Daniel E. Kremens, MD, JD

 How do you decide which on-demand therapies to begin when you want to treat somebody’s morning OFF?

It’s a collaborative decision. I have to vest the patient or the patient’s caregiver into this. If I don’t, we probably won’t have good adherence to medication. I want to get an idea of what their goals are and give them an idea of what the medication expectations are, and we meet somewhere in the middle. If I have somebody who is mildly OFF but needs enough to be able to get going, I might use 1 therapy that is an inhaled or a sublingual option.

If I have somebody who’s fully akinetic, who can’t move or can barely move, then we’d probably go with the subcutaneous option. Stratifying by severity is very important. It’s equally important to stratify based on use. Not every therapy can be given to everybody equal in the same situation. If a patient can’t take therapy on their own, they can’t take the inhaled. It requires them to do the process but to be able to actively inhale the medication. If they can’t inhale the medication, it does them no good.

At a bare minimum they have to be able to open their mouth and put a strip under their tongue, and to be able to hold that without swallowing it. In the most passive patient who isn’t able to cooperate, the spouse or caregiver can give them a subcutaneous injection. With these factors, the answer presents itself. If it doesn’t present itself, you could at least discuss the choices within individuals, and then they vest in the decision of saying, I’ll choose A. If A doesn’t work, I’ll chose B. At least you have a paradigm to work with for that individual patient.

 What advice do you have for community neurologists who may be initiating on-demand therapies in particular. How do you decide which drug to use specifically?

My first piece of advice to the neurologist who isn’t as familiar with on-demand therapies is to point out how it’s been a paradigm shift. This is something that as a neurologist you’re probably comfortable with already. That’s the notion of how we treat migraine: we don’t treat migraine with prophylactic therapies only; we use abortive therapies as well. Neurologists are comfortable doing that. We’re seeing this now in Parkinson disease. We can use the longer-acting preparations for prophylactic and then use the on-demand therapies for abortive therapies in Parkinson disease. That’s a paradigm shift that I encourage the nonmovement disorder community to embrace.

The second thing I recommend to them is don’t let the lack of trimethobenzamide, or Tigan, be a barrier to using the drug. Many of us have experience with this, and there are lots of data—as Bill’s study showed and some other studies have showed—that you can initiate these drugs safely without an antiemetic drug. If you go low and slow, you can use these medications.

The final point is what medication do I choose. It’s an individual discussion with that patient. Each of the medications has advantages and disadvantages, and it comes down to how will that medicine fit into that patient’s lifestyle, taking into the fact that you want something rapid, reliable, robust, and convenient. Looking at those together, what works for that patient?

 As I said before, even in case 2, emphasize on-demand. What’s missing in our fill for the general neurologist is recognition of OFF episodes. My position for them is that our goal in Parkinson disease is minimizing OFF, and if it’s possible, to get it to 0.

On-demand therapies are 1 of the tools, and patients can use it as needed. Therefore, they should get familiar with on-demand therapies as 1 of the tools we have to treat OFF episodes.

Because there’s a lack of head-to-head studies, the best way is to get their hands into different ones—there are 3 available, and they come up being able to introduce it to their patients. In less than 1 minute, I review the complexity, the efficacy, and the adverse effect of each. Then I classify for my patient and then let them decide. But it’s best for the general neurologists to get familiar with medication as well.

I absolutely agree that OFF episodes are underrecognized. To get a clear pattern, it sometimes does take a couple of minutes of conversation. I’ve seen general neurologists make this mistake where they give these drugs when the patients are on. You do have to make sure, especially in the apomorphine preparations in which we’re trying to dose these medications. You have to know how to artificially let them come off to be able to determine the optimal dose.

 Educate your patients somewhat on what OFF is and what symptoms they have, motor and nonmotor. Ask about them routinely, including all types of OFF, like morning OFF. Be aware that when they’re taking levodopa or extenders, these on-demand therapies can work more rapidly and reliably and can work as robustly as levodopa to turn patients from OFF to ON.

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Expert neurologists provide insight on how to decide on an on-demand therapy for Parkinson’s disease and provide some general advice.

Parkinson’s Disease: Advice for Community Neurologists

Laxman, you’ve had a lot of patients you’ve treated recently where Tigan has not been available. What’s your experience?

There are variations of what Khas has done. The first thing I’ll do is look at my patients and say, “Are they a moderate dose of levodopa, plus a dopamine agonist?” If they are, I’m going to start them at 0.2 mL. If they get nausea at that point, I’d titrate and I’d start them at 0.2 mL and see how they do. Maybe I’d keep them at 0.2 mL a little longer, so we don’t advance and optimize in this quickly. That’s group 1.

If they’re on lower dose of levodopa instead of a dopamine agonist, I’d say, “Let’s start at 0.1 mL. Once you’ve tolerated this to 0.1 mL, we’ll migrate it over to 0.2 mL gradually and still be optimized.”

I’ll stratify my patients and start some at 0.2 mL. If they get nauseated, they come back down to 0.1 mL. If they don’t, they stay there and then optimize. Others will start at 0.1 mL tolerate and then go up there, and that’s a good way to do it. Part of my experience with this has been anecdotal with patients coming into the clinic. We gave them a Tigan prescription based on the dogma of the time. They forgot to fill it, or they filled it but the medication was on back order, and they’re showing up to my clinic with everything ready. Many times they’ll say, “I didn’t take it.” I say, “That boat has sailed. Let’s start.” We discovered that they weren’t having nausea, and that’s when Tigan was available.

