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Brain Injury, April 2010; 24(4): 636641

Continuous subcutaneous apomorphine for severe disorders of

consciousness after traumatic brain injury


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Neurorehabilitation Section and Spasticity Clinic, Institute for Neurological Research, F.L.E.N.I., Buenos Aires,
Argentina, 2CONICET, Buenos Aires, Argentina, 3Neuroscience Department, Institute for Neurological Research,
F.L.E.N.I., Buenos Aires, Argentina, 4Intensive Care Unit Loewenstein Rehabilitation Center, Raanana, Israel,
NeuroHealing Pharmaceuticals Inc. (NHPI), Massachusetts, USA, and 6Spaulding Rehabilitation Hospital,
Harvard Medical School, Boston, MA, USA
(Received 24 June 2009; revised 4 January 2010; accepted 10 January 2010)

Background: The prognosis of long-term severe disorders of consciousness due to traumatic brain injury is discouraging.
There is little definitive evidence of the underlying mechanisms, but a deficiency of the dopaminergic system may be
Methods: In a prospective open-labelled clinical study, the feasibility, relative efficacy and safety of continuous subcutaneous
(s.c.) administration of apomorphine in Vegetative State (VS) or Minimally Conscious State (MCS) patients due to severe
traumatic brain injury (TBI) was tested. Apomorphine was administered to eight patients. Outcome measures were the
Coma Near-Coma Scale (CNCS) and Disability Rating Scale (DRS).
Results: Drug management was implemented without any problems. There was improvement in the primary outcomes
for all patients. Awakening was seen as rapidly as within the first 24 hours of drug administration and as late as 4 weeks.
Seven of the patients had completely recovered consciousness. All improvements were sustained for at least 1 year, even
after apomorphine was discontinued. Drug-related adverse events were all anticipated and resolved after the dose was
Conclusion: Based on this open-label pilot study, continuous s.c. apomorphine infusion appears to be feasible, safe and
potentially effective in improving consciousness in patients in VS and MCS due to severe TBI.
Keywords: Brain injury, vegetative state, minimally conscious state, dopaminergic, apomorphine

Patients who remain in a prolonged state of
unconsciousness following a severe TBI usually
evolve to a VS or MCS. Both conditions are
characterized by the regaining of arousal, but without awareness in VS and a very low capacity in MCS
[1, 2]. To date, there is no proven treatment for
these low functioning post-TBI patients.

The neurobiological basis of prolonged unconsciousness is not completely understood. Severe

closed-head injury produces focal lesions of the
brain and/or, more frequently, a diffuse axonal injury
[3, 4] that results in a wide range of patient
heterogeneity. There is imaging evidence of functional neural activity in isolated groups of neurons or
cortical areas in patients with severely limited

Correspondence: Esteban A. Fridman, MD, PhD, Neurorehabilitation Section and Spasticity Clinic, Neurology Department, Institute for Neurological
Research, FLENI, Montaneses 2325 Buenos Aires, Argentina (C1428AQK). Fax: (0054) 11-5777-3209. E-mail: efridman@fleni.org.ar
ISSN 02699052 print/ISSN 1362301X online 2010 Informa Healthcare Ltd.
DOI: 10.3109/02699051003610433

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Apomorphine for prolonged unconsciousness

consciousness, suggesting the existence of residual
cognitive abilities that cannot be appropriately
accessed [57]. This lack of integration could be
due to selective damage of the thalamus, present
in more than 80% of these patients [4].
Thalamocortical projections from the intralaminar
nucleus are reduced following a severe TBI [8],
affecting the nigro-striatal dopaminergic system.
Indeed, in post-traumatic VS or MCS patients,
abnormalities of dopaminergic neurotransmission
such as reductions of the dopamine transporter and
expression of D2 receptors have been reported [9].
Several different dopaminergic agents have been
used in attempts to stimulate VS and MCS patients
[10, 11]. All the available information to date arises
from case reports using levodopa [1214], bromocriptine [15], amantadine [16] and one single case
using apomorphine [8]. However, levodopa undergoes an extensive first-pass hepatic metabolism and
only a small portion crosses the bloodbrain barrier
[17]. Additionally, in VS and MCS patients continuous parenteral feeding is generally used, while the
absorption of levodopa is known to be compromised
by concomitant administration of proteins in PD
patients [18]. Bromocriptine and amantadine are
weaker dopamine agonists than levodopa, which is
the reason these medications are often used as a
first step treatment in patients with Parkinsons
Disease (PD) in order to delay the administration of
levodopa [19, 20]. Although amantadine has shown
utility in a placebo-controlled study in post-TBI
patients, these patients were not in VS or MCS since
they were capable of being assessed on the
Mini Mental State Evaluation at baseline (mean
value 6) [16].
The present work reports a prospective
open-labelled clinical trial of the feasibility, safety
and potential efficacy of continuous s.c. administration of apomorphine HCl to patients in VS or MCS
due to severe TBI. Among dopaminergic agonists,
apomorphine has many advantages for patients in
VS and MCS. It is a potent, direct-acting agonist
at both the D1 and D2 classes of dopamine receptors
[17], as demonstrated by the fact that apomorphine
is used as the drug of last resort when off-periods can
no longer be decreased with levodopa in PD patients
[21]. Secondly, apomorphine can be administered
continuously s.c. via an external pump and is rapidly
and completely absorbed, allowing for constant drug
levels during treatment [22].

