1. Wearing-off workshop resource kit

2. Wearing-off
Long-term management of PD: Development of levodopa-associated complications
Introduction to wearing-off
Symptoms of wearing-off
The wearing-off study
The wearing-off Patient Questionnaire Card
Management of wearing-off
New perspectives

3. Long-term management of PD: Development of levodopa-associated complications

4. Long-term management of PD with levodopa
Provides antiparkinsonian benefit over the course of the disease
Well tolerated
“Levodopa is currently the most effective antiparkinsonian drug and all PD patients eventually require it”
Agid et al 2002
Advantages of levodopa
This graph (based on data from Hoehn 1967) demonstrates the dramatic impact levodopa has had in the treatment of PD since its introduction. Compared with the pre-levodopa era (salmon bars), levodopa treatment (green bars) has significantly reduced the amount of disability and mortality associated with PD.
Since its introduction more than 30 years ago, levodopa therapy has revolutionized the treatment of PD, providing dramatic symptomatic benefits to virtually all PD patients and increasing the duration of time that PD patients can enjoy independent activities of daily living, and employability.
Levodopa treatment is associated with decreased morbidity and mortality in comparison to the pre-levodopa era.
Levodopa remains unrivalled as the most effective symptomatic PD treatment. Consequently, regardless of where levodopa is administered in the course of therapy, all patients will, at some point, require the symptomatic efficacy of levodopa therapy.
Importantly, levodopa continues to provide antiparkinsonian benefits over the entire course of the disease.
Dopamine replacement with oral levodopa remains the most effective and best-tolerated approach.
Agid et al. Lancet 2002; 360: 575.
Hoehn. Neurological Clin 1992; 10: 331–9.
Olanow et al. Neurology 2001; 56: S1–86.
Olanow et al. Mov Disord 2004; 19: 997–1005.
Poewe. Neurology 2004; 62: S31–8.
Hoehn, 1992

5. Beneficial effect of levodopa on life expectancy
This study included patients seen at a Movement Disorder Clinic over a 32 year period.
The evidence provided is based on epidemiological observations of 934 consecutive Parkinson syndrome (PS) patients assessed during 22 years.
The top figure shows survival in 215 patients who had the most restricted levodopa access compared with that expected in the regional matched population. Survival in this patient population is significantly reduced.
The lower figure shows survival in 565 parkinsonian patients who had an unrestricted levodopa access compared with the age and sex matched regional population. The survival is significantly shorter in this patient population as well.
The survival rate in PD is compromised and even today, remains significantly shorter than expected.
The benefit of levodopa to survival is evident when the shortened life expectancy in those who had a restricted levodopa access (p<0.0001) is compared with the group receiving unrestricted leodopa (p= 0.029)
Rajput. Parkinsonism Relat Disord 2001; 8: 95–100.
Rajput, 2001

6. Long-term challenges: Changes in levodopa response
In the early stages of PD there is a large therapeutic window, and the response to levodopa is excellent. Even if treatment is withdrawn or a dose missed the benefits of levodopa therapy persist for many hours or even days after discontinuation of treatment.
At this stage the antiparkinsonian benefits are associated with a low incidence of dyskinesia.
As the disease progresses, even in moderate disease, the long-duration response to levodopa diminishes and the response to levodopa begins to more closely reflect its short half-life (~1.5 hours). Antiparkinsonian control becomes increasingly governed by fluctuations in plasma levodopa levels.
In more advanced PD, the short-duration response to levodopa predominates. The therapeutic window narrows, and adequate control of symptoms becomes increasingly difficult.
Initially this is manifested by an end-of-dose deterioration, where PD symptoms return before the next scheduled medication dose.
Patients are often either 'off', or 'on' with dyskinesia and other complications.
The loss of the long-duration response is thought to be related to:
Degeneration of striatal dopamine nerve terminals as disease progresses
The relatively short half-life of levodopa
Obeso et al. Trends Neurosci 2000; 23: S2–7.
Olanow et al. Neurology 2001; 56: S1–86.
Obeso et al. 2000

7. Incidence of complications in levodopa-treated patients at two years
Incidence of complications in levodopa-treated patients at 2 years
These are results from a multicenter, parallel-group, double-blind, randomized controlled trial comparing the development of dopaminergic motor complications after initial treatment of early PD with pramipexole vs levodopa.
This graph depicts the incidence of wearing-off, dyskinesia and on-off effects in the levodopa treated patients over 2 years showing that wearing-off was the most commonly encountered motor complication.
Parkinson’s Study Group. JAMA 2000; 284: 1931–8.
Wearing-off
Dyskinesias
On-off effects
Wearing-off was the most commonly encountered motor complication
PSG, 2000

8. Introduction to wearing-off

9. Typical pattern of wearing-off
This schematic depicts a typical pattern of ‘wearing-off’.
NB: it is intended to represent the clinical situation (i.e. control of PD symptoms), and does not depict plasma levels (although these may be similar).
Importantly, it highlights the relevance of the timing of antiparkinsonian medications to the re-emergence of symptoms (wearing-off).
In this schematic, wearing-off is depicted as the period when the symptoms of PD are not adequately controlled; thus it contains two main components:
The ‘wearing-off’ of the therapeutic benefit of the first dose
The time lag to when the second dose provides therapeutic benefit – this is known as ‘time-to-on’.
M Stacy et al. Mov Disord In Press.
Daily fluctuations in wearing-off

10. Impact of wearing-off

11. clinicians and patients
The PRELUDE survey
Objective: To understand perceptions of levodopa therapy among
clinicians and patients
Physician survey
Patient survey
328 Neurologists
74 Movement Disorder Specialists
54 PCPs
All physicians surveyed treated patients with PD
300 patients with PD treated with carbidopa/levodopa
Sampled through the National Parkinson’s Foundation
The PRELUDE survey
PRoject to Evaluate Levodopa Utilization DEcisions.
The PRELUDE survey, sponsored by Novartis Pharmaceuticals (i.e. Novartis US) was undertaken by Harris Interactive, a leading independent internet market research company.
The study was conducted throughout the US in 2003.
The key objective was to gain an understanding of the perceptions and utilization of levodopa therapy among physicians and patients.
Physician survey
To qualify for the survey, all physicians had to treat patients with PD (at least some with carbidopa/levodopa) and have been in practice for 2–30 years (inclusive).
In total, 402 interviews were conducted between April 16–29, 2003, including 328 Neurologists, 74 Movement Disorder Specialists, and 54 Primary Care Physicians.
Patient survey
Patients were sampled through the National Parkinson’s Foundation (NPF) database. Each patient was assigned an individual identification (ID) and password, so that no one patient could complete the survey more than once.
A total of 300 patients were surveyed between 13–20 May, 2003.
Lieberman and Vijay, Abstract of the 8th International Congress of the European
Federation of Neurological Societies, P1284.
Koller and Vijay, Abstract of the 8th International Congress of the European
Federation of Neurological Societies, SC104.

