Jill M. Giordano Farmer, DO, MPH: I think what you’re describing is a good way to sometimes wrap your head around trying to explain a very complex concept. If you can discuss it with patients in the setting of, “Because of the gastrointestinal [GI] dysmotility, you might have a delayed reaction of your medications turning on. Because of the GI dysmotility, you might have an issue with the medications wearing off too soon. Because of the amount of time the medications are in and out of your system,” you can talk about morning OFF periods or different types of OFF periods as well. Those might be ways in which you can help educate the patient as well as the caregiver as to what an OFF time might be. And then you can describe what the symptoms of those OFF periods might look like to them.
If you think about the idea of delayed onset as being under the OFF category, or morning OFF period as an OFF category, or wearing off before the next dose as an OFF category, those are 3 distinct episodes that you would be able to then have the discussion with the patients and the caregivers about. About what that might look like for them as far as their symptoms go, whether it’s motor symptoms or non-motor symptoms for Parkinson.
Stuart Isaacson, MD: Jill, you bring up this new way of thinking about OFF. We’re focused as a field on OFF time; and 6 hours of OFF time, when people enter trials and we reduce it by an hour and a half or 2 hours. But what is OFF time made up of? All of these OFF episodes throughout the day—the morning akinesia you point out, between doses, this dose or that dose, a mealtime dose with protein effect—it gets really complicated, and these OFF episodes begin with these initial symptoms of OFF motor, non-motor. And they get worse and worse. They transition into a full OFF state. The medication is taken, but then they have to wait until it begins to work. Then they gradually have improvement to begin to turn on, and finally they’re ON again.
The 1 study that was done by Eldad Melamed, MD’s group really demonstrated that the time for wearing off until the next dose was only about half the amount of time that patients actually took a dose and then waited for it to begin to work. I think this makes us realize that we don’t only need medicines that work centrally to make levodopa doses last longer. We need medicines that can work quicker and more reliably by maybe non-oral means.
Daniel E. Kremens, MD, JD: Yes. And I think, again, it’s really important to emphasize. I think patients and many neurologists think about OFF, or even OFF episodes as this predictable sort of classic wearing off. The patient has been taking their medication, or carbidopa, levodopa, 3 times a day, let’s say 5 to 6 hours apart; and now, all of a sudden it’s not working any more. That is 1 very common type of OFF—this wearing off. But as Jill just described, there are multiple ways to think about OFF episodes. There’s the morning akinesia when the patient has woken up. They haven’t had their first dose of levodopa yet. They’re OFF. There’s the patient, probably related to the gut, as you brought up, they take their medicine and it never turns on, right? Why? Maybe they had it with too much protein and there’s competition? Maybe there was gastroparesis and it failed to move forward? Then there’s the completely unpredictable OFF, and I don’t think we know the mechanism of that.
Peter LeWitt, MD, M.Med.Sc: They’re multiple, maybe simultaneous in the same patient. And I guess for the practical application, how do you talk to the patient? How do you get this information in? It’s nice to ask the question, “Do you have motor fluctuations?” But don’t assume the answer, when it comes back, “Yes,” is that you or the patient have any inkling of whether it’s 1 or multiple mechanisms. It would be nice if there was a simple form that someone could fill out before coming into your office where it’s all laid out. We try that in our clinic.
But I think it’s a conversation. It’s an ongoing dialogue that creates the notion of what you can try among the armamentarium of medications; or just counseling on what to do with meals, the timing of medication, how to deal with that bad day versus the rest of the week when they’re doing well and put that information together in a synthesis that leads to practical things to try. And often, it’s multi-step. It’s a titration process, and it’s feedback from the patient that makes the decisions of what to do. And that’s a burden on the physician who likes to think that you can make a decision on the spot. It’s obviously this, it’s obviously that, but it’s often possibly several things going on in terms of mechanisms.
Rajesh Pahwa, MD: And the thing is, we talk about the patient getting up in the morning and being OFF. Of course, some other people wake up in the morning and that’s their best time of the day. But the other challenge we and patients and other physicians have is, what is delayed ON? We talk about delayed ON, because whenever a patient gets up in the morning and takes a pill, it is going to take a while for the dopamine to get to the brain, so to speak.
But practically, if I look at it—and I know, Stu, you did that early morning study—in clinics if someone says it takes more than 30 minutes for their morning dose to work, we need to look at another way to get them going faster. And there are patients who say it takes until they take their second dose before they get going. I think that’s an important thing to check with a patient, how long their first dose takes to get going. Because really, someone saying, “I don’t get ON until I take my second dose,” that should not be happening.
Stuart Isaacson, MD: Yes, patients may think it’s 30 minutes, but we actually had them go home and do a diary. It wound up being 45 minutes, or an hour. And remarkably, many patients had dose failure at the first dose and didn’t even report it. So it’s not just wearing off or delayed ON. Sometimes it’s suboptimal on or a no on—this dose failure idea. It can be very hard for patients to understand these types of varying degrees of how well they respond to a single dose, and that every day is different.
Peter LeWitt, MD, M.Med.Sc: Right.
Stuart Isaacson, MD: And you have the morning time, you have mealtime, and doses may work differently. So it probably isn’t the sinusoidal, Dan, as you pointed out. It’s probably this jagged mountain range, and every day is a different pattern.
Daniel E. Kremens, MD, JD: Every day and every dose.