Materials and methods

The study was conducted at two clinical sites, the
FLENI Hospital in Argentina and the Lowenstein
Rehabilitation Center in Israel, with the approval of


both the local Helsinki/Ethics Committees and the

National Health Agencies in charge of experimental

To be eligible, patients had to be between the ages
of 1840 years (one exception of a 41-year old
patient was approved by the medical monitor prior
to entry), clinically stable and had to have remained
in VS or MCS for at least 1, and no more than
4 months following a severe closed head TBI.
No neurological medications other than antiepileptic or anti-spasticity drugs were allowed
during the protocol. Any history of previous neurological functional impairment was also a reason for
exclusion. All informed consent forms were signed
by the patients legal representative according to the
declaration of Helsinki.

Drug administration
Because of the known emetic effects of apomorphine, 2 days prior to the initiation of apomorphine
treatment, patients received 20 mg t.i.d. of domperidone, a peripherally acting dopamine antagonist
that does not cross the bloodbrain barrier [23] and
therefore does not interfere with the CNS activity of
Apomorphine was diluted to a concentration of
5 mg ml1 with isotonic saline and administered
using an external continuous s.c. infusion pump
(Graseby MS16A, Graseby Medical Ltd, UK or
CADD-Legacy PLUS pump Model 6500, Smiths
Medical US).
Initially, dose titration was started at an infusion
rate of 2 mg h1, for 12 hours per day and reached
up to 8 mg h1, for 1216 hours per day, to mimic
the diurnal cycle. Flexibility of the dose titration to
a slower rate and lower top dose was introduced
with continued experience. Treatment with apomorphine was planned for 84 days, with provision
to extend for up to 180 days, under some

Patient management
The nursing staff was instructed to change the
abdominal quadrant of the subcutaneous needle
each day in order to minimize the possible formation
of skin nodules. Additionally, they received instructions to maintain the patients at 30% to prevent any
potential aspiration pneumonia and to be aware
of possible orthostatic hypotension if, and when,
the patient was transferred.


E. A. Fridman et al.

Outcome measures
Two outcome measures were used: ComaNear
Coma Scale (CNCS) and Disability Rating
Scale (DRS).

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Coma-Near Coma Scale [24]. The CNCS measures

small clinical changes in patients with severe brain
injuries at very low levels of consciousness by the
evaluation of 11 items covering sensory, perceptual
and primitive response deficits. Each item is assessed
as absent, partially present or present and scored
4, 2 or 0, respectively. The maximum score of 44
represents the most severe loss of consciousness.
A score of 0 represents a normal level of consciousness. This study reports the total score on
the CNCS.
Disability Rating Scale [25]. The maximum score a
patient can obtain on the DRS is 29 (extreme
vegetative state). A patient without disability would
score 0. The scale is intended to measure general
functional changes over the course of recovery.
One advantage of the DRS is its ability to track an
individual from severe disability to reintegration into
the community.
Safety measures. All serious and non-serious
adverse events were recorded and assessed for
treatment relatedness. Laboratory safety observations included complete blood count and laboratory
chemistries. Each day that the dose was increased,
ECGs were performed 30 minutes prior to and 1 and
4 hours after initiation of dosing, in order to monitor
potential prolongations in the QTc interval.
Standard rehabilitation programme
In addition to the apomorphine treatment, patients
received 1 hour of general mobilization daily in order

to prevent and/or treat spasticity. Patients received

a sensory stimulation programme at least once a
day, for 5 days a week (including motor, visual,
auditory, tactile, olfactory and gustatory stimulation). As patients were recovering consciousness,
speech and physical therapy were introduced.
Since this was an open label study, there were no
pre-specified statistical analyses and all data are

