Special Report
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Noninvasive options for ‘wearing-off’ in
Parkinson’s disease: a clinical consensus from
a panel of UK Parkinson’s disease specialists
Robin Fackrell*,1, Camille B Carroll2, Donald G Grosset3, Biju Mohamed4, Prashanth
Reddy5, Miriam Parry5, Kallol Ray Chaudhuri6 & Tom Foltynie7
1Department of Geriatric Medicine, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK
2Faculty of Medicine & Dentistry, University of Plymouth, Plymouth, UK
3Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK
4Department of Medicine and Gerontology, University Hospital of Wales, Cardiff, UK
5Department of Clinical Gerontology, King’s College Hospital NHS Foundation Trust, London, UK
6Institute of Psychiatry, Psychology & Neuroscience at King’s College & Parkinson Foundation International Centre of Excellence,
King’s College Hospital NHS Foundation Trust, London, UK
7Unit of Functional Neurosurgery at UCL Institute of Neurology and the National Hospital for Neurology & Neurosurgery, London,
UK
*Author for correspondence: robin.fackrell@nhs.net
Practice points
• At each consultation, ask whether your patient is experiencing motor fluctuations, such as end-of-dose
wearing-off and dyskinesia. Patient diaries or wearing-off questionnaires can be helpful here.
• Be aware that dopamine fluctuations can manifest in a range of nonmotor symptoms; these may include pain,
problems swallowing, depression, anxiety and cognitive impairment.
• Consider the relative merits of adjusting your patient’s existing regimen, for example, levodopa dose adjustments
versus incorporating an adjuvant treatment into their polypharmacy regimen.
• Consider whether your patient exhibits any special features of Parkinson’s disease (e.g., fatigue, psychosis), and
how this affects the clinical decision in choice of agent.
• Be aware that, at some stage, your patient may need to be evaluated for advanced Parkinson’s disease therapies.
• Monitor the outcome of any major change in prescription, for example, initiating adjuvant treatment.
In the past 4 years, two adjunctive treatment options to levodopa have been licensed for use in the UK
in patients with Parkinson’s disease (PD) and motor fluctuations: opicapone, a third-generation catechol-
O-methyl transferase inhibitor, and safinamide, a monoamine oxidase B inhibitor. This clinical consensus
outlines the practical considerations relating to motor fluctuations and managing wearing-off in patients
with PD, and provides a clinical insight to adjunctive treatment options, including opicapone and safi-
namide. Practice-based opinion was provided from a multidisciplinary steering Group of eight UK-based
movement disorder and PD specialists, including neurologists, geriatricians and a nurse specialist, from
England, Scotland and Wales.
First draft submitted: 4 May 2018; Accepted for publication: 19 June 2018; Published online: 5 July 2018
Keywords: opicapone • Parkinson’s disease • safinamide
Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world after Alzheimer’s [1].
The annual incidence of PD in the UK is 15–20 individuals per 100,000 [2], with a significantly higher incidence in
males (1.5 times greater) compared with females [3]. With an increasing aging population, the estimated prevalence
of PD in the UK is expected to rise by approximately 18% in the next 7 years; however, about 7% of people living
with PD in 2018 will be under 60 years old [4].
This progressive disorder is characterized by motor symptoms (rigidity, bradykinesia, tremor, postural insta-
bility) [5] and a range of nonmotor symptoms (NMS) such as pain, constipation, problems with swallowing,
depression, anxiety and cognitive impairment, which can occur from disease onset [6,7], and often before the onset
of motor symptoms [8]. The gold standard treatment for PD is still considered to be levodopa (L-dopa) [9]. Initial
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Special Report Fackrell, Carroll, Grosset et al.
treatment with L-dopa allows for better symptom control and patient-related quality of life (QoL) for at least
7 years [10], compared with initial L-dopa sparing regimens (dopamine agonists [DAs] or monoamine oxidase B
[MAO-B] inhibitors) [10]. There remains uncertainty about the optimum first drug class treatment choice in young
onset PD, diagnosed at 45 years or younger, given the even greater long-term duration that these patients will
require [10]. However, long-term use of L-dopa has its limitations: patients develop motor complications, such as
motor fluctuations including end-of-dose wearing-off and L-dopa induced involuntary movements or dyskinesia [11]
that impact on QoL [12]. Higher doses of L-dopa, which may be required in later disease, can also result in a greater
frequency of dyskinesia as well as wearing-off symptoms [13]. Therefore, to improve motor fluctuations, ideally
without exacerbating dyskinesia, many patients with PD will eventually require add-on therapies [2].
