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Drug selection and timing of initiation of treatment in early Parkinson's disease.

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CLINICAL ISSUES
Drug Selection and Timing of Initiation of
Treatment in Early Parkinson’s Disease
Anthony H. V. Schapira, MD, DSc, FRCP, FMedSci,1 and C. Warren Olanow, MD, FRCPC2
There is increasing evidence to challenge the traditional view that the initiation of drug treatment in Parkinson’s disease (PD)
should be delayed until the patient has significant disability such as to affect work or social function. Firstly, to delay treatment
sentences the patient to protracted impairment of quality of life that could be improved by therapy. Secondly, there is evidence
to support the notion that earlier rather than later initiation of treatment leads to better long term motor benefit. The selection
of which drug to begin must be tailored to the patient’s individual characteristics and circumstances. Monoamine oxidase B
inhibitors result in a mild improvement in motor function compared to dopamine agonists or levodopa. They are well tolerated,
easy to use once a day drugs and there is evidence that early use of Rasagiline improves motor outcome. Dopamine agonists lead
to a substantial improvement in motor function and are, or will shortly be, available as once a day drugs. They are generally well
tolerated but can be associated with exacerbating confusion or hallucinations and with behavioral changes. Levodopa is the most
potent of the dopaminergic drugs. It is routinely combined with a dopa decarboxylase inhibitor and can also be used with a
catecholo-o-methyl transferase inhibitor for enhanced absorption. The most important limiting factor for the use of levodopa is
the emergence of motor complications. These are related to a number of factors including the dose of levodopa and the duration
of its use.
Ann Neurol 2008;64 (suppl):S47–S55
Parkinson’s disease (PD) is the second most common
neurodegenerative disease after Alzheimer’s disease.
The incidence of PD is estimated to be 8 to 18 per
100,000 person-years, and its prevalence rate is approximately 0.3% of the entire population, affecting more
than 1% of those older than 60 years and up to 4% of
those older than 80 years.1
Clinically, PD is diagnosed in its early stages by the
asymmetric onset of a bradykinetic rigid syndrome
with resting tremor. However, several studies have
shown that certain nonmotor symptoms such as olfactory dysfunction, depression, and rapid eye movement
sleep behavior disorder may precede the motor features.2,3 Not withstanding the fact that PD is a multicentric neurodegenerative disease, the dominant early
clinical features of PD are a consequence of degeneration of the dopaminergic neurons of the substantia
nigra pars compacta. The additional pathological hallmark of PD is the presence of Lewy bodies in a proportion of surviving neurons. Braak and colleagues4
have suggested that these inclusions may be present in
the olfactory bulb and lower medulla before the loss of
dopaminergic nigral neurons, and that the progression
of PD is marked by the cephalic spread of ␣-synuclein
pathology through the upper brainstem and cortex.4
Thus, the classic concept of the symptomatic and
pathological features that define early PD is evolving
and is no longer constrained by the notion that dopaminergic dysfunction and motor abnormalities are the
sole expression of early disease.
From the 1University Department of Clinical Neuroscience, Institute of Neurology, London, United Kingdom; and 2Department of
Neurology, Mount Sinai School of Medicine, New York, NY.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ana.21460
Received Mar 29, 2008, and in revised form Jun 6. Accepted for
publication Jun 13, 2008.
Potential conflict of interest: This article is part of a supplement
sponsored by Boehringer Ingelheim (BI). A.H.V.S. has received
honoraria as a consultant for BI, GlaxoSmithKline, Teva, Lundbeck,
Novartis, Orion, and Solvay. C.W.O. has served as a consultant to
BI, Novartis, Teva, Merck Serono, and Ceregene.
Drugs Available for Parkinson’s Disease
Most of the drugs currently available for therapy in PD primarily act on the dopaminergic system and consist of L-dopa,
dopamine agonists, monoamine oxidase B (MAO-B) inhibitors, and catechol-O-methyl transferase (COMT) inhibitors.
Anticholinergics and amantadine are also available but are
not commonly used in routine practice.5 Later, we will consider the pros and cons of each of these therapies, particularly with reference to early treatment.
