Expert Opinion on Orphan Drugs

ISSN: (Print) 2167-8707 (Online) Journal homepage: https://www.tandfonline.com/loi/ieod20

Complications of levodopa therapy in Parkinson’s

disease

Jordan Dubow & C. Warren Olanow

To cite this article: Jordan Dubow & C. Warren Olanow (2019): Complications of levodopa therapy
in Parkinson’s disease, Expert Opinion on Orphan Drugs, DOI: 10.1080/21678707.2019.1662294

To link to this article: https://doi.org/10.1080/21678707.2019.1662294

Published online: 16 Sep 2019.

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EXPERT OPINION ON ORPHAN DRUGS
https://doi.org/10.1080/21678707.2019.1662294

REVIEW

Complications of levodopa therapy in Parkinson’s disease

Jordan Dubowa and C. Warren Olanowb
a
Avadel Pharmaceuticals PLC, Chesterfield, MO, USA; bDepartment of Neurology and Neuroscience, Mount Sinai Health System, New York City, NY,
USA

ABSTRACT ARTICLE HISTORY

Introduction: Levodopa remains the most effective treatment for the motor symptoms of Parkinson’s Received 16 April 2019
disease (PD). However, with chronic treatment, PD patients develop motor complications, which consist Accepted 28 August 2019
of motor fluctuations and dyskinesia. Many new treatments, both medical and interventional, have KEYWORDS
been developed for the treatment of motor complications but there continues to be an unmet medical Parkinson’s disease; motor
need for further treatments. complications; dyskinesia;
Areas covered: This manuscript summarizes the phenomenology, pathophysiology, prevalence and wearing off; levodopa
current and future treatments of motor complications in PD patients based on a PubMed literature
search from 1950s to present.
Expert opinion: Motor complications are prevalent in PD and risk factors for developing these
complications are well-known and well characterized. There are many effective medical and interven-
tional treatments for both motor fluctuations and dyskinesia in PD patients. Despite these treatments,
many patients still suffer from many hours of ‘Off’ time or dyskinesia that have a profound negative
impact on quality of life. There are many exciting treatments under development for motor complica-
tions that may provide additional benefit for PD patients.

1. Introduction in the same individual. The mechanism by which motor compli-

cations occur are only partially understood but are thought to
Parkinson’s disease (PD) is the second most common neurode-
relate to standard oral levodopa providing restoration of brain
generative disease after Alzheimer’s disease. PD has a prevalence
dopamine in a non-physiologic manner, with pulsatile rather
of approximately 0.5% to 1% among persons 65 to 69 years of
than continuous stimulation of post synaptic dopamine recep-
age, rising to 1% to 3% among persons 80 years of age and older
tors. This leads to the development of molecular and neurophy-
[1]. The incidence of Parkinson’s disease is estimated to be 20/
siologic changes and ultimately the development of motor
100,000 or 60,000 new cases per year in the United States. The
complications [4,5]. Numerous medical and surgical therapies
disease is characterized by progressive degeneration of the
have been developed to try and manage these problems (see
nigrostriatal system with depletion of dopamine [2], which
below), but there remain a large number of patients in whom
results in the core motor symptoms of bradykinesia, rigidity,
motor complications are not adequately controlled despite all
rest tremor, gait disturbance and postural instability. Levodopa
available therapies. While the precise number of subjects in the
has been available for more than 50 years, and remains the most
United States who suffer from such motor complications despite
effective anti-parkinsonian drug. However, with chronic levo-
available therapy has not been specifically calculated, it is esti-
dopa treatment, PD patients develop motor complications con-
mated to be fewer than 200,000 subjects, and thus qualifies for
sisting of dyskinesia (involuntary movements) and fluctuations in
orphan drug designation, as reflected by the recent approval of
motor response [3]. Dyskinesia most commonly manifests as
Duodopa® for orphan exclusivity. This article summarizes the
choreiform movements, that are most prominent at times of
phenomenology, pathophysiology, prevalence and treatment
peak plasma levodopa concentration and peak anti-
of complications due to levodopa treatment for Parkinson’s dis-
parkinsonian response (peak dose dyskinesia). Patients may
ease based on a PubMed search from the 1950s to present.
also experience di-phasic dyskinesia (which occurs when plasma
levodopa levels begin to rise and begin to fall) and early morning
dystonia. Motor fluctuations represent periods in which patients 2. Phenomenology of motor complications
cycle between periods in which they experience a good anti-
The manifestations of motor fluctuations and dyskinesia have
parkinsonian response following a dose of levodopa (ON time)
been well characterized. The most common type of motor com-
and periods in which there is a loss of anti-parkinsonian response
plication is the wearing ‘Off’ response or end of dose deterioration,
(OFF time). These OFF episodes include wearing Off, delayed On,
which entails a return of parkinsonian features (i.e. tremor, brady-
or no-ON responses following a dose of levodopa, as well as
kinesia, rigidity) following a given levodopa dose prior to the onset
unexpected and rapid changes between the ON and OFF states.
of benefit from the subsequent dose. Early in the disease, the
Indeed, motor response may differ following a dose of levodopa