The lack of Tigan availability in some ways hasn’t been as much of a hindrance as we were led to believe initially.

I wonder if some of the barriers we spoke about with this remarkably rapid, reliable, and robust therapy relates to the need to pretreat in the label—at least it’s recommended. With Tigan, I’ve begun to see that. Now that we no longer rely on Tigan, patients seem more readily to want to adopt this therapy. What’s your experience over the past 4 to 8 months when Tigan has become unavailable? Do we know now that many patients, if not most patients, are beginning apomorphine injections without Tigan? What’s your experience like?

The experience at my center is similar to what the others have suggested. If you start low and go slow, doing the 0.5 mL, then do the 0.1 mL for a few days, make sure the patient is doing OK, then go up to 0.2 mL slowly. Patients who’ve been exposed to dopamine agonists already have a low likelihood of experiencing nausea.

One of the nice things that we also have available with the subcutaneous form of apomorphine is a program called the “Circle of Care,” a company-sponsored program that provides nurses and nurse educators to help with that titration process, even in the days with COVID, so that they can go out to the patient’s home and do the titration if you don’t want the patient coming into the office for some reason. Some physicians prefer to do the titrations in the office. Other people don’t have as much office space for the patient to do it at home. Some patients with COVID-19 don’t want to travel. Having a Circle of Care program is an advantage in terms of initiating a drug.

 It’s important to recognize that this has been a well-established therapy for a long time. Apomorphine is a molecule that’s been used in Parkinson disease in Europe and Asia for decades and in this country for 15 years.

There’s been concern that some patients don’t want to use a needle; there’s needle phobia. Now that we have a new formulation available sublingually for morphine formulation, how is it used? What’s its dosing? What was seen in the pivotal trials in terms of efficacy, safety, and tolerability?

Apomorphine is the most important thing. I always mention to my patients that this isn’t a morphine preparation. I’m not putting them on an opioid medication. It has that name from a chemical relation to morphine, but it’s not a physiological relation at all.

One of the problems apomorphine historically has is that it’s somewhat acidic. It has a pH of about 5.7. There have been previous attempts at sublingual preparations that the acidity of the drug seems to have gotten in the way with a significant amount of gingival irritation and things like this.

This is a new strip of apomorphine that has been buffered to minimize the effect of the acidity. It comes in a Listerine-type strip of apomorphine in doses from 10, 15, 20, 25, and 30 mg. Typically, you put it under your tongue. On average, it will take about 2 minutes to dissolve. Then there’s a very quick onset to action.

There are 2 parts of the studies. There was the inpatient part, where people are looking at the drug vs placebo and how fast it turns on. There was a robust and rapid onset to ON time, which seems to be similar to the ON time patients had with levodopa. There was a series of extensive open-label components where patients took it home. Officially, they could use it up to 5 times a day. I didn’t have anyone that used it over 3 times a day, or at OFF times.

In these open-label trials, they continue to show efficacy. There are 2 adverse-event profiles. The first is the known April morphine adverse event: nausea, hypotension being the most common 1, and sedation. These typically resolve in most patients with subsequent use.

There are some long-term issues, where you still can get irritation in the gums. They buffer the acidity, but with chronic use in some of our patients that were taking this for 4 or 5 years, they did have some irritation, sometimes even some teeth irritation, enamel breakdown because of the acidity.

It’s something that you have to keep in mind. Sometimes we did take some little breaks for this to improve, and then patients would start up again. The bottom line is that it’s meant for as-needed therapy and on-demand therapy with patients wearing off. It’s very consistent and robustly effective with a fairly established adverse-effect profile that most people tolerate reasonably well.

 Does anybody have any thoughts on how they might deal with the oral erythema issues that can that emerge?

One thing we often recommend doing with chronic therapy is to use an alkaline toothpaste. The toothpaste would have a baking soda in them. There’s never been a study to show whether that’s helpful, but it’s something that we often recommend to our patients.

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Key opinion leaders explain the use of sublingual apomorphine and trimethobenzamide for Parkinson’s disease.

Sublingual Apomorphine for Parkinson’s Disease

 Like any therapy, there are advantages and disadvantages. We know [the rate of] orthostatic hypotension is about 11%, and nausea and vomiting. Bill, you’ve looked specifically at the use of the apomorphine injection subcutaneously in terms of nausea and the use of Tigan that’s recommended on the label. What are your feelings on this because we’ve have some difficulty in the United States of having availability of Tigan now?

 Nausea is one of the main potential adverse effects of any apomorphine preparation. In the studies, Tigan has been used, which is kind of a dirty drug but largely an antihistamine-type medication. The first person who did one of the studies in the United States in the early ’90s used Tigan, and it became dogma that you use Tigan for this.

We looked at a real-world open-label series in patients who took Tigan versus patients who did not, and we really didn’t see any increase in nausea in patients who were not taking Tigan. In fact, there was a trend toward increased nausea in patients who took Tigan. That was not a controlled trial in any way, shape, or form. I can’t speak for other antinausea medications, most of which you can’t use in Parkinson disease because they block dopamine receptors, which makes them contraindicated. But there isn’t compelling information that these medicines reduce the rates of nausea with apomorphine.

 Khash, how about you? What’s your experience using the injection of apomorphine in terms of both nausea and is Tigan necessary in your experience, as well as other injection-site reactions?