New nondopaminergic drugs are under development, for
example, ␣2-adrenergic antagonists, serotoninergics, and
Address correspondence to Prof. Schapira, University Department of
Clinical Neurosciences, Institute of Neurology, Rowland Hill Street,
London, NW3 2PF, United Kingdom.
E-mail: a.schapira@medsch.ucl.ac.uk
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
S47
adenosine A2a antagonists, but are not currently available,
and they currently are not being tested for use as initial therapy in PD.6
Levodopa
L-Dopa was the first drug used to treat the dopamine deficiency of PD, and it is considered the gold standard against
which other drugs must be judged. L-Dopa is administered
routinely in combination with a dopa-decarboxylase inhibitor to reduce peripheral metabolism to dopamine, and
thereby decrease dopaminergic side effects such as nausea,
vomiting, and postural hypotension. L-Dopa is typically initiated in dosages of 200 to 300mg/day in two to three divided doses. The drug provides rapid and effective relief of
bradykinesia, rigidity and associated pain, and tremor in
many patients. In one of the few double-blind, placebocontrolled trials of L-dopa in patients with early PD, L-dopa
was shown to have dose-related benefits, and 600mg L-dopa
daily improved Unified Parkinson’s Disease Rating Scale
(UPDRS) scores compared with placebo by 6 points at 8
weeks and by 10 points at 24 weeks.7 L-Dopa has also been
reported to improve both the quality of life and life expectancy of PD patients.8 Initial concerns regarding the potential
for levodopa to be toxic have not been reflected in clinical
practice.9 No other medical or surgical therapy has been
demonstrated to provide greater efficacy than can be
achieved with L-dopa.
L-Dopa treatment is associated with both acute and
chronic side effects. The initiation of L-dopa can be associated with nausea, vomiting, and anorexia. These side effects
usually disappear over 2 to 3 weeks but may persist in some
patients. They are thought to relate to activation of dopamine receptors in the brainstem that are not protected by the
blood–brain barrier. These can usually be prevented or attenuated by treating with the peripheral dopamine receptor
antagonist domperidone 10 to 20mg three times a day, taken
for approximately 2 to 4 weeks. In the United States where
domperidone is not available, other approaches can be tried
such as slow titration, the addition of supplemental doses of
the decarboxylase inhibitor carbidopa (Lodosyn), and administration of the drug with foods. Constipation, orthostatic
hypotension, akathisia, and daytime sleepiness are less common and are seen more often in the elderly population. Hallucinations are a recognized consequence of PD pathology
that develop in the mid to advanced stages of the disease,10
and can be aggravated by L-dopa and other dopaminergic
medications. These neuropsychiatric problems may respond
to dose reduction but sometimes require the use of antipsychotic medications. Atypical neuroleptics are usually administered in low doses to avoid exacerbation of PD and sedative
side effects. Some patients experience additional psychiatric
effects from L-dopa including obsessive traits, punding, and
impulse control disorders (pathological gambling, hypersexuality, and compulsive eating and shopping). Punding is
thought to represent a form of the dopamine dysregulation
syndrome and is most typically seen with L-dopa.11 It consists of repeated purposeless activities such as gathering or
assembling and disassembling objects for no apparent reason.
In contrast, impulse control disorders can be seen with
L-dopa but have primarily been described in association with
the use of dopamine agonists.12,13
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Annals of Neurology
Vol 64 (suppl)
December 2008
The most common problem that occurs in association
with chronic L-dopa treatment is motor complications (motor fluctuations and dyskinesia). L-Dopa has a relatively short
half-life of about 60 to 90 minutes. Despite this, in early
disease, L-dopa has a long-duration effect that enables adequate symptomatic control to occur with no interdose loss of
benefit even when the drug is administered two or three
times daily. However, as PD progresses, an increasing proportion of patients begin to experience reemergence of symptoms before the next L-dopa dose, the so-called wearing-off
effect. Over time, the duration of benefit after each dose progressively shortens, approaching the half-life of the drug. In
addition, a significant number of patients experience development of involuntary movements or dyskinesias. The (Earlier versus Later LevoDOPA) ELLDOPA study showed that,
in patients with early PD treated with 600mg L-dopa daily,
16.5% developed dyskinesias within 9 months compared
with 3.3% taking placebo, 3.3% taking 150mg L-dopa daily,
and 2.3% taking 300mg L-dopa daily.7 Similarly, at this time
point, wearing off was observed in 13.3, 16.3, 18.2, and
29.7%, respectively, for patients treated with placebo, 150mg
L-dopa daily, 300mg L-dopa daily, and 600mg L-dopa daily.