CONTACT Jordan Dubow drdubow14@gmail.com Avadel Pharmaceuticals PLC, Chesterfield, MO, USA
© 2019 Informa UK Limited, trading as Taylor & Francis Group
2 J. DUBOW AND C. W. OLANOW

normal conditions, dopamine neurons fire continuously, and

Article highlights dopamine release and uptake are regulated such that dopamine
● ;Levodopa is the most effective treatment for PD but results in the
levels are maintained at a relatively constant level [5]. This serves
development of long-term motor complications to maintain the stability of the basal ganglia network and to
● Motor complications are common and occur in almost all PD patients permit the selection of desired movements with rejection of
with long-term treatment
● Most data suggests pulsatile stimulation of the dopamine receptor
undesired movement. In PD patients, with a dopamine-
induces motor complications depleted state, brain dopamine levels are dependent on the
● Various treatments for motor complications are approved around the availability of peripheral levodopa. However, intermittent doses
world and have a great impact on motor fluctuations and dyskinesia;
however, some patient still need interventional procedures to control
of standard levodopa result in fluctuating plasma and brain
their motor fluctuations dopamine levels due to the short half-life of the drug and the
● Many new treatments are in development for the treatment of motor variability in GI transport and absorption. Thus, standard levo-
complications
dopa as currently administered does not restore brain dopamine
This box summarizes key points contained in the article. in a physiologic manner and results in pulsatile activation of
striatal dopamine receptors leading to molecular changes and
altered neuronal firing patterns in basal ganglia neurons that
lead to motor complications.
A vast amount of preclinical data has shown that pulsatile
benefit following a dose of levodopa may last for 6 hours or
stimulation of dopamine receptors induces the development
longer, but as the disease progresses the duration of benefit
of both motor fluctuations and dyskinesia. For example, inter-
begins to shorten and to approximate the half-life of the drug
mittent doses of the short acting D2 dopamine receptor ago-
(approximately 90 minutes). Additionally, with continued levo-
nist U915356A resulted in dyskinesias in MPTP-lesioned
dopa treatment and disease progression, patients can experience
monkeys, which was not seen with continuous infusion of
a variable response following each dose: this could include
the same compound [7]. Similarly, administration of levodopa
a normal full response, a delayed response (delayed-on), a partial
in a pulsatile manner results in marked dyskinesia in MPTP
response (partial ON) and no response at all (no-‘On’ response).
marmosets compared to long-acting dopamine agonists [8].
Typically, a patient will notice an improvement in motor symp-
Similarly, continuous delivery of the dopamine agonist rotigo-
toms within about 45 minutes after taking a standard levodopa
tine in MPTP-treated common marmosets was associated with
dose. However, these responses can be variable and unpredict-
a significant reduction in dyskinesia in comparison to inter-
able, leaving a patient unsure when, and to what extent, their dose
mittent or pulsatile delivery of the same drug [9] Based on
of levodopa is going to work. Although less common today, PD
these observations it has been postulated that levodopa-
patients can also experience sudden ‘Offs’, where the benefit of
induced motor complications result from intermittent discon-
medication suddenly stops working and parkinsonian symptoms
tinuous levodopa administration, and have led to the hypoth-
rapidly recur. This is known as the ON-OFF response.
esis that more continuous levodopa delivery would reduce or
Dyskinesias, are involuntary movements that typically mani-
prevent the development of motor complications.
fest as chorea, but ballism, dystonia, myoclonus or other move-
ment disorders may occur. The most common form of is peak-
dose dyskinesia, which consists of non-patterned, choreiform or 4. Prevalence of motor complications
ballistic movements involving the head, trunk, and limbs. These
Approximately 40% of patients with PD experience motor
tend to occur at the time of the maximal plasma levodopa
fluctuations and/or dyskinesias within 5 years of initiating
concentration and peak anti-parkinsonian effect. A less common
levodopa therapy, with close to 90% of patients experiencing
form of dyskinesia is diphasic dyskinesia. In contrast to peak dose
these symptoms after 9 or more years of treatment [10]. Motor
dyskinesia, diphasic dyskinesia occurs at relatively low plasma
fluctuations, however, can be present much earlier in the
levodopa concentrations (i.e. as the concentration rises or falls).
disease. One study looked at rates of motor complications in
The effects tend to be short-lasting (seconds to minutes), and to
PD patients with less than 2 years of duration with a modified
disappear with higher concentrations (which may be associated
Hoehn & Yahr stage of 1–2.5 treated with either pramipexole
with peak dose dyskinesia) or lower concentrations (which are
or levodopa. This study found that after two years of treat-
associated with worsening parkinsonism). Diphasic dyskinesias
ment, 23% of patients on pramipexole and 34% on levodopa
typically effect the lower extremities, are patterned, often dys-
had developed motor complications [11]. By 5 years, 47% of
tonic, and potentially associated with parkinsonian features in
pramipexole-treated patients and 63% of levodopa-treated
other body regions. A sustained form of diphasic dyskinesia can
patients had developed wearing off [12]. Another study
be seen with continued low plasma levodopa levels such as
showed that after 5 years of treatment, 23% of ropinirole-
following a levodopa infusion or transplantation of dopaminer-
treated patients and 34% of levodopa-treated patients had
gic cells [6].
developed wearing off [13]. Finally, a double-blind prospective
study showed that as many as 50% of patients developed
dyskinesia and wearing off within 3 years of starting levop-
3. Pathophysiology of motor complications
dopa [14].These studies illustrate the frequency of motor com-
Preclinical data has demonstrated that motor complications in plications, as well as the increased risk of treatment with short-
the dopamine-denervated state are associated with intermittent acting levodopa in comparison to a long-acting dopamine
administration of standard short-acting oral levodopa. Under agonist. Motor complications also have been shown to affect
 EXPERT OPINION ON ORPHAN DRUGS 3

