Episode 167: Exploring Carbidopa-Levodopa for Treating Parkinson’s Symptoms

Dan Keller 0:08 Welcome to this episode of Substantial Matters: Life and Science of Parkinson's. I'm your host, Dan Keller. At the Parkinson's Foundation, we want all people with Parkinson's and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research—the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow.

Several medications are known to treat Parkinson's disease symptoms, but one size does not fit all, and each person with Parkinson's needs a personalized treatment approach for managing their unique needs. Carbidopa/levodopa is commonly prescribed for people with PD and is known as the gold standard treatment for motor symptoms in Parkinson's. In today's episode, we invited Dr. Emily Peron and Dr. Leslie Cloud from Virginia Commonwealth University Health, who were part of the team that played a key role in writing and reviewing our newly updated Parkinson's Foundation medications book. They do a deep dive into how carbidopa/levodopa works in the body, its impact on PD symptoms, pros and cons of its short-term and long-term use, and the different medication forms currently available to the public. I began by asking Dr. Peron to provide an overview of how carbidopa/levodopa works.

Dr. Emily Peron 1:50 When we think of carbidopa/levodopa, I always like to point out that although carbidopa is the first one in the name that we use, levodopa is actually what we would consider to be the more active component of the drug. So there's two parts to it. Levodopa is the part that's actually converted into dopamine in the brain, since dopamine is what's lost in the case of Parkinson's disease. Giving levodopa, which can then turn into dopamine in the body, is going to replace the dopamine that's lost with the levodopa.

It's important to recognize, though, that ultimately it needs to go into the brain, but as it makes its way through the rest of the body, it can get lost along the way. When we have levodopa converted into dopamine as it goes through the body, it can create side effects—most commonly what we think of would be nausea and vomiting. Ultimately, some of it still would make it into the brain if we just gave levodopa alone, but what they found was that when you added this carbidopa component, it acted as a bodyguard to levodopa. It basically helps levodopa get through the body without being broken down as much as it would if we had just given it alone. Then, as the combination of carbidopa/levodopa gets toward the brain, the carbidopa falls away, the levodopa gets taken up into the brain and converted into dopamine, and that's where we have the main benefit as it relates to managing Parkinson's symptoms.

Dan Keller 3:13 So, let me see if I can summarize what's going on. The blood-brain barrier, which is specialized vessels in the brain, doesn't let a lot of things into the brain, including dopamine itself. So, you give levodopa, which can cross the blood-brain barrier and is converted to dopamine in the brain. The downside is levodopa is still circulating in the body in the general circulation, and it can get converted to dopamine in the general circulation and cause side effects. So carbidopa inhibits the conversion of levodopa to dopamine in the rest of the body and prevents those side effects, and at the same time allows levodopa to still circulate, which is now available to go across the blood-brain barrier and turn into dopamine in the brain. How's that? Is that a decent summary?

Dr. Emily Peron 4:10 That's beautiful. Leslie may have a more succinct way of putting it as well.

Dr. Leslie Cloud 4:15 No, I don't think I could have said that better myself. That was beautiful. Fantastic.

Dr. Emily Peron 4:20 I kind of want a recording of that to just play for students. That's wonderful.

Dan Keller 4:24 Well, just pull it out of the podcast. So, could one of you discuss the use of carbidopa/levodopa as a combined treatment, and why that treatment has been considered the gold standard in Parkinson's treatment for many years now?

Dr. Leslie Cloud 4:43 It's always a combined treatment. We never give levodopa alone for the reasons that Emily just discussed, because the side effects would be too great. So anytime we talk about using levodopa to treat Parkinson's disease, it's implied that we're talking about the combined treatment with carbidopa.

Carbidopa/levodopa has been the gold standard for decades now because it really is the most effective treatment that we have, even after all of these years. It is really the most logical and direct way to treat the disease because we're essentially just giving the brain back the dopamine that it's not making enough of, and so in that way, it makes sense that it's the most effective and the most potent symptomatic treatment that we have. It's also the safest in many ways. A lot of the other drugs that we have to treat the symptoms are not only not as potent or effective, but they have more potential for drug-drug interactions, they have more potential for unwanted side effects, and so all of that has culminated in levodopa remaining the drug of choice and the gold standard across the decades, despite the development of multiple other medications throughout the years.

Dan Keller 6:06 What are some of the challenges of using carbidopa/levodopa, such as potential side effects or motor fluctuations? How can you adjust dosages, things like that?

Dr. Emily Peron 6:19 Leslie, if you want to take that, and then I can always chime in if there's other stuff.