This study was the first double-blind, placebo-controlled
study to demonstrate that both motor benefits and motor
complications are dose related.7 Overall, the motor complications of wearing off and dyskinesias develop at a rate of
10% per annum in late-onset patients and 20% per annum
in young-onset patients,14 so that as many as 90% of PD
patients eventually experience these problems after 10 years
of treatment.15 The symptom of wearing off requires modification of L-dopa dosage and/or dose frequency, or the introduction of additional or alternative therapies. Dyskinesias
most often occur at the time of the maximal clinical benefit
and peak concentration of L-dopa (peak-dose dyskinesias). A
less common form of dyskinesia emerges at the onset and
wearing off of the L-dopa effect (diphasic dyskinesias). In extreme cases, patients may cycle between disabling “off” and
“on” periods that are complicated by disabling dyskinesias.5
The mechanisms by which these motor complications develop are not completely understood, but abnormal, nonphysiological, pulsatile stimulation of dopamine receptors by
short-acting agents such as L-dopa, the dose of L-dopa used,
and the degree of striatal denervation have each been implicated.16,17 The emergence of motor complications indicates a
transition to a more complex phase of PD requiring management strategies that may involve multiple drugs, frequent
dosing, the use of parenteral dopaminergic therapy, and/or
surgical procedures, and is associated with impaired quality
of life, increasing caregiver burden, and increasing cost. Furthermore, the evolution of dyskinesias often limits the ability
of physicians to optimally prescribe L-dopa to control motor
features. For these reasons, it is desirable when introducing
therapy to tailor the approach to individual patients to minimize the risk for motor complications.
Notably, almost 50 years after the introduction of L-dopa,
still the most effective drug for the treatment of PD, few
studies have attempted to define how to best use this drug to
restore brain dopamine in a physiological manner to optimize efficacy and minimize adverse events.18
Catechol-O-Methyl Transferase Inhibitors
COMT inhibition improves L-dopa absorption and
pharmacokinetics (PK), increasing its elimination halflife and the total bioavailability (area under the curve)
of the drug. Two COMT inhibitors have been approved and are available for clinical use for the treatment of PD.
Entacapone is a selective, reversible inhibitor of
COMT. It does not cross the blood–brain barrier and
acts primarily in the gut and plasma. The recommended dose of entacapone is a 200mg tablet administered with each dose of L-dopa/carbidopa, up to a
maximum of 10 times daily in Europe and 8 times
daily in the United States. It should be noted that
COMT inhibitors act by increasing L-dopa availability,
and titration to address the need for enhanced efficacy
or side effect should be restricted to the dose of L-dopa;
the dose of entacapone administered with each dose of
L-dopa should remain the same, that is, 200mg. Entacapone is effective in patients with wearing-off–type
motor fluctuations and can produce an increase in
“on” time and a reduction in “off” time by an average
of 90 min/day.19 There has also been considerable interest in the potential of L-dopa plus entacapone to reduce the risk for motor complications (see later). The
most common adverse effects seen with the introduction of entacapone are dopaminergic, reflecting increased central dopaminergic activity. Problems can include nausea, vomiting, orthostatic hypotension, and
dyskinesia. These problems tend to occur with L-dopa
doses greater than 700mg daily and are usually easily
treated by reducing the daily L-dopa dose whereas
maintaining COMT inhibition. Diarrhea may occur in
about 10% of cases, and in some may be intractable
and necessitate discontinuing the drug. Entacapone
metabolites may also cause discoloration of the urine,
but this is harmless. Entacapone may be combined
with both standard and controlled-release formulations
of L-dopa/carbidopa, and may be administered with or
without food. The introduction in 2003 of Stalevo, a
combination of L-dopa, dopa-decarboxylase inhibitor,
and entacapone, offered an opportunity to simplify the
dosage regimen for patients taking entacapone. Patients
requiring additional dopaminergic support with L-dopa
may be initiated on Stalevo (although this is not currently a licensed use) or converted from existing L-dopa
therapy to an equivalent dose of Stalevo.
