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Trenkwalder et al: Parkinsonism & Related Disorders Review article
Expert Consensus Group Report on the use of apomorphine in the
treatment of Parkinson’s disease – clinical practice recommendations
Authors: Claudia Trenkwaldera*, K. Ray Chaudhurib, Pedro J. García Ruizc, Peter
LeWittd, Regina Katzenschlagere, Friederike Sixel-Döringf, Tove Henrikseng, Ángel
Sesarh and Werner Poewei on behalf of an Expert Consensus Group for the Use of
Apomorphine in Parkinson’s Disease†
aCentre of Parkinsonism and Movement Disorders, Paracelsus-Elena Hospital, Kassel,
Germany; Department of Neurosurgery, University Medicine, Goettingen, Germany
bNational Parkinson Foundation Centre of Excellence, Kings College Hospital, Denmark
Hill Campus, London, UK
cMovement Disorders Unit, Department of Neurology, Fundacion Jimenez Diaz, Madrid,
Spain
dWayne State University School of Medicine, Parkinson's Disease and Movement
Disorders Program, Henry Ford West Bloomfield Hospital, West Bloomfield, Michigan,
USA
eDepartment of Neurology and Karl Landsteiner Institute for Neuroimmunological and
Neurodegenerative Disorders, Danube Hospital, Vienna, Austria
fParacelsus-Elena-Klinik, Centre of Parkinsonism and Movement Disorders, Kassel;
Department of Neurology, Philipps-University, Marburg, Germany
gMovement Disorder Clinic, Bispebjerg Hospital, Copenhagen, Denmark
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Trenkwalder et al: Parkinsonism & Related Disorders Review article
hDepartment of Neurology, Hospital Clínico Universitario, Santiago de Compostela,
Spain
iDepartment of Neurology, University of Innsbruck, Austria
†Contributors to the Expert Consensus Group:
Mary Baker, President, European Brain Council Brussels, Belgium
Andres Ceballos-Baumann, Department of Neurology, Neurologisches Krankenhaus
München, Munich, Germany
Günther Deuschl, Christian-Albrechts-University Kiel, Germany
Sophie Drapier, Centre Hospitalier Universitaire de Rennes, France
Georg Ebersbach, Movement Disorders Clinic, Beelitz-Heilstatten, Germany
Andrew Evans, Royal Melbourne Hospital, Melbourne, Australia
Hubert Fernandez, Center for Neurological Restoration, Cleveland Clinic, Cleveland,
Ohio, USA
Stuart Isaacson, Florida International University, Herbert Wertheim College School of
Medicine, Miami, Florida, USA
Andrew Lees, UCL Institute of Neurology, London, UK
Simon Lewis, Parkinson’s Disease Research Clinic at the Brain and Mind Research
Institute, University of Sydney, Australia
Juan Carlos Martínez Castrillo, Department of Neurology, Hospital Universitario Ramón
y Cajal, Madrid, Spain
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Trenkwalder et al: Parkinsonism & Related Disorders Review article
Pablo Martinez-Martin, National Center for Epidemiology and CIBERNED, Carlos III
Institute of Health, Madrid, Spain
Per Odin, Department of Neurology, Lund University Hospital, Lund, Sweden
John O’Sullivan, Royal Brisbane Clinical School, School of Medicine, University of
Queensland, Brisbane, Australia
Georgios Tagaris, Department of Neurology, Georgios Gennimatas General Hospital of
Athens, Greece
Teus Van Laar, Department of Neurology, University Medical Center, Groningen, The
Netherlands
Karoline Wenzel, Medical University of Graz, Graz, Austria
*Corresponding author: Professor Claudia Trenkwalder
Address for correspondence: Paracelsus-Elena Hospital, Centre of Parkinsonism and
Movement Disorders, Klinikstr. 16, DE-34128 Kassel, Germany
Email: [email protected]
Tel: +49-561-6009-200
Fax: +49-561-6009-126
Search term: Parkinson’s disease/Parkinsonism [165]
Key words: Parkinson’s disease; treatment; clinical practice; apomorphine injection;
apomorphine pump
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Trenkwalder et al: Parkinsonism & Related Disorders Review article
Author contributions: All authors participated in the Expert Consensus Group
Meetings and contributed to manuscript preparation. All contributors participated
in the Expert Consensus Group Meetings and reviewed and approved the
manuscript.