12. PRELUDE survey: Importance of wearing-off for patients and healthcare professionals
What is the biggest challenge with levodopa therapy?
Dyskinesia
Wearing-off
Managing dyskinesia #1 for Movement Disorder Specialists
Managing wearing-off #1 for PD patients and PCPs
PRELUDE survey: Importance of wearing-off for patients and healthcare professionals
Key findings:
Whereas Primary Care Physicians (PCPs) and patients indicated that they felt that wearing-off was the biggest challenge when administering carbidopa/levodopa, Movement Disorder Specialists (MDSs) felt that they were more challenged by the development of dyskinesia.
This may reflect the stages of the disease that the two physician groups see most often. For example, PCPs often see the PD patient at an earlier stage of the disease and are therefore likely to see the patient when the symptoms of wearing-off first emerge. Conversely, MDSs tend to see the more complicated patients (who often already suffer dyskinesia) who have been referred to them.
Lieberman and Vijay, Abstract of the 8th International Congress of the European Federation
of Neurological Societies, P1284.
Koller and Vijay , Abstract of the 8th International Congress of the European Federation of
Neurological Societies, SC104.

13. Comtan Diagnostic survey, 2002
Within two years 12% of neurologists recognize wearing-off but 54% modify the levodopa regimen
Within two years, 12% of neurologists recognize wearing-off but 54% modify the
levodopa regimen
This graph reports the results of a market research survey of 300 neurologists conducted
in the US (February 21–March 15, 2002).
While 54% of neurologists believed that their patients typically require modifications to their levodopa medication within 2 years following commencement of therapy, only 12% of these neurologists believed that their patients typically experience wearing-off in this early treatment period.
Although not all patients in need of a modification of their levodopa regimen have reached the end of the honeymoon/entered the wearing-off stage, the large discrepancy in the numbers (54% vs 12%) highlights the difficulty in identifying the first signs of wearing-off.
Comtan Diagnostic survey, (Novartis / Orion Pharma Data on File)
The large discrepancy in the numbers (54% Vs 12%) highlights the difficulty in identifying the first signs of wearing-off
Comtan Diagnostic survey, 2002

14. No universal definition of wearing-off
Study, year
Definition and Incidence
Rajput et al. 2002
A predictable decline in motor function at the end of dose in a patient with previously stable response receiving 3 or more daily levodopa doses
25% of patients had wearing-off after 4.9 years
Parkinson Study Group, 2000
A perception of loss of mobility or dexterity, usually taking place gradually over minutes and usually bearing close resemblance to the timing of antiparkinsonian medications
38% of patients had wearing-off after only 2 years
No universal definition of wearing-off
In their comprehensive review of the cumulative literature (1966–2000), Ahlskog and Muenter found that there was considerable scatter of motor fluctuation (wearing-off and on-off) frequencies among studies with the same duration of follow-up.
For example, depending on the study, the frequency of wearing-off within 2 years of therapy ranged from 0–50.4% (mean of 47.9%).
Ahlskog and Muenter attributed a large part of this large variability to:
Variance in study design.
Differing methods and levels of scrutiny for detecting motor complications.
The slide shows two contrasting examples of definitions used in the identification of wearing-off. These differences in methodology gave rise to a considerable difference in the frequency of wearing-off reported.
In the Rajput study, all observations were made by the same investigator and identified 25% of patients with wearing-off after 4.9 years of levodopa therapy. This definition was limited to a predictable decline in motor function.
The CALM-PD study (Parkinson Study Group) identified 38% of patients with wearing-off within 2 years of levodopa therapy. Although generally limited to a decline in mobility, this definition was one of the first to refer to the timing of antiparkinsonian medications.
Ahlskog and Muenter. Mov Disord 2001 May;16(3): 448–58.
Parkinson Study Group. JAMA. 2000; 284: 1931–1938.
Rajput et al. Mov Disord 2002; 17: 289–96.
The lack of a universal definition of wearing-off may be reflected in its reported incidence in patients
PSG, 2000
Rajput et al., 2002

15. Useful definitions of wearing-off
For the physician:
For the patient:
“Wearing-off refers to the predictable emergence of one or more PD signs or symptoms before the next scheduled antiparkinsonian medication dosage.”
“Wearing-off happens when a dose that previously used to help your symptoms does not last as long and your next dose is needed sooner. Symptoms of wearing-off include changes in movement and mobility, thoughts and feelings, sensations and sense of well being.”
Useful definitions of wearing-off
This slide provides two useful definitions for wearing-off that have recently been proposed
The definition proposed by Stacy et al, refers more generally to PD signs or symptoms and is not limited to motor function. Moreover, it refers to the timing of the antiparkinsonian medication.
This definition was used as the basis for the wearing-off study (see later slides)
The definition proposed by the PinK (Parkinson’s Information Network) working group was proposed following a survey of 80 Parkinson's Disease Nurse Specialists in the UK.
In this survey, the timing of medication was judged an essential component. It was decided that the definition should not impose a time frame as to when symptoms may reoccur as this time would vary from patient to patient. Individual symptoms could not be defined but would be described as motor, psychiatric, sensory and autonomic, but in terms that a patient would understand.
M Stacy et al. Movement Disorders In Press.
A Bowron. Abstract of the 7th International Congress of Parkinsons Disease and Movement
Disorders, P137.
Stacy et al, 2004
PinK working group

16. Consensus definition of wearing-off
In September 2004, a wearing-off working group meeting of
leading international Movement Disorder Specialists arrived
at a consensus definition.
“A generally predictable recurrence of motor or non motor symptoms that
precedes a scheduled dose and usually improves with antiparkinsonian
medication.”
The purpose of this consensus definition of WO is both to provide a common definition
to aid in the identification of wearing-off and as a tool for a second evaluation of the WO
survey.

17. Symptoms of wearing-off

18. Wearing-off symptoms Professor Fabrizio Stocchi
“When I say re-emergence of parkinsonian symptoms that characterize wearing-off, there are symptoms which are very obvious, like tremor, stiffness, bradykinesia, difficulty in walking. But there are many other symptoms which are less known to doctors such as fatigue, anxiety, depression, urgency in micturition, confusion in mind, panic attack and sweating. These are all symptoms that are related to the disease and occur when the levodopa tone/dopaminergic tone or the plasma level of levodopa actually goes down and wears off. So they usually occur at the end of the given dose of levodopa and before taking the next one.”
Professor Fabrizio Stocchi

19. Wearing-off symptoms
Professor Fabrizio Stocchi

20. Challenges in identification of wearing-off
“Because patients may not be aware that the changes they are experiencing are related to their PD and are treatable, they may not spontaneously discuss their symptoms…”
“…It is, therefore, important that physicians treating PD be aware of the many different symptoms of wearing-off and specifically ask about the occurrence of such changes.”
Stacy, 2003
Challenges in the identification of wearing-off
As the symptoms of wearing-off are neither well established nor the same for all patients, they may not be easily recognized by the physician or the patient.
Importantly, although wearing-off has often been characterized by a return of the cardinal motor symptoms of PD, it can also include non-motor symptoms. For example, wearing-off may include changes in mood, sensations and sense of well being which many patients do not associate with PD or with timing of their medication.
Both motor and non-motor symptoms can be disabling, and therefore wearing-off can be a significant treatment issue.
Koller and Tse. Neurology. 2004; 62: S1–8.
Stacy et al. Movement Disorders In press.

