ADMET considerations when prescribing novel therapeutics to treat restless legs syndrome.

Expert Opinion on Drug Metabolism & Toxicology

ISSN: 1742-5255 (Print) 1744-7607 (Online) Journal homepage: http://www.tandfonline.com/loi/iemt20

ADMET considerations when prescribing novel therapeutics to treat restless legs syndrome Stefano de Biase MD, Giovanni Merlino MD PhD, Simone Lorenzut MD, Mariarosaria Valente MD & Gian Luigi Gigli MD To cite this article: Stefano de Biase MD, Giovanni Merlino MD PhD, Simone Lorenzut MD, Mariarosaria Valente MD & Gian Luigi Gigli MD (2014) ADMET considerations when prescribing novel therapeutics to treat restless legs syndrome, Expert Opinion on Drug Metabolism & Toxicology, 10:10, 1365-1380 To link to this article: http://dx.doi.org/10.1517/17425255.2014.952629

Published online: 22 Aug 2014.

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Date: 11 October 2015, At: 01:34

Review

Expert Opinion on Drug Metabolism & Toxicology 2014.10:1365-1380.

ADMET considerations when prescribing novel therapeutics to treat restless legs syndrome 1.

Introduction

2.

Dopamine agonists

3.

a2d calcium channel ligands

4.

Other drugs

5.

Conclusion

6.

Expert opinion

Stefano de Biase, Giovanni Merlino, Simone Lorenzut, Mariarosaria Valente & Gian Luigi Gigli† †

University of Udine Medical School, Department of Experimental and Clinical Medical Sciences, Neurology Unit, Udine, Italy

Introduction: Restless legs syndrome (RLS) is a commonly occurring sensory motor disorder that might impair nocturnal rest causing decreased alertness, depression, reduced job performance and poor quality of life. In patients affected by severe RLS, a pharmacological treatment is mandatory. Areas covered: The present review is based on a search using PubMed from 1994 to 2014. It is focused on the Absorption, Distribution, Metabolism, Elimination and Toxicology (ADMET) characteristics of drugs currently used and under development for the treatment of RLS. Expert opinion: The drugs currently available for RLS treatment do not always provide an optimal control of symptoms. There is still need for effective and well-tolerated new drugs. Long-acting dopamine agonists showed better efficacy than short-acting compounds in the treatment of severe RLS. There seems to be an inverse relationship between the half-life of the compound and the development of augmentation. Monoamine oxidase B inhibitors could be good candidates for initial treatment of RLS, sparing stronger dopaminergic agents for later stages of the disease. Oxycodone-naloxone demonstrated a significant and sustained treatment effect for patients with severe RLS insufficiently treated with first-line drugs and could be used as a long-term treatment in severe RLS when alternative satisfactory drug regimens are unavailable. Keywords: absorption, augmentation, distribution, dopamine, elimination, metabolism, monoamine oxidase B inhibitors, oxycodone-naloxone, pharmacokinetic, toxicology Expert Opin. Drug Metab. Toxicol. (2014) 10(10):1365-1380

1.

Introduction

Restless legs syndrome (RLS) is a commonly occurring neurological sensory motor disorder [1]. The diagnosis of RLS is clinical. According to the 2012 revised criteria, diagnosis is based on the presence of the following five criteria: i) an urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs; ii) the urge to move begin or worsen during periods of rest or inactivity such as lying or sitting; iii) the urge to move is partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues; iv) the urge to move is worse in the evening or at night than during the day or only occur in the evening or night and v) the occurrence of the above features are not solely accounted for as symptoms primary to another medical or a behavioral condition [2]. Many patients with RLS (about 80%) present periodic involuntary and stereotyped jerks in the lower limbs known as periodic limb movements (PLMs), which may lead to sleep disruption [3]. Not surprisingly, the majority of RLS patients complain of insomnia and daytime sleepiness. RLS can have a serious impact on quality of life and RLS patients had significantly higher incidence of 10.1517/17425255.2014.952629 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted

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Article highlights. .

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Restless legs syndrome (RLS) is a sleep-related movement disorder characterized by an urge to move legs, usually accompanied by unpleasant sensation of the legs. The urge to move the legs begin or worsen during period of rest and is relieved by movement. The urge to move the legs is worse in the evening or at night. The drugs currently available for the treatment of the disease do not always allow to obtain an optimal control of symptoms, in particular in the long-term treatment. Long-acting dopamine agonists showed better efficacy than short-acting compounds in the treatment of severe RLS. There seems to be an inverse relationship between the half-life of the compound and the development of augmentation. Monoamine oxidase B inhibitors could be good candidates for initial treatment of RLS, sparing stronger dopaminergic agents for later stages of the disease. Oxycodone-naloxone demonstrated a significant and sustained treatment effect for patients with severe RLS insufficiently treated with first-line drugs, and could be used as a long-term treatment in severe RLS when alternative satisfactory drug regimens are unavailable and the severity of the symptoms warrants it.

This box summarizes key points contained in the article.

anxiety and depression compared with general population [4]. In addition, recent studies showed that RLS is able to induce cognitive dysfunction and to increase the risk of cardiovascular disease [5,6]. RLS is a common disorder affecting between 5 and 10% of the general population. RLS prevalence increases with age and is higher in women than in men [7]. RLS can be distinguished in primary and secondary forms. Primary RLS is characterized by a positive family history and younger age at onset (< 45 years old) [8]. To diagnose a primary form of RLS, all the conditions known to cause the disease should be excluded. RLS has been associated with iron deficiency, end-stage renal disease, diabetes, polyneuropathy, multiple sclerosis, Parkinson’s disease (PD), pregnancy and medications that can induce RLS (e.g., neuroleptics, selective serotonin reuptake inhibitors, lithium) [9-14]. Symptomatic forms of RLS may improve or disappear treating the underlying disorder. The underlying pathophysiology of RLS is not fully understood and the most accredited hypothesis recognizes an involvement of the diencephalic A11 dopaminergic neurons [15]. Dysfunctional dopaminergic modulation of neuronal excitability is generally thought to be the main underlying pathophysiological mechanism of RLS, as suggested by the well response to dopaminergic agents in RLS patients [16]. However, there is increasing evidence that the interaction with other transmitter systems, such as opioids and GABAergic system, as well as iron deficiency, is crucial for the manifestations of RLS [17]. 1366

Management of RLS involves both nonpharmacological and pharmacological approaches. Patients affected by mild and intermittent RLS may undergo nonpharmacological treatment. This approach consists of sleep hygiene, behavioral therapy and lifestyle interventions (avoiding caffeine and alcohol intake, heavy meals and drugs able to induce or to worsen RLS) [18]. Patients reporting frequent and severe RLS symptoms should be treated pharmacologically. There are multiple therapeutic options. Levodopa used occasionally or in low doses is an option in patients with mild symptoms, but because of its short half-life, patients often encounter symptoms rebound [19]. Moreover, the long-term use of levodopa often reveals a typical complication called augmentation. Augmentation is characterized by an earlier onset of symptoms, a shorter latency to onset of symptoms when at rest, an expansion of symptoms to the upper limbs and the trunk, an overall increase in the intensity of symptoms and a shorter effect of the medications [20]. Dopamine agonists are generally considered first-line treatment for RLS. Dopamine agonists are commonly well tolerated and effective in RLS even at low dosages and already during the first night of treatment [21]. Although less common than levodopa, patients treated with a dopamine agonist may develop augmentation. At the moment augmentation remains the main challenge in RLS therapy. If dopaminergic drugs are not well tolerated, or if loss of efficacy and augmentation develops, nondopaminergic drugs as adjunctive or substitute medications (i.e., gabapentin enacarbil, pregabalin, opioids and benzodiazepines) should be considered for the treatment of the disease. Considering that RLS is common among the elderly, and in light of an increasing aging population, it is possible that RLS prevalence will increase in the coming years. There is still need for more efficacious and safe medications for the treatment of the disease. The aim of this review is to describe the Absorption, Distribution, Metabolism and Toxicology (ADMET) characteristics of the most prescribed drugs and of novel therapeutics for the treatment of RLS. Among novel therapeutics we also consider drugs currently in development for RLS that could change the therapeutic approach to the disease in the next years. 2.

