Expert Briefing: Parkinson's Medications 101

Dr. James Beck 00:00:00
Hello everyone, and welcome to the Parkinson's Foundation Expert Briefing. I'm Dr. James Beck, Chief Scientific Officer of the Parkinson's Foundation, and it's a pleasure to have you with us today.

In today's briefing, which is one that I think a lot of people look forward to, we'll gain a deeper understanding of how medications work, their intended benefits and common side effects. We'll also address the natural progression of Parkinson's and the changes in medication regimens that may be necessary over time for some individuals.

Before we get started, like we always do, we'd like to understand who's joining us today. We'll launch a poll that should appear on your screen right now. If you're on Facebook Live, please respond in our comment section because you won't be able to answer this poll.

We want to know: are you a person with PD, or are you a care partner? Do you have a family member with PD? Let us know your background and who you are as part of that. We want to know what your best connection is to Parkinson's disease. Then we'll close the poll in just a little bit as part of this process and just see where we stand for who's joining us today.

We've got a lot of people in here, and not surprisingly, again, a lot of people with Parkinson's disease. Good to see some family members, or children of those living with Parkinson's disease, as well as some healthcare professionals joining us. That's fantastic. Thank you, everyone, for sharing your connection to Parkinson's disease.

It's always good to help ground this as part of the process. Before we begin, I'd just like to take a moment to introduce the Parkinson's Foundation. We are a nonprofit organization that is dedicated to improving the lives of those living with Parkinson's by enhancing care and advancing research. Our efforts are truly deeply rooted in collaboration with the Parkinson's community, ensuring that everything we do aligns with your needs and your priorities.

Today's program is an excellent example of how we are working with you to meet those goals. One of the things that we're doing is investing in breakthroughs, and PD GENEration is a key aspect of that. The Foundation itself has invested nearly $500 million in research and care to improve the diagnosis and treatment and scientific breakthroughs for those living with Parkinson's disease.

Dr. James Beck 00:01:57
PD GENEration is at the forefront as part of that process, and it offers free genetic testing and counseling to those living with Parkinson's disease. Practically everyone in the Western Hemisphere, certainly within the U.S., PD GENEration is available to you if you have a diagnosis of Parkinson's disease. We encourage you to share this opportunity with your community, and I think together we can make a difference in Parkinson's disease.

As a reminder, we're going to record today's Expert Briefing. The recording will be available online shortly, so there's no need to check back to see if it's posted. We'll email you a link to let you know when the recording is available, as well as some other resources that are going to be covered in today's Expert Briefing. For everyone who's registered, that will happen.

If you're joining us late, you'll really be in for a treat as part of that process. I would also like to thank our sponsor for today, UCB Pharmaceuticals. They are supporting the mission of the Parkinson's Foundation with a generous educational grant to support our Expert Briefings. Thank you very much to those at UCB.

We're honored to welcome our expert presenter for today's webinar. I'm really pleased to introduce Dr. Danny Bega. Dr. Bega is a neurologist who specializes in movement disorders and directs the Parkinson's Disease and Movement Disorders Center at Northwestern in Chicago. He also leads clinics focused on Huntington's disease and Wilson's disease. He's deeply involved in clinical trials.

In addition to his clinical focus on PD and other movement disorders, Dr. Bega has a strong interest in integrative medicine, where he brings a whole-person approach to patient care. He also serves as the neurology residency program director and helps shape the next generation of neurologists training at Northwestern. Dr. Bega, thank you for joining us today.

Dr. Danny Bega 00:03:57
Thank you so much for having me here. I really want to thank the Parkinson's Foundation and everybody who put this talk together today. I'm just going to share my screen here.

I've been asked to cover what I think is a pretty big topic today: Parkinson's medications 101, with the objective of providing some education about Parkinson's medications and their use, but also giving a flavor for the entire trajectory of the disease and where these medications fit in. I think that's a big topic. Here are my disclosures, and here are the objectives.

It's really to try to cover a lot of information, and we have a big audience today. I know that people are going to be coming at this with a lot of different experiences, and I'm hoping to provide some foundation for everybody who may be at all different stages or caring for someone at all different stages of the disease.

I want to give you some insight into where medications fall into the spectrum of the disease and their pros and cons, and the benefits and some of the side effects of medications. I want to talk a little bit about Parkinson's disease and how it evolves over time, and give you some expectations for what medications can do and what they can't do. In that regard, where a comprehensive approach to care fits in as well in managing the disease beyond just medications.

Hopefully, this will set the stage for you to talk to your healthcare provider about your own individual care. Today will serve as general information. Certainly, I can't provide individualized information, but that is something that you should work with your primary neurologist on in terms of individualizing your personal care plan. This is not meant to serve as individual recommendations for any one particular person.

Dr. Danny Bega 00:05:58
Parkinson's disease is a neurodegenerative disease that affects people particularly as they get older, although we know there's a spectrum of ages where people can be affected. What happens in Parkinson's is a constellation of different symptoms, which include movement and non-movement-related symptoms. In this puzzle you see here, parkinsonism is highlighted. That refers to the motor symptoms of Parkinson's disease, things like tremor, stiffness, slowness of movement, and trouble with walking. That's what we refer to as parkinsonism.

You also see all these other words here that refer to some non-motor symptoms: mood symptoms, cognitive symptoms, fatigue, lightheadedness, all these different components of the disease. What this is showing is that it's really a snowflake disease, that people with Parkinson's disease all experience different combinations of symptoms, different severities of symptoms, and their progression will be different. The components you see here in the picture will all actually vary from person to person. We really need to individualize and tailor treatment, but we need to focus on all these different aspects of the disease as we do that.

We're going to spend most of the time, when we talk about medications, talking about the motor features, the parkinsonism. But I will bring in some of the management of some of the other features as well.

At the core of Parkinson's disease, we think about the neurotransmitter dopamine, and we know that the area of the brain where dopamine is produced and released is affected in Parkinson's disease early on. The depletion, the loss of dopamine, and the inability to release dopamine normally leads to the movement symptoms like tremor and slowness and stiffness and walking problems. Dopamine is an important chemical for that. As we think about medications to treat the movement symptoms, dopamine is going to be at the center of that story.

