Transcript Augmentation Clinical Presentation Biological Basis

RLS augmentation during long
term treatment.
Richard P Allen, PhD, DABSM
Johns Hopkins Univ.
What do we know about
augmentation
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

What is augmentation
 Biological/theoretical considerations
 Clinical identification - criteria
Why controversy
 Drug differences
 Dose considerations
 Time course: data needed over 5 - 10 years
 SignificanceWhy important
 Severe discomfort
 Limits dopamine treatment
Actions
 Limit use of offending Rx
 Find Treatments to reduce or avoid augmentation
Discovery of dopamine treatment for RLS
Akpinar S.
Treatment of restless legs
syndrome with levodopa
plus benserazide.
Arch Neurol 1982, 39:739.
Also Montplaisir
Clin Neuropharmacol 1986, 9:456
Low dose dopamine (Sinemet)
more effective treatment than
moderate dose opioid (propoxyphene)
for treatment of PLMS and RLS
Allen, et al, 1992
Recognition of augmentation
with longer term treatment
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Levodopa dramatic relief to severely affected RLS patients
seemed 100% effective in all RLS1986 - 1990: JHU using levodopa observed ‘time-shift’ in RLS
symptoms to earlier in the day
1990:
2-year follow up study reported no problems with
levodopa treatment of RLS for 26 of 30 patients
(von Scheele C & Kempi V, Arch Neurol 47:1223-4, 1990)
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1989-1995: JHU observed dramatic ‘augmentation’ cases
1996:
Reported augmentation for about 80% of all RLS
cases and offered 1st definition of augmentation
(Allen R & Earley C, Sleep 19:205-13, 1996)

2003:
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2006:
NIH consensus workshop produced an
operational definition of augmentation
Munich consensus conference
Improved dx criteria
Augmentation Concept
Biological definition

Drug treatment made a major aspect of
the RLS disease process worse.
 Not
a result of change in metabolism of
treatment medication
 Not treatment medication failing to reduce
RLS symptoms
 The
Disorder is worse NOT
the Rx less effective
Augmentation:
RLS is worse with Rx treatment



Disorder worse - requires
 All RLS symptoms become worse
 Augmentation symptom development follows the
natural history of symptom progression
Rx caused, not natural progression of RLS - requires
 Rate of progression of Sx faster than occurs
naturally
 RLS symptoms less after withdrawal of Rx
Rx caused, not change in life style, medical status or
non-RLS Rx
 Occurs under conditions controlled for activity and
alertness
 In theory would be revealed by repeated SIT tests
Clinical Features of Augmentation
Compared to status just before treatment
1. Earlier onset of symptoms
(AM ‘protected period’ less involved)
2. Shorter rest time to provoke symptoms
3. Increased intensity of symptoms
4. Involvement of more of the body (Usually
arms but occasionally trunk)
5. Time course: treatment benefit slower and
shorter
6. Degree of severity and stability:
severe vs mild, continuing vs stable
One week in the life of an RLS
patient
% of Augmentation by characteristics and % rebound
for 30 patients treated with carbidopa/levodopa
80.00%
70.00%
60.00%
50.00%
40.00%
30.00%
20.00%
10.00%
0.00%
Earlier onset
Increased
intensity
Quicker rest onset
Other limbs
All Augmentation
Characteristics
(Allen and Earley, Sleep, 1996)
AM rebound
NIH Consensus Workshop 2003
Operational definition of augmentation
Earlier onset (>= 2 hours)
Or two of the following
1. Intensity increase with increasing dose
2. Decreased intensity with decreasing dose
3. Shorter rest time to provoke symptoms than before Rx
4. RLS Sx occur in previously unaffected limbs or body parts
5. Shorter duration of Rx benefit than with initial treatment
6. PLMS or PLMW occur for the first time or are worse than
either before treatment or after initial treatment
ROC: agumentation vs hours of
symptom advance
Updated augmentation dx
Max-Planck 2007
Compared to before treatment:
Either A or B:
A. Earlier onset of symtptoms with
1. Earlier by at least 4 hrs
or
2. Earlier onset of any duration with one of the following
(compared to before tx):
A. Shorter latency to symptoms when at rest
B. Expansion to other body parts
C. Greater intensity of symptoms
D. Shorter duration of relief from treatment
Clinical Relevance
I: Clinically significant augmentation
At least one of the following occurs:
Change in daily activities and/or behavior (e.g. the
patient stops riding in cars in the afternoon);
Negative impact on the patient’s quality of life (sleep,
mood, etc.);
Need to change the treatment dose or the patient needs
to take the dose earlier in the day (e.g., dividing the
dose);
Adjustments in concomitant medication are made to
compensate for augmented RLS symptoms (e.g., an
increased intake of analgesics or hypnotics to cover an
increase in symptom intensity);
Any other aspect as judged by the evaluator (should be
specified).
II: Not clinically significant augmentation
None of the above mentioned criteria (a-e) are met.
What do we know about
augmentation