Although recent 2017 NICE guidance provides recommendations for first- and second-line adjunctive therapies
for patients currently receiving L-dopa, the choice of drug class, treatment preference within a class, drug admin-
istration alone or in combination, when to prescribe and in what order to prescribe these treatments are personal
decisions made jointly between physician and patient [2]. Furthermore, the fact that only two new oral treatments
have been developed over the last 10 years has added to the challenge of individualizing and personalizing treatment
for people living with PD; personalized medicine in PD is therefore a key unmet need [14].
Recently, however, two adjunctive treatment options have been licensed for use in the UK: opicapone is a
third-generation catechol-O-methyl transferase (COMT) inhibitor [15] and safinamide has a main mechanism of
action as a selective and reversible MAO-B inhibitor [16]. Safinamide is known to have additional activity as a
selective sodium channel blocker and calcium modulator although the clinical utility of these properties is yet to
be established [16,17]. To determine where these new therapies are to fit within the currently available treatment
options requires expert advice and opinion from practical clinical experience.
A multidisciplinary steering group of eight UK-based experts (neurologists, geriatricians and a nurse specialist)
who are all movement disorder and PD specialists from England, Scotland and Wales convened in November 2017
to put forward a clinical consensus of practical considerations for managing motor fluctuations in patients with
PD that complement current national guidelines from NICE (England, Wales and Northern Ireland) [2] and SIGN
(Scotland) [18]. The group had direct clinical experience of using PD therapies available in the UK, including the
newer adjunctive therapies.
It is important to highlight that this article is not a review of the current literature, but practice-based opinion,
including experience of using the two more recently available therapies, opicapone and safinamide. Differences in
trial design have resulted in greater UK-wide clinical experience with opicapone within the Phase IV trial setting
compared with safinamide, and this is reflected in the steering group’s current clinical practice and experience. Also,
with formulary applications for opicapone and safinamide still in progress across the UK, the ability to prescribe
one or both agents is limited in some regions.
When considering a treatment regimen, key to the decision-making process is the agreement of a comprehensive
care plan between the patient, family members/carer(s), specialist and secondary health providers [2].
Challenges to manage wearing-off in patients with PD on L-dopa
Although L-dopa is still the most effective antiparkinsonian drug [19], the development of a treatment strategy that
provides the benefits of L-dopa with reduced motor complications, including wearing-off, remains a significant
clinical challenge for patients with PD [20].
Wearing-off occurs toward the end of the treatment interval between individual doses of L-dopa, and occurs
earlier and becomes more severe with disease progression and duration of drug treatment [21]; it often consists not
only of motor symptoms (e.g., recurrent tremor, walking impairment) but also NMS (e.g., anxiety) [22]. Wearing-
off generally improves with the next dose of antiparkinsonian medication [22]. Wearing-off eventually affects the
majority of patients with PD [13,20,23,24]. Observational data from the DEEP study have shown that for patients
receiving L-dopa therapy, wearing-off was experienced by: 63.0–75.6% of patients (diagnosed by neurologist and
19-item Wearing-Off Questionnaire (WOQ-19), respectively) at 1–2 years, 55.1–66.3% at 3–5 years and 76.8–
80.4% at >10 years [24]. Wearing-off of motor symptom control (e.g., recurrent tremor, slowing of walking) is
generally easier for patients and physicians to identify than NMS (e.g., anxiety, restlessness). Day-to-day variability
in symptom severity can also be dependent on how well a patient has slept, their specific activity or particular mood.
The wearing-off questionnaire can be used to help patients and clinicians identify and monitor wearing-off [25,26].
As well as wearing-off, long-term treatment with L-dopa is associated with the development of other ‘off ’
episodes [27]. One of the most frequent motor fluctuations is early-morning off periods [28], with the re-emergence
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Management of ‘wearing-off’ in Parkinson’s disease Special Report
of parkinsonian symptoms in the morning before the first L-dopa dose. Other motor fluctuations include dose
failures (individual L-dopa doses that do not result in the patient achieving the ‘on’ state) or delayed on-periods;
these motor fluctuations can either be predictable or unpredictable [27].
Considerations in managing wearing-off in patients with PD on L-dopa
Modifiable factors
Advice from a PD specialist with expertise in managing wearing-off is essential. Before making dose adjustments
to the L-dopa regimen, or adding another class of drug, a number of modifiable factors that directly impact on
wearing-off need to be considered. These include: therapy compliance (which is influenced by depression, cognitive
function and apathy), dietary factors (such as quantity and timing of protein intake) and gastrointestinal (GI)
absorption (including Helicobacter pylori status and constipation). Other associated factors, such as insomnia and
depression, can influence overall function in patients with PD, although depression can be a nonmotor manifestation
of wearing-off [22].
