CNS Drugs 2003; 17 (7): 475-489

THERAPY IN PRACTICE 1172-7047/03/0007-0475/$30.00/0

© Adis Data Information BV 2003. All rights reserved.

Levodopa-Induced Response
Fluctuations in Patients with
Parkinson’s Disease
Strategies for Management
Teus van Laar
Department of Neurology, Groningen University Hospital, Groningen, The Netherlands

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
1. Clinical Symptomatology of Motor Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
2. Pathophysiology of Motor Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
2.1 Peripheral Pharmacokinetics of Levodopa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
2.2 Central Pharmacokinetics and Pharmacodynamics of Levodopa . . . . . . . . . . . . . . . . . . . . . . . . 478
3. Influence of Age and Duration/Dose of Levodopa on Motor Complications . . . . . . . . . . . . . . . . . . . 479
4. Preclinical Data on the Treatment of Response Fluctuations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
4.1 Role for Dopamine D1 Receptor Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
4.2 Possible Influence of Priming . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
5. Clinical Treatment Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
5.1 Wearing-Off Phenomena . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
5.1.1 Optimisation of Dopamine Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
5.1.2 Increasing the Duration of Effect of Levodopa Doses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
5.2 At-Random Response Fluctuations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
5.2.1 Rescue Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
5.2.2 Continuous Stimulation of Dopamine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
5.3 Dyskinesias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
6. Stereotactic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487

Abstract Fluctuations in response to levodopa in patients in the advanced stages of

idiopathic Parkinson’s disease occur frequently and are a difficult problem to
treat. Patients who are treated with levodopa have an additional 10% risk of
experiencing response fluctuations with each year of treatment: 50% of patients
have this problem after 5 years of receiving levodopa therapy and almost 100% of
patients after 10 years.
The mechanisms by which response fluctuations occur are only partially
understood and can be divided into three main types: (i) presynaptic neuronal
degeneration leading to a lack of buffering of released levodopa, which is mainly
related to wearing-off phenomena; (ii) postsynaptic changes in dopamine receptor
sensitivity and number, partially caused by the presynaptic changes, which are
clinically related to at-random response fluctuations; and (iii) pharmacokinetic
476 van Laar

and pharmacodynamic influences of exogenously administered dopaminergic

agents.
Several oral and parenteral treatment strategies are recommended to manage
response fluctuations, such as optimisation of dopamine receptor agonist therapy
in combination with a reduction of the levodopa load; use of slow-release
levodopa formulations; use of catechol-O-methyltransferase inhibitors; an
increase of levodopa dose frequency; use of high-dose amantadine; and intermit-
tent or continuous use of apomorphine and/or levodopa. Continuous stimulation
of dopamine receptors with dopaminergic agents is one of the crucial basic steps
in the treatment of patients at an advanced stage of Parkinson’s disease, and the
preferential use of dopamine receptor agonists has proven to be successful in the
prevention and treatment of response fluctuations.

Idiopathic Parkinson’s disease (IPD) is a progres-
sive neurodegenerative disorder for which no restor-
ative or neuroprotective therapy is available. As a
result of a continuous cell loss in the nigrostriatal
system of about 10% per year, as measured by
positron emission tomography (PET),[1,2] the disease
progresses despite the use of currently available
medications.
The administration of dopamine precursors,
levodopa in particular, has been the gold standard in
the treatment for IPD since the discovery of a defi-
ciency of dopamine in the basal ganglia of patients
with Parkinson’s disease. Because levodopa is de-
graded by peripheral decarboxylase to dopamine,
which does not pass the blood-brain barrier (BBB),
it has to be coadministered with a decarboxylase
inhibitor (carbidopa or benserazide).
The majority of patients respond well to
levodopa treatment, at least during the initial years
of therapy. Individual differences in the degree of
symptom improvement have been reported, and ap-
proximately 15–20% of patients do not respond to
levodopa,[3] very probably because they do not have
Parkinson’s disease but rather one of the parkinsoni-
an syndromes such as multiple system atrophy or
progressive supranuclear palsy (PSP). The UK
Brain Bank mentions that a positive response to
levodopa is one of the supportive criteria for the
clinical diagnosis of IPD.[3]
Even in patients who respond well to levodopa
initially, control of motor symptoms gradually di-
minishes during the course of treatment.[4] After an
initial period of stable response, mostly lasting 2–5
years, about 70% of patients develop a variety of
incapacitating motor adverse events in response to
levodopa treatment, mainly consisting of at-random
response fluctuations and dyskinesias.[4] Data on the
occurrence of motor fluctuations show a huge vari-
ance. The Sinemet CR First study described motor
fluctuations in only 20% of the patients after 5 years
of levodopa use.[5] This is in contrast to other data,
which suggest that, in young-onset IPD patients, up
to 30% of the patients show dyskinesia after only 1
year of levodopa therapy.[6] About 30% of all
patients with Parkinson’s disease remain very stable
throughout the course of the disease and seem not to
be affected by these adverse motor reactions.[4] At
the other end of the spectrum, almost 100% of
patients with young-onset disease develop motor
complications. These complications are less likely
to occur in patients whose symptoms start after the
age of 70 years.[6,7]
It is clear that both levodopa and the progressive
degeneration of the nigrostriatal system in IPD are
responsible for the occurrence of these motor com-
plications. In recent years, a variety of possible
approaches to managing these fluctuating motor
problems have been suggested. This review pro-
vides an overview of the different possible strate-
gies, including some theoretical background. The
challenge for every neurologist involved in extra-
pyramidal disorders will be to individualise these
basic rules for their own patients with IPD.

© Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (7)
Levodopa-Induced Response Fluctuations
1. Clinical Symptomatology of
Motor Complications
Motor complications may have various phenom-
enologies. The most important drug-related motor
complications are summarised in table I.
The first sign of the loss of symptom control,
usually occurring after a few years of therapy, is
called end-of-dose deterioration (or ‘wearing-off’).
This term refers to the observation that the duration
of response to levodopa administration appears to
have become shorter. The patient loses the smooth
response during the day and starts to feel the effect
of single oral levodopa doses. The duration of the
beneficial effect of each levodopa dose becomes
progressively shorter. On average, the effects of a
dose of levodopa last about 2–3 hours in patients
with wearing off phenomena.[8] If the interval be-
tween doses in these patients happens to be longer,
nocturnal or early-morning akinesia may be the ulti-
mate wearing-off phenomenon.
Besides this ‘short-duration’ response, a ‘long-
duration’ response also exists. This is the time from
complete withdrawal of levodopa until the parkin-
sonian deterioration is maximal. This process may
last up to 2 weeks.[9] This long-duration response is
important, because it determines the baseline func-
tion on which the other motor fluctuations are super-
imposed. The long-duration response is a very slow
fluctuation, but nevertheless it is important in ana-
lysis of the whole picture.
Table I. Subtypes of drug-related motor complications that can
occur in patients with Parkinson’s disease
Response fluctuations
Predictable
Wearing-off
Nocturnal akinesia
Early-morning akinesia
Delayed on/no-on phenomena
Long-duration response
Unpredictable
At-random on-off fluctuations
Dyskinesia
Peak/interdose dyskinesia
Diphasic dyskinesia
Off-period dystonia
© Adis Data Information BV 2003. All rights reserved.
477
A variant of the wearing-off phenomenon is the
delayed-on or ‘no-on’ response, in which the latency
of effect increases.[10] Patients with this complica-
tion may have to wait 45–90 minutes before a dose
of levodopa results in a clinical benefit. In the no-on
phenomenon, a single dose predictably or randomly
does not give any benefit at all.[11]
With continuing levodopa treatment, the loss of
symptom control progresses to a situation character-
ised by severe, disabling motor oscillations (‘on-off’
phenomena) and dyskinesias, the latter occurring
predominantly during ‘on’ periods. Patients seem to
go through alternating periods of overtreatment and
undertreatment in a totally unpredictable way. Peri-
ods of immobility (‘off’) and episodes of normal or
involuntary movements (on) occur at random, show-
ing no apparent relationship to levodopa dosing.
