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Treating Parkinson’s Off Episodes

The Latest Treatment For Parkinsons Disease

Stuart Isaacson, MD: The Challenge of OFF Episodes in Parkinson Disease

Inbrija is the latest treatment for Parkinson’s disease. It was approved by the Food and Drug Administration in late 2018 after two decades of research and development. Inbrija is a new form of levodopa that allows systemic delivery of the medication through inhalation, allowing higher doses of medication to enter the bloodstream.

This new drug from Acorda Therapeutics will treat the intermittent symptoms of OFF episodes on demand and comes in the form of a powder capsule and inhaler. Inbrija is the first and only inhaled levodopa medication to be approved for Parkinsons disease by the FDA. It is available by prescription through your doctor.

The Michael J. Fox Foundation helped to fund the early development of this new treatment for Parkinson’s disease due to the impact OFF periods have on patients’ lives.

Many Dont Manage Off Time Well

In the Parkinsons Disease in America 2017 survey, 80% of people with PD reported they currently use a carbidopa/levodopa therapy to treat their symptoms. Carbidopa/levodopa treatment is the most effective treatment available for the management of motor symptoms of PD.

However, half of the survey respondents who use carbidopa/levodopa therapy are experiencing off times. Twenty-five percent of those experiencing off times notice their symptoms for 3 to 6 hours a day.

Another 52% report 1 to 3 hours a day when their symptoms are noticeable and affecting their daily activities. Yet 43% of those experiencing an off time report that they dont take any action to manage these episodes.

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Key Takeaways For Treating Off Episodes In Pd

Stuart Isaacson, MD: That was a fascinating discussion with everyone. Take home messages perhaps. Laxman, do you have a take home message for a neurologist treating OFF episodes?

Robert A. Hauser, MD, MBA: Probably 2. One, query your patients about OFFs. If they don’t know what you mean, educate your patients and their caregivers about what OFFs occurs. Because when they emerge, you want to have some vocabulary that’s in common. Probably the second is we have numerous therapies coming out, we have numerous therapies that have come out. And if your patients are experiencing OFFs, it’s worth trying these on-demand class of therapies, future class when they come out with the long acting levodopas or the subcutaneous infusions. Parkinson’s has changed so much even in the last 5, 6 years. I suspect in the next 5, 7 years it will be even differently treated than how we treat it now.

Stuart Isaacson, MD: Raj, last take home message.

Stuart Isaacson, MD: Bob?

Robert A. Hauser, MD, MBA: Yes as a field, we continue to make good progress in longer duration therapies and continuous delivery of efficacious medications, so that continues onward. And I’m also struck by the fact that the answers to a lot of your questions were talk to the patients and understand how they’re doing through the day so you can make appropriate adjustments.

Transcript Edited for Clarity

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What Is The On/off Phenomenon In Parkinsons

The ON/OFF phenomenon in PD happens when someone experiences flares of symptoms between regularly scheduled doses of levodopa.

During an ON episode, the levodopa is working well and symptoms improve. During an OFF episode, the levodopa isnt working and symptoms return or get worse.

A 2018 review found that 25 to 50 percent of people with PD developed OFF episodes within 2 years of beginning treatment with levodopa. Within 10 years of starting treatment, most people with PD had OFF episodes.

OFF episodes can affect different people in different ways. They may follow a predictable pattern or occur unpredictably. They may set in suddenly or gradually.

The researchers behind a

Treatment Options For Off Episodes

Medication resembling a breath strip could treat Parkinson

If you show signs of the Parkinsons disease ON-OFF phenomenon, your doctor may wish to adjust or change your medication. You might be advised to shorten intervals between doses or take your medication on a different schedule. Your doctor may also suggest taking a dopaminergic agent to keep you ON for longer periods.

Scientists are also working on new treatments to reduce OFF episodes in PD patients. Inbrija a new levodopa drug in the form of an inhalation powder will launch in the first quarter of 2019. This new treatment has been approved by the FDA to treat OFF periods by administering levodopa directly to the bloodstream. It will become available on prescription through a network of specialty pharmacies in the U.S.