GI absorption of L-dopa
Constipation
Constipation is a frequent NMS and the most common GI symptom of PD [29], affecting 60–80% of patients
with PD [30] and negatively impacting on QoL [31]. Constipation is characterized by infrequent bowel movements
and hard stools that are difficult to pass, as well as straining and pain when passing stools [32]. Constipation
may interfere with L-dopa absorption, worsening motor fluctuations [31]. Dietary intervention is recommended,
including increasing fiber intake and drinking plenty of fluids throughout the day [30]. If diet, fluid intake and
exercise do not alleviate constipation, use of osmotic laxatives may be necessary [32].
Delayed gastric emptying
Impaired mobility of the stomach results in gastroparesis that can impact on the absorption and action of L-dopa [33].
Dietary changes to help improve symptoms of delayed gastric emptying, such as multiple small meals limited in fat
and fiber content [34], together with exercise and, if necessary, pharmacotherapy, are all management options [35].
Dietary protein intake
A large protein meal can delay gastric emptying and competes with the absorption of L-dopa; therefore, the
timing of L-dopa dosing around mealtimes is an important consideration [30]. Best practice guidance on managing
patients with PD suggests a 40-min delay between L-dopa dosing and protein intake to help reduce wearing-
off symptoms [30]. Data on dietary protein intake and GI absorption of L-dopa show improvements in motor
fluctuations with dietary modifications, such as low protein diets and daily dietary protein consumed at the final
main meal of the day (protein redistribution diet). Improvements have been observed in clinical response ranging
from 30% (protein redistribution diet) to 82% (low protein diet) [36–38]. Recent recommendations advise that
clinicians should discuss the potential of a protein redistribution diet with patients who are beginning to fluctuate
in their response to dopaminergic medication [2]. Specialist advice from a dietician should also be considered [2].
Helicobacter pylori
The gut microbiome is increasingly recognized as playing an important role in the etiology of PD [39]. A high
prevalence of one such microbe in patients with PD, the Gram-negative H. pylori bacterium, is thought to affect
the absorption of L-dopa with the potential to cause motor fluctuations [40]. There are conflicting views as to
whether patients with PD should be tested for H. pylori status and treatment initiated to eradicate infection in
positive cases [40]. Further studies are needed to fully elucidate the relationship of L-dopa absorption in the presence
of H. pylori and its impact on clinical outcomes [40,41]. Currently, there is no direct guidance in this area, with
NICE guidance simply stating that “antiparkinsonian medicines should not be allowed to fail suddenly due to poor
absorption” [2].
Other modifiable factors that can influence overall function in patients with PD
Assessments are recommended to monitor unintentional weight loss or gain, bone health (reduced bone density
may indicate low vitamin D levels), insufficient fluid intake (which may indicate potential swallowing problems
or concerns about bladder urgency), postural hypotension (potential fluid/salt intake imbalance) and physical
difficulties that impair eating, drinking and preparing meals [30].
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Special Report Fackrell, Carroll, Grosset et al.
Increase dose Decrease inter-dose interval Controlled-release preparations
Increase dosing frequency
Unpredictable drug absorption
Higher peak concentrations
May work in earlier stages
Limited utility and complicated Delayed ‘on’ or occasional
Peak-dose dyskinesias dosing schedule beyond lack of ‘on’ response with
4 to 5 doses/day advancing disease
Variable /short-term control
Figure 1. Traditional strategies to treat wearing-off. Adapted from Olanow, 2001 [42].
In patients with PD, other NMS including cognitive and mood dysfunction (e.g., anxiety, apathy, depres-
sion, cognitive impairment), postural hypotension, sleep disturbance and pain can impact on overall function.
These NMS require appropriate investigation and individualized management with nonpharmacological strategies,
followed by drug treatment, where appropriate [2].
Dose-adjusting strategies for L-dopa
Several strategies involving L-dopa alone are available to treat wearing-off, including increasing the dose of L-dopa,
increasing the dosing frequency, using different formulations and adjusting dosing times (e.g., controlled-release
preparations taken at bedtime) [42]. These traditional strategies, however, usually only offer variable, short-term
control (Figure 1) [42].
Adjuvant treatment
Recent NICE guidelines recommend that patients with PD who have developed wearing-off or dyskinesia despite
optimal L-dopa therapy should be offered a choice of COMT inhibitors, DAs or MAO-B inhibitors as adjunctive
therapy to L-dopa (Figure 2) [2]. However, the decision regarding which adjunctive therapy to use or not to use,
requires considerable clinical experience from the treating clinician.
