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Continuous dopaminergic therapy in Parkinson disease Time to stride back.

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Continuous Dopaminergic Therapy in
Parkinson Disease:
Time to Stride Back?
-dopa remains the mainstay of treatment for Parkinson disease (PD) and is the single most effective treatment for all its cardinal features. However, although
L-dopa remains effective throughout the course of the illness, its use is associated with fluctuations in motor function and dyskinesias in about 50% of patients within 5
years. A very substantial body of literature based on studies conducted in both rodent and nonhuman primate
models of PD suggests that dyskinesias arise from the pulsatile stimulation of dopamine receptors in the presence
of severe dopamine denervation.1– 4 Pulsatile stimulation
of the dopamine-denervated striatum results in or enhances the likelihood of a cascade of events downstream
to dopamine receptors, including D1 receptor-dependent
induction of immediate early genes, increased proteinDNA binding, and phosphorylation of the striatal signaling protein DARPP-32,5 and loss of depotentiation of
long-term potentiation.6 Enhanced sensitivity to dopamine D1 receptor stimulation is associated with induction
of extracellular signal-regulated kinases in the direct striatonigral pathway.7 These processes have a molecular
memory, may be associated with structural changes and
altered receptor trafficking,8 and are essentially irreversible
once they occur, at least in the presence of dopaminergic
stimulation sufficient to relieve symptoms.
Studies in animal models of PD have demonstrated
sensitization of behavioural responses to dopaminergic
stimulation and/or dyskinesias when dopamine denervated animals undergo repeated treatment with L-dopa or
with short-acting dopamine agonists. Such responses are
not seen when L-dopa is administered continuously or
when long-acting dopamine agonists are used. This body
of evidence led to the concept of continuous dopaminergic stimulation (CDS) and appeared to receive partial
support from the consistent observations that introduction of therapy with dopamine agonists with relatively
long half-lives was associated with a lower incidence of
dyskinesias (if also less benefit) compared to L-dopa.9,10
If it could be given continuously, might one be able
to enjoy the clear advantages of L-dopa therapy while still
avoiding the undesired side effects down the road? Controlled release L-dopa preparations result in only slightly
longer duration of action compared to the standard preparation, and their use is not associated with a reduced rate
of motor complications at 5 years11 (although the complication rate was low in both treatment arms in this
study). Continuous enteral infusion is not practical for a
majority of patients and is extremely expensive. Although
its use may be beneficial for the management of complications once they have occurred in some patients with
advanced disease,12 it has never been tested for its ability
to reduce the later development of complications when
used from the outset of therapy. It was therefore hoped
that combination of L-dopa with an inhibitor of catechol
O-methyltransferase (COMT) might serve this purpose.
COMT inhibitors are well accepted as adjunctive therapy
with L-dopa for the management of motor fluctuations
once they occur and typically add approximately 1.5
hours of ON time per day in such patients.13–15
The purpose of the STRIDE-PD study, published
after much anticipation in this issue of the Annals of Neurology,16 was to determine whether the early use of the
COMT inhibitor entacapone could prevent the later
emergence of dyskinesias. Nearly 750 PD patients from
77 centers were studied over 2 to 4 years following initiation of therapy with L-dopa/carbidopa alone or with
L-dopa/carbidopa ⫹ entacapone (LCE). Medication was
administered 4⫻ daily at intervals of 3.5 hours. In contrast to expectations, the use of entacapone was associated
with a shorter time to onset and an increased risk (hazard
ratio, 1.29; p ⫽ 0.04) of dyskinesias. The increased risk
of dyskinesias in patients randomized to receive LCE was
restricted to those taking dopamine agonists at baseline
(hazard ratio, 1.55; p ⫽ 0.006). These patients were
younger ( p ⬍ 0.001), were also younger at disease onset,
and had a longer duration of disease ( p ⬍ 0.001). Other
factors associated with an increased risk of dyskinesias included short disease duration (presumably reflecting more
© 2010 American Neurological Association
of Neurology
aggressive disease) and concomitant use of monoamine
oxidase type B inhibitors. There was a nonsignificant reduction in the incidence of wearing-off phenomenon in
patients receiving LCE, although the time to onset of this
related complication was similar between groups.
This carefully conducted study showed the exact opposite of what the investigators (and sponsors) had hoped
to demonstrate. Does this disappointing outcome mean
that the theory of pulsatile stimulation of dopamine receptors leading to complications of therapy (and its corollary, that CDS is beneficial) is wrong? Probably not.
First, LCE at the dose regimen employed (4⫻ daily, at
intervals of 3.5 hours) may not have resulted in true
CDS. Second, the increased risk of dyskinesia associated
with LCE use was restricted to subjects who probably had
more severe disease (by virtue of requiring dopamine agonists) and with other risk factors for this complication.
Third, when one accounts for the pharmacokinetic effects
of COMT inhibition, the LCE patients received significantly higher equivalent L-dopa doses at all relevant time
points. It is worth remembering that at least in rodent
studies, continuous L-dopa administration is associated
with lower peak drug levels than intermittent administration, and that higher doses, even administered in a continuous fashion, may elicit behavioural and metabolic effects similar to those of acute administration.17 Thus, to
achieve levels satisfactory for symptom control in humans,
continuous administration of L-dopa may inevitably result
in doses higher than intended. Finally, studies using
positron emission tomography indicate that PD patients
with dyskinesias have a relatively greater magnitude but
shorter duration of dopamine release following each dose
of L-dopa,18 but that similar changes are seen in patients
who go on to develop fluctuations, even at a time when
they still have a clinically stable response to medication.19
An unanticipated outcome of the study was an increased rate of prostate cancer in the patients randomized
to receive LCE. This has not been seen in prior trials of
entacapone, but catechol estrogens and their quinone derivatives may be relevant to prostate cancer induction, and
COMT may play a protective role.20 –22 The US Food
and Drug Administration has recently announced a safety
review of this issue.
It should not be forgotten that the motor effects of
sensitization to dopaminergic stimulation are paralleled by
behavioural problems that may be even more distressing
to patients and their families.23 Although sustained stimulation of cortical dopamine receptors may contribute to
an increased tendency to risk-taking,24 the avoidance of
sensitization remains an important goal in the management of PD. The current study suggests that there is no
role for the adjunctive use of entacapone in early PD, but
this does not of course diminish its potential utility in the
management of motor fluctuations once they occur. Attempts to recapitulate physiological patterns of dopamine
receptor stimulation remain an important goal of longterm therapy.
The author’s work is supported by the Canadian Institutes of Health Research, the Michael Smith Foundation
for Health Research, the Pacific Alzheimer Research
Foundation, and the Canada Research Chairs program.
Potential Conflicts of Interest
Nothing to report.
A. Jon Stoessl, MD
Pacific Parkinson’s Research Centre
University of British Columbia
Vancouver Coastal Health
Vancouver, BC, Canada
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