Dr. Leslie Cloud 6:24 Sure. So, in terms of common side effects, initially when people first start levodopa, I usually counsel them that early side effects to look out for would be those peripheral side effects—so things like nausea, vomiting, and dizziness from lowered blood pressure. Those are probably the most common side effects that we see early on, although certainly others are possible.

Then over the years, as people live with their Parkinson's disease for a while, we start to see the emergence of some of the long-term complications of levodopa therapy. The two that we see are what are called motor fluctuations and dyskinesia. The motor fluctuations are when levodopa begins to not work consistently throughout the day as it does early on in therapy. In the early years when someone first starts levodopa therapy, they take their medication and it works throughout the day smoothly, their symptoms are nicely alleviated, and life is pretty good. But then after some number of years, they leave what we call that honeymoon phase and they develop motor fluctuations, where each dose of levodopa may not last as long as it used to. The medications start to wear off in between doses, and that can be predictable at the end of each dose, or for some people it can even be unpredictable, where the medication wears off and they're not even at the end of the dose. So they wear off when they least expect it, and that can be quite frustrating for people because when medications wear off, their Parkinson's symptoms come back, sometimes full force, and that can be quite disabling for some people. So that's what we mean when we say motor fluctuations.

Dyskinesia is a term that describes a long-term side effect of levodopa therapy, where people develop involuntary movements that are sort of slow, wiggly, writhing type movements that just appear to the onlooker like the person is restless and wiggly. These often start very subtle and mild, and may not even be noticed by the individual, but over time they can become more pronounced and even really quite severe. Those are long-term complications of levodopa therapy.

Dan Keller 9:09 When people do have fluctuations and their symptoms are getting worse over time, is it possible to do adjustments in the dosage of the levodopa, and separately, can you do adjustments of the carbidopa? Does that kind of formulation exist?

Dr. Leslie Cloud 9:30 Actually, both early on and later on, when people are having side effects, you can make dose adjustments to address their symptoms. Early on, as people are having nausea, vomiting, etc., adjusting the ratio of carbidopa to levodopa can help. Most of the formulations that are available have a 1:4 ratio of carbidopa to levodopa, like 25 to 100 or 50 to 200, and that, in the clinical trials that led up to the approval of the drug, was enough for most people. But some people are just more sensitive than others to the nausea and vomiting, and so for those people we want to shift that ratio a little bit, give them a little bit more carbidopa with each dose of levodopa. What we'll often do is just give an extra 25 milligrams of carbidopa with each 100 milligrams of levodopa, and that will often solve the short-term side effects of nausea, vomiting, and sometimes even dizziness.

In terms of the long-term, more central side effects and complications, there are ways that we can deal with that by adjusting the timing of the medications, the dose of the medications, or even the formulation of levodopa that people take. I love the idiom, "there's always more than one way to skin a cat." It's a weird expression, but I think it really applies here because there's so many different ways that we can tweak the medication regimen to address motor fluctuations and dyskinesia when they emerge. These are not insurmountable problems; it just means that the management becomes more complicated and nuanced.

Dr. Emily Peron 11:21 As Leslie was saying, it's important to keep in mind that not only do we have the option to adjust the carbidopa and levodopa themselves, but also thinking about the fact that it's not the only treatment we have available. I know we're focusing on it today, but certainly there are other medications that we can look at in the toolbox that can be added, moved, and adjusted around the carbidopa/levodopa.

I think this is also an opportunity to think a little bit more holistically about care, in the sense that we oftentimes will educate folks about food that could be interacting with their response, if they need to maybe think about physical therapy, looking at different ways in which we can help them achieve the goals that they have in terms of managing their Parkinson's disease. There's a whole host of things that go into managing the disease and working around whatever it is that they're experiencing with the carbidopa/levodopa specifically.

Dan Keller 12:16 It seems if the carbidopa is preventing symptoms like nausea and vomiting and blood pressure fluctuations, you might want to have the carbidopa in your system before the levodopa hits it. Can someone take carbidopa separately, or are there pills that release carbidopa first so that they don't get the symptoms when the levodopa comes on board?

Dr. Leslie Cloud 12:42 You can take it separately. It is manufactured as a separate pill, and for people with really severe nausea and vomiting, many movement disorder specialists will premedicate with carbidopa for a week before reintroducing a carbidopa/levodopa combined tablet so that their system is completely flooded with carbidopa. That will often lead to a successful reintroduction of levodopa without nausea and vomiting.

