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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.

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Presentation on theme: "Wearing-off workshop resource kit. Wearing-off 1.Long-term management of PD: Development of levodopa-associated complications 2.Introduction to wearing-off."— Presentation transcript:

1 Wearing-off workshop resource kit

2 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

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

4 Hoehn, 1992 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

5 Beneficial effect of levodopa on life expectancy Rajput, 2001

6 Long-term challenges: Changes in levodopa response Obeso et al. 2000

7 Dyskinesias Wearing-off On-off effects (n=150) PSG, 2000 Wearing-off was the most commonly encountered motor complication Incidence of complications in levodopa-treated patients at two years

8 Introduction to wearing-off

9 Typical pattern of wearing-off Daily fluctuations in wearing-off

10 Impact of wearing-off

11 Physician surveyPatient 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 Objective: To understand perceptions of levodopa therapy among clinicians and patients

12 PRELUDE survey: Importance of wearing-off for patients and healthcare professionals Managing dyskinesia #1 for Movement Disorder Specialists Managing wearing-off #1 for PD patients and PCPs Dyskinesia Wearing-off What is the biggest challenge with levodopa therapy?

13 Within two years 12% of neurologists recognize wearing-off but 54% modify the levodopa regimen Comtan Diagnostic survey, 2002 The large discrepancy in the numbers (54% Vs 12%) highlights the difficulty in identifying the first signs of wearing-off

14 Study, yearDefinition and Incidence Rajput et al 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 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 “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 “Wearing-off refers to the predictable emergence of one or more PD signs or symptoms before the next scheduled antiparkinsonian medication dosage.” For the physician:For the patient: Stacy et al, 2004

16 Consensus definition of wearing-off “A generally predictable recurrence of motor or non motor symptoms that precedes a scheduled dose and usually improves with antiparkinsonian medication.” In September 2004, a wearing-off working group meeting of leading international Movement Disorder Specialists arrived at a consensus definition.

17 Symptoms of wearing-off

18 Wearing-off symptoms “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

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 Marsden and Parkes, 1976 Riley and Lang, 1993 Hillen and Sage, 1996 Witjas et al, 2002

23 Non-motor fluctuations in wearing-off Non-motor fluctuationFrequency (%)Frequency during off state (%) Anxiety6688 Drenching sweats6459 Slowness of thinking5883 Fatigue5675 Akathisia5463 Irritability5288 Hallucinations4925 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 Witjas et al. 2002

24 150 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% US telephone survey 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.

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 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. Stacy et al., 2004

29 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

30 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 Prototype patient questionnaire 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 32 symptoms addressed on questionnaire: 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 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 Principal Investigator reviews all survey data prior to entry into the question database Stacy et al., 2004

33 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

34 Baseline demographics (n=289) Male/Female (%) 62/38 Age (years)72.0  9.6 [42  92] Levodopa therapy (%) 87.5 Duration of levodopa therapy (years)1.96  1.53 Total UPDRS 36.3  17.9 Hoehn & Yahr Stage 1 7 Stage 2 77 Stage Stage 3 84 Stage 4 14 Stacy et al., 2004

35 Results of the wearing-off study * p<0.05 n=289 total patients n% Clinician assessment UPDRS Patient Questionnaire * The Patient Questionnaire was superior in identifying wearing-off Stacy et al., 2004

36 The Patient Questionnaire was more sensitive at identifying wearing-off than the Clinician Assessment (57.1 % vs 29.4%, respectively) Patient Questionnaire versus Clinician Assessment Stacy et al., 2004

37 The Patient Questionnaire was more sensitive at identifying wearing-off than UPDRS question 36 (57.1 % vs 43.9%, respectively) Patient Questionnaire versus UPDRS 36 UPDRS Q36. Are “off” periods predictable? 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. Stacy et al., 2004

39 The wearing-off study “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.” 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.

43 Development of the Patient Questionnaire Card 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). 1.Prototype Patient Questionnaire Card data merged on a patient by patient basis with data from the wearing-off study database.

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% + next 3 explain 97.5% + next 4 explain 100%

45 Patient Questionnaire Card Q2: Most troublesome symptoms n=165 SymptomTotal % patients Tremor Problems with balance Reduced dexterity Difficulty in speech General stiffness Tiredness Slowness Slowness of movement Slowness of thinking Difficulty getting out of chair Weakness Pain Muscle cramping Cloudy Mind All others <5

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.

47 The consolidated Wearing-off Patient Questionnaire Card

48 Adapted Patient Questionnaire Cards

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 Reduction in the capacity of the striatum to store dopamine Fluctuations in plasma levodopa levels due to the drug’s short half-life Progressive degeneration of dopamine neurons Wearing-off Advancing PD Dyskinesia

55 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

56 Limitations of traditional strategies to treat wearing-off Increase dosing frequency Increase doseDecrease interdose intervalControlled-release preparations 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 Variable/Short-term Control Higher peak concentrations May work in earlier stages Unpredictable drug absorption

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.” Nyholm et al., 2002

58 Optimizing levodopa pharmacokinetics Dual inhibition leads to increased access of levodopa to the brain Gordin et al. 2003

59 Optimizing levodopa therapy: Combining levodopa with entacapone 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

65 Increasing awareness and improving diagnosis of wearing-off

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


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