APA ReferenceSmith, E. . Parkinsons Disease OFF Episodes: Physical & Emotional Effects, HealthyPlace. Retrieved on 2021, December 23 from

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New Formulation Of Old Drug Shows Promise For Off Episodes

Administering an approved drug, apomorphine, by a new method dissolving it under the tongue can relieve wearing off episodes for people with Parkinsons disease , according to the results of a small, phase II clinical trial. The study appears in the July 19 online edition of Movement Disorders.

Levodopa, usually given as Sinemet®, is the gold-standard therapy for PD movement symptoms. But most people who take the drug for several years eventually experience fluctuations in its effectiveness, known as off periods, when movement symptoms return. While medication adjustments can help in the long term, the only approved therapy to rapidly address or rescue someone from such off periods is apomorphine, a drug that is injected under the skin. Although it is effective, injectable apomorphine is not widely used.

Seeking a more convenient way of giving the drug, Cynapsus Therapeutics, Inc., a company based in Toronto, Canada, developed APL-130277. It is a thin strip, about the width of a penny and very similar in appearance to a Listerine® breath strip, and is infused with apomorphine and a substance to prevent skin irritation. Holding the strip under the tongue quickly releases the drug.


What Does It Mean?


Hauser RA, Olanow CW, Dzyngel B, et al. . Sublingual Apomorphine for the Acute Conversion of OFF to ON in Parkinsons Disease. Movement Disorders DOI: 10.1002/mds.26697

Initiating Treatment For Off Episodes In Parkinson Disease

Stuart Isaacson, MD: Raj, how soon after you recognize OFFs do you think treatment to reduce OFFs should be begun? And of all the different classes of treatments that we now have available, can you talk to us a little about how you view those classes individually or grouped between pre- and postsynaptic, or dopaminergic or non-dopaminergic, or GI absorbed and non-GI absorbed? How do you wrap your head around all the different options we have? And tell us about the mechanisms and how you think about getting some.

Transcript Edited for Clarity

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What Causes On/off Episodes In Parkinson’s Disease

On/off episodes, also known as off time, typically happen more often as Parkinson’s disease progresses, and levodopa becomes less effective.

Carbidopa/levodopa is considered the gold standard in Parkinson’s disease treatment, meaning it’s the most effective for treating motor symptoms, such as tremor, rigidity, and bradykinesia . Levodopa works by crossing the blood-brain barrier and converting into dopamine, low levels of which are believed to be the cause of Parkinson’s symptoms. Adding carbidopa to levodopa helps prevent levodopa from breaking down before it crosses into the brain, which helps reduce side effects like nausea and vomiting.

Some people who have Parkinsons start taking levodopa at around three doses per day. If you start experiencing off episodes, your doctor may increase your dose to four or more times per day.

Off time is common: According to patient surveys, around half of patients who take levodopa report experiencing wearing off periods. Of those patients, 25% experience it 3 to 6 hours per day, and 52% have symptoms for 1 to 3 hours a day.

The Importance Of Treatment Nuance And Novel Options In Treating Parkinson Disease

Differentiating Off Episodes in Parkinsons Disease

In a presentation at the 2022 ATMRD Congress, Jill Farmer, DO, MPH, outlined several novel options for the treatment of OFF episodes in Parkinson disease, and stressed the need for individualized approaches to maximize patient quality of life.

It is commonly known among movement disorder specialists and neurologists that patients with Parkinson disease experience OFF episodes, when there is a so-called wearing-off effect of their therapy. This occurs in patients who are treated with the gold standard treatment, levodopa, and in recent years has begun to be addressed with adjunctive therapy, dosing regimen adjustments, and on-demand therapies.

Some of these classes of medications include ON time extenders, such as monoamine oxidase type B inhibitors or catechol-o-methyl transferase inhibitors, as well as dopamine agonists. Although clinical trials have suggested these medicines can reduce patient OFF time, they are not one-size-fits-all, and much of their benefit results in reductions of fewer than a few hours, and their administration can carry burdens for patients. Ultimately, in common practice, it seems there has been a reliance on levodopa without consideration for newer options.

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What Are The Latest Approved Treatments For Parkinsons Disease

Several medicines have been approved for the treatment of Parkinsons disease. Here are some of the available medicines for Parkinsons disease:

Nuplazid 3,4

Nuplazid was approved for the treatment of patients with hallucinations and delusions associated with Parkinsons disease psychosis by the Food and Drugs Administration on April 29, 2016. On December 3, 2020 The approved an update to the prescribing information for Nuplazid that will allow the medication to be taken more easily by Parkinsons patients who have difficulty swallowing.

