A new look at levodopa based on the ELLDOPA study

Summary

Levodopa has been the gold standard for Parkinson’s disease (PD) therapy since it was successfully introduced in 1967. But in the years since then, after recognizing that levodopa often leads to the motor complications of wearing-off and dyskinesias, there have been debates among clinicians as to when levodopa therapy should be started. Delaying therapy was advocated for the purpose of delaying the development of these motor complications. This became more popular as the dopamine agonists became available. Although less potent than levodopa in ameliorating the symptoms of PD, they were much less likely to produce the unwanted motor complications, even though they had their own adverse effects. When it was recognized that dopamine, itself, might be a factor leading to the death of dopaminergic neurons through its contributing to the formation of oxyradicals, a new concern arose, namely that levodopa, through its conversion to brain dopamine, might add to the existing oxidative stress and possibly enhance neurodegeneration of dopaminergic neurons. Though widely debated and without definite evidence, this possibility was sufficient to make some clinicians have further reason to delay the start of levodopa therapy. The ELLDOPA study was created to test this hypothesis. The clinical component of the study failed to find an enhancement of PD symptoms after levodopa was withdrawn following 40 weeks of levodopa therapy. Rather, the clinical results indicated that the symptoms had progressed much less than placebo, and in a doseresponse manner. This suggests that levodopa may actually have neuroprotective properties. The uncertainty that a 2-week withdrawal of levodopa may not have entirely eliminated its symptomatic benefit and the discordant results of the neuroimaging component of the ELLDOPA study have created even more uncertainty that levodopa is neuroprotective. A survey of neurologists who treat PD patients showed that the vast majority of these clinicians do not believe levodopa is neuroprotective, and they remain concerned about the drug’s likelihood of inducing motor complications. Thus, the ELLDOPA study failed to change the treating pattern of PD, and the clinicians require more convincing evidence of either neuroprotection or neurotoxicity of levodopa before they would alter their treatment approach.