21. Motor fluctuations in wearing-off
Return of parkinsonian symptoms
Tremor
Bradykinesia
Soft voice
Early morning stiffness
Dystonia - often early morning

22. Non-motor fluctuations (NMF)
1976: Marsden and Parkes recognized NMF in fluctuating PD
1993: Riley and Lang proposed a classification that is often used today
1996: Hillen and Sage studied the frequency of NMF in a fluctuating population
Using an open-ended question they identified NMF in 17% of fluctuating patients
2002: Witjas et al studied the frequency and disability caused by NMF in advanced PD patients
Using a structured questionnaire they identified NMF in 100% of patients experiencing motor fluctuations
Non-motor wearing-off fluctuations
While non-motor fluctuations (NMF) have been described for more than 20 years, they have probably been underestimated and research has tended to focus on motor symptoms.
Three categories have been proposed for the classification of non-motor symptoms:
Autonomic.
Neuropsychiatric/cognitive (anxiety, fatigue, mood changes, difficulty in thinking, restlessness)..
Sensory (sweating, increased salivation).
Similar to motor fluctuations, the reported frequency of non-motor fluctuations has varied widely depending on the methodology used:
By asking patients to “Tell us about any symptoms that are associated with the ‘off’ state”, Hillen and Sage (1996) identified non-motor fluctuations in only 17% of fluctuating patients.
In contrast, by questioning patients on the presence of specific non-motor symptoms, Raudino et al. reported that 58% of fluctuating PD patients were experiencing NMF.
Furthermore, Witjas et al conducted 50 interviews in a prospective study of PD patients experiencing motor fluctuations using a 54 item structured questionnaire regarding non-motor symptoms.
All patients reported the presence of NMF, with the majority experiencing a combination of symptoms.
Marsden and Parkes. Lancet 1976; 1: 292–6. – Reviewed in Neurology 2001; 56: S1–86.
Riley and Lang. Neurology 1993; 43: 1459–64
Hillen and Sage. Neurology 1996; 47: 1180–3.
Raudino. Acta Neurol Scand 2001; 104: 312–5.
Witjas et al. Neurology 2002; 59: 408–13.
Marsden and Parkes, 1976
Riley and Lang, 1993
Hillen and Sage, 1996
Witjas et al, 2002

23. Non-motor fluctuations in wearing-off
In a study of 50 patients with advanced PD and motor fluctuations:
All patients with motor ‘off’ periods had at least one non-motor fluctuation
Most non-motor fluctuations were associated with the ‘off’ state
Non-motor fluctuation
Frequency (%)
Frequency during off state (%)
Anxiety 66 88
Drenching sweats 64 59
Slowness of thinking 58 83
Fatigue 56 75
Akathisia 54 63
Irritability 52
Hallucinations 49 25
Witjas et al. study on NMF (depicted on slide)
In a prospective study of PD patients experiencing motor fluctuations, Witjas et al. conducted 50 interviews using a 54 item structured questionnaire regarding non-motor symptoms
All patients reported the presence of NMF, with the majority experiencing a combination of symptoms.
The most frequent non-motor symptom was anxiety, followed by drenching sweats, slowness of thinking and fatigue.
Interestingly, NMFs were reported to cause a greater level of incapacity than motor symptoms in 28% of patients.
Witjas et al. Neurology 2002; 59: 408–13.
Witjas et al. 2002

24. US telephone survey 150 levodopa treated PD patients were interviewed
91% with fluctuations in past 30 days
Motor symptoms were most bothersome
The most commonly reported symptoms were:
Tremor 82%
Fatigue 75%
Difficulty moving 68%
Balance 65%
Stiffness 55%
Pain/cramp 48%
Postural changes 47%
Swallowing/speaking 45%
Sweating 38%
Novartis telephone survey
Data on File

25. Rationale for the wearing-off study
Given the variability in the reported frequency of both motor and non-motor fluctuations, it is clear that there are deficits in the identification of wearing-off.
Consequently, there is a risk that wearing-off symptoms in patients who have been on levodopa therapy for <5 years may go unrecognized by clinicians during routine checks.
As a result of this, patients with wearing-off symptoms may not be receiving maximal benefit from their therapy.
The wearing-off study (Ali study) was therefore undertaken with the objective of developing a tool to enable neurologists and other clinicians to work with patients to rapidly and effectively identify wearing-off in their normal clinical practice.
It is well known that structured questioning leads to a better identification of potential issues; thus, it was suggested that the sensitivity of detecting the signs and symptoms of wearing-off would be enhanced by tools such as a patient questionnaire that specifically addresses the occurrence of both motor and non-motor fluctuations.
To test this hypothesis, the wearing-off study was designed to prospectively compare the frequency of wearing-off recognized by a Movement Disorder Specialist to that determined by a specifically designed structured Patient Questionnaire.
M Stacy et al. Mov Disord In Press.

26. The wearing-off study

27. The wearing-off study: Aim
To prospectively evaluate whether a specifically designed Patient
Questionnaire can identify the symptoms of ‘wearing-off’ in the same
number, or more, subjects than a clinical assessment conducted by a
Movement Disorder Specialist
Development of a wearing-off Patient Questionnaire: The wearing-off study
Aim
Given the variability in the reported frequency of both motor and non-motor fluctuations, it is clear that there are deficits in the identification of wearing-off.
Consequently, there is a risk that wearing-off symptoms in patients who have been on levodopa therapy for <5 years may go unrecognized by clinicians during routine checks.
As a result of this, patients with wearing-off symptoms may not be receiving maximal benefit from their therapy.
The Wearing-off Study
The wearing-off study was therefore undertaken with the objective of developing a tool to enable neurologists and other clinicians to work with patients to rapidly and effectively identify wearing-off in their normal clinical practice.
It is well known that structured questioning leads to a better identification of potential issues; thus it was suggested that the sensitivity of detecting the signs and symptoms of wearing-off would be enhanced by tools such as a patient questionnaire that specifically addresses the occurrence of both motor and non-motor fluctuations.
To test this hypothesis, the wearing-off study was designed to prospectively compare the frequency of wearing-off recognized by a Movement Disorders Specialist to that determined by a specifically designed structured Patient Questionnaire.
M Stacy et al. Mov Disord In Press.
Stacy et al., 2004

