Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: https://www.tandfonline.com/loi/ieop20

Advancing synthetic therapies for the treatment of

restless legs syndrome

Stefano de Biase, Gaia Pellitteri, Gian Luigi Gigli & Mariarosaria Valente

To cite this article: Stefano de Biase, Gaia Pellitteri, Gian Luigi Gigli & Mariarosaria Valente
(2019): Advancing synthetic therapies for the treatment of restless legs syndrome, Expert Opinion
on Pharmacotherapy, DOI: 10.1080/14656566.2019.1654997

To link to this article: https://doi.org/10.1080/14656566.2019.1654997

Published online: 19 Aug 2019.

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EXPERT OPINION ON PHARMACOTHERAPY
https://doi.org/10.1080/14656566.2019.1654997

REVIEW

Advancing synthetic therapies for the treatment of restless legs syndrome

Stefano de Biasea, Gaia Pellitteria, Gian Luigi Giglia,b and Mariarosaria Valentea,c
a
Neurology Unit, Department of Neurosciences, University Hospital of Udine, Udine, Italy; bDMIF, University of Udine, Udine, Italy; cDepartment of
Medicine, University of Udine Medical School, Udine, Italy

ABSTRACT ARTICLE HISTORY

Introduction: Restless Legs Syndrome/Willis-Ekbom disease (RLS/WED) is a common sensory-motor Received 23 April 2019
neurological disorder that impairs nocturnal rest causing decreased alertness, depressed mood, reduced Accepted 8 August 2019
job performance and poor quality of life. In patients affected by moderate to severe RLS/WED, KEYWORDS
a pharmacological treatment is mandatory. Augmentation; α2δ calcium
Areas covered: The present review is based on an extensive Internet and PubMed search from 1996 to channel ligand; dopamine;
2019. It is focused on drugs currently used and under development (phase III and beyond) for the investigational drugs; iron;
treatment of RLS/WED. MAO-B inhibitors;
Expert opinion: The drugs currently available for the treatment of the disease do not always allow for oxycodone-naloxone;
obtaining the optimal control of symptoms, in particular in the long-term treatment. Although initially restless legs syndrome
effective, long-term dopaminergic treatment tends to wane over time and augmentation can occur.
Updated international guidelines now recommend α2δ calcium channel ligand medications as the
initial drug of choice. Oxycodone-naloxone demonstrated a significant and sustained treatment effect
for patients with severe RLS/WED insufficiently controlled with previous treatments. Head-to-head trials
of different drugs, as well as more studies on nondopaminergic agents and combination therapy, are
greatly needed. Monoamine oxidase B inhibitors could be good candidates for the initial treatment of
RLS/WED, sparing stronger dopaminergic agents for later stages of the disease.

1. Introduction severity with age, and a strong familial link. Genetic studies identi-
fied several candidate loci associated with RLS/WED [11]. Family
Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is
and twin studies have estimated that RLS/WED heritability is 50%
a neurological sensory-motor disorder defined by an urgency
to 60%. Initially considered as mostly a Mendelian disease, it is now
to move the legs, usually combined with uncomfortable or
considered as a complex multifactorial disorder with both genetic
unpleasant sensations, which occurs or worsens during rest,
and non-genetic factors contributing to the susceptibility [12].
usually in the evening or at night, and disappears with move-
Significant findings have been obtained in several genome-wide
ment of the legs [1]. Many patients with RLS/WED (about 80%)
association studies (GWAS). A recent meta-analysis of several
present periodic involuntary and stereotyped jerks in the
GWAS databases replicated previously identified six risk loci,
lower limbs, known as periodic limb movements (PLMs) [2].
MEIS1, BTBD9, PTPRD, MAP2K5, SKOR1, and TOX3, and 13 new risk
Insomnia is the most common reason for a patient with RLS/
loci, with each genetic variant increasing about 50% the risk for
WED to search for consult in clinical practice.
RLS [13].
The prevalence of RLS/WED ranges from 5% to 10% of adults
The precise pathogenesis of RLS/WED is still under study,
in North America and Europe, while studies from Asian countries
but dysfunctional dopaminergic modulation of neuronal excit-
showed a lower prevalence [3]. Women are affected about twice
ability is generally thought to be the main underlying patho-
as often as men, and the incidence increases with age.
physiological mechanism of RLS/WED, as suggested by the
A large proportion of patients (70–80%) are affected by the
positive response to dopaminergic agents in patients with
primary or idiopathic form of RLS/WED [4]. To diagnose a primary
RLS/WED [14]. However, there is increasing evidence that
form of RLS/WED, all the conditions known to cause the disease
interaction with other transmitter systems, such as adenosine,
should be excluded. There are several well-established second-
opioids and the γ-aminobutyric acid-ergic system, as well as
ary causes of RLS/WED, including iron deficiency, end-stage renal
iron deficiency, is crucial for the manifestation of RLS/WED
disease, diabetes, polyneuropathy, multiple sclerosis, Parkinson’s
symptoms [11,15].
disease (PD), pregnancy and medications that can induce RLS/
Not all patients with RLS/WED need pharmacological treat-
WED (e.g., neuroleptics, selective serotonin reuptake inhibitors
ment. For patients with intermittent and mild symptoms, non-
(SSRI), lithium) [5–10]. Symptomatic forms of RLS/WED may
pharmacological remedies are often sufficient. This approach
improve or disappear treating the underlying disorder.
consists of sleep hygiene, behavioral therapy as well as the
Primary RLS/WED has an earlier onset (<45 years old), a slower
elimination of substances that might exacerbate RLS/WED
development, an higher incidence in women, an increasing
symptoms such as caffeine, nicotine, alcohol, and medications