 If the site reaction is basically more potent than some other on-demand therapies, then we can expect that you develop more adverse effects as well. One of them is sleepiness. This is the way that I measure if a medication kicks in because as soon as a patient’s medication kicks in they start to yawn. Sometimes they can handle it because they get this really good feeling of the medication kicking in so fast, and they [perceive it] as even stronger than levodopa. They perceive it that way because it kicks in so fast that they love it at the beginning.

However, because of that, we have to then deal with some adverse effects, like sleepiness and orthostasis. That’s why we keep them and check their blood pressure in the clinic.

With the Tigan, I used to use it when it was available. Now, since it’s not available, the way that I do it, I change my titration a little. I minimize the titration now to 0.1 mL instead of 0.2 mL, and ask the nurse specifically to not escalate it. Even if the patient tolerates it, let’s keep them at 0.1 mL for a while and then go back after a week or so to 0.2 mL.

I’m being more cautious because I’ve seen patients when they have nasty nausea and vomiting, they don’t want to touch it again, and I don’t blame them. Therefore, I try to avoid it as much as possible with these strategies. I use in some of my patients a very small dose of….. We have some data to support that with the apomorphine compounds, that when our patients are exposed to the…agonist oral before, they have less nausea.

I give them a very small dose without getting to the point that they have an adverse effect, for example, 0.25 mg, and then start apomorphine. These are the strategies that I use because it’s an excellent medication, and we have to be able to use it. It’s in the category of most potent medication. I advise my patients to inject and walk, this gives them the understanding of the potency of Apokyn that they can inject it and walk.

 We studied this in a placebo-controlled randomized large trial a few years back, and this was published. The primary end point was to see if, on the initiation day when patients came in and got 2 mg, and if they didn’t turn fully ON, 2 hours later they got 4 mg; almost no one went to 6 mg, but it was that one day. Some patients got Tigan, free treatment, beginning 3 days before, and some didn’t and just got placebo. There was no significant difference in nausea or vomiting or discontinuations in that initiation day. As a secondary end point, there was less nausea and vomiting over the next 8 weeks, but not at that initiation day. The evidence is lacking in that regard.

A panel of experts debate the disadvantages and side effects of apomorphine therapies for Parkinson’s disease.

Side Effects of Apomorphine Usage in Parkinson’s Disease

 Let’s turn now to another recently available on-demand therapy, the apomorphine subcutaneous injection. It’s been available for about 15 years in the country, but it’s not used as often perhaps, and there could be a lot of different reasons why, a number of different barriers. Laxman, what can you tell us about this injection of apomorphine subcutaneously; how is it used, what is its efficacy, safety, and tolerability?

You are absolutely right. As long as it’s been available, its uptake has been slower. The main reason is because it’s injectable, which is off-putting to a lot of folks up front. My patients are always looking for, “What’s the easiest thing I can administer?” But sometimes the most appropriate thing for you to administer isn’t always the easiest thing to administer. But from a dosing point of view when we look at apomorphine subcutaneous doses, you are looking at 0.2 to 0.6 mL dosing for the most part. The titration of dosing is incredibly important. We want you to titrate to a dose where you feel there’s a levodopa-like ON, you get a full ON. People must titrate to a point where they feel a full ON.

What’s interesting is the most commonly utilized dosing is 0.4 mL. That alone tells you that not everybody stays at 0.2 mL. If individuals stay at a lower dosage, they will discontinue therapy because A) they are injecting themselves, and B) they’re not achieving the desired results. That’s important from a dosing point of view.

From an efficacy point of view, optimally titrated patients will notice a full reduction of their OFF symptoms within about 10 minutes, maybe 12 minutes, and there are reports in the literature that it works as quickly as 7 minutes.

This can work as a bridge and a rescue. Bridge is taking you before you hit an OFF, from one ON to another ON, bridging over that valley of OFF. Rescue is when you’re already in the valley. You wake up in an OFF state, and we want to get you to a full ON, or close to a full ON as quickly as possible. From an efficacy point of view, it gives you the most robust efficacy with a reduction in the UPDRS [Unified Parkinson Disease Rating Scale] score that we see.

Safety-wise, we see typical dopaminergic adverse effects. We’re typically seeing issues with nausea, depending on the person. We might see orthostasis with this as it is a dopamine agonist, and it’s coming in more powerfully than other medications.

Some people may complain about skin reactions, though that didn’t show up in the study as much, but then there are other things that we don’t typically see as much, such as swelling of the legs. Orthostasis and nausea tend to be the bigger adverse effects that we want to caution our patients about. Just as we caution about a cough with the inhaled powder, we want to caution about nausea and orthostasis in this setting.

 This is a medication that has been studied for OFF episodes, and we also looked at it specifically for morning OFF. How do you use it, and what kind of an evidence base is there to use this specifically for morning OFF?

 This has been specifically looked at in the scenario of patients with OFF time. The study enrolled about 90 patients who tried the medication. These were patients who had some complaints that it took a little while to get going in the morning.

Otherwise, it was a standard group of patients with Parkinson disease. It didn’t have all of the inclusion/exclusion criteria that rarify a population when you’re looking to try to make a drug look good. They were given injections of apomorphine upon awakening. They could take the regular levodopa as well, and it was an open-label study. They were comparing diary data of how long it took to kick in with the regular levodopa, what they were doing, versus after they started and titrated subcutaneous apomorphine. The dose range was 2 to 6 mg.

