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Wearing-off workshop resource kit
Wearing-off
1. Long-term management of PD: Development of
levodopa-associated complications
2. Introduction to wearing-off
3. Symptoms of wearing-off
4. The wearing-off study
5. The wearing-off Patient Questionnaire Card
6. Management of wearing-off
7. New perspectives
Long-term management of PD:
Development of levodopaassociated complications
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
Hoehn, 1992
Beneficial effect of levodopa on life expectancy
Rajput, 2001
Long-term challenges:
Changes in levodopa response
Obeso et al. 2000
Incidence of complications in
levodopa-treated patients at two years
60
% of patients
50
40
38%
30%
30
(n=150)
20
10
5%
0
Wearing-off
Dyskinesias
On-off effects
Wearing-off was the most commonly encountered
motor complication
PSG, 2000
Introduction to wearing-off
Typical pattern of wearing-off
Daily fluctuations in wearing-off
Impact of wearing-off
The PRELUDE survey
Objective: To understand perceptions of levodopa therapy among
clinicians and patients
Physician survey
Patient survey
328 Neurologists
74 Movement Disorder
Specialists
300 patients with PD treated
with carbidopa/levodopa
54 PCPs
All physicians surveyed
treated patients with PD
Sampled through the National
Parkinson’s Foundation
PRELUDE survey: Importance of wearing-off
for patients and healthcare professionals
What is the biggest challenge with levodopa therapy?
Managing
dyskinesia #1 for
Movement
Disorder
Specialists
Managing
wearing-off #1
for PD patients
and PCPs
Dyskinesia
Within two years 12% of neurologists recognize
wearing-off but 54% modify the levodopa regimen
The large discrepancy in the numbers (54% Vs 12%) highlights
the difficulty in identifying the first signs of wearing-off
Comtan Diagnostic survey, 2002
No universal definition of wearing-off
Study, year
Rajput et al. 2002
Definition and Incidence
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
The lack of a universal definition of wearing-off may be reflected
in its reported incidence in patients
PSG, 2000
Rajput et al., 2002
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.”
Stacy et al, 2004
“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.”
PinK working group
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.”
Symptoms of wearing-off
Wearing-off symptoms
Professor Fabrizio Stocchi
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
Motor fluctuations in wearing-off
• Return of parkinsonian symptoms
• Tremor
• Bradykinesia
• Soft voice
• Early morning stiffness
• Dystonia - often early morning
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
Marsden and Parkes, 1976
Riley and Lang, 1993
Hillen and Sage, 1996
Witjas et al, 2002
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
88
Hallucinations
49
25
Witjas et al. 2002
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
Rationale for the wearing-off study
•
Given the variability in the reported frequency of both motor and nonmotor 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.
The wearing-off study
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
Stacy et al., 2004
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.
Stacy et al., 2004
Inclusion and exclusion criteria
Inclusion
• 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.
Stacy et al., 2004
Prototype patient questionnaire
32 symptoms addressed on questionnaire:
•
Reduced dexterity
•
(e.g. reduced ability to write, tie shoe laces etc) •
Slowness during the night time
Restlessness
•
Tiredness
•
Problems with balance
•
Difficulty in getting out of the chair
•
Slowness of thinking
•
Muscle cramping
•
Bladder problems – problems passing urine
•
Cloudy mind of dullness in thinking
•
Early morning muscle cramps in the feet
•
Difficulty in speech
•
Pain
•
Stiffness in the early morning
•
Slowness
•
Stiffness in the afternoon
•
General stiffness
•
Anxiety
•
Panic attacks
•
Mood changes
•
Chest discomfort
•
Weakness
•
Abdominal discomfort
•
Stiffness in the night time
•
Sweating
•
Difficulty in swallowing
•
Tremor
•
Abnormal sensations such as:
•
Slowness in the early morning
•
Hot/Cold
•
Slowness of movement
•
Aching
•
Numbness
or legs
Stacy et al., 2004
Clinical Assessment Question
In your opinion, does this patient have one or
more of the following based on this visit:
a)
b)
c)
d)
e)
f)
g)
Loss of medication efficacy
Wearing off
Sleepiness
Dyskinesia
Psychiatric complications
Other dopaminergic side effects
Morning akinesia
Symptom
(n)
(%)
37
12.8
85
29.0
45
15.6
30
10.4
20
6.9
15
5.2
37
12.8
Stacy et al., 2004
Data on File
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 Principal Investigator reviews all survey data prior to entry into the
question database
Stacy et al., 2004
Outcome measures
• Primary outcome:
• 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..