quality of life with all of types of motor complications being amantadine also had significant improvement in ‘On’ time
associated with impairment in quality of life as measured by without troublesome dyskinesia and ‘Off’ time compared to
the PDQ-39 [15]. placebo. However, treatment was complicated by adverse
Studies have also demonstrated that the risk of developing effects, particularly cognitive alterations and hallucinations
dyskinesia and wearing ‘Off’ increases in a levodopa-dependent and this can be problematic for PD patients who frequently
manner. Analysis of the 3-year prospective double-blind STRIDE- suffer cognitive impairments.
PD study, which compared initiation of treatment with carbi- For those patients who continue to have disabling dyskinesia
dopa/levodopa with carbidopa/levodopa/entacapone, demon- despite best medical management, interventional procedures
strated that the biggest risk factors for developing dyskinesia such as deep brain stimulation can be helpful [18]. Deep brain
and wearing ‘Off’ were young age at onset, and higher levodopa stimulation (DBS) involves placement of electrodes in the subtha-
dose [14]. Low body weight, female gender and more severe lamic nucleus, globus pallidus, or thalamus, has been approved by
baseline Unified Parkinson’s Disease Rating Scale Part II score the FDA for the treatment of PD. Two large studies comparing DBS
were also risk factors. This study specifically demonstrated that as to best medical therapy demonstrated that DBS-treated patients
the dose of levodopa is increased to levels greater than 400 mg had significant improvement in ‘Off’ time, ‘On’ time without trou-
per day, the risk of developing both dyskinesia and wearing blesome dyskinesia (‘On’ time with no dyskinesia + ‘On’ time with
motor fluctuations increases substantially. The authors recom- mild dyskinesia), ‘On’ time with troublesome dyskinesia and quality
mended that levodopa doses be increased incrementally and of life [18,19]. However, DBS carries the risk of potentially serious
only as necessary – in other words higher doses of levodopa have adverse events related to the procedure (intracerebral hemor-
a greater risk of causing motor complications and should not be rhage, infarct, infection), the device (infection, cutaneous lesion),
employed unless medically required. Importantly, these observa- or the stimulation itself (oculomotor dysfunction, speech impair-
tions suggest that motor fluctuations as well as dyskinesia are ment and cognitive disturbance). Continuous intrajejunal levo-
related to pharmacodynamic as well as pharmacokinetic factors. dopa (Duopa/Duodopa), provides continuous levels of levodopa.
A double-blind, double-dummy, study comparing intrajejunal
levodopa to standard immediate release levodopa demonstrated
5. Treatment of motor complications a significant improvement in ‘On’ time without dyskinesia and
quality of life in comparison to patients treated with standard
5.1. Treatment of dyskinesia
immediate release carbidopa-levodopa [20]. In a post-hoc analysis,
Until recently, there have been no pharmaceutical drugs evaluating PD patients with a Baseline of 1 or more hour of ‘On’
approved for the treatment of dyskinesia. Dyskinesia can initi- time with troublesome dyskinesia, intrajejunal levodopa also pro-