What is augmentation
 Biological/theoretical considerations
 Clinical identification - criteria

Why controversy
 Drug differences
 Dose considerations
 Time course: data needed over 5 - 10 years
 Clinical significance (why important)

Why important
 Severe discomfort
 Limits dopamine treatment
 Actions
 Limit use of offending Rx

Find Treatments to reduce or avoid augmentation
Percentage of Patients with RLS Augmentation
for each medication by RLS severity.
100%
90%
carbidopa/levodopa
pergolide
80%
70%
60%
50%
40%
30%
20%
10%
0%
All
Severe
MildModerate
Medication type
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All dopaminergic medications
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50 - 80% rate
9 - 35% rate
Tramadol
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Levodopa
Dopamine agonsits
Limited clinical series
45% rate
Not reported for other RLS medications
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Gabapentin
Oxycodone, hydrocodone
Methadone
Rates and presentation by increasing Half-life
1. Earlier time of onset of symptoms
2. Reduced latency to symptoms at rest
3. Increased severity/decreased therapeutic effect at stable dose
4. Expansion of symptoms to upper limbs
L-DOPA
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%
Becker, 1993
Early, 1996
Trenkwalder, 2003
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Garcia-Boreguero, 2005
PRAMIPEXOLE:
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Montplaisir, 2000
Ferini-Strambi, 2001
Silber, 2003
Winkelmann, 2004
36.2
69
52%
1
1-4, being 1 the principal
1, 3
49-78,4%
NIH, ASRS
0
8,8
33
56
1
not specified
1 or 3
1, 3, 4
27
27,3
15
0
1 or 3
1
1-4, being 1 the principal
(1, 3) not specif.
3
9
1-4
1-4
PERGOLIDE:
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Silber, 1997
Stiasny, 2001
Early, 1996
Trenkwalder, 2004
CABERGOLINE:
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Benes, 2004
Stiasny, 2004
% Augmentation for 30 RLS patients treated with
carbidopa/levodopa by RLS severity and dose
Carbidopa/levodopa dose
100.00%
90.00%
80.00%
70.00%
60.00%
50.00%
40.00%
30.00%
20.00%
10.00%
0.00%
low <50/200
High ≥50/200
Dose of levodopa and Augmentation
with <= 6 months of treatment
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100 mg
200 mg
300 mg
400 mg
500 mg
n% (of 49)
0%
14.3%
50%
28.6% AUG
(% )
7.1%
Aver. dose: 329.81 +
105mg
50
45
40
35
30
25
20
15
10
5
0
100 200 300 400 500
mg
85.7% of patients with AUG received dosages ≥ 300 mg/day!
The only dose free of augmentation was 100 mg
Development of Augmentation Over 1 - 3
years (but data limited beyond 2 years)
100
90
80
70
60
50
40
30
20
10
50
46
42
38
34
30
26
22
18
14
10
6
0
2
Pts without
augmentation
(%)
Months
(Silber et al., 2003)
What do we know about
augmentation