First-line adjuvant treatment choice considerations
As part of the steering group’s combined clinical experience, general factors influencing first-line adjunctive treatment
choice of drug class and preparation within class, are summarized as checklists in Table 1. For example, for an
elderly, frail patient with impaired cognition and difficulty swallowing, pill burden including complex daily regimens
and potential swallowing difficulties are important factors in the choice of adjunctive treatment. Similarly, for a
patient with recurring GI issues, tolerability and drug formulation with adequate absorption influence the choice
of adjunctive treatment. Young patients with a history of impulsive behaviors should be cautioned about the risks
of DAs.
Where do the opicapone & safinamide fit in the treatment of wearing-off?
Opicapone
Two Phase III randomized clinical trials have demonstrated efficacy of opicapone as an adjunctive therapy to L-dopa
in patients with PD and end-of-dose motor fluctuations, with both studies meeting primary end point criteria. In
the BIPARK-I trial, opicapone (50 mg) was superior to placebo and noninferior to entacapone. The primary end
point was the change from baseline to end of study treatment in absolute off-time based on patient diaries [61]. In
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Management of ‘wearing-off’ in Parkinson’s disease Special Report
Table 1. Factors influencing the choice of adjuvant treatment for wearing-off in patients with Parkinson’s disease:
clinical considerations from the Parkinson’s disease steering group’s experience.
What are the factors influencing adjuvant Clinical considerations Adjuvant drug class/drug considerations
treatment choice?
Symptoms: Are there any motor symptoms that are refractory to COMT inhibitors [43–45]:
How symptomatic is the patient? L-dopa (e.g., tremor)? If so, consider referral for DBS (NB: • Potency: opicapone  tolcapone  entacapone [15]
Which are the patient’s most troublesome none of the L-dopa augmenting strategies will improve • Can exacerbate postural hypotension
motor symptoms? symptoms that are truly L-dopa refractory) • Can exacerbate dyskinesia
What are the patient’s most troublesome What potential is there for exacerbation of dyskinesia? DAs [46–48]:
NMS? (NB: background doses of L-dopa may need to be • Can exacerbate dyskinesia
Is the patient very elderly and frail? reviewed early after initiating any adjuvant treatment.) • May cause or exacerbate postural hypotension
Does the patient have a history of If adjustment unsuccessful, consider referral/initiating • May result in, or exacerbate, cognitive impairment,
impulsive behaviors? advanced therapies (i.e., apomorphine, DBS, DuoDopa) impulsive behaviors or psychosis
Does the patient have any of the following NMS: • Potential for use in RLS [46]
cognitive impairment, psychosis, low mood, apathy, MAO-B inhibitors [16,49,50]:
fatigue, clouded thinking, excessive daytime • Can exacerbate postural hypotension
somnolence, postural hypotension? These can be • Can exacerbate confusion
differentially affected by the different adjuvant drug • Selegiline generally avoided in presence of postural
classes hypotension, dementia, psychosis, cardiovascular disease
and general frailty [51]
Patient preference: Consider adherence to treatment/compliance and Entacapone:
What are the patient’s priorities and contributory factors • Potential dark discoloration/staining of secretions with
treatment objectives? entacapone: urine, and to a lesser extent saliva and
Are there influencers for patient’s choice of sweat (not harmful) [51,52]
treatment?
Tolerability: Directly consider co-existing conditions: COMT inhibitors:
What are the tolerability issues with • GI tolerability • Hepatotoxicity with tolcapone requires monitoring [45]
existing and previous PD medications? • Neuropsychiatric problems, especially hallucinations, • Potential GI problems with entacapone: ∼10% of
What are the tolerability considerations impulsive behaviors patients develop diarrhea [53]; for prolonged/persistent
with adjunctive therapy? • Cardiovascular effects diarrhea, entacapone should be discontinued [44].