ally be managed by lowering the levodopa dose and increas- vided a significant reduction from Baseline in dyskinesia [21],
ing the frequency of administration. However, lowering the comparable to what was seen with DBS. A prospective study,
dose may increase the frequency and severity of off episodes. comparing Duopa to best medical therapy for the treatment of
Adding a dopamine agonist (i.e. pramipexole, ropinirole, roti- dyskinesia is currently ongoing, using the UDySRS as the primary
gotine) a COMT inhibitor, or a MAO-B inhibitor to levodopa endpoint [22]. However, Duopa/Duodopa carries potentially life-
may permit a reduction in levodopa dose and an improve- threatening risks related to the procedure (peritonitis, intestinal
ment in dyskinesia but this can lead to worsening of parkin- hemorrhage, intestinal obstruction intestinal perforation, pancrea-
sonian motor features and is typically limited to patients with titis and post-operative wound infection) and 50% of patients need
relatively mild motor complications [3]. Other adjunctive drug to have the jejunal tube replaced within one year of starting
treatments for the reduction of dyskinesia has been tested treatment. The treatment also requires wearing a cumbersome
targeting various mechanisms of action have for over the infusion pump. A safe and effective therapy that treats or prevents
last 20 years with little success. Strategies include NMDA dyskinesia remains an important unmet need.
antagonists, AMPA antagonists, MGluR5 modulators, alpha-
2-adrenergic receptor antagonists, nicotinic receptor agonists,
partial dopamine agonists, and 5HT antagonists. However,
5.2. Treatment of motor fluctuations
none of these agents were able to show a reduction of dyski-
nesia without worsening of parkinsonian motor features and Predictable motor fluctuations (i.e. end of dose wearing off)
none have been approved for this indication. Amantadine is can be treated by increasing the dose or frequency of levo-
the only drug that has demonstrated anti-dyskinetic effects dopa or by adding adjunctive Parkinson’s disease medications.
without worsening of parkinsonism in prospective, double- These include COMT inhibitors, MAO-B inhibitors and dopa-
blind controlled studies. Recently, a long-acting formulation mine agonists. However, higher doses of levodopa or dopa-
of amantadine (Gocovri, Adamas Pharmaceuticals) completed minergic drugs increases the risk of dyskinesia, so it is
2 large Phase 3 clinical trials in patients with dyskinesia and generally recommended that clinicians keep the dose of levo-
was approved by the FDA as the first labeled drug to treat dopa relatively low by using polypharmacy with COMT inhibi-
dyskinesia. One study demonstrated a significant 7.9 point tors, MAO-B inhibitors, or dopamine agonists.
improvement in the Unified Dyskinesia Rating Scale compared Currently, there are two approved COMT inhibitors in the
to placebo at 12 weeks, and the second study demonstrated US for the treatment of motor fluctuations, entacapone and
a significant 14.4 point improvement on the Unified tolcapone. Tolcapone is a more potent inhibitor of COMT with
Dyskinesia Rating Scale compared to placebo at 12 weeks its predominant site of action in the periphery but some
[16,17]. In both studies, patients treated with long-acting activity in the CNS, while entacapone acts only in the
4 J. DUBOW AND C. W. OLANOW

