METHODS
We performed a review of the literature based on review articles, expert opinion manuscripts
and clinical trial reports from the PubMed database, using the following descriptors:
apomorphine, Parkinson's disease, motor fluctuations, deep brain stimulation and intestinal
levodopa/carbidopa. The search was limited to articles published between 1984 and
2017.
Historical review
Apomorphine was the first dopamine agonist with powerful antiparkinsonian effects
used in clinical practice[2] and predated levodopa by ten years[7]
-
[12]. Derived from morphine, it was initially used as an emetic, expectorant, sedative,
antipsychotic and anticonvulsant, as well as for managing drug and alcohol addiction
([Figure 1])[8],[13]. Apomorphine is a highly-lipophilic, short-acting, nonergot dopamine agonist that
acts on D1 and D2 dopamine receptors[8],[9],[13],[14]. It was synthesized for the first time in 1869 by Matthiessen and Wright[9] and, although Weill recommended its use for PD in 1884, the first trials started
in 1950, according Wenzel,[9] Cotzias,[15] and Lees[16]. In 1951, Schwab et al.[17] observed improvements in rigidity and tremor in PD patients 5-10 minutes after subcutaneous
administration of a 0.5 to 1.0 mg dose of apomorphine. These findings were later corroborated
by Cotzias et al.[13],[15],[16].
Figure 1 Apomorphine: molecular structure.(Extracted from Google Images: Pharmajet, August
6, 2017)
Oral administration of apomorphine required large doses to achieve the desired clinical
response, and an exacerbated peripheral response was therefore common. This could
include nausea, vomiting, postural hypotension and impaired kidney function, reflected
in elevated urea and creatinine[16]. Various administration routes were explored to avoid these adverse effects, the
most successful of which proved to be the subcutaneous[7],[8],[9],[18],[20],[21],[22].
Apomorphine is superior to other dopamine agonists such as lisuride because it has
fewer adverse effects and induces significant improvement in motor and nonmotor symptoms,
including hyperhidrosis, nocturia, urge incontinence, fatigue and mood disturbances,
in addition to been well tolerated in patients with visual hallucinations, illusions
and paranoid ideation[23],[24]. It also improves sleep disorders, such as insomnia and restless legs syndrome,
without worsening daytime drowsiness[24].
In 1988, a group led by Lees, developed a mechanism for continuous subcutaneous apomorphine
infusion, which was later routinely recommended for patients with severe, refractory
“off” periods[10]. Although continuous apomorphine treatment was first introduced by Stibe et al.[10] in 1988, subcutaneous injections were only approved by the FDA for use in motor
“off” periods in 2004[14]. The long-term effectiveness of apomorphine as a rescue medication was also investigated
in study APO302, in which 62 patients who had been having rescue injections for at
least three months were assessed[25]. In a comparative assessment on the UPDRS scales, there was a significant reduction
in motor score after 10 and 20 minutes[25].
Mechanism of action of apomorphine
Apomorphine binds to pre- and postsynaptic receptors and exerts a therapeutic effect
by direct stimulation of postsynaptic striatal dopamine D2 receptors, resulting in
activation of the direct pathway and inactivation of the indirect striatopallidal
pathways[1],[7],[8],[11],[15],[26],[27]. The motor response occurs after a single dose of subcutaneous apomorphine and is
similar to that of levodopa but with faster onset (approximately 4-12 minutes), with
a mean effect duration of 45-60 minutes[1],[16]. In light of these therapeutic effects, it became one of the prototypic “rescue
medications” in cases of unpredictable “off” periods, as in the case of patients with
advanced PD and poorly-controlled motor fluctuations, who experience erratic gastric
emptying[7],[8],[9],[10],[12],[22],[25],[28],[29],[30],[31],[32]. Furthermore, it does not share transport mechanisms or metabolic pathways with
levodopa and, unlike levodopa, does not require an active transport mechanism to reach
the central nervous system[7],[8],[9],[10],[18],[28],[31]. Absorption varies with skin temperature and blood flow, and the best absorption
is achieved when it is injected into the subcutaneous tissue of the abdominal wall.