CONTACT Gian Luigi Gigli gigli@uniud.it Neurology Unit, Department of Neurosciences, University Hospital of Udine, Udine, Italy
© 2019 Informa UK Limited, trading as Taylor & Francis Group
2 S. DE BIASE ET AL.
Article highlights
● Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is a neurological
sensory-motor disorder defined by an urgency to move the legs, usually
combined with unpleasant sensations, which occurs or worsens during
rest, and disappears with movement of the legs.
● Although initially effective, long-term dopaminergic treatment tends
to wane over time and/or augmentation can occur.
● Updated international guidelines now recommend α2δ calcium chan-
nel ligand medications as the initial drug of choice.
● Monoamine oxidase B inhibitors could be good candidates for initial
treatment of RLS/WED, sparing stronger dopaminergic agents for
later stages of the disease.
● Oxycodone-naloxone demonstrated a significant and sustained treat-
ment effect for patients with severe RLS/WED insufficiently controlled
with previous treatments.
This box summarizes key points contained in the article.
known to enhance RLS/WED [16]. If symptoms remain uncon-
trolled and disruptive, then the addition of pharmaceutical
medication is clinically recommended intermittently [17].
The symptoms of chronic, persistent RLS/WED are character-
ized as moderate to severe, occurring at least twice a week,
thereby requiring treatment [18]. Chronic RLS/WED should be
treated with either a non-ergot dopamine agonist (pramipexole,
ropinirole, and rotigotine) or an α2δ calcium channel ligand
(pregabalin, gabapentin, and gabapentin enacarbil) [19].
Although less common than levodopa, augmentation with
dopamine agonists represents the main challenge in RLS/WED
treatment. To date, the exact pathophysiological mechanism caus-
ing augmentation is unknown. It has been hypothesized that
augmentation might be the result of a relative predominance of
D1 receptor stimulation, caused by a hyperdopaminergic state.
Augmentation refers to the worsening of RLS/WED symp-
tom severity from pretreatment levels following an initial
benefit, with an earlier onset of symptoms by at least 2–4 h,
often associated with a shorter latency to RLS/WED symptoms
at rest, extension of symptoms to other body parts and
increased intensity of symptoms [20–23]. Compared to dopa-
mine agonists, α2δ ligands have little or no risk of augmenta-
tion. For this reason, updated international guidelines now
recommend α2δ ligand medications as the initial drug of
choice [22]. Utilization of α2δ ligands should be given further
preference over dopamine agonists in patients with comorbid
insomnia, anxiety, pain, or impulse control disorders (ICD) [22].
In refractory RLS/WED, combination treatment should be
considered for patient with symptoms that cannot be con-
trolled with a low-dose monotherapy of either treatment class.
Opioids as monotherapy or add-on treatment should be con-
sidered when alternative satisfactory regimens are unavailable
and the severity of symptoms warrants it [24].
The aim of this review is to describe the drugs currently
used and under development (phase III and beyond) for the
treatment of RLS/WED (Table 1).
2. α2δ Calcium channel ligands
α2δ ligands are effective and safe in the treatment of RLS/
WED, with low risk of augmentation. A combined task force of
the International Restless Legs Syndrome Study Group
(IRLSSG), the European Restless Legs Syndrome Study Group
(EURLSSG) and the RLS Foundation (RLS-F) suggest to choose
an α2δ ligand for intial treatment of RLS/WED, considering the
low risk of augmentation [22].
2.1. Pregabalin
2.1.1. Mechanism of action
Pregabalin is an α2δ ligand, an auxiliary protein associated
with voltage-gated calcium channels. It binds α2δ subunit
reducing calcium influx at nerve terminals of central nervous
system (CNS). This, in turn, limits the release of several neuro-
transmitters, including glutamate, norepinephrine, and sub-
stance P. Pregabalin may also modulate pain transmission
through interactions with noradrenergic and serotonergic cir-
cuits directed from the brainstem to the spinal cord.
Pregabalin is a structural derivative of gamma-aminobutyric
acid (GABA), although in vitro and in vivo studies have shown
no direct binding to GABA receptors [25].
2.1.2. Efficacy and tolerability
Pregabalin is effective for the treatment of RLS/WED symptoms.
It may be considered as a first-line treatment, particularly in
patients with comorbid anxiety, insomnia or neuropathic pain.
In a double-blind, randomized, crossover study, pregabalin
300 mg/day improved subjective RLS/WED symptoms (IRLSSG
rating score and Clinical Global Impression of Improvement
(CGI-I)) more than placebo or pramipexole 0.5 mg/day. The
effect of pregabalin on arousals associated with PLM was similar
to pramipexole, despite smaller reductions in PLMs [26].
A large-scale, 52-week, randomized, double-blind trial has
assessed the efficacy between pregabalin, pramipexole
0.25 mg, pramipexole 0.5 mg, and placebo (3 months of
placebo followed by 40 weeks of a randomly assigned active
treatment) [27]. With 719 participants, the study found that
pregabalin had greater efficacy than 0.25 mg of pramipexole.
Furthermore, the augmentation rates were significantly
greater in the pramipexole 0.25 mg and 0.5 mg group (6.6%
and 9.0%, respectively) than pregabalin group (1.7%) [27].
Pregabalin is safe and well tolerated. Dizziness and somno-
lence are the most common side effects, but are usually dose-
dependent and are typically worse in the first weeks of treatment
[28]. Other reported side effects are ataxia, weight gain, dry
mouth, and blurred vision.
2.1.3. Evidence and guidelines
Although effective in the treatment of RLS/WED, the US Food
and Drug Administration (FDA) and the European Medicines
Agency (EMA) have not approved pregabalin for the treatment
of RLS/WED. According to American Academy of Neurology
(AAN) guidelines, there is evidence (Level B) to support the
use of pregabalin in the treatment of RLS/WED [29]. The
IRLSSG guidelines suggest the use of pregabalin as a first-
line treatment [22]. The suggested initial dose is 50–75 mg/
day; recommended therapeutic dose is 150–450 mg/day.
 EXPERT OPINION ON PHARMACOTHERAPY 3