Dan Keller 13:16 If any of our listeners are wondering: If carbidopa is supposed to prevent the conversion of levodopa to dopamine, why doesn't it do it in the brain and prevent the effect of the levodopa? The fact is, the carbidopa is designed so it does not cross the blood-brain barrier and stays in the general circulation where those side effects would arise. So I just wanted to add that carbidopa is not crossing the blood-brain barrier and is really doing its effect where it should be. Emily, what are some of the levodopa/carbidopa formulations that are now currently available that are FDA approved?

Dr. Emily Peron 14:01 So we have the immediate-release formulation, which is the standard—we've had that for decades, as Dr. Cloud mentioned. That formulation is given, it kicks in typically within 15 to 30 minutes, and then folks will see benefit for up to several hours, depending on where they are in the course of the disease and how they're responding.

What we find with that, though, is that for some folks, they end up needing to take it frequently throughout the day, and that can create some challenges for them in terms of adherence and symptom control. So, there have been some longer-acting formulations that have been developed. The immediate-release formulation is carbidopa/levodopa, Sinemet being the brand name, and then they developed a controlled-release formulation known as Sinemet CR. That formulation was intended to extend the benefit of the Sinemet, although we typically don't see it used as much throughout the day anymore. Some folks will use it at night to help give them control through the night and into the morning a little bit, but for some folks, it doesn't work quite as well throughout the day as other formulations, so we don't see it as much right now.

This is especially true because there's been another new extended-release formulation that came out in recent years known as Rytary, which is a combination, actually, interestingly enough, of an immediate-release and an extended-release, so that the drug essentially is released through the body at different time points. That's intended to extend the benefit that someone experiences. If they've been taking the immediate-release formulation Sinemet six or more times a day, they can then switch over to this Rytary and potentially use it less frequently, and it would actually replace the Sinemet in many cases.

The other options that we have: There's an orally disintegrating tablet, so for some folks who have difficulty swallowing, that can be beneficial. The other one that is a bit more invasive—it's actually administered through a tube in the gut—is what we call an intestinal gel or intestinal suspension, and that one is known as Duopa. That has been available in other countries for years, and the US approved it several years ago, but that's another option typically reserved for folks who have kind of used all of the oral formulations, used other medications, and really need something to smooth out the peaks and valleys that Dr. Cloud mentioned with motor fluctuations and dyskinesia. Anything I'm missing, Leslie?

Dr. Leslie Cloud 16:29 The only one I guess that wasn't mentioned was Dhivy, which is for people who really need fractionated doses, doses less than half a tablet of a 25/100 milligram Sinemet. Dhivy is just a formulation that can be split into four pieces so that people can get 25 milligrams of levodopa if need be accurately, because trying to cut a tablet that's only scored in the middle into four pieces without it just crumbling is impossible. So there's that formulation on the market now as well.

Dan Keller 17:08 How should they approach having a discussion with their healthcare providers about adjusting their current medications, or even exploring a change to a different medication?

Dr. Leslie Cloud 17:21 I would say that the key data that the healthcare team needs to know is what exactly are you taking and at what time of day, so the details really matter there. And then, what hours of the day on average are good for you? What hours are you feeling like your medicine is working well, you're moving well, and your symptoms are well controlled? And then, what hours of the day are you feeling as though your medications are not working well, and you're "off," so to speak? Finally, if you're having any side effects throughout the day, what time of day are those most likely to occur?

Keeping a diary for one or two days, where you write all of this down, can be extremely helpful—not only for you to figure out the answers to those questions, but for you to be able to then communicate that back to your healthcare team, because those are the types of details that they need to make really informed decisions. It can be really hard, I think, even though you're living with these symptoms day in and day out, if you don't keep a diary, to tease out those patterns. So, if you don't intuitively know the answers to those questions, I highly recommend keeping a diary for a couple of days.

Dan Keller 18:42 Can some of these problems be solved just by adjusting timing or dosage of the same medication? Or when does the physician consider switching medications?

Dr. Leslie Cloud 18:54 Oftentimes they can be solved by just adjusting the timing or the dose of the same medication. It's always our hope that we can stick with the medication that someone is already taking and just tweak the timing or the dose before we go and add another medication. It's really not until someone is already on what we consider to be a dose that's too frequent for them—and what's too frequent for one person might not be too frequent for the next person, so there's no one-size-fits-all answer—but if we think they're already on dosing that's too frequent for them, or on a dose of levodopa that's too high for them, then that's really when I think most people start to think about adding in another drug. Or, if they're having side effects of levodopa and we want to try to minimize those side effects, then we might think about folding in another drug.

