Evidence-based review of current
Parkinson’s disease treatments
This educational material has been supported by Abbott
Evidence-based review of current Parkinson’s
disease treatments
Subcutaneous apomorphine infusion treatment
<<Insert speaker’s name and affiliation here>>
Learning objectives
At the end of this section you will:
• Be aware of the current evidence base for subcutaneous
apomorphine infusion in the treatment of advanced Parkinson’s
disease
• Know the clinical findings for subcutaneous apomorphine
infusion in the alleviation of motor complications
• Gain greater knowledge of the tolerability profile of
subcutaneous apomorphine infusion
Apomorphine
• Most potent dopamine agonist
• Low bioavailability  parenteral use
Clinical effect:
•
•
•
Extent: identical to levodopa
Onset: faster (5-20, max 60 min)
Duration: shorter ( 40 min)
Randomised controlled study:
•
•
‘Off’  34% = 2 hours (p=0.02)
Dyskinesias: Apo  35%, placebo 11%
Review:
•
‘Off ’  46%, ‘ON’ with dyskinesias: +33%
Dewey RB, et al. Arch Neurol 2001;58:1385-92. Deleu D, et al. Drugs Aging 2004;21:687-709.
Subcutaneous apomorphine infusion
•
Apomorphine is administered
subcutaneously into the fatty tissue of
the abdominal area, or alternatively
into the upper thighs and arms
•
Almost 100% of the drug is absorbed
into the blood stream
•
The apomorphine pump is about the
size of a mobile phone and may be
worn on a waistband of trousers or a
skirt or alternatively hidden under
clothes
Frankel JP, et al. J Neurol Neurosurg Psychiatry 1990;53:96-101.
European Parkinson’s Disease Association. Available at; http://epda.eu.com/medinfo/apomorphine (accessed 24 June 2010)
Subcutaneous apomorphine infusion:
Practical issues
• Patient selection and information
• Reimbursement issues
• Baseline assessments including blood tests, Coombs test
• Premedication: domperidone 60 mg/d for ≥ 3 days
• Hospital admission
• Initial flow rate 1 mg/h which is gradually increased, depending on
tolerability and efficacy
• Target dose:
– Mean doses: studies where monotherapy was aimed at 100 mg/d
– Add-on to oral treatment approximately 70 mg/d
• Concomitant reduction of oral medication, starting with dopamine
agonists, monamine oxidase inhibitors, amantadine, then levodopa
Subcutaneous apomorphine infusion:
Practical approach
• Instruction and training in pump handling and later supervision is
given to patients and carers
• Infusion is given ideally by the patients themselves or if necessary
carers
European Parkinson’s Disease Association. Available at: http.//epda.eu.com/medinfo/apomorphine (accessed 24 June 2010).
Subcutaneous apomorphine infusion:
Overview of clinical efficacy
Study
Difference in recordings within a motor state (%) before and after
subcutaneous apomorphine infusion treatment
Patients (N)
Time
(months)
Time in ‘off’ (%)
Time in ‘on’ with
dyskinesias (%)
Dyskinesia intensity
1
- 85
NR
- 45
7
11
2
- 67
NR
- 20
9
10
3
- 77
NR
NR
14
26
4
- 57
NR
- 40
10
12
5
- 59
NR
NR
22
36
6
- 58
NR
NR
7
3
7
- 50
-12
- 14
25
44
8
- 42
NR
NR
34
30
9
- 40
NR
NR
11
12
10
- 80
-61
NR
12
24
11
- 60
NR
- 48
12
24
12
- 38
NR
- 58
12
6
13
- 51
NR
+3
13
12
Apomorphine in Parkinson’s disease, 2nd edition. Ed. Odin P, Hagell P, and Shing M. 2008. Uni-Med Verlag.
Reproduced with kind permission of Per Odin
NR=not reported
Subcutaneous apomorphine infusion
Early literature:
•
Mean ‘off’ duration 65% 
Reduction in dyskinesias observed
in some studies:
•
Levodopa 1260  280 mg/d
Frankel JP, et al. J Neurol Neurosurg Psychiatry 1990;53:96-101. Hughes AJ, et al. Mov Disord 1993;8:165-70. Pietz K, et al. J Neurol Neurosurg
Psychiatry 1998;65:709-16. Poewe W, et al. Adv Neurol 1993;60:656-9. Wenning GK, et al. Adv Neurol 1999;80:545-8.
Subcutaneous apomorphine infusion
Monotherapy = apomorphine only during waking day except morning / night time
Study
Number
Follow-up
Monotherapy
Colzi
et al,
1998
19
12 m
19
‘On’-duration
‘Off’duration
Dyskinesias
71%
↓65% severity
↓85% duration
Manson
et al,
2002
63
36 m
45/63
↑ 52%
monotherapy
↓63% monotherapy
↑ 32%
polytherapy
↓32% polytherapy
Time to significant
reduction 4.6 m
Colzi A, et al. J Neurol Neurosurg Psychiatry 1998;64:573-76. Manson AJ, et al. Mov Disord 2002;17:1235-41.
Subcutaneous apomorphine infusion:
Short-term prospective analysis
•
Levodopa/apomorphine single dose
challenges before/after 6 months’
treatment, blinded raters
•
AIMS and Rush scores ↓ 36-44%;
correlation of improvement with oral
dose reduction
•
Daily ‘off’ time: ↓ 38% (=2.4 hours)
Katzenschlager R, et al. Mov Disord 2005;20:151-7.