When we think about the goal of treatment in Parkinson's disease, we wish that goal, and the Parkinson's Foundation and all of the doctors who are involved in managing Parkinson's, and all the scientists and researchers are working on a way to stop it, to slow it down, to end the disease. But the actual practical goal day to day today in our clinics is to improve symptoms and to improve quality of life.

What that means is that if there's actually no significant impact on quality of life and no significant disability, we at times may consider not treating certain people for a period of time. We may think more about clinical trials to try to involve people in trials to try to slow down and one day cure the disease. Then we'll focus on lifestyle-oriented things like exercise, rehab-oriented services and education like what we're doing today.

In terms of our arsenal of treatment options to manage symptoms and to improve quality of life, we have a lot of medication options listed here under the pharmacological therapies, with levodopa at the top and many different classes of medications listed beneath, as well as medications for non-motor symptoms. Then we have non-medication options, which are important at all stages of the disease, and then advanced therapies, which I'll talk about a little bit as well today.

Dr. Danny Bega 00:09:04
I'm going to set the stage for the categories of Parkinson's severity, in my opinion. What I'm going to give you is really variable and not meant to be a template for every individual person. But it's my experience as generalities of where people fall into, and the terms I'm going to use. Very early, this is my term. I think of this in general as people, five years before the disease may be diagnosed up to five years after the disease is diagnosed. Again, these asterisks that I have here are meant to imply there's a lot of variability with any of what I'm going to say.

But I think of very early disease as having mild symptoms that don't impact daily activities and may not need pharmacological treatment for the motor symptoms for some people. When I think of mild disease, I think about anywhere from diagnosis to up to 10 years. Again, really I'm giving big ranges on purpose because it's really different from person to person. This is where symptoms start to interfere with activities, and there's typically a good, smooth response to medications to help with those symptoms.

In my practice, when I think about moderate severity disease, I think about having inadequate or more complicated responses to simple regimens of medications or to low doses of medications, and narrowing of therapeutic windows. What that means is that medications work, but for shorter or less sufficient periods of time as the disease progresses. Some disability can be accumulating, and balance and gait can become more impacted. I think of that in general anywhere from five to 20 years into the disease.

Then advanced disease I think about as people are having more significant complications and fluctuations, freezing and falling when they're walking, often with more non-motor symptoms starting to become problematic, like sometimes even dementia. That can be year 10 to more than 20. You can see I'm giving these big ranges because it really will vary from person to person.

As we introduce treatments to try to improve quality of life and improve symptoms in those different areas as the disease progresses, I mentioned dopamine is at the core of the motor problem. We know that there's a deficiency of dopamine release and an inefficient dopamine release that leads to the movement symptoms of Parkinson's disease.

There are two main categories of drugs that are ways of addressing dopamine more directly. We have levodopa, which is actually DOPA turned into dopamine. And we have dopamine agonists, which bind to the dopamine receptors and sort of create effects that are similar to what dopamine would do.

Dr. Danny Bega 00:11:44
These are the main core ways that we manage the symptoms that we think are due to inefficient dopamine, and they work a little differently. In the dopamine agonist category, the examples are pramipexole, ropinirole and rotigotine. They can treat the different movement symptoms of Parkinson's, and for some people quite well. But they do have side effects, and in some people that can include sleepiness, dizziness, nausea, confusion and, importantly, impulse control disorders in up to 13% of people. That can include things like spending money excessively, obsessively thinking about sexual thoughts, compulsive eating, gambling, things like that.

These are the things we need to screen for and watch for in people on these medications. With dopamine agonists, however, we have less risk of some movement side effects. Movement side effects that we typically think about are things like dyskinesia. A dyskinesia is an abnormal increased movement of any part of the body that sort of looks like fidgeting, like dancing or restless-looking movements of the body. We don't see quite as much of that with dopamine agonists, which is nice. But we do see some of these other potential concerns with some people, and different people will tolerate these to different degrees.

We find that about 28% do stop these medications due to side effects. About 40% will need another medication like levodopa added by about two years. It gives you just a general sense of how well people do with them.

If we compare that to levodopa, levodopa is our gold standard. It comes in different forms. The main one we think about is Sinemet, which is a combination of carbidopa-levodopa. There are many other forms of levodopa. Levodopa is turned into dopamine, so it's always going to be the most effective way to treat the movement symptoms of Parkinson's because we think that those are due to inefficient release of dopamine, and we're replenishing that with levodopa.

It is known to be the most effective, and this is actually showing in this chart on the left. You're seeing improvement. The bars that are lower are better, and you can see that the levodopa bar is lower than the pramipexole bar. It's showing that, in this particular important study, the levodopa worked better than the pramipexole, than the dopamine agonist in this case.

We know it's the most effective at treating the movement symptoms. It can have side effects. Nausea is the most common one. Nausea is something that we can address in different ways if someone has nausea with levodopa. Sometimes taking it with food can help with the nausea.

Dr. Danny Bega 00:14:13
If we're trying to avoid taking it with food, sometimes giving it with more carbidopa can help with the nausea. Actually, the carbidopa that is in the carbidopa-levodopa combination is the component that helps with the nausea. The word Sinemet actually comes from the Latin for no nausea. Sin and emet actually means no nausea, and that's because of the carbidopa. Sometimes adding carbidopa can help with the nausea if that's an issue.

The other side effect that we can see with levodopa is dyskinesia, which is again those motor, restless-looking movements of the body that can occur from levodopa. To address that, there are various things we can do. We can lower the levodopa to improve that, or we can try to treat the dyskinesia directly with a medication such as amantadine. I'll talk about that in a moment.

With levodopa, you can see tolerability in general is actually better. Only about 2% stop it due to side effects. In terms of benefits, you can see it's also better. About 15% need another medication added by two years, compared to about 40% on dopamine agonists. You can see some of the differences in the comparison and why levodopa remains and continues to be our gold standard way of treating the movement symptoms.

Other classes of medications, just to cover some of them: we have a class called anticholinergic medications. The examples are trihexyphenidyl or benztropine. This is effective at treating tremor and at treating dystonia. Dystonia is like a twisting or a contorting of a part of the body that can happen sometimes.

