Defining the Patient Experience in Parkinson Disease

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EP: 1.Defining the Patient Experience in Parkinson Disease

EP: 2.Predictability of Dyskinesia and OFF Episodes in Parkinson Disease

EP: 3.Treatment of OFF Time in Parkinson Disease

EP: 4.Amantadine Extended Release for the Management of Dyskinesia and OFF Episodes

EP: 5.Unmet Needs and Future Considerations in Parkinson Disease

Robert Hauser, MD, MBA: We use several different terms to describe a patient’s Parkinson disease motor state [throughout] the day. One term we use is called ON. ON describes time when a patient is experiencing benefit from their Parkinson disease medication, regarding the motor signs of Parkinson disease, especially mobility, slowness, stiffness and tremor. OFF, on the other hand, is a time when medication has worn off or has not yet kicked in and the medication is not providing benefit for the motor signs of Parkinson [disease], including mobility, slowness, stiffness and tremor. Over time, some patients develop dyskinesia. Dyskinesia is extra movements which are induced by medication. These typically occur at the peak of levodopa concentration in the blood and dopamine concentration in the brain. These are called peak levodopa-induced dyskinesias, and they commonly consist of twisting, turning movements in the trunk, arms, and legs. So these dyskinesias are then an effect of medication [that] occur during ON time. So…the time is called ON with dyskinesia, and we separate that out into troublesome and nontroublesome dyskinesia. Troublesome dyskinesia is dyskinesia that interferes with function or causes meaningful discomfort, whereas nontroublesome dyskinesia doesn’t interfere with function or doesn’t cause discomfort to the patient.

One of the interesting things about treatment of Parkinson disease is that we commonly use carbidopa/levodopa immediate release, and levodopa has a very short half-life. When we give it with carbidopa, its half-life is really only about 90 minutes. And I think of it as maintaining so-called therapeutic concentration in the blood for only about 2 and a half hours, but we commonly give it 3 times a day in early Parkinson disease. Patients with Parkinson will say, “Oh, my slowness and stiffness are improved.” I will say that many patients with Parkinson don’t get a very good response with regard to tremor. So that’s a separate issue. But with regard to slowness and stiffness, they often say, even as I take it 3 times a day, maybe at 7 AM, noon and 5 PM, the benefit kicks in and it lasts all day long. And I’m the same all day long, including when I wake up and through the day. And that’s despite the fact that levodopa only has that 90-minute half-life.

So what’s going on there? Well, we think what’s happening is that levodopa is getting up into the brain, is being taken up by remaining dopamine neurons, is being converted to dopamine and then slowly released over time to maintain that good benefit through the day. But as time goes by and Parkinson disease patients lose more and more dopamine neurons, that ability to take up levodopa, convert it to dopamine and store it, and most importantly, slowly release it over time, diminishes. Many patients then after a few years, start to say, “Hey, doctor or care provider, my levodopa is not lasting from dose to dose anymore. It’s lasting about 4 and a half hours and then it wears off. My Parkinson motor symptoms are coming back. My slowness, stiffness and tremor are reoccurring. I take my next dose and it takes some minutes for it to kick back in, maybe 20 to 30 minutes.” And that initially can be pretty consistent. But as time goes on and patients lose more and more dopamine neurons, these problems get worse and worse. Patients begin to notice that the duration of benefit gets shorter and shorter. They begin to say, “Well, the duration was only 4 hours down, 3 and a half hours, then 3 hours.” And, ultimately, they experience motor fluctuations, where the benefit is really dependent on them getting levodopa up into the brain. Ultimately these episodes of ON time are only lasting a little over 2 hours or so.

The other thing that happens is that things become very variable, and one of the reasons for that is that it’s not only the Parkinson disease pathologies in the brain, it’s also in the nerves to the gut. And many patients with Parkinson disease have gastroparesis. Levodopa has to get down through the esophagus, past the stomach, and into the small intestine to get absorbed. And if there’s slow transit through the stomach, patients will notice that it takes a longer time for the medication to get absorbed and for benefit to kick in, and it also becomes quite variable. So after a number of years, particularly toward the end of this period of, let’s say, 7 to 10 years, many patients will begin to say, “Well, my immediate release carbidopa/levodopa is only lasting about 3 hours.” And it’s very variable as to how long it will take until it kicks in. It may be 40 minutes or maybe an hour and a half, and sometimes it doesn’t kick in at all. So these patients then experience a shortening of the benefit from each dose, and it becomes much more variable with regard to how long it takes for it to kick in and how long that benefit lasts for each dose.

Transcript is AI-generated and edited for clarity and readability.