Dopamine agonists

The nonergot dopamine agonists pramipexole, ropinirole and rotigotine are approved by the FDA and the European Medicines Agency (EMEA) for the treatment of moderate to severe idiopathic RLS. 2.1

Pramipexole Overview

2.1.1

The chemical name of pramipexole dihydrochloride is (S)2-amino-4,5,6,7-tetrahydro-6 (propylamino) benzothiazole dihydrochloride monohydrate. Pramipexole is a nonergoline dopamine agonist with a high selectivity for D2 and D3

Expert Opin. Drug Metab. Toxicol. (2014) 10(10)

ADMET considerations when prescribing novel therapeutics to treat restless legs syndrome

receptors, with a 7- to 10-fold higher affinity to D3 receptors [22]. In 2006, pramipexole became the second drug approved by FDA for the treatment of moderate to severe idiopathic RLS. There are both immediate-release (IR) and extendedrelease (ER) formulations. Pramipexole ER is not approved by the FDA for RLS treatment. ADMET Pramipexole is given orally; pramipexole IR is rapidly absorbed from the gastrointestinal tract, with peak concentration (Tmax) attained within 2 h (6 h for ER formulations) and an absolute oral bioavailability > 90% [23]. The absorption of pramipexole is not affected by food, although Tmax is increased by 1 h when the drug is taken with a meal. The pharmacokinetic profile is linear with dose. Pramipexole is about 15% bound to plasma proteins and is widely distributed throughout the body, with an apparent volume of distribution (Vd) of about 500 l [24]. Pramipexole undergoes minimal hepatic biotransformation; > 90% is excreted unchanged in urine. Pramipexole can be safely used in patients with hepatic failure or in patients using multidrugs [25]. Pramipexole shows a half-life of 8 -- 12 h. Pramipexole half-life is prolonged to 36 h in patients with a creatinine clearance of 30 -- 50 ml/min. Renal insufficiency necessitates dosage adjustment [18]. Pramipexole is usually well tolerated, main side effects are nausea, headache, somnolence, dizziness, orthostatic hypotension and hallucinations. Patients should be warned about drowsiness and even falling asleep while engaged in activities of daily living [22]. Although rare, RLS patients taking pramipexole may experience compulsive behaviors [26]. Even if lower than levodopa, significant rates of augmentation (8 -- 56%) have been reported for pramipexole [27,28]. A recent paper by Silver et al. showed that risk of augmentation due to pramipexole persisted for up 10 years of treatment in RLS patients. In particular, the authors reported an annual augmentation rate of 7% [29]. Maestri et al., in a case series of 24 patients, demonstrated that the shift from IR to ER formulation may be an effective option to treat augmentation, sustaining the hypothesis that the half-life of the drug plays an important role in the mechanism of augmentation [30].


2.1.2

50% [32]. The absorption of ropinirole is not affected by food; however, when ropinirole is taken with a high-fat meal, its Tmax is increased by 2.5 h and its Cmax is decreased by ~ 25% [24,33]. Ropinirole ER reaches peak concentration in 6 -- 10 h. The Cmax for ropinirole ER is higher (15%) and Tmax delayed (~ 2 h) in the fed state compared with the fasted state. This small increase in Cmax and delay to Tmax are unlikely to be of clinical relevance; therefore, ropinirole ER can be taken without regard to food [34]. Ropinirole is 10 -- 40% bound to plasma proteins and is widely distributed throughout the body, with an apparent Vd of about 7.3 l/kg [35]. The elimination half-life is ~ 6 h. Ropinirole is cleared primarily by metabolism in the liver, with only 10% of an administered dose excreted as unchanged drug in the urine [35]. The predominant metabolite in urine (40%) is N-despropyl ropinirole followed by the carboxylic acid metabolite (10%) and the glucuronide of the hydroxy metabolite (10%). At clinically relevant doses, CYP1A2 is the major hepatic enzyme responsible for clearance of ropinirole. Inducers of this isozyme, such as omeprazole and smoke, and inhibitors such as fluvoxamine, mexiletine ciprofloxacin and norfloxacin, are able to alter ropinirole’s clearance [36]. No dosage adjustment is necessary in moderately renally impaired patients, whereas the pharmacokinetics of ropinirole have not been studied in hepatically impaired patients. Ropinirole should be titrated with caution in this population [34]. The most common side effects are nausea, dizziness, headache and somnolence. Most adverse events are mild or moderate in severity and are typically worse in the first weeks of treatment. As with pramipexole, patients should be aware that they may experience extreme daytime drowsiness or even fall asleep during their daily activities. Like pramipexole, ropinirole might cause compulsive behaviors in RLS patients [26]. In a recent study over a period of 66 weeks, Garcia-Borreguero et al. reported an incidence rate of augmentation of 3.5% in patients treated with ropinirole. Discontinuation of treatment occurred in 50% of all patients with augmentation [37]. 2.3

Rotigotine Overview

2.3.1 2.2

Ropinirole Overview

2.2.1

The chemical name of ropinirole hydrochloride is 4-(2-dipropylaminoethyl)-1,3-dihydroindol-2-one. Ropinirole is a nonergoline dopamine agonist that act at dopamine D2/D3 receptors. Its affinity and activity at the D3 receptor is 20 times higher than at the D2 [31]. Ropinirole was the first drug to receive FDA approval for the treatment of moderate to severe idiopathic RLS in 2005. There are both IR and ER formulations. Ropinirole ER is not approved for RLS by the FDA. ADMET After oral administration, ropinirole IR is rapidly absorbed and reaches Tmax in 1 -- 2 h. The oral bioavailability is about 2.2.2

The chemical name of rotigotine is S-(-)-2-(N-propyl-N2-thienylethylamino)-5-hydroxytetralin hydrochloride. Rotigotine demonstrates D1, D2 and D3 agonist activity, with an almost 15-fold higher affinity for the D2 receptor than for the D1 receptor. Rotigotine has also b2 adrenergic receptor antagonist activity and 5-HT1a agonist activity [38]. In 2012, rotigotine received FDA approval for the treatment of moderate to severe idiopathic RLS. ADMET Rotigotine is given as transdermal patches because of a low oral bioavailability due to an extensive first-pass effect. Rotigotine patch provides continuous drug delivery and stable plasma concentrations when the patch is replaced once every 2.3.2


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24 h [39]. Independently from patch size, ~ 46% of the applied dose is systematically absorbed [38]. As rotigotine is administered transdermally, food does not affect its absorption. Tmax typically occurs between 15 and 18 h and steady state plasma concentration is achieved within 2 -- 3 days [40]. Rotigotine is ~ 90% bound to plasma proteins; the apparent Vd is about 84 l/kg after repeated dose administration [38]. Rotigotine is extensively metabolized by conjugation and N-dealkylation. The major Phase I metabolites are N-desalkylation products (N-despropyl and N-desthinienylethyl rotigotine). These metabolites are conjugated to form glucuronides or sulfates and are excreted into urine and bile [41]. The main metabolites have no pharmacological activity. Rotigotine is primarily renally eliminated (~ 71%) as inactive metabolites, only a small amount of unconjugated rotigotine is excreted in urine (< 1%). The pharmacokinetic profile shows biphasic elimination with an initial half-life of 3 h, after patch removal plasma concentrations decrease with a terminal half-life of 5 -- 7 h [42]. Dose adjustment is not required in subjects with moderate impairment of hepatic function and in patients with mild to severe stages of chronic renal insufficiency, including patients requiring hemodialysis [42,43]. No data are available in patients with severe hepatic dysfunction, therefore rotigotine should be used with caution in this population. Rotigotine is usually well tolerated. The most common side effect is represented by application site reactions [44]. Other common side effects are those typical of dopaminergic drugs: nausea, somnolence, dizziness, orthostatic hypotension, headache. Augmentation is reported in patients receiving rotigotine for RLS. It was found to be clinically relevant in 1.5% of 748 patients treated with rotigotine for 6 months in a double-blind, randomized setting (compared with 0.5% of 214 patients on placebo) [45], and in 2.9% of 620 patients treated with rotigotine in a 1-year open-label setting [46]. Levodopa 2.4.1 Overview 2.4

The chemical name of levodopa is (-)-3-(3,4-dihydroxyphenyl)l-alanine, the immediate metabolic precursor of dopamine. Levodopa is almost invariably available in a fixed-combination formulation with a peripheral decarboxylase inhibitor (PDI), either carbidopa (1-methyldopahydrazine) or benserazide [(+)D, L-seryl-(2,3,4-trihydroxybenzyl)-hydrazine] that blocks the peripheral breakdown of levodopa [47]. Levodopa is mainly prescribed for the treatment of PD. It is rarely used for the treatment of RLS as on demand treatment for patients reporting intermittent symptoms. ADMET Levodopa is given orally and is rapidly absorbed in the proximal one-third of the small intestine (duodenum/jejunum). Bioavailability of levodopa is < 1% in the absence of benserazide or carbidopa, whereas it is > 90% in combination with PDI. Ingestion of food delays the appearance of 2.4.2

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levodopa in the plasma [48]. Certain amino acids can compete for absorption from the gut because levodopa is absorbed by an active saturable carrier system for large neutral amino acids [49]. Therefore, levodopa should be taken on an empty stomach at least 30 min before meals. The plasma half-life is about 2 h. Levodopa is transported across the blood--brain barrier by the large neutral amino acid system. In striatal neurons, levodopa is decarboxylated to dopamine and, then, stored and released from presynaptic neurons. Vd is about 1.6 l/kg. The protein binding in plasma is negligible. Levodopa is metabolized through two major pathways: decarboxylation and O-methylation. Aromatic amino acid decarboxylase converts levodopa to dopamine. The major end products of this pathway are homovanillic acid and dihydroxyphenylacetic acid. Catechol-O-methyltransferase (COMT) methylates levodopa to 3-O-methyldopa. This metabolite has a longer half-life (15 h) and accumulates to steady state plasma concentrations greater than those for levodopa [50]. When levodopa is co-administered with carbidopa the decarboxylase enzyme is inhibited so that metabolism via COMT becomes the dominant metabolic pathway. The dose of levodopa generally does not need be adjusted in patients with renal or hepatic disease; however, pharmacokinetic data in these populations are not available and therefore levodopa should be used with caution. The classical side effects reported are nausea, vomiting, headache, dizziness and fatigue. The most important complications in the treatment of RLS are rebound, tolerance and augmentation. Rebound phenomenon is due to the short half-life of levodopa. It is a worsening of symptoms at the end of a dosing period leading to late-night or morning recurrence of symptoms [51]. Rebound occurs in ~ 25% RLS patients [52]. Tolerance is the need for larger dosage to maintain the original effect. Finally, augmentation may occur in up to 80% of patients receiving daily dosing of levodopa [53]. 3.