While these classes are effective at treating those symptoms, they do come with side effects, particularly cognitive side effects that we worry about. There is some increased risk of cognitive problems over time in people who are on those medications. For that reason, they're less commonly used.

Another class are the MAO-B inhibitors. This would include rasagiline, selegiline and safinamide. In general, we consider these well-tolerated but pretty mild kind of medication for Parkinson's. It's not specifically adding more dopamine; it is slowing the breakdown of the levodopa and of dopamine overall. It can have a mild, small impact on the movement symptoms alone. It can also extend how long the levodopa will last, so it can be used alone or in combination with levodopa. Generally, it's well tolerated, but its effects tend to be fairly small, not as significant as the effects of something like levodopa.

Dr. Danny Bega 00:16:41
About 70% need another medication by about two years, just to give you a sense of the effectiveness of it. There are other similar medications that can also extend the duration that the carbidopa-levodopa lasts. That would include the class called COMT inhibitors, such as entacapone or opicapone, and then another class called A2A receptor antagonists. The example there would be istradefylline. Those are medications that are used to extend how long the carbidopa-levodopa lasts, or the effects of the carbidopa-levodopa.

Another medication I've listed here is amantadine. Amantadine is a medication that works a little differently. It blocks a chemical called NMDA, or a receptor called NMDA that is an excitability chemical in the brain. By blocking that, it can actually reduce tremors and it can also reduce dyskinesia, which is that movement side effect that you can get from levodopa.

If someone were to get dyskinesias or extra movements of the body from levodopa, but presumably needs to be on the levodopa for the benefits of it, sometimes we can add amantadine to counteract the side effect of the dyskinesia. Amantadine does have some side effects itself. It can cause, in older people, particularly people over 75, about a 20% risk of confusion or hallucinations. Some people can get leg swelling or skin changes over the legs with amantadine.

I know this is kind of a whirlwind of throwing out a lot of names of medications, and if you're not an expert in these medications, it can be hard to keep track of this. But this is just to kind of set the stage for the variety and flavors of medications, and hopefully something you can talk to your doctor about.

Coming back to levodopa again, the gold standard medication, I mentioned that it's the one that's most effective. It does have some side effects that we talked about, and particularly the dyskinesias that people sometimes worry about. The question I often get is, is it too soon to start it? If it's the best medication and everybody with Parkinson's is going to end up on some form of levodopa generally, is there a problem with starting it now versus a year from now?

Dr. Danny Bega 00:18:20
The answer is really that it should be used when it's needed. When quality of life is declined or suffering, it will improve someone's quality of life, and it can improve their symptoms. That's when it often should be used.

What's shown here is starting levodopa at day zero in this graph compared to a year later. What you're seeing here is that the group that starts early has improved motor scores and improved general quality of life scores for that whole year that they're on the medication compared to the group that's not on it. Then after a year, both groups go on the medication and then they're pretty similar. You can see there's no real difference in the group that started a year later. The only difference is that they lost a year of some good benefit in that delay. The argument would be, if you want that year to be a better year, then you may need to start that medication.

If there's some suffering or some decline in quality of life that can be treated, then it ought to be treated. A year later, delaying starting and going a year later, you don't really see a difference. We do know that the severity of the disease itself is associated with getting more dyskinesias and more complications, and having the effects of the levodopa last for shorter periods of time. It's not directly related to when the levodopa is started. Those problems are more related to how long someone has been on the medication because of how long they've had the disease.

At five years on levodopa, about 50% of people will develop some motor complications like dyskinesias and fluctuations in the effects of the medication. Unfortunately, by about 10 years plus, it's about 90% of people that will experience some of these fluctuations. But that happens regardless of when the levodopa was necessarily started. That is more related to how long and how more advanced the disease is, in terms of how well the brain handles the levodopa.

The dose required also is related. A higher dose of levodopa will be associated with a little bit higher risk of getting some of these motor complications. Then individual factors: again, it's an individualized disease. The body size of the person, their genetics, their absorption of the medication, even gender can affect how sensitive someone is to the effects of levodopa, which is why you may be different from your friend or colleague in a support group or in an exercise program that you've seen. You may be experiencing very different effects because of various factors like these.

Dr. Danny Bega 00:21:09
It also turns out the majority of people, if you ask them, are you more bothered by the symptoms of Parkinson's, which we call off-time, or are you more bothered by the side effect of the medication, like the dyskinesia? The vast majority of people are more bothered by the off-time or the symptoms of Parkinson's than they are by the dyskinesia or the complication of the medication.

Some people will be on levodopa and not have the typical experience. The typical experience is a good, robust effect, a response to the levodopa that's noticeable and beneficial. Some people will say, why isn't it working that way for me? There are various reasons. The dose could be too low. That could be a reason why you're not noticing the benefit.

It could be that the symptom that you're bothered by or that you're focused on is a symptom that's not as responsive to levodopa for you. For instance, maybe the levodopa is helping stiffness and slowness, but you're really bothered by your walking, and maybe your walking is not responding as well to the levodopa. Or maybe you have a non-movement symptom that's bothering you, like fatigue. For some people, the fatigue responds to levodopa, but for you the fatigue is not as responsive to levodopa because it's being caused by bad sleep at night. There are various reasons why it might not be as noticeable.

It's possible that you're not absorbing it well. Levodopa is absorbed in the GI tract, in the gastrointestinal tract, differently in different people. The gastrointestinal system is moving differently for different people, and even on different days it may be working differently, so you may not be absorbing the medication efficiently.

It's possible you don't have classic Parkinson's disease. Classic Parkinson's disease, in one of the criteria for the disease, is a robust response to levodopa. For some people, not having a response even at a good dose of levodopa may suggest that there's something atypical about their Parkinson's diagnosis.

Then it could be that the duration of the effect is just too short, or the threshold for you for side effects is lower than typical, and so your brain is not handling it as smoothly as is average. The average person can tolerate X amount of levodopa without any problems tolerating it, and for you, your brain just doesn't tolerate it as well. That could be why you're not able to get through a dose that's working for you. Again, that speaks to the variability from person to person.

