CURRENT MEDICAL RESEARCH AND OPINIONÕ 0300-7995

VOL. 25, NO. 4, 2009, 841–849 doi:10.1185/03007990902779319

ß 2009 Informa UK Ltd. All rights reserved: reproduction in whole or part not permitted

REVIEW

Levodopa-related wearing-off in
Parkinson’s disease:
identification and management
Curr Med Res Opin Downloaded from informahealthcare.com by University of California San Francisco on 09/16/10

Rajesh Pahwa and Kelly E. Lyons

University of Kansas Medical Center, Kansas City, KS, USA

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Address for correspondence: Kelly E. Lyons, PhD, Department of Neurology, University of Kansas

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Medical Center, 3599 Rainbow Blvd, Mailstop 2012, Kansas City, KS 66160, USA.

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Tel.: þ1 913 588 7159; Fax: þ1 913 588 6920; lyons.kelly@att.net

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Key words: Levodopa – Motor complications – Parkinson’s disease – Wearing-off

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ABSTRACT
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Background: Levodopa is currently the most effective
le is al complications. A number of therapeutic options are
fo

treatment for Parkinson’s disease (PD); however, long-term available to optimize therapeutic outcome, including
For personal use only.

ng or ci

levodopa therapy often results in motor complications, such modification of the levodopa dose or dosing schedule,
d p ibi om In

co ed
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as motor fluctuations and dyskinesia. The initial compli- switching to another levodopa formulation and the use of
t a . Au e
09

cation is commonly wearing-off, which is the re-emergence adjunct therapies, such as catechol-O-methyl transferase
rin ted m

of motor and non-motor symptoms before the next inhibitors, dopamine agonists and monoamine oxidase-B
si th
20

scheduled levodopa dose. inhibitors. The management of wearing-off is dependent

Objective: The purpose of this article was to review upon the early identification of symptoms and the initiation
©
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published literature that discusses wearing-off, focusing on of effective treatment. Key issues are the need to educate
the role of the healthcare professional, including the pri- patients and to facilitate good communication with both
ew p r
ht
vi e o

mary care physician, in the effective management of primary and secondary healthcare professionals. In most
an h
au fo rig

la d le

wearing-off. cases, patients with PD initially present to primary

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Methods: An electronic literature search was conducted healthcare professionals who may refer the patient to a
sp ize a
y

using MEDLINE and EMBASE to find articles discussing neurologist once disease management becomes more
di hor r S
y, us
No op

wearing-off and its management using the following key complex. However, in many cases, especially in rural areas
words: ‘Parkinson’s disease’; ‘wearing-off’; ‘levodopa’; where neurologists may not be widely available, the pri-
C

‘primary care’. mary healthcare professionals may manage the patient

Un t

Findings and conclusions: Current evidence indicates throughout the disease course. Limitations of this review
t

that a consistent delivery of levodopa should improve long- include the restricted search criteria and selected search
term symptomatic efficacy and may prevent or delay motor period.

Introduction throughout adulthood. In the United States the pre-

Parkinson’s disease (PD) is a progressive, neurodegen-
erative disorder, the primary symptoms of which
include bradykinesia, rigidity and resting tremor, as
well as postural instability as the disease progresses.
Although motor symptoms classically define the dis-
order, various non-motor symptoms are frequently
seen, including autonomic dysfunction, cognitive
and psychiatric changes, sensory symptoms and
sleep disturbances1. The average age of PD onset is
60 years; however, onset can occur at any time
valence of PD, or the number of persons currently
affected, has been estimated to be approximately
1 million2. There are no tests to definitively confirm
the diagnosis of PD, which is based upon the experi-
ence of the diagnosing healthcare professional in
assessing symptoms, reviewing patient history and
ruling out alternative diagnoses3. For the majority
of patients, at the time of the initial diagnosis, symp-
toms are generally mild and multiple treatment
options are available that provide adequate symptom
control1. However, as the disease progresses,

Article 4852/378101 841

 symptoms progress and treatment adjustments are
necessary.
Levodopa is the most effective symptomatic treat-
ment for PD, and eventually nearly all patients will
require levodopa therapy. While levodopa continues
to benefit patients even as PD progresses, chronic use
of levodopa is associated with the development of
motor complications, such as dyskinesia and wearing-
off, that can lead to an increase in disability1. This
article reviews the published literature that discusses
wearing-off, focusing on the role of the healthcare pro-
fessional, including the primary care physician, in the
effective management of this complication.
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carbidopa or benserazide, has remained the most effec-
tive symptomatic treatment for PD1,5 and, since its
introduction, has dramatically improved survival and
quality of life for people with PD6,7.
During the first years of treatment with levodopa,
the therapeutic response is usually stable, and the ben-
efits are sustained even if an individual dose is missed8.
However, chronic use is associated with the develop-
ment of motor complications (Table 1), which can lead
to significant disability9–11. Often, the first motor com-
plication to occur is symptom re-emergence due to
wearing-off or end-of-dose deterioration. Here, the
therapeutic benefit from a given dose of levodopa
lasts for progressively shorter periods of time, and