Table 1. Drugs currently used and under development for the treatment of RLS.
Starting dose;
FDA EMA therapeutic dose (mg/
approval approval day) Common side effects
Pregabalin No No 50–75; 150–450 Dizziness, somnolence, ataxia, weigh gain
Gabapentin No No 100–300; 900–2400 Dizziness, somnolence, headache, nausea
Gabapentin Yes No 300–600; 600–1200 Dizziness, somnolence, headache, nausea
enacarbil
Pramipexole Yes Yes 0.125; 0.25–0.75 Dizziness, headache, nausea, insomnia, somnolence, orthostatic hypotension, impulse
control disorders
Ropinirole Yes No 0.25; 0.25–4.0 Dizziness, headache, nausea, insomnia, somnolence, orthostatic hypotension, impulse
control disorders
Rotigotine Yes Yes 1; 1–3 Local sitereactions, dizziness, headache, nausea, insomnia, orthostatichypotension,
somnolence, impulse control disorders
Rasagiline No No 1 Headache, nausea, dyspepsia
Levodopa No No 100–200 (on demand) Nausea, headache, dizziness
Oxycodone- No Yes 5.0/2.5 bid, 10/5.0–40/ Constipation, dizziness, somnolence, nausea
naloxone 20 mg/day
Topiramate No No 25; 25–150 Paresthesia, fatigue, headache, somnolence, dizziness, weightloss, depression
Bupropion No No 150 Agitation, tremor, insomnia, headache, nausea, constipation
Iron No No 500–1500 mg iv, 325 mg Nausea, abdominal pain, epigastric discomfort, diarrhea; anaphylactoid reactions with iv
oral formulations
Vitamin D No No Notavailable Fatigue, somnolence, dizziness, constipation, abdominalpain, nausea, diarrhea
Abbreviations: bid = twice a day; iv = intravenous

2.2. Gabapentin 2.3. Gabapentin enacarbil

2.2.1. Mechanism of action
Gabapentin is a structural derivative of the inhibitory neuro-
transmitter GABA. Similar to pregabalin, it does not interact
directly with GABA receptors and binds to the α2δ subunit of
the voltage-dependent calcium channel, with specific affinity
for α2-δ1 subunit. It reduces synaptic transmission by decreas-
ing presynaptic voltage-gated calcium and sodium channels. It
also reduces exocytosis of presynaptic vesicles [30].
2.3.1. Mechanism of action
Gabapentin enacarbil (GE) is an extended-release prodrug of gaba-
pentin, synthesized to overcome limitations in intestinal adsorp-
tion of gabapentin. There are no differences in the mechanisms of
action. When orally administered, the drug is absorbed throughout
the intestine via non-saturable high capacity nutrient transporters.
Thus, the absorption of GE shows no evidence of saturation and
the exposure to gabapentin is dose-proportional [34].