28. The wearing-off study: Methods
300 consecutive male and female patients with PD were included in the survey.
All treating physicians were blinded to the survey.
Clinician Assessment
UPDRS part IV, question 36.
Clinical Assessment Question.
Patient evaluations were assessed using a specifically designed Patient Questionnaire including 32 (motor and non-motor) symptoms.
Development of a wearing-off Patient Questionnaire: The wearing-off study
Methods
Subjects with idiopathic PD were eligible for inclusion into the study if they were >30 years old, had a duration of illness of <5 years and had provided written informed consent. There were no restrictions on the choice of treatment received by the subjects.
All clinical information was collected using the wearing-off study, a systematized PD data evaluation tool routinely used by participating centers, designed to capture clinical data for research purposes. All subject visits and surveys were completed between December 2, 2002 and March 24, 2003.
The clinician assessments were carried out by a movement disorders specialist (not the principal investigator) during a regularly scheduled office visit for managing PD.
Ratings involved standardized assessments including: interval medical and PD history, concomitant medication use, Hoehn and Yahr staging, Schwab & England and the Unified Parkinson’s Disease Rating Scale (UPDRS) Parts I–IV.
In an effort to contrast the recognition of wearing-off by the clinician to the Patient Questionnaire results, the following ‘Clinical Assessment Question’ was introduced to the database rating scheme immediately after the completion of the UPDRS: “In your opinion, does this patient have one or more of the following based on this visit:
“(a) loss of medication efficacy, (b) wearing-off, (c) sleepiness, (d) dyskinesia, (e) psychiatric complications, (f) other dopaminergic side effects, (g) morning akinesia, (h) none of the above.”
All clinicians participating in the study were blinded to the study hypothesis and were unaware of the specifics of the Patient Questionnaire. The question was added to the database with other routine program upgrades approximately one month prior to the initiation of this study.
M Stacy et al. Movement Disorders In Press.
Stacy et al., 2004

29. Inclusion and exclusion criteria
Able to provide informed consent.
Male or female 30 years of age.
Diagnosis of idiopathic PD.
Duration of illness <5 years.
Exclusion
Duration of PD >5 years.
Subject unwilling to participate in Patient Questionnaire completion.
Any other condition or clinical finding that, in the opinion of the Investigator, made the patient unsuitable for enrolment.
Subjects with idiopathic PD were eligible for inclusion into the study if they were > 30 years old, had a duration of illness of <5 years and had provided written informed consent. There were no restrictions on the choice of treatment received by the subjects.
M Stacy et al. Mov Disord In Press.
Stacy et al., 2004

30. Prototype patient questionnaire
32 symptoms addressed on questionnaire:
Reduced dexterity
(e.g. reduced ability to write, tie shoe laces etc)
Tiredness
Difficulty in getting out of the chair
Muscle cramping
Cloudy mind of dullness in thinking
Difficulty in speech
Pain
Slowness
General stiffness
Panic attacks
Chest discomfort
Abdominal discomfort
Sweating
Tremor
Slowness in the early morning
Slowness of movement
Slowness during the night time
Restlessness
Problems with balance
Slowness of thinking
Bladder problems – problems passing urine
Early morning muscle cramps in the feet
or legs
Stiffness in the early morning
Stiffness in the afternoon
Anxiety
Mood changes
Weakness
Stiffness in the night time
Difficulty in swallowing
Abnormal sensations such as:
Hot/Cold
Aching
Numbness
Prototype patient questionnaire
During the course of three meetings, a group of PD specialists (A. Bowron, M. Guttman, R. Hauser, JP. Larsen, P. LeWitt, W. Oertel, N. Quinn, K. Sethi, M. Stacy and F. Stocchi) representing 10 treatment centers in Europe and North America developed a patient questionnaire based on a review of the literature and a consensus view of the most common motor and non-motor symptoms associated with wearing-off of levodopa benefit.
The 32 resultant symptoms were listed in a randomized order in a four-page document that included a brief set of instructions and definitions, as well as a representative graph illustrating a temporal pattern of wearing-off in relation to levodopa dosing (see slide entitled: Typical pattern of wearing-off).
Subjects were asked to indicate whether they experienced these symptoms during a typical day and whether these symptoms improved following dosing with anti-parkinsonian medications.
Both motor and non-motor symptoms were listed.
Subjects were also asked how troublesome these symptoms were in their daily routine and whether the symptoms had been discussed with the clinician.
M Stacy et al. Mov Disord In Press.
Stacy et al., 2004

31. Clinical Assessment Question
In your opinion, does this patient have one or more of the following based on this visit:
Symptom (n) (%)
a) Loss of medication efficacy
b) Wearing off
c) Sleepiness
d) Dyskinesia
e) Psychiatric complications
f) Other dopaminergic side effects
g) Morning akinesia
All clinicians participating in the study were blinded to the study hypothesis and were unaware of the specifics of the Patient Questionnaire.
In an effort to contrast the recognition of wearing-off by the clinician to the Patient Questionnaire results, the following ‘Clinical Assessment Question’ was introduced to the database rating scheme immediately after the completion of the UPDRS: “In your opinion, does this patient have one or more of the following based on this visit:
“(a) loss of medication efficacy, (b) wearing-off, (c) sleepiness, (d) dyskinesia, (e) psychiatric complications, (f) other dopaminergic side effects, (g) morning akinesia, (h) none of the above.”
M Stacy et al. Mov Disord In Press.
Novartis / Orion Pharma Data on File.
Stacy et al., 2004
Data on File

32. The wearing-off study: Protocol
Principle investigator assesses subject’s eligibility
Blinded clinician performs routine wearing-off study evaluation of the patient’s parkinsonian evaluation, including the Clinical Assessment Question and the UPDRS
Patient completes Questionnaire. Immediately after survey completion, an independent administrative assistant reviews the completed Questionnaire with the patient for comprehension and accuracy
The wearing-off study
Protocol
A total of 300 consecutive office visits by early PD patients to these centers were recorded.
All clinical information was collected using the Ali Project, a systematized PD data evaluation tool routinely used by participating centers, designed to capture clinical data for research purposes.
Following the clinical visit, the physician entered relevant information into the database.
In order to keep the physician blinded to the purpose of the study, a question on wearing-off was added to the database one month prior to the initiation of the study, along with other routine program updates.
The hidden ‘Clinical Assessment Question’ asked whether the clinician felt that the patient had any of range of conditions, including wearing-off (see notes for previous slide).
The Patient Questionnaire was completed by the subject at the end of the routine outpatient visit.
To assess subject fatigue, two forms of the survey were administered, with the only change being a reversal in the order of the 32 items listed to capture PD symptoms.
Immediately after completion, an administrative assistant reviewed the Questionnaire with the subject to assess whether the explanations, visuals and questions were easily understood and to ensure that all questions were answered completely.
The Principal Investigator reviewed all survey data prior to entry into the question database.
Primary outcome measure
The primary outcome measure for this study compared the frequency of wearing-off recognized by the clinician to that determined by the Patient Questionnaire.
For the Patient Questionnaire assessment, the subject was classified as experiencing wearing-off if they reported that one or more of the symptoms included on the Questionnaire improved or disappeared following a dose of antiparkinsonian medication.
M Stacy et al. Mov Disord In Press.
The Principal Investigator reviews all survey data prior to entry into the question database
Stacy et al., 2004