The subcutaneous apomorphine was very effective at getting patients ON quicker. It went from about 61 minutes to about 24 minutes on average. And many of the patients who were enrolled in this study did have dose failures. Sometimes the levodopa just never kicks in, and it’s considered a dose failure. In the diary data, at least 46% of patients over a course of a week reported at least 1 dose failure on levodopa. When they started the subcutaneous apomorphine, it went down to 7%. That consistency of turning ON is arguably the most impressive finding in this study of subcutaneous apomorphine. It’s a very nice niche for apomorphine preparations as a first dose in the morning to get people up and ON faster.

 We were surprised by those dose failures, at least I would define it not turning ON within an hour. We didn’t expect that. These were patients who at a clinic visit said the first dose might not work quickly enough, and we sent them home to do 5-minute diaries till they turned ON, and we were surprised at how long some patients would wait. One of my patients I remember came in and said, “Geez doctor, I had no idea that I waited an hour for this medicine to work.”

It really speaks to this idea of reliability. In all the studies, the subcutaneous apomorphine injection has turned people from OFF to ON in 95% to 97% of uses of injections. That’s pretty reliable, and the speed of onset is certainly very quick.

A discussion on the use of apomorphine subcutaneous injections in managing Parkinson’s disease.

Apomorphine Subcutaneous Injections for Parkinson’s Disease

 We have a lot of these new on-demand therapies that are not absorbed through the GI [gastrointestinal] system that have become available. We have the levodopa inhalation powder. We have the sublingual apomorphine strip film. We also continue to have the injection subcutaneously of apomorphine that’s been available for 15 years. Let’s talk a little bit more about these therapies and see if we can understand maybe which ones we might choose here, or there, or what patient scenarios. Khash, do you want to tell us a little bit about your understanding and experiences with the levodopa inhalation powder, how it works, how it’s delivered, its mechanism of action and any advantages or disadvantages when you think about prescribing this drug?

 When I introduce my patients to this on-demand therapy, I go through the pros and cons of each one, such as inhaler levodopa. One big advantage is that it’s levodopa. We know that levodopa is one of the most potent medications and is the safest medication because of the adverse effect profile. That applies to when we use an inhaler as well.

One of the distinct adverse effects about inhaler levodopa comes from the mode of delivery of that. Coughing is one of its adverse effects. In comparison to other on-demand therapies, the rest of the adverse effects are definitely minimal, which is a big advantage.

There is some caution that you have to exercise when you use it with a patient with COPD [chronic obstructive pulmonary disease] or asthma. As we know, those type of patients were excluded from the clinical trial. There are some post hoc analyses that showed that even patients with asthma use that. But we know that it can cause bronchospasm. I try to avoid that if I have other options that I have that I can apply.

If the patient is suffering from even a tiny bit of cognitive impairment, for them it can be a little harder to open the device and put the capsule in. If you smash it a little bit, if you don’t puncture it properly, it’s not going to deliver the powder very well. Depending on the weight of the patient who has to use it, they cannot apply it very fast and use strong inhalation because it can cause severe cough. On the other hand, you don’t want to be too shallow that you do not even inhale it at all.

The advantage is it is one of the on-demand therapies that doesn’t need a titration, and this is the reason that several times I just hand it to a patient in the clinic and say, “Just go ahead and use it.” You don’t need to titrate it, you don’t need to prepare the patient, as we do for some others, to prepare the patients for an antiemetic, so we have an option to avoid that. These are pros and cons that I consider regarding levodopa inhalation.

 What have you found when prescribing the inhaled levodopa powder to your patients?

 The key to successful prescribing of inhaled levodopa is 2 things. The main thing first is that I have to warn them about the cough. It’s not a normal thing to inhale powder into your lungs, right? It takes a little practice. I tell the patients, “You don’t have to suck on it hard. You can just do a gentle deep breath in. You may feel a little tickle from the powder. If you cough a little bit, there’s still a little powder left typically in the capsule that you can take another bit of inhalation to make sure that you’re getting the dose.” I remind them that it’s 2 capsules per dose because some people feel that it may not be as robust and that’s because the dose is about 50 mg equivalent of oral levodopa.

The other key to using new medications successfully is to make sure you take it at the right time. This is not a medicine that I typically would recommend for somebody who’s experiencing a deep OFF. You want to take this at the first sign of the symptoms returning, so you can use it as a bridge. So rather than getting into that deep OFF, when you start to feel yourself turning OFF, you bridge yourself until your next dose of medicine. If you do those, many people are happy with the way the drug works. The other thing that is nice is that it’s pretty convenient. You can carry it with you, and it doesn’t need anything like refrigeration or any special preparations or anything like that. We know that 99% of the patients, 628 out of 629 in the study, were able to use the inhalation after they were instructed.

Neurologists debate the use of levodopa inhalation powder in managing Parkinson’s disease.

Levodopa Inhalation Powder for Parkinson’s Disease

 When we start thinking about OFF episodes and treating them with on-demand therapies, sometimes we think about the morning OFF as a place where we can begin these things. But how long do you wait? How many things do you try between long-acting 24-hour dopamine agonists and MAO [monoamine oxidase] inhibitors and increasing the doses of levodopa? When do you consider adding an on-demand therapy to manage a patient’s morning OFF episode?

 Our goal in Parkinson disease is achieving complete ON time, during the day and during sleep, therefore, my patient wakes up ON. And as soon as patients have motor fluctuation, I want to touch on overall OFF time even before we get to the morning OFF time. Every single patient with motor fluctuation deserves that on-demand therapy.

As soon as my patient is fluctuating, I oblige myself to explain what on-demand therapy is, and I tell them about the pros and cons of each one. I always use this analogy that they are exactly like a patient with migraine. Patients with migraine, regardless of whether the headaches are under control, they are carrying over the counter headache medication. On-demand medication has to be carried by our patients; when to use it, it’s up to them after they have a good understanding about how they respond to their medication. That’s a general statement about mortal fluctuation and OFF time.