There is no interaction with cytochrome P450 inhibitors, and the cytochrome P450 system
does not interfere with the metabolism of this dopamine agonist. Age, gender, disease
duration, levodopa dosage or duration of apomorphine therapy do not appear to play
any role in the clearance of the medication.[11],[23]
-
[25]
When should apomorphine be used?
The first consideration for the use of apomorphine must be the confirmed diagnosis
of levodopa-responsive PD[1],[11],[33],[34]. Age is typically not a limiting factor, and mild cognitive impairment and axial
symptoms are not contraindications.[35],[36],[37],[38],[39] Indications for apomorphine include patients with refractory “off” periods, e.g.,
when there is a delay in the onset of the effects of orally administered medication;
patients who have major “off” periods upon waking up; and patients with significant
wearing-off periods[7],[8],[9],[10],[11],[27],[28],[32],[38],[40],[41]. It can also improve nonmotor symptoms such as urinary disturbances[3],[24],[35] and serve as a diagnostic clue when diagnosis of PD is uncertain[1],[18],[33].
The therapeutic response to maximum levodopa doses does not vary in PD but is less
consistent in patients with multiple system atrophy. Some patients with other parkinsonian
syndromes are unresponsive or do not respond well to levodopa[1],[11],[33]. A study by the group led by Lees showed that apomorphine can be used as a diagnostic
test of response to levodopa and has an accuracy of 90%[1]. The study concluded that a response to apomorphine supports a diagnosis of PD,
while failure to respond indicates that this diagnosis is extremely unlikely[1].
Routes of administration for apomorphine
Various routes of administration have been investigated[8],[11],[19]
-
[22],[27],[40]. Oral administration was first tried by Cotzias, who increased the dose gradually
to 1,500 mg a day[15]. Tolerance of 150 to 1,440 mg daily doses was generally good, but higher doses caused
azotemia[7],[10],[11],[39]. The bioavailability of apomorphine administered by this route is less than 4% and
this route was therefore considered unfeasible, as it required very high doses to
achieve the desired effect, leading to significant side effects such as nephrotoxicity,
reflected in elevated creatinine and urea[11],[18]. Bioavailability of sublingual apomorphine is also low (10-22%), and a 3 mg subcutaneous
dose and 30 mg sublingual dose have similar pharmacological profiles and clinical
responses[11],[27]. Using this route, Ondo et al.[42] reported an effect duration of between 60 and 130 minutes, while Hughes et al.[29] reported a latency of up to 25 minutes and effect duration of 118 minutes. Apomorphine
can cause nausea,, orthostatic hypotension, an unpleasant taste and severe stomatitis,
the latter being reported in about 50% of patients[7],[8],[9],[10],[11],[18],[39]. The intranasal spray has a pharmacokinetic profile similar to that of subcutaneously
administered apomorphine but requires pretreatment with domperidone[11],[20],[27],[42],[43]. Latency to effect has been shown to be between 5 and 15 minutes, and the effect
duration between 30 and 60 minutes[11],[20],[27],[43]. In a study by Obering et al.[27], the “off” period was significantly reduced from 5.3 hours/day to 3.8 hours/day.
In another study on the use of apomorphine in PD, no statistically significant difference
was observed between levodopa and apomorphine in terms of the UPDRS score[18].
Intermittent apomorphine injection
Ideally, the first dose should be administered in a hospital setting so that the clinical
response can be observed and a tailored therapeutic dose identified[1],[6],[11].
Peripheral dopaminergic adverse events can occur as a complication of injections of
apomorphine, particularly nausea. Oral domperidone (10-20 mg three times a day, should
be started one to three days before apomorphine therapy[1],[11] (Box 1).