What is augmentation
 Biological/theoretical considerations
 Clinical identification - criteria
 Why controversy
 Drug differences
 Dose considerations
 Time course: data needed over 5 - 10 years
Clinical significance (why important)
Why important
 Severe discomfort
 Limits dopamine treatment



Actions
 Limit use of offending Rx

Find Treatments to reduce or avoid augmentation
Examples of severe augmentation
Mirapex 10-year survival curve
Percentage continuing on treatment
discontinuing treatment each year ( 5 - 10 year follow-up)
Mostly due to augmentation
Note from year 2 on 90 - 100%
discontinued Rx due to augmentation
Augmentation persists when dose
is increased to maintain efficacy.
What do we know about
augmentation

What is augmentation
 Biological/theoretical considerations
 Clinical identification - criteria
 Why controversy
 Drug differences
 Dose considerations
 Time course: data needed over 5 - 10 years
 Why important
 Severe discomfort
 Limits dopamine treatment

Actions
 Limit use of offending Rx
 Find Treatments to reduce or avoid augmentation
Minimize augmentation risk:
Limit use of offending Rx
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L-dopa - risk:benefit consideration
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Use only for intermittent treatment ( <2 days/week)
Increasing dose or the times covered by the dose
delays but does not prevent augmentation
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Very long term use of very long acting DA not known
Very long term consequences are unknown
BUT Appears always reversible with d/c Rx
Recovery after d/c Rx may take 4 or more days
some cases may take much longer (2 weeks+)
Treatments to
reduceAugmentation
Low dose dopamine agonist
 Longer acting dopamine agonist?
 Low serum ferritin may contribute

 Consider
oral or IV iron treatment ?
Treatments to
avoid augmentation

Alpha-2 delta Rx
 Gabapentin
 Gabapentin
 Pregabalin

pro-drug
Opioids and Morphine
 Short-acting
oxycodone, hydrocodone, propoxyphene codeine
 Long-acting
Methadone

Alternate dopaminergics ?
Future needs

Methods for clinical evaluation and early
detection of RLS augmentation
 Afternoon SIT test
 Electronic diary
 Structured clinical interview
 Severity assessment

Research on mechanisms of
augmentation
 Animal analogs - effects of chronic DA use
 Theoretical models that can be tested
PLW/hr on Afternoon SIT after placebo
for patients on dopaminergic Rx
225
200
Error Bars: ± 1 Standard Error(s)
Cell Mean
175
150
125
100
75
50
25
0
Diphenhydramine
Lorazepam
Cell
Condition
Normal at NIGHT
RLS not treated Night
(Michaud et al, Eur Neurol, 2002)
Placebo for DA RLS afternoon
(Allen et al, abstract SfN 2008)
Placebo
PLMW/hr mean ±sd
9.0 ± 21.7
53.3 ± 62.8
95.3 ± 88.5
ASRS validation study
Validity
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Internal consistency: Cronbach`s alpha: 0,506
Convergent validity: 0,23 (item 2) to 0,87 (item 1)
Criterion validity: 0,59
Discriminant validity: 0,04+0,6 vs. 2,1+1,1
Reliability
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
Inter-rater:
Test-retest:
0,906 + 0,05
0,734 + 0,09
When is the ASRS total score
clinically relevant?
Rate of patients (%)
L-dopa trial distribution of ASRS scores
50
40
30
20
10
0
0
>0-2
>2-4
>4-6
>6-8
>8-10
>10-12
>12-14 >14-16 >16-18
ASRS total s core
White bars: patients without augmentation,
black bars: patients with definite augmentation according to experts.
Range of the ASRS total score: 0 to 24
(Garcia-Borreguero et al Sleep med 2007)
Augmentation is under-recognized
Marvin has
4 limbs affected
Intense symptoms
All night - no relief
Marvin severe augmentation?
Maybe Marvin had too much
Dopamine treatment