Eight patients were enrolled, four male, four female,
aged 2241 years. Six of them were in a VS and two
in an MCS on entry into the study. All had a DAI
between II and III. More details of their baseline
characteristics and functional score are given in
Table I. Patients 1, 3 and 8 were treated at the
FLENI, all the others at the Loewenstein Hospital.
Apomorphine dosing
Of the eight patients treated with apomorphine, only
the first three patients received the originally planned
maximal dose (i.e. 8 mg h1). In all three cases the
dose was lowered to 6 mg h1 because of the presence of mild adverse events (see below). Of the other
five patients, patients 5 and 6 received up to
6 mg h1, patients 4 and 8 received up to 4 mg h1
and patient 7 up to 2 mg h1. It is important to note
that in the case of patient 1, due to his favourable
response and an initial loss of function on attempts
to withdraw the treatment, apomorphine treatment
was maintained until day 180 (see efficacy observations for more details).

Table I. Patient characteristics at entry into the study.

Pt Age, Gender



25, M






(*): # of days after TBI.


Drugs prior to Apo

Methylphenidate (15 mg qd  12 d), bromocriptine
(10 mg qd  8 d)
Amantadine (50150 mg qd  34 d)

l-dopa/carbidopa (250/25 mg  1.5  11 d)

Amantadine (200 mg bid), l-dopa/carbidopa (250/25 mg)
l-dopa/carbidopa (250/25 mg  11 d, 250/25 mg  1.5  4 d)
l-dopa/carbidopa (250/25 mg  35 d)
Methylphenidate (5 mg bid  28 d), bromocriptine
(5 mg tid  21 d), zolpidem (10 mg qd  28 d)

1 year









Apomorphine for prolonged unconsciousness


Table II. Possibly and probably related adverse events.

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Possibly and probably related AEs

Local AEs
Skin inflammation, skin nodules/Panniculitis
Neuropsychiatric AEs
Dyskinesia(*) 8 mg h1
Sleeping disturbances
Teeth grinding
Cephalic tremor
Hallucination(*) 8 mg h1
Systemic AEs
Vomiting(*) 8 mg h1 and 4 mg h1
Mild eosinophilia(^)
Sporadic penile erection
QTcprolongation (0.44 sec)(*) 4 mg h1

No of pts
(total sample 8)


Figure 1. Point chart of CNCS values from Baseline to 1 year

post-apomorphine initiation of each patient. On the x-axis,
numbers refer to day of evaluation; on the y-axis, numbers refer
to the score on the CNCS. To track individual cases follow
the legend mark for each patient. Group data demonstrates a
progressive and linear improvement that reached normal values
at day 360.

(*) Resolved with 2 mg h1 dose reduction.

(^) Treatment continued. Eosinophilia resolved after discontinuation of the drug.

Apomorphine safety observations

Overall, apomorphine infusion was well tolerated.
Side-effects were deemed to be relatively minor and
manageable, in some cases by lowering the dose
(Table II). Two serious adverse events (SAEs)
occurred and were judged to be unrelated to
apomorphine treatment. Patient 2 experienced a
spontaneous severe subdural bleed with intracranial
hypertension and symptoms of substantial herniation on day 47. The patient was then transferred
to the ICU and apomorphine was discontinued.
The patient died 9 days later. Patient 3 experienced
a seizure that occurred at 6 am on day 38, 10 hours
after the previous days drug infusion was stopped.
Apomorphine was reintroduced 7 days later without
any recurrence.
Apomorphine efficacy observations
Prior to apomorphine administration, none of the
eight patients had responded to commands. All of
them responded to commands after commencing
apomorphine treatment, with the onset of response
occurring from 162 days (four patients within
10 days and the others above 4 weeks) (Figure 1).
Two aspects of these data are worth noting. The
first is the rapidity of the changes in the CNCS
during the first 2 weeks. Secondly, all (but patient 2

Figure 2. Point chart of DRS values from Baseline to 1 year

post-apomorphine initiation of each patient. On the x-axis,
numbers refer to day of evaluation; on the y-axis, numbers refer
to the score on the DRS. To track individual cases follow
the legend mark for each patient. Group data demonstrates
a progressive and linear improvement that reached normal values
at day 360.

who died) reached a CNCS of 0 within 1 year.