2.2.2. Efficacy and tolerability

2.3.2. Efficacy and tolerability
Gabapentin is a preferential treatment for patients with painful RLS/
Numerous randomized controlled trial have demonstrated the
WED and comorbid neuropathic pain. Gabapentin has been stu-
efficacy of GE in the treatment of RLS/WED [35–37]. GE sig-
died in comparison with other agents [31,32]. A study compared
nificantly improves RLS/WED symptoms and sleep quality ver-
the efficacy of gabapentin (200 mg) and levodopa/carbidopa (-
sus placebo [38]. GE also improves quality of life and mood
110 mg) in hemodialysis patients with RLS/WED. Both drugs were
disturbances [39]. To our knowledge, the longest clinical trial
found effective for the management of RLS/WED, but the effect of
regarding GE is a 52-week study [40]. As with previous studies,
gabapentin was more significant [31]. A placebo-controlled poly-
responses to the drug (evaluated with IRLSSG and CGI scores)
somnographic and psychometric study compared the acute effects
were superior to placebo [41].
of gabapentin and ropinirole in RLS/WED. Gabapentin, compared
The efficacy and tolerability of GE is not influenced by prior
with placebo and ropinirole, improved more objective and subjec-
exposure to dopamine-agonists and can provide a valid alter-
tive sleep and awakening quality. On the other hand, ropinirole
native in non-responder patients [40].
showed more efficacy in reducing PLMs [32].
A clinical trial started to compare safety, effectiveness and
Gabapentin is usually well tolerated. The most common
tolerability of gabapentin versus gabapentin enacarbil started
side effects are dizziness, somnolence, headache, and nausea.
in 2014. The study terminated without any results in 2016.
In a recent review, the use of gabapentin in pregnancy was
Recruitment was not successful due to overly restrictive inclu-
reported safe. However, further studies with a pregnancy reg-
sion/exclusion criteria [42].
istry are needed to confirm these results [33].
GE is generally safe and well tolerated. The most common
adverse effects are somnolence and dizziness. Other common
2.2.3. Evidence and guidelines side effects are headache and nausea [40].
Gabapentin is not approved by FDA and EMA for the treat-
ment of RLS/WED.
According to AAN guidelines, there is insufficient evidence 2.3.3. Evidence and guidelines
to support or refute the use of gabapentin in the treatment of GE is approved by FDA, but not by EMA, for the treatment of
RLS/WED (Level U) [29]. The recommended starting dose in RLS/WED. The AAN guidelines supports with strong evidence
the IRLSGG guidelines is 100–300 mg/day; daily therapeutic (Level A) the use of GE at doses of 600 mg/day [29]. The
dose is 900–2400 mg/day [22]. IRLSSG guidelines suggest starting with GE 600 mg/day
4 S. DE BIASE ET AL.
(300mg/day in patients > 65 years); the recommended ther-
apeutic dose is 600–1200 mg/day [22].
3. Dopamine agonists
The nonergot dopamine agonists pramipexole, ropinirole, and
rotigotine are approved by FDA and EMA for the treatment of
moderate to severe idiopathic RLS/WED. Dopamine agonists
are clearly effective in the treatment of RLS/WED. Although
initially effective, long-term dopaminergic treatment can result
in loss of efficacy, difficulties with tolerability, or augmenta-
tion, necessitating a change of drug regimen. Updated inter-
national guidelines now recommend α2δ ligand medications
as the initial drug of choice. Dopamine agonists can be con-
sidered in circumstances where the patient presents with
severe symptoms of depression, obesity/metabolic syndrome,
a risk of falls, or cognitive impairment, as these conditions may
be exacerbated with α2δ ligand integration [22].
3.1. Pramipexole
3.1.1. Mechanism of action
Pramipexole is a nonergoline dopamine agonist with a high
selectivity for D2 and D3 receptors, with a 7- to 10-fold higher
affinity for D3 receptors [43].
3.1.2. Efficacy and tolerability
Pramipexole is effective in improving RLS/WED symptoms, as
proved in several Phase II and III trials [22]. Two open-label
studies reported that efficacy on RLS/WED symptoms con-
tinues up to 1 year [44,45]. A study comparing pramipexole
with dual-release levodopa/benserazide found that both drugs
are effective in reducing RLS/WED symptoms and PLMs, but
levodopa had a higher rate of augmentation (21%) compared
with pramipexole (6%) [46].
Pramipexole is usually well tolerated, main side effects are
nausea, headache, somnolence, dizziness, orthostatic hypoten-
sion, and hallucinations. Patients should be warned about drowsi-
ness and even falling asleep while engaged in activities of daily
living [43]. Even if lower than levodopa, significant rates of aug-
mentation (8–56%) have been reported for pramipexole [47]. Silver
et al. showed that risk of augmentation due to pramipexole per-
sisted for up 10 years of treatment in RLS/WED patients. In parti-
cular, the authors reported an annual augmentation rate of 7%
[48]. Maestri et al., in a case series of 24 patients, demonstrated that
the shift from immediate-release (IR) to extended-release (ER) for-
mulation may be an effective option to treat augmentation, sus-
taining the hypothesis that the half-life of the drug plays an
important role in the mechanism of augmentation [49].
3.1.3. Evidence and guidelines
In 2006, pramipexole was approved by FDA and EMA for the
treatment of moderate to severe idiopathic RLS/WED.
Pramipexole is available as IR and ER formulations, only the first
one was approved for RLS/WED treatment. According to AAN
guidelines, strong evidence (Level A) supports the use of prami-
pexole in the treatment of RLS/WED. There is also evidence (Level
B) of benefit on PLM disorder and subjective sleep measures. The
recommended starting dose is 0.125 mg/day; then it may be
gradually increased to 0.25–0.5 mg/day [29]. The IRLSSG guidelines
suggest 0.75 mg as maximum recommended daily dose [22].
3.2. Ropinirole
3.2.1. Mechanism of action
Ropinirole is a nonergoline dopamine agonist. Its affinity and
activity at the D3 receptor is 20 times higher than at the D2 [50].
3.2.2. Efficacy and tolerability
Ropinirole is effective in improving RLS/WED symptoms and
PLM, as proved in several studies [22]. A randomized, double-
blind, 26-week clinical trial followed by a 40-week open-label
extension in patients with baseline IRLS total scores ≥24 has
confirmed efficacy and tolerability of ropinirole in the treat-
ment of RLS/WED. Ropinirole compared with placebo alle-
viated RLS/WED symptoms, enhanced sleep, and improved
disease-specific quality of life. The post hoc analysis of the
IRLSSG total score and the CGI-I responders consistently
showed improvement in the ropinirole arm [51].
The most common side effects are nausea, dizziness, head-
ache, and somnolence. Most adverse events are mild to mod-
erate 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/WED patients [52].
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 [53].
3.2.3. Evidence and guidelines
In 2005, ropinirole was approved by FDA and EMA for the treat-
ment of moderate to severe idiopathic RLS/WED. There are both
IR and ER formulations, but the latter is not approved for the
treatment of RLS/WED. The AAN guidelines report strong evi-
dence (Level A) to support the use of ropinirole in patients with
RLS/WED and concomitant PLM disorder. There is also evidence
(Level B) of positive effects on RLS/WED symptoms and subjec-
tive sleep measures. The recommended starting dose is 0.25 mg/
day, that may be gradually increased up to 4 mg/day [22,29].
3.3. Rotigotine
3.3.1. Mechanism of action
Rotigotine is a nonergoline dopamine agonist with an almost 15-
fold higher affinity for the D2 receptor than for the D1 receptor.
Rotigotine is administered as transdermal patches because of
a low oral bioavailability due to a large first-pass effect [54].
3.3.2. Efficacy and tolerability
Several clinical trials investigated the efficacy and safety of
rotigotine in the treatment of RLS/WED. Rotigotine has been
shown to reduce RLS/WED symptoms up to 6 months in 2
class I and 3 class II studies (level A) and reduce PLMI in 1 class
I study (level B) [22]. A Japanese phase III, multicenter, rando-
mized, double-blind study confirmed that rotigotine at 2 mg/
24 h and 3 mg/24 h was superior to placebo in improving IRLS