Is the patient very elderly and frail? Approximately 1% of patients will discontinue
treatment due to diarrhea [53]; it is not possible to
predict which patients will experience diarrhea
MAO-B inhibitors:
• Generally well tolerated [54]
• Selegiline, specific caution: cardiovascular disease,
especially arrhythmias [50]
DAs:
• May be poorly tolerated in frail, elderly patients [55]
Polypharmacy: Consider drug interactions with common concomitant COMT inhibitors:
What other medications is the patient medications (e.g., antidepressants) • Avoid treatment/concomitant use with nonselective
taking? MAO inhibitors (e.g., phenelzine,
tranylcypromine) [44,45]; concomitant use of opicapone
with MAO inhibitors used to treat PD is acceptable [43]
MAO-B inhibitors:
• For rasagiline and safinamide, avoid concomitant use
with fluoxetine and fluvoxamine [16,49]
• Forselegiline, contraindicated with antidepressants in
general [50]
DAs:
• For rotigotine patch, caution when taking CNS
depressants (e.g., benzodiazepines, antipsychotics,
antidepressants) [46]
Pill burden: Complicated daily oral regimens may be a challenge for COMT inhibitors:
Can the patient manage the frequency of patients with impaired cognition • Opicapone is once-daily dosing taken at bedtime 1 h
doses? Consider timing of adjuvant dose in relation to L-dopa before/after L-dopa [43]
What is the total number of tablets dosing • Tolcapone has a shorter duration of action versus
(including tablets for other conditions) that Consider nonoral drug preparations opicapone and requires t.i.d. dosing [45]
this patient is taking? • Entacapone available in combination formulation with
L-dopa/DDCI [52]
MAO-B inhibitors:
• Rasagiline, selegiline and safinamide available in
once-daily formulations [16,49,50]
DAs:
• Newer (nonergot) DAs available in once-daily
preparations: oral formulations – pramipexole [56] and
ropinirole [57]; transdermal patch – rotigotine [46]
• Transdermal skin patch formulations are less potent
(24-h effect) [46]
MAO-B inhibitors are also licensed for early PD.
COMT: Catechol-O-methyl transferase; DA; Dopamine agonist; DBS: Deep-brain stimulation; DDCI: Dopa decarboxylase inhibitor; L-dopa: Levodopa; MAO-B: Monoamine oxidase
B; NMS: Nonmotor symptom; PD: Parkinson’s disease; RLS: Restless leg syndrome; t.i.d.: Three times daily.
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Special Report Fackrell, Carroll, Grosset et al.
Table 1. Factors influencing the choice of adjuvant treatment for wearing-off in patients with Parkinson’s disease:
clinical considerations from the Parkinson’s disease steering group’s experience (cont.).
What are the factors influencing adjuvant Clinical considerations Adjuvant drug class/drug considerations
treatment choice?
Swallowing: Large tablet size may be an issue, especially with some COMT inhibitors:
Does this patient have trouble swallowing? combination formulations • Opicapone’s capsule form and size may offer a
What are the swallowing considerations Consider nonoral drug preparations potential advantage for patients with swallowing
with adjunctive therapy? difficulties (capsule 19 × 6.9 mm) [43,58], compared with
L-dopa/carbidopa/entacapone (oval, round or
ellipse-shaped tablets up to 16.2 × 10.2 mm) [59]
MAO-B inhibitors:
• Sublingual preparation available for selegiline [60]
DAs:
• DA patch formulation
• Easier alternative for patients who have difficulties
swallowing; however, as the patch needs to be applied
to dry skin and pressed down firmly [46], difficulties may
arise if skin is sweaty
MAO-B inhibitors are also licensed for early PD.
COMT: Catechol-O-methyl transferase; DA; Dopamine agonist; DBS: Deep-brain stimulation; DDCI: Dopa decarboxylase inhibitor; L-dopa: Levodopa; MAO-B: Monoamine oxidase
B; NMS: Nonmotor symptom; PD: Parkinson’s disease; RLS: Restless leg syndrome; t.i.d.: Three times daily.
the BIPARK-II trial, opicapone (50 mg) was associated with a significant reduction in mean daily off-time, with
effect maintained for at least 1 year. Primary end point was the change from baseline in absolute off-time based on
patient diaries during the double-blind phase [62]. Opicapone was well tolerated in both studies [61,62]. Marketing
authorization in the EU was granted in June 2016 as an adjunctive therapy to L-dopa and decarboxylase inhibitors
in adult patients with PD and end-of-dose motor fluctuations [15].
Clinical insights & scenarios for using opicapone
Opicapone is a long-acting, once-daily, purely peripheral COMT inhibitor [15], with more sustained COMT
inhibition than tolcapone and entacapone. COMT inhibition at 1 h is 99, 82 and 68% with opicapone, tolcapone
and entacapone, respectively, and at 9 h, 91, 16 and 0%, respectively [63,64]; the corresponding average treatment
Adult diagnosed with PD
General principles
A choice of adjuvant drug class
should be made after discussing with
First-line L-dopa treatment the patient: COMT inhibitor
• Their individual clinical
  circumstances (e.g. symptoms,
Adjuvant treatment   comorbidities, polypharmacy risks) Dopamine agonist
• Their individual lifestyle
  circumstances, preferences,
  needs and goals
Advanced therapies: MAO-B inhibitor• The potential benefits and harms
• Deep-brain stimulation   of the different drug classes
• L-dopa/carbidopa intestinal gel
• Continuous subcutaneous
  apomorphine infusion
Figure 2. Managing motor symptoms in Parkinson’s disease: patient choice in adjuvant treatment.
