Parkinson's Disease Prescribing Guidelines for use in Primary and Secondary Care
2015
Parkinson’s Disease Prescribing Guidelines for use in Primary and
Secondary Care
Document Description
Document Type
Prescribing Guidance
Service Application
Primary and Secondary Care
Version
3.0
Ratification date
May 2015
Review date
May 2017
Lead Author(s)
Dr Janine Barnes
Dr Alistair Lewthwaite
Neurology Specialist Pharmacist
Consultant Neurologist, DGoH
Change History
Version
Date
Comments
0.1
0.2
14/1/10
28/1/10
0.3
0.4
0.5
0.6
1.0
2.0
9/2/10
23/2/10
April 2010
June 2010
Sept 2010
Oct 2012
2.1
May 2015
Developed by Dr Barnes and Dr Etti
Updated with comments from Mehul Amin, Team Leader
of Primary Care Neurology Team
Amended by Clair Huckerby-Pharmaceutical Advisor
Updated with comments from AMMC
Final comments from neurology consultants
Changes to formatting
Final Ratified edition
Guidelines reviewed – Ropinirole XL info updated due to
license change
Amended by Dr Barnes
Link with Care Quality
Commission Essential
Standards of Quality &
Safety
Regulation 10, Outcome 16- Assessing and
monitoring the quality of service provision.
Regulation 13, Outcome 9- Management of
medicines.
Link with Trust Purpose
and Values statements
These guidelines are aimed to improve the health
and wellbeing of our local community. They link
with:
‘We will support, deliver and develop our staff’
‘We will work to continuously improve services’.
Reviewers - This Document has been reviewed by
Version
Date
Name
Title/Responsibility
2.1
May 2015 Dr J Barnes
Neurology Specialist Pharmacist
Approvals - This document has been approved by
Version
Date
Name
Title/Responsibility
DOCUMENT STATUS:
This is a controlled document. Whilst this document may be printed, the
electronic version posted on the intranet is the controlled copy. Any
printed copies of the document are not controlled.
Related Documents
Reference No.
Document Title
Applicable Legislation
Glossary of Terms
Term
Acronym
Clinical
Commissioning
Group
CCG
Definition
Version
Summary Sheet
These guidelines have been drawn up to promote the safe, effective and
economic use of medication for Parkinson’s disease patients, aiming to
improve the quality of patient experience for this group of patients.
Recommendations for prescribing are based on NICE and SIGN guidance
and from consultations with clinicians from both primary and secondary care
in the Dudley Health Economy.
These guidelines are for use by all staff within the Dudley Health Economy,
who manage patients with Parkinson’s disease.
Produced in consultation with:
Dr R Etti
Dr M Douglas
Clair Huckerby
Jane Elvidge
Mehul Amin
Dr J Stellman
Dr S Duja
Dr A. Banerjee
Dr A McGrath
Dr A Michael
Primary Care Neurology team
AMMC members
Practice based Commissioning
Clusters
Consultant Neurologist, DGoH
Consultant Neurologist, DGoH
Pharmaceutical Adviser, Dudley PCT
Principal Pharmacist, DGoH
Team Leader, Primary Care
Neurology Team
Elderly Care consultant, DGoH
Elderly Care consultant, DGoH
Elderly Care consultant, DGoH
Elderly Care consultant, DGoH
Elderly Care consultant, DGoH
The guidelines will be subject to review in two years time or sooner depending
on changes in national guidance.
Contents
Introduction
Treatment pathway for Parkinson’s disease
Levodopa: Co-careldopa, Co-beneldopa
Dopamine agonists: Ropinirole, Pramipexole, Rotigotine
Monoamine oxidase B inhibitors: Rasagiline, Selegiline
Antimuscarinics: Trihexyphenidyl
COMT (catechol-o-methyl-transferase) inhibitors: Entacapone
Stalevo (Levodopa/Carbidopa/Entacapone)
Amantadine
Apomorphine
References
Pg No
5
6
7
12
14
15
15
15
16
16
17
Introduction
Aims
 To provide a simple pathway for the treatment of Parkinson’s disease
 To promote the safe, effective and economic use of Parkinson’s disease
medication
 To minimise the risk of medication related side effects experienced by
this patient group
Principles of Treatment
This guidance is based on the best available evidence but its application
must be modified by professional judgement
The pathway and prescribing guidelines are produced as an aide to
prescribing for GPs and specialists within Dudley although often it is not
possible to identify a universal first choice therapy for patients with early or
late Parkinson’s disease and so the choice of drug prescribed should take into
account:
•
•
Clinical and lifestyle characteristics
Patient preference
Roles and Responsibilities
It is essential that in order for these guidelines to be implemented that they
are easily and conveniently accessible to all healthcare professionals.