both motor and non-motor symptoms of the disease

Methods
A literature review was conducted through MEDLINE
and EMBASE to find articles published between
January 2000 and October 2008 that discuss
wearing-off and its management. The primary search
parameters were ‘Parkinson’s disease’, ‘wearing-off’,
‘levodopa’ and ‘primary care’. English language articles,
references from bibliographies of review articles, origi-
nal research articles and other articles of interest were
reviewed. Data quality was determined by publication
For personal use only.
reappear before the next dose of levodopa is due.
With disease progression, the response to levodopa
further deteriorates and becomes unpredictable1, and
treatment is often associated with the development of
dyskinesias, which are involuntary movements and can
be disabling in some cases. As the duration of response
to levodopa becomes shorter, it increasingly mirrors the
plasma pharmacokinetic profile of levodopa and may
lead to pulsatile stimulation of the post-synaptic dopa-
minergic receptors. The development of both wearing-
off and dyskinesia is thought to result from this pulsa-

in the peer-reviewed literature and the most important
information identified. Data from published clinical
trials, general review articles and meta-analyses are
summarized in this article.
Results
Levodopa therapies
Given that PD is a chronic, progressive disorder and
the economic and social burden of the disease is
considerable4, healthcare professionals treating PD
must consider treatment options carefully. Since the
symptoms are largely due to the loss of dopamine in
the substantia nigra, most treatment strategies focus on
replenishing dopamine levels1. For over 40 years the
dopamine precursor levodopa combined with a periph-
eral dopa-decarboxylase inhibitor (DDCI), such as
tile stimulation of the receptors and the subsequent
molecular changes that occur12. In addition, levodopa’s
therapeutic window begins to narrow and the larger
doses required to manage wearing-off are complicated
by the presence of dyskinesia, thus making it harder to
achieve an optimal dose of levodopa that provides suf-
ficient symptomatic control without the presence of
disabling dyskinesia12.
As motor complications can have a significant impact
on patients and can be an important source of disability,
one of the most important goals in long-term levodopa
therapy is to prolong the duration of symptomatic effi-
cacy of each dose while delaying the onset of motor
complications. To do this, the therapy must be opti-
mized as soon as these complications begin to emerge.
As wearing-off is usually the first to develop, it is
important that the signs and symptoms of wearing-off
are recognized as early as possible.

Table 1. Levodopa-induced motor complications

Motor fluctuations Alternations between ON time when symptoms are well controlled and OFF time when
symptoms re-emerge
Wearing-off The re-emergence of symptoms towards the end of a levodopa dose
ON/OFF periods Unpredictable and sudden periods when Parkinson’s disease symptoms occur
Delayed ON Increased period of time before a dose of levodopa improves symptoms
Dose failure Individual levodopa dose fails to provide usual improvement in symptoms
Dyskinesia Involuntary dance-like movements