Tolcapone has a similar half-life to entacapone; however, because of a greater bioavailability and smaller
volume of distribution, tolcapone produces a greater
inhibition of COMT such that it requires administration only in a three times a day regimen.20 It has also
been shown to be effective in reducing “off“ time and
increasing “on” time.21 Adverse effects are similar to
what has been described with entacapone, except that
there is a greater risk for patients suffering an explosive
diarrhea that necessitates drug discontinuation.22 In
addition, tolcapone can be associated with a potentially
fatal hepatic toxicity.23 For this reason, use of the drug
has been substantially curtailed. Although tolcapone is
now available both in Europe and North America, it
should not be given to patients who have not tried entacapone or who have impaired liver function. PD patients who receive tolcapone should have regular monitoring of hepatic enzymes, and the drug should be
stopped if enzyme levels exceed twice the upper limit
of normal.24 This effect on liver function has not been
seen with entacapone and may reflect their differing
potency in blocking COMT or inducing mitochondrial permeabilization.25
There has been recent interest in combining L-dopa
with a COMT inhibitor from the time that L-dopa is
first initiated to minimize the risk for motor complications. Several studies have shown that continuous infusion reduces established motor complications in advanced PD patients.26 –27 Administration of L-dopa
plus a COMT inhibitor at 3-hour intervals provides a
plasma PK curve that mirrors a continuous L-dopa infusion,17 and it is anticipated that L-dopa plus a
COMT inhibitor given at frequent intervals (every 3– 4
hours) might provide similar benefits. Levodopa effectiveness can be augmented by bi-model use of entacapone with levodopa.28 Indeed, multiple doses of
L-dopa plus the COMT inhibitor entacapone induce
significantly less dyskinesias in MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine) monkeys than does
29
L-dopa alone.
The (STalevo Reduction in Dyskinesia
Evaluation) STRIDE-PD study is currently testing this
hypothesis in PD patients.
Dopamine Agonists
Several dopamine agonists are available for treating
PD, and they can be classified as ergot or nonergot.
Ergot agonists include bromocriptine, cabergoline, lisuride, and pergolide; nonergot agonists include apomorphine, piribedil, ropinirole, pramipexole, and
rotigotine. Bromocriptine, cabergoline, pergolide,
pramipexole, ropinirole, and rotigotine have all been
studied as monotherapies for use in the early treatment
of PD,30 –38 as well as for adjunctive treatment in more
advanced patients.39 – 46 They have all demonstrated a
significant beneficial effect on motor function, activities of daily living, and quality of life. Dopamine agonists improve total UPDRS in early PD by approximately seven points. Although it is difficult directly to
compare studies, L-dopa improves total UPDRS score
in early PD by approximately five points more than a
dopamine agonist, although quality of life is not statistically different at 4 years.47
The major focus of interest in dopamine agonists in
recent years has related to their reduced potential to
induce motor complications in comparison with
Schapira and Olanow: Treatment Initiation in PD
S49
48
L-dopa.
Indeed, several prospective, double-blind
clinical trials have now demonstrated that dopamine
agonists such as pergolide, pramipexole, ropinirole, and
cabergoline are associated with a significantly reduced
risk for development of motor complications in comparison with L-dopa.49 –52 Interestingly, long-term
follow-up studies indicate that approximately 85, 68,
55, 45, and 35% of PD patients initiated on
pramipexole or ropinirole are still able to be controlled
on monotherapy at 1, 2, 3, 4, and 5 years, respectively.49,50 However, virtually all PD patients eventually
require L-dopa, and the introduction of L-dopa increases the risk that the patient will develop motor
complications, even when it is administered in combination with a dopamine agonist.49,50 Indeed, the time
to onset of motor complications after the initiation of
L-dopa is the same whether L-dopa is used as initial
therapy or is administered as a supplement to a dopamine agonist.53 Thus, the major value of dopamine
agonists for motor complications appears to be in delaying the time until L-dopa is required and permitting
L-dopa to be used at a lower dose (which is associated
with less dyskinesia).
