Expert Opinion on Drug Safety

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Therapeutic strategies to prevent and manage dyskinesias in Parkinson’s disease Manuela Pilleri & Angelo Antonini To cite this article: Manuela Pilleri & Angelo Antonini (2015) Therapeutic strategies to prevent and manage dyskinesias in Parkinson’s disease, Expert Opinion on Drug Safety, 14:2, 281-294, DOI: 10.1517/14740338.2015.988137 To link to this article: http://dx.doi.org/10.1517/14740338.2015.988137

Published online: 06 Dec 2014.

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Date: 26 September 2017, At: 08:29

Review

Therapeutic strategies to prevent and manage dyskinesias in Parkinson’s disease 1.

Introduction

2.

Antidyskinetic treatment strategies

3.

Therapeutic algorithm for dyskinesias treatment

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4.

Expert opinion

Manuela Pilleri & Angelo Antonini† Parkinson Disease and Movement Disorders Unit, "Fondazione Ospedale San Camillo" - I.R.C.C.S, Venice Lido, Italy

Introduction: Chronic treatment with levodopa is associated with the development of motor fluctuations and dyskinesias particularly in young Parkinson patients. In some cases, dyskinesias become so severe that they interfere with normal movement and negatively impact quality of life. Areas covered: In this review, we discuss benefits and limits of available therapeutic approaches aimed at delaying or managing dyskinesias as well as new strategies that are currently under investigation. Expert opinion: Among available treatments, monotherapy with dopamine agonists in the early phases of the disease reduces the risk for dyskinesias compared with levodopa. Nevertheless, dopamine agonists are unable to prevent dyskinesias once levodopa is added, which is always required once disease severity progresses. Convincing evidence of dyskinesia improvement has been shown only for deep brain stimulation and to some extent also for duodenal levodopa infusion and subcutaneous apomorphine. These approaches are expensive, have restrictive inclusion criteria and can cause potentially serious side effects. Alternative therapies include drugs targeting nondopaminergic neurotransmitter systems. Amantadine improves dyskinesias but its long-term effect is often unsatisfactory. Glutamatergic and gabaergic compounds have been tested in clinical trials, with promising results. By contrast, adrenergic drugs, fipamezole and idazoxan, did not show antidyskinetic effect. Keywords: dyskinesias, motor complications, Parkinson’s disease, therapy Expert Opin. Drug Saf. (2015) 14(2):281-294

1.

Introduction

Treatment with levodopa in Parkinson’s disease (PD) is associated with stable response and good motor control but almost inevitably, after a variable time interval, most patients develop motor complications, such as predictable and unpredictable motor fluctuations and dyskinesias. It is consistently reported that up to 50% of PD patients present dyskinesias 5 years after initiation of levodopa [1]. Although dyskinesias are considered an adverse event of dopaminergic treatment [2], the stage of pathological degeneration is also recognized to play a crucial role in the pathogenesis of dyskinesias [3,4]. Moreover, patient-related and disease-related factors may affect the risk to develop dyskinesias (Figure 1). Patient-related predisposing factors are female gender [5] and low body weight/mass index [6]. Among disease-related factors, the age of onset is reversely associated with the risk of developing dyskinesias [7]. After 5 years of levodopa treatment, dyskinesia risk for patients with onset age 40 -- 49 is about 70%, decreasing to 42% for onset ages 50 -- 59, 33% for onset ages 60 -- 69 and 24% for onset ages 70 -- 79 [8]. PD clinical phenotype may also affect the expression of dyskinesias, with tremor dominant showing a lower risk compared with akiynetic-rigid patients [9]. 10.1517/14740338.2015.988137 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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Dyskinesias are a frequent complication of levodopa therapy and produce negative impact on patients’ quality of life. The onset and severity of dyskinesias is related not only to the exposure to levodopa, but also to the degree on neurodegenerative process. Monotherapy with dopamine agonists may delay, but not avoid, the onset of dyskinesias, and is not feasible in the long term. Among marketed oral drugs, only amantadine has sufficient data from randomized control trials supporting its efficacy. Advanced therapies, such as dopamine infusion and deep brain stimulation, provide significant improvement of dyskinesias, but are not suitable for all patients and have potential severe complications. Experimental drugs targeting extradopaminergic pathways (i.e., serotoninergic, glutamatergic, gabaergic, noradrenergic) are under investigation for the treatment dyskinesias. Partial dopamine D2 agonist, pardoprunox and glutamate metabotropic receptor’s inhibitor AFQ056 have been tested in humans (Phase III and Phase II clinical trials, respectively) and gave promising results.

This box summarizes key points contained in the article.

Clinical features of dyskinesias Dyskinesias are abnormal involuntary movements affecting upper and lower limbs, trunk and/or facial muscles. Initially, dyskinesias may present as small, barely noticeable, involuntary movements but as disease progresses they become more severe, producing social stigma, physical exhaustion and pain. Dyskinesias may also affect drug management because they hinder required increases of antiparkinson medications needed to obtain satisfactory control of wearing-off [10]. Dyskinesias may have different clinical manifestations [2]. Choreic dyskinesias are characterized by irregular, purposeless and unpersisting movements, with variable duration and severity. At first, low-amplitude choreic dyskinesias appear in correspondence with plasma pick concentration of levodopa (pick dose dyskinesias), eventually triggered by voluntary actions, such as walking or talking, or mental tasks. With the progression of the disease, choreic movements become more persistent, and may also last for the entire on phase, paralleling the symptomatic effect of levodopa; in some cases, they can turn into large amplitude flinging movements, which are referred to as ballism. Dystonic dyskinesias consist of sustained contractions of agonist and antagonist muscles of one or more body districts, producing fixed posture or slow twisting movements; less frequently they affect facial muscles, producing blepharospasm or mandibular dystonia. This pattern may be present in the on, but also in the off phase, especially in the 1.1