842 Management of wearing-off in Parkinson’s disease ß 2009 Informa UK Ltd - Curr Med Res Opin 2009; 25(4)
 Motor complications
Impact on patients and healthcare
professionals
One survey of 300 patients with PD, sampled from the
National Parkinson Foundation (Miami, FL), receiving
conventional levodopa found wearing-off to be the
most difficult aspect associated with their levodopa
therapy13. Wearing-off was also reported to be the
biggest levodopa-related challenge for physicians
participating in the survey. Interestingly, primary care
physicians were more concerned with wearing-off than
movement disorder specialists, who found dyskinesia
the biggest challenge of conventional levodopa ther-
apy14. With disease progression, most patients report
Curr Med Res Opin Downloaded from informahealthcare.com by University of California San Francisco on 09/16/10
non-motor features of wearing-off, which may even-
tually become more disabling than motor
fluctuations15.
Underlying mechanisms
The pathophysiological mechanisms underlying the
development of motor complications are now begin-
ning to be elucidated; current evidence suggests that
disease severity (degree of nigrostriatal degeneration)
and the half-life of the dopaminergic agent used to
For personal use only.
treat the parkinsonian symptoms are the factors that
best correlate with the development of motor compli-
cations16. In PD, the loss of striatal dopamine neurons
and terminals leads to a diminished ability to form,
store and regulate the release of dopamine17,18. It is
believed that conventional dosing strategies provide
intermittent delivery of levodopa to the brain, leading
to pulsatile stimulation of dopamine receptors12.
Consequent changes in intracellular signals and neuro-
nal firing patterns lead to dysregulation of the basal
ganglia motor circuit, which has been proposed to
underlie the development of motor complications19.
Evidence suggests that if levodopa could be delivered
in a more consistent manner, this may reinforce long-
term symptomatic efficacy and prevent or delay the
development of motor complications20–22. In addition,
it has been suggested that the early initiation of an
effective dopaminergic therapy may result in prolonged
long-term clinical benefit23.
Motor and non-motor symptoms of
wearing-off
There is wide variability in the literature regarding the
incidence of levodopa-induced motor complications.
A literature review from 1966 to 2000 found that
there was considerable variability in motor fluctuation
frequencies among studies with the same duration of
follow up24. The frequency of wearing-off within
ß 2009 Informa UK - Curr Med Res Opin 2009; 25(4)
2 years of therapy ranged from 0 to 50% and after
9 years it ranged from 41 to 83%. This variability was
attributed to both variance in study design and differing
methods for detecting motor complications. A study of
patients with young-onset PD reported the develop-
ment of motor complications in greater than 90% of
participants after 5 years of levodopa therapy25. In a
more recent study, 100% of patients taking levodopa
for 5 years had at least one symptom of wearing-off and
52% experienced wearing-off within the first year26.
The ELLDOPA study also reported the early develop-
ment of levodopa-induced motor fluctuations27. In this
study, subjects without prior treatment, who were not
expected to need treatment for the following 9 months,
received either placebo or daily doses of levodopa of
150, 300 or 600 mg for 40 weeks. Wearing-off was
reported in 13% of the placebo group, 16% of the levo-
dopa 150 mg/day group, 18% of the 300 mg/day group
and in 30% of the 600 mg/day group, suggesting that as
the levodopa dose increases, so does the risk for the
development of wearing-off, even early in the disease.
A wide range of clinical features related to wearing-
off are seen in patients with PD. These features can be
classified into either typical motor symptoms, such as
tremor, rigidity and bradykinesia, or the less obvious
non-motor fluctuations, such as mood changes, anxi-
ety, fatigue, pain, cognitive changes and sensory pro-
blems28. The non-motor symptoms associated with
wearing-off have been described for more than 20
years, but are often overlooked and consequently
often underestimated. Similar to motor fluctuations,
the reported frequency of non-motor fluctuations has
varied widely depending on the methodology used for
detection. For example, by asking patients with motor
fluctuations to report any symptoms that are associated
with the OFF state, Hillen and Sage identified non-
motor symptoms in only 17% of patients29. By contrast,
when questioning patients on the presence of specific
non-motor fluctuations, Raudino reported that 60% of
PD patients with motor fluctuations were experiencing
these non-motor symptoms30.
A prospective study of non-motor fluctuations in 50
patients with PD reporting motor fluctuations was car-
ried out using a 54-item questionnaire28. In this study,
100% of patients reported the presence of non-motor
fluctuations. The most frequent non-motor symptoms
were anxiety (66%), drenching sweats (64%), slowness
of thinking (58%), fatigue (56%), akathisia (54%), irrit-
ability (52%) and hallucinations (49%). The occurrence
of most of these symptoms was found to coincide with
the patient’s OFF state in 88% of the cases of anxiety,
59% of drenching sweats, 83% of slowness of thinking,
75% of fatigue, 63% of akathisia, 88% of irritability and
25% of hallucinations. Of the subjects experiencing
Management of wearing-off in Parkinson’s disease Pahwa & Lyons 843
 non-motor fluctuations, 28% reported
caused greater disability than their motor
An increased recognition of the
symptoms of wearing-off is particularly
as they are relatively common and can
significantly to patients’ disability, quality
institutionalization31.
The healthcare professional’s roles
As the signs and symptoms of wearing-off vary greatly
among patients and may be under-recognized by
healthcare professionals, they may often go untreated
before becoming prominent and disabling, leading to an
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that they These results suggest that early identification and treat-
symptoms. ment of wearing-off would be facilitated by the use of a
non-motor patient-driven clinical assessment tool, and this tool
important, may aid clinicians in treating patients.
contribute
of life and
Patient Wearing-Off Questionnaire
The initial patient WOQ included 32 symptoms26.
To increase ease of use in clinical practice, abbreviated
versions of the WOQ were developed. The first was a
19-item questionnaire, the WOQ-19, which with
further refinement led to the development of a nine-
item questionnaire32 (WOQ-9; Table 2). The WOQ-9
was found to have a sensitivity of 96% and specificity of
41%33. The low specificity observed may have been