periphery. Tolcapone is the more potent and is typically given ‘Off’ time and ‘On’ time without troublesome dyskinesia
up to three times a day. It has demonstrated an improvement (approximately 4 hours from Baseline and 2 hours compared
in ‘Off’ time of 1.8 hours compared to placebo [23]. to placebo) [18–20]. As noted, these treatments are limited by
Entacapone is typically given with each levodopa dose and their procedure and/or device-related complications. However,
has demonstrated a reduction in ‘Off’ time of 0.7–1.2 hours given their robust efficacy, many patients elect to continue
while also improving ‘On’ time without troublesome dyskine- with these treatments despite procedure/device complica-
sia [24]. Both entacapone and tolcapone can cause diarrhea, tions. Continuous apomorphine infusion has been available
severe enough to lead to discontinuation in approximately 5% in Europe for the treatment of motor complications but is
of patients and can transiently worsen dyskinesia. Tolcapone not yet approved in the US. A recent double-blind, placebo-
carries a black box warning for hepatotoxicity and requires controlled study demonstrated that continuous apomorphine
frequent liver function monitoring. Opicapone, a long-acting infusion improves ‘Off’ time and ‘On’ time without trouble-
once daily COMT inhibitor, has demonstrated improvement in some dyskinesia by approximately 2 hours compared to pla-
‘Off’ time and ‘On’ time without troublesome dyskinesia in cebo [34]. Continuous subcutaneous apomorphine infusion is
studies conducted in Europe [25]. It is currently approved in limited by the development of subcutaneous nodules at the
Europe but not yet in the US. infusion site and has a similar adverse event profile to the
There are currently three approved MAO-B inhibitors for other dopamine agonists.
the treatment of motor fluctuations in PD, selegiline, rasagiline Multiple new oral and interventional therapies are in develop-
and safinamide. Selegiline is available as a twice a day tablet ment for the treatment of motor fluctuations. Intec Pharma is
or a once daily orally disintegrating tablet and has demon- developing an accordion pill levodopa/carbidopa that consists of
strated a reduction in OFF time of approximately 1-hour com- both immediate and controlled release levodopa in one pill. The
pared to placebo [26]. Rasagaline, a once-daily, second accordion pill technology is designed to overcome the impaired
generation highly-selective MAO-B inhibitor, is also effective gastric motility in PD patients and deliver levodopa in a relatively
for the treatment of ‘Off’ time and also reduces ‘Off’ time by continuous manner. Phase 2 data has demonstrated improvement
approximately 1-hour compared to placebo [27,28]. in ‘Off’ time compared to standard treatment and preliminary
Safimamide, a MAO-B inhibitor which also blocks activated pharmacokinetic data demonstrated less plasma levodopa varia-
sodium channels and thereby reduces calcium-mediated glu- bility compared to standard levodopa [35]. A large phase 3 study is
tamate release, was recently approved by the FDA for the currently underway. Adenosine A2a antagonists have been in
treatment of motor fluctuations. Similar to the other MAO-B development for many years for the treatment of motor fluctua-
inhibitors, safinamide has been shown to increase ‘On’ time tions in PD. Preladenant showed early efficacy but failed in later