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early morning when levodopa concentration is at its lowest level. Dystonic and choreic patterns may appear in combination, manifesting as twisting of legs while walking or pulling movements of the arms behind the back. A less common but quite disabling phenomenon is biphasic dyskinesia, which generally appears after levodopa administration, before the drug reaches its therapeutic effect or when the medication wears off. They are characterized by variable combination of choreic and dystonic movements or by rapid alternating leg movements lasting several minutes until the peripheral levodopa concentration drops well below the effective threshold and causing important physical distress to the patient. Pathogenesis of dyskinesias Dyskinesias develop as consequence of dopaminergic therapy, but nigrostriatal degeneration definitively contributes to their expression and severity. The contribution of levodopa exposure is supported by basic clinical observations. First, in the pre-levodopa era PD patients did not present dyskinesias. Second, the expression of dyskinesias shows a temporal relationship with levodopa administration: the most common pattern is related to the plasmatic peak of the drug, starting 30 -- 60 after dosing, while biphasic dyskinesias start either few minutes after levodopa administration, when the drug plasma concentration is rising or 2 -- 3 h later when it is decreasing. Off dystonia is related to low plasma levels of LD, and often occurs at night or early in the morning [2]. Moreover, several studies indicate that the development and the severity of dyskinesias have a clear relationship with levodopa exposure, which depends on duration [11] and dosage [12] of treatment. The role of nigrostriatal degeneration in the development of dyskinesias has been clarified both by experimental studies and clinical observation. Animal models showed that the severity of levodopainduced involuntary movements is strongly related to dopamine cell loss in the substantia nigra [3,4,13]. On the other hand, short latency onset of dyskinesias, within few days since treatment start, has been reported in patients with parkinsonism due to severe striatal damage produced by MPTP intoxication [14] as well as in patients of sub-Saharan Africa who had never been exposed to medications [15]. The current pathogenetic model of dyskinesias explains how the combination of pharmacological and degenerative factors contributes to the development of dyskinesias. Oral levodopa, due to its short half-life and irregular absorption secondary to erratic gastric emptying, does not ensure a constant plasmatic bioavailability despite the intake of multiple doses throughout the day [16]. In early stages of the disease, levodopa is taken up into spared dopamine neurons and terminals, where it is converted to dopamine, stored into synaptic vesicles and released in a physiologically regulated manner. As degeneration progresses, dopaminergic cells number declines, and the residual terminals lose the ability first to store and then to produce and release dopamine derived 1.2

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Therapeutic strategies to prevent and manage dyskinesias in Parkinson’s disease

Disease related Neurodegeneration

Abnormal dopaminergic pharmacodynamics -Presynaptic (altered dopamine production, storing and release) -Postsynaptic (D1 supersensitivity and downstream proteins activation, D3 overexpression)

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Abnormal extradopaminergic function -Dopamine production and release by serotoninergic terminals -Increased glutamatergic activity -Decreased gabaergic activity

Treatment related L-dopa

exposure (therapydurationanddosage) Pulsatile dopaminergic delivery

Figure 1. Main pathogenetic mechanisms of dyskinesias.

from exogenous levodopa. Eventually, synaptic dopamine levels become strictly dependent and synchronous with plasma levodopa concentrations [16,17]. Pulsatile stimulation leads to pathological maladaptive changes at postsynaptic level contributing to dyskinesias development [18]. Experimental studies suggest that chronic treatment with levodopa induces an increase of D1 receptor sensitivity and their downstream signaling, D2 heterodimerization and increased D3 expression, leading to modified striatal plasticity [19,20]. Moreover, converging data indicate that nondopaminergic pathways such as glutamatergic [21,22] serotoninergic [23,24], gabaergic [25] and adrenergic [26] play a role in the development of dyskinesias. Particularly, serotoninergic neurons have the enzymatic ability to convert exogenous levodopa to dopamine but lack a reuptake control mechanism to regulate its extrasynaptic concentration [23,24]. In this review, we will discuss therapeutic approaches already available aimed at delaying and treating dyskinesias, as well as new possible strategies currently under investigation. For each cited treatment, we also briefly explain the potential mechanism of action and summarize the main findings of experimental research. Data sources included English-language clinical trials published in the last 10 years identified via MEDLINE, setting the following research terms: ‘Parkinson’s disease-treatment’, ‘levodopa induced dyskinesias-treatment’ and ‘motor complications-treatment’. The website www.clinicaltrials.gov was also searched for additional information about ongoing or unpublished studies.

2.

Antidyskinetic treatment strategies

As patient-related factors are unavoidable and no treatment is available to counteract neuronal degeneration, marketed and experimental strategies for the treatment of dyskinesias are mainly focused at: i) Reducing levodopa exposure: ii) Providing continuous dopaminergic delivery: iii) Contrasting the postsynaptic changes occurring in dopaminergic and extradopaminergic pathways due to the combination of neurodegeneration and chronic levodopa administration [27].

Treatment strategies targeting dopamine transmission 2.1.1 Levodopa sparing 2.1

As previously stated, there is an association between dyskinesias and levodopa dose. In the Elldopa study at 9 months, ~ 13% of patients exposed to the highest levodopa dose (600 mg/day) developed dyskinesias as opposed to 3% with lowest dose (150 mg/day) [12]. These data indicate that to prevent motor complications, the levodopa prescribed dosage should not exceed the minimum providing symptomatic control, and, whenever possible, it should be under 300 -- 400 mg/day in the early stages. In advanced disease, when dyskinesias are already present, reduction of levodopa dose can be attempted to attenuate their severity but this may lead to increased off time duration and severity [27].