Acknowledgments including sources of support
The Expert Consensus Group was convened and their advisory meetings supported by
Britannia Pharmaceuticals Ltd. Editorial assistance was provided by Dr Karen
Wolstencroft, Helen Lawn Associates, supported by Britannia Pharmaceuticals Ltd.
Abstract
Extensive published evidence supports the use of subcutaneously-administered
apomorphine as an effective therapy for Parkinson´s disease (PD) but to date no
consensus recommendations have been available to guide healthcare professionals in
the optimal application of apomorphine therapy in clinical practice. This document
outlines best-practice recommendations for selecting appropriate candidates for
apomorphine intermittent injection (the pen-injection formulation) or apomorphine
continuous infusion (the pump formulation), for initiating patients onto therapy and for
managing their ongoing treatment.
Apomorphine is a suitable therapeutic option for PD patients who experience
troublesome ‘off’ periods despite optimized treatment with oral PD medications. Due to
its speed of onset, apomorphine injection is particularly suited to those patients requiring
rapid, reliable relief of both unpredictable and predictable ‘off’ periods, those who require
reliable and fast relief when anticipating an ‘off’, those with levodopa absorption or
gastric emptying problems resulting in delayed or failed ‘on’, or for rapid relief of early
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morning dystonia or akinesia. Apomorphine infusion1 is suited for patients whose ‘off’
periods can no longer be adequately controlled by standard oral PD treatment or for
those in whom rescue doses of apomorphine injection are effective but either needed
too frequently (more than 4–6 times per day), or are associated with increasing
dyskinesia. In addition to treating motor fluctuations, there is evidence that apomorphine
infusion may be effective for the management of specific non-motor symptoms of PD
associated with ‘off’ periods. Apomorphine infusion is less invasive than other non-oral
treatment options for advancing disease, intrajejunal levodopa infusion and deep-brain
stimulation.
Introduction
Clinical experience in treating Parkinson’s disease (PD) with apomorphine goes back to
1951 when limited experimentation with this drug showed its potential for relief of
parkinsonian symptomatology [1]. For the past three decades, clinical practice in Europe
and elsewhere has adopted the use of apomorphine for both intermittent and continuous
subcutaneous administration. Although an extensive clinical literature has described the
various applications and outcomes from apomorphine therapy in PD, and Level 1
evidence from randomized, placebo-controlled studies is available for the injection
formulation, a consensus view has not evolved to summarize best practices. To address
this unmet need, an international group of specialists was convened to discuss and
develop recommendations for how to use apomorphine in PD therapeutics. This article
summarizes a consensus of views regarding clinical practice recommendations for using
apomorphine in PD. It is intended for those clinicians who may be unfamiliar with
apomorphine and who might be prescribing the product for the first time, who have not
1 Apomorphine infusion has not received marketing authorization in the USA.
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had the opportunity to judge its effectiveness, or who are continuing to prescribe
apomorphine after specialized centers have initiated this therapy.