COMT: Catechol-O-methyl transferase; L-dopa: Levodopa; MAO-B: Monoamine oxidase B; PD: Parkinson’s disease.
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Box 1. Clinical scenario – switching from levodopa/carbidopa/entacapone combination to opicapone
plus levodopa/decarboxylase inhibitor.
1. Patients to continue on the L-dopa/carbidopa/entacapone combination until the penultimate dose of that day
2. For the last dose of that day:
• Take L-dopa without entacapone, as either L-dopa/carbidopa (Sinemet), or L-dopa/benserazide (Madopar)
• Take opicapone, either 1 h before or 1 h after L-dopa/carbidopa or L-dopa/benserazide
3. For the next 5–7 days:
• Keep the L-dopa dose the same at each dose intake
• Continue once-daily dosing with opicapone
4. Phone the patient to check for any adverse effects, including peak L-dopa effects (e.g., postural hypotension,
psychosis, dyskinesia)
5. If peak L-dopa effects have occurred, then advise appropriate reductions in the dose of L-dopa/carbidopa or
L-dopa/benserazide preparation (possibly by increasing the dose interval in the first instance)
L-dopa: Levodopa.
effect (off-time reduction vs placebo) is 60 min for opicapone [61], 90 min for tolcapone [65] and 40 min for
entacapone [65].
Furthermore, opicapone has a favorable tolerability profile with a lack of hepatotoxicity in clinical trials and
no severe diarrhea issues [43]. Opicapone does not produce the harmless, but often troublesome, reddish brown
discoloration/staining of secretions (urine, sweat, saliva, semen) sometimes observed with entacapone [51,52]. The
capsule formulation of opicapone, together with its size (19 mm in length and 6.91 mm in width) [43,58] offers
a potential advantage for patients with swallowing difficulties, when compared with the tablet formulations of
L-dopa/carbidopa/entacapone which have sizes ranging from a round tablet of 11.3 mm diameter at the lowest
dose to an elongated ellipse-shaped tablet of 16.2 mm by 10.2 mm at the highest dose [59]. A benefit of once-daily
dosing of opicapone is that it allows titration, where necessary, of L-dopa dosing independently of opicapone [43].
It is dosed at bedtime, 1 h before or 1 h after the last L-dopa dose of the day [43].
The steering group’s combined clinical experience suggests that there are particular patients with PD where there
are important clinical drivers for switching from entacapone to opicapone. It is the group’s opinion that opicapone
may be especially suited for patients who experience intermittent dose failures (individual L-dopa doses where the
clinical effect is either none or negligible), who fail to reliably achieve good quality on time and who experience
persistent wearing-off despite entacapone. The reason for switching in these scenarios is that COMT inhibition is
both more complete and more prolonged with opicapone compared with entacapone [15]; this has been shown to
translate to additional clinical benefit [66], and is consistent with the clinical experience of the group. Diarrhea is a
common side effect (8–10%) for patients using entacapone [44,53] and the L-dopa/carbidopa/entacapone (Stalevo)
combination tablet (12%) [52]. In cases where the severity of diarrhea leads to discontinuation of treatment,
switching to opicapone is also an option. Moreover, entacapone nonresponders may be potential candidates for
opicapone.
In these switching scenarios, the last entacapone dose of the day can be directly replaced by once-daily opicapone.
Where entacapone is part of a combination tablet, for example, L-dopa/carbidopa/entacapone (Stalevo), in addition
to replacing the entacapone component with opicapone, the L-dopa/decarboxylase inhibitor component must be
substituted by either L-dopa/carbidopa (Sinemet) or L-dopa/benserazide (Madopar). Adjustment of the L-dopa
dose is not usually required with the initial switch, but may need to be adjusted at a later stage depending on response;
for instance, to avoid excessive L-dopa peaks that may cause peak dose dyskinesia, other hyperdopaminergic CNS
effects, or to optimize L-dopa levels by a reduction in L-dopa dose and/or dose frequency to give further options
as the disease progresses. The clinical team needs to make certain that patients do not inadvertently add opicapone
to entacapone (resulting in a double dosage of COMT inhibitor) or, in the case of entacapone combination drugs,
substitute this with opicapone but without L-dopa/carbidopa (Sinemet) or L-dopa/benserazide (Madopar), which
would result in no L-dopa component. For patients currently using entacapone combination preparations, clear
guidance needs to be given explaining that they are being switched from a combination tablet (entacapone/L-
dopa/carbidopa) to an individual drug regimen (see Box 1).