Dyskinesias are a common problem, occurring in
30–80% of patients treated over the long term.[12,13]
The dyskinesias can be categorised according to
their time-relationship with the levodopa dose. Most
patients begin to experience dyskinesias at times of
peak effect of levodopa (‘peak-dose dyskine-
sia’).[12,13] Although they may actually be linked to
plasma concentration peaks, most affected patients
have dyskinesias during the entire period of the
effect of a single levodopa dose, making the term
‘interdose dyskinesia’ more appropriate. Most com-
monly choreic movements (hyperkinesia) are seen
in the trunk and extremities, whereas dystonic
movement patterns prevail in the craniocervical re-
gion. In a subgroup of patients, the dyskinesias are
associated with the onset of clinical benefit. They
appear to be linked to a critical plasma levodopa
concentration and may occur during this critical
level at the beginning and the end of the dose effect
and are therefore called ‘diphasic dyskinesias’.[14] A
particularly common form of diphasic dyskinesia is
represented by stereotypic movements such as kick-
ing with one or both legs.
Off-period dystonia is related to low plasma
levodopa concentrations and occurs in 20–30% of
patients treated long term.[15-17] It is a dystonic pos-
turing, generally of the feet or legs, and is almost
always painful. It most commonly occurs early in
CNS Drugs 2003; 17 (7)
478
the morning (without levodopa overnight) or in be-
tween levodopa doses during the day. It is worse on
the side most affected by parkinsonism.[18]
2. Pathophysiology of
Motor Complications
The short-lived and unpredictable response to
oral levodopa is caused by either the peripheral
pharmacokinetic properties of the drug or the central
pharmacokinetic and pharmacodynamic factors.
2.1 Peripheral Pharmacokinetics
of Levodopa
The plasma elimination half-life of levodopa is
short (about 2 hours), which explains the short dura-
tion of action (2–3 hours) in patients with advanced
disease.[19] Strategies to compensate for this are to
increase the amount of levodopa passing the BBB or
to delay the breakdown of dopamine in the brain.
Figure 1 shows the routes by which levodopa is
metabolised.
A decarboxylase inhibitor is given to prevent the
peripheral metabolism of levodopa. To prevent the
breakdown of dopamine in the brain, a monoamine
oxidase (MAO) inhibitor, such as selegiline (depre-
nyl), can be given. A third method to increase the
Periphery
3-OMD
COMT COMT
Blood-brain barrier
Levodopa Levodopa
AADC AADC
Dopamine Dopamine
MAO-B
DOPAC
COMT
Fig. 1. Metabolism of levodopa. 3-MT = 3-methoxytyramine;
3-OMD = 3-O-methyldopa; AADC = aromatic amino acid decarbox-
ylase; COMT = catechol-O-methyltransferase; DOPAC =
3,4-dihydroxyphenylacetic acid; HVA = homovanillic acid; MAO-B =
monoamine oxidase type B.
© Adis Data Information BV 2003. All rights reserved.
van Laar
peripheral concentration of levodopa is to inhibit
catechol-O-methyltransferase (COMT), using drugs
such as entacapone.
Other factors causing changes in the pharmaco-
kinetics of levodopa are variability in gastric
motility (mostly too slow) and competition for trans-
port across the BBB with large neutral amino acids
(LNAAs). The LNAAs mainly originate from pro-
tein-rich meals, including meat. The influx of
levodopa into the brain directly correlates negative-
ly with the sum of all circulating LNAAs.[19] Periph-
erally acting dopamine receptor antagonists such as
domperidone and cisapride are able to improve slow
gastric emptying and may therefore improve the
effect of the administered levodopa. Strategies to
improve gastric emptying and/or absorption may be
effective, especially if ‘no-on’ or ‘delayed-on’ phe-
nomena occur; these strategies may include taking
levodopa at least half an hour before meals, crushing
the levodopa and suspending it in sparkling water or
taking dispersible levodopa formulations, and com-
bining these approaches with protein reduction dur-
ing day-time hours.[20-22]
2.2 Central Pharmacokinetics and
Pharmacodynamics of Levodopa
Current evidence suggests that wearing-off phe-
Brain nomena are closely related to the extent of degenera-
tion of dopaminergic neurons. As neurodegenera-
tion progresses, the neuronal dopamine stores be-
3-OMD
come increasingly dependent on the precursor
levodopa. Levodopa turnover in the remaining neu-
rons is possibly increased, and the newly synthesis-
ed dopamine is released more rapidly. Moreover,
extraneuronal dopamine synthesis, by glia cells and
other levodopa decarboxylase-containing cells, may
COMT become more important for intrasynaptic dopamine
3-MT
levels. Thus, the functional status of the dopaminer-
gic neurons begins to reflect the availability of exog-
MAO-B enous levodopa, and the neurons lose their ability to
HVA
maintain an adequate dopaminergic tone by the end
of each levodopa dosing interval.[23]
The view that wearing-off reflects the loss of
functional dopaminergic neurons is supported by a
study comparing the kinetic profiles of the reappear-
CNS Drugs 2003; 17 (7)
Levodopa-Induced Response Fluctuations
ance of parkinsonian symptoms and circulating
levodopa concentrations in patients with Parkin-
son’s disease after abrupt cessation of optimal intra-
venous levodopa administration.[24] From studies in
a range of patients, varying from patients who had
never been treated to those experiencing on-off fluc-
tuations, it was concluded that the progressive
neurodegeneration in Parkinson’s disease reduces
the ability of the brain to buffer the fluctuations in
synaptical concentrations of levodopa. This idea
was also supported by the fluorodopa PET study,
which showed less striatal accumulation of [18F]-
dopa in patients experiencing motor fluctuations
than in those with a stable response.[25]
However, wearing-off is not only caused by pre-
synaptic neuronal degeneration; it is also influenced
by postsynaptic alterations.[24] Patients with Parkin-
son’s disease who received a continuous apomor-
phine infusion showed clear differences in the rate
of decline of their motor responses, with a faster
decline occurring in the more severely affected
patients.[26] These findings suggest a postsynaptic
involvement of wearing-off phenomena, because
apomorphine mainly acts via postsynaptic dopamine
receptors.
Response variations of the on-off type and dys-
kinesias are at least partially caused by hypersensi-
tivity of postsynaptic receptors, resulting from expo-
sure to fluctuating dopamine levels. Fluctuations in
dopaminergic tone are considered to be the result of
intermittent levodopa administration and the gradual
loss of the buffering capacity of the dopamine sys-
tem as described above. This also explains the tem-
poral relationship between the occurrence of wear-
ing-off and on-off motor fluctuations. With disease
progression, the shape of the dose-response curve of
levodopa changes dramatically.[27] Patients with ear-
ly Parkinson’s disease who have never been treated
with levodopa show a smooth, slowly rising dose-
response curve. In patients at more advanced disease
stages, the dose-response curves become increasing-
ly steeper to become an all-or-nothing response. In
these patients, a small change in the plasma concen-
tration of levodopa has a profound effect on the
control of motor symptoms. The threshold dose for
© Adis Data Information BV 2003. All rights reserved.
479
the antiparkinsonian effect of levodopa remains
largely unchanged with disease progression, but the
threshold for the induction of dyskinesia is gradually
reduced as patients move to a more advanced dis-
ease stage.[27] Thus, the therapeutic window for
levodopa progressively decreases with disease se-
verity and becomes almost nonexistent in patients
with on-off fluctuations (see figure 2).
3. Influence of Age and Duration/Dose
of Levodopa on Motor Complications
It has been suggested that the rate at which re-
sponse fluctuations after levodopa treatment devel-
op is associated with the age of the patient at the
onset of IPD. A study by Kostic et al.[28] showed that
response fluctuations developed more rapidly in
patients with young-onset disease (onset of Parkin-
son’s disease between 21 and 40 years) than in a
matched population of older patients (>40 years at
onset of Parkinson’s disease). About 30% of the
patients with young-onset disease had developed
response fluctuations after 1 year of levodopa treat-
ment.