There has also been interest in the potential of dopamine agonists to provide neuroprotective effects in
PD, based on their capacity to protect dopamine neurons in the laboratory in both in vitro and in vivo
models.54 –56 In the clinic, both ropinirole and
pramipexole have been shown to reduce the rate of decline of a surrogate imaging biomarker of nigrostriatal
function in comparison with L-dopa.57,58 This result is
consistent with the possibility that the agonist has a
protective effect, or that L-dopa has a toxic effect on
dopamine neurons. As neither study included a placebo
group, these two effects cannot be differentiated. Furthermore, in both studies, patients in the L-dopa group
had improved UPDRS scores in comparison with the
agonist-treated patients (although both arms were considered to be treated comparably by the investigators
and patients. It has also been suggested that the results
obtained in these studies could be accounted for by the
L-dopa and dopamine agonists having different pharmacological effect on the biomarker (ie, downregulation) rather than on neuronal function or survival.59
These issues remain to be resolved, although the recent
(INvestigating the effect of short-term treatment with
pramipexole or levodopa on [123I]␤-CIT and SPECT
imaging) INSPECT study showed no evidence that either pramipexole or L-dopa has a short-term pharmacological effect.60
The side-effect profile of dopamine agonists is similar to L-dopa for dopaminergic symptoms such as nausea, vomiting, and postural hypotension. Dopamine
agonists are, however, associated with a greater rate of
peripheral edema, somnolence, and hallucinosis, particularly in the elderly. Ergot dopamine agonists can also
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Annals of Neurology
Vol 64 (suppl)
December 2008
be associated with the development of pleural, pericardial, or peritoneal fibrosis.61 Recent reports have also
linked the ergot alkaloids pergolide and cabergoline
with fibrotic cardiac valvular disease.62– 64 These reports have led to the restricted use of these agents.
Somnolence with excess daytime sleepiness has specifically been observed with dopamine agonists. This
problem was highlighted by reports of several PD patients who were taking dopamine agonists and fell
asleep while at the wheel of their motor vehicle.65
These problems have primarily been seen in association
with high doses of dopamine agonists and can frequently be improved by decreasing the dose. Patients
should be warned of this potential problem.66 More
recently, dopamine agonists have been reported to be
associated with a variety of impulse control disorders,
particularly pathological gambling and hypersexuality,13,67 and patients should be warned and monitored
for these problems.
In conclusion, dopamine agonists can provide effective control of PD-related motor symptoms, delay the
onset of motor complications, delay the introduction
of L-dopa, and enable a lower dose of L-dopa to be
used. The potential of this class of drugs to have
disease-modifying effects has not been established, but
has not been excluded. As with all drugs, these benefits
must be considered in light of the side-effect profile of
the agent.