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Table 1. Available and experimental treatments for levodopa-induced dyskinesias. Intervention

Targeted pathogenetic mechanism

Available evidence

Delay L-DOPA start (DA monotherapy in early stages) Reduce L-DOPA dose (L-DOPA sparing)

L-DOPA

RCT (reduced risk for dyskinesias at 4 and 8 years) [28-31]

Continuous dopaminergic delivery Apomorphine

Pulsatile dopaminergic stimulation

exposure

RCT in early stages (daily dosage 300 mg produce less dyskinesias than 600 mg) [12] Clinical observation in advanced stages(possible worsening of motor signs) [27]

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Intraduodenal L-DOPA Ipx066* Dopamine partial agonist Aripiprazole Pardoprunox*

Postsynaptic dopaminergic pharmacodynamics

Glutamate inhibitors Amantadine

Extradopaminergic dysfunction

Memantine AFQ056 (mavoglurant)* AFQ48621 (dipraglurant) Perampanel* Serotoninergic inhibitors Clozapine

Retrospective studies (improvement of dyskinesias with monotherapy) [46,47] RCT (improved duration and severity of dyskinesias) [52] RCT in advanced PD (increased time in on without dyskinesias) [57] Small RCT (12 patients, possible worsening of motor signs) [59] RCT in advanced PD (increased time in on without dyskinesias) [62] RCT (reduced dyskinesias severity and impact on quality of life) [63-66] Small RCT (25 patients, improvement of dyskinesias severity) [67] RCT (reduced dyskinesias severity) [68] RCT safety study (reduced dyskinesias severity) unpublished data [69] RCT (no improvement of dyskinesias) [70] Small RCT (50 patients, improvement of dyskinesias without motor side effects) [72] RCT in advanced PD (improvement of dyskinesias possible motor side effects) [74]

Sarizotan* Gabaergic drugs Preladenant, istradefylline*

RCT (reduction of off time, no effect or worsening of dyskinesias) [77-82] Small RCT (7 patients, reduction of dyskinesias) [84] Small RCT (17 patients, no effect on dyskinesias) [86]

Nabilone* Oral cannabis Adrenergic inhibitors Fipamezole*

RCT (no improvement of dyskinesias, different effect in different countries’ populations) [87] Open-label (18 patients, reduced dyskinesias severity after levodopa challenge) [88] RCT (38 patients, improvement of dyskinesias; possible worsening of motor signs) [91]

Idazoxan* Levetiracetam

This table summarizes main published results of clinical trials testing available and experimental approaches for dyskinesias management *investigational drugs; RCT enrolling £ 50 patients are referred as SMALL RCT and the number of included patients included in each trial is indicated. RCT: Randomized controlled trial.

Another major determinant of dyskinesia development is levodopa duration of exposure. Patients with a shorter time from symptom onset to initiation of levodopa develop dyskinesia earlier [11]. Thus, delaying the introduction of levodopa by administrating other symptomatic treatments such as dopamine agonist (DA) in the early stages, it is considered a viable strategy to reduce such risk in early de novo PD [27-31]. Dopamine agonists Randomized controlled studies in early PD patients showed that monotherapy with ropinirole [28], pramipexole [29], pergolide [30] and cabergoline [31] can relieve Parkinson 2.1.2

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features with lower risk for dyskinesias and motor fluctuations than levodopa therapy. Although dyskinesias have been described in patients treated with DA monotherapy, they are rare and generally not severe (Table 1) [28,29]. Rotigotine shares a similar pharmacodynamic profile and provides similar motor benefit as the other non-ergot DA [32,33], but no randomized trial has been specifically designed to assess its ability to prevent dyskinesias in early PD. In an open-label 6 years follow-up study on 65 patients chronically treated with rotigotine the total prevalence of dyskinesias was 17%, but only 5% of patients treated with DA monotherapy developed dyskinesias [34], whereas in the

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Therapeutic strategies to prevent and manage dyskinesias in Parkinson’s disease

majority of patients dyskinesias started after levodopa is added. The low pro-dyskinetic potential of DA in the early stages is largely attributed to their pharmacokinetics [28-34]. Indeed, DA have a long half-life, ranging from 6 h for standard release ropinirole up to 24 h for extended release ropinirole and pramipexole, rapidly cross the blood--brain barrier and ensure steady stimulation of dopamine receptors, preventing the occurrence of postsynaptic modifications leading to the onset of dyskinesias [18]. According to this hypothesis, prolonged release compounds would be expected to provide better results on dyskinesias, due to their more favorable pharmacokinetics. Surprisingly, prolonged release of ropinirole and pramipexole obtained better results on motor fluctuations compared with an equivalent dosage of the correspondent immediate release compound, but showed similar effect on dyskinesias risk reduction [35,36]. These data indicate that DA with half-life of 6 -- 8 h, administered three times per day, might be sufficient to ensure continuous dopaminergic delivery such that no further benefit on dyskinesias is obtained by longer acting compounds. A specific antidyskinetic activity has also been supposed for DA targeting D3 receptors. Indeed D3 receptors are overexpressed in dyskinetic animal models of PD and may contribute to the development of dyskinesias. Experimental studies showed that D3 receptor agonists can attenuate dyskinesias, probably by restoring balance in the basal ganglia direct pathway [37,38]. By contrast, in clinical studies, overnight switching from ergot-derived dopamine agonists to pramipexole, a non-ergot agonist with selective affinity for D3--D3 receptors, did not produce any change in motor fluctuations and dyskinesias (scored by UPDRS IV) at 12 weeks [39] Although DA use is associated with a low risk of motor complications, this therapeutic strategy is not always feasible even in the early stages and can be hardly maintained in the long term. A Cochrane review comparing benefits and risks of different therapeutic strategies in early PD, showed that in randomized trials comparing dopamine agonist with levodopa, patients taking DA had a higher rate of dropouts, due to adverse events or lack of efficacy [40]. Two studies comparing early treatment with non-ergot dopamine agonists pramipexole (CALM --PD, 4 years follow-up) [29] and ropinirole (INT 065, 5 years follow-up) [28] versus levodopa therapy, had higher withdrawal rate in the DA agonist versus levodopa arm (45 vs 33.3% for pramipexole, and 52 vs 49.4% for ropinirole). Only the ropinirole study detailed the causes of withdrawals showing little differences in dropouts for insufficient therapeutic effect between DA and levodopa-treated patients (7.8 vs 5.6%, respectively). Higher rates of withdrawals from DA therapy have been reported by studies with longer follow-up period. In a study comparing patients started on bromocriptine versus levodopa