Dan Keller 19:49 Finally, is there anything important we've missed, or that you want to add? Either Dr. Peron or Dr. Cloud.

Dr. Emily Peron 19:58 We've talked about a lot of information today, but I do think that there's so many opportunities that folks have in terms of communicating with their movement disorder specialist and with other healthcare professionals. Really helping as much as we can to get a team built around someone early on can be helpful early in the diagnosis, just so that there are folks they know they can go to if they have questions.

I always recommend, of course, from the perspective of a pharmacist, that folks build a relationship with their pharmacist if they can. Just knowing that there's someone they can go to if it's after hours, if they have an issue with a new manufacturer that's been making their medication and they want to talk to somebody about those specifics, or just have a go-between with one of their prescribers—certainly, using your pharmacist for those things is appropriate.

Looking at building out the team, I always encourage folks to establish a relationship again with a movement disorder specialist specifically early on because, as Dr. Cloud mentioned, the movement disorder specialist has additional training in movement disorders. I think that really is an opportunity to ensure that the diagnosis is accurate, the medications are correct, and that you're supported throughout the course of the disease. Even if you can't see that person on a regular basis, you at least have that kind of stopping point that you can always go back to intermittently and just make sure that things are going okay. So I'm big on that team-based approach and thinking about the different folks that you might need along the way, and getting them in communication with each other.

Also, as Dr. Cloud mentioned, recognizing something like a symptom diary and tracking medications, tracking what someone's experiencing from day to day, can be challenging because there is variability from person to person, but also from day to day for an individual person. The more information that we have, the more informed decisions we can make when it comes to adjusting medications.

My last piece is that I think it's really important for patients and for care partners to advocate. If there are questions that you have, if there are concerns that you have, reach out and ask the questions; try to find resolution to the questions and concerns that you have. That's what we're here for. We work with folks with PD every day, and we recognize some of the trends in what folks are experiencing, but just because it's not listed on a website as being a common side effect, it doesn't mean that it's not important to you and something that we shouldn't explore as potentially being related. Recognizing what differences you notice in yourself, whether it's related to the Parkinson's or to the medications or something entirely different, and communicating that with your healthcare team can be vitally important to making sure that everyone's on the same page.

Dan Keller 22:33 One thing that just occurred to me is: Are there generic versions of these drugs, and do people react to different generics differently? Say the pharmacy buys it from one company one year and buys it from another company the other year, and the pills look a little different. Do they act a little different?

Dr. Leslie Cloud 22:52 I'm so glad you brought this up because this has been a recent problem, actually a very recent development. I'm sure Emily has thoughts on this and can comment on this as well. So, I'm actually going to let Emily start, but I have something to add when she's done.

Dr. Emily Peron 23:09 Sure, yeah, it's a bit of a loaded question. As Leslie said, this is something we've seen recently. I work with folks who have had experiences where they have had a manufacturer change, and they do find that they see a difference in terms of how they respond—that one manufacturer's formulation just works better for them, for whatever reason. There can be some variability between the brand and the generic, and even from generic to generic, because they're all manufactured by different companies. In truth, there shouldn't be a significant variability, and we often talk about certain diseases, like I think of something like a seizure disorder, where we're very tuned into the fact that we know that brand and generic can make a difference.

But with Parkinson's, I think that's really something that's just come out in recent years—that folks have been more tuned in as their manufacturers have changed and we've had more manufacturers of these meds. Although it's not something that you'll necessarily commonly read about, it absolutely does happen. Part of the reason I mentioned building a relationship with your pharmacist is that I have some patients who actually work with their pharmacist to identify which manufacturer works best for them, and if they can, the pharmacist will try to hold back some of that manufacturer or do their best to make sure that they have a given manufacturer's medications on hand for them. It's not always a guarantee, but at least if you have an idea of what works best for you, you may be able to check if a different pharmacy has that manufacturer in place, or perhaps your pharmacist at your local store can help make sure that you have that medication if they have it in stock. But yeah, absolutely, there can be some variability. I think it depends on the person. I've worked with many patients, and very few have had that issue, but I do think that if folks are tuned into it, if it's something that affects them, then it's something that affects them, and it's not my place to tell them that that's not the case. So, I definitely think that it's something to be aware of. It's again typically not an issue for most folks, at least that I hear of, but it's certainly something that we're hearing more about.

Dr. Leslie Cloud 25:17 First of all, I'll say I agree, and second, what Emily just said, that problems with generic formulations not being as effective as brand name is not something that we run into very often with levodopa formulations—so that's not a typical thing that we run into.