Monoamine Oxidase B Inhibitors
Two compounds, selegiline (deprenyl) and rasagiline,
both of which are irreversible MAO-B inhibitors, have
demonstrated symptomatic effect in PD patients. Both
drugs incorporate a propargylamine group within their
molecular structure and have been shown to provide
neuroprotective efficacy in the laboratory.68
Selegiline was approved initially as adjunctive treatment to L-dopa in advanced PD patients. The (Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism) DATATOP study was designed as a
prospective, double-blind, placebo-controlled trial to
investigate the possibility that selegiline 5mg twice
daily or 2,000IU of vitamin E had putative neuroprotective therapies in PD.69 Selegiline was shown to significantly delay the need for L-dopa compared with
placebo, an effect consistent with slowing of disease
progression. However, selegiline was also shown to exert a mild symptomatic effect that confounded interpretation of the study. The clinical benefit of selegiline
is relatively mild, with most studies showing a total
UPDRS improvement of 2.7 points at 3 months.70 In
a long-term follow-up study of the DATATOP cohort,
L-dopa–treated patients who were originally randomized to selegiline had significantly less decline, with less
wearing off, on-off, and freezing episodes.71 Similar
benefits of early selegiline treatment together with re-
duced L-dopa dose requirements were observed in the
long-term Nordic study.72 Selegiline is generally well
tolerated and has few adverse effects. Dopaminergic
side effects can be seen, and increased dyskinesia and
confusion may occur in more advanced patients. Selegiline is also metabolized to form an amphetamine that
could cause insomnia; for this reason, it is typically not
administered after noon. Selegiline is currently used
primarily early in disease course based on its small
symptomatic benefit and the potential that it may have
neuroprotective effects.
Rasagiline is structurally related to selegiline but is
approximately 10 to 15 times more potent as an
MAO-B inhibitor. It has good central nervous system
penetration and a long half-life that allows for a oncedaily dosage schedule. Rasagiline is metabolized to
form aminoindan and does not generate amphetamine
or methamphetamine metabolites. This difference may
have clinical relevance for side-effect profile and the
potential for disease modification. In patients with
early PD, rasagiline in doses of 1 and 2mg improved
UPDRS score compared with placebo by 4.2 and 3.56
units, respectively.73 The drug was well tolerated, and
there were no significant differences in the adverse
event profile between the rasagiline arms and placebo.
Of particular interest in this study was the finding that
patients who were randomized to initiate rasagiline at
the beginning of the study (early start) had better UPDRS scores at the final visit (12 months) than did
those who began the drug at 6 months (delayed start),
even though patients in both groups were taking the
same medication at the time of the final visit.74 This
has been interpreted as possibly representing a diseasemodifying effect of the drug.75
Other Drugs
Clinical trials have shown a modest benefit for anticholinergics in improving bradykinesia and rigidity,5,76 but
this is often at the expense of impaired cognitive function. Although often considered particularly effective
for tremor, benztropine was no more efficacious than
clozapine in producing a mild improvement in tremor.77 Amantadine produces mild improvement in PD
symptoms, but the duration of benefit is variable, with
some finding that benefits disappear after 1 year.78,79 It
is generally considered unsuitable for monotherapy in
PD and is mostly used as an adjunct where it can be
helpful in providing antidyskinetic effects without
worsening parkinsonism. Improvements in bradykinesia and rigidity are generally of the same order of magnitude as anticholinergics, but their combination is additive.80,81 Amantadine use is limited by its potential
to induce cognitive defects and by withdrawal symptoms that can be associated with its discontinuation.
Treatment Initiation: General Considerations
The individual characteristics of any given patient dictate which drug to start and when. Important factors in
the selection process include disease severity, age, quality of life, employment, and concomitant disease.82
Chronological age is a marker for life expectancy
and, in turn, is influenced by comorbidities and health
status. The life expectancy of a healthy 70-year-old individual in Western societies is approximately 13 to 15
years. However, this age group is often affected by current or impending illnesses that limit life both quantitatively and qualitatively. In contrast, many patients
manifest PD while still at work, and this can be an
important factor in timing the initiation of therapy so
as to help them maintain earning capacity and work
status. Improved disease awareness has generally led to
PD patients presenting at a relatively early stage of
their disease when motor features are not severe, although this is not invariable. Mildly affected patients
may not require symptomatic treatment for reasons of
disability. However, it has been proposed that the earlier treatment is initiated, the better the long-term outcome.83– 85 This view is discussed in more detail in the
following section.