at 10 years follow-up the global dropout rate was 71.8% in the DA patients and 32% in the levodopa-treated patients. Adverse events accounted for 85% of dropouts in the bromocriptine arm, while the remaining 15% stopped DA treatment due to lack of efficacy [41]. Taken together, these data suggest that more than half of the patients started on DA would need to switch to levodopa monotherapy (in case of adverse event) or to an association of DA and levodopa (to obtain a satisfactory clinical benefit) within 4 -- 5 years since disease onset, and reaching almost 100% at 10 years. After the introduction of levodopa, DA no longer provides a preventive effect on the development of motor complications. In a randomized clinical study in early PD, the onset of dyskinesias was delayed by ~ 3 years in ropinirole compared with levodopa-treated patients. However, when patients initially treated with ropinirole were supplemented with levodopa, their dyskinesias risk was the same of those who had received levodopa from the beginning [42]. In patients with advanced PD, adding DA may improve dyskinesias by preventing an increase of levodopa dose or when parallel levodopa dose decrement is feasible, without worsening of motor fluctuations [42,43].

Continuous dopaminergic delivery As previously discussed, levodopa pulsatile delivery is one of the main factors in the development of dyskinesias. Continuous subcutaneous or intraduodenal delivery of dopaminergic drugs allows primarily achievement of smoother plasmatic curves and more constant stimulation of striatal receptors, mimicking the normal physiological state [44]. Apomorphine is a D1--D2 dopamine agonist, which can be delivered subcutaneously by a portable pump system, usually 12 -- 16 h/day. Converging evidence indicates that apomorphine can reduce off periods [45]. By contrast, the effect of this treatment on dyskinesias is debated. While some studies showed a reduction of dyskinesias in patients treated with apomorphine [46,47], other authors failed to replicate these findings [48]. The best results on dyskinesias are obtained when oral levodopa is discontinued during the infusion of apomorphine. In a retrospective study by Manson and colleagues, there was greater dyskinesia reduction (64%) in the apomorphine monotherapy group, compared to 30% in patients with polytherapy (apomorphine + levodopa). However, among 64 patients treated with apomorphine pump, only 45 successfully converted to monotherapy, indicating that a relevant quote of apomorphine-treated patients still needs the association of considerable doses of levodopa to achieve a good control of motor fluctuations, which is reflected by poor benefit on dyskinesias [47]. As a matter of fact, worsening of dyskinesias has been reported as a possible adverse event of apomorphine treatment sometimes leading to treatment discontinuation [49]. 2.1.3

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Other adverse events may limit the use of apomorphine, such as nausea, daytime somnolence, neuropsychiatric effects and skin complications [46-49]. The gel formulation of levodopa with carbidopa can be continuously infused directly into the duodenum, by a portable pump and a permanent transabdominal tube. Levodopa continuously delivery in the upper jejunum permits to bypass the stomach, and avoid irregular absorption due to slow and erratic gastric emptying. This system allows achievement of constant levodopa plasma levels resulting in more continuous dopamine production and release at the synaptic level. Patients treated with levodopa duodenal infusion generally experience an increase of on time, with improvement of dyskinesias duration and severity [50,51]. In a, randomized, cross-over double-blind trial, enrolling 24 PD patients with motor complications, intraduodenal levodopa significantly decreased off time and increased on time without troublesome dyskinesias, compared with best optimized oral therapy [52]. In a recent open-label study, 41 patients treated with intraduodenal levodopa long-term (mean duration treatment 25 months) dyskinesia duration was reduced by 30%, dyskinesia disability improved by 48% and painful dyskinesia improved by 78% [53]. Adverse events related to the infusion devices, such as intestinal tube dislocation, kinking or occlusion, are the most common complications of intraduodenal levodopa and may result in treatment withdrawal [50-53]. Other strategies have been tested, to provide more continuous delivery than standard oral formulation, but failed to show a reduction of dyskinesias. Controlled-release carbidopa/levodopa preparations, provided with an erodible polymer matrix that retards the release of levodopa, produce more sustained plasma levels of levodopa than standard levodopa/carbidopa, but show lower bioavailability (71 vs 99%) and slower time to peak levodopa concentration (2.3 vs 1.1 h), resulting in delayed onset of clinical response (2.2 vs 1.1 h) [54]. Due to these characteristics, although controlled release formulations allow reduction of dosing frequency, higher total daily dosage is needed to maintain an adequate control of motor symptoms, with possible increase of dyskinesias [55]. Another strategy aimed at modifying pharmacokinetics of levodopa is use of catechol-O-methyl transferase (COMT) enzyme blockers. Entacapone, a peripheral COMT inhibitor, increases levodopa half-life by 25 -- 50% without increasing peak concentration. Early treatment with combination of levodopa/carbidopa/entacapone in naı¨ve PD patients does not reduce the risk of dyskinesia. To the contrary, despite providing more continuous dopamine delivery, this treatment increased the risk to develop dyskinesias compared with levodopa/carbidopa alone, probably due to increased levodopa exposure. For the same reason, the add-on of entacapone in the advanced stages results in improvement of motor fluctuations, but may produce parallel worsening of dyskinesias [56]. 286