-
Pretreatment with domperidone. (10-20 mg three times/day, started one to three days
before apomorphine therapy)
-
Performed when the patient has been off dopamine medication for 12-24 hours. Levodopa
should be suspended the night before the test.
-
Measure blood pressure with the patient lying down, and seated, before the test.
-
Start with 1 mg to 1.5 mg subcutaneous apomorphine. Record the UPDRS-III score (pre-
and post-apomorphine - ON, OFF) and any adverse effects (nausea, orthostatic hypotension,
drowsiness, and dyskinesias).
-
Repeat administration of apomorphine at intervals of 1 to 1.5 hours, increasing the
dose by 1 mg until a good or acceptable clinical effect is observed.
No more than 7-8 mg per hour of apomorphine should be administered.
Currently, penject (intermittent injection) and portable minipumps (continuous infusion)
have been approved in most European countries ([Figures 2] and [3]), where they play an important role in advanced PD treatment and have yielded good
results[11],[14],[15],[30],[31],[35]. Hughes et al.[1] published a study of 71 patients treated with intermittent injections (10/day) or
continuous infusion (when more than 10 injections were needed). In 49 patients treated
with intermittent injections, there was a 50% reduction in “off” time. After one year
of treatment, 80% of the patients reported that the therapy was still effective[1].
Figure 2 Apomorphine: penject.(Extracted from Google Images: Drugs.com, August 6, 2017)
Figure 3 Apomorphine: pump.(Courtesy Prof. Andrew Lees.)
Intermittent infusion of apomorphine (penject) is performed with an insulin syringe
mounted in an injector pen with premarked doses for ease of administration[11],[15],[23]. Injections sites can be administered in the abdominal region, arms and thighs[11],[12]. The number of injections can vary between 1 and 30, and the dose can vary between
1 mg and 10 mg per injection[11],[23]. Apomorphine solution is supplied at a concentration of 1 mg/0.1 mL in 3 mL (30
mg) glass cartridges with a manual reusable multidose injector pen that releases doses
from 0.02 mL to 1 mL (10 mg)[11],[15],[23]. To minimize mistakes, the apomorphine dose should be prescribed in milliliters
(rather than milligrams) as the injector pen uses this unit. An optimal therapeutic
dose is between 0.3 mL and 0.5 mL, or 3 mg and 5 mg[11],[23]. Once a suitable dose has been identified, it rarely needs to be adjusted. The half-life
of apomorphine is 45 minutes, and the minimum recommended time between injections
is 60 minutes[11],[23]. The drug is absorbed quickly after subcutaneous injection, reaching maximum serum
levels in 20 minutes, and the clinical effect can be observed between 5 and 15 minutes
after administration[11],[13],[23]. Apomorphine is generally indicated for short periods. The mean daily dose is 3-30
mg/day, and it is important to determine the dose required to reverse the “off” period[11],[23]. Intermittent apomorphine infusion is a good rescue therapy in cases of motor fluctuations,
such as wearing-off and on-off fluctuations, because of its fast action[11],[12],[23]. When required, apomorphine should be used as a rescue medication during “off” periods,
without changing the levodopa schedule. It can reverse predictable and unpredictable
“off” periods and is indicated when the “on” period is delayed[11],[15],[23]. It helps with morning or nocturnal akinesia as well as painful dystonias, and is
a suitable choice when absorption of orally administered levodopa is hampered by delayed
gastric emptying[11],[12],[23]. Apomorphine can also improve psychiatric symptoms such as depression and panic
attacks[24]. Some surgical centers use apomorphine administered by penject as a rescue medication
in preoperative patients when oral medication cannot be administered[11],[23].
