard therapy for Parkinson's disease. However, long-term treatment leads to involuntary movements and response fluctuations which add to the complexities of later disease-management. In addition, preclinical evidence suggests that levodopa is toxic to dopaminergic neurons. These problems have led to a move away from levodopa towards initial monotherapy with a dopamine agonist.
Starting point: Positron-emission tomography (PET) and single-photon emission computed tomography (SPECT) tracers have been developed which may be considered surrogate markers for remaining dopaminergic neurons. In a randomised controlled trial in patients with early Parkinson's disease, the Parkinson Study Group used 123I-beta-CIT SPECT (JAMA 2002; 287: 1653-61). Those patients given pramipexole had significantly reduced loss of striatal uptake at 46 months compared with those given levodopa (16.0% vs 25.5%). In a similar trial, Alan Whone and colleagues used 18F-DOPA PET (Neurology 2002; 58 [suppl 3]: A82-83). Patients given ropinirole had significantly reduced loss of striatal uptake at 24 months compared with those given levodopa (13% vs 20%). These studies suggest that agonist monotherapy may be neuroprotective and/or that levodopa is toxic. This work has been criticised as the SPECT results may have resulted from a differential effect of the agonist and levodopa on the regulation of the dopamine transporter, thereby influencing the imaging outcome measure. Other criticisms include insufficient data on the use of the potential neuroprotectant selegiline and patients on pramipexole in the SPECT study appear to have been clinically slow progressors. Single clinical trials with each of the four modern agonists compared with levodopa show that as monotherapy the agonists delay the onset of involuntary movements, although at the expense of poorer treatment of motor impairments and disability and more dopaminergic adverse events. The only health-related quality of life data show no difference between pramipexole and levodopa after 4 years. No information on health-economics measures is available but agonists cost two to three times as much as levodopa. WHERE NEXT? Young patients should be treated with agonist monotherapy since the trials included predominantly younger patients who have a higher incidence of motor complications. Those with significant co-morbidity, dementia, or a short life-expectancy should be treated with the lowest dose of levodopa required to maintain motor function. For the vast majority though, no clear guidance can be given. Further large-scale pragmatic trials in large numbers of patients over prolonged periods are urgently required.