In the last years, novel formulations have been developed to overcome pharmacokinetic limitations of levodopa by providing more continuous delivery. A double-blind trial including 393 fluctuating PD patients, compared the pharmacokinetic and clinical effect of the novel controlled release formulation IPX066 and standard levodopa, IPX066 reduced variability in levodopa plasmatic levels, decreased off time and increased on time without troublesome dyskinesias compared with carbidopa--levodopa. These findings indicate that IPX066 maybe a viable strategy to improve motor fluctuations without worsening dyskinesias in advanced PD [57]. Antidopaminergic drugs Denervation-induced supersensitivity of dopamine receptors (D1-like and D2-like) may be a plausible pathogenetic mechanism of dyskinesias [58] and on this rationale several full or partial dopamine receptors antagonists have been tested. Aripiprazole is a partial agonist of D2 receptors, marketed for the treatment of psychosis. An open-label pilot study on 12 patients showed that aripiprazole, at a dosage of 0.625 mg/day decreased the severity and duration of dyskinesias in a group of 12 patients with dyskinesias refractory to amantadine [59]. To our knowledge, these results have not been replicated in larger trials. To the contrary, this drug causes potential extrapyramidal adverse effects [60]. Pardoprunox, a partial DA D2 agonist, had beneficial effects on motor symptoms inducing only mild dyskinesia in MPTP-treated marmosets [61]. In a controlled randomized 19 weeks clinical study including 299 PD patients with motor complications, pardoprunox increased ‘on’ time without troublesome dyskinesias indicating that this drug may alleviate dyskinesia without negatively affecting levodopa’s beneficial action [62]. 2.1.4

2.2

Treatments targeting nondopaminergic pathways Antiglutamatergic drugs

2.2.1

Converging data suggest an active involvement of glutamate receptors in the acute expression and development of dyskinesias. Indeed, the striatum receives cortical and thalamic glutamatergic inputs [21,22]. Chronic L-DOPA treatment causes profound changes in striatal glutamatergic signaling, with adaptive modifications of NMDA receptor (NR 1 and NR 2) subunits. Moreover, in PD patients with dyskinesias, an increase in NMDA-, metabotropic Glu- and AMPA-receptor binding has been reported [22]. In a randomized, double-blind, placebo-controlled study in 19 patients, amantadine did not change the severity of dyskinesias, but reduced their duration and impact on activities of daily living [63]. However, the time span of the antidyskinetic effect of amantadine is still debated. One study suggested loss of amantadine effect in the long period. Among 20 patients, who had been treated with amantadine for 3 -- 8 months and had shown improvement of dyskinesias, only 11 reported a slight increase of dyskinesias after amantadine

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Therapeutic strategies to prevent and manage dyskinesias in Parkinson’s disease

discontinuation [64]. By contrast, two other randomized placebo-controlled, wash-out studies reported long-term efficacy of chronic treatment with amantadine [65,66]. The first, enrolled 32 PD patients with dyskinesias, treated with amantadine for at least 1 year. Patients were switched in a double-blind manner to amantadine or placebo and followed for 3 weeks. At follow-up evaluation, there was a significant increase of UPDRS IV items scoring dyskinesias in patients treated with placebo, while those following on amantadine showed no change [65]. Another study (the AMANDYSK trial), with a similar design but with longer follow-up (3 months) enrolled 57 amantadine-treated dyskinetic PD patients, which were randomized to either continuing or withdrawing amantadine treatment and switching to placebo. Patients discontinuing amantadine showed a worsening of dyskinesias, as assessed by UPDRS items 32 and 33, increase in ‘on’ time with troublesome dyskinesia, and worsening of Abnormal Involuntary Movement Scale score. Moreover, a large number of withdrawals for worsening of dyskinesias were observed in patients switched to placebo [66]. Memantine, another NMDA antagonist, marketed for the treatment of dementia, has also demonstrated some improvement of levodopa-induced dyskinesias in a small placebocontrolled study of 25 patients [67]. Selective metabotropic glutamate receptor (mGluR5) antagonists have been evaluated in phase II randomized controlled trials. Among them, mavoglurant (AFQ056) was tested in a 13-week, double-blind, placebo-controlled trial. The study enrolled 133 PD patients and moderate-to-severe levodopa (L-DOPA)-induced dyskinesia. Patients were randomized to receive either AFQ056 at different doses (20, 50, 100, 150 or 200 mg daily). A dose-related response was observed, with 200 mg/day demonstrating greater improvement of dyskinesias severity, without worsening of PD motor symptoms [68]. Another glutamate receptor inhibitor, dipraglurant (ADX 48621), has been tested in a randomized, double-blind, placebo-controlled safety study, demonstrating tolerability and positive exploratory secondary outcomes of reduced dyskinesia (www.clinical trials.gov; ADX48621 for the Treatment of Levodopa Induced Dyskinesia in Patients With Parkinson’ s Disease) [69]. The AMPA receptor antagonist, perampanel, was tested in two phase III clinical trials enrolling more than 700 patients, but did not provide any benefit on motor fluctuations and dyskinesias [70].