a2d calcium channel ligands

3.1

Gabapentin and gabapentin enacarbil Overview

3.1.1

Gabapentin is a water-soluble 1-(aminomethyl)-cyclohexaneacetic acid and is a structural analog of the inhibitory neurotransmitter GABA. The chemical name of gabapentin enacarbil is ((±)-1-([a-isobutanoyloxyethoxy) carbonyl]-aminomethyl1)-1-cyclohexane acetic acid). It is a prodrug of gabapentin designed to overcome the pharmacokinetic limitations of gabapentin [54]. Gabapentin, even if was designed as an analog of GABA, does not interact directly with GABA receptors, whereas it interacts with a2d-1 subunit of the voltagedependent calcium channel [55]. Gabapentin can be a good choice for patients who have RLS with neuropathic pain and an alternative choice for whom dopamine agonist are not effective or tolerated. In 2011, gabapentin enacarbil has been



approved by the FDA (not by EMEA) for the treatment of moderate to severe idiopathic RLS. ADMET Gabapentin and gabapentin enacarbil ER tablets are given orally. Absorption of gabapentin is mediated by a low capacity nutrient transporter (an L-type amino acid transporter) located in a narrow region of the small intestine [56]. Gabapentin absorption is saturated at therapeutic doses; therefore, gabapentin exhibits dose-dependent bioavailability. At subtherapeutic doses, 60% of gabapentin is orally bioavailable, but at higher doses its bioavailability drops to 35% or less. Tmax is attained within 2 -- 3 h. Gabapentin enacarbil is absorbed by highcapacity nutrient transporters that are broadly distributed in the gastrointestinal system (monocarboxylate transporter 1 and sodium-dependent multivitamin transporter). The absorption of gabapentin enacarbil shows no evidence of saturation and the exposure to gabapentin is dose-proportional [57]. Moreover, the presence of food in intestine significantly enhances gabapentin exposure from the ER formulation of the prodrug. Clinical trials showed that the Tmax of gabapentin enacarbil ER is 8.40 and 5.08 h with or without food, respectively. Bioavailability is 75% in the fed state, while under fasting conditions about 45% [58]. Gabapentin enacarbil undergoes extensive first-pass hydrolysis by nonspecific human carboxylesterases primarily in enterocytes (~ 80%), and to a lesser extent in the liver (~ 10%), to form gabapentin [57]. Hydrolysis of gabapentin enacarbil yields gabapentin and equimolar amounts of isobutyric acid, acetaldehyde and carbon dioxide. Plasma protein binding of gabapentin is negligible. The apparent Vd of gabapentin is 58 l, whereas for gabapentin enacarbil is 76 l. Gabapentin is excreted in the urine without further metabolism, the elimination half-life is about 5 -- 7 h. Dose adjustment is required in patients with renal impairment [59]. Gabapentin and gabapentin enacarbil are usually well tolerated. The most important side effects are dizziness, headache, somnolence and nausea. Patients should be cautioned to not drive until they gain experience with these drugs. Augmentation is not a known side effect and therefore are used as alternative medications when augmentation develops with dopamine agonists.


3.1.2

3.2

Pregabalin Overview

3.2.1

The chemical name of pregabalin is (S)-3-(aminomethyl)5-methylhexanoic acid. Pregabalin is an a2d ligand, an auxiliary protein associated with voltage-gated calcium channels, reducing calcium influx at nerve terminals [60]. Although not FDA approved, pregabalin is effective for treatment of RLS symptoms and should be considered as initial treatment in patients with comorbid insomnia, anxiety or neuropathic pain. A recent study comparing pramipexole and pregabalin over 52 weeks has shown lower rates of augmentation for pregabalin, with similar or better long-term efficacy [61].

ADMET Pregabalin is given orally and is rapidly absorbed from the gastrointestinal tract, with Tmax achieved within 2 h and an absolute bioavailability > 90% [62]. The nonsaturable absorption at clinically relevant dosages results in linear pharmacokinetics. Administration of pregabalin with food reduces the maximum plasma drug concentration (Cmax) by 25 -- 31% and Tmax increases by 1 h. However, the extent of pregabalin bioavailability is not affected by food, therefore pregabalin can be given without regard to meals. Pregabalin has a negligible protein binding and the estimated Vd is ~ 0.5 l/kg [63]. Pregabalin is eliminated by renal excretion as unchanged drug. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, account for < 1% of the dose. The plasma half-life is about 6 h. Dosage adjustment is necessary in patients with renal impairment [64]. Dizziness and somnolence are the most common side effects, but are usually dose-dependent and are typically worse in the first weeks of treatment [65]. 3.2.2

4.

Other drugs

In this section, we wanted to evaluate the ADMET characteristics of drugs that are currently under development for RLS or drugs that are approved for other indications, but have shown some efficacy in RLS treatment. 4.1

Bupropion Overview

4.1.1

The chemical name of bupropion is (±)-1-(3-chlorophenyl)2-[(1,1-dimethylethyl)amino]-1propanone hydrochloride. The precise mechanism of action is unknown, although bupropion selectively inhibits dopamine and norepinephrine reuptake. Due to the dopaminergic effects, bupropion may be a treatment option in RLS [66]. Case reports have documented beneficial effects of bupropion in the management of RLS symptoms and PLMs reduction in depressed patients [66,67]. In a recent Phase II/III trial, 29 participants with moderate to severe RLS received 150 mg sustained-release bupropion once daily, and 31 control participants received placebo. Bupropion significantly improved the symptoms of RLS compared with placebo at 3 weeks. The difference at 6 weeks was not statistically significant because of improvements in the placebo group; however, the improvements in the bupropion group persisted through 6 weeks. Bupropion did not exacerbate the symptoms of RLS, making it a possible therapeutic option for treating depression in individuals with RLS [68]. ADMET Bupropion is given orally and it is available in three formulations: IR, sustained release (SR) and bupropion extended/ modified release (XL). Bupropion is rapidly absorbed with Tmax of 1.5 h for IR tablet and 3 and 5 h for SR and XL 4.1.2


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formulations, respectively [69]. Absorption of bupropion is nearly 100%. The absorption is not significantly affected by the presence of food. Bupropion is ~ 84% bound to plasma protein and the estimated Vd is ~ 2000 l [70]. Bupropion is extensively metabolized in the liver, mainly by CYP2B6 isoenzyme to hydroxybupropion, the primary active metabolite. Cmax values of hydroxybupropion are four to sevenfold those of bupropion, whereas total exposure to hydroxybupropion (based on AUC) is 10-fold that of the parent drug [71]. A potential for interactions with drug metabolized by CYP2B6 (e.g., cyclophosphamide, clopidogrel, ticlopidine) exists. Instead, other two active metabolites threohydrobupropion and erythrohydrobupropion are formed by reduction of the carbonyl group [72]. The mean elimination half-life of bupropion is 20 -- 21 h. Hydroxybupropion also has a mean half-life of 20 h, whereas threohydrobupropion and erythrohydrobupropion have longer half-life of 33 and 37 h, respectively. After an oral dose of 14C-bupropion, radioactivity was recovered predominantly as metabolites (only 0.5% as unchanged drug), mostly in the urine (87%) and to a lesser extent in the faeces (10%) [70]. Dose adjustment is required in patients with mild to moderate hepatic impairment, whereas bupropion should be used with extreme caution in patients with severe hepatic impairment. Bupropion should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered as bupropion and its metabolites may accumulate in such patients [70]. The most common side effects are headache, nausea, insomnia, dry mouth and agitation. The most medically important serious adverse event reported with bupropion is seizure, which occurs infrequently (< 1%). The risk is dosedependent and also related to patients factors (e.g., history of trauma or seizures), clinical situations (e.g., excessive use of alcohol, sedatives, stimulants) and concomitant medications [69]. 4.2