total score and Pittsburgh Sleep Quality Index (PSQI) in
patients with RLS/WED [55].
Rotigotine is usually well tolerated. The most common side
effect is represented by application site reactions [56]. Other
common side effects are those typical of dopaminergic drugs:
nausea, somnolence, dizziness, orthostatic hypotension, head-
ache. Augmentation is reported in patients receiving rotigo-
tine for RLS/WED. 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) [57], and in 2.9% of 620 patients
treated with rotigotine in a 1-year open-label setting [58]. In
a 1-year observational study regarding patients with RLS/WED
and augmentation with oral dopamine-agonist treatments,
switching from oral therapies to rotigotine was effective in
improving RLS/WED symptoms in 37 of the 43 patients (from
the original population of 99 patients) who remained in the
study over 13 months [57]. Rotigotine has been shown to
provide long-term efficacy and safety at a stable dose in
a 5-year open-label extension study [56].
3.3.3. Evidence and guidelines
In 2012, rotigotine received FDA and EMA approval for the
treatment of moderate to severe idiopathic RLS/WED.
According to AAN guidelines, strong evidence (Level A) sup-
ports the use of rotigotine in RLS/WED symptoms; there is also
evidence (Level B) of benefit on PLM disorder and subjective
sleep measures. The guidelines indicate therapeutic doses
between 1 and 3 mg/day, starting with 1 mg [29].
4. Other drugs
4.1. Rasagiline
4.1.1. Mechanism of action
Rasagiline is a selective, irreversible monoamine oxidase-B
(MAO-B) inhibitor, leading to increased levels of dopamine in
the striatum [59]. Oral rasagiline as monotherapy or as adjunc-
tive therapy to levodopa provides an useful option in the
treatment of adult patients with PD.
4.1.2. Efficacy and tolerability
To our knowledge, there are only two case reports describ-
ing rasagiline as a useful therapeutic option for RLS/WED:
the former in a patient already affected by PD, the latter in
two sisters with RLS/WED, involving also the arms [60,61].
In 2010, a phase II-III trial started to evaluate if rasagiline at
a dosage of 1 mg/day is effective and safe for the treat-
ment of RLS/WED. To our knowledge, no trial results have
been reported [62].
Rasagiline is usually well tolerated and side effects are mild
or moderate. The most common adverse effects are headache,
dyspepsia, somnolence, dizziness, and depression [63].
4.1.3. Evidence and guidelines
FDA and EMA have not approved rasagiline for the treatment
of RLS/WED. Rasagiline is not included in the most recent AAN
and IRLSSG guidelines for the treatment of RLS/WED [22,29].
EXPERT OPINION ON PHARMACOTHERAPY 5
4.2. Levodopa
4.2.1. Mechanism of action
Levodopa is the immediate metabolic precursor of dopamine.
Levodopa is almost invariably combined with a peripheral
decarboxylase inhibitor, either carbidopa or benserazide, that
blocks the peripheral breakdown of levodopa. Levodopa
crosses the blood-brain barrier and once has entered the
CNS, it is converted into dopamine by the enzyme dopa
decarboxylase [64].
4.2.2. Efficacy and tolerability
Levodopa is mainly prescribed for the treatment of PD, it is also
rarely used for patients with intermittent RLS/WED symptoms as
on demand treatment. In a double-blind, randomized, cross-
over trial, levodopa/benserazide was compared to pramipexole.
Results have shown comparable effects on patients with mild to
moderate RLS/WED, while augmentation was observed more
frequently in patients treated with levodopa [47].
The classical side effects reported with levodopa are nausea,
vomiting, headache, dizziness, and fatigue. The most important
complications in the treatment of RLS/WED are rebound, toler-
ance, and augmentation. Rebound phenomenon is due to the
short half-life of levodopa. Augmentation may occur in up to
80% of patients receiving daily dosing of levodopa [65].
4.2.3. Evidence and guidelines
FDA and EMA have not approved levodopa for the treatment
of RLS/WED. The AAN guidelines report a weak evidence
(Level C) to support the use of levodopa (100–200 mg/d) on
RLS/WED symptoms, PLM disorder and subjective sleep mea-
sures [29]. According to IRLSSG guidelines, levodopa may be
considered for intermittent treatment (two or three times
a week). Daily treatment with levodopa is not recommended
because of the high risk of augmentation [22].
4.3. Oxycodone-naloxone
4.3.1. Mechanism of action
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 [66]. The mechanisms by which
endogenous opioids contribute to the pathophysiology of
RLS/WED remains unknown. It has been hypothesized
a protective effect of opioids against the dopaminergic cell
degeneration [67].
4.3.2. Efficacy and tolerability
Trenkwalder et al. published the result of a phase III trial that
investigated the efficacy and safety of oxycodone-naloxone
prolonged release (PR) for patients with severe RLS/WED
inadequately controlled by previous, mainly dopaminergic
treatment [68]. 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 oxycodone-naloxone 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
6 S. DE BIASE ET AL.
oxycodone-naloxone PR. The mean change of the IRLSSG rat-