The timing of treatment initiation in PD requires informed patient agreement. Likewise, the choice of drug
needs to be discussed carefully and a long-term therapeutic strategy agreed on. Regarding efficacy, L-dopa is
the most effective of the oral dopaminergic preparations,
followed by dopamine agonists and then MAO-B inhibitors. On the other hand, L-dopa is associated with a
high risk for the development of motor complications,
particularly in younger patients; this may be less of a
concern in the elderly, in whom the brain is less plastic
and motor complications less likely to develop. Studies
to determine the potential benefits of initiating L-dopa
therapy in combination with a COMT inhibitor at frequent intervals are currently under way. Early dyskinesias may be mild and do not interfere with general activities. However, their appearance portends the
development of more severe motor complications that
may be difficult to treat and can have a significant effect
on quality of life.86,87 In the majority of patients, a desire to delay the onset of these complications may lead
the physician to prefer initiating therapy with a drug
that is less effective than L-dopa but less prone to induce
motor complications such as a dopamine agonist or an
MAO-B inhibitor.
The development of a drug to slow or prevent the
progression of PD remains the major unmet need for
PD patients.88 If such a drug were available, it would be
logical to begin it as early as possible in the course of the
disease.5 However, no drug has yet been proved to have
such a disease-modifying effect, although many have
been tested and some encouraging results produced. We
review the topic of neuroprotection in another section of
Schapira and Olanow: Treatment Initiation in PD
S51
Fig. Treatment algorithm for management of early Parkinson’s disease (PD). Therapy for each patient must be individualized. We
favor initiation of therapy at or soon after the time of diagnosis. In an average patient who is relatively young and without cognitive impairment, we begin treatment with a monoamine oxidase B (MAO-B) inhibitor and follow with a dopamine agonist. In
patients with more prominent PD features, we start with a dopamine agonist. L-dopa is added when satisfactory control cannot be
maintained. Current studies are examining whether L-dopa should be initiated in conjunction with a catechol-O-methyl transferase
(COMT) inhibitor. We believe this approach maximizes PD symptom control and minimizes the risk for motor complications. (Reproduced by permission.82)
this supplement and do not include this consideration in
the next section. The following, therefore, represents our
personal views and is a practical guide for when to initiate therapy for PD and with which drug.
Timing of Initiation
At clinical presentation, many PD patients have significant disability. This is reflected in the expression of the
core motor features that reflect degeneration of about
50% of dopamine neurons and enable a diagnosis of PD
to be made. The early phase of PD is a time of relatively
rapid progression for most patients, with the UPDRS
declining by 8 to 10 points per annum. Also, studies of
early PD patients show that many have impaired quality
of life even at the time of diagnosis. Those trials that
have sought to compare treatments in patients with early
PD with placebo (eg, DATATOP, ELLDOPA, (Rasagiline Mesylate [TVP-1012] in Early Monotherapy for
PD Outpatients) TEMPO) have shown that those who
begin dopaminergic therapy even 6 to 9 months earlier
appear to have sustained motor improvement greater
than those who began treatment later.83 It can be hypothesized that early dopaminergic support for the
dopamine-deficient basal ganglia can preserve compensatory responses that maintain motor functions, limit the
effect of deleterious compensatory mechanisms, and enhance a return to a normal pattern of basal ganglia cir-
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Vol 64 (suppl)
December 2008
cuit function. Furthermore, early dopaminergic intervention will improve motor function, and maintain and
improve quality of life. Our current practice is to discuss
the initiation of therapy with the patient at an early
stage, including the advantages of symptom improvement and the potential for long-term benefit, and set
these against the disadvantages of taking medication and
the risk for side effects. On balance, our view is to begin
treatment earlier than later, and in our own personal
view, we generally start treatment at or soon after the
time of diagnosis.
Selection of Initial Therapy
As emphasized earlier, the selection of which drug to
initiate is based on the individual characteristics of the
patient. Nevertheless, this still allows for some general
observations and recommendations to be made.82
MAO-B inhibitors are an appropriate choice as initial therapy for those patients with relatively mild
symptoms. They produce a modest but significant improvement in motor function, can be prescribed as a
once-daily oral treatment with no titration, and are
well tolerated with few serious side effects. Almost 50%
of patients can be maintained on rasagiline monotherapy for 2 years.89 On the other hand, these drugs
are best avoided in the elderly because of their potential for causing confusion.