without troublesome dyskinesia and reduce ‘Off’ time by Phase 3 trials, likely due to problems related to the operational
approximately one hour [29]. execution of the study [36]. Tozadenant demonstrated positive
Given the dual mechanism of action, safinamide may also be Phase 2 data but Phase 3 development was stopped due to
effective at reducing dyskinesia. MAO-B inhibitors are generally agranulocytosis in several patients. Istradefylline, is approved in
safe and well tolerated and are not associated with the tyramine Japan but not yet available in the US. In Phase 3 studies, there
effect as they preferentially effect the B-isoform of the enzyme. have been mixed results and the sponsor initially received
Dopamine agonists are also an effective adjunctive treat- a complete response from the FDA in 2008 [37,38]. Since that
ment for motor fluctuations in PD patients; those currently time there were two positive studies in Japan and the sponsor is
available in the US include pramipexole, ropinirole, rotigotine looking to refile the new drug application this year [39,40].
and apomoprhine. Pramipexole and ropinirole, available as Neuroderm is developing a subcutaneous formulation of
short acting or extended release tablets are oral formulations levodopa/carbidopa. Phase 1 pharmacokinetic data demon-
approved for the adjunctive treatment of PD, while rotigotine strated reduced plasma variability of levodopa compared to
is a transdermal dopamine agonist approved for the treatment standard levodopa and open-label Phase 2 data showed
of PD. Adjunctive dopamine agonists improve ‘Off’ time by a significant reduction in ‘Off’ time compared to baseline in
approximately 1 hour compared to placebo in clinical studies advanced PD patients [41]. Synagile is developing continuous
[30,31] Apomorphine, only currently available as an injection, intra-oral levodopa that is infused through a retainer device.
is approved as a rescue therapy for the acute treatment of Phase 2a open-label data showed less plasma fluctuation com-
individual OFF periods in patients with advanced PD. It is the pared to standard oral levodopa as well as improvement in ‘Off’
only dopamine agonist that produces levodopa-like efficacy time [42]. Voyager Therapeutics and Oxford therapeutics are
[32,33]. Adverse events associated with dopamine agonists developing a gene therapy for the treatment of motor fluctua-
include orthostatic hypotension, somnolence hallucinations, tions based on increasing synaptic dopamine. This involves
nausea and vomiting. Additionally, they also have been recog- a neurosurgical procedure where the vector is infused directly
nized to be associated with impulse control disorder and into the putamen. Preliminary open-label Phase 1b data has
sudden episodes of unwanted sleepiness [32,33]. shown a reduction in ‘Off’ time compared to Baseline [43].
As with dyskinesia, interventional procedures are available There are also two new treatments in development for the
for the treatment of severe motor complications that continue acute, intermittent treatment of “Off’ episodes. In Phase 3
despite medical therapy. DBS and intrajejunal levodopa trials, both CVT-301, an inhaled levodopa formulation and
(duopa/duodopa) have demonstrated large improvements in APL-130277, a sub-lingual formulation of apomorphine,
 EXPERT OPINION ON ORPHAN DRUGS 5