When it gets to the morning OFF, there is no difference when it comes to the treatment. I do my best to keep my patients ON. If they get a good sleep, there’s a chance that they’ll basically wake up in ON condition. It doesn’t work all the time. I try to give them long-acting levodopa when they go to bed, so therefore maybe they can wake up ON. But several times we fail at that point. When they are OFF in the morning or any other time, that’s the time when I consider using one of the on-demand therapies.

 Dan, what’s your rationale for using an on-demand therapy, and when do you begin it for morning OFF?

 I tend to be a relatively early adapter. Once the patient is having these difficulties, I don’t think that taking another pill is going to solve it due to gut problems. And I think that they really need to start considering on-demand therapies, particularly in the morning because in the morning they’ve got an empty stomach, right? So presumably the dietary protein is not a big issue there, and it really is purely the gastroparesis and the slowing. I’m relatively aggressive about encouraging the patient to consider an on-demand therapy so they can get their day started and get on with things.

A lot of times patients with Parkinson disease sort of start to accept a quality of life that many of us wouldn’t feel is acceptable because it’s an insidious disease. It comes on slowly. Michael J. Fox described it as the gift that keeps on taking, and that’s a pretty accurate description of it. We need to be aggressive to help our patients maintain the best quality of life that they can have.

 When patients are taking carbidopa/levodopa, and they may be using this alone as monotherapy and then we may increase it or adjust the timing. Do you think about these on-demand therapies even before other adjunctive extender type of medications? Or do you think that you have to try other classes first before you go to an on-demand therapy?

No. I like to think of them earlier, especially if they’re having what I call unpredictable ones or these one-offs, like, “I start with OFF in the morning, and the rest of my day I’m pretty good unless I miss a dose, or I’ve taken it too close to food.” I say, “That can be fixed. You need to take doses on time, and take them apart from food.” If that’s not a problem, you still have this problem in the morning. If they’re having these one-off problems or there’s no pattern to them, I often will tell them, “It’s very easy for me to tell you, take more levodopa, or just take it more frequently. Or just add an adjunct. Understandably, if you’re having OFF at 8 o’clock in the morning, and then another day you’re having OFF at 12 o’clock, another day you’re having OFF at 8 and 5 or some other time, there’s no pattern to this. I can’t give you a pill that can kick in only at this time and not affect the rest of the day, and vice versa.”

We need to be able to solve these issues. The way I liken it to my patients in an analogy is, “Imagine you’re driving a car and you hit a pothole. You’ll hit potholes at different times and the key is to fix potholes, not to build you a whole other road. By adding adjuvants, we’re kind of widening the road, but the road still has potholes in it. Fix the potholes, and that’s how we fix the potholes, with on-demand therapy.”

 As soon as you start your add-on therapy, you offer them on-demand therapy at the same time, correct?

It depends. Let’s say I have somebody who is on levodopa only. In theory, most patients of mine may be on 1 add-on therapy because they may have started it first, or we may have added it when they would have experienced some end of dose wearing OFF. Let’s say they’re having mornings OFFs twice a week, and they’re having some other OFFs somewhere in the middle of the day. There are 2 different patterns to this, or maybe there’s no pattern to this. Rather than adding another adjunct of medication that they would have to take once a day every day that may or may not fix this, I would rather just add an on-demand medication here that they can take as needed. If they don’t need it, they don’t need it. They might only use it 3 times a week, or maybe 4 times a week.

 My philosophy is, as soon as you need to add another adjunct therapy, that’s the time when you have to introduce your patients to on-demand therapy. As soon as patients start to show motor fluctuation, they’re going to continue it because that motor fluctuation is unpredictable and each OFF time or ON time are not the same. A patient can say they are ON, but they are not fully ON, or they have delayed ON. Therefore, when a patient gets to the point that you’re thinking about an add-on, at the same time you have to introduce them to on-demand therapy as well.

 What do you think about this idea that when patients have OFF and we’re thinking about adjusting levodopa or adding an adjunctive medicine, that we should also offer an on-demand therapy to treat their OFF while we’re attempting to lessen their overall OFF time?

 It’s a case-by-case basis. I wouldn’t be quite so aggressive as Dash. I do think there are times with all of the options we have, including long-acting levodopa, that you can for at least a while get no OFF time. So that being said, there’s really not that much downside from a purely medical standpoint to using as-needed therapies like levodopa and apomorphine. These drugs have been around for a long time, so we’re fairly comfortable with using them.

If it is some modest predictable OFF time, I’m not sure if I would use them necessarily in the first line. If it’s unpredictable, then they certainly come up to first-line therapy for that. Otherwise, it’s kind of a case-by-case basis, depending on the needs of the patient.

Physicians discuss when to add on-demand therapies to Parkinson’s disease management.

When to Use On-Demand Therapies in Parkinson’s Disease

 What are some of the important attributes of on-demand therapy, thinking about this variability of gut absorption. What do you look for?

We want to have medications that bypass the gut so that we don’t run into those problems. We want something that works rapidly. You don’t want to remain in that OFF state for a long time because it’s incredibly uncomfortable for patients; they hate it. We want something reliable. We want to know that it’s going to break the OFF and do it reliably. We want something robust. Levodopa is thought to be the most robust medication for Parkinson disease, but apomorphine is quite robust in its ability to resemble levodopa in terms of response under the Unified Parkinson’s Disease Rating Scale.