Other determinants of response fluctuations have
been suggested to include the severity of disease at
the onset of treatment, the duration of disease and
the duration and the dose of levodopa therapy.[29,30]
Response fluctuations were reported to be more
Dyskinesia threshold
Stable
Levodopa concentration
Wearing-off
Therapeutic window At random
Minimal effective concentration
Stages of IPD
Fig. 2. Change in the therapeutic window of levodopa related to the
stage of idiopathic Parkinson’s disease (IPD), showing the narrow-
ing of the window (difference between the concentration that has
therapeutic versus adverse effects) as the disease progresses.
CNS Drugs 2003; 17 (7)
480
likely to occur in patients who started with levodopa
in Hoehn and Yahr stage I or II. However, another
study could not show any relationship between re-
sponse fluctuations and the age at onset, presenting
symptom, duration of illness, stage of the disease at
the time of initiation of levodopa or the mean or last
daily dose of levodopa. Nevertheless, response fluc-
tuations were less likely in patients who were at least
60 years old at the onset of Parkinson’s disease and
had started levodopa >2 years after the first symp-
toms of disease.[31] In keeping with this pattern, it
was also shown that response fluctuations are a
likely event in those patients who had required a
recent increase in their levodopa dose.
A randomised controlled study in previously un-
treated patients with Parkinson’s disease assessed
the effect of delaying the onset of treatment with
levodopa. The study compared the effect of initiat-
ing treatment with bromocriptine and later adding
levodopa with initiating treatment with levodopa. A
significant decrease in motor complications in fa-
vour of the patients who used bromocriptine mono-
therapy for as long as possible was reported. The
patients receiving bromocriptine alone initially
showed a mean delay in the onset of response fluctu-
ations of 4.9 years (n = 25), whereas the group that
started therapy on levodopa showed a mean delay of
just 2.7 years (n = 29) before onset of response
fluctuations. The percentage of patients with fluctu-
ations increased directly after the start of levodopa
therapy.[32] This study clearly showed the benefit of
delaying levodopa as long as possible with respect
to the reduced risk of developing response fluctua-
tions.
4. Preclinical Data on the Treatment of
Response Fluctuations
Part of the evidence for the pathophysiology of
motor fluctuations (see section 2) is derived from
experimental studies in primates treated with
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP). MPTP is an impurity in certain illicit drugs
and has been identified as the cause of parkinsonian
syndromes in addicts who had been using them.
MPTP is able to induce a stable parkinsonian syn-
© Adis Data Information BV 2003. All rights reserved.
van Laar
drome in primates. MPTP is known to stimulate the
production of neurotoxic substances in the brain that
are able to damage dopaminergic neurons in the
substantia nigra.
4.1 Role for Dopamine D1
Receptor Stimulation
Shortly after the discovery of dopamine receptor
heterogeneity, it was recognised that dopamine re-
ceptors of the D2 type primarily mediate the motor
effects of central dopamine stimulation. However,
various lines of evidence now support the view that
dopamine D1 receptors are also able to mediate
central motor effects. Experimental data, obtained in
MPTP-treated primates, support a role for D1 recep-
tors in the motor effects of dopaminomimetic drugs.
For instance, studies with selective D1 and D2 ago-
nists have clearly demonstrated that selective D1
agonists, such as the benzazepine SKF 81297, have
profound antiparkinsonian effects in MPTP-lesion-
ed animals.[33] Also, the coadministration of a selec-
tive D2 agonist, such as bromocriptine or quinpirole
(LY171555), with a selective D1 agonist produced
synergistic antiparkinsonian effects compared with
a D2 agonist alone.[34] Evaluation of the potent selec-
tive D1 agonist A-86929 as a new therapeutic mo-
dality in the treatment of Parkinson’s disease has
recently been proposed, particularly in patients with
dyskinesias.[35]
It is generally recognised that levodopa and apo-
morphine are currently the most potent drugs avail-
able for the treatment of Parkinson’s disease.[36,37]
The striking fact is that these drugs are both D1 and
D2 receptor agonists. This seems to support the
synergistic effect of D1 receptor agonists on the
action of D2 receptor agonists. Unfortunately, no
clinical comparisons have been done between selec-
tive D2 and combined D1/D2 agonists. Looking at
the monotherapy trial data of dopamine receptor
agonists that have different affinities for D1 and D2
receptors versus placebo, no clinically significant
differences in effect could be determined.[38] Unfor-
tunately, these trials had different designs and so a
real comparison is not possible, and it may be a
result of methodological differences that no clear
CNS Drugs 2003; 17 (7)
Levodopa-Induced Response Fluctuations
differences could be detected. Nevertheless, the
preclinical data with respect to the affinities of cur-
rently available dopamine agonists for dopamine
receptor subtypes do not provide enough guidance
to select a particular agent.
4.2 Possible Influence of Priming
Several MPTP experiments with primates have
provided the insight that the potential of levodopa to
induce dyskinesia is much higher than that of the
different dopamine agonists.[39,40] Once the dyskine-
sias were established by levodopa, treatment with
any of the dopaminergics could easily induce subse-
quent dyskinesia. Selective D1 receptor compounds
produced less dyskinesia than selective D2 receptor
compounds at lower doses, and both produced less
dyskinesia compared with levodopa. Once primed,
the message for the production of dyskinesia seems
to be permanently stored. The same phenomenon
can be seen in patients with Parkinson’s disease.
Primate research has shown that levodopa is able to
change the balance in the direct and indirect path-
ways in the striatum. Levodopa increases direct
pathway firing and decreases indirect pathway fir-
ing, leading to dyskinesia.[41]
These data should encourage great caution with
the practice of administering test doses of levodopa
in order to see if a patient is levodopa responsive.
This can be the start of very difficult-to-handle
dyskinesia and should therefore be avoided.
5. Clinical Treatment Strategies
In the following sections, the rationale for the use
of different drugs or treatment strategies and their
efficacy in the management of response fluctuations
in patients with Parkinson’s disease will be re-
viewed. Readers should also refer to several review
articles on the treatment of response fluctua-
tions.[42-46]
5.1 Wearing-Off Phenomena
In general, wearing-off can be treated adequately
by striving for a longer duration of action of the
dopaminomimetics to overcome the end-of-dose de-
© Adis Data Information BV 2003. All rights reserved.
481
terioration. This can be achieved via several routes,
which are summarised in figure 3. The initial ap-
proach is to optimise dopamine agonist therapy as
far as possible (see section 5.1.1) by titrating up to
maximally tolerated dosages of the individual ago-
nists. If this is ineffective, an attempt should be
made to increase the duration of effect of levodopa
(see section 5.1.2).
5.1.1 Optimisation of Dopamine Agonists
All dopamine agonists share a potent activity at
D2 receptors, but they differ with respect to their
effects on other types of CNS receptors (including
D1 receptors), their pharmacokinetic profile and the
optimal daily doses (table II). Differences in the
elimination half-life are the main determinants of
the duration of action of orally administered dop-
amine agonists, which ranges from 4–8 hours for
bromocriptine to 70–105 hours for cabergoline.[47]
Most dopamine agonists have to be administered
3–4 times per day to achieve stable responses over
24 hours. Agonists circumvent some of the limita-
tions inherent in the use of levodopa. Directly acting
dopamine agonists do not require metabolic activa-
tion and are therefore not dependent on the function-
al status of presynaptic dopaminergic neurons. In
addition, they do not compete with amino acids for
absorption sites and are not subject to peripheral
metabolism, which may interfere with the effects of
levodopa. Finally, dopamine agonists with a long
First step
Try to optimise dopamine agonist doses
(combined with reduction in levodopa dose)
If not effective enough
Secondary steps
Try to increase duration of effect of levodopa:
• increase frequency of levodopa doses
• increase levodopa dose per administration
• use slow-release levodopa formulations
• use MAO-B and/or COMT inhibitors
Fig. 3. Treatment schedule for wearing-off phenomena in patients
with Parkinson’s disease who are receiving levodopa. COMT =
catechol-O-methyltransferase; MAO-B = monoamine oxidase type
B.