33. Outcome measures Primary outcome: Secondary outcomes:
The frequency of wearing-off as determined by a Clinician Assessment compared to the Patient Questionnaire.
Secondary outcomes:
Identification of the types of wearing-off symptoms from Clinician Assessment and Patient Questionnaire.
Identification of the most troublesome wearing-off symptoms per the Patient Questionnaire.
The frequency of subjects with troublesome wearing-off symptoms per the Patient Questionnaire..
The primary outcome measure for this study compared the frequency of wearing-off recognized by the clinician (responding in the affirmative to the Clinical Assessment Question item “b”) to that determined by the Patient Questionnaire.
For the Patient Questionnaire assessment, the subject was classified as experiencing wearing-off if they reported that one or more of the symptoms included on the Questionnaire improved or disappeared following a dose of antiparkinsonian medication.
Secondary outcome measures included: the frequency of subjects with ‘wearing-off’ identified by UPDRS question 36 (presence of predictable ‘off’ periods), identification of the types of wearing-off symptoms from the Patient Questionnaire and identification of the most troublesome wearing-off symptoms by survey subject.
M Stacy et al. Move Disord In Press.
Stacy et al., 2004

34. Baseline demographics (n=289)
Male/Female (%) /38
Age (years)  9.6 [4292]
Levodopa therapy (%)
Duration of levodopa therapy (years) 1.53
Total UPDRS  17.9
Hoehn & Yahr
Stage
Stage
Stage
Stage
Stage
298 subjects were evaluated.
The average subject age was years and 60.2% were men.
Subjects reporting wearing-off were younger (69.95 vs years; p<0.001) and differed regarding duration of PD symptoms (3.75 vs 3.13 years, p<0.05).
M Stacy et al. Mov Disord In Press.
Stacy et al., 2004

35. Results of the wearing-off study%
Clinician assessment 85
29.4
UPDRS 36
127
43.9
Patient Questionnaire
165
57.1*
The Patient Questionnaire was more sensitive at identifying wearing-off than a clinicians assessment
Overall, wearing-off was identified in 62.6% of patients by one or more of the measures used in the study
Of those patients on levodopa therapy, 65.2% experienced wearing-off
Interestingly, it was found that the patient questionnaire was more sensitive at identifying wearing-off than the clinicians evaluation (as assessed by the Clinical Assessment Question) with 57.1% of patients identified as having wearing-off by the patient questionnaire compared with 29.4% of patients identified by the Clinical Assessment Question and 43.9% by question 36 of the UPDRS.
The length of levodopa therapy correlated with the occurrence of wearing-off, with patients with wearing-off having received levodopa for an average of 9.6 months longer than their counterparts who were symptom-free (2.24 vs 1.44 years, p<0.05).
The results of this study suggest that early identification and treatment of predictable wearing off may be advantageous to the long term care of PD patients and a patient-driven clinical assessment tool for symptoms of wearing-off may aid clinicians in treating patients.
This data is represented in the form of a Venn diagram on the next slide
M Stacy et al. Mov Disord In Press.
n=289 total patients
* p<0.05
The Patient Questionnaire was superior in identifying wearing-off
Stacy et al., 2004

36. Patient Questionnaire versus Clinician Assessment
The patient questionnaire was more sensitive at identifying wearing-off than a
clinicians assessment
This slide shows the proportion of patients included in the wearing-off study that were identified as having wearing-off using the Patient Questionnaire, or the Clinical Assessment Question, or both in a typical Venn diagram format. This diagram reflects the data from the previous slide.
Overall, a total of 165 patients (n=69 + n=96) were identified as having wearing-off by the patient questionnaire compared with 85 patients (n=69 + n=16) identified as having wearing-off by the Clinical Assessment Question.
33.2% (n=96) patients were identified as having wearing-off by only the patient questionnaire
5.5% (n=16) patients were identified as having wearing-off by only the Clinical Assessment Question
23.9% (n=69) patients were identified as having wearing-off by both the patient questionnaire and Clinical Assessment Question
This indicates that the specifically designed structured patient questionnaire was more sensitive at identifying wearing-off than the clinicians evaluation (as assessed by the Clinical Assessment Question).
Further details
Overall, wearing-off was identified in 62.6% of patients (181 of 289) by one or more of the three measures used in the study.
Of those patients on levodopa therapy, 65.2% had wearing-off.
The length of levodopa therapy correlated with the occurrence of wearing-off, with patients with wearing-off having received levodopa for an average of 9.6 months longer than their counterparts who were symptom-free (2.24 vs 1.44 years, p<0.05).
M Stacy et al. Mov Disord In Press.
The Patient Questionnaire was more sensitive at identifying wearing-off than the Clinician Assessment (57.1 % vs 29.4%, respectively)
Stacy et al., 2004

37. Patient Questionnaire versus UPDRS 36
UPDRS Q36. Are “off” periods predictable?
The Patient Questionnaire was more sensitive at identifying wearing-off than UPDRS
question 36 (57.1 % vs 43.9%, respectively)
Overall, a total of 165 patients (n=75 + n=90) were identified as having wearing-off by the patient questionnaire compared with 127 patients (n=90 + n=37) identified as having wearing-off by UPDRS question 36.
26.0% (n=75) patients were identified as having wearing-off by only the patient questionnaire.
12.8% (n=37) patients were identified as having wearing-off by UPDRS question 36.
31.1% (n=90) patients were identified as having wearing-off by both the patient questionnaire and UPDRS question 36.
This indicates that the specifically designed structured patient questionnaire identified more patients with wearing-off than UPDRS question 36.
M Stacy et al. Mov Disord In Press.
Novartis / Orion Pharma Data on File
The Patient Questionnaire was more sensitive at identifying wearing-off than UPDRS question 36 (57.1 % vs 43.9%, respectively)
Stacy et al., 2004

38. The wearing-off study: Summary
With the aid of a questionnaire patients identified symptoms of wearing off more frequently than movement disorder specialists.
Wearing-off was not always noted by clinician, even though the UPDRS question 36 suggested this symptom was present.
Questions regarding re-emergence of non-motor symptoms may contribute to the identification of wearing-off.
M Stacy et al. Mov Disord In Press.
Stacy et al., 2004

39. The wearing-off study Professor Mark Stacy
“I don't believe anybody in the group was surprised that a patient questionnaire would pick up more symptoms and more frequent wearing-off symptoms than a programmed physician interview. I was personally surprised that it was such a large difference and I think it illustrates that physicians are programmed to think about other things during a Parkinson's interview while patients may be more interested in those specific symptoms on a card.”
Stacy, 2004
Professor Mark Stacy

40. The wearing-off study
Professor Mark Stacy

41. The wearing-off Patient Questionnaire Card

42. Development of the Patient Questionnaire Card
It was determined by the working group that:
A Patient Questionnaire Card of 32 symptoms would not be suitable for general use and that the symptom list should be shortened.
This procedure should also include reduction of any redundancies in the list of 32 symptoms included in the prototype.
For the purposes of developing the questionnaire into the final
Patient Questionnaire Card, the primary analyses were:
Ranked identification of the types of wearing-off symptoms included in the prototype Patient Questionnaire.
Identification of the most troublesome wearing-off symptoms by subject survey.
It was pre-determined by the panel that a Patient Card of 32 symptoms would not be suitable for general use, and that the symptom list should be shortened on the basis of the results of the evaluation of the prototype patient questionnaire.
It was agreed that this procedure should also include reduction of any redundancies in the list of 32 symptoms included in the prototype. Thus, for the purposes of developing the questionnaire into the final Patient Card, the primary analyses were:
Frequency of subjects with ‘wearing-off’.
Ranked identification of the types of wearing-off symptoms included in the Patient Questionnaire.
Identification of the most troublesome wearing-off symptoms by subject survey.
M Stacy et al. Mov Dis In Press.
Novartis / Orion Pharma Data on File.