Another thing that’s really important is that it’s convenient. It has to be a medication that the patient can use when they’re in an OFF-state and administered. Those are the things that are the main characteristics when we’re talking about on-demand therapies.

This oral medication route is a difficult problem. We’ve recently seen pharmacokinetic studies showing that whether you give oral carbidopa or levodopa in the fed state or the fasted state, the variability between doses, even in the same person, can be so diverse. What else do you look for in an nondemand therapy? You’ve had different routes of administration and different molecules. What’s important from a patient perspective, do you think?

I like to use the term non–GI [gastrointestinal] rather than oral because we have some on-demand therapies that are administered through the mouth but still avoid the gut.

 Patients are looking for the easiest way to deliver this medication. They are paramount in their mind. “Can I deliver it to myself easily? If I can’t, can my caregiver deliver it to me easily if I’m really in a bad OFF.” That’s the front-end consideration when we have multiple therapies in this situation, where they can use and bypass the GI tract and are able to reverse these episodes.

The way I look at it is, “Well, am I managing the therapy with the severity of OFF that you’re having? How severe is the OFF? I’m trying to get my hands around how bad of an OFF it is and maybe match the therapy with it. I’m trying to look for comorbidities, and some may prevent me from going in 1 direction or another. If somebody has pulmonary comorbidities, maybe I don’t want to go to a pulmonary therapy. Maybe somebody has orthostasis, and I don’t want to go toward apomorphine. Maybe I do want to go toward a levodopa-based therapy. I have different options there.

I want to understand the patients’ sense of urgency. How rapidly does it have to kick in? Must it go from a full off to a full on in 10 minutes or should you want to see some reduction of symptoms in about 10 minutes? How urgent is it and how severe is it are very important because it’s important for us to pick the right therapy for individuals based on what they’re looking for.

While patients are interested in the ease of dosing, we also want to talk about how the ease of dosing is as important from adherence, but if we give them a therapy that doesn’t match with their comorbidities or their severity or doesn’t kick in as quickly as expected, they’ll discontinue it. They’ll simply stop using it and say it doesn’t work.

Some patients resolve it in solution. Do you think you can achieve a quicker ON by giving higher or different doses of oral levodopa? Do you think you have to go to a non-GI formulation?

You can do some minimal improvement in the rapidity to ON. When you dissolve levodopa in a slightly acrylic solution, the most common 1 is a little water with vitamin C, or using an orange juice or a fruit juice and dissolving the levodopa in that. There have been other preparations of dissolvable levodopa, but it still dissolves and is absorbed in the gut. You can have some minimal improvement, but it’s not a dramatic improvement in duration to turning ON. As long it has to get absorbed all the way into the main intestine, that’s still a long way to travel.

Key opinion leaders explain the important attributes to consider when choosing an on-demand therapy.

Important Attributes of On-Demand Therapies for Parkinson’s Disease

 Initially, the carbidopa levodopa works so consistently, the so-called honeymoon period, and then we get these OFF episodes that disrupt, and the benefit of dose of medications are gone and the symptoms reemerge. What are some of the challenges with this oral carbidopa levodopa? Why does it not work so reliably every single dose? Is it the carbidopa levodopa itself? Is it the oral formulation? What’s the problem?

Bill focused primarily on the central mechanism of motor fluctuation, but he hinted that there’s this peripheral mechanism, and that was getting to the gut described as the second brain. In patients with Parkinson, the gut is loaded with Lewy body pathology, as we see in the brain. Some people have even suggested that Parkinson disease may begin in the gut and go up retrograde through the vagus nerve to cause Parkinson disease. There’s interesting but controversial data for that theory, but we know that the gut is highly involved in Parkinson disease.

The same way that we have the slowing of the body, we see the slowing of the gut, and patients may not even be aware. One study suggested that about over 80% of patients with Parkinson disease are experiencing gastroparesis, but only about 35% or so had symptoms and didn’t even know that they were having gastroparesis. The patient takes their medicine and it sits in the gut and doesn’t move into the small intestine, where it needs to get to to be absorbed. That’s how you get those delayed on, or those dose failures. Gastroparesis is very common.

Another issue is small intestine bacterial overgrowth, which may influence absorption of levodopa. A real problem for some patients, particularly as a disease progresses, is the relationship between dietary protein and Parkinson disease because levodopa is an amino acid. The dietary protein breaks down into amino acids, and these compete with the levodopa at the large neutral acid transporter that transports the levodopa from the gut into the blood stream. If you have a lot of protein in the diet, that’s going to compete with the levodopa to be transported into the bloodstream. That could be a real challenge for some people.

There are the obvious issues that some people have with things like swallowing. We have both mechanical issues, issues with gastroparesis, and issues with absorption at the large neutral amino acid transporter that are all impacting how the levodopa is getting from the mouth, down to the gut, into the bloodstream and, ultimately, up to the brain.

 Recently, there have been demonstrations of bacteria that can metabolize levodopa specifically.

Reports are relatively rare of levodopa eating bacteria in the gut of patients. For those patients who you are confident have Parkinson disease but don’t seem to be responding to levodopa, that’s something that we should now be routinely checking.

