Treatment of Restless Legs Syndrome: Evidence-Based Review and Implications for Clinical Practice (Revised 2017)
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REVIEW
Treatment of Restless Legs Syndrome: Evidence-Based Review
and Implications for Clinical Practice (Revised 2017)§
Juliane Winkelmann, MD,1,2,3†* Richard P. Allen, PhD,4,5 Birgit Ho
€gl, MD,6 Yuichi Inoue, MD,7,8 Wolfgang Oertel, MD,9
1,9 10,11
Aaro V. Salminen, PhD, John W. Winkelman, MD, Claudia Trenkwalder, MD,12,13 and Cristina Sampaio, MD14‡
1
Institute of Neurogenomics, Helmholtz Zentrum Mu €nchen, Munich, Germany
2
Department of Neurology and Department of Human Genetics, Klinikum rechts der Isar, Technical University, Munich, Germany
3
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
4
Sleep Disorders Center, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, USA
5
Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
6
Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
7
Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan
8
Department of Somnology, Tokyo Medical University, Tokyo, Japan
9
Department of Neurology, Philipps-Universita €t Marburg, Marburg, Germany
10
Harvard Medical School, Boston, Massachusetts, USA
11
Departments of Psychiatry and Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
12
Department of Neurosurgery, University Medical Center, Goettingen, Germany
13
Paracelsus-Elena Hospital, Kassel, Germany
14
CHDI Foundation, Princeton, Princeton, NJ, USA, and the Instituto de Medicina Molecular, University of Lisbon, Lisbon, Portugal
A B S T R A C T : The objective of the current review was to valproic acid are considered likely efficacious. Oral iron is non-
update the previous evidence-based medicine review of treat- efficacious in iron-sufficient subjects, but its benefit for patients
ments for restless legs syndrome published in 2008. All ran- with low peripheral iron status has not been adequately evalu-
domized, controlled trials (level I) with a high quality score ated. Restless legs syndrome augmentation has been identi-
published between January 2007 and January 2017 were fied as a significant long-term treatment complication for
reviewed. Forty new studies qualified for efficacy review. Pre- pramipexole more than pregabalin and possibly for all dopami-
gabalin, gabapentin enacarbil, and oxycodone/naloxone, nergic agents more than a2d ligands. Therefore, special moni-
which did not appear in the previous review, have accrued toring for augmentation is required for all dopaminergic
data to be considered efficacious. Likewise, new data enable medications as well as tramadol. Other drugs also require spe-
the modification of the level of efficacy for rotigotine from likely cial safety monitoring: cabergoline, pergolide, oxycodone,
efficacious to efficacious. Intravenous ferric carboxymaltose methadone, tramadol, carbamazepine, and valproic acid.
and pneumatic compression devices are considered likely effi- Finally, we also highlighted gaps and needs for future clinical
cacious in idiopathic restless legs syndrome. Bupropion and research and studies of restless legs syndrome. V C 2018 Inter-
clonidine were reviewed, but the lack of data determined a rat- national Parkinson and Movement Disorder Society
ing of insufficient evidence for efficacy. The following interven-
tions continue to be considered efficacious as in 2008: K e y W o r d s : restless legs syndrome (RLS); evi-
levodopa, ropinirole, pramipexole, cabergoline, pergolide, and dence-based medicine; guidelines; MDS recommenda-
gabapentin. Bromocriptine, oxycodone, carbamazepine, and tions; therapy; treatment; augmentation
------------------------------------------------------------------------------------------------------------------------------
*Correspondence to: Juliane Winkelmann, Institute of Neurogenomics, honoraria from UCB, Otsuka, and Mundipharma. Yuichi Inoue reports receiv-
€dter Landstrasse 1, 85764
€nchen, Ingolsta
Helmholtz Zentrum Mu ing honoraria from Astellas and Otsuka. Wolfgang Oertel reports consultancy
Munich-Neuherberg, Germany; juliane.winkelmann@tum.de with UCB. Aaro V. Salminen reports no conflicts of interest. John Winkelman
§ reports consultancy with Luitpold Pharmaceuticals. Claudia Trenkwalder
Produced by a task force commissioned by the International Parkinson reports receiving honoraria from UCB, Mundipharma, and Vifor. Cristina
and Movement Disorder Society Sampaio reports no conflicts of interest.