What we see over time as Parkinson's progresses, I mentioned what I consider mild disease is a response to levodopa that is smooth and balanced and comfortable. As the disease gets a little bit more advanced, one of the criteria that I use to call it a little bit more moderate or more advanced is that that response to levodopa becomes sort of shorter and less efficient. There is still a response. There will always be a response for the majority of people. It's just that that response, as the disease gets more advanced, gets shorter, the threshold for getting the side effects becomes lower, and the threshold for getting benefits becomes higher.

Dr. Danny Bega 00:24:00
What you start to see is the inefficiency of the medication. Carbidopa-levodopa in the form of Sinemet actually lasts a very short time in our bodies. The half-life of Sinemet is 90 minutes, which means that after 90 minutes, half of it is gone. It is a very short-lived medication, which explains why, for some people, the need to take it more and more frequently happens over time, especially as the brain does a worse job handling the medication as the disease progresses. What we naturally end up seeing is that we need to give it more and more often.

But as we give it more and more often, that means we may be giving more medication, which can lead to some side effects.

How do we deal with that? As we start to see these ups and downs in people who have the medication wearing off on them and their Parkinson's symptoms return, we call that off-time. On the upside, when their medication is working, it may be working too well, and they may be getting fidgeting or dyskinesia. How do we deal with these ups and downs as the disease progresses?

One option is we can try to improve the off-time or improve the Parkinson's symptoms without worsening the dyskinesia. We can do that by fractionating. What that means is something like: if I have someone on two pills of carbidopa-levodopa four times a day and it's wearing off on them too much, but I want to keep them from having to take more medication, maybe I'll try going to five times a day but lowering it to one and a half pills. Instead of two pills four times a day, I might try something like one and a half pills five times a day. The intervals are shorter, but the overall amount that they're taking in the day, I'm trying to keep fairly consistent.

I might switch to a longer-acting formulation of levodopa. There are other formulations that you may have heard of, like Rytary or Crexont. These are forms that have both immediate and longer-acting or delayed release all in one form of carbidopa-levodopa, and that can help improve the duration of the effect without necessarily worsening the dyskinesia. Or I might suggest avoiding food interactions to improve the absorption or to make the medication last longer.

Another option is I can try to improve the off-time or improve the Parkinson's symptoms with accepting that I might increase the dyskinesia on the other end. For that, I can add in medications that boost the duration or the effect of the levodopa, the result of which could mean sometimes being on the upper end and having a little bit more dyskinesia, if that's tolerable to that person. That can mean adding a dopamine agonist, or adding an MAO-B inhibitor, or a COMT inhibitor, or an A2A receptor antagonist in addition to the carbidopa-levodopa to make it last longer, to slow its breakdown and to make it more powerful. We can also do unscheduled things like on-demand therapies.

There is an inhaled form of levodopa that can be used just as needed. There is an injectable form of a dopamine agonist called apomorphine, which can be injected into the muscle as needed. These are options for people who just need occasional boosts or occasional return of control of their symptoms without necessarily something added, scheduled into their day.

Dr. Danny Bega 00:27:10
Then there's the potential to improve the off-time while also reducing the dyskinesia, which sounds like the best of both worlds. But there is really only one medication that's approved to do both of those, and that's the amantadine or amantadine extended-release formulation, which has a brand name. As I mentioned, this is helpful for many people, but it's not for everybody, because especially in people who are older or have cognitive impairment or have hallucinations, we do have to watch for some side effect potential for hallucinations and cognitive side effects in some of those older folks.

Beyond the medication adjustments that I just covered very broadly, what we really want to do is take these ups and downs, this windy, up-and-down road, and make it flat and smooth and even. If those oral medication options are exhausted, and there are a lot of oral medication options, I didn't really cover them fully, just gave you a flavor for them, what do you do next if all of that has been explored or exhausted, or someone's not a good candidate for some of those options?

In someone with more advanced disease who's having a lot of these fluctuations, we have more advanced therapy options, which can include delivering continuous levodopa directly into the gut through a pump. That's the Duopa or Duodopa pump that has been around for several years now. That is a surgically placed pump that goes directly into the gut, and the levodopa is infused directly into the gut 24/7. It gives a continuous delivery without these ups and downs.

More recently, we've had through-the-skin or subcutaneous ways of delivering medication, both a form of levodopa and a form of a dopamine agonist called apomorphine, which can be delivered, instead of surgically through the gut, using a device that almost looks like a patch that is delivering the medication through the skin continuously as a way of delivering medication throughout the day, and even throughout the night in some cases, without having to take these ups and downs with pulses of medication throughout the day. These are new options for people with more advanced symptoms.

Just to take a deeper dive into one of those, this is an example of the through-the-skin form of the levodopa pump. It's a foscarbidopa-foslevodopa pump that's delivered through the skin. This was approved about a year ago. What we see here is, in the studies, it showed an improvement of almost three hours of improved off-time. That means better control of Parkinson's symptoms throughout the day by nearly three hours compared to oral levodopa, and nearly four-hour improvement in the medication working without bothersome dyskinesia.

Dr. Danny Bega 00:29:54
There was improvement in feeling control in the morning when someone woke up, which is unusual because usually in the morning you have to wait for your oral medications to kick in. But if someone is on a continuous pump that's working through the night, they can wake up with the medication already working. This is something that's available for people with advanced Parkinson's disease who have bothersome wearing-off symptoms, initially with private insurance, but now recently starting to get Medicare approval as well.

What to be aware of with this, though, is it is a bit of a lifestyle change. This is not as simple as it sounds. While it is delivering medication continuously, it does require training. There are home nursing visits. It requires a commitment to good skincare and to managing the device and the pump. Skin irritation and skin infections are possible with this, and that is something that needs to be watched for and monitored for closely. The pump needs to be carried on you at all times and filled with medication. Depending on how your clinician does it, it can require a lengthy initiation session to figure out the right settings and dosage.