 It’s ironic, perhaps, that a miracle drug in Parkinson disease of giving this precursor to make an essential neurotransmitter dopamine is swallowed and heads to the place of the nervous system where Parkinson may begin in some patients. Certainly there’s autonomic degeneration and nervous system degeneration. This is an early problem with constipation, which an early risk factor for Parkinson disease and perhaps a prodromal. This is a relationship between the gut and the absorption of levodopa as a cornerstone therapy for our patients. You’ve done studies on this in the past, trying to better understand how to give formulations. What can you add to this idea? What’s this relationship between the slow gut in Parkinson and this oral levodopa in the absorption? How can that lead us to more rational therapies?

 There are a number of things inhibiting oral levodopa and, to some extent, other oral medications. It’s quite a journey from the mouth to the brain, down a slowed esophagus, a slowed stomach for levodopa’s sake, into the ileum where it has to be absorbed—a very small area, and it competes with other branch chain neutral amino acids. It is a problematic mechanism. Obviously, pills are the most common medicines given, but in something that has such minute-to-minute variability as Parkinson disease does, it can be particularly problematic.

It was a surprise that some people have tried to circumvent the problem with orally absorbed medications. There are a couple of medications that have been on the market for some time. Most notably the new rotigotine patch bypasses the gut and is used on a regular basis. When you want to circumvent this, it is when you want something to start to work faster. That’s the concept where this is most important. It’s nice for any drug to work fast, but where it’s important is for on-demand therapy.

There are several preparations of on-demand therapy to use when you think you’re wearing off that bypass’s oral absorption and is therefore much faster. We’ve had an injectable form of apomorphine for some time. More recently, there’s a sublingual preparation of apomorphine, which is absorbed in the mucosa of the mouth and bypasses the gut that way. There’s an inhaled form of levodopa, all which are used for as-needed therapy for fluctuating Parkinson disease. This is the scenario where it’s most important to have fast-acting medicines that bypass the gut in patients who do have fluctuations and do need to stay ON.

Experts debate the challenges of carbidopa/levodopa, and the relation between levodopa and the gut.

The Relationship Between the Gut and Parkinson’s Disease

 Dan, you mentioned this idea of motor and nonmotor symptoms. Do you try to link them when you educate your patients and their caregivers on what symptoms first occur? Tremor is often notoriously difficult to link to OFF, because sometimes it can occur just going ON. How do you educate patients who tell you in relation to motor and nonmotor symptoms?

 I definitely discuss that with patients because we find that many patients have concomitant nonmotor and motor symptoms. Oftentimes the nonmotor symptoms will precede the motor symptoms. It’s common for patients to describe a sense of dread, mental fogginess, and fatigue. Then they’ll note after that, “My tremor is reemerging; I’m having difficulty getting out of the chair; I’m freezing”—things like that. The key is to ask the questions, and they can be open-ended. “Tell me about what happens. Do you experience any strange feelings before you see your tremor?” A lot of times the patient will note the motor symptom because it’s obvious to them, but they may not link the fact that they have this anxiety or dread, or sweat before the motor symptoms emerge. I like to say, “Tell me about a typical episode,” and link it that way.

 Do you tend to rely on some symptoms or usually wearables? How do you educate patients of what they should report to you? Do they keep notes every single day of the month or only a day before they see you? Do you have observing in the clinics?

We have patients who bring in notes from every single day. I don’t necessarily encourage that, but we use written diaries in some cases, especially if there’s confusion and especially trying to sort out dyskinesia. Plenty of these patients have dyskinesia as well as the OFF-time, and the dyskinesia can interfere frequently with managing the OFF-time, especially with trying to make longer-acting medications.

We use written questionnaires sometimes, but it’s largely based on interview. I haven’t started to use wearables in clinical practice. We do that in research, but I’m not sure if people are doing that clinically yet.

 How is the diary used in research programs? Are there symptom diaries that patients can check off? What types of diaries do you use?

 Symptom diaries are probably the easiest ones where you can check off a symptom when you experienced it, and write down when you have symptoms and what it looks like. The simple diaries downloaded from the Internet have a 24-hour clock at the top, and you can edit it if you need to by checking off the medication and writing down the medication you took, for the most part some form of levodopa preparation. You can write down the other ones, but many of those are moved to once a day. You check off when you take that medication and eat—you can put M for meals, and O for OFFs. Extra medication is O for OFFs and M for meals.

They can take 3 or 4 days’ worth of that information and give it to me, preferably on 1 or 2 sheets that I can review quickly, so that I can see across multiple days. But there’s something between diaries and wearables that we haven’t discussed. Wearables are something kind of the promised land that’s coming up, and hopefully we’ll have the ability of it outside of research and diaries.

Videos are typically underutilized. Almost every 1 of our patients has a cell phone with a camera. If they’re not sure what OFFs look like, I want to see what OFFs look like. The same thing applies to tremor, though that’s beyond the scope of our conversation. When you say he or she has bad tremors, what does that mean? My definition of that is different from yours. I ask them to do a specific maneuver to find out when the individual is having an OFF. I have the house or caretaker do a get-up-and-go test.

I want them to sit in a chair and get up from that chair, go across the room and come on back. I want to see what that looks like during an OFF so that I can say that it’s an OFF, unless it might be obvious that it’s an OFF. Then video when you feel the medication is working well, and we can compare side-by-side, and I get to see exactly how difficult it is.

The main limitation is that you may have videos that show only part of the view. They may not be good-quality videos. A little education can help with that. The videos may just be motor based. Nonmotor components don’t get captured as much on videos.

The other thing I encourage is getting one or two 30-second, 1-minute videos to help illustrate how bad your OFFs are, because when we see patients in our office, the majority of the time they’re ON. The only times they’re OFF is when somebody else is taking care of their medications and responsible for their transportation. Virtual visits have given us a little more of a window, but 80 percent of my patients who complain about OFFs show up in the office ON.