Development of these clinical practice recommendations
An international group of specialists with extensive personal experience in treating PD
patients with apomorphine was invited by Britannia Pharmaceuticals Ltd., the
manufacturer of apomorphine injection and infusion, to participate in one or both of two
Advisory Board Meetings, supported by the company, to share their practical experience
of using the product. The aim of the meetings was to develop guidance for neurologists,
general practitioners (GPs) and other healthcare professionals on the optimal clinical
use of apomorphine. The first meeting was held in October 2012 and the second in May
2013 and they involved 26 advisors from 13 countries. All meeting participants were
included in the consensus group. The outcome of the two Advisory Board Meetings led
to a consensus of views on best clinical practice recommendations for subcutaneous
apomorphine in PD and included key findings from a questionnaire that panel members
completed in advance of the second meeting to provide their experience and perception
of treatment practices with apomorphine. In analyzing responses to the 26 completed
questionnaires, ‘consensus’ was considered to be achieved when ≥80% of the advisors
were in agreement. A summary of the questions and response is summarized in
Appendix 1. Due to the number of advisors involved, editorial assistance was provided
by a medical writer, supported by Britannia Pharmaceuticals Ltd, to develop the article
summarizing their consensus views and to obtain advisor input and agreement on the
clinical practice recommendations. All advisors reviewed and input into the manuscript at
all stages.
Initial treatment of Parkinson’s disease
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The overall goals of symptomatic treatment for PD are to provide control of the
symptoms of the disease while minimizing the adverse effects of medication. This
includes late complications such as motor fluctuations and dyskinesia. The most
effective initial treatment for PD is levodopa. Oral and transdermal dopaminergic
agonists (DA) can also achieve dopaminergic benefits and they can delay the
development of motor complications when administered as monotherapy or in
combination with the smallest dose of levodopa required for motor control in early PD.
Once motor fluctuations have developed, therapeutic approaches include increasing
levodopa doses or shortening the intervals between intakes, adding inhibitors of
catechol-O-methyl transferase (COMT) and MAO-B to block the degradation of levodopa
and dopamine, or adding a DA in patients who are not already receiving an agonist,
unless there are contraindications.
However, a sizable proportion of patients remain inadequately controlled despite a range
of oral (or transdermal) treatment options, with gaps in drug effects (switching ‘off’) as
well as involuntary movements (dyskinesias, including dystonia) [2-4].The problem
may be enhanced by alterations in gastric emptying, which is often compromised
as PD progresses; this can limit drug absorption and the reliability of levodopa
efficacy during the day [5, 6]. Difficulty swallowing is sometimes a problem for PD
patients and may interfere with a patient’s ability to adhere to an oral medication
regimen [7].
Beyond standard oral/transdermal therapies
For PD patients experiencing motor complications (including motor fluctuations and
dyskinesias) that cannot be adequately managed by adjustment of oral medications,
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there are a number of options. These include neurosurgical intervention with deep brain
stimulation (DBS) of the subthalamic nucleus or globus pallidus, continuous enteral
infusion of a levodopa/carbidopa intestinal gel (LCIG), and continuous subcutaneous
infusion of apomorphine.
DBS can be very effective for patients who are not well controlled or, or who cannot
tolerate, maximal dopamine replacement therapy [8, 9]. However, it involves invasive
stereotactic brain surgery which has relatively few but potentially serious risks, and it is
therefore generally discouraged in patients of advanced age and those with
neuropsychiatric features such as cognitive decline or severe depression. It is, however,
generally a one-time procedure that aims to improve motor control over the long term
while also enabling patients to reduce their intake of oral medication.
LCIG is a chronic treatment option that involves minor surgery to establish a route of
infusion directly into the jejunum by means of a percutaneous endoscopic jejunostomy
(PEJ) tube. It has proved effective in symptomatic control of advanced PD [10].
Maintaining the PEJ tube in place is sometimes problematic. Local infections can
develop at the site of tube insertion. Complications at the site of skin entry of the tube
may require further surgical interventions. More severe infections such as peritonitis are
rare but potentially life-threatening. Other risks of LCIG that need further investigations
are weight loss, possibly due to malabsorption, and a possible association with axonal
peripheral neuropathy, the mechanism of which is poorly understood. Neuropsychiatric
problems, however, are minimal and usually well controlled.