While today's session was really meant to be talking about medications, so I'm not going to be talking about surgery too much, I do want to cover that there are options beyond medications for dealing with more advanced symptoms because I want to cover the breadth of the disease. In more advanced symptoms, we also have surgical options like deep brain stimulation and focused ultrasound for people who either are having tolerability issues with medications, are exhausting what they can do with medications because they're hitting side effect limitations of medications, or their medications are having to be taken in a way that's not really feasible.

This is for someone with Parkinson's disease who responds to levodopa, but that response is not smooth enough or is limited by some side effect. It is not a good option for patients who have dementia, because it is brain surgery. We don't want to do brain surgery in people with dementia. We can sometimes see worsening cognitive problems when we do that. The goal is often to reduce the amount of medication that someone has to take but maintain the same benefit of medication while being able to take less of it and kind of smooth out that bumpy road that I described.

Dr. Danny Bega 00:32:06
Focused ultrasound, on the other hand, as opposed to deep brain stimulation, is a newer procedure. Right now, it's approved to treat tremor on one side of the body, tremor related to Parkinson's disease or tremor related to benign essential tremor. It requires having a specific skull thickness that can be measured on a special CT scan, and it can be used to reduce tremor specifically. For now, that is the main indication for it, although that may change in the future.

As we compare these two surgical options, deep brain stimulation is an actual physical surgery, whereas focused ultrasound has no cutting. There is still a lesion that's being made by it, but it's not with any incision. It's incisionless. DBS has a device that's implanted, whereas with focused ultrasound, there's no device that needs to be implanted.

However, focused ultrasound is not adjustable or reversible, whereas a deep brain stimulator is adjustable and reversible. We know more about the long-term benefits of deep brain stimulation because we've been doing it for about 50 years, whereas with focused ultrasound, it's newer, and so we know less about the long-term effects. With deep brain stimulation, we're approved to do both sides and more than just target tremor. It can target the slowness and stiffness as well, whereas with focused ultrasound, currently it's approved for one side, with tremor as the target.

That kind of is an overview of what we do practically with medications and surgery. Then we have to realize that that can't treat the whole disease. I showed you that puzzle of the disease, and not everything responds to medication or to the dopamine-focused medications. We find that sometimes even some movement symptoms don't respond always to just dopamine medication. Tremor, for some people, will respond to the medications we talked about. But for some people, tremor is really stubborn, and sometimes they don't get the relief they want from medication, in which case surgery like deep brain stimulation and focused ultrasound can actually help with tremor.

For some people, balance issues and freezing of gait, where the feet kind of get stuck and don't want to move, sometimes respond to the medications I talked about. But I do see that as the disease advances in some people, balance issues and freezing can sometimes become an issue that doesn't respond as well to medications. In which case, we have to think about physical interventions, things like exercise and balance training and thinking outside of the box, things like Tai Chi and dance and physical therapy, and using devices that have lasers that can be used as cues to help with freezing and to reduce falls. We have to think a little bit outside of just the medication box for things like that.

Dr. Danny Bega 00:34:43
Dopamine is only part of the story, and that's another reason we have to think outside of the box. We have to think in people with Parkinson's, while we focus a lot on dopamine, norepinephrine and serotonin, which are other chemicals, are also impacted in Parkinson's disease. You can see there's an overlap here of effects on things like mood and energy and different symptoms that we know are common in Parkinson's that can be related to other chemicals beyond just dopamine.

If we look at how common these non-movement symptoms are, they are common. We talk about them every day in our clinics. Again, it's not everybody that gets all of these problems, but some combination of this is common and to different degrees in different people. We deal with mood problems like anxiety and depression, autonomic problems like blood pressure drops that lead to dizziness, cognitive issues, fatigue is really common. I have percentages here for how common these are in different surveys and studies. You can see most of these are seen in up to about a third of people. So, really common sleep problems, urinary problems, you can see the whole combination of different things.

We need to address these as well, and dopamine alone doesn't typically do this, but it can have a role in some cases. Sometimes dopamine can be the opposite problem with some of these non-motor issues. Sometimes it's a tug-of-war trying to address one issue and not hurt another. For instance, I might want to raise dopamine with more levodopa to try to treat things like tremor, dexterity, stiffness and mobility, but I might want to lower the levodopa or the dopamine medications if someone's experiencing things like hallucinations or confusion or low blood pressure. Sometimes I have to find which is more important to treat.

If someone's having hallucinations or confusion, even if they're having tremors, I might want to actually lower their medication to address some of these non-motor issues. Finding the right balance is one thing you have to work with your doctor on.

Non-motor issues can be treated separately too. If someone has mood issues, we do use SSRIs and drugs like mirtazapine. These are typical mood medications, but what we don't use is antipsychotic medications as much because those can block dopamine. We use counseling. We use exercise and mind-body activities to try to address this. Sometimes Parkinson's medications can help mood in some people. Depression and anxiety sometimes respond, but if they don't, then we need to think about some of these other options.

Dr. Danny Bega 00:37:07
Autonomics: this is things like blood pressure drops and being lightheaded. Sometimes these can be worsened by Parkinson's medications, in which case we may have to pull back on them, or we may have to treat with other interventions like having more salt and hydration, or compression stockings. Sometimes we have to treat with medications like midodrine, fludrocortisone or droxidopa to raise blood pressure. Then there are other symptoms that are common in Parkinson's that also fall into this category: drooling, runny nose, sweating, erectile dysfunction and constipation. These are all part of the autonomic nervous system, all can be affected by Parkinson's, and don't necessarily respond to levodopa or dopamine medications and need to be treated separately.

Sleep and fatigue are very common. Sometimes Parkinson's medications can help these symptoms, but again, if they don't, then we need to think about other ways to treat these. Sleep hygiene and cognitive behavioral therapy, and I've listed some medications here that we'll often use for different sleep issues, but it depends on what the sleep problem is. The first step is trying to understand better what the sleep problem is.

Cognition and hallucinations can be worsened by Parkinson's medications in some people. We may need to lower the Parkinson's medications if these are becoming more problematic. Then we may need to address them with medications like donepezil or rivastigmine. If there are hallucinations, we can't use most antipsychotics, but we can use drugs like pimavanserin, quetiapine and clozapine. Again, exercise, mental and physical activities can actually help with this. If someone is developing impulse control issues, I mentioned up to 13% of people on dopamine agonists, we may need to slowly lower the medication to reduce the risk that someone could have to their social life.

