Rajesh Pahwa, MD

That leads us into this idea of motor fluctuations and how this cornerstone therapy of levodopa becomes variable. It gives rise to these OFF episodes. Bob, can you tell us, how do you define OFF, and probably more importantly, how do you identify and define good ON time? That’s the goal I think of treating Parkinson disease.

: There are a couple of questions layered in there. First of all, how do we define ON? ON refers to when medication is working, and more specifically, when Parkinson disease medication is providing good motor benefit. Usually, we’re talking about levodopa, but it can be other medications as well that have good benefit in Parkinson disease. ON is when patients are experiencing a good motor benefit from the Parkinson medication, and then to make it even more specific than that, I say it’s for mobility, slowness, and stiffness. The reason I define it that way is because as Raj said, tremor is kind of tricky. Tremor may not respond in some patients, and tremor is often quite variable. It often increases with emotional activation. To keep people from getting confused, I like to say it’s when Parkinson medication is providing good motor benefit for mobility, slowness, and stiffness. Then conversely, OFF is when the Parkinson medication through the day is no longer providing good benefit for mobility, slowness, and stiffness. Maybe the medication hasn’t kicked in yet, or it had kicked in, and now it’s not working at a given point through the day. When I think about that, what I do in the clinic is I always ask patients, is your Parkinson medication, particularly levodopa, lasting from dose to dose? If they say yes, or I’m not sure what you’re asking Dr Hauser, that’s a pretty good sign that it is lasting from dose to dose.

A lot of times they’ll say no, it kind of starts to wear off, and something comes back, and that could be tremor, could be slowness, stiffness, mobility. Or they could say, well, in the morning I have slowness, stiffness, or tremor. I also not only ask, is your medication lasting from dose to dose, I also always try to remember what’s happening first thing in the morning. Does it take a while for medication to kick in? I talked about ON and OFF; the other thing you asked me though was what is good ON? This gets tricky because it isn’t just a good ON, it’s not just benefit from medication. It’s a good benefit. It specifically refers to ON without troublesome dyskinesia. You and Raj both mentioned motor fluctuation. ON is when medication is working, OFF is when medication is no longer providing good benefit, has worn OFF. Some people develop a sensitivity to levodopa over time, where they experience hyperkinetic or increased movements. Typically, I call them twist and turning, which is called dyskinesia. If that’s bad enough, it can become troublesome to patients. That’s levodopa-induced dyskinesia, if it’s bad with troublesome dyskinesia that occurs when patients are ON. So, ON with troublesome dyskinesia is too much medication. OFF is too little medication. Both of those things define the bad zone, and in between is the good zone. When patients are ON without troublesome dyskinesia, that’s what we call good ON.

: One of the challenges that we as clinicians and patients face is ON and OFF is not like a light switch. It is not the patient is ON one minute and goes OFF the other minute. It’s kind of a dimmer switch, so to speak. When they take their medicine, they may gradually come ON, and same thing when their medicine is wearing off, they may gradually get OFF. Often the patients have a good idea, this is my best and I’m ON, and this is my worst, that I’m OFF. The time in between can be challenging for the patients to decide, am I really OFF at this stage, or am I fully ON? That’s where it gets challenging, and the timing on when it is happening does help us that, “OK, I take my pill. I’m not fully ON because my medicine is taking a while to get into my system and for me to be ON.” That’s a very important distinction because a lot of clinician and patients feel that this should be, I’m ON or OFF, but there’s always a zone through which they go.

: You hit it exactly right because initially patients just get a little wearing OFF, and it’s shallow, so it’s a bit of return of symptoms. As time goes on, that time when they lose their best response becomes greater and they go deeper and get greater return of symptoms. To just say to patients, “Well, are you OFF, or how much OFF,” gets a little tricky, and it’s much more important to ask the patient to describe what’s actually happening over both time and with severity of symptoms. That tells you what you need to do, and also of course ask about impact for them. That’ll help you decide what needs to be done.

Videos

Robert A. Hauser, MD, MBA, and Rajesh Pahwa, MD, define the difference between ON time and OFF episodes for patients with Parkinson disease.

ON Time vs OFF Episodes in PD

 titled, “Considerations for the Maintenance of ON Time in Parkinson Disease.” I am Dr Stuart Isaacson, an associate professor of neurology at the Florida International University Herbert Wertheim College of Medicine and the director of the Parkinson’s Disease and Movement Disorders Center of Boca Raton, in Florida. Joining me today in this discussion are my colleagues: Dr Rajesh Pahwa, professor of neurology and the director of the Parkinson’s Disease and Movement Disorder Center, from the University of Kansas Medical Center in Kansas City, Kansas; and Dr Laxman Bahroo, associate professor of the Department of Neurology, and the director of both the botulinum toxin clinic and the residency program at MedStar Georgetown University Hospital in Washington, DC; and Dr Robert Hauser, a professor of neurology, molecular pharmacology, and physiology at the University of South Florida [USF] Morsani College of Medicine, and the director of the Clinical Signature Interdisciplinary Program at the USF Health Byrd Parkinson’s Disease and Movement Disorders Center in Tampa, Florida.

Welcome everyone, and let’s get started. We’re going to talk about Parkinson disease and some of the issues we face in the management of it, using levodopa, and the ultimate emergence of OFF episodes. Raj, do you want to briefly review the use of levodopa in our management of Parkinson disease symptoms?