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Special Report Fackrell, Carroll, Grosset et al.
Box 2. Clinical scenario – considerations in the ‘tailoring’ of adjunct therapies (catechol-O-methyl
transferase inhibitors, monoamine oxidase inhibitors, dopamine agonists).
• A 64-year-old lady receiving:
• L-dopa/carbidopa/entacapone 125 mg taken five times a day (7 am, 10 am, 1 pm, 4 pm, 7 pm)
• Rasagiline 1 mg once-daily
• Ropinirole XL 8 mg (amantadine was not tolerated)
• The patient developed significant motor and nonmotor wearing-off, and experienced pain 30–40 min before her
next dose. Peak dose dyskinesia was also becoming socially embarrassing for her
• The L-dopa/carbidopa/entacapone dose was reduced, but taken more frequently (100 mg six times a day). At this
dose the patient felt undertreated; reducing the ropinirole dose caused excessive mood disturbance. She also
reported that she had never been convinced regarding the efficacy of rasagiline and thus a decision was made to
see if safinamide would be more effective
• Rasagiline was discontinued. After a washout period of 14 days (as advised in the safinamide summary of product
characteristics) [49], she was started on safinamide 50 mg
• Safinamide 50 mg had a positive impact on improving wearing-off, and when the dose was increased to 100 mg,
the patient felt generally better, with a good reduction in nonmotor symptoms, and without noticeably
worsening dyskinesia
L-dopa: Levodopa.
Safinamide
Two Phase III randomized clinical trials have demonstrated efficacy of safinamide as an adjunctive therapy to
L-dopa in patients with mid- to late-stage PD with motor fluctuations. In the 24-week, double-blind, placebo-
controlled SETTLE study, safinamide (50 mg/100 mg) significantly increased on-time without troublesome
dyskinesia compared with placebo [67]. In study 016/018, a 24-week/2-year, double-blind, placebo-controlled
study, safinamide (50 mg/100 mg) also significantly increased on-time without increasing dyskinesia compared
with placebo. However, the primary end point, mean change from baseline to end point of the total score of the
dyskinesia rating scale during on-time, was not met [68]. Both safinamide doses were well tolerated [67,68]. Marketing
authorization in the EU was granted in December 2014 as an add-on therapy to stable dose L-dopa, alone or in
combination with other PD therapies in mid- to late-stage fluctuating PD patients [17].
Clinical insights & scenarios for using safinamide
Safinamide is an α-aminoamide derivative that acts as a highly selective and reversible MAO-B inhibitor [17].
Safinamide has a favorable tolerability profile, but like rasagiline in this class, caution is needed with the concomitant
antidepressant medications, fluoxetine and fluvoxamine [16].
As part of the steering group’s combined clinical experience, there are particular patients with PD where clinical
drivers for using safinamide instead of rasagiline are warranted. Safinamide could be considered where patients
have been unable to tolerate rasagiline or in cases of worsening dyskinesia associated with rasagiline. Safinamide
could also be considered where patients continue to have wearing-off symptoms that have failed to respond to
rasagiline or COMT inhibitors. However, robust data are currently lacking in terms of a head-to-head clinical trial
comparison between safinamide and rasagiline. Clinical trial data have shown that safinamide reduces off-time by
about 0.62 h/day versus placebo [53], and a Cochrane review reports reduction in off-time by about 0.93 h/day for
rasagiline and selegiline [69], although comparisons of noncontemporaneous data can be misleading. Box 2 outlines
considerations in the ‘tailoring’ of these adjunct therapies.
Conclusion
This clinical consensus is not intended to provide formal guidance on managing wearing-off, but to complement
existing guidance and highlight areas of clinical practice that warrant further recognition in light of opicapone
and safinamide becoming available for patients with PD on L-dopa therapy. Individual clinical experience is
incorporated; while this experience is inevitably only anecdotal, it provides useful insights into current clinical
practice based on the experience of this steering group. It is important to note that there has been more opportunity
to gain clinical experience, including in Phase IV trials, with opicapone compared with safinamide in the UK, and
this is reflected in the greater anecdotal experiences provided by the assembled steering group.
