On-Demand/Rescue Therapies for the Management of Off Episodes


Daniel E. Kremens, MD, JD, discusses the current strategies for managing off episodes in Parkinson disease and reviews patient criteria that physicians should consider when choosing on-demand therapy.

Daniel E. Kremens, MD, JD: How do we currently treat off time and off episodes? We must distinguish between off time and off episodes. Off episodes are those discrete periods when a patient is off, and off time is the sum of those off episodes. Currently, most neurologists try to focus on off time, right? They don’t look at the individual off episode. The way we do this is by using additional doses of levodopa, switching to a longer-acting levodopa preparation, or using adjunctive therapies. There are over 15 adjunctive therapies and levodopa preparations available in the United States, and these are fine. The challenge is, though, when you look at all the studies, is that they reduce off time on average from about 7 hours to 5-4 hours. That’s still leaving the patient with about 5 hours of off time a day, and it’s not doing anything to address the fact that when a patient experiences an off episode, the off time medicines won’t do anything to help that discrete off episode. We have to treat both off time and off episodes because we know treating off time alone does not prevent off episodes.

Even with advanced therapies such as infusional therapies, carbidopa, levodopa, and intestinal gel, patients still have off episodes. Even after deep brain stimulation, patients still have off episodes, so we need to treat both the off time and the off episode. The way a lot of physicians are treating off episodes is they tell the patient just to take another levodopa, and sometimes they say, chew it and that will get absorbed faster and things like that. First, that hasn’t been studied very well, and secondly, it doesn’t solve the problem of the dysfunctional gut. Taking another dose of levodopa when one has failed is not going to solve that problem by putting another dose of levodopa into the dysfunctional gut. Even if it did, it will take an hour for it to kick in, so that’s not helping the patient; we must look to using an on-demand therapy, or sometimes people refer to it as a rescue therapy. I like on-demand therapy because I think that’s more empowering for the patient to give them a sense of control over their illness.

There are 3 on-demand therapies currently approved in the United States. One is inhaled levodopa, and the other 2 are forms of apomorphine: subcutaneous injection and a sublingual strip. Unfortunately, the sublingual strip is going to be removed from the US market as of June 30, 2023, and this has nothing to do with the safety or efficacy of the medication. It was a business decision, unfortunately, so patients are going to have a limit in what they can use. That leaves us with the inhaled levodopa and the subcutaneous apomorphine injection. Let’s talk a little bit about these. So, the subcutaneous apomorphine injection has probably the best data for reversing off episodes. Studies have demonstrated that it reliably and rapidly reduces off episodes in patients, in about 98% of patients, and it can work in as quickly as 4-8 minutes in patients; it’s generally well tolerated. The patient gives themselves a subcutaneous injection with an injection pen.

The main side effects are that they can have some injection site reaction and nausea, although this is in a very small percentage of patients and generally well controlled. Some patients can potentially have some orthostatic hypotension, but again, this is generally well controlled. The patient must start this therapy under medical observation, but in the United States, this can be done both in the doctor’s office or at home, so it’s generally relatively easily started. Another therapy that we have is inhaled levodopa, this is a product that the patient uses a breath-actuated inhaler, and they inhale the equivalent of about 50 mg of levodopa. It’s 2 42-mg capsules of powdered levodopa, which is the equivalent of about 50 mg of oral levodopa.

Now, the advantage of this therapy is that there’s no injection, it’s inhaled. It works best if patients use it when they first begin to feel off because it’s a relatively small dose of levodopa, so it’s not as effective at reversing a deep off the way that the subcutaneous apomorphine is. The main side effect that people have from using inhaled levodopa is cough; it’s a powder, and it takes getting used to when you inhale it, but with some practice, most people can learn to inhale it. The nice thing about these therapies is they’re not exclusive, you can use them in a complementary fashion. I have some patients who use subcutaneous apomorphine for their morning akinesia or their morning off because they’re deeply off then, and they find that the apomorphine works well for that. Over the course of the day, they may use an inhalation because they’re not getting into quite such a deep off and they don’t feel they need the injection. I think patients can use 1 therapy, the other therapy, or both therapies. The key is to empower the patient to treat their off episodes because we do have these 2 therapies, and there’s no reason that patients should be left stuck in an off episode.

We can adjust their off time medications and their adjunctive therapies, but they’re still going to have off episodes. Using another dose of levodopa doesn’t solve the gut problem. The on-demand therapies that we have, subcutaneous apomorphine and inhaled levodopa, both bypass that dysfunctional gut and avoid that problem, that’s why they’re able to address the off episode. I like to do a situation where we treat both the off time and the off episodes, so I may adjust the patient’s levodopa and may give them an adjunctive therapy, but I will also give them an on-demand therapy so that while they’re waiting or seeing how they do with that adjunctive therapy, they have the benefit of being able to treat the off episodes that they’re experiencing then. As I pointed out earlier, even with the best adjunctive therapy or adjustment of levodopa, many patients continue to experience off episodes, and we can’t ignore them, we must give the patients a way to treat them. As neurologists, if we think about the analogy with migraine, we don’t just give the patient a prophylactic medicine, we give them abortive therapies because we know even with the prophylactic therapies, some patients are still going to have some breakthrough migraine and they’re going to need treatment. It’s the same thing in Parkinson disease, we can use adjunctive therapies as sort of the analog to prophylactic medicines, but we still need to give them a rescue therapy. It’s the same way we would give a migraine patient an abortive therapy. There’s no reason that patients should suffer with off episodes.

When thinking about your choice of on-demand therapy, there are some considerations that I think people should have. First, with inhalation, because it involves inhaling a powder, it’s not appropriate for people with a history of COPD, asthma, or lung diseases, so we should avoid it in them. For patients who are experiencing deep offs or those hard, unpredictable offs, the data for apomorphine is a little more robust in that it’s going to reliably and rapidly reverse that off. However, some people have concerns about doing an injection, and some people have needle phobia. In those patients, inhaled levodopa may be a more appropriate choice. I think the key, though, is giving the patient some choice. These medicines can be used up to 5 times a day, both inhaled levodopa and subcutaneous apomorphine in clinical studies. I find as a practical matter, and what we also found in the studies, was that most patients tended to use on-demand therapies about twice a day. The key is to let the patient know that there are ways to treat these episodes, and we don’t have to simply keep manipulating their oral medicines because, again, even with the best management of the oral medicines, patients are still going to experience off episodes, and these off episodes are impactful and need to be addressed.

Transcript edited for clarity.

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