Specialist Initiation:
Where specialist initiation of a drug is suggested, this refers to consultant
neurologists, consultants within the elderly care team and prescribers within
the neurology primary care team.
Identified Standards
These guidelines should be read in association with NICE2 and SIGN3 clinical
guidelines.
Auditing
The Prescribing and Medicines Management team working with the Primary
Care Neurology team and Dudley group of hospitals, will be responsible for
the audit of the prescribing guidelines.
A. Levodopa:
Levodopa Formulations
Co-careldopa, Co-beneldopa
Levodopa is the amino-acid precursor of dopamine, acts by replenishing
depleted striatal dopamine; is given with an extracerebral dopa-decarboxylase
inhibitor that reduces the peripheral conversion of levodopa to dopamine
allowing less side effects and lower doses of levodopa to be used. The
extracerebral dopa-decarboxylase inhibitors used with levodopa are
benserazide (co-beneldopa) and carbidopa (co-careldopa). These
combinations are used in the elderly or frail, in patients with other significant
illnesses, and in those with more severe symptoms. The preparations are
effective and well-tolerated in most patients. Levodopa therapy should be
initiated at a low dose and increased in small steps, with the final dose as low
as possible. Intervals between doses should be suited to the individual patient
needs.
Levodopa treatment is associated with the development of potentially
troublesome motor complications including response fluctuations and
dyskinesias. Response fluctuations are characterised by large variations in
motor performance, with normal function during the ‘on’ period, and weakness
and restricted mobility during the ‘off’ period. ‘End-of-dose’ deterioration also
occurs, where the duration of benefit after each dose becomes progressively
shorter. Modified-release preparations may help with ‘end-of-dose’
deterioration or nocturnal immobility and rigidity. Motor complications are
particularly problematic in young patients treated with levodopa.
Co-careldopa:
Indicated for Parkinsonism (but not drug-induced extrapyramidal symptoms)
Dose
Expressed as
levodopa, initially
100 mg (with
carbidopa 25 mg)
or
initially 50–
100 mg (with
carbidopa 10–
12.5 mg)
or
initially 125 mg
(with carbidopa
12.5 mg, as ½
tablet of cocareldopa
25/250)
Dose Frequency
3 times daily
Dose Titration
increased by 50–
100 mg (with
carbidopa 12.5–
25 mg) daily or
on alternate days
according to
response
Maximum dose
up to 800 mg
(with carbidopa
200 mg) daily in
divided doses
3–4 times daily
increased by 50–
100 mg daily or
on alternate days
according to
response
up to 800 mg
(with carbidopa
80–100 mg) daily
in divided doses
1–2 times daily
increased by
125 mg (with
carbidopa
12.5 mg) daily or
on alternate days
according to
response
NB. At least 70 mg carbidopa daily is necessary to achieve full inhibition of
peripheral dopa-decarboxylase. When transferring patients from another
levodopa/dopa-decarboxylase inhibitor preparation, the previous preparation
should be discontinued at least 12 hours before.
Co-beneldopa:
Indicated for Parkinsonism (but not drug-induced extrapyramidal symptoms)
Dose
Dose Frequency
Dose Titration
Expressed as
3-4 times daily
increased by
Maintenance
dose
400–800 mg daily
levodopa, initially
50mg
Dose for elderly
patients
initially 50 mg
(100mg 3 times
daily in advanced
disease)
100 mg daily
once or twice
weekly according
to response
once or twice
daily
increased by
50 mg daily every
3–4 days
according to
response
in divided doses
NB. When transferring patients from another levodopa/dopa-decarboxylase
inhibitor preparation, the previous preparation should be discontinued 12
hours before (although interval can be shorter).