unnecessary reduction in quality of life. Patients may

also be unaware that the more subtle changes they are
experiencing are related to PD and, as such, they may
not spontaneously discuss the full range of their symp-
toms with their healthcare professional. It is, therefore,
important that the healthcare professional treating the
patient is aware of the many different symptoms of
wearing-off and specifically asks about the occurrence
of both motor and non-motor symptoms. Primary
healthcare professionals may see patients with PD
more frequently than specialists, especially in more
rural areas and, therefore, need to be aware of the
For personal use only.
due to the gold standard used in the study (clinician’s
assessment). Possible explanations include differences
amongst clinicians, insufficient patient assessment time
or the fact that the wearing-off symptoms were not
present during examination. Therefore, it can be con-
cluded that the WOQ-9 is a quick and easy tool that
can act as a useful screening tool or as an adjunct to the
clinical examination of a patient to help optimize the
limited time available at each consultation. In addition,
the WOQ-9 may facilitate earlier detection of wearing-
off and allow therapy optimization to be implemented.

symptoms of wearing-off when they first emerge in

order to treat them at an early stage. A better recogni-
tion of wearing-off may prompt modifications of the
treatment regimen, or referral to a specialist.
Assessment of wearing-off
A study by Stacy et al. found that a standardized patient
questionnaire designed specifically to assess wearing-off
was more sensitive than traditional strategies, such as a
clinician’s assessment, used to diagnose wearing-off.
The standardized patient questionnaire (the Wearing-
Off Questionnaire [WOQ]) aimed to capture the most
common motor and non-motor symptoms of wearing-
off, based on the consensus of a group of PD specialists
and a review of the current literature. When complet-
ing the questionnaire, subjects indicated whether they
experienced each symptom during a typical day and
whether the symptom improved after dosing with anti-
parkinsonian medication. Based on these answers, the
subject was classified as having wearing-off if one or
more of the reported symptoms disappeared or
improved following a dose of their medication26.
Of 289 patients with PD diagnosed within 5 years,
57% were identified as having wearing-off as measured
by the patient WOQ, compared with 44% identified by
the Unified Parkinson’s Disease Rating Scale (UPDRS;
item 36), and only 29% were identified according to the
clinician’s opinion after completion of the UPDRS26.
Treatment of wearing-off
There are various approaches to the treatment of wear-
ing-off (Table 3 and 4). The first approach may be to
discuss with the patient the importance of taking their
PD medications at the correct time and according to
their prescribed regimen, as with disease progression,
poor timing compliance can have a significant effect on
symptom control and the development of wearing-off.
One study highlighted the widespread problem of med-
ication compliance, as it was observed that although
overall compliance was satisfactory in 80% of patients
with PD, only 25% of these patients displayed satisfac-
tory timing compliance34. If poor compliance is recog-
nized, the patient should be counseled regarding the
importance of adhering to the prescribed regimen,
and medication alarms or other strategies to increase
compliance should be discussed.
Levodopa
If compliance is not the issue, common approaches to
reducing wearing-off are levodopa modification strate-
gies1, which include using smaller, more frequent doses
of levodopa, increasing the total dose of levodopa, and
changing to other formulations of levodopa. Although
more frequent dosing can reduce wearing-off in some
patients, it can lead to intermittent re-emergence of

