Episode 157: Pump Therapy

Dan Keller 0:02 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. In June 2023 leading Parkinson's disease researchers presented a course in Poland on infusion pump therapy, covering motor fluctuations and their treatment with levodopa carbidopa intestinal gel infusions and apomorphine and levodopa infusions under the skin. The idea of infusions is to give a more constant dose of the drug throughout the day. Topics included patient selection, management of the pump by both patients and caregivers, the importance of a multidisciplinary care team, and what's coming along in pump therapy research. One of the course presenters was Professor Ray Chaudhuri, Professor of Neurology at the Parkinson's Foundation Center of Excellence at King's College Hospital in London. We started off talking about who is a candidate for pump therapy?

Dan Keller 1:43 You were recently giving part of the course on pump therapy. So, first, let's talk about what's available today in pump therapy, and then what's coming. First, in general, when would you consider any form of pump therapy over oral medication or patches for a patient?

Prof. Ray Chaudhuri 2:07 So pump therapy for Parkinson's is not new. It's usually reserved for people we consider to have entered the advanced stage of Parkinson's, or some would call the complex state of Parkinson's, and that's when they're deemed suitable for what we call device-aided therapy, which pump-based therapy is one of them. Deep brain stimulation is the other. There are largely two pump-based therapies that are clinically widely available, and this is apomorphine infusion and intra-jejunal levodopa infusion, both being given by a patient-worn portable pump. And the selection of patients suitable for these therapies is based on several criteria, which we use to judge who has entered the Parkinson's advanced stage. Broadly, that relates to when oral or transdermal therapies of Parkinson's are not working that well. So clinically, the advanced stage is recognized by the fact that their oral therapies are not working that well anymore, in spite of all optimization. People might have tried transdermal therapy also, which may not be effective anymore. And when I say not effective anymore, people start showing or having more troublesome movement-related problems, such as persistent off periods or dyskinesias, and for non-motor problems, which could be sleep dysfunction, memory issues, also depression, anxiety, as well as autonomic problems. In addition to this, the person might also be having mobility issues, particularly balance issues and falls. When these things all come together, that's the time to reappraise the treatment the patients are on, and that's when pump therapy would benefit many.

Dan Keller 4:08 In general, how complicated is it to start a patient on pump therapy and management issues going forward?

Prof. Ray Chaudhuri 4:16 Pump therapies are not straightforward, so in other words, it needs a center which has relevant expertise and experience—very similar to deep brain stimulation, and you don't do deep brain stimulation in every center. And the mistake often people make is they just think, oh, I can start pump therapy. It's not just the start, it's also the maintenance and the sustenance. So, with both pump therapies that are available and the ones that are going to come in the future, such as the AbbVie 951 product, which will be also delivered by subcutaneous pump, or NeuroDerm, which will also be delivered by subcutaneous pump, all of these products will need a multidisciplinary team, not just the doctor. We need experience in maintaining treatment, because the problem with pump therapy often happens not at the start, but after a few months. People have device-aided issues, people might have other side effects. So, both the start and the maintenance are important. So, it's not straightforward, it needs training, and therefore centers which have the expertise in doing these therapies should be the ones doing it, because that's where you have the best outcome. How much patient training is involved? To some degree, there is patient training required for both therapies, in the sense of what to expect, what not to do, what to do, and there are some differences. Apomorphine infusion is a subcutaneous pump. In fact, in many young patients who are otherwise fit and active, they can do it themselves. The levodopa intestinal pump is through a port, through a PEG-J tube into the jejunum. It's a little bit more complicated. Often, either the caregiver or sometimes the patient would need to attach the infusion to start it off in the morning, because these therapies are not used usually for 24 hours. They are usually used for 12 to 14 hours, then the system is disconnected and it's restarted the next day. So therefore, there is some degree of difference about the patient training, but the patient training, and not just the patient training—

Unknown Speaker 6:30 Caregiver training is also very, very important.

Dan Keller 6:34 Do these drugs delivered by pump reduce off times and medication fluctuations?

Prof. Ray Chaudhuri 6:42 They have a much better effect of reducing what we call refractory off periods and also reducing troublesome dyskinesia and improving on times, which oral therapies can no longer do because they're bypassing the blocks and the barriers that are caused by dysfunctional stomach-related absorption. And they also have a beneficial effect on those non-motor symptoms, which are sometimes more important to the patient than their off periods. So overall, they have a greater efficacy profile in the advanced stages.

Dan Keller 7:20 You had mentioned delivering levodopa gel through a tube into the jejunum, which means into the top of the small intestine, so this would be through the skin and into the gastrointestinal tract directly.