Apomorphine is a highly potent DA selectively acting at both D1 and D2 dopamine
receptors. It differs substantially in its pharmacological profile from the 26 other DAs that
have been used (experimentally or in clinical practice) to treat PD [11]. Apomorphine
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was, in fact, the first DA used to treat PD [1], long before its dopaminergic properties
were understood and prior to the development of levodopa. In a number of published
clinical trials, apomorphine was shown to achieve anti-parkinsonian efficacy comparable
to that of orally-administered levodopa [12].
Apomorphine in the treatment of Parkinson’s disease
Apomorphine has poor oral bioavailability and due to extensive first pass metabolism,
high doses need to be given to elicit a clinical effect which early studies reported could
cause nephrotoxicity. As a result, apomorphine is given by the subcutaneous route,
either intermittently as an injection or as a continuous infusion. Studies of renal function
in animals chronically treated with subcutaneous apomorphine did not find any evidence
of renal toxicity using this route of administration [13].
Intermittent injections are useful for patients who experience refractory ‘off’ periods due
to a marked delay in the onset of clinical benefit from oral medication. It can also be
used as a rescue from an ‘off’ state, such as when a PD patient wants to become mobile
as soon as possible after awakening. Intermittent apomorphine injection is
recommended as a rescue treatment for those patients experiencing significant episodes
of wearing off. Apomorphine injection has a rapid onset of effect (typically within 4–12
minutes) with a rapid clearance half-life and a mean duration of anti-parkinsonian action
lasting about 45–60 minutes [14]. The most widely used formulations of the drug are
solutions of apomorphine hydrochloride in cartridges containing 10 or 20 mg/ml and a
multi-dose penject is available in some countries.
Administering apomorphine as an infusion is an option when continuous dopaminergic
stimulation is desirable. The dose can be adjusted to optimal effect for continuous
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delivery over a period ranging from 12–24 (usually 16) hours of the day. Apomorphine is
delivered via a subcutaneous catheter connected to a small portable pump, typically
worn on a waist belt or around the neck. The indications for continuous infusion typically
involve unpredictable or prolonged ‘off’ periods, motor fluctuations, or dyskinesias.
The subcutaneous administration of apomorphine is generally well tolerated. However,
skin nodules at the site of drug infusions are a common and sometimes bothersome
complication and typically develop over time. Strategies to minimize the occurrence and
to manage skin reactions are discussed later in this manuscript.
A range of double-blind, randomized, placebo-controlled clinical studies have
demonstrated that intermittent apomorphine injection is a rapid and effective acute
treatment for motor fluctuations in PD paients [15-19]. In the case of continuous
apomorphine infusion, no randomized, double-blind, placebo-controlled studies have
been published to date; however, a limited number of randomized controlled trials as
well as data from smaller open-label and observational studies undertaken over several
decades have confirmed its efficacy in controlling motor fluctuations, reducing ‘off’ time
and improving dyskinesias in PD patients; these findings have been summarized in a
recent review [20].
Clinical practice recommendations for the use of apomorphine in the treatment of PD,
including the selection of suitable candidates for intermittent apomorphine injection
(penject) or continuous apomorphine infusion (by pump) are outlined below.
Recommendations for initiating patients with apomorphine infusion therapy are also
discussed and illustrated with examples of real-life patient cases, as well as suggestions
for optimizing apomorphine treatment and managing adverse events.
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The panel stressed that the decision to use apomorphine should be based on a patient’s
symptoms and their disability as a result of motor complications that have become
refractory to adaptations of oral/transdermal treatment rather than on the perceived
stage of PD. However, there are currently still barriers for clinicians or patients to
commence apomorphine therapy.
Suitable candidates for intermittent apomorphine injection (pen)
The advisors agreed that suitable patients for intermittent apomorphine injection
(penject) are those with motor and non-motor fluctuations inadequately controlled by oral
treatments. Examples include patients with unpredictable ‘off’ periods, patients who
require reliable and fast relief when anticipating an ‘off’, such as in certain social
situations or when outside their home, those with levodopa absorption or gastric
emptying problems resulting in delayed or failed ‘on’, or for rapid relief of early morning
dystonia or akinesia.