When you put it this way, with all these motor symptoms and all these non-motor symptoms and finding the balance between them, we have to individualize our treatment plan. One thing that is useful for everybody is mind-body activities, because mind-body activities will help with both the motor and the non-motor together. By themselves, they're not enough. They don't replace medication, but they can really help, and they are unique in the fact that they can target both the movement and the non-movement symptoms at the same time.

Dr. Danny Bega 00:39:21
That can include whatever you enjoy in terms of mind-body: Tai Chi, yoga, dance, improv, therapy, artistic expression, boxing, physical therapy and other things that I've listed here.

I really encourage you to engage in these non-pharmacological therapies because they're safe and they can treat all aspects of the disease. I've listed several of those here that we often recommend for people as part of a healthy lifestyle too.

I often give people this exercise prescription. If you've been to any Parkinson's talk, you've probably heard about the importance of exercise in treating both the mind and the body and treating both the movement and the non-movement symptoms. This is just a general template: aerobic activity, strength-building activity and balance training. All are important in people with Parkinson's disease.

This is from a study from about 10 years ago, I think from Finland, that showed that the combination of diet, exercise, cognitive training and reducing vascular risk factors was overall predictive of better cognitive function over time in elderly people. If you want to protect yourself against cognitive decline, doing all these healthy lifestyle things can actually make you less likely to get cognitive problems over time, which is already a risk factor with Parkinson's disease.

When you're looking for exercise programs, you want goal-based practice for acquiring a new skill because that will help you physically, but it also helps you mentally to learn a new skill. Ideally, you want a supervised environment where you're learning through reinforcement, something enjoyable that you'll keep up with, something social. You want instructors who understand Parkinson's disease. You want to find appropriate-level classes for your abilities.

You also want to think about counseling and support groups. You want to think about your mental health and your physical health.

Sleep hygiene: I can't tell you how many people will tell me that if they have a good night's sleep, their physical symptoms are better the next day. If they had bad sleep, they don't function well physically the next day. It really matters. Your mental health matters. General medical well-being and general medical checkups matter too, because if you're unhealthy for other reasons, your Parkinson's symptoms will suffer too.

Jumping on to some of these general medical issues that are tied into Parkinson's, we can treat these. We can treat these separately, whether it's sleep or blood pressure or constipation or sleepiness. We want to address these if there's a problem, but it's not always with just medications.

Dr. Danny Bega 00:41:49
This is not meant for you to read all of this, but as an example, in our clinic we'll give out informational sheets about constipation, sleep hygiene or managing low blood pressure or orthostatic hypotension. The Parkinson's Foundation also has a lot of good information on their website for how you can address many of these common issues.

I'm going to wrap up here so that we can take some questions. Parkinson's disease is individualized. It is different for everyone, and it includes a combination of motor and non-motor symptoms that will respond differently to treatment. There are a lot of treatments in our arsenal, but they're going to be used differently from person to person. Levodopa is the gold standard for managing the motor symptoms. The data supports that. Our experience for decades with it supports that. It is turned into dopamine. There are complications as the disease progresses and as time passes that are related to motor fluctuations.

The ups and downs, the dyskinesias on the ups and the wearing off on the downs, and there are a lot of strategies that we can use to address that. There are advanced therapies, including surgical therapies and infusions now, that can be used to address these motor fluctuations. Those options are growing. But all medical options have their pros and cons that need to be individually weighed, with you and your family and your care and your doctor weighing in individually on what the benefits or side effects would be for you.

Many symptoms do require thinking beyond just dopamine. It's not that simple of a disease, as you saw from that complicated puzzle of symptoms, so the solution can't be that simple either. In some cases, there's a trade-off between managing the movement symptoms and the consequences of the non-movement symptoms, so it's that tug-of-war and trying to find the right balance. The non-medication options and lifestyle-focused interventions are non-negotiable, in my opinion. I think they're valuable in Parkinson's. They're safe. They are standard of care, and that includes everything from healthy eating to exercise, mind-body activities, mental health, good sleep, diet, all of that.

With that, hopefully I didn't overwhelm you. Thank you for your attention. We're going to, I think, shift gears into some question and answers.

Dr. James Beck 00:44:13
That's right. Thanks very much, Dr. Bega. This was a really fascinating overview of the many medications that are available for people with Parkinson's disease. I just want to address the elephant in the room that's out there. One of our listeners, Eduardo, asked this question, and this is something I'm sure you hear a lot from your patient community. The medications you've been discussing, levodopa, have a long history. They've been around for a long time.

What do you think is around the corner? I know you're involved in clinical trials. Is there hope that this is not going to be the status quo, that we'll be looking at some new medications in the future?

Dr. Danny Bega 00:44:52
Yes. I get the question a lot. Everyone seems to realize levodopa has been around for a very long time. If you've actually seen, I really like the movie Awakenings. It actually shows some of the initial uses of levodopa back, I want to say that was like the 1940s or 1950s, I think, and we're still using it.

People are like, why have we not gone beyond that? Why are we still using this drug from the 1950s? Well, first of all, just realize the reason is because it is that good. Levodopa is turned into dopamine. It is the precursor to dopamine that our bodies make, and it's a synthetic form of that that we're turning into dopamine. We know that a lot of the symptoms do respond to replenishing the dopamine. So for symptom treatment, we're always going to be focused on how we get dopamine into the brain as efficiently as possible.

When we look at what's advanced, though, there have been a lot of advances in dopamine and levodopa. What you're seeing as advances are more efficient ways of delivering it, more efficient ways of absorbing it, more ways of reproducing what our brains are naturally trying to do, of slow continuous release of dopamine rather than these random pulses of dopamine. That's where the advances have really come along in the last decade, with these new long-acting formulations and now the subcutaneous formulations, and that's where we've seen progress. The problem is that we're not treating the disease with levodopa. We're not treating the underlying cause. We're not slowing it down. We're not stopping it. We're really focusing on symptoms.