Istradefylline Overview

4.2.1

The chemical name of istradefylline is (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methyl-3,7-dihydro- 1H-purine-2,6-dione). Istradefylline is a selective adenosine A2A receptor antagonist [73]. Adenosine A2A receptors are specifically localized in the striatum, where they are coexpressed with dopamine D2 receptors in the GABAergic striatopallidal neurons. Co-localization of adenosine A2A and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The experimental data prove that the best improvement of mobility in patients with PD could be achieved with simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A2A receptors [74]. In a single-center prospective trial, istradefylline appeared to have clinical benefit in some patients with moderate to severe RLS who received istradefylline 80 mg once daily for 6 weeks [75]. Three of five evaluable patients 1370

experienced an improvement in symptoms, as measured by the PLM index and International Restless Legs Syndrome Study Group (IRLSSG) rating scale. Istradefylline was generally well tolerated, clinical worsening of insomnia occurred in two patients. ADMET Istradefylline is given orally. In rats, it showed high bioavailability following intraperitoneal application (97.2%) and moderate occurrence after oral intake (60.8%) [76]. In humans, pharmacokinetic studies demonstrate that istradefylline exhibits multiphasic disposition with a terminal elimination half-life of 70 -- 118 h and a Tmax of 2 -- 5 h [77]. Dose proportional increases in AUC and Cmax were seen following administration of sequential ascending doses of istradefylline in healthy subjects. The apparent Vd is ~ 500 l and istradefylline is about 95% bound to plasma proteins [78]. In vivo and in vitro studies have found that istradefylline mildly inhibits and is primarily metabolized by CYP3A4 and is an inhibitor of the efflux transporter P-glycoprotein [79]. Urinary recovery experiments suggest that the renal route of elimination is not a major pathway for drug clearance that is mainly excreted in faeces. At clinically relevant doses for patients with PD, the most common reported side effects include nausea, dizziness, insomnia, constipation and dyskinesia [80]. 4.2.2

4.3

Oxycodone-naloxone Overview

4.3.1

The chemical formula of oxycodone is 14-hydroxy-7,8-dihydrocodeinone. Oxycodone is a mu receptor opioid agonist whose principal therapeutic action is pain relief, whereas naloxone acts locally on the gut as an opioid receptor antagonist counteracting the opioid-induced constipation [81]. In a recent study, Trenkwalder et al. published the result of a Phase III trial that investigated the efficacy and safety of prolonged release oxycodone--naloxone (OXN PR) for patients with severe RLS inadequately controlled by previous, mainly dopaminergic, treatment [82]. The study consisted of a 12-week randomized, double-blind, placebo-controlled trial and 40-week open-label extension phase. A total of 306 patients were randomly assigned to OXN PR twice daily or placebo in a double-blind phase with 197 patients then entering a 40 weeks open-label extension in which all patients took OXN PR. The mean change of the IRLSSG rating scale score at 12 weeks was -16.5 ± 11.3 in the OXN PR group and -9.4 ± 10.9 in the placebo group (p < 0.0001) with maintenance of long-term improvement after the extension phase (mean sum score was 9.7 ± 7.8). OXN PR may be useful for patients with severe RLS who had no benefit with firstline drugs. ADMET Following oral administration, oxycodone displays high oral bioavailability (60 -- 87%). Unlike morphine, oxycodone 4.3.2




does not undergo high first-pass metabolism, possibly due to the protective effect of a methoxy group in the 3 position, which is a site of morphine glucuronidation [81]. The absorption profile of the prolonged-release tablet is best described using a bi-exponential absorption model, with a rapid initial absorption component (t1/2 abs 37 min) accounting for 38% of the available dose followed by a slow absorption phase (t1/2 abs 6.2 h) accounting for 62% of the available dose [83]. Naloxone possess low bioavailability after oral administration (< 3%) because of extensive first-pass hepatic metabolism. As a result, naloxone acts almost exclusively on opioids receptors in the gastrointestinal tract [84]. A pharmacokinetic study demonstrated that coadministration of oxycodone PR and naloxone PR in fixed doses does not significantly affect the bioavailability of either of its constituents. Food has no significant effect on the extent of absorption of oxycodone. Oxycodone is about 45% bound to plasma proteins (mainly albumin) and is widely distributed throughout the body, with an apparent Vd of about 2 -- 3 l/kg. Oxycodone is metabolized mostly in the liver to inactive noroxycodone via CYP3A4 and to a lesser extent to active oxymorphone through CYP2D6; both noroxycodone and oxymorphone are subsequently converted to noroxymorphone via CYP2D6 and CYP3A4, respectively [85]. The elimination half-life of oxycodone is ~ 4.5 h. Oxycodone is mainly excreted in urine after metabolism with limited amounts excreted as unchanged drug [86]. Oxycodone elimination is impaired with renal failure due to an increased Vd and reduced clearance. Patients with impaired renal function (creatinine clearance £ 60 ml/min) and patients with mild to moderate hepatic dysfunction showed peak plasma oxycodone and noroxycodone concentrations 50 and 20% higher, respectively, than normal subjects. OXN PR doses need to be reduced in patients with renal and end-stage liver diseases [84]. Common side effects with OXN PR treatment include constipation, dizziness, somnolence, pruritus, headache and fatigue. No augmentation was reported in RLS patients [82].

ADMET Rasagiline is rapidly absorbed by the gastrointestinal tract and the absolute bioavailability is ~ 36% [90]. Tmax is achieved within 0.5 -- 0.7 h after administration. Food has not been found to affect Tmax of rasagiline, although a high-fat meal was found to reduce Cmax and AUC by -60 and 20%, respectively. Because AUC is not substantially affected, rasagiline may be administered with or without food [91]. The mean Vd in patients with PD is 182 -- 243 l; plasma protein binding ranges from 60 to 70% [92]. Rasagiline undergoes almost complete biotransformation in the liver, biotransformation involves two main pathways: Ndealkylation and/or hydroxylation to yield 1aminoindan, 3-hydrox y-N-propargyl-1 aminoindan, and 3-hydroxy1-aminoindan. In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the CYP system, with CYP1A2 being the major isoenzyme involved in rasagiline metabolism [87]. Coadministration of rasagiline and ciprofloxacin (CYP1A2 inhibitor) increases the AUC of rasagiline by 83%. Thus, potent CYP1A2 inhibitors (e.g., cimetidine, ciprofloxacin, fluvoxamine) may significantly increase the rasagiline AUC and should be administered with caution [91]. The mean terminal half-life is 0.6 -- 2 h. Elimination of rasagiline is primarily via urine, where < 1% is excreted as unchanged drug [92]. Caution should be used when initiating rasagiline in patients with mild hepatic impairment, as rasagiline’s AUC and Cmax are increased in these patients by 80 and 38%, respectively [91]. In patients with moderate or severe hepatic impairment, rasagiline therapy is not recommended. No dose adjustment is needed for patients with mild and moderate renal impairment. Data are not available for patients with severe renal impairment. Rasagiline is usually well tolerated and side effects are usually mild or moderate. The most common adverse effects are headache, dyspepsia, somnolence, dizziness and depression [87]. 4.4.2

4.5

Safinamide Overview

4.5.1 4.4

Rasagiline Overview

4.4.1

The chemical name of rasagiline is [N-propargyl-l(R)-aminoindan]. Rasagiline is a selective, irreversible monoamine oxidase B (MAO-B) inhibitor, leading to an increase in striatal extracellular dopamine levels [87]. Oral rasagiline as monotherapy or as adjunctive therapy to levodopa provides a useful option in the treatment of adult patients with PD. To our knowledge, there is only a case report describing rasagiline as a useful therapeutic option for RLS, in a patient already affected by PD [88]. A Phase II/III trial to determine if rasagiline at a dosage of 1 mg/day, is effective and safe for the treatment of idiopathic RLS started in 2010. To our knowledge, no trial results have been reported [89].

The chemical name of safinamide is (S)-(+)-2-[4-(3-fluorobenzyloxybenzylamino)propanamide] methanesulfonate. Safinamide is a water-soluble, orally active a-amino-amide derivative with both dopaminergic and non-dopaminergic mechanisms of action. It is a potent, highly selective and reversible inhibitor of MAO-B. It also blocks voltagedependent sodium channels, calcium channels and reduces glutamate release in vitro [93]. For all these mechanism of action, safinamide was initially studied for the treatment of epilepsy, and successively shifted to the treatment of PD. In a small Phase II single-center pilot trial, safinamide significantly improved symptoms of RLS. A total of 10 patients with RLS were enrolled and each patient received safinamide 100 mg/day orally at bedtime for 2 weeks. Newron announced that safinamide resulted in a


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significant improvement in all efficacy parameters studied and sleep fragmentation was positively influenced [94]. ADMET Safinamide is given orally. Preclinical pharmacokinetic studies performed in mice, rats and monkeys demonstrated a high oral bioavailability (80 -- 92%) [93]. In humans the pharmacokinetic profile of safinamide was linear and directly proportional to the administered dose. Rapid absorption was noted, with Tmax at 2 -- 4 h. Food intake delays the absorption of the drug (Tmax ~ 5 h), but the extent of absorption is not affected by food [95]. Safinamide is about 92% bound to plasma proteins; the apparent Vd is about 150 l [96]. Safinamide appears to be extensively biotransformed. Unchanged safinamide in urine and faeces respectively accounted for 7 -- 10% and 1.5% of the administered dose. After a single oral administration of safinamide, the main components observed in plasma were the unchanged drug and two metabolites, the ‘safinamide acid’ and the Ndealkylated acid. In urine, the main metabolites were the safinamide acid and the glucuronide of the N-dealkylated acid. Based on plasma and urine data, the main Phase I enzymes involved in human safinamide metabolism are amide hydrolases and MAO-A. The main Phase II enzyme involved is a glucuronyltransferase [96]. The half-life of safinamide is about 24 h, allowing a once-a-day dosing [97]. In vitro studies showed that safinamide has no inhibiting activity on various CYP isoenzymes involved in the metabolism of drugs, except CYP1A1/2, but this is at a negligible level at therapeutic doses [95]. Safinamide was well tolerated in human studies. The most common side effects were nausea, dyspepsia, headache and dizziness [95]. The ADMET characteristics of all the drugs analyzed are summarized in Table 1. Data on drugs in special populations (hepatic and renal impairment) are summarized in Tables 2 and 3.