demonstrated significant improvement compared to placebo extended monologues devoid of content [49]. Punding tends to
in motor function and percentage of patients turning from the be associated with very high doses of levodopa; in one study
‘Off’ state to the ‘On’ state 30-minutes after drug administra- pudding was observed in 14% of PD patients taking more than
tion [44,45]. Both drugs’ new drug applications have been 800 mg levodopa per day [50]. PD patients can also develop
submitted to the FDA for approval. compulsive and repeated levodopa use, known as the dopamine
dysregulation syndrome. These patients repeatedly take levodopa
because it is associated with a ‘high’. In that regard it is noteworthy
5.3. Prevention of motor complications that dopamine is taken up by the cocaine receptor. Sensitization
of brain dopamine systems mediating reward is proposed to
As described above, there is considerable evidence indicating
underlie its development [51]. Uncontrolled data showed that
that intermittent dosing with standard levodopa results in the
continuous delivery of levodopa may improve punding and dopa-
development of motor complications. This has led to the
mine dysregulation syndrome. One study looking at risk factors
concept that continuous delivery of levodopa might amelio-
found that patients with dopamine dysregulation syndrome had
rate motor complications. There has thus been considerable
a younger age at disease onset, high dopaminergic drug intake,
interest in the potential of early treatment with continuous
a history of experimental drug use, more depressive symptoms,
levodopa delivery to prevent the development of motor com-
scored high on impulsive sensation-seeking behaviors and tended
plications. Entacapone extends the elimination half-life of
to have higher alcohol intake [52]. Physicians should be on guard
levodopa and when administered at sufficiently frequent
for this syndrome and prevent patients from taking excess and
doses can provide relatively continuous levodopa levels [46].
unnecessary levels of levodopa.
This combination has been shown to reduce the risk of motor
Finally, abrupt discontinuation of levodopa can also be
complications in MPTP primates [47]. The benefit of this
associated with a neuroleptic-malignant-like syndrome char-
approach in PD patients was tested in the STRIDE-PD study
acterized by fever, muscle rigidity, altered levels of conscious-
[14]. This was a prospective 3-year double blind trial compar-
ness, autonomic dysfunction and elevation of creatine kinase.
ing the risk of developing dyskinesia or off episodes when
Although this occurs very rarely, physicians should be aware of
treatment was initiated with levodopa/carbidopa or levodopa/
this potentially fatal complication and avoid abrupt decreases
carbidopa + entacapone. The study did not show a significant
in levodopa treatment.
benefit of adding entacapone, but doses were administered at
3.5–4-hour intervals which may not be sufficiently frequent to
provide continuous levodopa delivery. Future studies evaluat- 6. Expert opinion
ing the risk of developing motor complications when levo-
Levodopa has been the most effective treatment for PD since its
dopa is initiated in a formulation that has been established to
introduction in the 1960s and provides these patients with
provide continuous levodopa availability are anxiously
meaningful improvement in motor function and quality of life.
awaited. Such studies are long (years) but offer the potential
When used in low doses, with other adjunctive anti-PD medica-
to provide the benefits of levodopa without motor
tions, patients can go many years without the advent of motor
complications.
complications. However, due to treating patterns and patient
disability, once levodopa dose is increased (particularly over
a dose of 400 mg per day), patients are at a high risk for
5.4. Other adverse events
developing motor fluctuations and dyskinesia, both of which
Aside from the well-defined motor complications, levodopa can result in severe disability. Over the last two decades, adjunc-
use is also associated with a series of other adverse events. tive, dopaminergic treatment has been developed that can
These include dopaminergic and neuropsychiatric side effects. effectively reduce some of the ‘Off’ time experienced by PD
Dopaminergic side effects include nausea, vomiting, dizziness, patients particularly in the early stages of the disease. In general,
and orthostatic hypotension [20,48].These likely relate to acti- benefits are primarily for ‘Off’ time which they reduce by
vation of dopamine receptors in the area postrema, which is approximately 1 hour (from a mean of approximately
not protected by the blood brain barrier. Levodopa is typically 5–6 hours of off time per day). Thus, patients continue to suffer
administered with a decarboxylase inhibitor to prevent the a significant amount of ‘Off’ time with associated disability.
peripheral accumulation of dopamine, and this has dramati- Despite the many attempts at providing an effective treatment
cally reduced the risk and the severity of dopaminergic side for existing dyskinesia, there is only one approved drug for the
effects. When these do occur, they are typically mild and treatment of dyskinesia, and treatment is complicated by cog-
transient, and can be further minimized with a slow titration nitive deficits and hallucinations in many cases. Surgical thera-
scheme, taking levodopa with food, and on rare occasions pies such as DBS are more effective in treating off time and
adding additional doses of carbidopa. motor complications, but these therapies are associated with
Neuropsychiatric complications are less common but can be serious and even potentially fatal complications.
troublesome. Levodopa can cause punding which is the Swedish Developing effective treatments to prevent the onset of off
term for similar activities observed in amphetamine users. time and dyskinesia are likely easier to accomplish than treating
Punding is a complex, stereotyped behavior characterized by already established motor complications. However, these clinical
intense, purposeless, and repetitive activities such as the continual trials are complex, require a very long duration trial, and are very
handling, examining, and sorting of common objects, grooming, costly, and to date no treatment has been approved for this
hoarding, pointless driving or walkabouts, and the engagement in indication. Current evidence suggests that motor complications
6 J. DUBOW AND C. W. OLANOW