: Definitely. Levodopa, as you know, is a gold standard. Levodopa is the most efficacious treatment we have for Parkinson disease. It makes sense, right? In Parkinson disease, there is reduced dopamine, so when we use levodopa, it crosses the blood-brain barrier and is converted to dopamine, which is reduced in patients with Parkinson disease. Being the most efficacious medicine, once the patients are having difficulty with activities, we usually initiate levodopa. Levodopa has a marked improvement in Parkinson symptoms, whether it is tremor, bradykinesia, rigidity, or gait issues that the patient is having. A caveat to remember here is tremor only responds in about 50% of the patients as far as levodopa is concerned, and in fact despite that, levodopa still is the most effective treatment even for tremors. One of the challenges that we’ll discuss later is what happens with the long-term treatment of Parkinson disease with levodopa, which is motor fluctuations and dyskinesias.

Rajesh Pahwa, MD, reviews the use of levodopa for the management of Parkinson disease symptoms.

Role of Levodopa in Managing Parkinson Disease

The challenges and problems patients with Parkinson disease face in later stages, we cannot help with levodopa.

Parkinson disease (PD) is characterized by a multitude of individualized issues including cognitive impairments, motor fluctuations, increased number of comorbidities, and more. Carbidopa-levodopa remains 1 of the few FDA-approved treatments to help with patients’ OFF time but does not fully mitigate a lot of the remaining issues.

As PD continues to progress into its later stages, the problems patients face can sometimes be untreatable, especially with levodopa-carbidopa. Rajesh Pahwa, MD, noted his belief that the patient community is unaware of these limitations of the treatment. Pahwa, who is director of the Parkinson’s Foundation Center for Excellence at the University of Kansas Medical Center, sees the potential of levodopa-carbidopa intestinal gel as an option that will be not only be incorporated more commonly in future trials, but across clinical care as a whole.

 to detail the limitations of the available options in treating patients with PD and the future outlook for those who are more willing to undergo treatment with carbidopa-levodopa intestinal gel.

The director of the Parkinson’s Foundation Center for Excellence at the University of Kansas Medical Center provided insight on the lapses in levodopa-carbidopa treatment and what potential changes could come in the future.

Rajesh Pahwa, MD: Understanding Levodopa-Carbidopa Treatment Impact

On the other side, people are fine undergoing deep brain stimulation, where they’re doing brain surgery. That part I’ve never quite figured out. A person is more willing to do brain surgery than abdominal surgery?

Post-hoc analysis from a randomized, controlled study demonstrated that patients with Parkinson disease (PD) treated with levodopa-carbidopa intestinal gel (LCIG) experienced a 

faster time to ON without troublesome dyskinesia

 (ON-woTD) compared to levodopa-carbidopa oral capsules (LCIR). Additionally, there were some hour-by-hour benefits shown, with 65.5% of LGIC patients achieving ON-woTD 1.5 hours after turning the pump on compared to 61.7% of LCIR patients after 2.5 hours.

Despite all the results of the study highlighting the benefit of LGIC, Rajesh Pahwa, MD, still feels as though it is underused in clinical care. Pahwa, the Laverne and Joyce Rider Professor of Neurology; chief of the Parkinson’s and Movement Disorder Division; and director of the Parkinson's Foundation Center for Excellence at University of Kansas Medical Center, cited a lack of awareness, incorrect public perception, and insurance technicalities all as factors contributing to the underutilization.

, Pahwa further detailed the reasons for the lack of LCIG utilization and why the myths associated with its use play a big part in patients potentially opting against the treatment.

The director of the Parkinson’s Foundation Center for Excellence at the University of Kansas Medical Center shared the reasons why LCIG is underused in clinical care.

Rajesh Pahwa, MD: Underutilization of Levodopa-Carbidopa Intestinal Gel

"If a medicine is not going into your blood or your brain, but rather is just sitting in your stomach, then it is as good as you not taking it.”

, September 12–16, 2020, by Rajesh Pahwa, MD, revealed that patients with Parkinson disease (PD) who were treated with levodopa-carbidopa intestinal gel (LCIG) experienced a faster time to ON without troublesome dyskinesia (ON-woTD) compared with immediate-release levodopa-carbidopa oral capsules (LCIR). Within 30 minutes of waking up, 11.3% of patients on LCIG had ON-woTD compared to 20% of those on LCIR.

Pahwa, the Laverne and Joyce Rider Professor of Neurology; chief of the Parkinson’s and Movement Disorder Division; and director of the Parkinson's Foundation Center for Excellence at University of Kansas Medical Center, feels as though the advantages clear enough to where LCIG should be more normalized into clinical care. The major difference between the 2 options is that LCIG is administered through a port, whereas LCIR is taken orally.

, Pahwa explained the concepts behind how LCIG is administered, and why its mechanism of action allows for faster ON-woTD in patients with PD.

The director of the Parkinson’s Foundation Center for Excellence at University of Kansas Medical Center detailed the pros and cons of levodopa-carbidopa intestinal gel. 

Rajesh Pahwa, MD

Articles

ON Time vs OFF Episodes in PD

Role of Levodopa in Managing Parkinson Disease

Rajesh Pahwa, MD: Understanding Levodopa-Carbidopa Treatment Impact

Rajesh Pahwa, MD: Underutilization of Levodopa-Carbidopa Intestinal Gel

Rajesh Pahwa, MD: Advantages of Levodopa-Carbidopa Intestinal Gel

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