Different Delivery Systems Of Apomorphine
Subcutaneous delivery of apomorphine, a dopamine agonist, is a clinically established therapy shown to be effective in reducing off-time in patients with motor fluctuations. The first double-blind, placebo-controlled, randomized test of this delivery of apomorphine was conducted in the phase 3 TOLEDO study.2 The subcutaneous infusion resulted in an absolute change in off-time, with achieved secondary endpoints of the percentage of patients with off-time reduction of at least 2 hours, absolute change in on-time without troublesome dyskinesia, change in oral levodopa and levodopa equivalent dose, change in the United Parkinsons Disease Rating Scale during on periods, and change in quality of life .
The results of the TOLEDO study confirm what clinicians had observed and reported in uncontrolled studies for several decades: good efficacy and tolerability of apomorphine subcutaneous infusion, principal investigator Regina Katzenschlager, MD, the head of the Department of Neurology at the Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders at Danube Hospital in Vienna, told NeurologyLive.
Screening Selection And Data Extraction
Identified publications were initially screened by title to remove duplicates and papers of a type not meeting with the PICOS eligibility criteria. Screening and data extraction were conducted independently by two reviewers . Results were matched between reviewers and discordance was resolved by consensus through a third reviewer .
Data on off-time at all reported timepoints were collected from each selected publication. Other available information that was extracted from the selected publications, where reported and at all reported timepoints, was: study characteristics , change from baseline in motor symptoms , change from baseline in motor complications , change from baseline in dyskinesia duration, change from baseline in motor experiences of daily living , change from baseline in QoL scores, change from baseline in non-motor symptoms and safety outcomes.
These data were extracted independently by both reviewers from selected publications using a standardised Microsoft Excel-based form. Extracted data were verified in the drafting of this manuscript by a third reviewer. As identified studies were not RCTs, the domains to address in a risk of bias assessment, according to the Cochrane Collaboration , were absent in most studies. Therefore, we did not draw a funnel plot or conduct a formal assessment of the risk of bias of included publications.
Patient Demographics Personal Circumstances Clinical Characteristics And Current Treatment
A total of 130 neurologists provided data for 722 patients who were receiving carbidopa/levodopa and had all data available required for the analyses. Patients ranged in age from 26 to 90years, and most were male , retired , and living with their spouse or partner . Slightly over half of the patients had a Hoehn and Yahr score of < 3, indicating mild PD, and only 13% had a Hoehn and Yahr score of 4 or 5, indicative of PD symptoms resulting in significant disability. Mean age at diagnosis was just over 60years, and the mean duration of PD was slightly over 4years but ranged to over 20years . In addition to carbidopa/levodopa, patients were also prescribed antiparkinsonian treatments from other pharmacologic classes, including dopamine agonists , catechol-O-methyl transferase inhibitors , monoamine oxidase type B inhibitors , and N-methyl-D-aspartate antagonists .
Table 1 Patient demographics, personal circumstances, clinical characteristics, and current treatment
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How To Help Reduce Episodes
Off times become more common after people with PD have been taking medication for a longer time and as their disease progresses. While the presence of off times happens as a normal progression of PD, there are things that can help manage or reduce these episodes:
Implications Of Elusive On
Trials to establish the efficacy of established medications utilizing perhaps more efficient delivery systems have so far failed to prove complete reduction in off-time.
Theres a lot that isnt logical about it, or conceptually, we have the wrong message that off-time is always a deficiency of dopaminergic stimulation to be improved by better delivery of drugs or blocking the breakdown of drugs we currently use, said LeWitt. To him, the emerging story has been that the emergence of Parkinsonian symptoms can be, and is, a complex tale.
You can also criticize the studies, like the TOLEDO study, that maybe they didnt enough apomorphine in the dosing with levodopa, to try to explain why the effect was as limited as it was. But that might not be the right answer to it, LeWitt said. It might just be that theres some black box in the brain that fails to respond fully to continuous dopaminergic stimulation to relieve all of the Parkinsonian symptoms. Im thinking more and more that it might be something weve yet to learn about this disorder, that as the disease goes by the responses to dopaminergic stimulation may fluctuate in a manner that doesnt really suggest what to do about it now.
The Symptom Spectrum Of Wearing
In a satellite symposium held at the 2019 EAN Congress, the speakers discussed the spectrum of motor and non-motor fluctuations associated with the wearing-off of levodopa treatment for Parkinsons disease, and steps to prevent and manage these troublesome symptoms.