844 Management of wearing-off in Parkinson’s disease ß 2009 Informa UK Ltd - Curr Med Res Opin 2009; 25(4)
 Table 2. The 9-item Wearing-Off Questionnaire*
Symptom
1. Tremor (e.g., shaking of hands, arms or legs)
2. Any slowness in movement (e.g. walking, eating or dressing)
3. Mood changes
4. Any stiffness (e.g., rigidity of arms or legs)
5. Pain/aching
6. Reduced dexterity (e.g. difficulty buttoning or writing)
7. Cloudy mind/slowness of thinking
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8. Anxiety/panic attacks
9. Muscle cramping (e.g., arms, legs or feet)
Table adapted from Stacy et al. Clin Neuropharmacol 2006;29:312–21
*The WOQ-9 contains five motor and four non-motor symptoms. For each symptom, subjects reported whether the symptom was present
and whether the symptom improved after a subsequent dose of their antiparkinsonian medication. Based on these answers, the subject was
classified as having wearing-off if one or more of the reported symptoms disappeared or improved following the next dose of their medication
Table 3. Treatment options for wearing-off
Assess compliance with current treatment regimen
If non-compliant suggest aids/methods to enhance
For personal use only.
compliance
Increase levodopa dose
Increase the frequency of levodopa dosing
Addition of controlled-release levodopa
Addition of the triple combination formulation of
carbidopa/levodopa/entacapone
Addition of a COMT inhibitor
Addition of a dopamine agonist
Addition of an MAO-B inhibitor
COMT, catechol-O-methyl transferase; MAO-B, monoamine
oxidase type B
symptoms due to suboptimal levodopa exposure, and a
repeated need for dose adjustments. Increasing the total
amount of individual levodopa doses can be beneficial
in reducing wearing-off but may lead to the develop-
ment of, or an increase in, dyskinesia. Studies in which
immediate-release levodopa was switched to the sus-
tained-release formulation have shown conflicting
results, and the majority of reviews have reported
little evidence of improvements in wearing-off with
this strategy35–37.
Adjunctive therapies to levodopa
Another approach to the treatment of wearing-off is
the use of adjunctive therapies to levodopa1. The
American Academy of Neurology (AAN) reported an
evidence-based review of various treatment options for
ß 2009 Informa UK - Curr Med Res Opin 2009; 25(4)
Experience Usually improves
symptoms? after my next dose
PD patients with levodopa-induced motor fluctua-
tions35. The American Academy of Neurology recom-
mendations were based on a review of the published
literature and an evaluation of the strength of the
evidence reported in each study. Studies were given
ratings of Class I, II or III, with Class I studies being
those with the strongest level of evidence based on
the data reported and consequently receiving the high-
est recommendations for use (Table 4). Studies that did
not receive at least a Class III rating were not included
in the AAN report. The AAN classifications and
recommendations are based on multiple aspects of
the studies, such as the study design, primary outcome
variables, inclusion/exclusion criteria, dropout rates
and characteristics of the study groups; not just the
efficacy data that are reported.
Catechol-O-methyltransferase
A strategy to reduce wearing-off is the addition of a
catechol-O-methyltransferase (COMT) inhibitor to
levodopa. COMT inhibitors allow more levodopa to
reach the brain by blocking the levodopa degrading
enzyme, COMT. Currently available COMT inhibi-
tors are entacapone (Comtan) and tolcapone
(Tasmar) (Table 4). The AAN evidence-based prac-
tice guidelines for the treatment of motor fluctuations
gave entacapone the highest recommendation for use,
indicating that it is effective and should be used as a
strategy to reduce OFF time35. The AAN review
reported reductions in OFF time with entacapone
from 12 to 22%, which is up to 1.2 fewer OFF
hours per day.
Management of wearing-off in Parkinson’s disease Pahwa & Lyons 845
 Curr Med Res Opin Downloaded from informahealthcare.com by University of California San Francisco on 09/16/10
For personal use only.

Table 4. Treatment options for wearing-off: available strengths, starting doses and titration*

846
Treatment Strengths (mg) Starting doses and titration Effectiveness in reducing OFF timey

Carbidopa/levodopa/entacapone 12.5/50/200, 18.75/75/200, Replace each levodopa dose up to a maximum of 1600 mg/qd entacapone —
(Stalevo 50, Stalevo 75, Stalevo 25/100/200, 31.25/125/200, and/or 1200 mg/qd levodopa
100, Stalevo 125, Stalevo 150, 37.5/150/200, 50/200/200
Stalevo 200)
Entacapone (Comtan) 200 200 mg with each dose of levodopa up to eight times daily or 1600 mg/qd Effective (two Class I studies)
Tolcapone (Tasmar) 100, 200 100 mg tid increased to 200 mg tid as needed Probably effective (two Class II studies)
Pramipexole (Mirapex) 0.125, 0.25, 0.5, 1.0, 1.5 Weekly titration as needed: 0.125 mg tid; 0.25 mg tid; 0.5 mg tid; 0.75 mg Probably effective (one Class I study and one
tid; 1.0 mg tid; 1.25 mg tid; up to 1.5 mg tid Class II study)
Ropinirole (Requip) 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0 Weekly titration as needed: 0.25 mg tid; 0.5 mg tid; 0.75 mg tid; 1.0 mg Probably effective (two Class II studies)
tid; 1.5 mg tid; 2.0 mg tid; 2.5 mg tid; 3.0 mg tid with further increases
as needed up to 24 mg/qd

Management of wearing-off in Parkinson’s disease

Bromocriptine (Parlodel)
Rotigotine (Neupro) transdermal
patchz
Rasagiline (Azilect)
Selegiline (Eldepryl)
Orally disintegrating selegiline
(Zelapar)
2.5, 5 Initiate with half a 2.5 mg tablet bid at mealtimes. Dose can be titrated up Does not decrease OFF time (one Class II
by 2.5 mg/day every 14–28 days until maximum therapeutic response study)
is reached. Safety has not been demonstrated in doses exceeding
100 mg/day
1, 2, 3, 4, 6, 8 mg/24 h Early-stage Parkinson’s disease: Initiate at 2 mg/24 h once daily and Not approved at time of publication
increase in weekly increments of 2 mg/24 h for 3–4 weeks up to a
maximal dose of 8 mg/24 h. Advanced-stage Parkinson’s disease with
fluctuations: Initiate at 4 mg/24 h once daily and increase in weekly
increments of 2 mg/24 h over 3–7 weeks up to a maximal dose of
16 mg/24 h
0.5, 1.0 When used as an adjunct to levodopa – 0.5 mg qd increased to 1.0 mg qd as Effective (two Class I studies)
needed
5 5 mg bid taken at breakfast and lunch Possibly effective (one Class II and one
Class III study)
1.25 1.25 mg qd increased to 2.5 mg qd after 6 weeks as needed