There are two important aspects to apomorphine treatment: the speed of drug effect
onset after intermittent apomorphine injection, making it desirable for the patient who
has a predictable but delayed response to levodopa of 15–30 minutes or longer; and the
reliability of its effect at recovering an ‘on’ state (as compared to the effects of oral
dosing with levodopa). Finally the short half-life of apomorphine induces a response of
about 45–60 minutes, which does not generally interfere with the basal drug regimen,
but fills the gaps in motor functioning.
On account of its unique speed of onset, apomorphine is particularly suited to those
patients requiring rapid, reliable relief of both unpredictable and predictable ‘off’ periods,
provided the patient or a caregiver can perform the injection at these times. Off
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symptoms that may improve include off-related dystonia, freezing, and non-motor
symptoms, including pain. Early morning ‘off’ states such as those involving painful
dystonia are particularly suited to apomorphine injection. Some PD patients can
experience a warning that they are about to switch ‘off’. If an under-medicated state is
unacceptable to a patient’s lifestyle, apomorphine injection can provide rapid and reliable
relief of parkinsonian signs and symptoms. Intermittent apomorphine injection also
provides an option for reliable control of parkinsonism when absorption of oral levodopa
is impaired (as, for example, shortly after ingestion of a meal or when gastrointestinal
illness prevents use of the oral route for PD medication).
The consensus reached regarding the reasons for considering treatment with
intermittent apomorphine injection (penject) are summarized in Figure 1.
Suitable candidates for continuous apomorphine infusion (pump)
In determining the profile of suitable candidates for changing to treatment with
subcutaneous apomorphine infusion (pump), the consensus was that this option should
be chosen when ‘off’ periods can no longer be adequately controlled by oral treatment,
or when rescue doses of apomorphine injection are effective but either needed too
frequently (for example, more than 4–6 times per day), or are associated with increasing
dyskinesia. This does not mean that all patients should be initiated on apomorphine
injection first; in fact in most centers, the majority of patients who start apomorphine
pump have not used apomorphine injection previously. The short-half-life of
apomorphine is also an advantage when given as a continuous infusion, because each
change in infusion rate will quickly result in a change of effect.
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A potential benefit of subcutaneous apomorphine infusion was recognized to be the
management of peak-dose dyskinesias. Continuous infusion (usually applied during the
waking day) can achieve a continuous ‘on’ state, which may alter the motor response of
the basal ganglia in such a way that dyskinesia may improve. While this is often
observed in clinical practice and has been repeatedly reported in open, uncontrolled
studies [21-24], no randomized, controlled studies have been performed to date that
confirm the effect of apomorphine infusion on dyskinesias definitively. Improvement in
dyskinesia usually requires a concomitant reduction in levodopa dose and may be
delayed by weeks after starting apomorphine pump therapy.
In addition to treating motor fluctuations, there is accumulating evidence (from non-
randomized studies) that treatment of PD patients with apomorphine infusion is of
benefit for the management of specific non-motor symptoms of PD associated with ‘off’
periods. These problems include ‘off’ pain, mood disturbances and slowness of thinking
[25, 26].
Apomorphine infusion may fulfill the needs of patients for whom enteral LCIG infusion or
DBS are contraindicated for medical reasons, or when these invasive interventions are
not desired by the patient. Unlike DBS, advanced age or the presence of
neuropsychiatric features (e.g. mild hallucinations, moderate cognitive impairment) are
not absolute contraindications to treatment with apomorphine. While hallucinations may
occur or worsen as an adverse effect of apomorphine infusion, the treatment has been
found to be well tolerated in some patients experiencing visual hallucinations and
paranoid ideations [27, 28], and one study reported a reduction in hallucinations in
patients receiving apomorphine infusion as they were able to reduce their oral PD
medication [28]. A study comparing DBS with apomorphine infusion in 25 patients with
advanced PD followed-up for 5 years demonstrated a worsening of Neuropsychiatric
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Inventory (NPI) scores in the DBS group that was not observed in the apomorphine
group [29]. Better neuropsychological performance in apomorphine-treated patients
compared with those treated with DBS has also been shown in other studies [30, 31].