Ongentys 5,6

Ongentys is a medication used for the treatment of Parkinson disease. It is indicated for the treatment of adult patients with Parkinson disease. It is used as an add-on to levodopa/DOPA decarboxylase inhibitors in patients who are having fluctuations in the control of their condition.

Opicapone was approved for treating patients with Parkinsons Disease as an add-on to levodopa/DOPA decarboxylase inhibitors in patients who are having fluctuations in the control of their condition by the European Medicines Agency on June 24, 2016 and by the Food and Drug Administration on April 24, 2020.

Nourianz/Nouriast 7,8,9

Nourianz/Nouriast was approved by the Food and Drug Administration , USA, on August 27, 2019 and by the Pharmaceuticals and Medical Devices Agency , Japan, in June 2013.

Inbrija 10,11,12

What Does The On/off Phenomenon Feel Like

Off time is different for everyone, and depends on how your Parkinson’s symptoms normally present themselves. Also referred to as motor fluctuations, you can tell your medication is wearing off early if some of your symptoms return. For some, tremor may be the first symptom to re-appear, while for others, it could be muscle stiffness, or non-motor symptoms such as a change in mood or thinking, or fatigue.

If you notice a change in your symptoms, especially if they interfere with your daily activities, its important to talk to your doctor. Before your appointment, try tracking when your off time starts and stops. Take note of how you feel when your medication is working optimally, compared with the changes you’re experiencing.

On/off time is different from dyskinesia, which is uncontrolled movements that can look like smooth tics. Levodopa use can lead to dyskinesia, typically after a few years or more.

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Off Periods For Me Are Best Defined As Not Knowingwhat Is Going To Happen

Israel R., Living with Parkinsons Since 2007

Lynn H., Living with Parkinsons Since 2010

Michael B., Living with Parkinsons Since 2011

Brenda V., Living with Parkinsons Since 2012

Steven D., Living with Parkinsons Since 2005

Gary R., Living with Parkinsons Since 2008

Steven D., Living with Parkinsons Since 2005

Israel R., Living with Parkinsons Since 2007

Will New Treatments Really Help

Episode 10

According to multiple clinical studies, treatment with Inbrija led to significant improvement in motor function, with an onset of 10 minutes. A review of 900 patients showed a reduction in the Unified Parkinson’s Disease Rating Scale, 30 minutes post-dose, after 12 weeks of treatment. Overall, 75% of patients who took Inbrija experienced a decline of daily OFF times.

According to Robert A. Hauser, MD, professor of neurology and director of the Parkinsons Disease and Movement Disorders Center at the University of South Florida:

Inbrija helps address a significant unmet need for people with Parkinsons, and we look forward to adding this new treatment option to our armamentarium.

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Many Don’t Manage Off Time Well

In the Parkinsons Disease in America 2017 survey, 80% of people with PD reported they currently use a carbidopa/levodopa therapy to treat their symptoms. Carbidopa/levodopa treatment is the most effective treatment available for the management of motor symptoms of PD.

However, half of the survey respondents who use carbidopa/levodopa therapy are experiencing off times. Twenty-five percent of those experiencing off times notice their symptoms for 3 to 6 hours a day.

Another 52% report 1 to 3 hours a day when their symptoms are noticeable and affecting their daily activities. Yet 43% of those experiencing an off time report that they dont take any action to manage these episodes.

New Therapies For The Acute Treatment Of Off Episodes In Parkinsons Disease

Fabrizio StocchiDepartment of Neurology, IRCCS San Raffaele Pisana, Rome, Italy

The symptoms of OFF episodes can be caused by various factors including abnormal lingual control of swallowing and lingual festination. Patients with PD can also have a delayed swallowing reflex, which increases the risk of swallowing during inspiration, causing aspiration. Patients can also have a repetitive and involuntary reflux from the vallecula and piriform sinuses into the oral cavity.51 More importantly, many patients with PD have gastroparesis, which appears as postprandial bloating, early satiety, nausea, and vomiting.52,53 Delays in gastric emptying can cause slow delivery of levodopa to intestinal absorption sites, which, in turn, delays peaks in plasma levels leading to erratic drug responses, slow onset of action or dose failure.53â55 These issues were emphasized by gastroscopic examination of a patient, which found an intact levodopa/carbidopa tablet in the stomach 1.5 hours after it was swallowed.56 Furthermore, daytime gastroscopy has found food from the previous evening remaining in the stomachs of many patients with PD.

