Treatment Selection for Managing OFF Episodes in Parkinson Disease


Drs Robert A. Hauser, Rajesh Pahwa, and Laxman Bahroo discuss factors to consider when approaching treatment selection for managing OFF episodes in Parkinson Disease.

Stuart Isaacson, MD: I would like to come back to something earlier that you had pointed out and it’s a seminal difference between how Parkinson’s specialists view treating OFF from perhaps others. And this idea of how long a dose gives benefit and then how much benefit it gives or how much OFF you have when you lose benefit. How does the frequency of OFF episodes, how many times a day, for instance, and the severity of OFF episodes, how do you distinguish between these and how do they impact your decision to treat? And, more specifically, with what treatments to choose to treat with?

Robert A. Hauser, MD, MBA: You’re exactly right. Basically, these 2 axes that you just mentioned, the amplitude of benefit and the duration of benefit that you have to think about. And that the easier one is the duration of benefit because you get at that pretty easy, when you start to say, how long does your levodopa dose last? How long does it take for the next dose to kick in? What are you like when you wake up in the morning and how long does it take for that dose to kick in? It’s harder to understand the amplitude of benefit. I do try to get at that by saying, “What are you like when you wake up and what happens when the medication kicks in? What benefit do you get or how much trouble do you have when you wake up and then how much benefit do you get?” And, as I pointed out earlier, it’s a question of, “OK, I’m seeing you now and where are you in the levodopa cycle? Is this your best? Is this closer to the middle? Is this an average? OK, compared to where you are now, what are you like at your best?” And it’s hard to get the right language for this. I don’t know, are you 10% better? Are you walking much better? But you do your best to get that notion. And then what happens as a physician providing care in Parkinson’s disease, you try to get an idea in your head, what will this person look like with good benefit with their medication? And that’s not always easy because if they’re 78 years old and they’ve got all the typical morbidities and arthritis and hip problems and all that, what do they look like with good response? And you must make that decision. “OK, they’ve got some trouble walking. How much of it is Parkinson’s disease? How much is it these other problems?” And let’s say he says, “Well, I’m not quite at my best right now.” And you say, “It’d be good if he were doing better, you don’t know.” A lot of times you may ask yourself, well, maybe we should try to take the dose up a little bit to see if I can improve the amplitude of benefit and we’ll find out. Now, we do that not infrequently and we’ll say, “Well, here are the potential adverse effects you might run into. If that happens, you may need to come down. Or if we don’t get any benefit, you may have to come back down.” It’s a very important part of making that judgement, and it often is not super easy but sometimes it is. If they’re too slow and it’s obviously Parkinson’s, you do want to get the amplitude of benefit higher and usually that’s done by increasing the levodopa dose, the individual doses.

Rajesh Pahwa, MD: It’s important to remember, it’s not the number of episodes or day or how long the episodes last that can be important. It could be the severity. Even if a patient is having 30 minutes of OFF a day but they are absolutely not functional at all, cannot get up from a chair, cannot walk to the bathroom as opposed to another person who is having 4 episodes of OFF a day where they have more tremor but otherwise, they are functioning fine, it is not the time and duration. It also has to be how severe they can get. And the other thing is, even if they have 1 severe episode and 3 nonfunctional or non-severe episodes, it’s still an important part of the treatment paradigm to actually help this patient.

Stuart Isaacson, MD: Laxman, what role does the presence, or the absence of dyskinesia play in managing OFF symptoms? Because obviously we could double or triple or quadruple the levodopa doses and have a whole lot less OFF, but probably a whole lot more dyskinesia and other peak adverse effects. How much do you put stop in whether dyskinesia is present and to its degree in managing OFF and choosing to treat OFF?

Laxman Bahroo, DO: Dyskinesia certainly complicates management of OFF in many ways, as mentioned. If somebody was having OFFs, I have a much more free hand in adjusting dosage, whether that’s going to long-acting levodopa or adding adjuncts or all of the above combination. Once dyskinesias come in, and this is a discussion with patients that I have, I say, “When I add an adjunctive medication that’s going to raise your overall levodopa dosage, that’s going to change the pharmacokinetics of it. Either it’s going to make it last longer or allow more of it to get to the brain.” We are treating OFFs but we may potentially worsen dyskinesias. And for some patients, if they have very mild, infrequent dyskinesias, that’s not as much of a concern. Maybe a little bit of an uptake might not be an issue. But for patients who are fluctuating with moderate to severe dyskinesias and then moderate to severe OFFs, this becomes a big challenge. How do I adjust your dosage so that I can give you coverage of those OFFs without making the dyskinesias worse? And thankfully, we have a bunch of different classes of medications that we can use that can allow us to fine tune it. I believe going to longer acting levodopa formulations is helpful with the different pharmacokinetics not having as high of a peak is helpful in some cases to be able to fine tune the levodopa dosing. In other cases, sometimes I might say, “I understand you have OFFs, you have dyskinesias, but every time we've adjusted a medication to reduce your OFFs, we’ve worsened your dyskinesias. Maybe we’re approaching it the wrong way. Maybe we approach it by reducing your dyskinesias, managing that first then coming in and adding in more medications to treat OFFs.” And sometimes I like using medications that can work on both that take the extremes and bring me more to the middle. And those may not be dopaminergic compounds in that sense. Maybe we need to look beyond just dopaminergic targets for this. And for so long, so many medications have been dopaminergic that maybe we need to look at glutamate as a target to be able to get rid of the excessive high dyskinesias in the OFFs and modulate towards the middle. And there are different ways around it but dyskinesias certainly make treatment of OFFs interesting, complicated—choose your favorite word here.

Transcript Edited for Clarity

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