Prof. Ray Chaudhuri 7:36 Yeah, I mean the process needs a very small surgery, which is a very standard surgery where they make a small incision into the skin in the stomach area. The gastroenterologist does it so that a tube can then be inserted from externally into the stomach, and through that lead-in tube, another smaller tube is inserted, which goes into the jejunum, which is below the stomach, as you said, at the top of the small intestine. The reason why this jejunal placement is very important is this is from where most of the levodopa, which is the gold standard treatment for Parkinson's, is absorbed—not from the stomach but from the jejunum. So the advantage of jejunal levodopa infusion is that you're delivering the drug straight into the area from where it's being absorbed and not relying on oral tablets, which have to go all the way to the stomach, then into the jejunum to be absorbed to have an effect. Can patients eat normally? Yeah, with both therapies, patients can eat daily normally. If they've got an intra-jejunal tube, we give some advice, particularly in earlier stages of treatment, perhaps to avoid too much long green vegetables, because sometimes these can become like a mass in the stomach or in the jejunum, and it can block the tube. So these are some practical advices. Apart from that, patients can eat anything that is related to their normal diet.

Dan Keller 9:11 I suppose they still have to look out for a high protein diet. They are dealing with levodopa absorbed and delivered one way or another.

Prof. Ray Chaudhuri 9:20 The protein intake issue is very interesting, because if they were taking tablets, then the advice now, as per the dashboard we published, is that you must keep your stomach free from milk or other protein for at least 45 minutes after oral tablet intake, because if the stomach is full of milk, full of cheese, or other protein, then it significantly reduces the absorption of levodopa, sometimes so much so the patient doesn't show any effect at all. But that's very relevant to oral medication. To some extent, when you're giving it jejunally, it's less of a problem, but we still ask the patients to be cautious with protein, particularly milk products, when they're taking jejunal infusion.

Dan Keller 10:15 What do you see as some of the side effects or adverse effects of either of these pump therapies delivered either under the skin or directly into the jejunum?

Prof. Ray Chaudhuri 10:28 Oh, there are many adverse effects. It's been very widely written up. Apomorphine is a dopamine agonist—it's a very powerful dopamine agonist. It is a very strong emetic, so it can cause significant nausea and vomiting, and we need to block that by giving a drug called domperidone. And because it involves a regular injection, it can form skin nodules, just like any other skin-active drug, like insulin injection or interferon injection—it can form nodules, but one has to be very careful about it, and skin hygiene is very, very important. Apart from this, they also have dopamine agonist-related side effects, like confusion, hallucination in big doses, and impulse control disorder in some patients. Levodopa infusion has levodopa-based side effects, but the side effects are again related to the device. So the tube can be pulled out, the tube can get blocked, there might be a small infection at the surgical site—all of this can be handled if recognized properly. As per the gel itself, the side effects are the same as levodopa, which is the gold standard. But some additional things we've noticed is some people might lose weight, some people might become low on certain vitamins, like vitamin B12 and folate, and some people can also have more mild inflammation of the nerve (neuropathy), the cause of which is not clearly known, but might be linked to low vitamin B12 and folate levels, and this can all be related to a malabsorption syndrome. So there might be some of these local side effects, but you wouldn't get the other sort of side effect profile as you're getting with apomorphine.

Dan Keller 12:28 Are there other drugs coming along or other pump delivery sites or methods?

Prof. Ray Chaudhuri 12:33 Yeah, there's lots of research, because what we realized is, as the condition enters into an advanced state, you have to really look at non-oral strategies as much as possible, because the stomach and the absorption, even from the jejunum, become erratic. So there are two products that are going to be coming very soon, which is subcutaneous levodopa, which will be the first time in the history of Parkinson's management that levodopa is being given subcutaneously. There are two products: NeuroDerm is one, which will employ two syringes, and that will give levodopa straight through the skin through a small pump—so that's subcutaneous levodopa. And then there is also the foslevodopa, which is a precursor of levodopa combined with foscarbidopa, which is the standard levodopa combination we use orally. So the foslevodopa and foscarbidopa is also going to be given via subcutaneous injection, in this case a single device, and both have been in clinical trials, and the data looks promising, apart from skin-related side effects. So, we will see them, hopefully, in the market by next year. Apart from this, there are other device-based therapies that are also being looked at, like an inhaler or inhaled levodopa. There is similarly buccal apomorphine—so apomorphine given under the tongue would rapidly dissolve, although that is not really a device, because you're just using a different format of the medication, and that's going to be used for rescue therapy. Apart from this, people might be also looking at once-a-week infusions, either subcutaneous or others, and there are drugs, such as ropinirole and other drugs, that are being looked at for this longer period for device-aided therapy, but with a longer duration of action.

Dan Keller 14:15 Where does pump therapy fit in versus deep brain stimulation? Both of them seem to be later therapies when oral medication is losing effectiveness.