Levodopa controlled release formulations:
Co-careldopa, Co-beneldopa
Indicated for idiopathic Parkinson's disease, in particular to reduce off-period
in patients who previously have been treated with levodopa/decarboxylase
inhibitors, or with levodopa alone and who have experienced motor
fluctuations. The experience is limited with 'Sinemet CR' and 'Half Sinemet
CR' in patients who have not been treated with Levodopa before. In clinical
trials, patients with motor fluctuations experienced reduced 'off'-time with
'Sinemet CR' when compared with 'Sinemet'. The reduction of the 'off'-time is
rather small (about 10%) and the incidence of dyskinesias increases slightly
after administration of 'Sinemet CR' compared to standard 'Sinemet'. Global
ratings of improvement and activities of daily living in the 'on' and 'off' state, as
assessed by both patient and physician, were better during therapy with
'Sinemet CR' than with 'Sinemet'. Patients considered 'Sinemet CR' to be
more helpful for their clinical fluctuations, and preferred it over 'Sinemet'. In
patients without motor fluctuations, 'Sinemet CR‘ under controlled conditions,
provided the same therapeutic benefit with less frequent dosing than with
'Sinemet'. Generally, there was no further improvement of other symptoms of
Parkinson's disease. (see BNF for prescribing advice¹)
Co-careldopa CR: (Caramet CR, Half Sinemet CR and Sinemet
CR)
Co-careldopa CR
preparation:
(strength expressed
as
carbidopa:levodopa)
Caramet® CR
co-careldopa
25/100
50/200
Sinemet® CR
50/200
Co-careldopa CR
preparation:
(strength expressed
as
carbidopa:levodopa)
Caramet® CR
co-careldopa
25/100
50/200
Sinemet® CR
50/200
Dose for patients Dose frequency
not receiving
levodopa/dopadecarboxylase
inhibitor
preparations,
expressed as
twice daily (at
levodopa,
least 6 hours
initially 100–
between doses)
200 mg
Dose titration
dose adjusted
according to
response at
intervals of at
least 2 days
initially, 1
Sinemet® CR
tablet
twice daily
both dose and
interval then
adjusted
according to
response at
intervals of not
less than 3 days
Patients
transferring from
immediaterelease
levodopa/dopadecarboxylase
inhibitor
preparations,
discontinue
previous
preparation at
least 12 hours
before first dose
of Caramet®
CR;
Dose frequency
Dose titration
substitute
Caramet® CR to
provide a similar
amount of
levodopa daily
and extend
dosing interval
by 30–50%;
(substitute
Sinemet® CR to
provide approx.
10% more
dose then
adjusted
according to
response at
intervals of at
least 2 days
1 Sinemet® CR
tablet twice daily
can be
substituted for a
dose and interval
then adjusted
according to
response at
daily dose of
levodopa 300–
400 mg in
immediaterelease
Sinemet®
tablets
levodopa per
day and extend
dosing interval
by 30–50%);
intervals of not
less than 3 days
Co-beneldopa CR: (Madopar)
Co-beneldopa CR
Dose and
preparation:
frequency
(strength expressed
as 25/100
beneldopa:levodopa)
Maximum dose
Dose for patients not
receiving
levodopa/dopadecarboxylase
inhibitor
preparations,
Patients transferring
from immediaterelease
levodopa/dopadecarboxylase
inhibitor
preparations,
6 capsules daily
initially 1 capsule
3 times daily
initially 1 capsule
substituted for
every 100 mg of
levodopa and
given at same
dosage frequency
Dose titration
increased every
2–3 days
according to
response;
average increase
of 50% needed
over previous
levodopa dose
and titration may
take up to 4
weeks
Supplementary dose of immediate-release Madopar® may be needed with
first morning dose; if response still poor to total daily dose of Madopar® CR
plus Madopar® corresponding to 1.2 g levodopa, consider alternative therapy.
Levodopa dispersible formulation:
Co-beneldopa:
Patients requiring a more rapid onset of action, e.g., from early morning or
afternoon akinesia, or who exhibit ‘delayed on’ or ‘wearing off’ phenomena,
are more likely to benefit from Co-beneldopa dispersible. (see BNF for
prescribing advice1) The tablets can be dispersed in water or orange squash
(not orange juice) or swallowed whole.
B. Dopamine Agonists:
Ropinirole:
Licensed to treat Parkinson’s disease, either used alone or as an adjunct to
levodopa with a dopa-decarboxylase inhibitor. When administered as adjunct
to levodopa, concurrent dose of levodopa may be reduced by approx. 20%.