These developments in rescue therapies have the potential to substantially improve quality of life and help patients deal with the otherwise untreatable symptoms of OFF episodes, which are a serious burden and involve both motor and non-motor symptoms.

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How The Parkinson’s On

Ideally, when you take doses of a medication like levodopa on a regular schedule, you shouldn’t notice much of a difference in your symptoms between doses. In other words, your symptoms should remain relatively constant over time, regardless of when you last took your medication.

However, when the on-off phenomenon starts in Parkinson’s disease, you’ll feel better as a new dose of your medication starts to take effect, and worse before you’re due for another dose. Eventually, the duration of on states becomes shorter and the wearing off happens sooner .

Some experts have described the “on” period as akin to switching on a light, and the “off” period as the lights going off.

In an “on” state, the person with Parkinson’s disease may feel energetic and able to move around more easily. However, in an “off” state, the person may become very stiff, slow, and may even be unable to move at all for a few minutes. A person may also have difficulty speaking, and you may notice him or her slurring their words. As you can imagine, the “off” state can be quite uncomfortable.

Help Your Patients Uncover The Troublesome Symptoms Of Off Periods9

Reviewing a Case of Parkinson Disease OFF Episodes

Both physicians and patients agree: OFF periods can be one of the most difficult aspects of Parkinsons disease. Its understood that recognizing the symptoms of OFF periods is challenging because of a variety of reasons, including interpatient symptom variability and reliance on patient reporting.9

People with OFF periods may not discuss their symptoms or communicate the impact of the symptoms to their healthcare provider as they may be unaware that the changes they are experiencing are a result of OFF periods. Because patients may not recognize the more subtle changes they are experiencing as symptoms of OFF periods, enhancing communication around the full spectrum of symptoms is important.9

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Pathophysiology And Risk Factors For The Development Of Off Episodes In Parkinsons Disease

C Warren OlanowDepartment of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Levodopa has been used as a treatment for PD for 50 years and remains the most effective therapy available. There are, however, limitations with levodopa, including a lack of control of non-dopaminergic features of PD such as falls and dementia, failure to stop disease progression, and the development of motor complications in the majority of patients.27 Risk factors for the development of these complications have been studied in both open-label and long-term prospective studies which indicate that both OFF time and dyskinesia are associated with young age, high doses of levodopa, and disease severity.8,28 Among these, levodopa dose is the one factor that can be controlled by physicians.

Analyses in this study further indicate that female gender and lower weight correlate with the development of motor complications this likely reflects the same dose resulting in higher plasma levels in these individuals.28 Recommendations arising from this work suggest that physicians should use the lowest levodopa dose that provides satisfactory symptom control, should consider alternative medications to minimize levodopa dose, and should pay particular attention to the dose given to young women. It may also be necessary to consider patient weight and prescribe the dose on a mg/kg basis.

Can An Off Episode Be Prevented

Eventually, most people with PD develop OFF episodes. Some people develop OFF episodes sooner than others.

Researchers have found evidence that taking high doses of levodopa may increase your risk of OFF episodes. It may cause greater fluctuations in your dopamine levels.

Its important for your doctor to prescribe the lowest dose of levodopa necessary to manage your symptoms. This may help limit fluctuations in dopamine and reduce your risk of OFF episodes.

If you think you might be experiencing OFF episodes, let your doctor know. They may adjust your prescribed dose or formulation of levodopa/carbidopa. They may also prescribe other treatments to manage OFF episodes.

If youre experiencing OFF episodes, your doctor may recommend one or more changes to your treatment plan.

They may:

In some cases, your doctor may recommend deep brain stimulation . In this procedure, a surgeon implants electrodes in the brain and a small internal pulse generator in the chest or abdomen. The internal pulse generator sends electrical signals to the brain to help control symptoms of DB.

Each treatment option carries a different risk of side effects. Ask your doctor about the potential benefits and risks of different treatment approaches.

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