What I have run into very recently, quite often, is that there is a generic manufacturer of carbidopa/levodopa that is apparently the most inexpensive and therefore the one that's now being purchased by most commercial retail pharmacies, and they don't score their tablets. While they're just as effective, for the hundreds of thousands of patients out there who take one and a half or two and a half tablets and have to cut their tablets in half, these tablets are not easy to cut in half. Even if you have a pill cutter, because these tablets aren't scored, when people try to cut them, they crumble. People aren't able to get the right dose because they can't cut the tablets effectively, and we have had to get on the phone with multiple pharmacies to try to negotiate for them procuring a different type of generic levodopa because of this problem. Most of the big retail pharmacies won't because these decisions are made at such a high level, and so for a lot of our patients, they've actually switched to locally owned and operated pharmacies, who are less likely to buy from month to month from whoever is supplying the cheapest bottom dollar, so that they can get the same formulation from month to month and be guaranteed that they're getting something that's scored.

Dan Keller 27:04 Just to clarify, when you say "scored," it doesn't mean the tablet is rated 1, 2, 3, 4, 5. A score is that little line on the tablet where it's supposed to break when you cut it, correct?

Dr. Leslie Cloud 27:16 Yes. Thank you for clarifying that. And it's just a bad idea—I mean, I don't know whose idea it was to make carbidopa/levodopa tablets that aren't scored.

The only other thing that might be worth mentioning is that there's a lot of "levodopa phobia" out there, and a lot of people that are afraid to take levodopa, especially early on after their diagnosis. I would just encourage people to have a discussion with their provider and trust their provider. There really is no reason to fear levodopa. Levodopa is your friend, and the latest guidelines from the American Academy of Neurology and the Movement Disorder Society really strongly encourage levodopa as a first-line drug, even for the newly diagnosed, because in the long run, it really is still the best option. So, there's no reason to fear levodopa.

Dan Keller 28:12 I suppose that fear started with a thought or a myth that it eventually wears off and your symptoms get worse, but that's really a function of the disease progressing, not the drug becoming ineffective, isn't it?

Dr. Leslie Cloud 28:25 Correct, exactly. You have a loss of dopaminergic cells in the brain over the years, and so you have to take more levodopa over time to control your symptoms, but it's not because you're becoming immune to levodopa, it's because your disease is progressing.

Dan Keller 28:42 So you may as well get the benefit of it early on, because it's not going to harm you.

Dr. Emily Peron 28:46 Correct.

Dan Keller 28:48 Good. I appreciate it all from both of you. Thank you. You've covered this subject pretty extensively, and I think with good terminology that our audience can pick up on. So, thanks a lot. Bye.

The Parkinson's Foundation offers resources that provide life-changing support to people living with Parkinson's and their care partners. To order our free printed publications, visit parkinson.org/store. To view or download our digital resources, including our newly updated medications book, fact sheets, and other books, visit parkinson.org/pdlibrary. In addition to integrating key Parkinson's medication updates, our medications book reduces health literacy barriers through plain, concise language in text tables, providing medication information at a glance, larger font size, and a streamlined layout that will make home printing easier.

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Emily Peron, PharmD, MS, is Associate Professor of Geriatrics at Virginia Commonwealth University (VCU) School of Pharmacy. Among her faculty commitments, Dr. Peron practices as a clinical pharmacist and conducts research with the VCU Parkinson's and Movement Disorders Center (a Parkinson's Foundation Center of Excellence). She regularly speaks at movement disorder support groups and teaches students from pharmacy and other health professions programs about movement disorders. Dr. Peron also contributes to medication-related education materials for the Parkinson's Foundation and has served as a member of the Parkinson's Foundation Aware in Care Advisory Committee, which seeks to make hospitals safer for people with PD. 

Dr. Peron earned her Doctor of Pharmacy degree from Butler University and completed two years of clinical pharmacy residency training at the Louis Stokes Cleveland VA Medical Center, specializing in geriatrics. Dr. Peron then went on to complete a two-year research fellowship and Master of Science degree in Clinical Research at the University of Pittsburgh. She is currently pursuing a PhD in Health-Related Sciences with a Concentration in Gerontology through the VCU College of Health Professions. Her dissertation will explore the experiences of loneliness and ageism among people with Parkinson's.

Dr. Cloud received her MD in 2004 from the Medical College of Georgia. She then completed her neurology residency (2008), clinical movement disorder fellowship (2009), and Master’s Degree in Clinical Research (2011) at Emory University. She joined the VCU faculty in 2011. She is currently the Medical Director of the Parkinson’s Foundation Center of Excellence at VCU.