Continuous apomorphine infusion
An infusion pump is recommended when “off” periods are poorly controlled by oral treatment
or when apomorphine injections are effective but required more frequently (more than
4-6 times a day)[11],[23],[44],[45]. The patient can be kept in a continuous “on” state with an improvement in dyskinesias,
and the levodopa dose can be reduced[11],[23],[36]. Like intermittent infusion, continuous infusion of apomorphine helps nonmotor symptoms
such as pain and mood swings. This form of administration is recommended for patients
in whom duodenal levodopa infusion and DBS are contraindicated. Of the options available
for advanced stages of the disease, it is the least invasive[36]. Unlike with DBS, age and neuropsychiatric changes are not absolute contraindications
for apomorphine infusion[11],[46],[47]. Continuous apomorphine infusion is also an alternative to oral treatment, which
is complex and may have limited adherence or may not result in adequate absorption,
as it minimizes drug interactions when the patient is taking several medications[6],[11],[23]. Various studies have shown that the levodopa dose can be reduced by between 16%
and 18% after apomorphine is started[1],[11],[23]. Apomorphine can also reduce the “off ” period by 50% to 80% and guarantees patient
mobility during the day even in the absence of levodopa[6],[11],[23].
The initial assessment should include an electrocardiogram to exclude the presence
of a long QT interval, tachycardia, bradyarrhythmias, atrial fibrillation and premature
ventricular contractions, and should exclude pre-existing hemolytic anemia[4],[11]. Box 2 shows the main contraindications for use of apomorphine.
Box 2
Contraindications for apomorphine.
-
Hemolytic anemia
-
ECG changes (prolonged QT, atrial fibrillation, tachycardia, bradyarrhythmias, premature
ventricular contractions)
-
Use of anticoagulants
-
Diabetes and other diseases that inhibit healing of surgical wounds
-
Cellulite and other local infections
-
Hypersensitivity to apomorphine or components of the formulation, such as sodium metabisulfite.
-
Severe psychiatric symptoms.
One day before starting apomorphine treatment, patients should be pretreated with
10 mg of domperidone, which can be discontinued as soon as possible, when the adverse
effects of apomorphine have been controlled[6],[11]. The teflon delivery needle is inserted in the subcutaneous tissue of the abdominal
wall, and the site is changed at least every day. Continuous infusion is usually started
in a hospital setting, with a flow rate of 0.5 or 1 mg/hour during the first day.
The infusion cycle is generally 12-24 hours a day (typically 16 hours), and the usual
dose is 4-7 mg/hour[11],[46]. The hourly flow rate is adjusted depending on its effectiveness and patient tolerability.
Generally, the rate is increased by 0.5-1.0 mg/hour every day during the initial period
and more slowly after that at weekly intervals. Some patients are encouraged to use
a booster dose in anticipation of “off” periods[11],[46].
In patients being treated with continuous subcutaneous infusion of apomorphine, oral
dopamine agonists can gradually be discontinued during the apomorphine titration period[12]. Sudden interruption of these agonists can lead to dopamine agonist withdrawal syndrome[11],[12]. Other antiparkinsonian medications (monoamine oxidase-B inhibitors, catechol-O-methyltransferase
inhibitors, amantadine, anticholinergics) should then be discontinued gradually, usually
in the first seven days[11],[12]. Levodopa is generally reduced when the desired therapeutic dose of apomorphine
is reached but can be reduced when apomorphine is started if dyskinesia is present[11],[12],[37].
Adverse events
The most common long-term side effect, which occurs in up to 70% of individuals, is
nodules at the injection site[11],[14]. Some patients may develop itching, bruising or pain. These local adverse effects
are related to drug concentration, infusion time or injection depth[11],[14]. In some patients (10-20%) reactions may be more severe, and necrotic nodular ulcerations
or panniculitis may occur. This can be solved by rotating the injection site every
day, ensuring asepsis, applying silicone gel patches or, in some cases, it may be
necessary to use ultrasound treatment[11],[14]. García Ruiz et al.[40] found that sedation occurred in 29% of patients using an apomorphine pump. Orthostatic
hypotension can be a manifestation of dysautonomia or due to dopamine stimulation
and can be improved with domperidone. In some cases, patients may need to wear compression
stockings, keep their legs raised and take salt tablets or even fludrocortisone together
with midodrine[11],[12]. Hematological tests at regular intervals are recommended to avoid the risk of hemolytic
anemia[11],[12].