Dopamine agonists are suitable as initial therapy for
PD patients with mild-to- moderate motor deficits.
They produce a significant improvement in motor control, are well tolerated in the majority of patients, and
are associated with a low risk for motor complications.
Approximately 50% of patients can be maintained on
agonist therapy alone for 3 years. They may also have
benefit in treating the depression in PD. For instance,
pramipexole was as effective as 50mg sertraline in improving depression scores, and with a greater responder
rate.90 Rotigotine is now available in once-daily patch
administration. Ropinirole will shortly be available
as a once-daily sustained-release preparation, and
pramipexole once a day is currently in phase III development. These formulations should enhance convenience and compliance, and possibly nighttime symptoms. Benefits associated with dopamine agonists must
be weighed against their adverse event profile. Ergot
dopamine agonists such as cabergoline and pergolide
are associated with cardiac valve fibrosis, which leads us
to prefer nonergot agonists. Dopamine agonists are
best avoided in the elderly, in whom they have a
greater risk for causing confusion and hallucinations.
The frequency of impulse control disorders is currently
being investigated, and the potential for these problems, as well as sedation and leg swelling, should be
considered in choosing initial therapy.
For most PD patients, we would advocate the initiation of either an MAO-B inhibitor or a dopamine agonist. This is based on their ability to provide good
symptom control for prolonged periods with good tolerance and an ability to postpone the introduction of
L-dopa, and thus delay the onset of motor complications. Indeed, we frequently combine MAO-B inhibition plus a dopamine agonist to try and enhance efficacy and further delay the need for L-dopa; studies
testing these hypotheses are currently under way.
L-Dopa is an important choice for initial therapy in
a proportion of patients. This would include those patients who have cognitive impairment and the elderly
(perhaps 75 years or older), in whom there is a relatively low risk for motor complications and where neuropsychiatric complications of dopamine agonists are
more likely to occur. In addition, there may be an occasional younger patient in whom special circumstances such as employment or public life demand optimum control of symptoms.
In considering initiating therapy with L-dopa, it
should be noted that in the ELLDOPA study, a daily
L-dopa dose of 300mg was associated with no greater
risk for motor complications than placebo, but only
over a 9-month period.7 It is not known whether this
dyskinesia rate would be maintained over a longer term
if the dose was not increased, or whether the subsequent addition of a dopamine agonist would have the
same effect in delaying the onset of motor complica-
tions as when given as initial therapy. The
STRIDE-PD study may help to inform this situation.91 L-Dopa plus a COMT inhibitor provides a PK
pattern similar to an infusion, and it has been hypothesized that this combination might provide enhanced
benefits with reduced motor complications in comparison with standard L-dopa. In the STRIDE-PD study,
patients are randomized to initiate L-dopa therapy
alone or in combination with a COMT inhibitor. Outcome measures include the time to onset, frequency of
dyskinesia, and other motor complications. This study
should help guide whether L-dopa plus a COMT inhibitor should become the preferred formulation for
initiation and continuation of L-dopa treatment. PK
studies indicate that it is necessary to administer L-dopa
plus a COMT inhibitor at least four times per day (every 4 hours) to prevent the low troughs in plasma
L-dopa concentration that may underlie the generation
of motor complications.26 The development of an
L-dopa formulation that could deliver dopamine to the
brain in a physiological manner may provide the optimal benefits of the drug without motor complications,
and may eliminate the need for polypharmacy and
most surgical interventions for PD.
Conclusion
In this article, we have provided a rationale for the
timing of initial treatment in PD and for which drug
to select in different patients (Fig). Inevitably, whichever treatment is begun, many patients will require additional drugs as their disease progresses, and this will
ultimately include L-dopa. Present studies will determine whether it is preferable to administer L-dopa with
a COMT inhibitor. The options now available for
drug initiation in PD should contribute to improved
motor control, a delay in motor complications, and an
amelioration of their effect. We advocate initiation of
therapy at an early stage after diagnosis both to improve symptoms and quality of life, and to contribute
to long-term benefit. Treatment always should be individualized and the side-effect profile of each drug
considered in light of its potential benefits.
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