4.5.2

5.

Conclusion

RLS is a disease for which there are already some drugs approved by FDA and EMEA, that is, ropinirole, pramipexole, rotigotine and gabapentin enacarbil (the last one is approved only by FDA). Although initially effective, longterm dopaminergic treatment can result in loss of efficacy, difficulties with tolerability, or augmentation, necessitating a change of drug regimen. Therefore, in particular for the long-term treatment and for the most severe forms of the disease, there is still need of new drugs. In summary, this review analyzed the ADMET characteristics of drugs currently approved for RLS, drugs not approved for RLS that demonstrated some efficacy in the treatment of RLS and drugs currently under development for RLS treatment. 1372

Several drugs can be used for RLS treatment; ADMET characteristics and patients comorbidities allow the physician to choose which one can be mostly effective and tolerated. 6.

Expert opinion

RLS is a neurologic disorder that affects ~ 10% of Caucasian populations. RLS is common among the elderly, and in light of an increasing aging population, it is possible that RLS prevalence will increase in the coming years. The primary goal of RLS treatment is to reduce or eliminate symptoms and improve patient sleep and quality of life. The drugs currently available for the treatment of the disease do not always allow to obtain an optimal control of symptoms, in particular in the long-term treatment. Augmentation is the main complication of long-term dopaminergic treatment and frequently requires a reduction of current dopaminergic dose or a switch to nondopaminergic medications. Differently from ropinirole and pramipexole that are given orally, rotigotine is given as transdermal patches. The patch allows once-daily administration, improves compliance in patients that have swallowing difficulties and gives continuous and stable dopaminergic stimulation over 24 h compared with the more pulsatile application of oral therapies. Not surprisingly, long-acting compounds showed better efficacy results in patients with severe RLS symptoms. In a recent study, Maestri et al. demonstrated that there is an inverse relationship between the half-life of the compound and the development of augmentation. In all 24 patients, the shift from IR dopamine agonist to pramipexole ER was effective for augmentation and improved RLS symptoms with long-term sustained results [30]. However, the efficacy and tolerability of ER dopamine agonists need to be confirmed in further longer-term studies. In addition, head-to-head comparisons among dopamine agonists are needed to confirm the findings regarding the relative efficacy and safety profile of these drugs. Rasagiline and safinamide act as MAO-B inhibitors, inhibiting the breakdown of dopamine in the brain. If currently ongoing trial will confirm the efficacy of MAO-B inhibitors in the treatment of RLS, although they are clearly inferior to dopamine agonists for the dopaminergic effect, they could be good candidates for initial treatment of RLS. This choice may be advantageous sparing stronger dopaminergic agents for later stages of the disease. Depression is common in RLS and most commonly prescribed antidepressants exacerbate the symptoms of RLS. Bupropion have shown to not exacerbate RLS symptoms, making it a possible therapeutic option for treating depression in individuals with RLS. Further studies are needed to clarify if bupropion is effective as a primary treatment for moderate to severe RLS. Alpha-2 delta ligands represent at the moment the most important alternative to dopamine agonists, in particular when augmentation occurs. The use of alpha-2 delta ligands should be considered for initial treatment of patients with



Oral administration; Tmax 1 -- 2 h (6 -- 10 h for ER formulations); bioavailability 50%. The absorption is not affected by food [24,32,33]

Transdermal administration, once daily. Tmax 15 -- 18 h; approximately half of the administered dose is systemically absorbed. As it is given transdermally, food does not affect its absorption [40] Oral administration; Tmax 2 h; bioavailability > 90% in combination with PDI. It is absorbed by an active saturable system for large neutral amino acids. Should be taken on an empty stomach [48,49]

Ropinirole

Rotigotine

Apparent Vd 1.6 l/kg. The protein binding is negligible [48,50]

Apparent Vd 84 l/kg. It is 90% bound to plasma proteins [38]

Apparent Vd 7.2 l/kg. It is 10 -- 40% bound to plasma proteins [35]

Apparent Vd 7.1 l/kg. It is 15% bound to plasma proteins [24]

Distribution

It is extensively metabolized by the liver. The major metabolic pathways are N-despropylation and hydroxylation to form the inactive N-despropyl metabolite and hydroxy metabolites. The hydroxy metabolite of ropinirole is rapidly glucuronidated [35,36] It is extensively metabolized by conjugation and N-dealkylation. N-despropyl and N-desthinienylethyl rotigotine are conjugated to glucuronides or sulfates [41] It is metabolized through two major pathways: decarboxylation and O- methylation. Metabolites are homovanillic acid, dihydroxyphenylacetic acid and 3-Omethyldopa [50]

Minimal hepatic biotransformation [22]

Metabolism

The metabolites formed are excreted in the urine. T1/2 is 1 -- 2 h [48,50]

It’s excreted in urine (~ 71%) and bile. < 1% is excreted unchanged in urine. Initial half-life of 3 h, after patch removal terminal half-life of 5 -- 7 h [42]

It is excreted in the urine. Only 10% is excreted unchanged. T1/2 is 6 h [35]

It is > 90% excreted unchanged in urine. T1/2 is 8 -- 12 h [22]

Elimination

Main side effects: rebound, tolerance and augmentation. Other side effects: nausea, vomiting, dizziness, headache, fatigue, postural hypotension, cardiac arrhythmias and psychological effects [51-53]

Main side effects: application site reactions. Other side effects: nausea, vomiting, headache, somnolence, dizziness and asthenia [44-46]

Main side effects: nausea, fatigue, dizziness, headache, nasopharyngitis. Other side effects: orthostatic hypotension, hallucinations, insomnia, confusion, compulsive behaviors [22,26-29] Main side effects: nausea, dizziness, headache, and somnolence. Other side effects: asthenia, orthostatic symptoms, confusion, compulsive behaviors, hallucination and abnormal vision [26,37]

Toxicology

ADMET: Absorption, Distribution, Metabolism, Elimination and Toxicology; ER: Extended-release; IR: Immediate-release; MAO-A: Monoamine oxidase-A; PDI: Peripheral decarboxylase inhibitor; SR: Sustained-release; Vd: Volume of distribution; XL: Extended/modified release.

Levodopa

Oral administration; Tmax 2 h (6 h for ER formulations); bioavailability > 90%. The absorption is not affected by food [23]

Pramipexole

Absorption

Table 1. ADMET characteristics of drugs used and under development for RLS.



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Oral administration; bi-exponential absorption with a rapid component (t1/2 abs 37 min) accounting for 38% of the dose and a slow absorption phase (t1/2 abs 6.2 h) accounting for 62% of the available dose; oxycodone bioavailability 60 -- 87%. It can be given without regards to meals [81-84]

Oxycodone is metabolized mostly in the liver to inactive noroxycodone via CYP3A4 and to a lesser extent to active oxymorphone through CYP2D6; both noroxycodone and oxymorphone are subsequently converted to noroxymorphone via CYP2D6 and CYP3A4, respectively [85]

Apparent Vd 2 -- 3 l/kg. It is 45% bound to plasma proteins [81,85]


It is metabolized mainly by CYP2B6 to hydroxybupropion. Other two active metabolites threohydrobupropion and erythrohydrobupropion are formed by reduction of the carbonyl group [71,72] It is metabolized by the liver, mainly by CYP3A4 isoenzyme [79]

The N-methylated derivative of pregabalin, the major metabolite find in urine, account for < 1% of the dose [60]

Hydrolysis of gabapentin enacarbil produces one molecule each of carbon dioxide, acetaldehyde, and isobutyric acid [58,59]

Metabolism


Apparent Vd 0.5 l/kg. The protein binding is negligible [63]

Apparent Vd 1.1 l/kg. The protein binding is negligible [57,58]

Distribution

It is mainly excreted in urine, with limited amounts of oxycodone excreted as unchanged drug. T1/2 is 4.5 h [86]

It is mainly excreted in faeces. T1/2 is 70 -- 118 h [77]

The metabolites formed are mainly excreted in the urine (only 0.5% as unchanged drug). T1/2 is 20 -- 21 h [70]

It’s almost entirely excreted unchanged in the urine. T1/2 is 6 h [63]

Urinary excretion. T1/2 is 5 -- 7 h [58,59]

Elimination

Main side effects: nausea, dizziness, insomnia, constipation and dyskinesia [80] Main side effects: constipation, dizziness, somnolence fatigue, headache. Other side effects: pruritus, nausea, dyspepsia, blurred vision [81,82]

Main side effects: nausea, dizziness somnolence and headache. Other side effects: blood count abnormalities, rash, weight gain, peripheral edema [57,58] Main side effects: dizziness, somnolence. Other side effects: blurred vision, ataxia, weight gain, dry mouth, peripheral edema [60,65] Main side effects: headache, nausea, insomnia, dry mouth and agitation. Other side effects: constipation, excessive sweating, blurred vision, appetite increase [69,70]

Toxicology


Oxycodonenaloxone

Istradefylline

Oral administration; Tmax 1.5 h for IR tablet; 3 and 5 h for SR and XL formulations, respectively. Absorption has been found to be nearly 100%. It can be given without regards to meals [69] Oral administration; Tmax 2 -- 5 h; bioavailability 60.8% (in rats) [76]

Oral administration; Tmax 2 h; bioavailability > 90%. It can be given without regards to meals [62]

Pregabalin

Bupropion

Oral administration; Tmax 5 -- 8 h; bioavailability is 75% in the fed state, under fasting conditions 45% [57,58]

Gabapentin enacarbil

Absorption

Table 1. ADMET characteristics of drugs used and under development for RLS (continued).