Panelists describe the motor and non-motor symptoms of Parkinson’s disease, linking symptoms to OFF episodes, and how to educate patients.

Motor and Non-Motor Symptoms in Parkinson’s Disease

 How do you evaluate your patients for OFF, and how do you evaluate patients from morning OFF? Patients don’t always come in and say that they have a morning OFF. How do you look for it, and what questions do you ask? Which patients do you ask?

 After asking about how they’re doing, typically my next question is, “Tell me the exact times you’re taking your levodopa”—7:11, 3:08, whatever. “At any point in between these doses, are your symptoms changing? Is anything worse?” I often say, “Around the time you’re taking a pill,” because some patients think that when they take the pill, in 2 seconds the pill is going to have its effect, but it’s typically at least 30 minutes.

“Is anything worse? Are there any changes through the day?” We try to ask, “Is there any pattern that you can come up with this?”

Sometimes you get these nice stories with a straightforward pattern. Other times it’s much more inconsistent. It’s like, “Usually I’m doing well, but every now and then, at 11 PM, I’m freezing up.” I keep it open-ended because OFFs can be quite a few types of symptoms. There are the obvious OFFs, where the tremor comes back or they can’t walk, but there’s this whole spectrum of nonmotor OFF symptoms. They break down into 2 groups, which are opposite in some way.

The first group of nonmotor OFF is this anxiety, sometimes palpitations, or even breaking out into a drenching sweat, called “the drenching paroxysmal sweat,” or Parkinson disease. These patients can look like they’re having an MI [myocardial infarction], and I’ve had plenty of patients with this sort of wearing OFF that have been evaluated with ECGs [electrocardiograms] and gone to the emergency department.

The other general nonmotor wearing OFF is the opposite, where people get fatigue or anhedonia. They don’t want to do anything, but they may be physically able to do that. I keep it very open-ended when I’m looking for anything that’s changing through their day, then looking for a pattern or not a pattern with these changes.

In the morning, some patients expect to take a little while for that first dose to kick in. We try to quantify that, and it largely comes down to how it impacts their life. This often comes down to whether they’re working or retired, and those sorts of things.

There is a small subgroup of people who do very well in the morning. Historically, in the literature this was called the sleep-sparing effect. I don’t think it has anything to do with sleep-sparing effect, but it’s more just natural circadian patterns. Our own natural dopamine levels peak, maybe 4:30 to 5 AM, or maybe 6:37 AM, and then they start to come down. This occurs in 5% of patients who have this nice time when they first wake up. Those are the ones telling you, “I’m doing fine until I take my levodopa, and then I’m doing worse.” You especially see this if they wake up very early, but that’s a minority. In most patients, the problem is the other way around: they’re taking a little while to get going in the morning. How aggressive you are with this depends on how aggressive the patient needs to be in addressing that.

 One thing that happens is that the patients accommodate it, and that’s not necessarily a good thing. They take their medicine and lie around in bed for a long time waiting for it to kick in. They delay activities in the morning or they change their social situation because they’re not going to turn ON.

They accept it. I tend to be a little more aggressive with questioning about that, like how much is it really impacting their day? If they say it’s not, I push them a little and ask, “Tell me about your morning.” When they tell me, “Well, I’m lying around in bed until 10 o’clock because my levodopa takes an hour or more to kick in, so I’m not going out to walk with my friends who take their 9 o’clock walk,” or things like that. They’ve gotten used to it, and the patients don’t appreciate necessarily the impact it may be having on their lives if we don’t explore it.

What does the conversation sound like in California? How do your patients feel in the morning? Is that a problem on the West Coast?

 I start with education because I can get important information from my patient if I educate them about why I’m asking the question. It usually starts with when I look at the status of my patient, if my patient is ON or if my patient is OFF. When the patient is OFF, I tell them that I’m asking because I don’t want you to feel like this the rest of the day, and I ask them, “Are you having this condition the rest of the day?”

Also, a patient can come to the clinic ON condition, and I ask them, “Is this the way you are 24-7?” All of us get this response: “Doctor, you’re so lucky. This is the only time he’s doing that well. The majority of the time, he is not like this.” Correct? Therefore, I always bring this to the front of their face. But I say, “If you can be this good, like speaking nicely, having the body language, and you can walk well, there’s no reason I cannot extend this and you’d be continuously ON.”

When they understand the importance of what I’m asking them, then I start to ask them about how they are doing from 1 dose to the other. The conversation doesn’t go the way we want, or they’re not the best historian to tell you exactly what happened during the day. I ask them chronologically, “Can you tell me how do you in the morning when you wake up? Based on what I told you what is OFF and ON, do you wake up OFF or not?” Then they tell me, step by step. I say, “If you take your first dose in 7 AM, how do you do after you take your 7 AM until your next dose?”

They walk me through that. How many times we heard from our own colleagues, “I don’t see that much unpredictable OFF time.” Patients teach us that it’s more than we expected. The first thing the patient says is, “Doctor, that’s not the way you’re asking me. It’s not the regular matter. One day my dad is doing good, the other time he’s not.” They’re telling us that these OFF times are unpredictable and not always in a regular fashion.

That’s the best way that I found to educate them about ON and OFF. Second, I emphasize that it’s important for me to know that because that’s the goal that they’re going to achieve. You’re going to achieve that if a patient is ON continuously during the day.

A discussion on how patients are evaluated for OFF episodes, by expert neurologists.