Dose
initially
750 micrograms
daily in 3 divided
doses
Dose Frequency
increased by
increments of
750 micrograms
at weekly
intervals to 3 mg
daily
Dose Titration
further increased
by increments of
up to 3 mg at
weekly intervals
according to
response; usual
range 9–16 mg
daily (but higher
doses may be
required if used
with levodopa);
Maximum dose
24 mg daily
Ropinirole XL:
Stable Parkinson’s disease in patients transferring from ropinirole immediaterelease tablets, initially Requip® XL once daily substituted for total daily dose
equivalent of ropinirole immediate-release tablets; if control not maintained
after switching, in patients receiving less than 8 mg once daily, increase in
steps of 2 mg at intervals of at least 1 week to 8 mg once daily according to
response; in patients receiving 8 mg once daily or more, increase in steps of
2 mg at intervals of at least 2 weeks according to response; max. 24 mg once
daily. Patients can also be initiated on Requip XL with a usual starting dose of
2mg once daily. After a week this dose can be increased to 4mg once daily,
when a therapeutic response may be seen. If sufficient symptom control is not
achieved or maintained, the daily dose may be increased by 2mg at weekly or
longer intervals. NB. When administered as adjunct to levodopa, concurrent
dose of levodopa may be reduced.
Pramipexole:
Licensed to treat Parkinson’s disease, used alone or as an adjunct to
levodopa with dopa-decarboxylase inhibitor.
NB. Doses and strengths are stated in terms of pramipexole (base);
equivalent strengths in terms of pramipexole dihydrochloride monohydrate
(salt) are as follows:
88
micrograms base
≡ 125 micrograms salt;
180
350
700
micrograms base
micrograms base
micrograms base
Dose
Initially 88
micrograms
≡ 250 micrograms salt;
≡ 500 micrograms salt;
≡ 1 mg salt
Dose Frequency
3 times daily
Dose Titration
dose doubled
every 5–7 days if
tolerated to
350 micrograms
3 times daily;
further increased
if necessary by
180 micrograms
3 times daily at
weekly intervals
Maximum dose
3.3 mg daily in 3
divided doses
During pramipexole dose titration and maintenance, levodopa dose may be
reduced. Pramipexole has been associated with somnolence and episodes of
sudden sleep onset in a rare number of cases. Patients should be informed of
this and advised to exercise caution when driving or operating machinery
during treatment with the medication.
Pramipexole prolonged release:
The majority of patients are able to switch from immediate release
Pramipexole to the prolonged release formulation without the need for dose
adjustment.
Rotigotine patch: 4,5 (specialist initiation recommended)
Licensed to treat Parkinson’s disease, either used alone or as an adjunct to
levodopa with dopa-decarboxylase inhibitor.
monotherapy
Dose Frequency
‘2 mg/24 hours’
patch to dry, nonirritated skin on
torso, thigh, or
upper arm,
removing after 24
hours and siting
replacement
patch on a
different area
(avoid using the
same area for 14
days)
Dose Titration
increased in
steps of 2 mg/24
hours at weekly
intervals if
required
Maximum dose
8 mg/24 hours
adjunctive
therapy with
levodopa
apply ‘4 mg/24
hours’ patch to
dry, non-irritated
skin on torso,
thigh, or upper
arm, removing
after 24 hours
and siting
replacement
patch on a
different area
(avoid using the
same site for 14
days);
increased in
steps of 2 mg/24
hours at weekly
intervals if
required
16 mg/24 hours
Rotigotine patches (Neupro®) are licensed as a monotherapy or as an adjunct
to Levodopa with a dopa-decarboxylase inhibitor and it is a useful product
where the transdermal route facilitates treatment.
C. Monoamine oxidase B inhibitors:
Rasagiline, Selegiline
Rasagiline:
Licensed to treat Parkinson’s disease, used alone or as adjunct to levodopa
with dopa-decarboxylase inhibitor.
Dose-1mg daily.
Selegiline:
Licensed to treat Parkinson’s disease, used alone or as adjunct to levodopa
with dopa-decarboxylase inhibitor.
Dose-10 mg in the morning, or 5 mg at breakfast and midday. To avoid initial
confusion and agitation, it may be appropriate to start treatment with a dose of
2.5 mg daily, particularly in the elderly.
Selegiline oral lyophilisate: 6 (Zelapar)
(specialist initiation recommended)
The lyophilisate (1.25mg) can be taken daily before breakfast. The tablets
should be placed on the tongue and allowed to dissolve. The patient should
be advised not to drink, rinse or wash mouth out for 5 minutes after taking the
tablet.