*United States prescribing information

yStrength of evidence taken from American Academy of Neurology guidelines:
(1) Class I: Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required:
(a) Primary outcome(s) is/are clearly defined
(b) Exclusion/inclusion criteria are clearly defined
(c) Adequate accounting for dropouts and cross-overs with numbers sufficiently low to have minimal potential for bias
(d) Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
(2) Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets (a)–(d) above OR a randomized controlled trial in a representative population that lacks
one criterion (a)–(d)
(3) Class III: All other controlled trials including well defined natural history controls or patients serving as own controls in a representative population, where outcome assessment is independently assessed or
independently derived by objective outcome measurement
zEuropean-specific product characteristics

ß 2009 Informa UK Ltd - Curr Med Res Opin 2009; 25(4)

qd, per day; tid, three times daily; bid, twice daily
 A levodopa formulation containing carbidopa, levo-
dopa and entacapone in one tablet (Stalevo) is
approved for patients experiencing wearing-off. In the
United States, carbidopa/levodopa/entacapone is cur-
rently approved in six strengths (Stalevo 50, 75, 100,
125, 150, 200). Each strength contains either 50, 75,
100, 125, 150 or 200 mg of levodopa combined with
carbidopa at a dose that is one-quarter of the levodopa
dose and 200 mg of entacapone.
The COMT inhibitor tolcapone can also be used to
reduce wearing-off. The AAN evidence-based guide-
lines concluded that tolcapone is probably effective in
reducing motor fluctuations with an average reduction
in OFF time of 12–28% or up to 1.8 hours per day, and
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should be considered as a treatment option. However,
due to potential hepatotoxicity, tolcapone should be
used with caution and liver enzyme testing is recom-
mended every 2–4 weeks for 6 months, with further
testing as clinically necessary35.
Dopamine agonists
The addition of a dopamine agonist, which stimulates
the postsynaptic dopamine receptors, is another option
for the treatment of wearing-off. The most commonly
used dopamine agonists to reduce wearing-off include
For personal use only.
pramipexole (Mirapex), ropinirole (Requip), bromo-
criptine (Parlodel) and rotigotine (Neupro) (Table 4).
According to the AAN evidence-based guidelines for
the treatment of motor fluctuations, pramipexole and
ropinirole are probably effective at reducing OFF time
and should be considered as a treatment option for
patients with motor fluctuations35. The AAN guide-
lines reported a reduction in OFF time of 12–24%
with pramipexole and 7–19% with ropinirole immedi-
ate-release. Ropinirole extended-release has also been
shown to significantly reduce OFF time by an
average of 1.7 hours per day38. According to the
AAN guidelines, bromocriptine does not reduce OFF
time compared with placebo35. Rotigotine was not
approved for use at the time the AAN guidelines
were established and was, therefore, not included in
the recommendations.
Monoamine oxidase type B inhibitors
Monoamine oxidase type B (MAO-B) inhibitors have
also been shown to reduce wearing-off in patients
with PD. The MAO-B enzyme reduces the amount
of dopamine that reaches the brain; these medications
block MAO-B, thereby allowing more dopamine to
reach the brain. The MAO-B inhibitors currently
available in the United States are rasagiline
(Azilect), selegiline (Eldepryl) and orally disintegrat-
ing selegiline (Zelapar) (Table4). According to the
ß 2009 Informa UK - Curr Med Res Opin 2009; 25(4)
AAN guidelines, rasagiline received the highest
recommendation for use in reducing motor fluctua-
tions, indicating that it should be offered to patients
experiencing motor fluctuations. It was reported to
reduce OFF time by 8–14%, which translates to
0.5–1.0 hours daily35. On the other hand, the AAN
guidelines concluded that the evidence for the effect
of selegiline on motor fluctuations is inconsistent.
Results from studies of selegiline and orally disinte-
grating selegiline, a dissolvable formulation of selegi-
line that eliminates the need for swallowing a tablet
and has a reduced level of amphetamine metabolites
when compared with traditional selegiline, were com-
bined. The AAN guidelines concluded that selegiline
is possibly effective in reducing motor fluctuations
and may be considered to reduce OFF time35. One
selegiline study reached the level of inclusion in the