Serotoninergic drugs Serotonin neurons can convert exogenous levodopa to dopamine by the amino acid decarboxylase, store it and release it through vesicular monoamine transporter [23]. However, these cells are not equipped with the proper mechanisms to regulate release and presynaptic reuptake resulting in abnormal and 2.2.2

irregular stimulation of postsynaptic dopamine striatal receptors. Dopamine released from serotonin neurons is responsible for L-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats [24]. Thus, blockade of serotonin activity is considered a possible target for antidyskinetic therapy [71]. Clozapine, a neuroleptic acting as 5-hydroxytryptamine (5-HT) 2A/2C antagonist, significantly reduced peak-dose dyskinesias, in a double-blind, placebo-controlled study, including 50 patients [72]. However, clozapine has potentially severe adverse effects including sedation, drooling, orthostatic hypotension and rarely neutropenia, requiring regular strict blood cell count [73]. Sarizotan, a 5-HT1A agonist, which also shows high affinity for D3 and D4 receptors, was tested in a placebocontrolled trial in 381 PD patients with moderately disabling dyskinesias. Patients were randomized to receive different doses of sarizotan or placebo. No significant changes occurred with sarizotan compared to placebo on severity and duration of dyskinesias. By contrast, off time significantly increased at the highest dosage (10 mg/day), suggesting a potential negative effect of this drug on motor symptoms [74]. Interestingly, in experimental studies on MPTP-treated macaques combinations of subthreshold doses of 5-HT(1A) and 5-HT(1B) agonists, which individually produced no effect, were able to reduce the abnormal involuntary movements by up to 80% and to prevent the development of dyskinesia, without worsening motor symptoms [75]. This strategy has not been tested in clinical trials.

Drugs acting on GABA transmission Presynaptic A2A adenosine receptors are abundantly expressed in basal ganglia, and modulate GABAergic synaptic transmission by increasing the excitability of medium spiny neurons in the striatum and by enhancing GABA inhibition in globuspallidus projections [25]. For this reason, a potential antidyskinetic effect of adenosine A2A-receptors antagonists had been hypothesized [76]. Preladenant, a potent and selective competitive antagonist of the A2A adenosine receptor was tested in PD patients. In a double-blind trial, 204 patients were randomized to receive different doses of preladenant and 49 were treated with placebo. Patients of the active group reported significant decrease in ‘off’ time with no effect on dyskinesias [77]. By contrast, in a subsequent long-term, multicenter, open-label study the preladenant group showed worsening of dyskinesias [78]. Istradefylline, another adenosine A2A antagonist, proved to be mildly effective in relieving wearing-off fluctuations in PD patients [79]. However, similarly to preladenant, this drug slightly increased ‘on’ time with dyskinesia [80,81]. In a large randomized study, including 610 patients with PD and motor fluctuations, 40 mg istradefylline per day significantly improved UPDRS, but dyskinesia was the most 2.2.3

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commonly reported drug-related adverse effect in the istradefylline-treated patients [82]. Cannabinoids have been also tested for the treatment of dyskinesias. Cannabinoid receptors are concentrated in the basal ganglia and their stimulation increases GABA transmission in the lateral segment of globuspallidus reducing glutamate release in the striatum. Stimulation of cannabinoid receptors in the internal globuspallidus (GPi) reduces GABA reuptake and enhances GABA transmission [83]. The cannabinoid receptor agonist nabilone was shown to alleviate levodopa-induced dyskinesia in the MPTP-lesioned marmoset model of PD chronically treated with levodopa. In a small clinical trial involving seven PD patients, nabilone significantly reduced levodopa-induced dyskinesias [84]. Similarly, the endocannabinoid analog oleoylethanolamide, an agonist of PPAR-a and antagonist of transient receptor potential cation channel subfamily V (TrpV or capsaicin receptor) receptors, was shown to reduce L-DOPA-induced dyskinesia in a mouse model of PD [85]. Oral cannabis was tested in a randomized doubleblind crossover study in 17 patients, but showed no objective or subjective improvement in dyskinesias or parkinsonism [86]. Other drugs tested for the management of dyskinesias

2.2.4

Noradrenergic a-2A antagonists fipamezole and idazoxan have also been tested for the treatment of dyskinesias, but despite promising results from animal studies, clinical trials did not provide definite evidence of efficacy in PD patients with dyskinesias. In a double-blind, randomized, placebo-controlled, study conducted on 115 US patients and 64 Indian patients fipamezole reduced dyskinesias only in the US, but not in the Indian subjects [87]. One clinical study assessed the effects of idazoxan on dyskinesias induced by an acute levodopa challenge in 18 patients with advanced PD: the severity of L-DOPA-induced dyskinesia improved after 20 mg idazoxan pretreatment, without deterioration in the antiparkinsonian response to levodopa [88]. Unfortunately, these findings were not confirmed by further trials [89]. Levetiracetam ([LEV] (S)-ethyl-2-oxo-pyrrolidine acetamide) is marketed as antiepileptic, but has shown powerful antidyskinetic action in MPTP-lesioned macaques [90]. The mechanism of action of levetiracetam on levodopa-induced dyskinesias is not clear. Levetiracetam could modulate the pathological synchronization/desynchronization of basal ganglia neuronal circuits regulating maladaptive dopamine release and uptake [91]. In a clinical, double-blind, placebocontrolled, crossover trial, levetiracetam was administered to 38 patients with levodopa-induced dyskinesias at the dosage of 500 and 1000 mg/day. The study showed a dosedependent decrease of time spent in on with dyskinesias and an increase of time spent in on without dyskinesias. UPDRS part IV (motor complications) showed significant reduction of dyskinesia duration, without increase of off time [92]. 288