ing scale score at 12 weeks was −16.5 ± 11.3 in the oxyco-
done-naloxone 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) [68].
A further analysis on the same population showed positive
effects of oxycodone-naloxone PR also on the quality of life,
sleep efficiency and daytime sleepiness [69].
Common side effects with oxycodone-naloxone PR include
constipation, dizziness, somnolence, pruritus, headache, and
fatigue. No augmentation was reported in RLS/WED
patients [68].
4.3.3. Evidence and guidelines
In 2015, oxycodone-naloxone PR received a positive European
Commission decision as second-line symptomatic treatment for
patients with severe to very severe idiopathic RLS/WED after
failure of dopaminergic therapy. However, FDA have not
approved oxycodone-naloxone PR for the treatment of RLS/WED.
According to AAN guidelines, there is a weak evidence
(Level C) for the use of oxycodone-naloxone PR in RLS/WED
symptoms. Its use is suggested in patients who have not
responded to other treatments, only after an appropriate risk-
benefit assessment [29]. In patients with severe augmentation,
a low dose of oxycodone-naloxone PR can be considered
instead of an α2δ ligand, or if previous approaches fail [22].
The recommended starting dose is 5mg/2.5 mg of oxycodone-
naloxone PR at 12 h intervals; usually, effective dose is up to
40/20 mg/day [22].
4.4. Topiramate
4.4.1. Mechanism of action
The anticonvulsant action of topiramate may be mediated by
different mechanisms of action. It blocks voltage-dependent
sodium and calcium channels. It also inhibits the excitatory
glutamate pathway while enhancing the inhibitory effect of
GABA [70].
4.4.2. Efficacy and tolerability
In 2004, a study involving 19 outpatients has shown good
tolerance and efficacy of topiramate on RLS/WED symptoms
[71]. A phase IV trial investigating the use of topiramate in
RLS/WED started in 2005. To our knowledge, no results have
been published [72]. Korkmaz and Aksu reported the case of
a woman who had RLS/WED after using topiramate, as
a prophylactic treatment of migraine. The authors supposed
a possible antidopaminergic effect of topiramate [73].
The most common side effects are paresthesia, fatigue,
headache, somnolence, dizziness, weight decrease, depres-
sion, and nausea [70]. Most adverse events are mild to mod-
erate in severity and dose-related.
4.4.3. Evidence and guidelines
Topirimate is not approved by FDA and EMA for the treatment
of RLS/WED. It is not included in the most recent RLS/WED
treatment guidelines of AAN and IRLSSG [22,29].
4.5. Bupropion
4.5.1. Mechanism of action
Bupropion is an inhibitor of the neuronal uptake of norepi-
nephrine and dopamine [74]. Due to the dopaminergic effects,
bupropion may be a treatment option in RLS/WED patients.
4.5.2. Efficacy and tolerability
Antidepressant drugs, such as SSRIs and selective serotonin
and norepinephrine reuptake inhibitors (SNRIs), may exacer-
bate RLS/WED and PLM disorders. On the other hand, bupro-
pion may have a positive effect on RLS/WED symptoms, as
initially reported in a small study [75].
In a Phase II/III trial, 29 participants with moderate to severe
RLS/WED received 150 mg sustained-release bupropion once
daily, and 31 control participants received placebo. Bupropion
significantly improved RLS/WED symptoms compared to pla-
cebo 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/WED, making it a possible therapeutic option for treat-
ing depression in individuals with RLS/WED [76].
Bupropion is usually well tolerated. Most common adverse
effects are mild, including agitation, tremor, insomnia, head-
ache, nausea, and constipation [74].
4.5.3. Evidence and guidelines
Bupropion is not approved by FDA and EMA for the treatment
of RLS/WED. According to AAN guidelines, there is insufficient
evidence (Level U) to support or refute its use [29].
4.6. Iron
4.6.1. Mechanism of action
There is accumulating evidence concerning the role of iron in
the pathophysiology of RLS/WED. Although the serum iron is
often normal, people with RLS/WED have a state of low iron in
the brain. Brain iron deficiency in the substantia nigra and
putamen has been noted in individuals with RLS/WED [77]. In
the CNS, iron, and dopamine appear to co-work: dopamine
production via tyrosine hydroxylase needs iron as cofactor. In
animal models, iron deficiency leads to abnormal function of
dopamine transporters [78]. All patients presenting with symp-
toms consistent with RLS/WED should have iron studies com-
pleted. For those individuals with serum ferritin levels that fall
below 75 ng/mL, iron supplementation is warranted [79]
Several oral iron salts (ferrous sulfate, ferrous gluconate, ferrous
fumarate) as well as intravenous iron (iron-dextran, iron sucrose,
ferric carboxymaltose) can be used in clinical practice [80].
4.6.2. Efficacy and tolerability
Patients with serum ferritin below 75 ng/mL have demon-
strated an improvement of symptoms with iron supplementa-
tion [17,81]. Intravenous (IV) formulations are usually
considered when oral therapy cannot be tolerated by the
patient, if the iron formulation cannot be orally absorbed, or
oral iron therapy cannot keep pace with rapid iron loss (eg.
acute blood loss) [17,81].