AAN report; however, it did not include specific data
regarding the reduction of OFF time. For orally dis-
integrating selegiline, the AAN guidelines reported an
average reduction in daily OFF time of 23% or 1.6
fewer hours per day35.
Discussion
The re-emergence of symptoms due to wearing-off
leads to increased disability in patients with PD and is
an indication of disease progression. Recognition of
wearing-off, particularly in the earlier stages, can be
complicated by the failure of the patient and healthcare
professional to recognize the motor and non-motor
symptoms associated with wearing-off. The availability
of a wearing-off screening assessment tool, such as the
WOQ-9, is an important tool that can be useful in
identifying the initial development of wearing-off and
its associated symptoms.
After the identification of wearing-off there are var-
ious treatment options available for reducing wearing-
off and other motor fluctuations, including adjustment
of levodopa doses and frequency, and switching to a
different levodopa preparation. Other strategies
include addition of adjunctive therapies to levodopa,
such as dopamine agonists, MAO-B inhibitors or
COMT inhibitors.
It is important to recognize that this article has cer-
tain limitations. The primary limitation is that the
selected search criteria terms and search period may
have impaired the ability to find all pertinent informa-
tion relating to wearing-off in PD and its management.
Consequently, although every effort has been made to
review available literature, and it is believed that the
most important information has been included, there
may be certain peer-reviewed publications that were
Management of wearing-off in Parkinson’s disease Pahwa & Lyons 847
 not included. In addition, although articles were speci-
fically selected to present a balanced discussion of the
current literature, the healthcare professional is
encouraged to interpret the information contained
here in conjunction with their clinical experience and
judgment.
Conclusions
The early recognition and effective alleviation of
wearing-off symptoms is important in order to
improve the functional ability, quality of life and
long-term control of symptoms in patients with
Curr Med Res Opin Downloaded from informahealthcare.com by University of California San Francisco on 09/16/10
Parkinson’s disease.
Acknowledgments
Declaration of interest: This study was funded by
Novartis. R. P. has received grant funding, participated
in clinical trials and consulted or been on the speaker
bureau for GlaxoSmithKline, Novartis, Boehringer
Ingelheim, Medtronic, Advanced Neuromodulation
Systems, Teva Neuroscience, UCB and Valeant.
For personal use only.
K. E. L. has received consulting fees from
GlaxoSmithKline, Novartis, Teva Neuroscience,
UCB, Valeant, Medtronic and Advanced
Neuromodulation Systems. Editorial support for this
manuscript was provided by Diya Lahiri, PhD, and
was funded by Novartis.
References
1. Olanow CW, Watts RL, Koller WC. An algorithm
(decision tree) for the management of Parkinson’s
disease (2001): treatment guidelines. Neurology 2001;56:
S1-S88
2. Strickland D, Bertoni JM. Parkinson’s prevalence estimated by a
state registry. Mov Disord 2004;19:318-23
3. Hughes AJ, Daniel SE, Kilford L, et al. Accuracy of
clinical diagnosis of idiopathic Parkinson’s disease: a clinico-
pathological study of 100 cases. J Neurol Neurosurg Psychiatry
1992;55:181-4
4. Huse DM, Schulman K, Orsini L, et al. Burden of illness in
Parkinson’s disease. Mov Disord 2005;20:1449-54
5. Agid Y, Olanow CW, Mizuno Y. Levodopa: why the contro-
versy? Lancet 2002;360:575
6. Hoehn MM. The natural history of Parkinson’s disease in the pre-
levodopa and post-levodopa eras. Neurol Clin 1992;10:331-9
7. Uitti RJ, Ahlskog JE, Maraganore DM, et al. Levodopa therapy
and survival in idiopathic Parkinson’s disease: Olmsted County
project. Neurology 1993;43:1918-26
8. Zappia M, Oliveri RL, Montesanti R, et al. Loss of long-duration
response to levodopa over time in PD: implications for wearing-
off. Neurology 1999;52:763-7
9. Schrag A, Quinn N. Dyskinesias and motor fluctuations in
Parkinson’s disease. A community-based study. Brain 2000;
123:2297-305
848 Management of wearing-off in Parkinson’s disease
10. Adler CH. Relevance of motor complications in Parkinson’s
disease. Neurology 2002;58:51-6
11. Stocchi F. Prevention and treatment of motor fluctuations.
Parkinsonism Relat Disord 2003;9:73-81
12. Obeso JA, Rodriguez-Oroz MC, Chana P, et al. The evolution