What we're seeing where the research is focusing on, and we didn't talk about research at all today, is what can we do to actually get at the mechanism of the disease and slow it down? Where I'm excited, I see this as a few branch points. We're looking at the genetics, and you talked about PD GENEration and why that's so important. We know if we can target something, then we might be able to slow it down. If we can find out who has these genetic markers, maybe we can target those genetic markers with future treatments to try to actually slow down the disease progression.

We know that the protein that builds up in the brain, which I didn't mention, is called alpha-synuclein. That protein builds up in the brain in people with Parkinson's, and we think part of the damage that's caused in the disease is related to that protein buildup. Some companies right now are aggressively working on trying to block that protein, try to prevent it from building up in the brain, or try to clear it. We're really hopeful. There has been some positive progress in that area of trying to slow down the disease by targeting the protein from building up. I'm very excited about that as well.

Stem cells is another kind of third category. Can we regrow, can we regenerate dopamine-producing neurons in the brain? Instead of having to take medication, can we fix the factory itself so the factory starts making the dopamine in the brain again? That's also another area that's starting up now in early phases of research. I'm very excited about all of those as potential, but unfortunately, we have to be patient. If you're living with Parkinson's, it's easy for me to say be patient. You can't be patient when you're living with it. It's really frustrating how slow this moves, and we get that. We want it to move along fast, but these trials do take time, unfortunately.

Dr. James Beck 00:48:20
Agreed. Yeah, for certain. We definitely feel the sense of urgency from the community. So thank you for that answer.

Another question is, I think you touched on this a little bit coming through here, just broadly, how do people with Parkinson's get the maximum benefit from their medications? Is there a simple way for them to really achieve the benefit from you, as a prescriber, giving this, you know, here's the medication I want you to take? What advice do you give to your patients?

Dr. Danny Bega 00:48:51
I think there are ways to optimize it. One is it is really important to take it as prescribed and then adjust from there. The reason I say that is I have people who struggle with the medication, and they start to do their own thing a little bit with it, take it a little bit randomly, miss doses, or they try to fine-tune when they think they should take it, and they adjust their schedule. The problem with that, not that we don't want you engaged in your care, we do want you engaged in your care, is that it's really hard to understand what the medication is doing when it's being taken differently each day.

The best thing we can do is be predictable and consistent and then adjust to fix the problem. If someone is thinking their medication is not working well, the best thing they can do is take it exactly as prescribed at the right time. Keep a diary. I took it at 8:00 in the morning, at 1:00 p.m. and at 7:00 p.m. I noticed that it's doing this at this time and it's doing that at that time, and that's what I'm not liking about it, and it's consistent. Then they can bring that information to me and I can go, okay, I see where the problem is. I can adjust it. Let's adjust it based on that. But if someone is just doing it randomly and differently each day, it's really hard for me to know if they're having a side effect or if they're having an inadequate benefit and where to adjust it. So that's one. Talk to your doctor and work with them, but be sure to keep track and be consistent.

Number two is how and when you take your medication, in particular with levodopa, can really matter. I mentioned the GI absorption issues, and how well it's absorbed will be why some people say a dose worked and another dose didn't work, or one day was good and another day was bad. It could be related to your absorption. Some tips and tricks we usually recommend, if you're able to tolerate it on an empty stomach, we do think the absorption may improve, may be better. It may last longer, it may kick in better if it's taken away from food.

The challenge is some people get nauseous if they take it on an empty stomach. For those people, they have to take it with a little bit of food. In those cases, trying to avoid protein with the medication can still be helpful. Taking it with some crackers, some toast, but not with protein, because it's really proteins and fats that will sometimes compete with the medication for absorption. Trying to time it in a way that is favorable for your absorption, talking to your doctor about how to troubleshoot for you personally.

We even have involved dietitians in this because I have some people who say, 'I take my medication five, six times a day. How do I avoid protein or meals with my medication?' Working with our dietitians, we've been able to help people come up with meal plan strategies for how to optimize that with their day, because you still need to have a normal diet and protein in your diet. Things like that can help.

Dr. James Beck 00:51:39
Yeah, fantastic. It seems taking your medications on time, that's a good start, and be consistent. If you do make adjustments, you and your physician can do the troubleshooting to make those adjustments as part of it.

What we've heard, and I know you mentioned it briefly in your talk, and some of the questions coming in have talked about this too. Maya, one of our listeners, is asking about this issue and misconception that may still be out there, that carbidopa-levodopa should be reserved because its effect wears off over time. I think you hit it when you described it's really the brain changes that are happening. It's the disease progressing. It's not that the medication is changing. It's how your body processes it. Is that an accurate way to describe it?

Dr. Danny Bega 00:52:32
Yeah, so I specifically had that slide about it because over 10 to 15 years of practice, it's the most common question I get from newly diagnosed patients or patients who are not yet on medication. They're worried about starting it, and I get it. You have this medication that we're telling you is the gold standard. You don't want to waste the gold and not have it for later. Logically, it makes sense, because also what you see is, over time, people are not responding quite as well as they did early on. Our brain's interpretation of that is it's sort of building a tolerance or something like that. That's why I have that.

I think it's really important to realize we know for sure that if someone needs it and they're delaying taking it, and when I say they need it because they're struggling in some way, their quality of life has gone down, they're not able to exercise as well because they're not on treatment. That period of time where someone would be on treatment versus not on treatment, there's a clear improvement in quality of life if you're on treatment during that time. Meaning, if you have symptoms and you're putting it off because you're worried about losing the benefit, you're clearly losing benefit during the time that you've been putting it off, and you're losing quality of life. That time is important. It's just as important now as it is going to be later on.

I would remind patients of that. Don't suffer now because you're saving it for later. You should feel good now. You should be able to exercise now. You should be able to do the things you want to do now. You don't know what's going to happen later.

The second thing is, we know that it turns out that later, regardless, is going to be a more complicated time for most people, even if they delayed taking it. That is because the brain changes, and we can't stop that yet. As the brain changes and you've had Parkinson's for a longer period of time, that same levodopa just doesn't get handled as well. You may have put off taking it and now you've missed out on the smooth, good time with it. When you start it, you're already a little bit more advanced. You're going to start to see it shift into those fluctuations naturally anyway. It can seem like you've put it off without the benefit that you were hoping for, and you'll still see those fluctuations as the disease gets more advanced, unfortunately.