Electrocardiographic changes (QT prolongation) can occur with doses of 6 mg or more.
Prophylactic treatment with dopamine antagonists (e.g., metoclopramide and prochlorperazine)
and serotonin receptor antagonists (e.g., granisetron and ondansetron) should be avoided
because these agents cross the blood-brain barrier and can interact with apomorphine[6],[11]. When used with ondansetron, apomorphine can cause severe hypotension and loss of
consciousness[6],[11]. Concomitant use of 5-HT3 antagonists is contraindicated. Doses of more than 6 mg
do not lead to additional benefits and are not recommended[11],[12].
[Table 1] summarizes the main adverse effects of subcutaneous apomorphine.
Table 1
Adverse effects associated with apomorphine.
|
Local
|
Subcutaneous nodules, local allergy, panniculitis.
|
|
Systemic
|
Fatigue, nausea, dizziness, orthostatic hypotension and mental confusion, yawning.
|
|
Hematological
|
Hemolytic anemia.
|
|
Psychiatric
|
Psychosis (associated with the patient's cognitive decline and disease duration and
severity), dopamine dysregulation syndrome and impulse control disorder.
|
Conventional oral treatment vs. apomorphine
The quality of the response to oral levodopa is indistinguishable from the quality
of the response to apomorphine[11],[16]. Apomorphine, however, produces a shorter motor response, supporting the idea that
the integrity of the postsynaptic receptors is the key factor that determines the
dopamine response in Parkinson's disease treatment. In other words, the clinical responses
to the drugs are the same although they have different mechanisms of action[11],[16].
Apomorphine has various advantages over levodopa, such as the fact that it is a monotherapy
and increases the “on” period by maintaining a continuous dopamine stimulus, reducing
the need for levodopa and, in turn, reducing dyskinesias and motor fluctuations[6],[11],[37],[44],[45].
As it is administered parenterally, apomorphine improves treatment adherence in patients
who cannot tolerate oral medicine or in whom absorption is erratic[6],[11]. However, it requires help from relatives or caregivers to handle the pump. Furthermore,
apomorphine crosses the blood-brain barrier quickly without depending on an active
transport system and without competing with proteins in the circulation[1],[11].
Other device-aided therapy strategies vs. apomorphine
Deep brain stimulation is currently widely accepted as an alternative in stages of
PD when motor complications are significant, or the symptoms of the disease are not
well controlled[37],[38],[47]. Deep brain stimulation of the subthalamic nucleus and apomorphine infusion produces
significant improvements in parkinsonian symptoms and motor fluctuations through different
mechanisms[2],[11],[38],[39],[47]. The choice of therapy depends on the profiles of individual patients. Although
the surgical procedure is considered relatively safe, it obviously is not risk-free
and potential adverse effects of DBS include hypophonia and other bulbar symptoms,
behavioral and cognitive changes, infections, transient confusion, seizures, intracranial
bleeding, and various forms of hardware dysfunction[11],[38],[47],[48]. For example, a Spanish study that compared DBS and treatment with apomorphine showed
that neuropsychological testing for the apomorphine group did not change, while for
the patients who underwent DBS surgery, verbal phonemic fluency and word-naming speed
were affected negatively[47]. Additionally, apomorphine infusion therapies can be used in patients with severe
cognitive impairment and psychiatric disorders. Borgemeester et al. published a retrospective,
long-term follow-up study about continuous subcutaneous apomorphine infusion in PD
patients with cognitive dysfunction.[49] The study demonstrated that apomorphine infusion is an effective treatment in advanced
PD patients with cognitive dysfunction, including visual hallucinations and orthostatic
hypotension.[49] Combined use of DBS and an apomorphine pump can be considered in patients with adverse
effects on axial functions, such as altered gait or dysarthria[47],[50].