As the least invasive of the advanced treatment options, apomorphine infusion can be
tried as first-line therapy in patients who require treatment escalation before more
invasive procedures (LCIG/DBS) are applied.
Use of the apomorphine pump can also simplify the treatment of PD by providing a
convenient alternative to complex oral dosing regimens which are known to impact on
adherence to therapy [32, 33]. It can also potentially minimize drug–drug interactions
that might arise from taking multiple oral medications [34], or may be used temporarily
when oral intake or absorption is limited for surgical or other reasons.
The consensus regarding the reasons for considering treatment with continuous
apomorphine infusion (pump) are summarized in Figure 1.
Starting patients on continuous apomorphine infusion (pump)
With regard to how a patient should be started on treatment with subcutaneous
apomorphine infusion (pump), the consensus was that a patient experiencing problems
with current PD therapy should be referred to a specialist neurologist (or, where
appropriate, to a geriatrician specializing in PD) who can prescribe apomorphine after
evaluating treatment goals, comorbidities, and the use of other medications.
Good clinical practice would include prior evaluations of the patient to include ECG (to
exclude prolonged QT duration, tachy- and brady-arrhythmias, atrial fibrillation, and
premature ventricular contractions), and exclusion of pre-existing hemolytic anemia.
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How apomorphine therapy should be initiated is shown for the inpatient setting in Figure
2. In many countries, it is not necessary to hospitalize patients for initiation of
apomorphine infusion.
Examples of real patient cases provided by members of the advisory group to help
illustrate best practice in the initiation of apomorphine infusion (pump) in a range of
patient types. are listed in Appendix 2.
Adherence to and optimization of apomorphine therapy
The consensus was that continuous apomorphine pump therapy is recommended due to
its persisting efficacy and tolerability. There is some suggestion – although no firm
evidence – from clinical studies that infusion of apomorphine for the full 24-hour period
may potentially lead to the development of tolerance in some patients and a reduction in
response but that this is rapidly reversible [35-37]. In such cases it is recommended that
the infusion period is reduced. Availability of ongoing support from healthcare
professionals, caregivers and/or spouses/partners is required (including the availability
for ‘troubleshooting’ strategies if difficulties should arise). It was stressed that
commitment and motivation on the part of the patient, clinician, caregiver, and
spouse/partner are generally vital to successful therapy, as are adequate education,
background information and hands-on training (including learning and managing the
expectations of patients receiving this treatment). In many countries the manufacturer of
apomorphine provides an information service to assist neurologists with experience in
the management of motor complications in PD to start using apomorphine infusion.
When to switch from or to stop apomorphine therapy
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The consensus was that many patients are likely to have apomorphine treatment
stopped for the wrong reasons. The view of the panel was that a transient or reversible
adverse event is generally not a valid reason for stopping treatment. The significance of
adverse events differs between patients and their individual circumstances need to be
taken into account when making treatment decisions. The additional demands and
discomfort associated with injection or infusion compared to oral therapy may influence
compliance with apomorphine and tolerability of adverse effects. Depending on the
needs of the individual patient, it may not be necessary to discontinue apomorphine
treatment for mild-to-moderate skin nodules, for dyskinesias (if due to concomitant oral
medication, as these can often be managed ), for non-hemolytic anemia, for mild, non-
threatening hallucinations/illusions, for orthostatic hypotension (which may have another
cause and which has several treatment options), or for perceived lack of efficacy (which
might be attributable to suboptimal dosing). In fact, a common reason for a perceived
inadequate response to apomorphine infusion may be an insufficient infusion rate to
achieve a meaningful improvement after a short observation period (unpublished
observation).