However, other studies reported no beneficial effect of levetiracetam, or even possible worsening of parkinsonism [93]. Histamine H2 and H 3 receptors are highly expressed in basal ganglia (globuspallidus, substantia nigra), maybe involved in motor activity and could be another potential target for antidyskinetic treatments. The H2 receptor inhibitor famotidine had a significant effect on chorea induced by high-dose levodopa and increased on time not associated with disabling dyskinesia in MPTP monkeys. The results of clinical trials have not been published so far [94]. Surgical therapies Although the main issue of this review is pharmacological treatment, surgical approaches deserve a mention, since deep brain stimulation (DBS) represents a valid therapeutic option in the management of refractory dyskinesias. Two surgical targets, subthalamic nucleus (STN) and GPi are currently used in PD patients with motor complications resulting in improvement of motor fluctuations and dyskinesias. Stimulation of GPi provides a direct antidyskinetic effect, despite unchanged or even increased dopaminergic medication schedule. In patients implanted in the STN, the reduction of dyskinesias is obtained mostly by reducing dopaminergic therapy requirements [95,96]. 2.3

Therapeutic algorithm for dyskinesias treatment

3.

One of the main goals of antiparkinson therapy, since first prescription, is to achieve a satisfactory control of symptoms, preventing or delaying the onset of motor fluctuations and dyskinesias [97]. Since levodopa exposure is one of the main determinants for motor complications development, levodopa sparing and DA monotherapy is largely considered a reasonable strategy to start treatment. Indeed, in the early stages of PD, DA monotherapy ensures a satisfactory motor control, with low risk to induce dyskinesias [28-31]. Nevertheless, DA therapy may produce adverse events, such as somnolence [98], impulse control disorders [99,100], that may hamper dosage titration up to efficacious levels or may also induce treatment withdrawal. Moreover, DA monotherapy may be insufficient to ensure a good symptomatic control, with a rate of dropouts due to lack of efficacy around 10% in the early stages and increasing up to 15% in the longest follow-up studies [40]. With disease progression, virtually all patients require levodopa to achieve a satisfactory control of parkinsonian features [41]. In the early stages, levodopa dosage should be possibly kept below 300 mg/day to minimize dyskinesias risk [12], but further increases are always needed with the progression of the disease to achieve a satisfactory symptomatic control. Once dyskinesias develop, their management becomes challenging. A possible therapeutic algorithm is reported in Figure 2.

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Not troublesome dyskinesias

Troublesome dyskinesias

No intervention

Reduce levodopa Impaired motor control

Persisting dyskinesias

Middle stages Objective: attenuate dyskinesias

Therapeutic strategies to prevent and manage dyskinesias in Parkinson’s disease

Advanced stages Objective: manage refractory dyskinesias

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Add on amantadine Refractory troublesome dyskinesias

Contra

indicati

Considere indications for: • Subcoutaneous apomorphine -Possibly monotherapy • Intraduodenal L-DOPA infusion • STN or GPI DBS

Poor

ons

y fficac

e

Side

Test off label strategies (monitoring efficacy and side effects) -Clozapine -Levetiracetam -Memantine

ts

effec

Figure 2. Therapeutic algorithm to manage dyskinesias. DBS: Deep brain stimulation; GPi: Globuspallidus; STN: Subthalamic nucleus.

An attempt to reduce dopaminergic drugs dosage must be always tried: in some patients, lower doses administered more frequently may reduce dyskinesias. Nevertheless, in many cases, the reduction of dopaminergic therapy is frustrated by worsening of parkinsonian symptoms and motor fluctuations [27]. In patients with mild or moderate dyskinesias, introduction of amantadine may be helpful [63,64], and its effect may persist even after chronic long-term treatment [65,66]. However, in some patients dyskinesias become refractory to oral therapeutic strategies and infusion therapies such as subcutaneous apomorphine and duodenal levodopa maybe considered [44]. Tonic dopaminergic stimulation provided by continuous drug delivery, would result in smoother fluctuations of motor state, with reduced plasmatic peak of dopaminergic drugs and consequent reduction of dyskinesias. Moreover, continuous dopaminergic stimulation is thought to revert, or even prevent, pharmacodynamic changes, which determine motor complications [18]. However, infusion therapies are limited by possible complications related to administration route (subcutaneous nodules for apomorphine and stoma infections for intraduodenal levodopa) or devises problems [49,53]. Moreover, these systems are

suitable only for patients able to manage the treatment either independently or with the help of their caregiver. A number of drugs marketed for other indications, have been tested for management of dyskinesias. Memantine, which similarly to amantadine acts on NMDA glutamate receptors, has shown some efficacy on dyskinesias in a small clinical trial [67]. In PD patients with dementia and prominent dyskinesias, it may be tried, as an alternative to amantadine, to take advantage of its potential effect on both cognitive and motor features. The antipsychotic aripiprazole [59] and the antiepileptic levetiracetam [90-92] were shown to improve dyskinesias in small studies (enrolling 12 and 50 patients, respectively), but there is no sufficient evidence supporting their effectiveness. Moreover, the off-label use on these drugs for the treatment of dyskinesias should be cautiously considered, since levetiracetam trials reported several withdrawals for somnolence [93], and aripiprazole has potential extrapyramidal side effects [60]. Clozapine, which is indicated for the treatment of PDrelated psychosis, may also improve dyskinesias [72]. However, the potential risk for agranulocitosis should induce special caution in prescription and regular monitoring of leucocytes is required [73].