A recent meta analysis considered 10 different studies, to
assess the efficacy of iron in the treatment of RLS/WED [80].
Nine studies compared iron to placebo and one study com-
pared iron to a dopamine agonist (pramipexole). The authors
concluded that iron therapy probably improves restlessness
and RLS/WED severity in comparison to placebo. Iron therapy
may make little or no difference to pramipexole in restlessness
and RLS/WED severity, as well as in the risk of adverse events.
The effect on secondary outcomes such as quality of life,
daytime functioning, and sleep quality, the optimal timing
and formulation of administration, and patient characteristics
predicting response require additional study [80].
Most common side effects with oral iron therapy are gastro-
intestinal (nausea, abdominal pain, epigastric discomfort, and
diarrhea) and dose-related. On the other hand, side effects
associated with IV iron supplementation are anaphylactic-type
reactions, bronchospasm, dyspnea, convulsions, flushing, head-
ache [82]. Finally, because there is no mechanism for excretion
of iron, long-term monitoring for hemochromatosis is necessary.
4.6.3. Evidence and guidelines
Iron is not approved by FDA and EMA for the treatment of
RLS/WED. According to AAN guidelines, there is evidence
(Level B) to support the use of oral iron and IV ferric carbox-
ymaltose in the treatment of RLS/WED symptoms, but there is
insufficient evidence (Level U) to support or refute the use of
iron to improve PLM and subjective sleep measures [29].
The IRLSSG guidelines recommend supplementation with
oral or IV iron if serum ferritin levels are <50–75 ng/mL or
transferrin saturation is less than 20% [22]. The general con-
sensus is to prescribe 325 mg of oral ferrous sulfate to be
taken daily along with 100 mg to 200 mg of vitamin C to
increase iron absorption [19]. Finally, iron may be considered
as a first-line treatment during pregnancy.
4.7. Vitamin D
4.7.1. Mechanism of action
Cholecalciferol deficiency may have a role in RLS/WED. It
seems that brain dopaminergic dysfunction plays a key role
in the development of RLS/WED. Vitamin D is essential for
protecting dopaminergic neurons from toxins and increases
the levels of dopamine or its metabolites in the nigrostriatal
dopaminergic pathway [83].
4.7.2. Efficacy and tolerability
A recent case-control study examined the association between
RLS/WED and vitamin D level [84]. The risk for the development
of RLS/WED was significantly higher in vitamin D deficient cases
compared to those who were vitamin D sufficient. Additionally,
the mean serum 25(OH) vitamin D level was significantly lower in
patients with RLS/WED than in normal controls. Data also
revealed an association between increased IRLSSG severity rating
score and decreased serum vitamin D level [84].
To our knowledge, only one study evaluated the effect of
vitamin D supplementation on RLS/WED symptoms. Twelve
adults with primary RLS/WED and vitamin D deficiency were
recruited. Patients were treated with vitamin D3 supplements
(high oral dose or intramuscular injection). Results showed
EXPERT OPINION ON PHARMACOTHERAPY 7
a remarkable improvement in severity of RLS/WED with vita-
min D supplementation [85].
A phase IV, double-blind, randomized, placebo-controlled
clinical trial in patients with chronic kidney disease and con-
comitant RLS/WED started in 2017 to further investigate the
benefits of cholecalciferol on RLS/WED symptoms. The study is
currently recruiting participants [86].
4.7.3. Evidence and guidelines
Vitamin D is not approved by FDA and EMA for the treatment
of RLS/WED. It is not included in the most recent AAN and
IRLSSG guidelines for the treatment of RLS/WED [22;29].
5. Conclusion
RLS/WED is a neurologic disorder that affects 5–10% of
Caucasian populations. Treatment should be considered if
RLS/WED symptoms interfere with sleep or daytime function.
The primary goal of RLS/WED treatment is to reduce or elim-
inate symptoms and improve patient sleep and quality of life.
Three dopamine agonists (ropinirole, pramipexole, and roti-
gotine) and one calcium channel α2δ receptor ligand (GE) are
currently approved by FDA and EMA (with the exception of GE
that is not available in Europe) for pharmacological treatment
of moderate to severe RLS/WED. Considering the proven effi-
cacy, the positive safety profile and the low risk of augmenta-
tion, α2δ ligands are increasingly used as initiation treatment
in patients with RLS/WED. This recommendation is limited by
lack of availability or regulatory approval for α2δ ligands in
certain regions of the world (e.g., Europe). In 2015, oxycodone-
naloxone PR, received a positive European Commission deci-
sion as second-line symptomatic treatment for patients with
severe to very severe idiopathic RLS/WED after failure of
dopaminergic therapy.
In summary, this review analyzed the main drugs currently
used and under development (phase III and beyond) for the
treatment of RLS/WED.
6. Expert opinion
RLS/WED is a common neurologic disorder. Updated interna-
tional guidelines now recommend α2δ calcium channel ligand