Impact of wearing-off on motor symptoms
As Parkinsons disease progresses over time from a stable treated disease to an advanced state there is a recurrence of motor symptoms during wearing-off including tremor, dystonia, muscle spasms, postural instability, slowness and gait difficulties. Wearing-off occurs frequently in about 80% of patients within 4 years from therapy initiation .1-3
Wearing-off during levodopa treatment may be detected even at the early stages of PD and is underestimated by routine neurological clinical evaluation. The number of symptoms, both motor and nonmotor, increases along with disease duration and unsurprisingly has a negative impact on patients quality of life.4
Patients with PD rate wearing-off as the greatest challenge with their levodopa therapy. Activities of daily living are rated as most bothersome by patients, because they are most limited during OFF time.5 Patients would prefer treatments that increase the amount of ON time, and for which they are able to predict the occurrence of OFF time to within 30 minutes.
Wearing-off is the greatest challenge of levodopa therapy, which occurs within 4 years of therapy initiation, and may be detected even earlier
Podcast Episode : How To Manage Parkinsons Off Time
Parkinsons can be unpredictable symptoms can come and go or get better and worse throughout the day. These so-called on-off fluctuations and dyskinesias can be troubling, but movement disorder specialists can help with the choice of medication, dosages, and timing. Dr. Irene Malaty explains more about what causes these changes and how you can work with your doctor to manage them.
Managing Wearing Off And Motor Fluctuations
If you think you are starting to experience wearing off or motor fluctuations, you should discuss this with your doctor promptly so that your medication can be adjusted to minimise your symptoms. Tell him or her how long your medication is lasting and what happens when it wears off. Remember to tell them about motor and non-motor symptoms.
Can The Parkinsons Disease Kill A Patient
Parkinsons disease is not really fatal in nature. However, the symptoms associated with Parkinsons disease is actually life threatening that may lead to fatal accidents. Injuries are quite common in Parkinsons disease due to inability to move around effortlessly. This is actually dangerous. Thus, efforts must be taken in order to create a safe environment for patients with Parkinsons disease.
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Carbidopa And Levodopa Controlled Release
A controlled release formulation of carbidopa/levodopa is also available. Four randomized, placebo-controlled studies of CD-LD CR versus CD-LD IR showed that although patients were able to reduce the number of medication administrations per day, there were no significant differences in motor response, including OFF time, between IR and CR CD-LD . In a more recent pharmacokinetic study, the plasma levodopa concentration-time profile of CD-LD CR was only marginally shifted to the right relative to CD-LD IR, with values for Tmax and duration of time during which levodopa concentrations are above 50% of Cmax both about 30 min longer than those for CD-LD IR . Overall, due to inconsistent absorption and pharmacokinetics, CD/LD CR does not provide significant advantages over CD/LD IR with respect to addressing motor complications, though some patients find nocturnal dosing to be helpful for nighttime symptoms. CD-LD CR is available as 25 mg/100 mg and 50 mg/200 mg tablets and is typically dosed in two or three divided doses daily .
Why Do Motor Fluctuations Happen
As Parkinsons disease progresses, it is common for more dopamine-producing brain cells to die, causing the benefits from Parkinsons medications to not last as long as they did before. The brain eventually reaches a point where it stops producing dopamine in large amounts and therefore must rely on medicine to replace dopamine. Researchers think this happens for two reasons:
- As Parkinson’s progresses, cells become less able to store dopamine. When this occurs, the cells are unable to release dopamine without medications, such as levodopa. When the dose fades, 60-90 minutes after taking it, there is no more levodopa for the cells to use, resulting in lower dopamine levels and a worsening of symptoms .
- The cells in your brain become more sensitive to both higher and lower concentrations of levodopa. There is a higher likelihood of experiencing off times when levodopa levels are too low and a higher likelihood of experiencing dyskinesis when levodopa levels are too high.
As a result, your doctor may advise you increase your medication doses to achieve optimal control of motor symptoms, such as tremor, slowness and rigidity. The goal is to maximize symptom control without increasing side effects.
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Despite Life Struggles Many Patients In Survey Open To Better Future
RISE-PDs main goal was to assess changes between weeks seven and 20 in Good On hours per day, defined as the sum of on time without uncontrollable involuntary movements and on time with non-troublesome dyskinesia.
Secondary goals included changes in daily off time and the proportion of patients who were either much improved or very much improved in Patient Global Impression of Change which reflects a patients beliefs about a treatments efficacy.
Changes in Parkinsons motor symptoms and overall symptoms also were assessed using the Movement Disorder Society Unified Parkinsons Disease Rating Scale.
The results showed that IPX-203 was associated with significantly greater efficacy, compared with immediate-release tablets, meeting the trials main goal and most secondary endpoints.