NB. Patients receiving the 10mg conventional Selegiline tablet can be
switched to Zelapar 1.25mg. The lyophilisate may be useful for patients who
have difficulty in swallowing as Zelapar dissolves completely within 10
seconds of placing on the tongue and, in contrast to conventional tablets,
Selegiline is absorbed primarily pregastrically.
D. Antimuscarinics:
Trihexyphenidyl: 7
(specialist initiation recommended)
Found to be useful in treating severe tremor in younger Parkinson’s disease
patients. Drug may also be useful in reducing sialorrhoea-but has little effect
on bradykinesia and propensity for causing neuropsychiatric side effects.
E. COMT (catechol-o-methyl-transferase) inhibitors:
Entacapone and tolcapone prevent the peripheral breakdown of levodopa, by
inhibiting catechol-O-methyltransferase, allowing more levodopa to reach the
brain. They are licensed for use as an adjunct to co-beneldopa or cocareldopa
for patients with Parkinson’s disease who experience ‘end-of-dose’
deterioration and cannot be stabilised on these combinations. Due to the risk
of hepatotoxicity, tolcapone should be prescribed under specialist supervision
only, when other catechol-O-methyltransferase inhibitors combined with cobeneldopa or co-careldopa are ineffective.
Entacapone:
Licensed as adjunct to levodopa with dopa-decarboxylase inhibitor in
Parkinson’s disease and ‘end-of-dose’ motor fluctuations.
Dose-200 mg with each dose of levodopa with dopa-decarboxylase inhibitor;
max. 2 g daily.
Stalevo: 8,9
(Levodopa/Carbidopa/Entacapone)
Licensed for Parkinson’s disease and end of dose motor fluctuations not
adequately controlled with levodopa and dopa decarboxylase treatment.
Only 1 tablet to be taken for each dose. See BNF1 for maximum amount of
tablets daily as depends on strength of tablet. Patients receiving standardrelease co-careldopa or co-beneldopa alone, initiate Stalevo® at a dose that
provides similar (or slightly lower) amount of levodopa Patients with
dyskinesia or receiving more than 800 mg levodopa daily, introduce
entacapone before transferring to Stalevo® (levodopa dose may need to be
reduced by 10–30% initially). Patients receiving entacapone and standard-
release co-careldopa or co-beneldopa, initiate Stalevo® at a dose that
provides similar (or slightly higher) amount of levodopa.
Stalevo is most cost effective at higher doses.
F. Amantadine: 10 (specialist initiation recommended)
Licensed for Parkinson’s disease (but not drug-induced extrapyramidal
symptoms).
Dose-Parkinson’s disease, 100 mg daily increased after one week to 100 mg
twice daily, usually in conjunction with other treatment; some patients may
require higher doses, max. 400 mg daily; elderly 65 years and over, 100 mg
daily adjusted according to response.
G. Apomorphine: 11,12 (specialist initiation recommended)
(intermittent injection, pre-filled syringe. ampoule)
Licensed for refractory motor fluctuations in Parkinson’s disease (‘off’
episodes) inadequately controlled by levodopa with dopa-decarboxylase
inhibitor or other dopaminergics (for capable and motivated patients under
specialist supervision). Dose-By subcutaneous injection, usual range (after
initiation as below) 3–30 mg daily in divided doses; subcutaneous infusion
may be preferable in those requiring division of injections into more than 10
doses daily; max. single dose 10 mg; child and adolescent under 18 years not
recommended.
By continuous subcutaneous infusion (those requiring division into more than
10 injections daily) initially 1 mg/hour daily increased according to response
(not more often than every 4 hours) in max. steps of 500 micrograms/hour, to
usual rate of 1–4 mg/hour (14–60 micrograms/kg/hour); change infusion site
every 12 hours and give during waking hours only (24-hour infusions not
advised unless severe night-time symptoms)—intermittent bolus boosts also
usually needed; child and adolescent under 18 years not recommended.
NB Total daily dose by either route (or combined routes) max. 100 mg.
Requirements for initiation:
Hospital admission and at least 2 days of pretreatment with domperidone for
nausea and vomiting, after at least 3 days withhold existing antiparkinsonian
medication overnight to provoke ‘off’ episode, determine threshold dose, reestablish other antiparkinsonian drugs, determine effective apomorphine
regimen, teach to administer by subcutaneous injection into lower abdomen or
outer thigh at first sign of ‘off’ episode, discharge from hospital, monitor
frequently and adjust dosage regimen as appropriate (domperidone may
normally be withdrawn over several weeks or longer)—for full details of
initiation requirements, consult product literature.