It should be noted that patient 6 was still in an MCS
when apomorphine was discontinued at day 56
and subsequently responded after reinstatement of
l-dopa/carbidopa at day 58.
Improvements in DRS were also seen in all
patients (Figure 2). Overall, four patients who
completed the protocol (patients 1, 3, 4 and 7)
reached an independent walking ability. Patients 1
and 4 regained full independence. All other patients
regained consciousness and returned home, but
still required moderate assistance in activities of
daily living. Most importantly, for all seven patients
who completed treatment the improvements were
maintained, even after the discontinuation of


E. A. Fridman et al.

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Selected clinical observations

Patient 1 showed the most rapid response to
apomorphine (for details see Fridman et al. [8]).
Patient 4 was the most severely compromised as
measured by the CNCS and DRS. On day 5,
he responded to commands. By day 56, he started
walking and doing simple arithmetic using his
fingers. He is now working in his familys business.
By day 28, patient 5 was able to obey more than
one command and on day 46 she was able to comb
her hair for the first time. On day 75, once the
patient had reached a CNCS 0, the PI decided
to discontinue the treatment. Patient 6 evolved from
VS to MCS over 4 weeks, but there was no further
improvement through day 56 when apomorphine
treatment was stopped at the request of the legal

Efficacy of continuous s.c. apomorphine administration
in MCS/VS patients
The Multi-Society Task Force on PVS reported that
of 443 patients in PVS for 3 months post-TBI, only
7% showed a good recovery after 1 year, while 17%
showed moderate disability [1]. In contrast, in this
study, six of the eight patients (75%) reached a
status of moderate disability or good recovery after
1 year. Clearly this is not a definitive comparison for
multiple reasons, not the least of which is the fact
that eligibility to participate in this study might have
eliminated some of the patients included in the 1994
study [1]. Nonetheless, the differences in distribution are notable and very encouraging. It should
also be noted that seven of the eight patients had
previously been exposed and failed to respond to
other less potent dopaminergic agonists (levodopa,
bromocriptine, amantadine and methylphenidate).

population that are of concern in VS and MCS

patients are: skin nodules at the site of injection,
nausea/vomiting and, in less than 5% of PD patients,
eosiniphilia and orthostatic hypotension [22, 26, 27].
In addition, apomorphine has been reported to cause
dose-dependent increases in the QTc interval in PD
when used as a single shot [28]; however, this effect
is minimal (i.e. mean increase of 1 millisecond) at
the maximum recommended dose of 6 mg [29].
The incidence and type of adverse events related
to study treatment suggested that apomorphine is
well tolerated in these patients when appropriate
prophylaxis is given. Nonetheless, in those cases
where the adverse event interfered with rehabilitation, a simple dose reduction resolved the problem.
The two SAEs: intra-cranial bleeding in patient 2
and a seizure in patient 3 were both judged as
unrelated to the study drug by externally appointed
committees. Apomorphine has never been associated
with intra-cranial bleeding and delayed traumatic
intra-cerebral haemorrhage in post-TBI patients is a
known phenomenon [30]. In addition, there is an
increasing risk of seizure after severe TBI [31] and
in patient 3 the seizure occurred 10 hours after
the last infusion of apomorphine which has an
elimination half-life of 70 minutes [17].

General conclusion

The use of 12 hours a day continuous s.c. administration of apomorphine in patients in VS or MCS
after severe TBI for many weeks was clearly manageable in two separate clinical settings using
a multidisciplinary team, including a physician,
a specialty trained nurse and physical and occupational therapists.

Continuous s.c. apomorphine infusion is feasible,

safe and may be effective in improving consciousness
in patients in VS or MCS due to severe TBI.
Evidence for efficacy is based on the overall patient
improvements vs historical responses. The rapidity
of the response to treatment from an otherwise
neurological stable state was also better than
expected from the literature and from physician
experience. The fact that seven of the eight patients
had been treated with other dopaminergic stimulants
without response is consistent with a potential
efficacy. Finally, the sustainability of the response
over a period of greater than 1 year adds to the
body of evidence. A limitation to be noted is that
the design used in this study does not allow the
dissociation of the response induced by apomorphine to the one occurring spontaneously. However,
these preliminarily data clearly support the initiation
of a double-blind placebo-controlled trial in this
population of patients.

Safety of continuous s.c. apomorphine administration

in MCS/VS patients


Continuous s.c. apomorphine has been used extensively and safely for many years to treat PD patients.
The most common side-effects reported in the PD

We wish to thank Claudia Navarro for all her efforts

at the ANMAT (Argentinean Drugs Administrative
Office) and manuscript edition.

Feasibility of continuous s.c. apomorphine administration

in MCS/VS patients

Apomorphine for prolonged unconsciousness

Declaration of interest: E.A.F. is an inventor
at the Institute for Neurological Research-FLENI
of the biotechnology used here. E.R.G. is the
Chairman of the Board, and at the time the study
was conducted was Acting Head of Clinical Trials
for NHPI and paid for his work. E.A.F is consultant
and advisor to NHPI, to which the biotechnology
has been licensed. NHI provided support for the
clinical study reported.

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