Confirming these views, the questionnaire completed by the expert panel established
that treatment with apomorphine should be continued if possible in the following
situations:
Dyskinesia occurring in combination with oral medication
Perceived lack of efficacy
If mild skin nodules occur, especially those that can be controlled with treatment
(see below)
Mild cognitive impairment
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Mild orthostatic hypotension
Managing adverse events
Effective management of adverse events is the key to long-term treatment with
apomorphine. The experts discussed the frequency and severity of a number of adverse
events and concluded that local reactions occurring with apomorphine infusion, such as
minimal to moderate nodule formation at the infusion site, are readily managed with
conventional methods. These include:
Rotation of the choice of infusion sites
Use of Teflon® needles
Adjusting delivery through the skin to an optimal angle (i.e. 45–90 degrees)
Maintaining good skin hygiene and using emollients at the infusion site
Choosing a lower concentration, e.g. 5 mg per ml; lower concentrations have
been used successfully
Massaging the infusion site (using a spiky rubber massage ball or vibrating
device)
Applying ultrasound treatment
Use of silicone gel dressings
These techniques are recommended on the basis of clinical experience; none have been
proven by means of formal clinical studies, with the exception of ultrasound, which has
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been shown to be effective for the treatment of skin nodules making the treated area
suitable for further injections [38].
The advisors noted that postural hypotension is relatively infrequent, generally mild, and
generally can be managed with non-pharmacological measures such as increased fluid
and salt intake, raised bed ends at night, slow changes of position, compression
stockings etc, or by adding specific drugs such as mineralocorticoids or midodrine.
Neuropsychiatric adverse events, such as confusion, are usually mild and infrequent but
in approximately 10% of cases can be severe. Impulse control disorders may occur as
with any other DA. Punding, the display of stereotyped, repetitive behaviours, may
become problematic and dopamine dysregulation syndrome has been observed.
Nausea is not a common or severe adverse effect of apomorphine infusion (even though
acute injections of apomorphine have had medical use in the past specifically to induce
emesis). Nausea can generally be controlled with domperidone pre-treatment in the
majority of cases (or trimethobenzamide as an alternative in countries where
domperidone is not available [39]). In March 2014, due to concerns about possible QT
prolongation, the European Medicines Agency issued updated treatment advice for
domperidone. While it may continue to be use for the relief of symptoms of nausea and
vomiting, doses should be reduced to no more than 10 mg up to three times daily and it
should not normally be used for longer than one week
(http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/
Domperidone_31/
Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/
WC500162559.pdf).
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Hemolytic anemia although a potentially severe idiosyncratic adverse outcome, is rare,
occurring in less than 1% of cases. Eosinophilic syndrome is also uncommon but can
very rarely present severe manifestations, including damage to heart and lung tissue,
requiring the drug to be stopped.
Summary and conclusions
This Expert Consensus Group was convened in order to develop clinical practice
recommendations on the use of apomorphine in PD for doctors and healthcare
professionals, in particular those unfamiliar with when and how to make best use of this
therapy.
The advisors recommended that apomorphine treatment, either with intermittent
apomorphine injection (penject) or continuous apomorphine infusion (pump), is suitable
for PD patients with troublesome ‘off’ periods despite optimized oral or transdermal
treatment. After consideration of the full range of non-oral/transdermal therapy options
(apomorphine, DBS, LCIG) clinicians should select apomorphine therapy based on a
patient’s symptoms and potential contraindications for alternative options, as well as the
patient’s preference.
It was recognized from extensive clinical experience over 25 years that apomorphine
can provide rapid (given as a ‘rescue therapy’) and consistent (given as a continuous
infusion) relief from the symptoms of PD. Although it requires subcutaneous
administration, its mode of delivery is less invasive than other therapies often considered
for managing the same stage of disease, namely DBS or LCIG, and is easily and
immediately reversed either when adverse events occur or at the patient’s request.
