Exploring The Clinical Burden Of Off Periods In Parkinson Disease
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ABSTRACT
Parkinson disease, the second-most-common neurodegenerative disorder, affects approximately 1 million individuals in the United States, and this number is projected to increase to 1.2 million by 2030. Characterized pathologically by degeneration of dopaminergic neurons, with widespread pathology in nondopaminergic systems, Parkinson disease leads to an array of motor and nonmotor symptoms that can significantly impact an affected individuals quality of life. Treatments for Parkinson disease typically focus on controlling the motor symptoms of the disease, including treating OFF periods when motor symptoms return. OFF periods can occur for many individuals with Parkinson disease, especially as the disease progresses, and can pose a substantial burden to those with the disease and their caregivers. Available treatments for OFF periods may help alleviate this burden.
Am J Manag Care. 2020 26:S255-S264.
For author information and disclosures, see end of text.
Introduction
Diagnosis of PD usually occurs after age 50 years, and incidence rises with increasing age.1 In most populations, incidence of PD is twice as common in men as in women.1 In a population-based study conducted in Olmsted County, Minnesota, incidence was observed to increase over a 30-year period, particularly in men 70 years or older .4
Etiology
Nonmotor Symptoms
Symptoms Of The Disease
One of the symptoms of Parkinsons disease are dystonias, sustained muscle contractions that cause forced and painful positions for patients. These dystonias are associated with fluctuating dopamine levels as a consequence of the destruction of the substantia nigra. The duration of these dystonias can last between thirty minutes and five hours and are highly disabling, considerably reducing patients quality of life and increasing pain. Patients may reach freezing of movement in moderate and advanced stages of the disease.
Pharmacological drugs such as levodopa are administered to treat this symptom . The treatment is complex because levodopa is not dopamine itself, but a precursor, since dopamine cannot cross the blood-brain barrier of the nervous system formed by the meninges in a graphic way, it could be said that it is a wall that protects us from external threats. Levodopa is the most effective treatment for the motor symptoms of Parkinsons, although it is not without side effects.
Levodopa does not have a permanent effect. It acts on some dopamine receptors found in the striatum, but eventually these receptors are affected by neurodegeneration, or become hypersensitive.
On / Off In Parkinsons
On/Off Motor Fluctuation in Parkinsons Disease
What does On/Off mean?
The On/Off Phenomenon in Parkinsons Disease is related to uctuating benet of the medications used to treat PD.
Being On describes the time when the Person with Parkinsons feels that their medication is benecial and that their symptoms are well controlled.
Being Off describes the time when the PwP feels that their medication is not working as well as usual, and some of their symptoms may have returned .
The On/Off phenomenon can best be described as a quick, unpredictable reappearance of PD symptoms. Likewise, switching from Off to On can occur just as suddenly. The speed of this shift can be so dramatic that some people have likened this effect to a light switch being turned on and off.
On/Off uctuations are different from the phenomenon known as Freezing, which can also affect people who have had Parkinsons for some time. Freezing is the word used to describe the experience of stopping suddenly while walking or when trying to initiating walking, and people feel as though their feet are frozen or stuck to the ground. While Freezing episodes tend to last only a few seconds, an Off period can continue for minutes, or even hours.
How is the On/Off Treated?
What Can People with Parkinsons Do to Help Themselves?
Acknowledgements:
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Q What Are The Key Signs Of Wearing Off That People With Parkinsons And Their Family Friends And Carers Should Look Out For
A. The usual signs of wearing off are slowness of movement or an increase increase in tremor before your next dose of medication is due. But wearing off can increase other symptoms associated with Parkinsons too, including fatigue and pain from dystonia . If you notice an increase in any of your Parkinsons symptoms before you take your medication, speak to your specialist or Parkinsons nurse to see if it could be related to wearing off.
Talking With Your Doctor
What should I tell my doctor before taking INBRIJA?
Give your doctor as many details as possible about any symptoms you experience between doses of your regular Parkinsonâs medication. It may be helpful to keep a journal that notes when you have symptoms, what they are, the time of day, and how long they last. Use our doctor discussion guide and the symptom checklist provided with it to help you prepare for discussions with your doctor.