S. de Biase et al.


Oral administration; Tmax 2 -- 4 h; bioavailability 80 -- 92%. Food intake delays the absorption of the drug, but the extent of the absorption is not affected [95]

Safinamide


Apparent Vd 3 l/kg. It is 60 -- 70% bound to plasma proteins [92]

Distribution

[95,96]

It is extensively metabolized in the liver, biotransformation involves two main pathways: N-dealkylation and/or hydroxylation to yield 1aminoindan, 3-hydrox yN-propargyl-1aminoindan, and 3-hydroxy1-aminoindan. CYP1A2 is the major isoenzyme involved in rasagiline metabolism [87] Safinamide is extensively biotransformed. The main Phase I enzymes involved in human safinamide metabolism are amide hydrolases and MAO-A. The main Phase II enzyme involved is a glucuronyltransferase

Metabolism

Unchanged safinamide in urine and faeces respectively account for 7 -- 10 and 1.5% of the administered dose T1/2 is 24 h [95,96]

It is mainly excreted in urine, with < 1% excreted as unchanged drug. T1/2 is 0.6 -- 2 h [92]

Elimination

Main side effects: nausea, dizziness dyspepsia and headache [95]

Main side effects: headache, somnolence, dyspepsia, dizziness. Other side effects: depression, flu syndrome, arthralgia [87]

Toxicology


Oral administration; Tmax 0.5 -- 0.7 h; bioavailability 36%. It can be given without regards to meals [90,91]

Rasagiline

Absorption

Table 1. ADMET characteristics of drugs used and under development for RLS (continued).



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Table 2. RLS drugs in patients with hepatic impairment. Pramipexole Ropinirole Rotigotine

Levodopa Gabapentin enacarbil Pregabalin Bupropion Istradefylline


Oxycodone-naloxone Rasagiline Safinamide

No dosage adjustment is needed in hepatic impaired patients [25] It is metabolized through hepatic P450 isoforms, therefore should be used with caution in this population [34] No dose adjustment is required in subjects with moderate hepatic impairment. No information is available in subjects with severe hepatic function. It’s advisable to use rotigotine with caution in patients with severe hepatic impairment [42] Should be administered cautiously in patients with severe hepatic disease [47,48] No dosage adjustment is needed in hepatic impaired patients [58] No dosage adjustment is needed in hepatic impaired patients [60] Dose adjustment is required in patients with mild to moderate hepatic impairment. It should be used with extreme caution in patients with severe hepatic impairment [70] No definitive data available, but it is metabolized through hepatic P450 isoforms, therefore should be used with caution in this population Dosage adjustment is needed in patients with severe hepatic impairment [84] Should be administered cautiously in patients with mild hepatic disease. It is not recommended in patients with moderate or severe hepatic impairment [87] No definitive data available, but it is metabolized through hepatic P450 isoforms, therefore should be used with caution in this population

Table 3. RLS drugs in patients with renal impairment. Pramipexole Ropinirole Rotigotine Levodopa Gabapentin enacarbil Pregabalin Bupropion Istradefylline Oxycodone-naloxone Rasagiline Safinamide

Dosage adjustment is required in patients with moderate renal impairment. Pramipexole is not recommended in patients with CrCl < 30 ml/min or on hemodialysis [18] No dosage adjustment is needed in moderately renally impaired patients. Ropinirole use has not been studied in patients with severe renal impairment [34] Patients with renal impairment don’t require dosage adjustment [43] Should be administered cautiously in patients with severe renal disease [47,48] Dosage adjustment is required in patients with moderate renal impairment. Gabapentin enacarbil is not recommended in patients with CrCl < 30 ml/min or on hemodialysis [59] Dosage adjustment is necessary in patients with renal impairment. For patients on hemodialysis dosing must be modified [64] Dosage adjustment is necessary in patients with renal impairment (CrCl < 90 ml/min) [70] No definitive data available, but the renal route is not a major pathway for drug clearance Should be administered cautiously in patients with renal impairment [84] No dosage adjustment is needed in moderately renally impaired patients. Rasagiline use hasn’t been studied in patients with severe renal impairment [87] No definitive data available, but should be administered cautiously in patients with severe renal disease

CrCl: Creatinine clearance.

comorbid insomnia or anxiety, severe sleep disturbance (disproportionate to other RLS symptoms) or comorbid pain syndrome [98,99]. A recent study comparing pramipexole and pregabalin over 52 weeks has shown lower rates of augmentation for pregabalin, with similar or better long-term efficacy [61]. Further longer-term comparative studies are needed, even considering ER dopamine agonists against alpha-2 delta ligands. Opioids seem to be effective in advanced and severe forms of RLS. OXN PR demonstrated a significant and sustained treatment effect for patients with severe RLS insufficiently treated with first-line drugs. In a 10-year longitudinal assessment, methadone showed neither augmentation with continued efficacy after the first year of treatment. About 15% of the 76 patients who were started on methadone in the first year discontinued due to lack of efficacy or side effects (e.g., sedation, depression and anxiety), but none discontinued it after 1376

the first year [29]. When alternative satisfactory drug regimens are unavailable and the severity of the symptoms warrants it, opioids could be used as a long-term treatment for RLS. Dopamine agonists represent at the moment the first-line treatment of primary RLS, however we cannot exclude that this indication could change in the future if supported by adequate studies.

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.



Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

..


2.

3.

4.

.

5.

.

6.

..

7.

8.

9.

10.

Trenkwalder C, Paulus W, Walters AS. The restless legs syndrome. Lancet Neurol 2005;4:465-75 Review that covers clinical and pathophysiological features of restless legs syndrome (RLS). Revised IRLSSG Diagnostic Criteria for RLS. 2012. Available from: http://irlssg.org/diagnostic-criteria/ [Last accessed 10 June 2014] Montplaisir J, Boucher S, Poirier G, et al. Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov Disord 1997;12:61-5 Allen R, Walters A, Montplaisir J, et al. Restless legs syndrome prevalence and impact, REST general population study. Arch Intern Med 2005;165:1286-92 The largest paper on the prevalence of RLS in the general population. Pearson VE, Allen RP, Dean T, et al. Cognitive deficits associated with restless legs syndrome (RLS). Sleep Med 2006;7:25-30 Correlation between RLS and cognitive impairment. Winkelman JW, Shahar E, Sharief I, Gottlieb DJ. Association of restless legs syndrome and cardiovascular disease in the Sleep Heart Health Study. Neurology 2008;70:35-42 Correlation between RLS and cardiovascular diseases. Merlino G, Valente M, Serafini A, Gigli GL. Restless legs syndrome: diagnosis, epidemiology, classification and consequences. Neurol Sci 2007;28(Suppl 1):37-46 Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of RLS identifies common variants in three genomic regions. Nat Genet 2007;39:1000-6 Earley CJ, Connor JR, Beard JL, et al. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 2000;54:1698-700 Gigli GL, Adorati M, Dolso P, et al. Restless legs syndrome in end-stage

..

11.

.

renal disease. Sleep Med 2004;5:309-15 Association between RLS and end-stage renal disease.

20.

Garcia-Borreguero D, Allen RP, Kohnen R, et al. International Restless Legs Syndrome Study Group. Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from a World Association of Sleep MedicineInternational Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute. Sleep Med 2007;8:520-30

Merlino G, Fratticci L, Valente M, et al. Association of restless legs syndrome in type 2 diabetes: a case-control study. Sleep 2007;30:866-71 Correlation between RLS and type 2 diabetes.

12.

Manconi M, Ferini-Strambi L, Filippi M, et al. Multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS study. Sleep 2008;31:944-52

21.

Merlino G, Dolso P, Canesin R, et al. The acute effect of a low dosage of pramipexole on severe idiopathic restless legs syndrome: an open-label trial. Neuropsychobiology 2006;54:195-200

13.

Manconi M, Govoni V, De Vito A, et al. Restless legs syndrome and pregnancy. Neurology 2004;63:1065-9 Correlation between RLS and pregnancy.

22.

MIRAPEX: Prescribing Information. 2014. Available from: http://www. mirapexer.com [Last accessed 10 June 2014]

23.

Wright CE, Sisson TL, Ichhpurani AK, Peters GR. Steadystate pharmacokinetic properties of pramipexole in healthy volunteers. J Clin Pharmacol 1997;37:520-5

24.