†
Chairperson RLS EBM Task Force Received: 19 October 2016; Revised: 25 October 2017;
‡
Member of the Committee of Evidence-Based Medicine Accepted: 27 October 2017
Relevant conflicts of interest/financial disclosures: no funding was Published online 00 Month 2018 in Wiley Online Library
received in support of this article. (wileyonlinelibrary.com). DOI: 10.1002/mds.27260
Juliane Winkelmann reports no conflicts of interest. Richard Allen reports
consultancy with Luitpold Pharmaceuticals. Birgit Ho €gl reports receiving
Movement Disorders, Vol. 00, No. 00, 2018 1W I N K E L M A N N E T A L
For almost 25 years patients with restless legs syn- movements. Single treatments are reviewed indepen-
drome (RLS) have been examined in controlled trials. dently rather than as part of a management strategy.
It is evident that the most common treatment side As in the previous review, combination therapies have
effect encountered in RLS, “augmentation,” is related not yet been investigated in level I RLS trials and
to dopaminergic treatment. Augmentation emerges as therefore could not be reviewed. The task force’s rec-
an adverse effect with the longer-term use of these ommendations for practical use are given in the Impli-
medications. Dopaminergic drugs were approved for cations for Clinical Practice sections after the
RLS treatment between 2004 and 2008. Nondopami- conclusions for each drug or class of drugs. These rec-
nergic substances, such as a2d ligands and opioids, ommendations cannot take into account country-
have been investigated in recent research programs. specific regulations, and therefore the task force is
They appear to be as effective as dopaminergic treat- only able to provide a general summary, including rec-
ment, can be used according to clinical needs, and ommendations for clinical practice, but does not pro-
provide alternative initial treatments for RLS. At this vide guidelines for RLS treatment.
time, the use of these drugs is somewhat less frequent Efficacy was determined through the evaluation of
worldwide than dopaminergic medications, as only level I studies; lower-quality studies were not reviewed
gabapentin enacarbil has received approval for the (see Table 1 for levels of evidence). All conclusions
treatment of RLS in the United States and Japan. Clin- were agreed on by the members of the task force. Def-
ical experience with very long-term use of nondopami- initions for specific recommendations are given in
nergic drugs in RLS has generally not been published. Table 2. This evidence-based review does not include
However, some agents have been evaluated in trials quantitative summaries (no meta-analyses were con-
lasting 1 year and, unlike dopaminergic medications, ducted) of the different data sets. The qualitative
have not been shown to cause augmentation. Gaps approach, such as the one undertaken here, is an
remain between current treatment trials and clinical important contribution to highlight the evidence avail-
practice, as treatment studies have failed to address able and facilitates the inclusion of some subjectivity
certain issues, such as the use of combinations of and expert opinion. This is explicitly limited to the 2
drugs and divided doses over the day, as well as the sections within each paragraph titled: (1) Implications
optimal management of augmentation under dopami- for Clinical Practice and (2) Implications for Clinical
nergic treatment. Independently, many case studies of Research.
various interventions have been reported. Still, there is Methodological limitations of this review have been
no new class of pharmacological substance available identified. Although publications in some non-English
for patients, and aside from iron replacement, only languages were not reviewed, the literature search
symptomatic treatment strategies are used. included English and several non-English languages
To assess the current state of treatment for RLS and (Italian, French, German, and Portuguese). This lan-
its implications for clinical practice and to ascertain guage bias may have inflated positive results.3-5
which gaps in the knowledge need to be bridged, it Another methodological limitation is caused by the
was necessary to perform an update of the previous primary sources of evidence being electronic data-
International Parkinson and Movement Disorder Soci- bases, which provide incomplete lists of articles.6
ety (MDS) evidence-based review of the literature.
Consequently, the MDS commissioned a task force to Aims and Goals
perform an evidence-based review of current treatment
strategies in RLS.1 The members of this MDS- The aims of this evidence-based review were to eval-
appointed task force, who are also the authors of the uate the evidence on therapeutic interventions for
present article, are movement disorder and/or sleep RLS. The current review includes articles published
specialists with extensive experience in treating RLS between January 2007 until January 2017. The clini-
from Europe, Asia, and North America. cal efficacy, safety, and RLS-specific safety problems
of these interventions are evaluated. In addition, the
Strategic Options implications of this evidence for clinical practice are
considered.
In this review, the task force evaluates the therapeu-
Similarly to the previous review, the specific goals of
tic efficacy of each drug, and reports on implications
the current review were to:
for clinical practice and research using the metho-
dology standardized by the MDS Committee for 1. Review the literature and identify the clinical evi-
Evidence-Based Medicine and used in the previous dence that supports specific pharmacological and
review (2008).2 The task force has also chosen to nonpharmacological treatments for RLS;
include a section on augmentation but decided not to 2. Determine which studies are scientifically sound
address the effect of medication on associated condi- so they can be used as evidence to support or
tions such as depression, sleep, and periodic leg condone specific treatments in clinical practice;
2 Movement Disorders, Vol. 00, No. 00, 2018T R E A T M E N T O F R L S
TABLE 1. Levels of evidence search of articles published between January 2007 and
January 2017.