Dr. James Beck 00:54:43
Yeah.

Dr. Danny Bega 00:54:44
We just deal with those fluctuations when they come.

Dr. James Beck 00:54:46
Yeah, absolutely. Another question that's come in that's kind of interesting is that there are people out there who've had trouble with weight in the past and they've undergone gastric bypass surgery, which can fundamentally change how their GI system works. Have you had patients like that who've come through, and have they had difficulty with dealing with the absorption of the levodopa? Would that be the kind of candidate you might consider for some of these novel formulations and maybe subcutaneous forms?

Dr. Danny Bega 00:55:17
Yes, I think gastric bypass and surgeries like that can certainly affect your gut motility and where your absorption occurs. Most of the absorption of levodopa happens in the first part of the small intestine, so right after the stomach. It can still be absorbed, but seeing how things move faster or slower through your gut will affect the way you absorb medication. That may need to be adjusted after changes in your gut habits and after gastric bypass surgeries.

Are there ways also to avoid the gut entirely? That's something that a lot of people ask about. Not just after gastric bypass, but if someone does have particularly bad constipation and they know their pills are not getting absorbed well, and they've tried to manage it and they're not getting good absorption, can we try to bypass the gut? There's inhaled levodopa, which is not a replacement for a baseline of medication. It's used as needed, but it is nice that that exists as a way to not rely just on the gut. There's injected into the muscle dopamine agonists, which also doesn't rely as much on the gut. Those are two things that we have as needed options to help people in between doses if they're having problems with gut absorption.

Now we have this whole new world of subcutaneous infusions, which deliver the medication through the skin. They're still new, and we're still evolving and learning, but that is a potential option for people who are having issues with gut absorption. Let's absorb the medication through the skin and get it more directly.

Dr. James Beck 00:56:54
Fascinating. Related to that, we've got several questions coming in here about upper limits of levodopa dosage and the idea of how soon Sinemet goes into effect after taking it, and different formulations, on versus off time for levodopa-carbidopa. I guess, what is your therapeutic approach when you see patients like this and the conversation you have with them, clearly because you're involving them as part of this decision-making?

How do you advise people going from the immediate forms of release to these extended forms of release to these other, you know, the pro-Duopa or the, I can't remember the subcutaneous form of it. How do you counsel your patients, and how is that interaction going? Is it really based upon their specific needs, controlling the motor symptoms specifically, or are people traveling a lot and finding that one form is better than the other? That's a question that comes in too, and as you can appreciate, when people are traveling, everything kind of gets messed up, it seems.

So a lot to unpack, Dr. Bega, but I'm just curious to hear your thoughts.

Dr. Danny Bega 00:58:10
When we start carbidopa-levodopa, typically we'll start Sinemet, which we think of as the regular immediate-release carbidopa-levodopa. People early in Parkinson's do well with that as a three-times-a-day medication and can usually manage that and get good continuous relief with that. As a rule, we always want to use the least amount that we need to give someone the good quality of life, the good symptom control, because higher doses are going to be more likely associated with more potential for side effects. With any medication, you always want to use the lowest amount that you need to see the benefits that you're looking for.

What we start to see over time as we start to need to go to four times a day or beyond that, it starts to become difficult for people, and it's hard to keep on a schedule when you're having to take it four times or more. For me, that's often when I will start to think about switching to some of the longer-acting formulations, the extended-release formulations, if I'm going beyond four times a day. They can be used initially even as three-times-a-day medications also. There are some cost differences and access differences that might affect that decision, but generally for me, I'm thinking about them more when I'm going to more than three times a day because of convenience, ease and stability.

I want to keep people as smooth as possible. I want to have minimal dyskinesia. Usually people are willing to accept some. I want to have minimal wearing off. Whatever I need to do to keep people feeling even, that may mean adding in as-needed inhaled levodopa. That might mean switching to the longer-acting formulations. But if I'm already on a complicated regimen, if I've added in medications to make the carbidopa-levodopa last longer and I'm on extended-release formulations and I'm still having issues with ups and downs, that's when we're starting to have a different discussion, what we call advanced therapies. That's when we're starting to introduce things like deep brain stimulation or subcutaneous infusions or things like that to try to smooth things out. Hopefully that answers that question.

Dr. James Beck 01:00:16
It does. Thank you very much, Dr. Bega. I think we're at time, so I want to thank you for your time and sharing your insights with us today. It's been really fantastic talking about medications for Parkinson's disease. I want to thank everyone out there who joined us today. Unfortunately, we weren't able to get to everyone's question. There are a lot coming in to the Q&A. If you have questions that weren't answered, our Helpline can certainly be there to help. Please feel free to call 1-800-4PD-INFO.

I would also like to thank our sponsor, UCB. They are supporting our mission at the Parkinson's Foundation through a generous unrestricted educational grant to support our Expert Briefing series. Here is an outline of what's to come. Our next session is going to be Wednesday, October 15. We've almost come to the finish line for the year for Expert Briefings, and it's going to be about improving gait and how to maintain steady steps. I encourage everyone who may have that as a concern or who is just interested, please join us on that date.

You can also learn more about future topics at our webpage listed there on the screen as well. I also want to highlight that we have weekly virtual programs in addition to the one we're hosting right now: Mindfulness Mondays, Wellness Wednesdays, our Fitness Fridays, and we also have our sessions in Spanish as well. Please feel free to visit Parkinson.org/PDHealth for more information and how to register.

Before you go, I just want to let you know we're here for you through our Helpline, website and Helpline email address, Helpline@Parkinson.org, so feel free to check those out. Also, before we depart, we're in the realm of Zoom, the screen will go black and then a survey will pop up on your screen. Please feel free to fill that out. We really value your input and use that to guide our future Expert Briefings, provide feedback to our presenters, and always keep in consideration what we're doing is aligned with the needs and priorities of those living with Parkinson's disease. Until next time, until October, take care and we'll see you at the next Expert Briefing.