Current Series: Managing OFF Episodes in Parkinson Disease

Daniel E. Kremens, MD, JD: I think that’s a nice transition to lead us into management. How do we manage OFF episodes? Stu, why don’t you give us your thoughts on approaching management. There are all sorts of options now.

Stuart Isaacson, MD: For so long, we’ve focused our management on thinking about levodopa. How can we give it in higher doses, closer together, fractionating the dosing? But we’re beginning to understand that there’s maybe a different approach when we’re trying to improve OFF time throughout the day and night, or we’re trying to focus on OFF episodes. We have adjunctive medicines that improve OFF time throughout the day. There might be once-a-day medicines, and then we have on-demand therapies that patients can use as needed that may empower them to be able to end an OFF episode or turn back ON more reliably. I think we have to think about all of these different ideas, and then also think about the mechanisms of OFF and the value, sometimes, for patients in using a non-oral medication. And now we have a new era that’s going to be heralded with infusion therapies, where we try to keep patients ON all the time. And management is complicated.

Jill M. Giordano Farmer, DO, MPH: One of the ways that I try to distill it so that it’s not quite as complicated is to start with the amount of OFF. If they are having OFF periods frequently throughout the day, if you can determine if it’s before most doses when they’re wearing off too soon, that might lead me down a different decision-making path than if it’s just happening every once in a while. Because ideally speaking, if our goal is to not necessarily eliminate OFF but to practically manage it as best as possible, it might not necessarily be an on-demand. It might just need to be a revamp of the scheduling of the medications that they’re already on. If they’re having unpredictable or more infrequent OFF episodes for which they can ideally determine exactly how they occur, what they feel like, then the on-demand therapies might be even better. And that sometimes helps stratify the decision-making process as opposed to feeling overwhelmed with all of the different options that are out there.

Rajesh Pahwa, MD: But the easiest way is a lot of people use more levodopa, like you mentioned earlier. The patient is already on levodopa, so why not give them more levodopa? But to me, we also know the more levodopa we give, the more fluctuations we see, the more OFF we see.

Stuart Isaacson, MD: Is it really fair for a patient to have to take a medicine 3 times a day, and then our best advice is take it 4 times a day, and then 5 times a day, and then 6 times a day? Is this the best way to approach life, to constantly be thinking about taking the next dose so many times a day when we have so many different options that might allow patients to stay on a 3-time-a-day regimen and then try to bolster and raise the trough?

Peter LeWitt, MD, M.Med.Sc: Especially since we know that compliance, as part of the human condition, drops off after 3-times-per-day dosing, even if it makes great pharmacokinetic sense.

Stuart Isaacson, MD: Our field has been proud to suggest that taking it 5 hours apart, and then 4 hours apart, and then 3 hours apart, and then 2.5 hours apart—and we can write out schedules—but maybe it’s not fair for patients. Maybe they are not part of that clinical decision making.

Peter LeWitt, MD, M.Med.Sc: If we have alternatives.

Rajesh Pahwa, MD: What if they use the long-acting ones? You could use long-acting levodopa and keep it at 3 or 4 times a day. So there are options, but I think long-acting preparations still have their challenges. I think the gut is still there. They still have to make it to the small intestine. It becomes a little bit more erratic in it’s absorption from that point. But I think, yes, you could use a longer-acting levodopa.

Jill M. Giordano Farmer, DO, MPH: But we’re also making the leap from levodopa to either as-needed levodopa or other adjunctive therapies. We’ve missed some of the other drug classes that can be brought on board before you have to add on more levodopa. So, if they are on 3-times-a-day dosing and they’re simply on levodopa, you can look to a dopamine agonist, or you can look to an MAO-B [monoamine oxidase-B] inhibitor or a COMT [catechol-o-methyl transferase] inhibitor before you need to get to the on-demand therapy or increase the frequency of the levodopa they’re already taking.

Rajesh Pahwa, MD: Dopamine agonists are pretty good as adjunctive therapy. There are 2 challenges that I personally see with agonists in my practice. One is with the older patients. They’re much more likely to run into trouble as far as hallucinations are concerned. And the other thing is, especially in the younger patients, there are compulsive disorders. Studies have shown up to 20% of the patients on dopamine agonists can have gambling, shopping, sexual compulsions. And often, the patients don’t talk about them. So unless they come with a caregiver, or some day you get a phone call from the caregiver saying, “Oh my god, he’s out gambling every night,” we don’t even know those things. That’s the challenge I struggle with at times with dopamine agonists.

Stuart Isaacson, MD: Sometimes it may just be the pulsatility of some of the older dopamine agonists, especially some of the oral ones. We’re trying to get a more level replacement of the dopamine agonist transdermally, subcutaneously, which may give better tolerability. And I think some of the newer studies suggest that dopamine agonists that are given on a more continuous delivery hopefully may have some of these less compulsive....

Peter LeWitt, MD, M.Med.Sc: But I think for the general physician, the fear that they feel liable, and not knowing how often to monitor, and not having tools to screen for the risk.... Obviously, most patients don’t develop these problems, but it’s an uncertainty in your life. The notion of these drugs being more efficacious than levodopa is not supported by studies.

Rajesh Pahwa, MD: It depends which agonist you talk about.

Peter LeWitt, MD, M.Med.Sc: Yes, and of course it’s a generalization. But there isn’t evidence that they protect against motor fluctuations or dyskinesias, as was the past marketing-driven hope, which tells us that they are adjunctive therapies that are quite useful. They clearly have a much longer duration of action, even in oral forms. But they join the COMT and MAO-B inhibitors as other ways to stretch out the effects of levodopa. This is the bottom line that comes from studies. They aren’t useful alternatives to using any levodopa, but the patient with an agonist on board often is doing much better. And certain problems like freezing of gait sometimes are helped as well as dystonic early morning symptoms. So they have a role to play, and they should be on the algorithm of what we consider. What else should we be thinking about with the use of COMT and MAO-B inhibitors?

Rajesh Pahwa, MD: Before we go there, the agonists also have some of these adverse effects and are dose dependent, too. Initially, we were pushing to the maximum dose with these agonists, and maybe there is a sweet spot? I agree with you that agonists can be very helpful in certain patients. We just have to be careful. Do we need to push the dose high enough, or are they long-acting infusions? But they definitely have a role.