Current Treatment Paradigm for Management of OFF Episodes


Stuart Isaacson, MD, FAAN, evaluates the current treatment paradigm and highlights new, ‘on-demand’ medication for management of OFF episodes in Parkinson’s disease.

Stuart Isaacson, MD, FAAN: When we evaluate patients and try to understand when they don’t have the full benefit of a dose of oral levodopa throughout the day or night and have these OFF episodes, we think about how we approach treating them. We have to treat them now but also have a strategy for treating them between visits, for 3 or 4 or 5 or 6 months. Over the years, as patients experience increased symptoms of motor and nonmotor symptoms, in 5, 10, 15, 20 years and beyond, how are we going to manage this disease? We have lots of ways. Taking levodopa at higher doses might improve OFF episodes, but it may come with peak adverse effects like dyskinesia, orthostatic hypotension, or psychosis. It’s a difficult trade-off trying to balance this.

Sometimes we fractionate levodopa and take the doses closer together at lower doses. This can be helpful, but patients have to remember to take their pills or set alarms. You may be able to do that at a 5-hour interval, sometimes 4. If you get less than 4 hours, it can get exceedingly difficult to remember to take the pills on such a tight schedule. With the variability of absorption through the gut, even taking them regularly can lead to variable responses. We can add on adjunctive medications and enzymatic inhibitors that prolong dopamine in the brain and prevent its metabolism, thereby blocking the MAO enzyme or peripherally blocking the COMT enzyme and enhancing its presence in the plasma. We can combine it with longer-acting dopamine agonists that mimic the effect of dopamine. We can use nondopamine medications to reduce the hyperactive glutamatergic and adenosine receptors that are present in Parkinson disease and impact OFF episodes.

We’re trying to reevaluate our paradigm—adjusting levodopa and using adjunctive medicines to enhance levodopa—by thinking about our patients and their plight: how they feel when they’re not getting benefit from a dose of levodopa and they’re having motor and nonmotor symptoms. What can they do about that? It’s led to a shift in our understanding of the paradigm of treating OFF episodes by understanding the value of newer medications and newer approaches using on-demand medications, sometimes called rescue medications or medications for acute OFF episodes. These medications can be used as needed by patients experiencing symptoms because they no longer have benefit from the last oral dose of levodopa and the symptoms are there. What can they do? These treatments should rise in our clinical treatment paradigm so patients have something that gives them a way out when they’re no longer having benefit from their last oral dose.

All of our treatment options aim to improve the striatal outflow pathways and the balance between direct and indirect pathways. We aim to give a more physiological replacement of dopamine by giving levodopa at different intervals and doses. We try different formulations—immediate-release and extended-release formulations—that can keep a presence in the plasma for a longer period of time and try to achieve a more continuous dopamine stimulation. We try to give medicines that mimic dopamine and that affect the metabolism of dopamine by inhibiting the enzymatic breakdown of levodopa and dopamine peripherally and centrally with MAO and COMT inhibitors. We have nondopamine treatments that try to help some of the overactivity that deranges some of the outflow pathways, the direct and indirect pathways.

But we also have to think about the route of administration and the bioavailability of medications. We have to think about the rapidity of the onset of action, the duration of benefit, and what you can do during certain times to take something as needed, not just as scheduled. It’s led to a new way of trying to fashion treatments that aren’t oral. The oral route is very compromised in general. Specifically in Parkinson disease, we know about the synuclein degeneration that begins very early, perhaps prodromally, causing degeneration in the enteric and autonomic nervous systems, resulting in derangements in GI [gastrointestinal] dysmotility. Trying to take an oral medicine through the part of the nervous system that’s already deranged leads to lots of variability in its delivery to where it needs to go and its absorption coupled with protein effect and short half-lives. We want to find a nonoral, non-GI absorption route.

That’s led to a number of therapies that use the pulmonary route, the subcutaneous route, the sublingual mucosal route. The newer ones being developed are trying to find different ways to give a medication that can work quickly and not be delayed by gastric and esophageal dysmotility, and not be affected by protein or by having to take it on a certain schedule but can be used as needed. We want a therapy that can not only work quickly but also be reliable, 1 that works not half the time you take it but almost every time. We want a therapy that works as well as levodopa, which is our cornerstone and gold standard. If we’re designing the best possible medication, we want 1 that can be taken when needed and delivered where it needs to go, that’s reliable and works almost every time. It needs to work as well or better than levodopa and therapies. It needs to work quickly, so you can benefit from it when you need to. There are a lot of ways of thinking about this emerging class of on-demand, rescue, or acute treatments for patients with Parkinson disease who experience times when they’re not benefiting from their oral levodopa doses and during OFF episodes.

As we begin to explain to our patients the utility of using medicine as needed on demand for OFF episodes, whether they happen expectedly or unexpectedly, unpredictably, acutely, whether they know what’s going to happen or don’t know when the next dose will work, we need to explain to them what it means to carry around a Parkinson pen, a Parkinson film, or a Parkinson inhaler. What does it mean to have these things? When would you use it? They’re really turning ON medicines. We can think about them as on-demand, as-needed, or acute OFF-episode medicines, but they’re turning ON medicines. They help a patient who has times when they don’t benefit from a dose of levodopa, has symptom benefit quickly and reliably when needed—to turn back ON, to get benefit. They’re turning ON medications, and we have to explain this to patients.

Individuals who have allergies, like peanut allergies, always carry 2 EpiPens in case they’re exposed. It’s life-threatening. They want to have something that can save their lives. It’s the same thing with Parkinson disease. Our patients are invariably going to have OFF episodes, no matter what we do with the medications. No matter how much we raise the dose or use different medications adjunctively together, they’re still going to experience time—1, 2, 3, or 4 times a day—when they’re not benefiting from their doses of oral levodopa. They have to stop what they’re doing and wait for that next dose. Well, they don’t need to do that if they carry around 1 of these turningON medicines, an on-demand medicine that can be used as needed. If they have 1 in their pocket, on their counter, or in their drawer, then they can pull out a Parkinson pen and take a quick injection and turn ONin a few minutes 95% of the time. They can take a film, open the packet, put it under their tongue, and 15 minutes later have benefit. They can breathe in orally inhaled levodopa and, in 10 minutes, notice onset of improvement. All these therapies that we have available, our patients should have.

Many of my patients have all of them or tried all of them, and they have them in case they need them. Some use them once a week, once a day, or several times a day. Every day might be different. Every week is different. They may use them more when they travel to Disney World with their grandchildren, when they’re playing golf, or when they’re going to their job. Everyone is different. We have to personalize treatment for our patients. We have to use shared clinical decision-making, informing our patients of all the options, the benefits of the options, and when they would use these options. Then we can get feedback of benefits, risks, and access to therapy, so we can choose the best therapy for each patient at each visit. Patients hopefully will be empowered to ask the right questions, to find out about the medications that are available. If they have them available, they can use them to get benefit when they’re sitting there and had to stop what they’re doing because they’re no longer having benefit, whether it’s first thing in the morning, between doses, around mealtime, overnight, or some other time.

Transcript edited for clarity

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