References:
1.
British National Formulary (2009) British National Formulary 58. Available at
www.bnf.org. (Accessed 10 September 2012).
2.
National Institute for Clinical excellence (2006) NICE clinical guideline 35
PARKINSON’S DISEASE National clinical guideline for diagnosis and
management in primary and secondary care. Available at : www.nice.org.uk
(Accessed 10 September 2012).
3.
Scottish Intercollegiate Guidelines Network (2010) SIGN 113 Diagnosis and
pharmacological management of Parkinson’s disease. Available at:
www.sign.ac.uk (Accessed 10 September 2012).
4.
Giladi, N., Boroojerdi, B., Ko/>rczyn, A.D., Burn, D.J., Clark, C.E., Schapira,
A.H.V. (2007) Rotigotine transdermal patch in early Parkinson’s disease: A
randomized, double-blind, controlled study versus placebo and ropinirole.
Movement Disorders, 22(16), pp 2398-2404.
5.
Poewe, W.H., Rascol, O., Quinn, N., Tolosa, E., Oertel, W.H., Martignoni,
E., Rupp, M., Boroojerdi, B. (2007) Efficacy of pramipexole and transdermal
rotigotine in advanced Parkinson’s disease: a double-blind, double-dummy,
randomised controlled trial. Lancet Neurology, 6, pp 513-520.
6.
Lew, M.F., Pawha, R., Leehey, M., Bertoni, J., Kricorian, G., Zydis
Selegiline Study, (2007) Safety and efficacy of newly formulated selegiline
orally disintegrating tablets as an adjunct to levodopa in the management of
‘off’ episodes in patients with Parkinson’s disease. Current Medical
Research and Opinion, 23(4) pp 741-750.
7.
Martin, W.E., Loewenson, R.B., Resch, J.A., Baker, A.B. (1974) A controlled
study comparing trihexyphenidyl hydrochloride plus levodopa with placebo
plus levodopa in patients with Parkinson’s disease. Neurology, 24/10 (9129), 0028-3878.
8.
Brooks, D.J., Agid, Y., Eggert, K., Widner, H., Ostergaard, K., Holopainen,
A., and the TC-INIT Study Group. (2005) Treatment of end-of-dose wearingoff in Parkinson’s disease: Stalevo (Levodopa/Carbidopa/Entacapone) and
Levodopa/DDCI given in combination with Comtess/Comtan (Entacapone)
provide equivalent improvements in symptom control superior to that of
traditional Levodopa/DCCI treatment. European Neurology, 53, pp197-202.
9.
Boiko, A.N., Batysheva, T.T., Minaeva, N.G., Babina, L.A., Vdovichenko,
T.V., Zhuravleva, E.Y., Shikhkerimov, R.K., Malykhina, E.A., Khozova, A.A.,
Zaitsev, K.A., Kostenko, E.V. (2008) Use of the new levodopa agent Stalevo
(levodopa/carbidopa/entacapone) in the treatment of Parkinson's disease in
out patient clinical practice (the START-M open trial). Neuroscience &
Behavioral Physiology, 38/9 (933-6), pp 0097-0549.
10. Verhagen Metman, L., Del Dotto, P., Van Den Munckhof, P., Fang, J.,
Mouradian, M.M., Chase, T.N. (1998) Amantadine as treatment for
dyskinesias and motor fluctuations in Parkinson’s disease. Neurology, 50/5
(1323-1326), 0028-3878.
11. Chen, J.J., Obering, C. (2005) A review of intermittent subcutaneous
apomorphine injections for the rescue management of motor fluctuations
associated with advanced Parkinson’s disease. Clinical Therapeutics,
27(11), pp1710-1724.
12. Ruiz, P.J.G., Ignacio, A.S., Pensado, B.A., Garcia, A.C., Frech, F.A., Lopez,
M.A.., Gonzalez, J.A., Octavio, J.B. (2008) Efficacy of long-term continuous
subcutaneous apomorphine infusion in advanced Parkinson’s disease with
motor fluctuations : a multicenter study. Movement Disorders, 23(8) pp
1130-1136.