Before using INBRIJA, tell your healthcare provider about your medical conditions, including:
- asthma, chronic obstructive pulmonary disease , or any chronic lung disease
- daytime sleepiness, sleep disorders, sleepiness/drowsiness without warning, or use of medicine that increases sleepiness, including antidepressants or antipsychotics
- dizziness, nausea, sweating, or fainting when standing up
- abnormal movement
- mental health problems such as hallucinations or psychosis
- uncontrollable urges like gambling, sexual urges, spending money, or binge eating
- pregnancy or plans to become pregnant. It is unknown if INBRIJA will harm an unborn baby.
- breastfeeding or plans to breastfeed. Levodopa can pass into breastmilk and it is unknown if it can harm the baby
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The Physical And Emotional Effects Of Off Episodes
The majority of patients experience Parkinsons disease ON/OFF time in the latter stages of the disease. 64% of people with PD reported having 2 hours or more of OFF time per day. Many of those same people feel frustrated and helpless when their medication stops working.
According to OFF Limits PD, there are four types of OFF episodes, each with different physical and emotional effects:
Morning OFF
Morning OFFs occur in roughly 60% of PD patients. They typically appear after a treatment-free night, making it difficult for people with Parkinsons to get up and on with their day. Symptoms may diminish after you take your first dose of Parkinsons disease medication, or they may linger throughout the morning. You may have a delayed ON or no ON at all. Morning OFFs can result in depression, lethargy, physical inactivity and pain.
Wearing OFF
Wearing OFF happens when the effectiveness of medication starts to deteriorate toward the end of a dose. Patients may feel frustrated and hopeless as they feel the medicine beginning to wear off and their symptoms returning. Not only does this take an emotional toll, but it can also be physically debilitating. The good news is, your doctor can help you manage your medication to reduce your wearing OFF episodes.
Delayed ON, partial ON, no ON
Unpredictable OFF
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What Makes Pd Hard To Predict
Parkinsonâs comes with two main buckets of possible symptoms. One affects your ability to move and leads to motor issues like tremors and rigid muscles. The other bucket has non-motor symptoms, like pain, loss of smell, and dementia.
You may not get all the symptoms. And you canât predict how bad theyâll be, or how fast theyâll get worse. One person may have slight tremors but severe dementia. Another might have major tremors but no issues with thinking or memory. And someone else may have severe symptoms all around.
On top of that, the drugs that treat Parkinsonâs work better for some people than others. All that adds up to a disease thatâs very hard to predict.
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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.
The Reality Of Managing Symptoms
Dr. Benjamin Walter, of the Center for Neuro-Restoration at Cleveland Clinic, said that the average person isnt accustomed to the strict regimen of multiple medications a day thats part of everyday life for people with Parkinsons.
Most people feel burdened just taking an antibiotic, which can be difficult to remember. Now, imagine someone who has Parkinsons the minimal dosing is usually three times a day, Walter said.
He explained that the need to frequently take medication is because it usually only lasts in a persons bloodstream for 90 minutes.
Once the medication gets into the brain, its converted to dopamine and stored in dopamine neurons, which recycles and reuses that medication over and over until it is depleted. Now, its not uncommon to have patients on meds four or five times a day, he said.
Walter stressed that when discussing Parkinsons and off periods, no two people are the same.
Parkinsons is a highly variable disease. Some people will experience different motor symptoms and tremors than others.
For example, some people freeze when they walk, while others dont.
He said the off periods can be terrifying for many people and also cause a different symptom anxiety.
Walter said that its important for those taking care of a person with Parkinsons to understand how dangerous off periods can be.
He stressed the importance of making sure patients get their medications on schedule so that everything is kept in working order.
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Parkinsons Treatment Plans Often Need Adjustments
Let your doctor know if youre having off and on periods and how theyre affecting your life. Are off times interfering with work, spoiling family time, or making it tough to perform daily activities like cooking and cleaning? Your doctor may be able to:
- Increase the dosage of your current medication
- Combine your current medication with another type
- Add rescue medication that works within 15 minutes to get you through off times
Certain medications, like dopamine agonists, are known to extend on periods and prevent off periods with levodopa. Adding them to your treatment regimen can help keep you on more often and for longer periods of time.
If your symptoms dont improve enough with medication, you may be a good candidate for deep brain stimulation . Its a minimally invasive surgical procedure that involves implanting a neurostimulator in the chest that sends electric pulses to the area of the brain that controls movement.
As a chronic, progressive condition, the symptoms of Parkinsons disease are expected to worsen over time, but your treatment plan is also expected to evolve in tandem. The goal remains to minimize symptoms and maximize quality of life. With the right treatment and a strong relationship with your care team, you can manage your Parkinsons for a long time and live a full, satisfying life.
