Challenges With Parkinson Disease Treatments


Drs Rajesh Pahwa and Daniel E. Kremens discuss challenges with Parkinson disease treatment and management of motor fluctuations, dyskinesia and OFF episodes in patients.

Daniel E. Kremens, MD, JD: Dr Pahwa, we have these medications, and Dr Hauser has given us some great ways to ask patients about what they’re experiencing. But what are the challenges that patients are facing with Parkinson disease treatment, specifically in terms of things such as motor fluctuations and dyskinesia, which we are going to discuss a lot more in this program, but also OFF episodes?

Rajesh Pahwa, MD: We talked about how levodopa works very well, it is a gold standard for the treatment of Parkinson disease, but we need a number of these other medications, because we know that once a patient is on levodopa, they will develop OFF time. In addition, they’ll develop dyskinesia, which is involuntary random movement that patients develop the longer they are on levodopa. The challenge is not that levodopa doesn’t work after time, the challenge is that patients develop motor fluctuations, or OFF time, and these involuntary movements, dyskinesia. Over time I usually say 10% of our patients will develop OFF time or dyskinesia for every year they are on the medication. So, by 10 years, 90% of our patients will be having motor fluctuations and dyskinesia, and that’s the challenge we start facing once a person has been on levadopa, trying to manage their OFF time as well as their dyskinesia.

Daniel E. Kremens, MD, JD: Would someone like to comment on why we think people develop OFF? Why, if I’m taking my pills, don’t I stay ON all the time?

Robert A. Hauser, MD, MBA: I’ll give a notion about that. I think the root of the problem starts with levodopa. Levodopa has a short half-life by itself, 60 minutes. We give levodopa with carbidopa, and together levodopa has a half-life of about 90 minutes. I think of it as, in its typical form immediate-release carbidopa/levodopa, as staying in a therapeutic zone for about 2 hours. But when we start immediate-release carbidopa/levodopa, we traditionally give it about 3 times a day, and patients typically say, “I get benefit for slow and small movement, stiffness, mobility, and that benefit lasts from dose to dose, and I get this good response through the day.” We think that’s due to the fact that at least early, there are enough remaining dopamine neurons that levodopa finds its way up to those remaining dopamine neurons, gets converted to dopamine, is stored, and released over many hours. That storage and release mechanism is important. But as patients lose more and more dopamine neurons, that storage and release component is diminished further. Patients begin to say, “My levodopa is only lasting 5 hours, then 4 and a half hours, then 4 hours,” and so on, until they’re fluctuating clinically, just like what’s happening to levodopa fluctuations in their serum. Ultimately, what I say about levodopa formulations is that pharmacokinetics is destiny once you’ve lost that storage and release capacity.

Rajesh Pahwa, MD: We need to remember the gut, the gut plays a very important role. Patients have delayed gastric emptying. In fact, 75% to 80% of patients with Parkinson disease have delayed gastric emptying. When they do take the levodopa, it takes a while to get to the small intestine, where it is absorbed, and there it may compete with amino acids. In addition, they may have small bacterial overgrowth, H pylori, which can also affect levodopa absorption. There is both a central and a peripheral mechanism that results in these OFF episodes.

Daniel E. Kremens, MD, JD: Also some potential competition, not just at the gut, but at the blood-brain barrier with dietary proteins.

Fernando Pagan, MD: Those are important, and it’s also important how frequently our patients have to take medications. Medications that aren’t taken as frequently have better compliance than medicines that must be taken several times a day. That also gets harder for patients to do as the disease progresses, especially if they’re taking medicine every 3 or 4 hours. For some of our patients, they are taking medicine every 2 hours, or every 90 minutes, and that’s difficult to do.

Rajesh Pahwa, MD: How often do patients tell us, “If I stay right on schedule, I’m fine. It’s once I miss a dose or if I forget to take it, then even 15 minutes can make a difference.”

Robert A. Hauser, MD, MBA: I agree that early on patients say, “If I stay on schedule, things go well, but if I miss it, it’s a problem.” As time goes on, one of the issues is that things get more variable. Patients begin to say, “Even if I take it on time, I can’t predict, a dose might not provide benefit, or it might take 20 or 90 minutes to kick in.” They just don’t know. That variability becomes an important problem for them with regard to response.

Transcript Edited for Clarity

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