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Its availability in two formulations – intermittent injection and continuous infusion –
means that apomorphine can be used for a variety of clinical problems. Apomorphine
injection is indicated for patients with both motor and non-motor ‘off’ periods in need of
rapid symptom relief, whereas apomorphine continuous infusion is an option to manage
motor fluctuations that have become refractory to any changes in the oral or transdermal
treatment, e.g. due to dyskinesia or due to intolerable non-motor ‘off’ symptoms or
unpredictability of ‘offs’. This includes the group of patients who respond well to
apomorphine injections but subjectively require too many daily injections.
Figures and Tables
Figure 1: Consensus: Reasons for considering treatment with intermittent apomorphine
injection (pen) and continuous apomorphine infusion (pump).
Figure 2: Consensus: Recommendations for apomorphine infusion (pump) initiation in
the inpatient setting (for outpatients the same protocol should be used but with different
timings).
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Figure 1: Consensus: Reasons for considering treatment with intermittent apomorphine
injection (pen) and continuous apomorphine infusion (pump).
Apomorphine is suitable for PD patients with troublesome ‘OFF’ periods
despite optimized treatment
PEN
Anticipated rescue when required during motor and non-motor off periods
When absorption of oral levodopa is impaired or the patient has gastric emptying problems (gastroparesis)
To treat delayed ‘on’
To treat early-morning motor problems (akinesia and dystonia)
PUMP
Patient considers that rescue doses required too frequently
Dyskinesias limit further therapy optimisation
Non-motor symptoms associated with ‘off’ periods
Simplify complex PD dosing regimens to improve convenience and compliance with therapy
As an alternative to surgical therapy or LCIG if these are contraindicated or because of patient preference
Absorption or gastric emptying of oral levodopa are impaired
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Figure 2: Consensus: Recommendations for apomorphine infusion (pump) initiation in the
inpatient setting (for outpatients the same protocol should be used but with different timings).
APOMORPHINE INFUSION (PUMP) INITIATION Commence 10 mg domperidone tds 1 day before apomorphine initiation then continue for
3–7 days in total. [NOTE: In countries where domperidone is not available , trimethobenzamide treatment tds for 3 days prior to and during apomorphine therapy is recommended as an alternative].
Either:
1. Use apomorphine challenge 1 or 1.5 mg per hour initially increased by 1 or 1.5 mg per hour (minimum interval: 40 minutes) until the minimum effective dose is achieved or adverse effects occur, to determine the range of expected required hourly flow rate and tolerability, or
2. More commonly today, treatment is commenced directly, at a starting dose of apomorphine 0.5 or 1 mg per hour on first day.
Duration of infusion cycle for initiation is waking time, i.e. approximately 16 hours.
Usual dosage 4–7 mg per hour.
Optimal dosage is the dose that leads to sufficient and satisfactory control of motor fluctuations and dyskinesias without, or with minimal, side effects.
The hourly flow rate is up-titrated depending on efficacy and tolerability. T is usually done at increments of 0.5 mg or 1 mg per hour every day during the initial in-patient stay and more slowly afterwards, for instance at weekly intervals.
Oral dopamine agonists are usually discontinued gradually during the up-titration phase of apomorphine. Depending on the dose of the oral dopamine agonist, this usually means that no oral dopamine agonist remains by the time of discharge from the hospital or within 5–7 days. If the dose is low, the oral dopamine agonist may be discontinued on the day of initiating apomorphine. Rapid discontinuation carries a risk of dopamine agonist withdrawal syndrome.
Other antiparkinsonian drugs (MAO-B inhibitors, COMT inhibitors, amantadine, anticholinergics) are subsequently discontinued in a gradual manner, usually within the first days.
Levodopa is usually reduced after the dopamine agonist but may be reduced atthe same time, particularly if dyskinesias are present. If dyskinesias are present, the aim is reduce levodopa substantially or to discontinue it entirely. This may take several weeks or up to a few months.
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