medications as the initial drug of choice [18]. Although initially
effective, long-term dopaminergic treatment can result in loss
of efficacy, difficulties with tolerability, or augmentation,
necessitating a change of drug regimen. Compared to dopa-
mine agonists, α2δ ligands have little or no risk of augmenta-
tion. 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 [27].
Further longer-term comparative studies are needed, even
considering extended release dopamine agonists against α2δ
ligands. Moreover, an α2δ ligand can be preferred in patients
with comorbid insomnia, painful RLS/WED, comorbid pain
syndrome, history of ICD, and comorbid anxiety. Dopamine
agonists can be considered in circumstances where the
patient presents with severe symptoms of depression, obe-
sity/metabolic syndrome, a risk of falls, or cognitive impair-
ment, as these conditions may be exacerbated with α2δ ligand
8 S. DE BIASE ET AL.
integration [22]. A treatment with a dopamine agonist requires
close follow-up to identify early signs of augmentation. The
risk of augmentation is associated with higher doses and
therefore it is important to keep the dose as low as possible
[87]. Furthermore, a longer acting version may reduce the risk
of augmentation. However, the efficacy and tolerability of
extended release dopamine agonists need to be confirmed
in further long-term studies. Given the high rate of augmenta-
tion for dopamine agonists, further study is needed exploring
the biology of augmentation and possible methods to reduce
the risk and severity of its occurrence.
When monotherapy proves ineffective, combination treat-
ment should be considered (e.g. an α2δ ligand for patients
treated with dopamine agonists or vice versa). Although
a substantial number of patients are treated with
a combination of dopaminergic and nondopaminergic medi-
cations in clinical practice, studies are needed to prove the
efficacy of a combination treatment in RLS/WED.
Opioids are still markedly underused in treatment of RLS/
WED in situations in which alternative therapy either does not
exist or is not effective. Opioids can be used as additional
therapy to either or both dopamine agonists and α2δ ligands
(combination therapy) or can be used alone as monotherapy.
Trenkwalder et al. confirmed the efficacy of oxycodone-
naloxone PR in the treatment of severe RLS/WED inadequately
controlled with previous treatment [68]. Further studies are
needed to evaluate if oxycodone-naloxone PR is equally effi-
cacious for first-line treatment. Additional controlled and com-
parative studies would be very helpful, even considering other
opioids rather than oxycodone-naloxone, such as methadone
and tramadol.
Depression is common in RLS/WED and most commonly
prescribed antidepressants exacerbate the symptoms of RLS/
WED. Bupropion have shown to not exacerbate RLS/WED
symptoms, making it a possible therapeutic option for treating
depression in individuals with RLS/WED. Further studies are
needed to clarify if bupropion is effective as a primary treat-
ment for moderate to severe RLS/WED [88].
The drugs currently available for the treatment of the
disease do not always allow optimal control of symptoms,
in particular in long-term treatment. This clearly questions
the long-term treatment strategies in RLS/WED and underlies
the need for complementary, alternative and novel therapies.
This would be better achieved when the pathophysiology of
RLS is deciphered [19]. To date, the pathogenetic mechan-
isms underlying RLS/WED have not been completely under-
stood and represent the most stimulating research field in
this pathology. Apart from dopamine and iron, ongoing
researches are showing that glutamatergic and adenosine
neurotransmitters might in fact play a role in the pathogen-
esis of RLS/WED, possibly leading to new treatments. An
integral model involving iron, dopamine, glutamate, adeno-
sine, and opiate pathways still needs to be fully understood.
Although many of the identified genes appear to be involved
in neural development, their specific functions and their role
in RLS/WED pathophysiology remain to be discovered.
A better understanding of the pathophysiology will ulti-
mately assist in the detection and development of new
treatments that will specifically target the disease [89,90].
Most new trials are now focusing on nondopaminergic treat-
ment options, and future studies will include IV iron treatments
and substances that act on adenosine and glutamate. MAO-B
inhibitors are discussed among potential candidates to spare
dopamine agonists, but further studies are needed to prove
their efficacy [91,92]. Finally, further studies are needed to confirm
the positive effect of vitamin D supplementation on RLS/WED
symptoms. There is also a greater need to identify and develop
effective non-pharmacologic strategies to treat RLS/WED.
Funding
This manuscript was not funded.
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.
Referee disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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