43. Development of the Patient Questionnaire Card
Prototype Patient Questionnaire Card data merged on a patient by patient basis with data from the wearing-off study database.
The relationship between questionnaire-identified wearing-off and individual symptoms explored using discriminate analysis and a stepwise approach to find which were the best predictors.
Multiple linear regression analysis undertaken to evaluate which symptoms contributed most to the perception of troublesomeness.
Data on File
Factor analysis used to identify the underlying dimensions within question one of the Patient Questionnaire Card (presence of symptoms).

44. 16 of the 32 questions identified 100% of patients with wearing-off using the prototype patient questionnaire
Tremor
Slowness in early morning
Anxiety
Slowness during night
Mood changes
Weakness
Problems with balance
Slowness of movement
Reduced dexterity
Numbness
Stiffness in the afternoon
Stiffness in the morning
Cloudy mind / dullness thinking
Abdominal discomfort
Slowness, muscle cramping
Difficulty getting out of the chair
1st 3 explain 75.2%
+ next 3 explain 78.7%
+ next 3 explain 93.3%
16 symptoms were required to identify 100% of patients with wearing-off using the patient
questionnaire
Using the Patient Questionnaire, 16 (out of the 32) symptoms were required to identify 100% of wearing-off patients.
Using just the three symptoms of tremor, slowness in early morning, and anxiety, 75% of wearing-off patients could be identified.
However, an additional 13 symptoms were necessary in order to identify all patients with symptoms of wearing-off.
Again highlighting the importance of NMF, five (out of the 16) symptoms were non-motor: anxiety, mood changes, numbness, cloudy mind/dullness of thinking and abdominal discomfort.
Further details
Overall, 165 patients (57.1%) were identified as experiencing wearing-off by the prototype patient questionnaire.
The most common wearing-off symptom reported using the questionnaire was tremor and the most common non-motor symptom was tiredness.
The mean number of wearing-off symptoms reported by the subjects was 6.25 (SD5.44). 18 patients reported only one symptom, while six patients reported at least 20 of the 32 symptoms listed.
When the subjects with wearing-off were queried regarding the difficulties associated with wearing-off symptoms, 37% of subjects indicated that the symptoms were very troublesome and 55.2% slightly troublesome.
M Stacy et al. Movement Disorders In Press.
+ next 3 explain 97.5%
+ next 4 explain 100%

45. Patient Questionnaire Card Q2: Most troublesome symptoms
Total % patients
Tremor
Problems with balance
Reduced dexterity
26.7
26.1
25.5
Difficulty in speech
General stiffness
Tiredness
16.4
15.2
Slowness
Slowness of movement
Slowness of thinking
12.7
12.1
Difficulty getting out of chair
Weakness
Pain
10.3
8.5
Muscle cramping
Cloudy Mind
All others
7.9
<5
Symptoms found to be most troublesome
Analysis of troublesome symptoms, found that in addition to the 12 symptoms identified as predictive symptoms, difficulty in speech and pain were also significant contributors.
In addition, regression analysis was performed to identify whether any other symptoms are correlated with being troublesome or wishing to change treatment. This further analysis identified an additional four symptoms for inclusion into the final Patient Card: experience sweating, experience hot and cold, experience panic attacks and aching.
Novartis / Orion Pharma Data on File.
n=165

46. 19 symptoms included in the consolidated Patient Questionnaire Card
16 symptoms were required to capture all subjects with wearing-off. These included 2 definitions of stiffness and 3 of slowness:
Simplified into general stiffness and slowness of movement.
Analysis of troublesome symptoms, identified:
Difficulty in speech.
Pain.
Regression analysis of other symptoms correlated with being troublesome or wishing to change treatment identified:
Sweating.
Experience hot and cold.
Experience panic attacks.
Aching.
19 symptoms included in the final Patient Questionnaire Card
It was pre-determined by the panel that a Patient Questionnaire Card of 32 symptoms would not be suitable for general use, and that the symptom list should be shortened on the basis of the results of the evaluation of the prototype patient questionnaire.
It was agreed that this procedure should also include reduction of any redundancies in the list of 32 symptoms included in the prototype. Thus, for the purposes of developing the questionnaire into the final Patient Card, the primary analyses were:
Frequency of subjects with wearing-off.
Ranked identification of the types of wearing-off symptoms included in the Patient Questionnaire Card.
Identification of the most troublesome wearing-off symptoms by subject survey.
19 of the 32 symptoms were found to be statistically relevant for inclusion into the final Patient Questionnaire Card.
Predictive symptoms of wearing-off
16 (out of the 32) symptoms were required to capture all subjects reporting wearing-off.
These included three definitions of stiffness (general stiffness, stiffness in the morning, stiffness in the afternoon) and three definitions of slowness (slowness of movement, slowness in the early morning and slowness in the night) which were subsequently simplified into slowness of movement and general stiffness, respectively.
Thus 12 of the 16 symptoms required to capture 100% of patients in this population were included in the final Patient Questionnaire Card.
Symptoms found to be most troublesome
Analysis of troublesome symptoms, found that in addition to the 12 symptoms identified above as predictive symptoms, difficulty in speech and pain were also significant contributors.
In addition, regression analysis was performed to identify whether any other symptoms were correlated with troublesomeness or the wish to change treatment. This further analysis identified an additional four symptoms for inclusion into the final Patient Card: experience sweating, experience hot and cold, experience panic attacks and aching.
M Stacy et al. Mov Disord In Press.
Novartis / Orion Pharma Data on File.

47. The consolidated Wearing-off Patient Questionnaire Card
The results of the wearing-off study suggest that the diagnosis of wearing-off by a physician can be facilitated by the use of a targeted questionnaire that addresses the symptoms most sensitive in identifying wearing-off.
By editing the questionnaire to include only the essential elements it is hoped that any risk of patient fatigue will be minimized and that the use of this tool will increase the thoroughness of the clinician’s interview without extending the length of time in which the visit takes place.
Furthermore, the streamlined questionnaire should focus patient-doctor discussions, allowing the physician to make an informed assessment more efficiently.
When viewed alongside the clinician assessment, the patient questionnaire card may prompt treatment modification for PD patients identified as experiencing wearing-off, which will enable the patient to maintain optimal symptom control and improve function throughout the day.
M Stacy. Mov Disord 18(9):1094 .

