Motor fluctations are common in
patients with advanced Parkinson discase (PD)
whose symptoms are managed with oral levodopa
and represent some of the most disabling
complications of the disorder. The transition
from good motor (on-state) function to that of
poor motor (off-state) function occurs when
brain levodopa levels fall below the threshold
needed to adequately stimulate striatal dopamine
receptors. Since the progression of PD is
typically accompanied by progressive shortening
of the clinical effect from each dose of
levodopa, off states often occur unless
strategies are used that can provide a more
contirmous stimulation of dopamine receptors. A
number of such strategies have been developed
including the use of dopamine agonists, catechol
O-methyl transferase inhibitors, and
controlled-release formulations of levodopa.
While these strategies are often helpful, some
patients continue to suffer from episodic, often
unpredictable, off states.
There are no agents available in the United
States that can provide a rapid reversal of an
individual off state, This "rescue" property is
highly desirable since off states can be very
disabling to some patients precipitating
immobility, panicattacks, pain, screaming, or
drenching sweats.
Apomorphine is a direct-acting dopamine
agonist with strong D1 and D2 dopamine
receptor-stiniulating properties that is
administered by a parenteral route
(intravenously, rectally, subcutaneously,
sublingually, or intranasally). It has similar
efficacy to levodopa with a substantially more
rapid time to onset. While an extensive
literature exists for apomorphine therapy for
PD, only a few studies have been conducted as
randomized, placebo-controlled trials using
subcutaneous injections of apomorphine to abort
offstate events.To our knowledge, only a single
study has been previously published evaluating
the drug in both inpatient and outpatient
settings; in the outpatient setting, all
patients received active drug without a placebo
comparator. To date there have been no
publislied studies attempting to correlate
inpatient efficacy incasures with outpatient
results. The present study was perforined to
establish the efficacy and safety of
subcutancous apomorphine injections in a
therapeutic setting and establish wheter
inpatient efficacy measures accurately predict
outpatient responses when both assements are
perfromed in a placebo-controlled, double-blind
fashion. [...]
Adverse effects : Adverse events
(mostly mild in severity) occurred in 85% of
apomorphine-treated patients and in 89% of
placebo-treated patients. A single serious
adverse event (chest pain, myocardial infarction
ruled out) occurred in a patient assigned to the
placebo study drug. Similar events, without
hospitalization, occurred in 3
apomorphine-treated patients. Injection site
complaints (including bruising, pain, skin
reaction, and nodule development) were
common.
Yawning was reported by 40% of the
apomorphine-treated group but none of the
placebo-treated group (P=.03). Thirty-five
percent of the apomorphine-treated patients (and
no placebotreated patients) experienced
drowsiness or somnolence (P=.07). Dyskinesias
were reported as an adverse event by 35% of the
apomorphine-treated group and 11% of the
placebo-treated group. Nausea or vomiting
occurred in 30% of the apomorphine-treated
patients and 11% of the placebo-treated
patients. In 1 apomorphine-treated patient,
nausea with vomiting at the 6-mg dose (given
during the inpatient phase) was severe and
resulted in discontinuation from the study.
Outpatient nausea was usually mild to moderate
in severity and was generally reported as an
isolated event (nausea was not seen in 96% of
all apomorphine-treated patients who reccived
outpatient injections).
Uric acid demonstrated statistically
significant change from the mean baseline value
(+0. 27 mg/dl for apomorphine, -0.34 mg/dL for
placebo, P=.02) but was never outside the normal
range. There were no statistically significant
changes in other safety measures (blood test
results, electrocardiograms, or physical
examination findings).
Comment : This study was conducted in
patients with significant residual off time
despite aggressive attempts to control symptoms
using both levodopa and oral dopamine agonists.
In this setting, outpatient subcutaneous
injections represent a reasonable therapeutic
option for acutely reversing individual off
events. This is the first clinical trial to
evaluate both inpatient and outpatient use under
placebo-controlled conditions, and it
established the predictive nature of inpatient
test responses on outpatient therapeutic
responses to injected apomorphine.
Our study showed that subcutaneous
apomorphine injections effectively reverse
off-state events that occur in advanced PD.
Outpatients or caregivers demonstrated the
capacity to prepare apomorphine from glass
ampules and inject it. While we did not use
formal quality of life measures, most patients
assigned to active drug were pleased with the
effects. Patients randomized to apomorphine
treatment had reduced total off time that was
not derived from lessening the number of
offstate events, but from shortening the
duration of individual off states. Although
within-day tolerance has been previously
demonstrated following intravenous infusions of
apomorphine, this phenomenon was not observed
with the subcutaneous injections used in our
study.
Since levodopa dosage was not predictive of
apomorphine dose requirements, individual
titration is required to establish the correct
dose. Under inpatient observation, the average
dose required to produce effects equivalent in
magnitude to oral levodopa was 5.4 mg, while the
average final outpatient dose was 5.8 mg. At
levodopa-equivalent doses, dyskinesias were
equal in magnitude to those produced by
levodopa, but these were mild and generally
nondisabling. The only adverse event that was
significantly more common in the
apornorphine-treated group was yawning. This
adverse effect has been reported in patients
treated with apomorphine in other studies but is
rare with levodopa and the oral dopamine
agonists. A review of the Physicians Desk
Reference revealed that of the oral dopamine
agonists and levodopa preparations available in
the United States, yawning is a listed
adverse effect only for ropinirole hydrochloride
occurring in 3% of patients. The 40% incidence
of yawning associated with apomorphine in our
study represents more than a 10-fold increase
compared with ropinirole. Studies of apomorphine
induced yawning in rats have indicated that
stimulation of D2 dopamine receptors on
paraventricular neurons of the hypothalamus
leads to increased nitric oxide synthase
activity and yawning behavior. Why levodopa,
which produces a similar degree of
antiparkinsonian efficacy, is associated with a
much lower incidence of yawning is
unknown.
Our data show that domperidone is not needed
to support the use of apomorphine in patients
selected and treated according to our protocol.
Clinically significant nausea and vomiting was
as rare in our study (only 4% of injections of
active drug caused nausea) as has been
previously reported in European studies of
apomorphine combined with domperidone. Our data
suggest that trimethobenzamide is an adequate
replacement for domperidone therapy.
Alternatively, it is possible that
down-regulation of dopamine receptors in the
area postrema had already occurred because of
chronic exposure to long-acting oral dopamine
agonists and that this patient group actually
does net require an antinauseant.
We conclude that subcutaneously injected
apomorphine rapidly and reliably reversed
off-state events in patients with advanced PD in
whom conventional antiparkinsonian medications
had been optimized. We believe that this study
confirms previous work and serves as proof of
the clinical effectiveness of subcutaneous
apomorphine injections when used to reverse off
events.