CNS Drugs 2003; 17 (7)
482
Table II. Overview of the pharmacokinetic, pharmacodynamic and therapeutic properties of currently available dopamine receptor
agonists[48]
Agonist Receptor profile Pharmacokinetics
D1 D2 serotonin bioavailability (%)
Apomorphine + +++ + 100
(subcutaneous)
Bromocriptine – ++ + 8
Cabergoline + +++ + 60–80
Pergolide + +++ + 20
Pramipexole 0 +++ 0 >90
Ropinirole 0 +++ 0 55
0 = no binding affinity; t1/2 = half-life; tmax = time to peak concentration; – indicates antagonist activity; + indicates binding affinity from
minimal (+) to strong (+++).
half-life theoretically provide a more natural tonic
stimulation of dopamine receptors.
Dopamine agonists have proven to be useful
agents in the treatment of levodopa-induced re-
sponse fluctuations in patients with advanced
Parkinson’s disease. All currently available oral
dopamine agonists have been studied primarily as
adjunct therapy to levodopa. All agonists are able to
provide significant improvement in the Activities of
Daily Living scores and/or motor scores after add-
on therapy (see review by Clarke[49]). Reductions in
levodopa dosage between 175 and 265 mg/day can
be achieved with concomitant administration of
dopamine agonists. The main adverse effects are
gastrointestinal complaints, postural hypotension,
confusion and hallucinations; these do not differ
greatly between the different dopamine agonists. If
gastrointestinal or hypotensive adverse effects arise,
domperidone up to 90 mg/day can be added to
reduce the peripheral dopamine agonistic-mediated
aspect of these effects. Pergolide is an extensively
studied add-on dopamine agonist, mainly in com-
parison with bromocriptine, and has been shown to
have a statistical benefit over bromocriptine.[50-53]
When using adjunct therapy with dopamine ago-
nists, physicians have to titrate to maximal tolerated
doses of the individual agonists in combination with
a maximal reduction of the levodopa dose. If these
two strategies are not combined optimally, patients
will very probably experience an increase of dys-
kinesia and no significant reduction in off time.
As a class, dopamine agonists are generally con-
sidered less effective than levodopa in terms of
© Adis Data Information BV 2003. All rights reserved.
van Laar
Optimal daily dose
tmax (min) t1/2 (h) (mg)
5–15 0.5 3–8 mg/h (infusion)
70–100 4–8 15–40
120–240 70–105 0.5–5
60–120 27 3–5
60–180 8–12 3–5
90 6 12–24
antiparkinsonian effect. Published data from the
dopamine agonist monotherapy trials versus
levodopa confirm this idea only partially. Based on
large, randomised, controlled trials, bromocriptine
proved to be less efficacious than levodopa as
monotherapy.[54,55] The statistical differences were
already clear within 1 year.[56-59] Ropinirole mono-
therapy effectively treated 50% of the patients for 3
years and 30% of the patients for 5 years, which is
still a lower efficacy than is seen with levodopa, but
not statistically significantly lower.[56] All studies
that have compared dopamine agonist monotherapy
with levodopa monotherapy have shown that
levodopa seems to be slightly more effective,
though this was not statistically significant using the
Unified Parkinson’s Disease Rating Scale (UPDRS)
III scores except in the study with bromo-
criptine.[47,56-59] The same studies showed a signif-
icant reduction in the occurrence of response fluctu-
ations and dyskinesia and a significant increase in
the latency of onset of fluctuations and dyskinesias
in patients receiving dopamine agonists (i.e. 5–10%
of patients receiving dopamine agonist monotherapy
developed response fluctuations/dyskinesia vs
31–36% in the levodopa groups). These important
data have shown that dopamine agonists as mono-
therapy are effective and that there are no significant
differences among the agonists. The effects are
comparable to those achieved with levodopa during
the first years of treatment, and their preventive
effect on the occurrence of response fluctuations is
proven. On this basis, dopamine agonist should be
CNS Drugs 2003; 17 (7)
Levodopa-Induced Response Fluctuations
prescribed as first-line therapy if possible and if
tolerated.
5.1.2 Increasing the Duration of Effect of
Levodopa Doses
The easiest way to increase the duration of a drug
effect per dose is to increase the dose. This is only
acceptable for levodopa if peak dose dyskinesias are
not already present or result from the dose increase.
If dyskinesias are present or result from the dose
increase, the other option is to prescribe the original
dose more frequently to avoid peak dose concentra-
tions and to overcome the end-of-dose deterioration.
Different technologies have been used to produce
controlled-release preparations of levodopa (e.g.
Sinemet®1 CR [carbidopa-levodopa] and Madopar®
Hydrodynamically Balanced System [HBS]).[60]
These formulations provide a mean increase of 1–2
hours in the duration of single-dose effects. How-
ever, there are some drawbacks. The plasma concen-
trations of levodopa build up slowly, leading to a
delayed on time, and patients do not experience the
‘kick on’ effect of a normal-release levodopa prepa-
ration. The total daily dose of slow-release formula-
tions has to be increased by 30–50% of the original
dose in order to achieve the same clinical response,
because the absorption of these formulations is less
than with the normal-release levodopa prepara-
tions.[61] The effect during daytime is very modest,
and the best way to use slow-release formulations is
to add them as evening doses, just before falling
asleep, in order to treat nocturnal akinesia and there-
by promote sleep. Sometimes a single evening dose
of a slow-release formulation is even effective in
preventing early-morning akinesia or dystonia. The
reason for this is unclear and does not seem to be
explained by the small increase of the elimination
half-life.
Dose fractioning does reduce dyskinesia. How-
ever, it worsens response fluctuations because most
of the reduced doses no longer elicit a clinical re-
sponse or elicit a very short response.
Finally, using enzymatic inhibition of conversion
steps from levodopa to its metabolites can increase
1 Use of tradenames is for product identification only and does not imply endorsement.
© Adis Data Information BV 2003. All rights reserved.
483
the duration of action of levodopa. The two pos-
sibilities are MAO-B or COMT inhibition.
Selegiline, a selective MAO-B inhibitor, blocks
the degradation of synaptic dopamine in the basal
ganglia, which theoretically increases the duration
of action of dopamine. Five monotherapy trials have
proven that the theoretical advantage of selegeline
also can be seen in clinical practice, because patients
showed improved UPDRS scores.[62] However, the
effects are small, and the duration of effects lasted
from 3 months up to 1 year. Add-on therapy to
levodopa dosages made a reduction of the levodopa
dose possible; however, this was not associated with
enhanced symptomatic control.
The other possibility is COMT inhibition. In
many European countries, the only drug currently
available is entacapone, a peripherally acting
COMT inhibitor. The other COMT inhibitor, tol-
capone, was withdrawn from the market in the EU
because of severe hepatotoxicity, leading to death in
a few patients. In Europe, tolcapone is only avail-
able in Switzerland, and use must be accompanied
by intensive monitoring of liver function. The drug
is also available in the US, where the labelling was
changed. Frequent monitoring of liver function is
mandatory in the US; serum levels of alanine amino-
transferase (ALT) and aspartate aminotransferase
(AST) should be determined at baseline and then
every 2 weeks for the first year of therapy, every 4
weeks for the next 6 months and every 8 weeks
thereafter. Another adverse event responsible for
many withdrawals from tolcapone was diarrhoea
(3–10%). Tolcapone and entacapone prevent the
(peripheral) conversion of levodopa to 3-O-
methyldopa, which delivers more levodopa at the
BBB. The percentage of levodopa from each tablet
that enters the central compartment is therefore in-
creased, creating a longer duration of action.[63,64]
The official indication to prescribe entacapone is
the presence of wearing-off symptoms. COMT in-
hibitors can be prescribed only as adjunct therapy,
because monotherapy with COMT inhibitors in
Parkinson’s disease is not effective (unpublished
observations). The benefit of entacapone is a quick-
CNS Drugs 2003; 17 (7)
484
er onset of effect of levodopa without increasing the
peak concentrations and a longer duration of effect.