Communication With Health Care Professionals About Off Periods
PwP and carepartners were asked to recall what aspects of OFF periods were discussed at the office visit. Discussion of motor aspects was reported by a higher proportion of both groups than non-motor aspects . A higher proportion of carepartners than PwP reported discussion of all aspects. Fifty nine percent of carepartners and 79% of PwP felt that the doctor understood the burden of OFF periods on their lives. Motor aspects of OFF periods were also the aspect most frequently reported as discussed by physicians , followed by the impact of OFF periods and on carepartners: 56% of general neurologists and 64% of movement disorder neurologists), followed by non-motor aspects .
The clinical interview was used by all neurologists to assess OFF periods. Including carepartners in the clinical interview was a frequent complementary method . The frequency of use of other methods such as questionnaires, diaries, wearable devices or direct observation are shown in .
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What Types Of Symptoms Might You Experience When Youre Off
Being OFF is more than just having a bad day. It involves experiencing a host of motor and non-motor symptoms that you have come to expect your medication to control.
While the number and severity of symptoms differ for everyone, here are the most common ones people experience when they are OFF:
Motor Symptoms of OFF
- Dystonia in hands, feet or legs
Non-Motor Symptoms of OFF
Many non-motor symptoms remain present in the ON state, and they do not respond to dopaminergic treatment. Therefore, you would not be considered OFF if those remain present. However, there are some non-motor symptoms that worsen or are more severe in the OFF state. These often include:
- Fluctuations in cognition, attention, anxiety, depression, apathy
- Sweating, lightheadedness, abdominal pain, bloating, urinary issues
- Visual disturbances, pain, dysesthesia, akathisia, restless legs syndrome
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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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Parkinsons Disease Symptoms Everyone Should Know
Parkinsons disease symptoms can include tremor and trouble with movement, along with emotional and cognitive changes.
Parkinsons disease symptoms can vary significantly from person to person. Some people may have range of motor symptoms, like tremor, stiffness, and slow movements. Others may also experience the non-motor symptoms of Parkinsons disease, such as anxiety, cognitive changes, and loss of smell.
It has to do with a chemical messenger known as dopamine, which plays a role in the brains ability to control movement, coordination, and emotional responses. In Parkinsons disease, the brain cells that produce dopamine either stop doing their job or they die out, resulting in both motor and non-motor symptoms. Its not always easy to tell if someone you care about has Parkinsons disease. Lets take a closer look at the symptoms of the disease and signs that someone should make an appointment with their doctor.
Characteristics Of The Clinicians
Fifty-one clinicians participated in this study. Among them, 20 clinicians worked in tertiary care hospitals and 31 clinicians worked in secondary care hospitals. Most of the clinicians majored in neurology , and four clinicians majored in traditional Chinese medicine. For the clinicians, the mean years in practice in the field of PD was 9.4 ± 7.8 and the mean number of PD patients that they served per week was 14.7 ± 14.0.
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How Is Parkinsons Disease Treated
There is no cure for Parkinsons disease. However, medications and other treatments can help relieve some of your symptoms. Exercise can help your Parkinsons symptoms significantly. In addition, physical therapy, occupational therapy and speech-language therapy can help with walking and balance problems, eating and swallowing challenges and speech problems. Surgery is an option for some patients.
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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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Types Of Motor Fluctuations
Motor fluctuations take a variety of forms:
On-off phenomenon. You cycle between good control and periods of symptoms. During the on times, your symptoms are well managed. In off periods, the problems come back.
Some people only get off periods when their levodopa starts to wear off. Others get symptoms at random times that arent related to their medicine. Your doctor may prescribe add-on medications which can lessen the off times.
Wearing off. The effect of your levodopa starts to fade before its time to take the next dose. You might be tempted to take your medicine earlier than usual to prevent symptoms.
Delayed on. You have to wait longer than usual after you take levodopa for your symptoms to improve. This delay can happen when you take your first dose in the morning. Its also common after meals, because the protein in your food can cause the medicine to get absorbed more slowly.
Delayed on is more common with time-release versions of levodopa. These drugs take a while to get from your stomach into your bloodstream and then travel to your brain.
Partial on or dose failure. Partial on means that your symptoms dont fully improve after you take a dose of levodopa. A dose failure is when you dont feel any better after taking your medicine.
Youre more likely to have freezing during an off period.
Dyskinesia. This is uncontrolled twitching, jerking, or other movements. It can affect one limb, such as an arm or leg, or your whole body.