What happens, however, though, is that people sometimes develop wiggly movements, which we call dyskinesias and the benefit from an individual dose gets less over time. So, for instance, if one pill gave you four hours of benefit at, say, year three of the disease, by year 10 of the disease, the same pill may now only give you two hours of benefit. So it always works, but the duration of benefit from an individual dose gets less and less over time.
Are there ways of getting the levodopa to last longer?
One of the main problems with the long-term use of levodopa is that its duration of effectiveness gets shorter and shorter over time. So there's been a lot of emphasis in making its duration of effect longer. The L-Dopa is metabolized by two enzymes in the body. One is called carbidopa, and the second enzyme is called COMT. And we now have inhibitors or blockers of that enzyme. When you block that enzyme, the blood level of levodopa is much extended in the patient. When you extend the blood level, you also extend the duration of the clinical response.
These drugs are called COMT inhibitors, and they've been very useful in the motor fluctuations and extending the duration of effect. You can imagine, if you are "off"—which in our terminology means the drug's not working—three to four hours a day and you're shaking and you're slow, you can't do the things you need to do. But with these drugs, sometimes the "off" time goes away, so the drug's working through the whole day, and that's of course, our goal in the treatment of Parkinson's disease.
How do the dopamine agonists work?
The dopamine agonists are a class of drugs that directly stimulate the dopamine receptor, so they make up for the dopamine deficiency in Parkinson's. They cause fewer long-term complications than levodopa-containing compounds such as the wearing-off problem. Their disadvantage is that they're not as good at controlling the symptoms as levodopa-containing compounds.
If you look at control of symptoms, in early disease, dopamine agonists and levodopa are somewhat equal. As the disease advances, however, levodopa-containing compounds are much more effective.
What is the current medication strategy for younger people with Parkinson's disease?
We use dopamine agonists in the young-onset patients, and the reason it's probably more important in them is that these patients are more likely to develop the levodopa-induced dyskinesia and the wearing-off problem. If you're 40 years old, you probably have 30 or 40 year's worth of life left, so you have a lot of time to develop these potential complications. So, with patients in their 40s or 50s, the common practice among neurologists now is to start the dopamine agonists first and save levodopa for later.