Particularly, 13 weeks of treatment with IPX-203 led to 0.53 more hours of Good On time relative to immediate-release CD/LD or 1.55 more hours, as assessed with a different method in which results are adjusted for means of other factors.
This translated into 0.48 hours less of feeling off with IPX-203 and in a significantly greater proportion of IPX-203-treated patients reporting to be much improved or very much improved as compared with those in the immediate-release tablets group
No significant group differences were observed in terms of changes in Parkinsons motor and overall symptoms.
A nine-month safety extension study is ongoing.
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.
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Understanding Of Off Periods
Two studies addressed the understanding of off periods .1). A questionnairebased study of patients and their carepartners found that a large proportion of patients and carepartners indicated that they understood the concept of wearing off. On further questioning, however, 53% of patients and 36% of carepartners did not answer the question about the meaning of wearing off and 17% of patients and 47% of carepartners gave incorrect answers . In interviews conducted in Dutch nursing homes, lack of staff knowledge regarding motor fluctuations in PD, including the importance of timely administration of levodopa and avoidance of proteinrich meals at the time of ldopa intake to minimize off time was one of residents’ and caregivers’ main complaints. This lack of understanding was felt to contribute to a lack of empathy. We identified no studies investigating physician understanding.
Current Approaches To The Treatment Of Off Episodes In Parkinsons Disease
Olivier RascolResearch Network Departments of Clinical Pharmacology and Neuroscience, Toulouse University Hospital, Toulouse, France
The poor efficacy of levodopa in treating the OFF phenomenon in PD is caused by several pharmacokinetic issues including poor bioavailability, being only absorbed through the jejunum. Levodopa tablets can remain in the stomach for several hours due to issues with gut emptying, delaying the drug reaching the brain. In addition, levodopa has a short plasma elimination half-life of 60â90 minutes.33,34 The pulsatility of levodopa plasma levels dysregulates the cerebral and synaptic mechanism, generating post-synaptic abnormal plasticity and abnormal motor function.35,36 Objectives in PD treatment development have therefore been to find faster-acting drugs, to improve the bioavailability of levodopa, and to stimulate dopamine receptors in a more continuous manner. Approaches include:37
- alternate formulations of levodopa with longer duration of action
- inhibitors of dopa decarboxylation at the periphery to increase availability of levodopa in the central nervous system
- inhibiting catechol-O-methyltransferase to increase availability of levodopa in the central nervous system
- inhibiting monoamine oxidase B to reduce dopamine elimination
- increasing dopamine release and
- dopamine agonists to mimic dopamine.
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Prevalence Incidence And Risk Factors For Motor Complications
Nearly all patients develop motor fluctuations and LID by 15 to 20 years from time of diagnosis . However, prevalence and incidence figures through the course of PD vary depending on the study methodology employed and by the predominant treatment strategies of the time. Early literature suggested that approximately 10% of patients per year following initiation of treatment with levodopa develop motor fluctuations, with 40% of patients developing these complications within 46 years of treatment . A large cross-sectional study of 617 patients with PD found an overall prevalence of wearing off of 57% as assessed by neurologists and 67% as assessed by a patient-completed questionnaire . Of patients with disease duration < 2.5 years, wearing off was identified in 41.8% by the WOQ-19 and in 21.8% by neurologists, indicating that motor fluctuations can emerge as early as several months to a few years after the initiation of levodopa, as has also been observed in other studies . A retrospective analysis of an incident cohort of PD found estimated rates of dyskinesia of 30% by 5 treatment years and 59% by 10 treatment years .
Does Parkinsons Disease Impair A Patient Cognitively
Since Parkinsons disease is neurological in nature it does have an effect on a patients cognition. Although the symptoms can be seen at a later stage of progression, the cognitive symptoms can be in form of delusions and hallucinations. The patient may also have issues with remembering events and can be diagnosed with dementia.
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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.
Come To A Common Definition Of Off
This is perhaps the most important action you can take to navigate and hopefully minimize OFF periods. When it comes to a definition of OFF, you dont have to agree with the rest of the medical community, you just have to agree with your doctor and care team.
For example, your doctor might not think that predictable wearing off is equivalent to an OFF state. You might think it is. In order to account for differences in how you define OFF, its important to determine what OFF means to both of you. And to come up with a working definition together. You might even have a code such as, When I say X, I mean Y.
You have Parkinsons, so chances are, youre going to be seeing your doctor on a regular basis for many years to come. The earlier you can establish a language for how you talk about OFF, the better chance you have of getting the interventions and treatment you need to live well with Parkinsons.
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