Jill M. Giordano Farmer, DO, MPH: One of the things that’s also important to talk about when you’re talking about OFF is whether the patient is adequately managed to begin with. There is a fear about using too much levodopa early on, which then makes patients ration it and not want to use it effectively.
One of the nicer things about the newer therapies and the on-demand therapies that are now available is that they’re able to manage their OFF symptoms after they’ve been adequately managed on levodopa, if it’s not adequate enough. They can do that without perpetuating a fear that they’re using too much levodopa.
The fear is unfounded in the sense that that’s not the way levodopa works. The sooner you use it, you don’t necessarily get used to it, or habituate to it, or use up its effectiveness. But that’s still something that permeates a lot of patients’ concern about their medications.
Rajesh Pahwa, MD: If you never have an ON, you’re never going to have an OFF. You have to be adequately treated so that your symptoms are improved and you are optimally controlled. And then when the disease progresses, you start having these time periods when, during the day, your symptoms are not optimally controlled, and that’s when there would be the OFF time and OFF periods patients are having.
Daniel E. Kremens, MD, JD: Right. And I think it’s fair to point out that when the patients are told about this, and the support groups, and there’s a lot of stuff out there on the Internet—and it’s not just the patients, it’s physicians too—there’s a true fear of levodopa, which 50 years later, is still the most effective treatment for Parkinson disease. I think most of us would agree that most patients remain undertreated. And so, that’s one of the big reasons why people are very confused about OFF.
Peter LeWitt, MD, M.Med.Sc: Some of the pharmacological underpinnings of levodopa therapy are as follows. There’s a threshold effect. You have to have enough drugs circulating and in every point in time to get the dopamine created in the brain. If you’re below that level, nothing happens. And unfortunately, a patient can’t sense where their blood level of levodopa is. They can’t be confident that despite having taken the medication right on time, that it necessarily got absorbed. We know the stomach and the entire gastrointestinal tract is taking a hit from chronic Parkinson disease. And so, it’s wishful thinking that because the drug was taken at least 30 minutes ago, it’s going to work for them.
So that’s where on-demand therapies can help. Also, drugs that are better at constant delivery, reaching that threshold for effect, is another unmet need of therapeutics. And perhaps adjunctive therapies, as we talk about them, will become critical to get more of an insurance policy that you’re getting the drug to the brain in a constant manner throughout the day, and even throughout the night if needed.
Stuart Isaacson, MD: Peter, you bring up this good point. We’ve often thought about OFF as wearing off, and reflecting changes that are bringing changes with the disease progression with striatal denervation and loss of buffering capacity. And this idea that we can’t keep recycling levodopa has been underpinning of the mechanism of how we thought about OFF. But we’ve learned so much more now about non-dopaminergic needs, the role of glutamatergic systems, and adenosine systems. And also, the gut. It may not be intuitive to replace an essential neurotransmitted dopamine by swallowing levodopa into where Parkinson may begin in the gut.