Subcutaneous apomorphine infusion:
Long-term prospective analysis
• Apomorphine (N=12) versus DBS (N=13)
• Average duration on apomorphine = 30
months
• Comparable levodopa equivalent dose
reduction between treatments
• Daily ‘off’’ time:
– ↓ 49% (Apo)
– ↓ 91% (DBS)
• DBS only: - 80% and - 83% dyskinesia
duration and severity, respectively
UPDRS-3 ON (OFF) score*
• Up to 5 years’ follow-up
• DBS only: significantly worsened
neuropsychological function (NPI, verbal
fluency; p<0.05 versus baseline)
*Intention-to-treat analysis; apomorphine: two of 12 subjects reached 5-year follow-up; DBS: 12 of 13 subjects were followed up at 5
years; DBS = deep brain stimulation; NPI = neuropsychiatric inventory
Antonini A, et al. J Neurol 2011;258:579-585.
Long-term subcutaneous apomorphine
infusion therapy
•
Long-term retrospective observational study,
35 centres
4 years: 82/166 patients remained on pump.
Levodopa dose (mg/d): 1405 → 800 (p<0.0001)
‘Off’: 6.64 → 1.36 hours/d (p<0.0001) (- 80%)
Dyskinesia severity: - 31%
•
Open, uncontrolled
Dyskinesia reduction maintained over 5 years
•
Compared to medical treatment (patients’ choice):
Mean APO dose: 100 mg/d
‘Off’ reduction: 40%
Dyskinesia reduction (AIMS): - 37%
Copyright 2001. Reprinted with permission of Springer Verlag, Inc
Stocchi F, et al. Neurol Sci 2001;22:93-4. Di Rosa AE, et al. Neurol Sci 2003;24:174-5.Garcia-Ruiz PJ, et al. Mov Disord 2008;23:1130-6.
Effect of apomorphine on non-motor
symptoms in advanced Parkinson’s disease
Naidu Y,et al. Mov Disord 2009;24(Suppl1):S360.
Effect of apomorphine on non-motor
symptoms and quality of life
Naidu Y,et al. Mov Disord 2009;24(Suppl1):S360.
Apomorphine adverse events
Side effects*
Intermittent injection
(N=165)
Continuous infusion
(N=212)
Local cutaneous/SC reactions
• Nodules, itching, bruises, etc.
69
159
Neuropsychiatric
• Non-defined
• Sedation
• Hallucination
7
21
7
9
39
23
Systemic/other
• Nausea
• Orthostatic hypotension
• Eosinophilia
• Rhinorrhoea
• Vertigo/dizziness
• Yawning
25
6
2
6
6
9
12
15
9
2
3
0
*In addition:
- Haemolytic anaemia: frequency unknown, positive Coombs test in ≤ 12.5%: Regular blood tests required (Manson et al. 2002)
- Dopaminergic dysregulation syndrome and punding
‘Apomorphine in Parkinson’s disease’, 2nd edition. Ed. Odin P, Hagell P, and Shing M. 2008. Uni-Med Verlag,
Manson AJ, et al Mov Disord 2002;17:1236-41.
Subcutaneous apomorphine infusion:
Neuropsychiatric adverse events
Study
Design / follow-up
Results
Alegret et al, 2004*
(1 year)
• DBS, N=9
• Apomorphine,
N=7
• DBS waiting list
• Apomorphine: no change
• DBS: at 6 months, significantly worse on word fluency
and Stroop naming; at 1 year, partially reversible
De Gaspari et al,
2006* (1 year)
• DBS, N=13;
• Apomorphine,
N=12
• Patients’ choice
• ‘Off’ : both; dyskinesias: only DBS significantly , but:
levodopa  only by 29%
• MMSE: unchanged
• Only DBS: significantly worse apathy, anxiety,
depression, hypomania (NPI), verbal fluency
Di Rosa et al, 2003*
(1 year)
• Levodopa (oral),
• Apomorphine,
N=12
• Apomorphine: 100 mg/d; levodopa: 55% ; ‘off’, AIMS
significantly improved
• 1 year: significant improvement in Beck Depression scale
on APO only
Morgante et al,
2004*
(2 years)
• Rater-blinded,
patients’ choice
• Cognition (MMSE; Brief Psychiatric Rating Scale): same
*Comparative but not randomized studies; patients on DBS waiting list or patients’ choice
DBS = deep brain stimulation; MMSE = Mini Mental State Examination
Alegret M, et al. Mov Disord 2004;19:1463-9. De Gaspari D, et al. J Neurol Neurosurg Psychiatry 2006;77:450-3. Di Rosa AE, et al. Neurol Sci
2003;24:174-5. Morgante L, et al. Arch Gerontol Geriatr Suppl 2004;9:291-6.
Subcutaneous apomorphine infusion:
Neuropsychiatric adverse events, continued
Study
Design/ follow-up
Results
Van Laar et al,
2010
• Uncontrolled study,
• 10 patients with
visual
hallucinations
• Apomorphine pump
• 6 weeks
• Significant improvement in hallucinations
(Neuropsychiatric Inventory) and caregiver distress
Evans et al, 2004
• 123 patients
• 17 patients (9 apomorphine) with punding associated with
high doses of dopamine replacement therapy
Tellez et al, 2006
• Case study, 1
patient
• Single case of patient with presumed dopamine
dysregulation syndrome (‘addiction’)
van Laar T, et al. Parkinsonism Relat Disord 2010;16:71-27. Tellez C, et al. Addiction 2006;101:1662-1665. Evans AH, et al. Mov Disord.
2004;19:397-405.
Summary
• Subcutaneous apomorphine infusion is effective for treatment of
the symptoms of Parkinson’s disease
• Subcutaneous apomorphine infusion has fewer
contraindications than deep brain stimulation (DBS)
• Observations of reversible motor complication phenomena with
subcutaneous apomorphine infusion are consistent with
concept of continuous dopaminergic stimulation
• Randomised controlled studies of subcutaneous apomorphine
infusion compared to oral treatment, intrajejunal levodopa and
DBS are warranted