48. Adapted Patient Questionnaire Cards
The patient questionnaire cards have been adapted and translated for use in different countries

49. Patient Questionnaire Card
“The role of the Patient Questionnaire, the card that we have developed, I think will vary between one clinic to the other. But in general, for a busy clinician who does not have time to explore every non-motor and motor symptom that can be associated with wearing-off, this patient card is going to facilitate interaction. So what is going to happen is patients are going to fill the card, come to you with some things already checked out and then the Doctor is going to go ahead and address those questions and more precisely identify the relation of those symptoms to the individual levodopa dose. So I think it is going to facilitate a dialogue, it is going to be a starting point, it is not an end in itself, so it is going to be a starting point and I think it is going to be very useful in most clinician’s offices.”
Professor Kapil Sethi

50. Patient Questionnaire Card
Professor Kapil Sethi

51. Management of wearing-off

52. Identification of wearing-off
“Wearing-off occurs fairly early in the illness and if a physician and patient have a chance to recognize and treat that symptom very early it helps in a long-term doctor-patient bond.”
“We don’t know from a scientific or a clinically scientific standpoint, if we identify wearing-off and prevent it now – will we have a patient do better in the long run. But I do believe it will make patients quality-of-life better when they have early symptoms of Parkinson’s disease and they still are doing a lot of things that are in the normal lifestyle.”
Professor Mark Stacy

53. Identification of wearing-off
Professor Mark Stacy

54. Development of complications related to dopaminergic therapy
Advancing PD
Progressive degeneration of dopamine neurons
Reduction in the capacity of the striatum to store dopamine
Fluctuations in plasma levodopa levels due to the drug’s short half-life
Development of complications related to dopaminergic therapy
In early PD, the capacity of the brain to store dopamine (converted from levodopa) for release when levels are low permits a relatively smooth release of dopamine in the brain, and a constant clinical effect.
With disease progression, the striatum has fewer dopaminergic neurons that can take up levodopa and store it as dopamine – in these circumstances the brain is said to have lost its ‘buffering’ capacity.
With the loss of striatal buffering capacity, the response to levodopa becomes more directly dependent on the manner of levodopa delivery to the brain. Even from the beginning of treatment, the short half-life of levodopa results in rapid changes in the levels of the drug in the plasma (peaks and troughs).
Because the short-duration response (SDR) to levodopa now predominates (see slide titled “Wearing-off: changes in levodopa response”), fluctuations in levodopa plasma levels translate into the development of fluctuations in symptom control, such as wearing-off and on–off fluctuations.
Chase. Neurology 1998; 50(suppl 5): S17–S25.
Olanow & Obeso. Ann Neurol 2000; 47 (suppl 1): S167–S78.
Nutt. Ann Neurol 1987; 22: 535–40.
Nutt et al. Ann Neurol 1996; 39: 561–73.
Wearing-off
Dyskinesia

55. Pulsatile dopaminergic receptor activation
Pulsatile stimulation contributes to the development of complications related to dopaminergic therapy.
Pulsatile stimulation of brain dopamine receptors results from:
Loss of striatal dopamine terminals.
The use of dopaminergic agents with short half-lives.
Levodopa has a relatively short half-life (60–90 min).
The therapeutic hypothesis:
Strategies that provide levodopa to the brain in a less pulsatile and ‘more continuous’ manner may reduce the risk of motor complications
Pulsatile dopaminergic receptor activation
There is a wealth of evidence indicating that motor complications associated with levodopa therapy are related, at least in part, to the short half-life of the drug and its potential to induce pulsatile stimulation of dopamine receptors.
While nothing can currently be done to modify disease progression, it is possible to extend the half-life of dopaminergic agents.
It is now believed that dopaminergic therapies that deliver more continuous dopaminergic stimulation provide a way of avoiding the oscillations in striatal dopaminergic delivery, thereby reducing the risk of motor complications.
It therefore follows that an optimized oral formulation of levodopa that provides a less pulsatile and more constant stimulation of dopamine receptors will offer the symptomatic benefits of the drug with a reduced risk of motor complications.
Olanow et al. Neurology 2001; 56: S1–S86.
Olanow and Obeso. Ann Neurol 2000; 47 (suppl 1): S167–S78.

56. Limitations of traditional strategies to treat wearing-off
Increase dosing frequency
Increase dose
Decrease interdose interval
Controlled-release preparations
Higher peak
concentrations
May work in earlier stages
Unpredictable drug absorption
Peak-dose dyskinesias
Limited utility and complicated dosing schedule beyond 4 to 5 doses/day
Delayed ‘On’ or occasional lack of ‘On’ response with advancing disease
Traditional strategies to improve levodopa therapy
A number of strategies can be employed to try to improve the delivery of oral levodopa.
A traditional approach is to manipulate the levodopa regimen, either by increasing the size of the levodopa dose, or by titrating the levodopa regimen to provide smaller, more frequent levodopa doses (fractionating).
Continually raising individual levodopa doses often has limitations, including a higher incidence of dyskinesia without marked prolongation of the benefit of levodopa.
Repeated doses of levodopa administered as frequently as every hour were not able to avoid low plasma trough levels.
A further strategy is the use of sustained release, or controlled release (CR), levodopa preparations. These can play an important role in tailoring to individual treatment needs. However, they have not been associated with a reduction in motor complications, as was first hoped, and have sometimes resulted in delayed ‘on’ due to erratic absorption and a need for higher levodopa doses because of reduced bioavailability.
Indeed, studies with CR levodopa preparations have shown conflicting results; some reporting a significant clinical benefit over standard preparations, others reporting erratic absorption and no additional therapeutic benefit.
Olanow et al. Neurology 2001; 56: S1–S86.
Stocchi and Olanow. Neurology 2004; 62 (Suppl 1): S56–S63.
Koller et al. Neurology 1999; 53: 1012–1019.
LeWitt and Nyholm. Neurology 2004; 62 (Suppl 1): S9–S16.
Variable/Short-term Control

57. Adjunct dopamine agonist therapy does not address the underlying problem of levodopa pulsatility
In a pharmacokinetic study of 10 patients receiving levodopa and adjunct bromocriptine:
Levodopa
Dose
Regardless of the effect of concomitant bromocriptine medication, fluctuations in motor performance are related only to levodopa plasma concentration.
“It seems like the synergistic stabilizing effects of a combination of levodopa with dopamine receptor agonists are less clinically important than previously suggested.”
Addition of DAs may not avoid motor fluctuations
Adjunct therapies with other modes of action than levodopa are sometimes used to address the symptomatic challenges of wearing-off, however, these do not necessarily address the underlying problem of levodopa pulsatiity.
In this study the pharmacokinetics and pharmacodynamics of levodopa were evaluated at a high-resolution level in a heterogeneous group of 10 patients with idiopathic PD during their normal daily activity.
A physician and a nurse spent 10 hours with each patient from the first morning dose of levodopa during daily activities at home and at work. Plasma samples were obtained every 20 minutes for analysis of levodopa and 3-O-methyldopa by high-performance liquid chromatography. To assess clinical response, mobility was rated on every test occasion by patients and by investigators.
The fluctuations of the levodopa concentration in plasma had a clear effect on the clinical parameters assessed, even during early disease stages.
Importantly, concomitant medication did not affect motor performance because the variations were related to changes in the plasma concentrations of levodopa.
From these observations, the authors concluded “it seems like the synergistic stabilizing effects of a combination of levodopa with dopamine receptor agonists are less clinically important than previously suggested”.
Nyholm et al. Clinical Neuropharmacol 2002; 25(2): 89–96.
Nyholm et al., 2002