and origin of motor complications in Parkinson’s disease.
Neurology 2000;55:S13-20; discussion S1-3
13. Lieberman A, Vijay M. Wearing-off of greatest concern for PD
patient. Eur J Neurol 2004;11:S109 (Abstr P1284)
14. Koller W, Vijay M. Physician beliefs and practices in levodopa
therapy for PD: results of a US National Survey. Eur J Neurol
2004;11:S9-35
15. Hely MA, Morris JG, Reid WG, et al. Sydney Multicenter Study
of Parkinson’s disease: non-L-dopa-responsive problems domi-
nate at 15 years. Mov Disord 2005;20:190-9
16. Colosimo C, De Michele M. Motor fluctuations in
Parkinson’s disease: pathophysiology and treatment. Eur J
Neurol 1999;6:1-21
17. Bravi D, Mouradian MM, Roberts JW, et al. Wearing-off fluc-
tuations in Parkinson’s disease: contribution of postsynaptic
mechanisms. Ann Neurol 1994;36:27-31
18. Obeso JA, Olanow CW, Nutt JG. Levodopa motor complica-
tions in Parkinson’s disease. Trends Neurosci 2000;23:S2-7
19. Olanow CW, Obeso JA. Pulsatile stimulation of dopamine
receptors and levodopa-induced motor complications in
Parkinson’s disease: implications for the early use of COMT
inhibitors. Neurology 2000;55:S72-7; discussion S8-81
20. Olanow CW, Stocchi F. COMT inhibitors in Parkinson’s dis-
ease: can they prevent and/or reverse levodopa-induced motor
complications? Neurology 2004;62:S72-81
21. Stocchi F, Olanow CW. Continuous dopaminergic stimulation
in early and advanced Parkinson’s disease. Neurology 2004;
62:S56-63
22. Stocchi F, Vacca L, Ruggieri S, et al. Intermittent vs continuous
levodopa administration in patients with advanced Parkinson
disease: a clinical and pharmacokinetic study. Arch Neurol
2005;62:905-10
23. Schapira AH, Obeso J. Timing of treatment initiation in
Parkinson’s disease: a need for reappraisal? Ann Neurol 2006;
59:559-62
24. Ahlskog JE, Muenter MD. Frequency of levodopa-related dys-
kinesias and motor fluctuations as estimated from the cumula-
tive literature. Mov Disord 2001;16:448-58
25. Schrag A, Ben-Shlomo Y, Brown R, et al. Young-onset
Parkinson’s disease revisited–clinical features, natural history,
and mortality. Mov Disord 1998;13:885-94
26. Stacy M, Bowron A, Guttman M, et al. Identification of motor
and nonmotor wearing-off in Parkinson’s disease: comparison of
a patient questionnaire versus a clinician assessment. Mov
Disord 2005;20:726-33
27. Parkinson Study Group. Levodopa and the progression of
Parkinson’s disease. N Engl J Med 2004;351:2498-508
28. Witjas T, Kaphan E, Azulay JP, et al. Nonmotor fluctuations in
Parkinson’s disease: frequent and disabling. Neurology 2002;
59:408-13
29. Hillen ME, Sage JI. Nonmotor fluctuations in patients with
Parkinson’s disease. Neurology 1996;47:1180-3
30. Raudino F. Non motor off in Parkinson’s disease. Acta Neurol
Scand 2001;104:312-15
31. Thanvi BR, Munshi SK, Vijaykumar N, et al. Neuropsychiatric
non-motor aspects of Parkinson’s disease. Postgrad Med J
2003;79:561-5
32. Stacy M, Hauser R, Oertel W, et al. End-of-dose wearing off in
Parkinson disease: a 9-question survey assessment. Clin
Neuropharmacol 2006;29:312-21
33. Stacy MA, Murphy JM, Greeley DR, et al. The sensitivity and
specificity of the 9-item Wearing-off Questionnaire.
Parkinsonism Relat Disord 2008;14:205-12
34. Grosset KA, Bone I, Grosset DG. Suboptimal medication
adherence in Parkinson’s disease. Mov Disord 2005;20:1502-7
ß 2009 Informa UK Ltd - Curr Med Res Opin 2009; 25(4)
 35. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treat-
ment of Parkinson disease with motor fluctuations and dyskine-
sia (an evidence-based review): report of the Quality Standards
Subcommittee of the American Academy of Neurology.
Neurology 2006;66:983-95
36. Horstink M, Tolosa E, Bonuccelli U, et al. Review of the
therapeutic management of Parkinson’s disease. Report of a
joint task force of the European Federation of Neurological
Societies (EFNS) and the Movement Disorder Society-
European Section (MDS-ES). Part II: late (complicated)
Parkinson’s disease. Eur J Neurol 2006;13:1186-202
37. Goetz CG, Poewe W, Rascol O, et al. Evidence-based medical
review update: pharmacological and surgical treatments
of Parkinson’s disease: 2001 to 2004. Mov Disord 2005;
20:523-39
38. Pahwa R, Stacy MA, Factor SA, et al. Ropinirole 24-hour pro-
longed release: randomized, controlled study in advanced
Parkinson disease. Neurology 2007;68:1108-15

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Paper CMRO-4852_4, Accepted for publication: 27 January 2009
Published Online: 19 February 2009
doi:10.1185/03007990902779319
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