Stacy et al., 2004
Baseline demographics (n=289)
Male/Female (%)
Age (years)
Levodopa therapy (%)
Duration of levodopa therapy (years)
Total UPDRS
Hoehn & Yahr
Stage 1
Stage 2
Stage 2.5
Stage 3
Stage 4
62/38
72.0  9.6 [4292]
87.5
1.96 1.53
36.3  17.9
7
77
82
84
14
Stacy et al., 2004
Results of the wearing-off study
n
%
85
29.4
UPDRS 36
127
43.9
Patient Questionnaire
165
57.1*
Clinician assessment
n=289 total patients
* p<0.05
The Patient Questionnaire was superior in identifying
wearing-off
Stacy et al., 2004
Patient Questionnaire versus Clinician
Assessment
The Patient Questionnaire was
more sensitive at identifying
wearing-off than the Clinician
Assessment (57.1 % vs 29.4%,
respectively)
Stacy et al., 2004
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)
Stacy et al., 2004
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.
Stacy et al., 2004
The wearing-off study
Professor Mark Stacy
The wearing-off Patient
Questionnaire Card
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.
Development of the
Patient Questionnaire Card
1.
Prototype Patient Questionnaire Card data merged on a patient by
patient basis with data from the wearing-off study database.
2.
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.
3.
Multiple linear regression analysis undertaken to evaluate which
symptoms contributed most to the perception of troublesomeness.
4.
Factor analysis used to identify the underlying dimensions within
question one of the Patient Questionnaire Card (presence of
symptoms).
16 of the 32 questions identified 100% of patients
with wearing-off using the prototype patient questionnaire
Tremor
Slowness in early morning
Anxiety
1st 3 explain 75.2%
Slowness during night
Mood changes
Weakness
+ next 3 explain 78.7%
Problems with balance
Slowness of movement
Reduced dexterity
+ next 3 explain 93.3%
Numbness
Stiffness in the afternoon
Stiffness in the morning
+ next 3 explain 97.5%
Cloudy mind / dullness thinking
Abdominal discomfort
Slowness, muscle cramping
Difficulty getting out of the chair
+ next 4 explain 100%
Patient Questionnaire Card Q2:
Most troublesome symptoms
Symptom
Total % patients
Tremor
26.7
Problems with balance
26.1
Reduced dexterity
25.5
Difficulty in speech
16.4
General stiffness
16.4
Tiredness
15.2
Slowness
15.2
Slowness of movement
12.7
Slowness of thinking
12.1
Difficulty getting out of chair
10.3
Weakness
8.5
Pain
8.5
Muscle cramping
8.5
Cloudy Mind
7.9
All others
<5
n=165
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.
The consolidated Wearing-off Patient
Questionnaire Card
Adapted Patient Questionnaire
Cards
Patient Questionnaire Card
Professor Kapil Sethi
Management of wearing-off
Identification of wearing-off
Professor Mark Stacy
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
Wearing-off
Dyskinesia
Pulsatile dopaminergic receptor activation
1. 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.
2. 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
Limitations of traditional strategies to
treat wearing-off
Increase dose
Decrease interdose interval
Controlled-release
preparations
Increase dosing frequency
Higher peak
concentrations
May work in earlier stages
Peak-dose
dyskinesias
Limited utility and
complicated dosing
schedule beyond 4 to 5
doses/day
Variable/Short-term Control
Unpredictable
drug absorption
Delayed ‘On’ or
occasional lack of
‘On’ response with
advancing disease
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.”
Nyholm et al., 2002
Optimizing levodopa pharmacokinetics
Dual inhibition leads to increased access of levodopa to
the brain
Gordin et al. 2003
Optimizing levodopa therapy:
Combining levodopa with entacapone
Stocchi et al. 2003
Optimizing levodopa therapy
Professor Fabrizio Stocchi
New perspectives
The wearing-off card – Facilitating a team
approach to the treatment of wearing-off
Professor Mark Stacy
Increasing awareness and improving
diagnosis of wearing-off
The management of wearing-off: Role of
COMT inhibition
Professor Kapil Sethi