Continuous enteral infusion of levodopa/carbidopa gel (LCIG) was tested in small studies
published in 1986[51] and 1988[52], and then in a long-term study developed at the University of Uppsala, Sweden[53], as a therapeutic alternative for the advanced stage of the disease. It is a combination
of levodopa (20 mg/mL) and carbidopa (5 mg/mL) in a pseudoplastic gel and is delivered
directly into the proximal jejunum by means of a portable infusion pump and duodenal
catheter[11],[53]. It has the advantage that it ensures a stable flow of dopamine into the striatum
and, consequently, an increase in “on” time without dyskinesias[11],[53]. It also improves nonmotor symptoms such as drowsiness, fatigue, impaired attention,
memory loss, and gastrointestinal, urinary and cardiovascular problems[53]. Ricciardi et al.[54] evaluated 24-hour infusion of LCIG in eight PD patients to address severe nocturnal
dyskinesia unresponsive to oral therapies. They found significant improvements in
fatigue and sleep quality, mood/cognition, hallucinations, and urinary function, and
there was no change in motor severity or motor complications. The most common adverse
effect is dyskinesia, although this is less common than with oral treatment[2],[28],[53],[55]. Long-term use of high doses of levodopa leads to increased homocysteine levels
and reduced cobalamin metabolism. The risk of severe infections such as peritonitis
is low. Nevertheless, such infections, if they occur, can lead to death[53],[55]. Other adverse effects may include skin problems at the surgical site, weight loss
and peripheral axonal neuropathy, the mechanism of which is poorly understood[53]. There are small trials comparing apomorphine infusion and LCIG, showing that the
apomorphine pump is easier for caregivers and patients to use, and is less expensive[56]
-
[58]. However, if apomorphine infusion does not yield satisfactory results, jejunal levodopa
may be indicated[11],[12],[58].
The choice of apomorphine or LCIG depends on the individual patient and should take
into account the adverse effects and technical aspects of each therapy[11],[12],[58],[59]. The expert consensus groups recognize the rapid and consistent relief from the
symptoms of PD provided by apomorphine. Its mode of delivery is less invasive than
DBS or LCIG, other therapies also considered for the treatment of this stage of the
disease. Also, apomorphine infusion can be easily and immediately reversed, either
when adverse effects occur or at the patient's request[60]. [Table 2] summarizes the main therapies discussed here.
Table 2
Comparison of the different treatment options.
|
Variable
|
Indication
|
Advantages of the procedure
|
Disadvantages of the procedure
|
Adverse effects
|
|
Deep brain stimulation
|
The best option in cases of dyskinesia
|
Less need for dopamine medication
|
Invasive therapy with surgical risks such as hemorrhage and infection
|
Worsening of neuropsychiatric function, cognitive changes
|
|
Reversible
|
Can lead to worsening of speech, postural instability and freezing of gait
|
|
Non-ablative
|
|
Better for refractory tremor
|
|
Apomorphine
|
Rescue from “off” episodes
Motor fluctuations
|
Mildly invasive
Parenteral administration (important for patients who cannot tolerate oral medication
or have poor absorption)
Crosses the blood-brain barrier quickly without any need for active transport and
without competing with proteins in the circulation.
|
Frequent blood tests and ECG are required Requires relatives or caregivers to handle
the pump
|
Local, systemic, hematological and psychiatric (see [Table 1])
|
|
Jejunal levodopa-carbidopa
|
Frequent “off” periods or severe dyskinesia When DBS and apomorphine are contraindicated,
ineffective or inappropriate
Can improve postural problems and produce some response in gait
|
More physiological release of dopamine and less pulsatile stimulus
|
Can worsen dyskinesia Can cause anxiety, depression, hallucination and confusion
|
Peripheral polyneuropathy
|
|
Less invasive than DBS Safe.
|
|
No age limit; mild and moderate dementia are not contraindications
|