58. Optimizing levodopa pharmacokinetics
When administered alone, levodopa is rapidly decarboxylated to dopamine in the peripheral circulation and only 1% passes into the brain where it is required.
By inhibiting the peripheral decarboxylation of levodopa, a DDCI such as carbidopa prolongs the plasma half-life of levodopa from 50 minutes to 1.5 hours, without increasing the time to reach maximum plasma levodopa concentration (tmax).
However, even with this inhibition still only about 10% of a given levodopa dose enters the brain.
By inhibiting the metabolism of levodopa to 3-methyldopa (3-OMD), co-administration of levodopa and a DDCI with the COMT inhibitor entacapone has been shown to:
Prolong levodopa’s elimination half-life in PD patients from 1.3 to 2.4 hours.
Increase levodopa plasma bioavailability (area under the time–concentration curve; AUC) between 25–50%.
Lead to a smoother delivery of levodopa to the brain.
At therapeutic doses of 200 mg, entacapone does not have central affects, acting only in the periphery to reduce COMT-activity by about 50%.
Gordin et al. Adv Neurol 2003; 91: 237–50.
Rx List. Accessed on 11/10/04.
Dual inhibition leads to increased access of levodopa to the brain
Gordin et al. 2003

59. Optimizing levodopa therapy: Combining levodopa with entacapone
CDS with levodopa: Combining oral levodopa with entacapone
This slide shows a patient receiving levodopa 100 mg five times a day (or every three hours).
The blue curve indicates the levodopa plasma profile throughout the course of the day, before entacapone is added.
When entacapone is added to the same dose of levodopa (as depicted by the green line), the plasma profile improves (the AUC increases) and becomes more stable, especially important is the avoidance of low trough levels.
These data therefore indicate that a more constant levodopa plasma profile can be obtained with levodopa combined with a COMT inhibitor (entacapone), but not with levodopa alone.
Strategies to improve levodopa delivery
Effect of entacapone on levodopa profile
Adding the COMT inhibitor entacapone to traditional treatment with levodopa/DDCI prolongs levodopa half-life and increases its bioavailability (AUC) without significantly affecting the maximum plasma concentration, or the time to peak plasma concentration.
The improvements in levodopa bioavailability afforded by the dual inhibition of DDC and COMT directly translate into improvements in clinical efficacy.
With advanced disease, the therapeutic response to levodopa closely parallels levodopa plasma levels.
Olanow et al. Neurology 2001; 56: S1–S86.
Ruottinen & Rinne. J Neurol Neurosurg Psychiatry 1996; 60: 36–40.
Poewe. Neurology 2004; 62 (Suppl 1): S31–8.
Stocchi et al. Neurol Sci 2003; 24: 217–8.
Stocchi et al. 2003

60. Optimizing levodopa therapy
“So, bearing in mind that many patients with wearing-off already take dopamine agonists in combination with levodopa or a dopamine agonist is usually added as first-line treatment to control wearing-off effect, these patients, despite their taking levodopa and a dopamine agonist, they actually have a wearing-off effect. So now we have to do something different.
The next step would be either to change the levodopa timing so increasing the number of levodopa dose, increase the single levodopa dose (it means if a patient is taking 100 mg it goes up to 150 mg and keeps the same interval) or try to extend the levodopa half-life and make a better plasma profile. So these are the most used strategies. But I personally believe that increasing the single levodopa dose is not a good strategy because it induces a high peak with a very profound trough immediately after and makes the plasma profile of the patient very fluctuating, and so immediately after the wearing-off reappears and the dyskinesias get worse.
Giving levodopa more frequently during the day might be a strategy which can lead to some success. But unfortunately we demonstrate this kind of strategy, despite it being successful at the moment in controlling the wearing-off effect, it still produces a very fluctuating plasma profile and eventually this patient ends up with on-off and terrible dyskinesias.
So today the best way to go is to probably combine levodopa with a COMT inhibitor which may provide more continuous and more stable plasma profile, increase the levodopa half-life and consequently improve wearing-off effect, but also provide a patient with a more stable and more continuous stimulation, which may also improve dyskinesia in the long run”.
Professor Fabrizio Stocchi

61. Optimizing levodopa therapy
Professor Fabrizio Stocchi

62. New perspectives

63. The wearing-off card – Facilitating a team approach to the treatment of wearing-off
“ In my opinion, a team approach to Parkinson’s disease becomes more and more important as symptoms progress, and so, early on in Parkinson’s disease it is a highly concentrated visit and conversation between a patient and a physician. As we move further and further in the disease, it becomes more important for a caregiver to become involved in the discussion and, at that point, it really does become important for physical therapy, occupational therapy, home-evaluations, to have an increasingly prominent role. In terms of the wearing-off card, I think the wearing-off card will allow physicians and patients to maintain a doctor-patient interaction for a longer period of time.”
Professor Mark Stacy

64. The wearing-off card – Facilitating a team approach to the treatment of wearing-off
Development of a wearing-off Patient Questionnaire: The wearing-off study
Aim
Given the variability in the reported frequency of both motor and non-motor fluctuations, it is clear that there are deficits in the identification of wearing-off.
Consequently, there is a risk that wearing-off symptoms in patients who have been on levodopa therapy for <5 years may go unrecognized by clinicians during routine checks.
As a result of this, patients with wearing-off symptoms may not be receiving maximal benefit from their therapy.
The Wearing-off Study
The wearing-off study was therefore undertaken with the objective of developing a tool to enable neurologists and other clinicians to work with patients to rapidly and effectively identify wearing-off in their normal clinical practice.
It is well known that structured questioning leads to a better identification of potential issues; thus it was suggested that the sensitivity of detecting the signs and symptoms of wearing-off would be enhanced by tools such as a patient questionnaire that specifically addresses the occurrence of both motor and non-motor fluctuations.
To test this hypothesis, the wearing-off study was designed to prospectively compare the frequency of wearing-off recognized by a Movement Disorders Specialist to that determined by a specifically designed structured Patient Questionnaire.
M Stacy et al. Mov Disord In Press.
Professor Mark Stacy

65. Increasing awareness and improving diagnosis of wearing-off
A number of resources are currently available to increase the diagnosis wearing-off including the patient questionnaire card and the parkinsonopoly resource.

66. The management of wearing-off: Role of COMT inhibition
“We have a variety of ways we manage wearing-off. We increase the dose of levodopa, we fractionate it, but I think sooner or later you run into a problem because the frequency goes up so high that the patients are a slave to their levodopa and they live this rollercoaster ride every day. And I think at some point you have to think about alternate strategies.
The currently available strategies like Sinemet CR are ineffective because CR has a very unpredictable pharmacokinetic pattern on repeat doses in between patients and so on and so forth. The dopamine agonists actually are a viable option, but in my experience a lot of my patients are already on a dopamine agonist when they are given levodopa-carbidopa and therefore I think in many cases it is advisable to add a COMT inhibitor.
Professor Kapil Sethi

67. The management of wearing-off: Role of COMT inhibition
Professor Kapil Sethi