Agonists vs levodopa in PD

Levodopa treatment has substantially improved the quality and duration of life for patients with PD. It was recognized early on, however, that symptomatic treatment of PD with levodopa had treatment-related complications such as dyskinesias, short-duration responses (SDRs), and behavioral and psychiatric problems. Further, patients with PD continue to decline in functional abilities and have a shortened life expectancy. A potential role for dopamine agonists in PD treatment was recognized by Cotzias et al.1 in the late 1960s with apomorphine being the first agonist to be evaluated in a PD clinical trial. Apomorphine was efficacious when administered orally, but a liver metabolite of the drug caused renal failure, prohibiting its use as an oral agent for the treatment of patients with PD. Agonists have several potential advantages over levodopa. Agonists do not require metabolism to an active form (as is the case for levodopa) and do not compete with dietary amino acids for active transport across the gut epithelium and blood-brain barrier. There may also be increased reproducibility of the dose-response and time-action curves. Further, unlike levodopa, agonists may not generate potentially toxic free radicals and may be neuroprotective. Four dopamine agonist drugs are approved for use in PD in the United States: bromocriptine, pergolide, pramipexole, and ropinirole. In general, there are more similarities than differences among these drugs.2 Direct clinical comparisons between these four dopamine agonists are limited; their relative clinical efficacy remains unclear, and no consistent differences have been established. Each agonist has a similar frequency of dopaminergic side effects: nausea, orthostatic symptoms, somnolence, and hallucinations. The two initial agonists, bromocriptine and pergolide, are ergot derivatives and occasionally result in leg edema, Raynaud’s phenomenon, erythromelalgia, and pleural and peritoneal fibrosis. Recent direct comparisons of dopamine agonists vs levodopa for patients with early and mild PD have provided …