The mean increase in on time is about 5% per day.
Other studies showed an extra duration per levodopa
dose of about 30 minutes and a total increase of
mean on time per day of about 2 hours.[65-67] Enta-
capone has to be coupled to each levodopa dose
because of its very short half-life (1–2 hours).
One study has been published in which selegiline
and entacapone were combined as adjunct therapy to
levodopa. The combination was more effective than
each individual adjunct therapy.[68] However,
selegiline plus entacapone may induce dyskinesia,
and selegiline also carries the risk of provoking
hallucinations.[68] If dyskinesias occur with enta-
capone therapy, the original levodopa dose should
be reduced by 15–30%.
5.2 At-Random Response Fluctuations
Although wearing-off phenomena can be treated
successfully, this is certainly not the case with at-
random response fluctuations. If the fluctuations
occur unpredictably, it is difficult to create a more
predictive and stable motor functioning. Figure 4
summarises the possible approaches before a patient
Rescue therapy:
• subcutaneous apomorphine injections
• soluble levodopa formulations (drink)
Optimisation of continuous dopamine receptor stimulation:
• subcutaneous apomorphine by pump/portacath
• intraduodenal levodopa
Reduce dyskinesias:
• high-dose amantadine
• D2 antagonists (tiapride/clozapine)
Stereotactic surgery:
• bilateral STN stimulation
• unilateral pallidotomy or pallidal stimulation
Fig. 4. Approaches to the management of at-random response
fluctuations and dyskinesias in patients with Parkinson’s disease
who are receiving levodopa. STN = subthalamic nucleus stimula-
tion.
© Adis Data Information BV 2003. All rights reserved.
van Laar
might be considered a candidate for stereotactic
surgery (see section 6).
5.2.1 Rescue Therapy
Apomorphine has been known since 1884 as an
emetic with antiparkinsonian properties. A very po-
tent dopamine agonist, it has to be administered
parenterally because of a strong first-pass effect.
Since the introduction of domperidone, a peripheral
dopamine antagonist that prevents the emetic action
of apomorphine on the chemoreceptor trigger zone
outside the BBB, apomorphine has been used in
clinical practice for the treatment of at-random re-
sponse fluctuations. It can be used in two ways:
intermittent treatment for off periods (as rescue ther-
apy) and continuous infusion by pump via the sub-
cutaneous or intravenous route.
Intermittent injections are helpful, because the
absorption half-life of apomorphine is short (min-
utes), leading to an onset of effect within 5–10
minutes. This gives patients a form of ‘kick on’
effect. The mean duration of effect is about 45–60
minutes. The optimal dose is determined by increas-
ing the dose in 1mg increments, starting with 1mg
per injection up to a maximum of 10mg per injec-
tion. Patients should not need more than five injec-
tions per day to overcome their sudden off periods.
If more than five injections are required, continuous
infusion of apomorphine is a better option in order to
create stable plasma concentrations, which are im-
portant in the treatment of response fluctua-
tions.[69,70]
Apomorphine injection therapy has recently be-
come available in some countries as a disposable
penject system, which is very convenient. In situa-
tions where this is not available, physicians can
prescribe syringes – the same as those used by
diabetic patients – to inject the apomorphine subcu-
taneously. Patients generally can inject themselves
without difficulty. Apomorphine injections do not
disturb the daily medication regimen but rather sup-
plement it to prevent gaps in motor functioning. If
patients do not like to inject themselves, they can
use apomorphine intranasal sprays. The only disad-
vantage is that black crustae can appear in the nasal
cavity; this is reversible by stopping the intranasal
CNS Drugs 2003; 17 (7)
Levodopa-Induced Response Fluctuations
application.[71,72] These intranasal sprays can be pro-
duced easily by local pharmacists.
Another alternative to apomorphine injection
therapy is a soluble levodopa solution, which can be
made by dissolving crushed levodopa tablets in car-
bonated water and adding vitamin C to prevent auto-
oxidation. However, the disadvantage of soluble
levodopa is the overall increase of the levodopa
load, with a possible negative impact on motor
complications. Patients can also use Madopar® Dis-
pers, which has about the same effect. However,
Madopar® Dispers does not provide the ‘kick on’
effect of apomorphine, because the latency of onset
of effect is about 30 minutes. The advantage of the
Madopar® Dispers on the other hand is the longer
duration of action, which may last up to 2 hours.[73]
5.2.2 Continuous Stimulation of
Dopamine Receptors
Clinical trials have shown that motor response
fluctuations in patients with Parkinson’s disease can
be improved by avoiding fluctuations in the supply
of levodopa to the remaining nigrostriatal dopamin-
ergic neurons. The validity of this approach has been
demonstrated in studies using continuous intrave-
nous infusion of levodopa to achieve stable plasma
concentrations and a constant supply to the brain
(see review by Coleman[61]). Patients with on-off
fluctuations generally remain on for the duration of
the infusion.
Obviously, continuous intravenous administra-
tion is a highly impractical way of treating patients
with a chronic disease. Also, continuous infusion
has its limitations. It was shown that constant-rate
levodopa infusions, able to turn the patients on
within 1–3 hours of starting the infusion, were una-
ble to keep patients on around-the-clock.[74] The off
periods still occurred, but later in the day, indicating
a diurnal pattern not related to stable plasma concen-
trations. Another influence was the increasing
LNAA load over the day, which seemed to be at
least partly related to the off periods. The severity of
the response fluctuations did not correlate with the
severity of the disease but rather with the size of the
oral levodopa doses taken before.
© Adis Data Information BV 2003. All rights reserved.
485
A good alternative to intravenous infusion of
levodopa is the intraduodenal route, which is also
suitable for patients not experiencing fluctuations
but with dysphagia.[74,75] The intraduodenal route is
tolerated quite well if a percutaneous endoscopic
gastrostomy is created.
Alternatively, parenteral administration of pro-
drugs of levodopa, the methyl and ethyl esters, can
be considered. These prodrugs can be given intra-
venously or subcutaneously. Good results have been
described with this strategy.[76]
Another approach is to stimulate dopamine re-
ceptors continuously by administering apomorphine
subcutaneously via a pump. The most important
indication for this treatment is response fluctuations
otherwise unresponsive to optimal oral treatment,
leading to more than five or six sudden, unpredict-
able off periods per day. Many of these patients
currently undergo stereotactic surgery (see section
6). However, those patients who do not fulfil the
rather strict criteria for stereotactic surgery, with
mood or cognitive problems, or who want to post-
pone surgery can be treated very well with a subcu-
taneous apomorphine pump.
The starting dose for subcutaneous infusion is 1
mg/hour, which is the same as for intravenous deliv-
ery, and can be gradually increased by 1 mg/hour up
to maximal 10 mg/hour every 2 hours. The delivery
should be as continuous as possible, which means
that the infusion rate should be kept the same as
much as possible. The infusion rate can only be
adapted, for a few hours, in the case of severe
afternoon motor worsening. Patients may develop
tolerance to apomorphine if the infusion is given 24
hours/day.[77] In these cases, the infusion should be
stopped at night or continued at a very low rate to
provide some night-time relief and to prevent the
catheter from becoming sludged. Using the pump
this way, patients can also give themselves boluses
of apomorphine during the night.
The main adverse event associated with this ap-
proach is the development of subcutaneous nodules,
caused by a toxic effect of apomorphine on the
subcutaneous tissue. These can be treated and pre-
vented by dilution of the apomorphine solution
CNS Drugs 2003; 17 (7)
486
(from 1% to, for example, 0.5%), daily change of the
injection site and treatment of the injection sites
with hydrocortisone cream (0.1%) after the needle
has been removed.[78] Dilution of the apomorphine
is the most powerful way to reduce subcutaneous
nodules and should be prescribed therefore as a
standard.