Kushida CA. Ropinirole for the treatment of restless legs syndrome. Neuropsychiatr Dis Treat 2006;2:407-19 Expert opinion on ropinirole’s Absorption, Distribution, Metabolism, Elimination and Toxicology (ADMET) characteristics and clinical trials.

.

14.

O’Keeffe ST. Secondary causes of restless legs syndrome in older people. Age Ageing 2005;34:349-52

15.

Ondo WG, He Y, Rajasekaran S, Le WD. Clinical correlates of 6hydroxydopamine injections into A11 dopaminergic neurons in rats: a possible model for restless legs syndrome. Mov Disord 2000;15:154-8

16.

17.

..

18.

..

19.

..

Hening W. The clinical neurophysiology of the restless legs syndrome and periodic limb movements. Part I: diagnosis, assessment, and characterization. Clin Neurophysiol 2004;115:1965-74

25.

Trenkwalder C, Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol 2010;6:337-46 Review that covers clinical and pathophysiological features of RLS.

Wynalda MA, Wienkers LC. Assessment of potential interactions between dopamine receptor agonists and various humas cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos 1997;25:1211-14

26.

Winkelman JW, Sethi KD, Kushida CA, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology 2006;67:1034-9

27.

Ferini-Strambi L. Restless legs syndrome augmentation and pramipexole treatment. Sleep Med 2002;3:23-5

28.

Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for restless legs syndrome. Agency for Healthcare Research and Quality (US), Rockville, MD; 2012

29.

Silver N, Allen RP, Senerth J, Earley CJ. A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep Med 2011;12:440-4

Merlino G, Serafini A, Robiony F, et al. Clinical experience with pramipexole in the treatment of restless legs syndrome. Expert Opin Drug Metab Toxicol 2008;4:225-35 A review that describes pramipexole’s pharmacokinetic characteristics and its clinical use in RLS. Zintzaras E, Kitsios GD, Papathanasiou AA, et al. Randomized trials of dopamine agonists in restless legs syndrome: a systematic review, quality assessment, and meta-analysis. Clin Ther 2010;32:221-37


1377

S. de Biase et al.

30.

31.


32.

33.

..

34.

35.

36.

37.

.

38.

Maestri M, Fulda S, Ferini-Strambi L, et al. Polysomnographic record and successful management of augmentation in restless legs syndrome/Willis-Ekbom disease. Sleep Med 2014;15:570-5 Coldwell MC, Boyfield I, Brown T, et al. Comparison of the functional potencies of ropinirole and other dopamine receptor agonists at human D2 (long), D3 and D4 receptors expressed in Chinese hamster ovary cells. Br J Pharmacol 1999;127:1696-702

41.

Tompson DJ, Vearer D. Steady-state pharmacokinetic properties of a 24-hour prolonged-release formulation of ropinirole Results of two randomized studies in patients with Parkinson’s disease. Clin Ther 2007;29:2654-66

42.

Merlino G, Gigli GL. Sleep-related movement disorders. Neurol Sci 2012;33:491-513 Review that describes clinical characteristics and treatment of RLS and other sleep-related movement disorders. REQUIP: Prescribing Information. 2009. Available from: http://www.requip. com [Last accessed 10 June 2014]

.

43.

.

Swart PJ, Oelen WE, Bruins AP, et al. Determination of the dopamine D2 agonist N-0923 and its major metabolites in perfused rat livers by HPLC-UV-atmospheric pressure ionization mass spectrometry. J Anal Toxicol 1994;18:71-7 Boroojerdi B, Wolff HM, Braun M, Scheller DK. Rotigotine transdermal patch for the treatment of Parkinson’s disease and restless legs syndrome. Drugs Today (Barc) 2010;46:483-505 Monograph that deals about pharmacokinetic properties, clinical efficacy, safety and tolerability of rotigotine in RLS and Parkinson’s disease patients. Cawello W, Ahrweiler S, Sulowicz W, et al. Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function. Br J Clin Pharmacol 2012;73:46-54 Rotigotine’s pharmacokinetic characteristics in patients with different stages of renal impairment.

48.

Katzung G. Basic & clinical pharmacology. McGraw-Hill, New York; 2007

49.

Wade DN, Mearrick PT, Morris JL. Active transport of L-dopa in the intestine. Nature 1973;242:463-5

50.

Sharpless NS, Muenter MD, Tyce GM, Owen CA Jr. 3-Methoxy-4hydroxyphenylalanine (3-O-methyldopa) in plasma during oral L-dopa therapy of patients with Parkinson’s disease. Clin Chim Acta 1972;37:359-69

51.

Guilleminault C, Cetel M, Philip P. Dopaminergic treatment of restless legs and rebound phenomenon. Neurology 1993;43:445

52.

Comella CL. Restless legs syndrome: treatment with dopaminergic agents. Neurology 2002;58(Suppl 1):87-92 A review on RLS treatment with dopaminergic agents: clinical efficacy and side effects.

.

53.

Earley CJ, Allen RP. Augmentation of the restless legs syndrome with carbidopa-levodopa. Sleep 1996;19:801-10

54.

Yaltho T, Ondo W. The use of gabapentin enacarbil in the treatment of restless legs syndrome. Ther Adv Neurol Disord 2010;3:269-75

55.

Trenkwalder C, Hening WA, Montagna P, et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord 2008;23:2267-302

Kaye CM, Nicholls B. Clinical pharmacokinetics of ropinirole. Clin Pharmacokinet 2000;39:243-54

44.

Bloomer JC, Clarke SE, Chenery RJ. An assessment of the potential of ropinirole, a dopamine receptor agonist, to inhibit various human cytochrome P450 enzymes. Br J Pharmacol 1998;124:41

45.

Garcia-Borreguero D, Ferini-Strambi L, Kohnen R. Augmentation in the therapy of restless legs syndrome with transdermal rotigotine: a retrospective systematic analysis of two large doubleblind 6-month trials. Eur J Neurol 2008;15(Suppl 3):110

56.

Stewart BH, Kugler AR, Thompson PR, et al. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharm Res 1993;10:276-81

46.

Benes H, Garcia-Borreguero D, Allen R, et al. Augmentation in long-term therapy of the restless legs syndrome with transdermal rotigotine - a retrospective systematic analysis of two large openlabel 1-year trials. Mov Disord 2009;24(Suppl 1):438

57.

47.

Deleu D, Northway MG, Hanssens Y. Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson’s Disease. Clin Pharmacokinet 2002;41:261-309 ADMET characteristics of dopaminergic agents.

Cundy KC, Annamalai T, Bu L, et al. XP13512 [(+/-)-1-([(aisobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: II. Improved oral bioavailability, dose proportionality and colonic absorption compared with gabapentin in rats and monkeys. J Pharmacol ExpTher 2004;311:324-33 Differences of absorption properties between gabapentin and gabapentin enacarbil.

Garcı´a-Borreguero D, H€ogl B, Ferini-Strambi L, et al. Systematic evaluation of augmentation during treatment with ropinirole in restless legs syndrome (Willis-Ekbom disease): results from a prospective, multicenter study over 66 weeks. Mov Disord 2012;27:277-83 Study that analyzes the rate of augmentation in RLS patients treated with ropinirole. Merlino G, Serafini A, Robiony F, et al. Restless legs syndrome: differential diagnosis and management with rotigotine. Neuropsychiatr Dis Treat 2009;5:67-80

39.

Pfeiffer RF. A promising new technology for Parkinson’s disease. Neurology 2005;65(2 Suppl 1):S6-S10

40.

Serafini A, Lorenzut S, Gigli GL, et al. The use of rotigotine in the treatment of

1378

..

restless legs syndrome. Ther Adv Neurol Disord 2010;3:241-8 Review on rotigotine’s ADMET characteristics and clinical applications in RLS patients.

.

Oertel WH, Benes H, Garcia-Borreguero D, et al. One year open-label safety and efficacy trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome. Sleep Med 2008;9:865-73


.

58.

Cundy KC, Sastry S, Luo W, et al. Clinical pharmacokinetics of XP13512, a


.

59.


.

novel transported prodrug of gabapentin. J Clin Pharmacol 2008;48:1378-88 Pharmacokinetic characteristics of gabapentin enacarbil. Lal R, Sukbuntherng J, Luo W, et al. Clinical pharmacokinetics of gabapentin after administration of gabapentin enacarbil extended-release tablets in patients with varying degrees of renal function using data from an open-label, single-dose pharmacokinetic study. Clin Ther 2012;34:201-13 Pharmacokinetic characteristics of gabapentin enacarbil in patients with different stages of renal impairment.

60.

LYRICA: Prescribing Information. 2013. Available from: http://www.lyrica. com [Last accessed 10 June 2014]

61.

Allen RP, Chen C, Winkelman J, et al. Long-term efficacy and augmentation assessment of an alpha2delta ligand (pregabalin) compared with a dopamine agonist (pramipexole) in restless legs syndrome: results of a randomized, double-blind, placebo-controlled trial. Mov Disord 2012;27:S576

62.

..

63.

64.

.

65.

66.

67.

Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet 2010;49:661-9 Review that compares pharmacokinetic properties of gabapentin and pregabalin. Bockbrader HN, Radulovic LL, Posvar EL, et al. Clinical pharmacokinetics of pregabalin in healthy volunteers. J Clin Pharmacol 2010;50:941-50 Randinitis EJ, Posvar EL, Alvey CW, et al. Pharmacokinetics of pregabalin in subjects with various degrees of renal function. J Clin Pharmacol 2003;43:277-83 Pharmacokinetic characteristics of pregabalin in patients with different stages of renal impairment. Allen R, Chen C, Soaita A, et al. A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome. Sleep Med 2010;11:512-19 Kim SW, Shin IS, Kim JM, et al. Bupropion may improve restless legs syndrome. A report of three cases. Clin Neuropharmacol 2005;28:298-301 Lee JJ, Erdos J, Wilkosz MF, et al. Bupropion as a possible treatment option

for restless legs syndrome. Ann Pharmacother 2009;43:370-4 68.

.

69.

70.

Bayard M, Bailey B, Acharya D, et al. Bupropion and restless legs syndrome: a randomized controlled trial. J Am Board Fam Med 2011;24:422-8 Bupropion for the treatment of RLS. Dhillon S, Yang LP, Curran MP. Bupropion: a review of its use in the management of major depressive disorder. Drugs 2008;68:653-89 WELLBUTRIN: Prescribing Information. 2014. Available from: http://www. gsksource.com/gskprm/htdocs/ documents/WELLBUTRIN-TABLETSPI-MG.PDF [Last accessed 10 June 2014]

71.

Jefferson JW, Pradko JF, Muir KT. Bupropion for major depressive disorder: pharmacokinetic and formulation considerations. Clin Ther 2005;27:1685-95

72.

Hsyu PH, Singh A, Giargiari TD, et al. Pharmacokinetics of bupropion and its metabolites in cigarette smokers versus nonsmokers. J Clin Pharmacol 1997;37:737-43

73.

Kyowa Hakko Kirin Co. Ltd. Approval for manufacturing and marketing of NOURIAST_ tablets 20 mg, a novel antiparkinsonian agent. 2013. Available from: http://www.kyowakirin.com/news_releases/2013/ e20130325_04.html. [Last accessed 10 June 2014]

74.

75.

.

76.

77.

Cies´lak M, Komoszyn´ski M, Wojtczak A. Adenosine A(2A) receptors in Parkinson’s disease treatment. Purinergic Signal 2008;4:305-12 DeCerce J, Smith LF, Gonzalez W, et al. Effectiveness and tolerability of istradefylline for the treatment of restless legs syndrome: an exploratory study in five female patients. Curr Ther Res Clin Exp 2007;68:349-59 Istradefylline for the treatment of RLS. Yang M, Soohoo D, Soelaiman S, et al. Characterization of the potency, selectivity, and pharmacokinetic profile for six adenosine A2A receptor antagonists. Naunyn Schmiedebergs Arch Pharmacol 2007;375:133-44 Knebel W, Rao N, Uchimura T, et al. Population pharmacokineticpharmacodynamic analysis of istradefylline in patients with Parkinson


disease. J Clin Pharmacol 2012;52:1468-81 78.

Rao N, Uchimura T, Mori A, et al. Evaluation of safety, tolerability, and multiple-dose pharmacokinetics of istradefylline in healthy subjects. Clin Pharmacol Ther 2008;83(Suppl 1):S99

79.

Rao N, Chaikin P, Dvorchik B, et al. Evaluation of the pharmacokinetic interaction of istradefylline and ketoconazole. Parkinsonism Relat Disord 2007;13(Suppl 2):S104

80.

Hauser RA, Shulman LM, Trugman JM, et al. Study of istradefylline in patients with Parkinson’s disease on levodopa with motor fluctuations. Mov Disord 2008;23:2177-85

81.

Product monograph Targin. 2014. Available from: http://www.purdue. ca/files/2014-08-05_Targin-pm-mktgeng.pdf [Last accessed 10 June 2014]

82.

Trenkwalder C, Benesˇ H, Grote L, et al. Prolonged release oxycodone-naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomised, placebo-controlled trial with an openlabel extension. Lancet Neurol 2013;12:1141-50 Oxycodone-naloxone for the treatment of RLS.

..

83.

Mandema JW, Kaiko RF, Oshlack B, et al. Characterization and validation of a pharmacokinetic model for controlledrelease oxycodone. Br J Clin Pharmacol 1996;42:747-56

84.

Coluzzi F, Mattia C. Oxycodone. Pharmacological profile and clinical data in chronic pain management. Minerva Anestesiol 2005;71:451-60

85.

Riley J, Eisenberg E, Mu¨ller-Schwefe G, et al. Oxycodone: a review of its use in the management of pain. Curr Med Res Opin 2008;24:175-92

86.

Lugo RA, Kern SE. The pharmacokinetics of oxycodone. J Pain Palliat Care Pharmacother 2004;18:17-30

87.

AZILECT: summary of product characteristics. 2014. Available from: http://www.ema. europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/ 000574/WC500030048.pdf [Last accessed 10 June 2014]

88.

Babacan-Yildiz G, Gursoy E, Kolukisa M, Celebi A. Restless legs

1379

S. de Biase et al.

Restless Legs Syndrome. Newron Pharmaceutical Spa. 2005. Available from: http://www. newron.com/user/download.aspx? FILE=OBJ00033.PDF&TIPO=FLE& NOME=SafinamideRLSPressRelease Final110105.pdf [Last accessed 10 June 2014]

syndrome responsive to rasagiline treatment: a case report. Clin Neuropharmacol 2012;35:88-9 89.

Safety and Efficacy of Rasagiline in Restless Legs Syndrome. NCT01192503. Available from: http://clinicaltrials.gov/ [Last accessed 10 June 2014]

90.

Chen JJ, Ly AV. Rasagiline: a secondgeneration monoamine oxidase type-B inhibitor for the treatment of Parkinson’s disease. Am J Health Syst Pharm 2006;63:915-28


91.

92.

Chen JJ, Swope DM. Clinical pharmacology of rasagiline: a novel, secondgeneration propargylamine for the treatment of Parkinson disease. J Clin Pharmacol 2005;45:878-94 Oldfield V, Keating GM, Perry CM. Rasagiline: a review of its use in the management of Parkinson’s disease. Drugs 2007;67:1725-47

93.

Caccia C, Maj R, Calabresi M, et al. Safinamide: from molecular targets to a new anti-Parkinson drug. Neurology 2006;67(Suppl 2):S18-23

94.

Newron Pharmaceuticals Successfully Completes Pilot Study of Safinamide in

1380

95.

Marzo A, Dal Bo L, Monti NC, et al. Pharmacokinetics and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity. Pharmacol Res 2004;50:77-85

96.

Onofrj M, Bonanni L, Thomas A. An expert opinion on safinamide in Parkinson’s disease. Expert Opin Investig Drugs 2008;17:1115-25

97.

Fariello RG. Safinamide. Neurotherapeutics 2007;4:110-16

98.

Garcia-Borreguero D, Kohnen R, Silber MH, et al. The long-term treatment of restless legs syndrome/ Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome


Study Group. Sleep Med 2013;14:675-84 99.

Winkelman JW, Bogan RK, Schmidt MH, et al. Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome. Mov Disord 2011;26:2065-72

Affiliation Stefano de Biase1,2 MD, Giovanni Merlino2 MD PhD, Simone Lorenzut1,2 MD, Mariarosaria Valente1,2 MD & Gian Luigi Gigli†1,2,3 MD † Author for correspondence 1 University of Udine Medical School, Department of Experimental and Clinical Medical Sciences, Neurology Unit, Udine, Italy 2 “S. Maria della Misericordia” University Hospital, Department of Neurosciences, Udine, Italy 3 Professor, Director of Neurology, University of Udine Medical School, Piazza Santa Maria della Misercordia, 15, 33100 Udine, Italy Tel: +39 0 432 989264; Fax: +39 0 432 989263; E-mail: [email protected]

Brainstem stroke-related restless legs syndrome: frequency and anatomical considerations.

Restless legs syndrome.

[Perioperative approach to restless legs syndrome].

Rotigotine transdermal system: developing continuous dopaminergic delivery to treat Parkinson's disease and restless legs syndrome.

Treatment of restless legs syndrome.

Bad medicine: restless legs syndrome.

Pediatric restless legs syndrome diagnostic criteria: an update by the International Restless Legs Syndrome Study Group.

Association of restless legs syndrome variants in Korean patients with restless legs syndrome.

Parkinson's disease and restless legs syndrome.

Pregabalin versus pramipexole for restless legs syndrome.

Sensory stimuli and the restless legs syndrome.

Characterization of the painful restless legs syndrome.

Pramipexole alters thermoregulation in restless legs syndrome.

Restless legs syndrome and pregnancy: a review.

Restless legs syndrome in opioid dependent patients.

Therapeutic dilemma for restless legs syndrome.

Is Restless Legs Syndrome Involved in Ambulation Related to Sleepwalking?

Restless legs syndrome: pathophysiology and treatment.

Pregabalin versus pramipexole for restless legs syndrome.

Pregabalin versus pramipexole for restless legs syndrome.

Myoclonus in familial restless legs syndrome.

Treatment of pediatric restless legs syndrome.

Restless legs syndrome in Parkinson's disease.

Restless legs syndrome induced by lithium.