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nale and clinical implications. Lancet Neurol. 2006;5:677–687.
continuous delivery of a dopaminergic agent that could poten-
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chronic D2 dopamine receptor agonist (U91356A) treatment of
jejunal levodopa or subcutaneous apomorphine. These
drug-naive 4-phenyl-1,2,3,6-tetrahydropyridine monkeys differen-
treatments have demonstrated a larger magnitude of improve- tially regulates brain D1 and D2 receptor expression: in situ hybri-
ment on ‘Off’ time and dyskinesia compared to other adjunctive dization histochemical analysis. Neuroscience. 1997;79:497–507.
treatments but carry and additional adverse event burden. One 8. Pearce RK, Banerji T, Jenner P, et al. De novo administration of
could design a study with a subcutaneous infusion of levodopa or ropinirole and bromocriptine induces less dyskinesia than L-dopa
in the MPTP-treated marmose. Mov Disord. 1998;13:234–241.
intrajejunal levodopa in early PD patients who are at high risk of
9. Stockwell KA, Scheller D, Rose S, et al. Continuous administration of
developing motor fluctuations, randomize them to receive con- rotigotine to MPTP-treated common marmosets enhances
tinuous or oral, intermittent levodopa and measure time to onset anti-parkinsonian activity and reduces dyskinesia induction. Exp
of first motor complications, as was done in the STRIDE-PD study Neurol. 2009;219:533–542.
[14]. This study would be welcomed by the movement disorders 10. Ahlskog JE, Muenter MD. Frequency of levopdopa-related dyskine-
sias and motor fluctuations as estimated from the cumulative
community and could potentially result in the first drug approved
literature. Mov Disord. 2001;16(3):448–458.
for delaying the onset of motor complications. Whether any of 11. Parkinson Study Group. Pramipexole vs levodopa as initial treat-
these treatments can prevent the onset of motor complications if ment for Parkinson’s disease. A randomized controlled trial. JAMA.
employed early in therapy is yet to be determined but is unlikely 2000;284:1931–1938.
to be pursued since therapy in early disease is usually safe and 12. Holloway RG, Shoulson I, Fahn S, et al. Pramipexole vs levodopa as
initial treatment for Parkinson’s disease: a 4-year randomized, con-
effective with current therapies. More promising are long-acting
trolled trial. Arch Neurol. 2004;61:1044–1053.
oral formulations of levodopa that might provide continuous 13. Rascol O, Brooks DJ, Korczyn AD, et al. A five-year study of the
availability of the drug without the need for a surgical intervention incidence of dyskinesia in patients with early Parkinson’s disease
or an infusion. Several such formulations are currently available. If who were treated with ropinirole or levodopa. N Engl J Med.
they can be demonstrated to provide stable plasma levels with 2000;342:1484–1491.
14. Olanow CW, Kieburtz K, Rascol O, et al. Factors predictive of the
less fluctuation that traditional levodopa it is reasonable to think
development of levodopa-induced dyskinesia and wearing-off in
that early treatment might avoid or markedly delay the develop- Parkinson’s disease. Mov Disord. 2013;28:1064–1071.
ment of motor complications and provide the benefits of levo- 15. Chapuis S, Ouchchane L, Metz O, et al. Impact of motor complica-
dopa without its major side effects. tions of Parkinson’s disease on the quality of life. Mov Disord.
2005;20(2):224–230.
16. Pahwa R, Tanner CM, Hauser RA, et al. ADS-5102 (amantadine)
Funding extended-release capsules for levodopa-induced dyskinesia in
Parkinson’s disease (EASE LID study). A randomized clinical trial.
This paper was not funded. JAMA Neurol. 2017;74:941–949.
17. Oertel W, Eggert K, Pahwa R, et al. Randomized, placebo-controlled
trial of ADS-5102 (amantadine) extended-release capsules for levo-
Declaration of interest dopa-induced dyskinesia in Parkinson’s disease (EASE LID 3). Mov
Disord J. 2017;32:1701–1709.
The authors have no relevant affiliations or financial involvement with any
18. Weaver FM, Follett K, Stern M, et al. Bilateral deep brain stimulation
organization or entity with a financial interest in or financial conflict with
vs best medical therapy for patients with advanced Parkinson’s
the subject matter or materials discussed in the manuscript. This includes
disease: a randomized controlled trial. JAMA. 2009;301:63–73.
employment, consultancies, honoraria, stock ownership or options, expert
19. Deuschl G, Schade-Brittinger C, Krack P, et al. A randomized trial of
testimony, grants or patents received or pending, or royalties.
deep-brain stimulation for Parkinson’s disease. N Engl J Med.
2006;355:896–908.
20. Olanow CW, Kieburtz K, Odin P, et al. Continuous intrajenjunal
Reviewer disclosures infusion of levodopa-carbidopa intestinal gel for patients with
Peer reviewers on this manuscript have no relevant financial or other advanced Parkinson’s disease: a randomized, controlled, dou-
relationships to disclose. ble-blind, double-dummy study. Lancet Neurol.
2014;13:141–149.
21. Antonini A, Fung V, Boyd J. Effect of levodopa-carbidopa intestinal
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