Levodopa remains the most potent symptomatic treatment for PD and the gold standard with which other drugs are compared, even after 35 plus years of availability. Over time, the strategies employed for its use have changed. We now use the lowest possible effective dose rather than the highest tolerated dose. We avoid frequent small doses, as this can contribute to unpredictable responses, and it is usually prescribed with adjunctive therapies, such as dopamine agonists and COMT inhibitors. As such, fewer early and late complications occur today than those reported in the past; however, late complications still occur and continue to be a concern in advanced PD.
The exact role of levodopa in the development of motor complications is controversial but it is likely to play some role, particularly in relation to the progression of already existing fluctuations to a more unpredictable pattern. In particular, it may be the pulsatile delivery of orally ingested levodopa that leads to this problem, not the drug itself. It is possible that fluctuations are a reversible pharmacological effect, as demonstrated with infusion therapies and deep brain stimulation. It is established that disease duration, progression, severity, and age of onset do play important roles in the development of fluctuations and dyskinesia, perhaps more important than the pulsatile delivery. Although dopamine agonists provide greater protection against the development of motor complications, this benefit in the long run is unclear. This is especially true since they are inferior to levodopa from a symptomatic standpoint and nearly all patients ultimately require levodopa. What is clear is that levodopa is consistently more potent at any stage of disease, and that its delay contributes to a higher degree of disability and possibly mortality and dyskinesia.
Recent studies have contradicted the findings of older ones regarding whether levodopa is toxic. A critical review of the literature demonstrates that if in vivo conditions are established, not only is levodopa not toxic but may in fact be protective. This is further supported by the improved mortality rates of PD since the availability of levodopa. Such a neuroprotective effect needs to be confirmed, especially since imaging studies have demonstrated the opposite result from clinical outcomes. Further confirmatory studies of the neuroprotective potential of levodopa are needed.
There is no study to date that can conclusively establish a causative link between the use of levodopa and the potential development and recurrence of malignant melanoma. However, a recent study suggested a small but significant increase in the risk of melanoma in PD but did not address the role of levodopa. Although the literature indicates that a history of melanoma should not keep a patient from taking the drug, it is reasonable to provide appropriate vigilance.
The connection between levodopa therapy and elevated HC is a newer concern. Although it is established that levodopa elevates HC, it is unclear if this change is clinically significant. HC is a risk factor for atherosclerotic disease and dementia, but the literature does not demonstrate an increase in cerebrovascular or coronary artery disease in PD. Any connection to dementia is not established and further research is needed.
Differentiating early PD from other forms of parkinsonism can be a challenge; most studies quote a clinical accuracy of 75% to 80% when compared with pathologic diagnosis. It is widely held that PD patients frequently show a significant and robust response to levodopa therapy when compared to other forms of parkinson-ism. Despite this, studies to date cannot recommend the use of a single acute lev-odopa challenge, as the results have not demonstrated accuracy superior to clinical diagnosis.
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