Selection of treatment for the management of OFF episodes in Parkinson’s disease

Stuart Isaacson, MD: I’d like to go back to something you pointed out earlier and that’s a fundamental difference between how Parkinson’s disease specialists view treatment OFF from maybe others. And this idea of ​​how long a dose provides benefit and then how much benefit it provides or how much OFF you have when you lose benefit. How the frequency of OFF episodes, how many times per day, for example, and the severity of OFF episodes, how do you distinguish them and how do they impact your decision to treat? And, more precisely, with what treatments should you choose to treat yourself?

Robert A. Hauser, MD, MBA: You are quite right. Basically, these 2 axes that you have just mentioned, the magnitude of the benefit and the duration of the benefit that you have to think about. And the simplest is the duration of the benefits because you get there quite easily, when you start saying, how long does your dose of levodopa last? How long does it take for the next dose to take effect? How do you feel when you wake up in the morning and how long does it take for this dose to take effect? It is more difficult to understand the magnitude of the benefits. I try to do that by saying, “What do you look like when you wake up and what happens when the medicine kicks in?” What benefit do you get or how many problems do you have when you wake up, then how many benefits do you get? And, as I pointed out earlier, it’s a question of, “OK, I see you now and where are you on the levodopa cycle?” Is this your best? Is it closer to the middle? Is it an average? OK, compared to where you are now, what do you look like best? And it’s hard to get the right language for that. I don’t know, are you 10% better? Do you walk much better? But you do your best to understand this notion. And then what happens as a Parkinson’s doctor, you’re trying to get an idea in your head, what will this person look like with good benefit on their medication? And it’s not always easy because if they’re 78 and they have all the typical morbidities and arthritis and hip issues and all that, what do they look like with a good answer? And you have to make that decision. “OK, they have trouble walking. What is the share of Parkinson’s disease? How much do these other problems cost? And let’s say he says, “Well, I’m not quite at my best right now.” And you say, “It would be nice if he got better, you don’t know.” Often you may wonder, well, maybe we should try increasing the dose a bit to see if I can improve the magnitude of the benefits and we’ll find out. Now, we do that quite often and say, “Well, here are the potential side effects you might encounter. If this happens, you may need to descend. Or if we don’t get any advantage, you may have to go back down. It’s a very important part of that judgment, and it’s often not very easy, but sometimes it is. If they’re too slow and it’s obviously Parkinson’s disease, you want a higher magnitude of benefit and that’s usually done by increasing the dose of levodopa, individual doses.

Rajesh Pahwa, MD: It is important to remember that it is not the number of episodes or days or the duration of episodes that may be important. Maybe it’s gravity. Even if a patient has 30 minutes of OFF a day but is absolutely not functional at all, can’t get up from a chair, can’t walk to the bathroom, unlike another person who has 4 episodes of OFF a day where they have more tremors but otherwise they work well, it’s not the time and duration. It also has to be how serious they can get. And the other thing is, even if they have 1 severe episode and 3 non-functioning or non-serious episodes, that’s still an important part of the treatment paradigm to actually help that patient.

Stuart Isaacson, MD: Laxman, what role does the presence or absence of dyskinesia play in the management of OFF symptoms? Because obviously we could double, triple or quadruple doses of levodopa and have a lot less OFF, but probably a lot more dyskinesia and other peak side effects. To what extent do you put a brake on the presence of dyskinesia and its degree in the management of OFF and the choice to treat OFF?

Laxman Bahroo, DO: Dyskinesia certainly complicates the management of OFF in several ways, as mentioned. If someone had OFFs, I have a lot more freedom to adjust the dosage, whether it’s long-acting levodopa or adding adjuvants or all of the above combination. Once the dyskinesias appear, and this is a discussion with patients that I have, I say: “When I add an adjunct drug that will increase your overall dose of levodopa, it will change its pharmacokinetics. Either that will make it last longer or allow more of it to reach the brain. We treat the OFFs but we can potentially aggravate the dyskinesias. And for some patients, if they have very mild and infrequent dyskinesias, it’s not as concerning. Maybe a little absorption may not be a problem. But for patients who fluctuate with moderate to severe dyskinesias and then moderate to severe OFF, it becomes a big challenge. How can I adjust your dosage so that I can cover these OFFs without making the dyskinesias worse? And luckily we have a bunch of different classes of drugs that we can use that can help us fine-tune it. I think it’s helpful to use longer acting levodopa formulations as the different pharmacokinetics don’t have such a high peak, which is helpful in some cases to be able to fine tune the levodopa dosage. In other cases, I might sometimes say, “I understand that you have OFFs, you have dyskinesias, but every time we adjusted a medication to reduce your OFFs, we made your dyskinesias worse. Maybe we’re approaching it the wrong way. Maybe we address it by reducing your dyskinesias, managing that first and then coming in and adding more drugs to treat the OFFs. And sometimes I like to use drugs that can work both on the extremes and get me more in the middle. And these may not be dopaminergic compounds in that sense. Perhaps we should look beyond dopamine targets for this. And for so long so many drugs have been dopaminergic that maybe we need to look at glutamate as a target to be able to get rid of excessive high dyskinesias in the OFFs and modulate towards the middle. And there are different ways around it, but dyskinesias certainly make dealing with OFFs interesting, complicated – choose your favorite word here.

Transcript edited for clarity

Martin E. Berry