356 Neurodegener. Dis. Manag. (2018) 8(5) future science group
Management of ‘wearing-off’ in Parkinson’s disease Special Report
Although both opicapone and safinamide are available in the UK, these agents are not universally available on
all formularies, and barriers exist in prescribing, more so in the community than the hospital setting. However,
locally conducted evaluations on the use of PD medications will help to inform local clinical practice. The sharing
of these methodologies will also be useful in facilitating the collection of data pertinent to UK clinical practice, and
to consolidate the position of new treatments in current treatment algorithms for patients with PD experiencing
wearing-off.
After more than 10 years without the development of new treatments for PD, opicapone and safinamide have
now widened the armamentarium, providing greater choice to individualize treatment for patients with PD on
L-dopa who have developed motor fluctuations.
Future perspective
The role of opicapone and safinamide alongside therapies for advanced PD in patients with wearing-off is an
area that warrants future investigation. There is a possibility that these new treatments could eventually be used
in combination with advanced PD therapies. In theory, opicapone could be used as an adjunctive therapy to
carbidopa and L-dopa gel (DuoDopa), as opicapone has the potential to increase the bioavailability of DuoDopa,
thereby reducing dosing/cassette requirements. Currently, there is no clinical evidence to support this strategy,
but it represents an example of the versatility of once-daily adjunctive therapies. Other areas that warrant future
investigation are the roles of opicapone and safinamide in early disease, the concomitant use of opicapone and
safinamide with deep-brain stimulation and the routine genotyping of patients with PD for COMT polymorphisms
to assess this as a predictor of opicapone response.
Financial & competing interests disclosure
R Fackrell has received honoraria over the last 36 months from Bial, Profile Pharma, Britannia and AbbVie for speaking engage-
ments, and received funding from Bial for the 2017 MDS congress in Vancouver. R Fackrell was part of the Guideline development
Group for the recent PD NICE guidelines. CB Carroll has received grants from NIHR, Horizon 2020, Cure Parkinson’s Trust, JP Moul-
ton Charitable Foundation; educational support from Bial; honoraria from Profile Pharma, Global Kinetic Corporation, Bial; and
advisory board fees from UCB Pharma and Bial. CB Carroll is the UK CI of the current Phase IV observational study of safinamide
– Synapses. DG Grosset has received grants from Michael’s Movers, The Neurosciences Foundation, Parkinson’s UK; honoraria
from Bial, UCB Pharma, GE Healthcare; and consultancy fees from Acorda Therapeutics, GE Healthcare. B Mohamed has received
grants from NeuroDem and Parkinson’s UK; honoraria for lectures at meetings sponsored by UCB Pharma and Profile Pharma;
and consultancy fees from AbbVie, Profile Pharma, Britannia and Bial. P Reddy has received consulting fees from AbbVie, Bial, GE
Healthcare and speaker fees from AbbVie, Britannia, UCB and Medichem. M Parry has received honoraria from UCB, Britannia,
AbbVie and Bial. KR Chaudhuri has received consultancy fees from Britannia, AbbVie, Neuronova, UCB; advisory board fees from
Britannia, AbbVie, UCB, Sunovion, Pfizer, Jazz Pharma, GKC, Bial; honoraria, symposium or lecture fees from AbbVie, Britannia,
UCB, Mundipharma, Zambon; grants from Britannia Pharmaceuticals, AbbVie, UCB, GKC, Bial; academic grants from the EU, in-
cluding EU (Horizon 2020), Parkinson’s UK, NIHR, PDNMG, Kirby Laing Foundation, NPF; industry support for investigator-initiated
studies from UCB, Britannia, AbbVie, Bial. He has no stock ownership in medically related fields, and no partnerships/employment
with pharmaceutical companies, or expert testimony given. KR Chaudhuri has intellectual property rights for the KPP scale, PDSS-2.
Some independent research in this paper is part funded by the National Institute for Health Research (NIHR) Biomedical Research
Centre at South London and Maudsley NHS Foundation Trust and King’s College London. T Foltynie has received honoraria for
speaking at meetings sponsored by Bial, Britannia, Profile Pharma, and has received consultancy fees from Celgene and Oxford
Biomedica. He has received grants from the Michael J Fox Foundation, European Union, John Black Charitable Foundation and
the Cure Parkinson’s Trust. The authors have no other relevant affiliations or financial involvement with any organization or entity
with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those
disclosed.
Writing assistance has been provided by Rachel Parratt and Gillian Wain from Cello Health Communications, funded by Bial
Pharma UK Ltd, which also funded the Steering Group meeting.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license,
visit http://creativecommons.org/licenses/by-nc-nd/4.0/
future science group www.futuremedicine.com 357
Special Report Fackrell, Carroll, Grosset et al.
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