Level of evidence Definition
Level I studies Randomized, controlled trials Evidence-Based Conclusions
Level II studies Controlled clinical trials or observational
controlled studies such as cohort or
Following a review of the literature, the EBM task
case-control studies force members determined the quality of evidence pro-
Level III studies Noncontrolled studies like case series vided by the studies (see table 3) and reached a consen-
sus on the efficacy and safety of each therapeutic
Adapted from the American Academy of Neurology classifications of evi- intervention (Table 4), as well as implications for clini-
dence (appendix E-1, the Neurology web ite at www.neurology.org).
cal practice and research. For those therapeutic agents
for which data were lacking, the task force was unable
to make a relevant recommendation pertaining to effi-
3. Identify where specific evidence is lacking, so
cacy. Where no evidence was available, this was clearly
future research efforts may be directed toward
stated. The criteria for specific recommendations are
addressing these specific areas of need; and
summarized in Table 2. No treatment recommenda-
4. Separately identify the RLS-specific side effect,
tions according to the quality of evidence were made.
which is augmentation.
Results
Methods
General Remarks
The methodological approach taken was that All new studies included in the current review
defined by the MDS Committee of Evidence-Based include patients with moderate to severe RLS symp-
Medicine with specific adjustments for RLS (see sup- toms and normal ferritin levels. The conclusions are
plementary material for details of methods and Sup- presented and compared with the previous treatment
plementary Evidence Tables e-1 and e-2 for an guidelines2 in Table 4, with new conclusions appear-
overview of studies reviewed) and included a literature ing in bold typeface.
TABLE 2. Definitions for specific recommendations
Efficacy conclusions Definition Required evidence
Efficacious Evidence shows that the intervention has a Supported by data from at least 1 high-
positive effect on studied outcomes quality (score > 75%) randomized, con-
trolled trial without conflicting level I data
Likely efficacious Evidence suggests, but is not sufficient to Supported by data from any level I trial with-
show, that the intervention has a positive out conflicting level I data
effect on studied outcomes
Investigational Evidence suggests that the intervention does Supported by data from any level I trial with-
not have a positive effect on outcomes out conflicting level I data
Insufficient evidence Evidence shows that the intervention does Supported by data from at least I high-
not have a positive effect on studied quality (score > 75%) randomized, con-
outcomes trolled trial without conflicting level I data
Nonefficacious There is not enough evidence either for or All the circumstances not covered by the
against efficacy of the intervention in the previous statements
treatment of restless legs syndrome
Safety conclusions
Acceptable risk without special monitoring
Acceptable risk, with special monitoring
Unacceptable risk
Insufficient evidence to make conclusions on the safety of the intervention
Implications for clinical practice
Clinically useful For a given situation, evidence available is sufficient to conclude that the intervention provides clinical benefit
Possibly useful For a given situation, evidence available suggests but is insufficient to conclude that the intervention provides
clinical benefit
Investigational Available evidence is insufficient to support the use of the intervention in clinical practice, but further study is
warranted
Not useful For a given situation, available evidence is sufficient to say that the intervention provides no clinical benefit
Efficacy unlikely Evidence suggests that the intervention does not have a positive effect on studied outcomes; supported by data
from any level I trial without conflicting level I data
Movement Disorders, Vol. 00, No. 00, 2018 3W I N K E L M A N N E T A L
TABLE 3. Rating scale for quality of evidence
Rating scale: efficacy
Results
Item 1 Is an estimate of the treatment effect given?
Item 2 Is the reported treatment effect of clinical importance?
Item 3 Is the estimate of treatment effect sufficiently precise?
Validity: selection
Item 4 Was the spectrum of patients well defined?
Item 5 Was the diagnosis of RLS well defined?
Item 6 Were the eligibility criteria used suitable for the study?
Measurement
Item 7 Was assignment to treatments stated to be random?
Item 8 If yes, was the method of randomization explained?
Item 9 Were all patients accounted for after randomization?