Prof. Ray Chaudhuri 14:26 Yeah, deep brain stimulation is a neurosurgical procedure. One mustn't forget that it involves placement of electrodes in a highly precision-based manner, usually to either the subthalamic nucleus or to the globus pallidus in the basal ganglia. It's a highly specialized procedure, which needs to be done in a specialist center. There are guidelines of which to go with what, but often it boils down finally to the choice of the patient and the caregiver, along with the clinician, and the clinician's familiarity with the procedure that they're undertaking. One of the things with deep brain stimulation at the moment, most centers will not operate beyond 65 years of age, perhaps in some centers up to 70, because the risks of injury, cerebral edema related to the placement of the tube, or even a small hemorrhage within the brain can occur as a side effect, and the older one gets, the more tricky the side effects could be. Whereas, for levodopa infusion, there is really no age bar—you can do it in any age group, really, because the patient is likely to stay on levodopa anyway. Apomorphine has to be used cautiously often in older people or those who have autonomic problems, but also if there's a history of impulse control disorders or any neuropsychiatric issues, such as hallucinations, etc. So there are do's and don'ts, and who you can use pump therapies in as in DBS, and that's why you really need an expert center, and ideally a center that does all three device-aided therapies.

Dan Keller 16:10 What symptoms do these pump therapy drugs address? Are there certain symptoms that are not alleviated by this kind of therapy?

Prof. Ray Chaudhuri 16:20 Yeah, it's important to remember that the efficacy of these pump therapies and deep brain stimulation extends not just only on motor symptoms, such as off periods and dyskinesia, etc., but also increasingly research is focused on non-motor symptoms. It's worth noting that if you ask an advanced Parkinson's patient, they'll often rate non-motor problems to be more troublesome to them than the motor problems. So, it's important that you look at these therapies and see whether they cover the non-motor aspects as well. And we do have good evidence now from studies—largely from our center, but collaborated with many other centers—showing, for instance, that apomorphine is very good for sleep, and there's been a recent double-blind trial on this from France. And in the future, one may be able to use apomorphine with Parkinson's patients who often experience sleep problems. Levodopa infusion therapy is also an excellent therapy for sleep problems in Parkinson's. In addition, these therapies might help with pain, particularly off-related pain. Levodopa infusion therapy also seems to have an effect on mood, as well as some autonomic issues, particularly bladder, as does apomorphine to help with bladder control in some patients that also have depression. Deep brain stimulation also has some specific non-motor effects, such as the improvement of pain. So there's a whole range of additional benefits of these therapies, not just motor.

Dan Keller 18:00 I suppose the ultimate question is, do people have a better quality of life when they switch to one of these pump therapies?

Prof. Ray Chaudhuri 18:08 Yeah, there's very good data on that, particularly with levodopa infusion, which has been reinforced by real-life data, not just by clinical trials data. Clinical trials data is often very refined data from a selected patient group, not with much comorbidity. So, what you really want is real-life data collected from registries and patients we actually see in clinics. And levodopa infusion therapy has been looked at in two massive global registry studies. One was called GLORIA, and the most recent one published this year is called CosmoGlobe. Both studies show that across centers around the world, there is a consistent effect of levodopa infusion in the studies up to three years, with persistent and sustained improvement of quality of life as measured by quality of life measures. If you look at the EuroInf 2 study, that was a smaller number of patients, but one compared DBS with apomorphine and levodopa infusion in an open-label manner—there also, again, we saw a robust improvement in quality of life with all three device-aided therapies, so there is that quality of life improvement, and that is particularly strong for levodopa infusion therapy.

Dan Keller 19:42 Good to hear. I really appreciate it. Thank you for putting all this in perspective.

Prof. Ray Chaudhuri 19:45 You're very welcome. Thank you.

Dan Keller 19:46 To learn more about pump therapy, visit our website at parkinson.org and search "pump therapy." There you'll find several articles about different treatment options, including subcutaneous or under-the-skin apomorphine infusions, intestinal gel pumps, as well as deep brain stimulation. You will also find blog posts about other treatment options to consider as PD progresses. Feel free to visit parkinson.org/pdlibrary to view and download our free books, including Surgical Options and Managing Parkinson's Midstride, which are resources for people with more advanced Parkinson's. If you want to leave feedback on this podcast or any other subject, you can do it at parkinson.org/feedback. If you enjoyed this podcast, be sure to subscribe and rate and review the series on Apple Podcasts, or wherever you get your podcasts. At the Parkinson's Foundation, our mission is to help every person diagnosed with Parkinson's live the best possible life today. To that end, we'll be bringing you a new episode in this podcast series every other week. Till next time, for more information and resources, visit parkinson.org or call our toll-free helpline at 1-800-4PD-INFO, that's 1-800-473-4636. Thank you for listening.

Professor of Movement Disorders 
Director, Parkinson Foundation Centre of Excellence, King's College, Denmark Hill Campus 
Research Director and Assistant Medical Director, King's College Hospital

Professor K. Ray Chaudhuri’s research concerns Parkinson's Disease and in particular, pioneering work on defining non-motor symptoms and non-motor phenotypes of Parkinson's disease. He is considered a world leader in non-motor aspects of Parkinson's people-based research. To date, he has published over 350 peer-reviewed papers, several book chapters on Parkinson's Disease, restless legs syndrome and dystonia. He is also the director of Parkinson's Foundation Centre of Excellence at King's, Research Director and Assistant Medical Director at King's College Hospital.