The alternative to the subcutaneous infusion of
apomorphine is intravenous administration, which
can be achieved by a portacath in the subclavian
artery. This may be a good alternative for patients
who have developed severe skin nodules, which
make inserting new needles painful and diminish the
subcutaneous absorption of apomorphine. Good re-
sults have been reported with these portacath
systems and apomorphine.[79]
5.3 Dyskinesias
If dyskinesias occur, dose fractionating should be
avoided, as although it reduces dyskinesia, it wors-
ens response fluctuations (see section 5.2.1). (Sub)-
threshold doses have a very short duration of action,
if any effect at all, especially in the advanced stages
of the disease.[80]
Two main approaches can be helpful in improv-
ing dyskinesias: dopamine antagonists and amanta-
dine. Amantadine is a glutamate NMDA receptor
antagonist. The usefulness of NMDA antagonists in
the suppression of motor complications due to long-
term levodopa therapy is supported by a recent
experimental study in MPTP-induced parkinsonism
in monkeys using the selective NMDA antagonist
LY235959.[81] Recently, several publications have
supported this concept. Dyskinesia severity was re-
duced by 60% in a group of 14 patients with a mean
amantadine dose of 350mg.[82] The authors also
showed a direct relationship between the plasma
concentration of amantadine and the dyskinesia re-
duction, which could be described by a logarithmic
function. A very important finding was that the
positive effects lasted for at least 1 year,[83] which
provides enough clinical evidence to use amanta-
dine in higher doses for dyskinesia. However, in
elderly patients, these higher doses of amantadine
increase the risk for hallucinations. An extra benefit
© Adis Data Information BV 2003. All rights reserved.
van Laar
of amantadine may be a possible neuroprotective
effect. A recently published study has claimed a
survival advantage in patients treated with amanta-
dine.[84]
Dopamine antagonists can also be used to reduce
fluctuations. Clozapine is the best-studied com-
pound and has been studied in dosages between 6.25
and 50 mg/day. It may be an alternative if amanta-
dine is not tolerated or effective.[85-87]
6. Stereotactic Surgery
Patients whose response fluctuations cannot be
controlled with the strategies mentioned in section 5
may be candidates for stereotactic surgery, which
has shown a revival during the past decade.
Two techniques are available: deep brain stimu-
lation and lesioning. The major advantage of stimu-
lation over lesioning is the reversibility of the tech-
nique. The disadvantage of stimulation is the exten-
sive postoperative management of the electrode
settings required to achieve an optimal result. There
are three main targets to which one of these two
techniques can be applied: the ventral intermediate
nucleus of the thalamus, the subthalamic nucleus
and the internal part of the globus pallidus. The
correct patient selection is crucial to achieve an
optimal effect, as is selection of the appropriate
target. Bilateral subthalamic nucleus stimulation is
currently the most popular approach, in part because
of the positive results and in part because of the
possibility of reducing dopaminergic medication
postoperatively, which significantly reduces drug-
related adverse events.
In addition to experiencing uncontrollable re-
sponse fluctuations or tremor, patients must meet
some additional criteria. There must be a good re-
sponse to levodopa. If the patient does not show a
good response to levodopa, no improvement with
surgery can be expected. No behavioural, mood or
cognitive impairments should be present, because
they have a negative impact on the final results.
Lesioning can only be done unilaterally, because
otherwise too many adverse effects, such as speech
and swallowing difficulties as well as pyramidal
disorders, occur.
CNS Drugs 2003; 17 (7)
Levodopa-Induced Response Fluctuations
Table III summarises the indications and magni-
tudes of effect of the different techniques. Adverse
effects more specific to the stereotactic procedure
are infections, intracranial haematoma and lead
breakage or disconnection, which induce permanent
neurological impairment in about 3% of all patients.
All these data are extensively discussed in a special
supplement of Movement Disorders published re-
cently.[88]
7. Conclusions
Currently, the most important goal in the treat-
ment of motor complications associated with
levodopa is achieving stable pharmacokinetic
profiles as much as possible.[89] Therefore, regular
administration of levodopa in combination with
dopaminomimetics, which all have a relatively long
half-life, seems to be the best strategy. It is impor-
tant to delay the use of short-acting formulations of
levodopa for as long as possible, especially in
patients with young-onset IPD, in order to delay the
onset of response fluctuations. However, it is also
clear that stable pharmacokinetics do not solve all
problems. The major challenge at this time is to gain
a better insight into the pharmacodynamic changes
accompanying the response fluctuations. Only if we
get a better understanding of these mechanisms will
we be able to make real progress in the treatment of
response fluctuations.
Table III. Indications and results of the different stereotactic targets
in patients with motor response fluctuations to levodopa
Decrease in Subthalamic Globus
nucleus pallidus
Tremor +++ ++
Akinesia +++ ++
Rigidity +++ ++
Dyskinesia + +++
Levodopa dose ++ 0 0
0 = no effect; + indicates minimal effect; ++ indicates moderate
effect; +++ indicates marked effect.
© Adis Data Information BV 2003. All rights reserved.
487
Acknowledgements
The author has not received any funding for the prepara-
tion of this manuscript. There are no conflicts of interest that
could be relevant to the contents of this manuscript.
References
1. Morrish PK, Sawle GV, Brooks DJ. The rate of progression of
Parkinson’s disease: a longitudinal [18F]DOPA PET study. In:
Battistin L, Scarlato G, Caraceni T, et al., editors. Advances in
neurology. Vol. 69. Philadelphia (PA): Lippincott-Raven Pub-
lishers, 1996: 427-31
2. Leenders KL. Pathophysiology of movement disorders studied
using PET. J Neural Transm Suppl 1997; 50: 39-46
3. Hughes AJ, Daniel SE, Kilford L, et al. Accuracy of the clinical
diagnosis of idiopathic Parkinson’s disease: a clinico-patho-
logical study of 100 cases. J Neurol Neurosurg Psychiatry
1992; 55: 181-4
4. Marsden CD, Parkes JD. Success and problems of long-term
levodopa therapy in Parkinson’s disease. Lancet 1977; I: 345-9
5. Block G, Liss C, Reines S, et al. Comparison of immediate-
release and controlled-release carbidopa/levodopa in PD: a
multicenter 5-year study. Eur Neurol 1997; 37: 23-7
6. Golbe LI. Young-onset Parkinson’s disease: a clinical review.
Neurology 1991; 41: 168-73
7. Schrag A, Quinn N. Dyskinesias and motor fluctuations in
Parkinson’s disease: a community based study. Brain 2000;
123: 2297-305
8. Fahn S. Fluctuations of disability in Parkinson’s disease: patho-
physiological aspects. In: Marsden CD, Fahn S, editors. Move-
ment disorders. London: Butterworth Scientific, 1982: 123-45
9. Nutt JG, Holford NH. The response to levodopa in Parkinson’s
disease: imposing pharmacological law and order. Ann Neurol
1996; 39: 561-73
10. Melamed E, Bitton V, Zelig O. Delayed onset of response to
single doses of L-dopa therapy. Clin Neuropharmacol 1986; 9:
182-8
11. Melamed E, Bitton V, Zelig O. Episodic unresponsiveness to
single doses of L-dopa in parkinsonian fluctuators. Neurology
1986; 36: 100-3
12. Marsden CD, Parkes JD, Quinn N. Fluctuations of disability in
Parkinson’s disease: clinical aspects. In: Marsden CD, Fahn S,
editors. Movement disorders. London: Butterworth Scientific,
1982: 96-122
13. Lees AJ, Shaw KM, Stern GM. Off-period dystonia and on-
period choreoathetosis in levodopa-treated Parkinson’s disease
[letter]. Lancet 1977; II: 1034
14. Muenter MD, Sharpless NS, Tyce GM, et al. Patterns of
dystonia in response to L-dopa therapy for Parkinson’s dis-
Ventral ease. Mayo Clin Proc 1977; 52: 163-74
intermediate 15. Melamed E. Early-morning dystonia: a late side effect of long-
nucleus of the term levodopa therapy in Parkinson’s disease. Arch Neurol
thalamus 1979; 36: 308-10
+++ 16. Nausieda PA, Weiner WJ, Klawans HL. Dystonic foot response
of parkinsonism. Arch Neurol 1980; 37: 132-6
0
17. Curtis L, Lees AJ, Stern GM, et al. Effect of L-dopa on course
+ of Parkinson’s disease. Lancet 1984; II: 211-2
+ 18. Poewe WH, Lees AJ, Stern GM. Dystonia in Parkinson’s dis-
ease: clinical and pharmacological features. Ann Neurol 1988;
23: 73-8
19. Nutt JG, Woodward WR, Carter JH, et al. Influence of fluctua-
tions of plasma large neutral amino acids with normal diets on
CNS Drugs 2003; 17 (7)
488
the clinical response to levodopa. J Neurol Neurosurg Psychia-
try 1989; 52: 481-7
20. Baruzzi A, Cantin M, Riva R. Influence of meal ingestion time
on pharmacokinetics of orally-administered levodopa in
parkinsonian patients. Clin Neuropharmacol 1987; 10: 527-37
21. Carter JH, Nutt JH, Woodward WR. Amount and distribution of
dietary protein affects clinical response to levodopa in Parkin-
son’s disease. Neurology 1990; 39: 401-4
22. Kurth MC, Tetrud LW, Irwin I, et al. Oral levodopa/carbidopa
solution versus tablets in Parkinson’s patients with severe
fluctuations: a pilot study. Neurology 1993; 43: 1036-9
23. Fabbrini G, Juncos J, Mouradian MM, et al. Levodopa pharma-
cokinetic mechanisms and motor fluctuations in Parkinson’s
disease. Ann Neurol 1987; 21: 370-6
24. Fabbrini G, Mouradian MM, Juncos JL, et al. Motor fluctua-
tions in Parkinson’s disease: central pathophysiological mech-
anisms. Pt I. Ann Neurol 1988; 24: 366-71
25. Mouradian MM, Juncos JL, Fabbrini G, et al. Motor fluctua-
tions in Parkinson’s disease: central and pathophysiological
mechanisms. Pt II. Ann Neurol 1988; 24: 372-8
26. Leenders KL, Palmer AJ, Quinn N, et al. Brain dopamine
metabolism in patients with Parkinson’s disease measured
with PET. J Neurol Neurosurg Psychiatry 1986; 49: 853-60
27. Bravi D, Mouradian MM, Roberts JW, et al. Wearing-off
fluctuations in Parkinson’s disease: contribution of postsynap-
tic mechanisms. Ann Neurol 1994; 36: 27-31
28. Kostic V, Przedborski S, Flaster E, et al. Early development of
levodopa-induced dyskinesias and response fluctuations in
young-onset Parkinson’s disease. Neurology 1991; 41: 202-5
29. Horstink MWIM, Zijlmans JCM, Pasman JW, et al. Which risk
factors predict the levodopa response in fluctuating Parkin-
son’s disease. Ann Neurol 1990; 27: 537-43
30. De Jong GJ, Meerwaldt JD, Schmitz PIM. Factors that influence
the occurrence of response variations in Parkinson’s disease.
Ann Neurol 1987; 22: 4-7
31. Roos RAC, Vredevoogd CB, Van der Velde EA. Response
fluctuations in Parkinson’s disease. Neurology 1990; 40:
1344-6
32. Montastruc JL, Rascol O, Senard JM, et al. A randomised
controlled study comparing bromocriptine to which levodopa
was later added, with levodopa alone in previously untreated
patients with Parkinson’s disease: a five year follow-up. J
Neurol Neurosurg Psychiatry 1994; 57: 1034-8
33. Vermeulen RJ, Drukarch B, Sahadat MCR, et al. The selective
dopamine D1 receptor agonist SKF 81297, stimulates motor
behavior of MPTP-lesioned monkeys. Eur J Pharmacol 1993;
235: 143-7
34. Vermeulen RJ, Drukarch B, Sahadat MCR, et al. The dopamine
D1 agonist SKF 81297 and the dopamine D2 agonist LY
171555 act synergistically to stimulate motor behavior of
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned
parkinsonian rhesus monkeys. Mov Disorder 1994; 9: 664-72
35. Grondin R, Bédard PJ, Britton DR, et al. Potential therapeutic
use of the selective dopamine D1 receptor agonist, A-86929:
an acute study in parkinsonian levodopa-primed monkeys.
Neurology 1997; 49: 412-26
36. Goetz CG, Koller WC, Poewe W, et al. Management of
Parkinson’s disease: an evidence-based review. Levodopa.
Mov Disord 2002; 17 Suppl. 4: S23-37
37. Goetz CG, Koller WC, Poewe W, et al. Management of
Parkinson’s disease: an evidence-based review. DA agonists –
non-ergot derivatives: apomorphine. Mov Disord 2002; 17
Suppl. 4: S83-9
© Adis Data Information BV 2003. All rights reserved.
van Laar
38. Lledo A. Dopamine agonists: the treatment for Parkinson’s
disease in the XXI century? Parkinsonism Relat Disord 2001;
7: 51-8
39. Bedard PJ, Di Paolo T, Falardeau P, et al. Chronic treatment
with L-dopa, but not bromocriptine, induces dyskinesia in
MPTP-parkinsonian monkeys. Brain Res 1986; 379: 294-9
40. Pearce RK, Banerji T, Jenner P, et al. De novo administration of
ropinirole and bromocriptine induces less dyskinesia than L-
dopa in the MPTP-treated marmoset. Mov Disord 1998; 13:
234-41
41. Obeso JA, Rodriguez-Oroz MC, Rodriguez M, et al. Patho-
physiology of the basal ganglia in Parkinson’s disease. Trends
Neurosci 2000; 23 Suppl. 10: S8-S19
42. Marsden CD. Parkinson’s disease. J Neurol Neurosurg Psychia-
try 1994; 57: 672-81
43. Wolters EC, Tissingh G, Bergmans PLM, et al. Dopamine
agonists in Parkinson’s disease. Neurology 1995; 45 Suppl. 3:
S28-34
44. Uitti RJ, Ahlskog JE. Comparative review of dopamine receptor
agonists in Parkinson’s disease. CNS Drugs 1996; 5 (5):
369-88
45. Stocchi F, Nordera G, Marsden CD. Strategies for treating
patients with Parkinson’s disease with disastrous fluctuations
and dyskinesias. Clin Neuropharmacol 1997; 20 (2): 95-115
46. Olanow CW, Watts RL, Koller WC. An algorithm for the
management of Parkinson’s disease (2001): treatment guide-
lines. Neurology 2001; 56 Suppl. 5: S1-S88
47. Kulisevsky J, Lopez-Villegas D, Garcia-Sanchez C, et al. A six-
month study of pergolide and L-dopa in de novo Parkinson’s
disease patients. Clin Neuropharmacol 1998; 21: 358-62
48. Watts RL. The role of dopamine agonists in early Parkinson’s
disease. Neurology 1997; 49 (1 Suppl. 1): S34-48
49. Clarke CE. Dopamine agonist therapy in advanced Parkinson’s
disease. Neurology Rev Int 1998; 2: 1-5
50. Boas J, Worm-Petersen J, Dupont J, et al. The levodopa dose-
sparing capacity of pergolide compared to that of bromo-
criptine in an open-label, cross-over study. Eur J Neurol 1996;
3: 44-9
51. Olanow CW, Fahn S, Muenter M, et al. A multicenter double-
blind placebo-controlled trial of pergolide as an adjunct to
Sinemet in Parkinson’s disease. Mov Disord 1994; 9 (1): 40-7
52. LeWitt PA, Ward CD, Larsen TA, et al. Comparison of
pergolide and bromocriptine therapy in parkinsonism. Neurol-
ogy 1983; 33 (8): 1009-14
53. Pezzoli G, Martignoni E, Pacchetti C, et al. Pergolide compared
with bromocriptine in Parkinson’s disease: a multicenter,
crossover, controlled study. Mov Disord 1994; 9 (4): 431-6
54. Comparisons of therapeutic effects of levodopa, levodopa and
selegiline, and bromocriptine in patients with early, mild
Parkinson’s disease: three year interim report: Parkinson’s
Disease Research Group in the United Kingdom. BMJ 1993;
307 (6902): 469-72
55. Hely MA, Morris JG, Reid WG, et al. The Sydney Multicentre
Study of Parkinson’s disease: a randomised, prospective five
year study comparing low dose bromocriptine with low dose
levodopa-carbidopa. J Neurol Neurosurg Psychiatry 1994; 57
(8): 903-10
56. Rascol O, Brooks DJ, Korczyn AD, et al. A five-year study of
the incidence of dyskinesia in patients with early Parkinson’s
disease who were treated with ropinirole or levodopa: 056
Study Group. N Engl J Med 2000; 342: 1484-91
57. Barone P, Bravi D, Bermejo-Pareja F, et al. Pergolide mono-
therapy in the treatment of early PD: a randomized, controlled
CNS Drugs 2003; 17 (7)
Levodopa-Induced Response Fluctuations
study: Pergolide Monotherapy Study Group. Neurology 1999;
53: 573-9
58. Parkinson Study Group G. Pramipexole vs levodopa as initial
treatment for Parkinson disease: a randomized controlled trial.