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Deep brain stimulation of the STN or GPi should be considered in patients with drug refractory motor complications satisfying inclusion criteria [94,95].

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4.

Expert opinion

Once dyskinesias appear their management becomes challenging and may require invasive treatment such as infusion therapies or surgical intervention. Thus, the maximum attention must be on the prevention of this phenomenon, since the first disease stages. As dyskinesias development and severity are related to levodopa exposure, levodopa sparing strategy is largely considered the main pillar for their prevention and management. Nevertheless, if there is a general agreement about maintaining the lowest levodopa dosage needed to ensure symptomatic control across all the stages of the disease, recent findings question the practice to delay its prescription to prevent dyskinesias. Recently, a cross-sectional study investigating the prevalence of motor complications in levodopa-treated patients from Italy and from Ghana, found that the two populations developed motor fluctuations and dyskinesias after similar disease duration, although the introduction of levodopa therapy was delayed of about 2 years in the African cohort. Moreover, the same study found that disease duration and treatment dosage, rather than treatment duration, were the main determinant factors for the onset of dyskinesias [101]. These results partially contrast with previous studies indicating that patients with a shorter delay from symptom onset to initiation of levodopa develop dyskinesia earlier [11] and that patients taking DA monotherapy in the early stages may achieve satisfactory motor control with reduced risk for motor complications [28-31]. In our opinion, DA monotherapy should be still preferred to levodopa as starting therapy, as long as it achieves good symptomatic control without bothersome adverse events. Nevertheless, there are some critical issues about the role of DA in the management of dyskinesias, which should be highlighted. First, only non-ergot drugs, namely ropinirole, pramipexole and rotigotine, should be used in the treatment of PD, since ergot DA are associated with potential fibrotic heart valve reactions [102,103]. Second, no clear indication states which DA should be prescribed, since no comparative study has ever compared their effectiveness. While ropinirole and pramipexole were proven to reduce the risk for dyskinesias when administered in monotherapy in early PD [28,29], only an open-label trial supports the potential role of rotigotine in preventing dyskinesias [32]. Continuous dopaminergic delivery has been shown to partially revert the maladaptive changes leading to dyskinesias, and provide clinical improvement. Experimental studies also indicate a potential role of continuous dopaminergic stimulation in the prevention of 290

dyskinesias. Nevertheless, subcutaneous apomorphine and duodopa are relatively invasive and would be hardly accepted by early-stage patients. Oral strategies able to obtain more continuous plasmatic levels of levodopa, such as adding on entacapone [56] or rasagiline [104] do not prevent dyskinesias. Additional noninvasive therapies, developed to ensure constant dopaminergic delivery such as the prolonged release levodopa formulation IPX 066 are worth further trails in early PD patients, to investigate their potential role in preventing or delaying dyskinesias. If the prevention of dyskinesias still remains an unmet need, symptomatic management of this phenomenon is even more challenging. Between the marketed drugs, only amantadine and duodenal infusion therapy with levodopa are supported by randomized control trials. Nevertheless amantadine reduces dyskinesias, but the extent of its effect is variable and most patients do not achieve a satisfactory control, while intraduodenal levodopa is quite invasive and device malfunctioning and other troublesome adverse events may limit its use. Offlabel prescription of antidopaminergics or levetiracetam is only supported by small trials, and may be associated with troublesome adverse events. Different experimental oral drugs with potential antidyskinetic effect have been evaluated in randomized-controlled clinical trials. Metabotropic glutamate receptor antagonist mavoglurant (AFQ056) showed a direct antidyskinetic effect without worsening of motor features [68]. Partial dopamine agonist pardoprunox [61,62] has been shown to increase time in on without troublesome dyskinesias in advanced PD and may be potentially useful in the early stages. By contrast, a number of compounds reported to achieve antidyskinetic effect in experimental studies, did not provide benefit in clinical trials. AMPA glutamate receptor perampanel did not improve motor fluctuations and dyskinesias in PD patients [70]. Noradrenergic a2A antagonists, fipamezole [87] and idazoxan [88], did not show efficacy on dyskinesias in clinical trials despite promising results in animal and initial explorative clinical studies. Adenosine agonists preladenant and istradefylline drugs were shown to improve motor fluctuations, but may worsen dyskinesias [77-82]. Clinical studies about the antidyskinetic effect of cannabinoids provided contrasting results [84-86] and deserve further investigation. Finally, serotonin receptor inhibitor sarizotan potentially reduces dyskinesias but may worsen PD motor symptoms [74]. Although symptomatic treatments may be useful in the management of dyskinesias, they only target drug-related pathogenetic mechanism of this complex phenomenon. Further investigation is needed to develop neuroprotective and disease-modifying treatments, able to slow down or stop neuronal degeneration, which largely contributes to dyskinesias and motor fluctuations development. Furthermore, since the development of motor fluctuations and dyskinesias is

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Therapeutic strategies to prevent and manage dyskinesias in Parkinson’s disease

strictly related to disease progression, the ability to prevent motor complications may be considered a suitable outcome measure for neuroprotection studies. Neurorestoration is also a potential strategy to contrast motor complications, as it may potentially restore dopaminergic activity, impaired by neurodegeneration. Unfortunately, clinical trials studying the implant of fetal dopamine cells in the striatum, reported severe worsening of dyskinesias in some patients [105].

Declaration of interest The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Affiliation

Manuela Pilleri MD & Angelo Antonini† MD † Author for correspondence Parkinson Disease and Movement Disorders Unit, “Fondazione Ospedale San Camillo” - I.R.C.C.S, Via Alberoni 7030126 Venice, Italy, Tel: +39 41 2207554, E-mail: [email protected]