JAMA 2000; 284: 1931-8
59. Rinne UK, Bracco F, Chouza C, et al. Early treatment of
Parkinson’s disease with cabergoline delays the onset of motor
complications: results of a double-blind levodopa controlled
trial. Drugs 1998; 55 Suppl. 1: S23-30
60. Poewe WH, Lees AJ, Stern GM. Treatment of motor fluctua-
tions in Parkinson’s disease with an oral sustained-release
preparation of L-dopa: clinical and pharmacokinetic observa-
tions. Clin Neuropharmacol 1986; 9: 430-9
61. Coleman RJ. Current drug therapy for Parkinson’s disease.
Drugs Aging 1992; 2 (2): 112-24
62. Goetz CG, Koller WC, Poewe W, et al. Management of
Parkinson’s disease: an evidence-based review. MAO-B inhib-
itors for the treatment of Parkinson’s disease. Mov Disord
2002; 17 Suppl. 4: S38-44
63. Kurth MC, Adler CH, Hilaire MS, et al. Tolcapone improves
motor function and reduces levodopa requirement in patients
with Parkinson’s disease experiencing motor fluctuations.
Neurology 1997; 48: 81-7
64. Parkinson Study Group. Entacapone improves motor fluctua-
tions in levodopa-treated Parkinson’s disease patients. Ann
Neurol 1997; 42: 747-55
65. Rinne UK, Larsen JP, Siden A, et al. Entacapone enhances the
response to levodopa in parkinsonian patients with motor
fluctuations. Neurology 1998; 51: 1309-14
66. Ruottinen HM, Rinne UK. Entacapone prolongs levodopa re-
sponse in a one month double blind study in parkinsonian
patients with levodopa related fluctuations. J Neurol
Neurosurg Psychiatry 1996; 60: 36-40
67. Nutt JG. Effects of COMT inhibition on the pharmacokinetics
of L-dopa. Adv Neurol 1996; 69: 493-6
68. Lyytinen J, Kaakkola S, Ahtila S, et al. Simultaneous MAO-B
and COMT inhibition in L-dopa treated patients with Parkin-
son’s disease. Mov Disord 1997; 12: 497-505
69. Lees AJ. Dopamine agonists in Parkinson’s disease: a look at
apomorphine. Fundam Clin Pharmacol 1993; 7: 121-8
70. Colosimo C, Merello M, Albanese A. Clinical usefulness of
apomorphine in movement disorders. Clin Neuropharmacol
1994; 17: 243-59
71. van Laar T, Jansen ENH, Essink AWG, et al. Intranasal
apomorphine in parkinsonian on-off fluctuations. Arch Neurol
1992; 49: 482-4
72. Dewey RB, Maraganore DM, Ahlskog JE. A double-blind pla-
cebo-controlled study of intranasal apomorphine spray as a
rescue agent for off-states in Parkinson’s disease. Mov Disord
1998; 13: 782-7
73. Merello M, Pikielny R, Cammarota A, et al. Comparison of
subcutaneous apomorphine versus dispersible Madopar laten-
cy and effect duration in Parkinson’s disease patients: a doub-
le-blind single-dose study. Clin Neuropharmacol 1997; 20:
165-7
© Adis Data Information BV 2003. All rights reserved.
489
74. Nutt JG, Carter JH, Lea ES, et al. Motor fluctuations during
continuous levodopa infusions in patients with Parkinson’s
disease. Mov Disord 1997; 12: 285-92
75. Melamed E, Zoldan J, Galili-Mosberg R, et al. Current manage-
ment of motor fluctuations in patients with advanced Parkin-
son’s disease treated chronically with levodopa. J Neural
Transm Suppl 1999; 56: 173-83
76. Djaldetti R, Melamed E. Levodopa ethylester: a novel rescue
therapy for response fluctuations in Parkinson’s disease. Ann
Neurol 1996; 39: 401-4
77. Gancher GT, Nutt JG, Woodward WR. Time course of tolerance
to apomorphine in Parkinsonism. Clin Pharmacol Ther 1992;
52: 504-10
78. Neef C, van Laar T. Pharmacokinetic-pharmacodynamic rela-
tionships of apomorphine in patients with Parkinson’s disease.
Clin Pharmacokinet 1999; 37: 257-71
79. Stocchi F, Farina C, Nordera G, et al. Implantable venous
access system for apomorphine infusion in complicated
Parkinson’s disease [letter]. Mov Disord 1999; 14: 358
80. Verhagen Metman L, Van den Munckhof P, Klaassen AAG, et
al. Effects of supra-threshold levodopa doses on dyskinesias in
advanced Parkinson’s disease. Neurology 1997; 49: 711-3
81. Papa SM, Chase TN. Levodopa-induced dyskinesias improved
by a glutamate antagonist in Parkinsonian monkeys. Ann
Neurol 1996; 39: 574-57
82. Verhagen Metman L, Del Dotto P, Van den Munckhof P, et al.
Amantadine as treatment for dyskinesias and motor fluctua-
tions in Parkinson’s disease. Neurology 1998; 50: 1323-6
83. Metman LV, Del Dotto P, LePoole K, et al. Amantadine for
levodopa-induced dyskinesias: a 1-year follow-up study. Arch
Neurol 1999; 56: 1383-6
84. Uitti Rj, Rajput AH, Ahlskog JE, et al. Amantadine treatment is
an independent predictor of survival in Parkinson’s disease.
Neurology 1996; 46: 1551-6
85. Bennett JP, Elke R, Landow RN, et al. Suppression of dyskine-
sias in advanced Parkinson’s disease. Neurology 1993; 43:
1551-5
86. Trosch RM, Friedman JH, Lannon MC, et al. Clozapine use in
Parkinson’s disease: a retrospective analysis of a large mul-
ticentered clinical experience. Mov Disord 1998; 13: 377-82
87. Durif F, Vidailhet M, Assal F, et al. Low-dose clozapine
improves dyskinesias in Parkinson’s disease. Neurology 1997;
48: 658-62
88. Deuschl G, Krack P, Volkmann J. Deep brain stimulation for
movement disorders. Mov Disord 2002; 7 Suppl. 3: S1-211
89. Chase TN. The significance of continuous dopaminergic stimu-
lation in the treatment of Parkinson’s disease. Drugs 1998; 55
Suppl. 1: 1-9
Correspondence and offprints: Dr Teus van Laar, Depart-
ment of Neurology, Groningen University Hospital,
Hanzeplein 1, Groningen, 9700 RB, The Netherlands.
E-mail: t.van.laar@neuro.azg.nl
CNS Drugs 2003; 17 (7)