Item 10 Were losses to follow-up low (T R E A T M E N T O F R L S
TABLE 4. Summary of recommendations (new conclusions in bold)
Intervention Efficacy in 2008 Efficacy in 2017 Safety
Levodopa Efficacious for the treatment of Efficacious for the treatment of Acceptable risk with special
RLS idiopathic and uremic RLS monitoring for augmentation
Ropinirole Efficacious for the treatment of Efficacious for the treatment of Acceptable risk with special
idiopathic RLS at a dose of idiopathic RLS at a dose of monitoring for augmentation
0.25-4 mg 0.78-4.6 mg
Rotigotine Likely efficacious for the Efficacious for the treatment of Acceptable risk with special
treatment of RLS idiopathic RLS at a dose of monitoring for local site
2-3 mg reactions and augmentation
Pramipexole Efficacious for the treatment of Efficacious for the treatment of Acceptable risk with special
idiopathic RLS at a dose of idiopathic RLS at doses of monitoring for augmentation
0.75 mg 0.25, 0.50, and 0.75 mg
Cabergoline Efficacious for the treatment of Efficacious for the treatment of Acceptable risk with
RLS RLS at a dose of 2-3 mg cardiopulmonary monitoring for
fibrosis, as well as special
monitoring for augmentation;
contraindicated in patients with
a history of cardiac,
pulmonary, or retroperitoneal
fibrosis or signs of cardiac
valve abnormalities
Pregabalin N/A Efficacious for the treatment of Acceptable risk without special
RLS at a dose of 150-450 mg monitoring
Gabapentin enacarbil N/A Efficacious for the treatment of Acceptable risk without special
RLS at a dose of 1200 mg; monitoring
insufficient evidence to
conclude on the efficacy at a
dose of 600 mg
Gabapentin Efficacious for the treatment of Efficacious for the treatment of Acceptable risk without special
RLS idiopathic RLS at a dose of monitoring
800 mg and uremic RLS at a
dose of 200 mg
Oxycodone/naloxone N/A Efficacious in patients with Acceptable risk with special mon-
severe treatment-resistant itoring in those with addictive
RLS tendencies. Possible sleep-
related respiratory problems
should be monitored
Oxycodone Likely efficacious for the relief of Likely efficacious for the relief of Acceptable risk with special mon-
the symptoms of RLS in those the symptoms of RLS in those itoring in those with addictive
with significant daily with significant daily tendencies. Possible sleep-
symptoms symptoms related respiratory problems
should be monitored
Bupropion N/A Insufficient evidence to Insufficient evidence to conclude
conclude on efficacy on safety
Clonidine Efficacious for the treatment of Investigational Insufficient evidence to conclude
RLS on safety
Oral iron preparations Not efficacious for the treatment Insufficient evidence to Acceptable risk without special
of iron-sufficient RLS patients; conclude on efficacy monitoring
investigational in the treatment
of iron-deficient RLS patients
Intravenous ferric carboxymaltose N/A Likely efficacious for the Acceptable risk without special
treatment of RLS monitoring
Intravenous iron sucrose N/A Insufficient evidence to Acceptable risk without special
conclude on efficacy monitoring
Intravenous high-molecular- Likely efficacious for the Likely efficacious for the Unacceptable risk
weight iron dextran treatment of uremic RLS; treatment of uremic RLS
investigational in the treatment
of idiopathic RLS
Vitamins C and E N/A Likely efficacious for the Acceptable risk without special
treatment of uremic RLS monitoring
Exercise Investigational Likely efficacious for the Acceptable risk without special
treatment of uremic RLS monitoring
Pneumatic compression devices N/A Likely efficacious for the Acceptable risk without special
treatment of RLS monitoring
Movement Disorders, Vol. 00, No. 00, 2018 5W I N K E L M A N N E T A L
Conclusions. The new level I studies reported here Implications for Clinical Practice. There is sufficient
enable the efficacy conclusion for transdermal rotigo- evidence to conclude that ropinirole is clinically useful for
tine to be changed from likely efficacious to efficacious both RLS symptoms and improving sleep in patients with
at doses of 2-3 mg. There is insufficient evidence for the moderate to severe clinical symptomatology. One trial
1-mg dose, and 0.5 mg is considered nonefficacious. comparing ropinirole with gabapentin found that they
were equally efficient in treating RLS, but this study only
Safety. Acceptable risk with special monitoring for included 16 patients who were treated for 4 weeks.24
local site reactions and augmentation.
Implications for Clinical Research. Given the high
Implications for Clinical Practice. There is sufficient rate of augmentation for ropinirole, further study is
evidence to conclude that rotigotine transdermal patch needed exploring the biology of augmentation and
is clinically useful for the management of RLS in possible methods to reduce the risk and severity of its
patients with moderate to severe clinical symptomol- occurrence.
ogy. Special concerns about “sleep attacks” have not
been raised, whereas application-site reactions have Pramipexole: 6 New Studies31-36;
been relatively frequent. No New Conclusions
Five level I trials were included in the previous
Implications for Clinical Research. Long-term trials
review37-41; these studies, varying in duration from 3 to
with rotigotine need to be undertaken to monitor local
12 weeks, found pramipexole at doses of 0.25, 0.50, and
site reactions and augmentation, and dose and treat-
0.75 mg to be effective in reducing RLS symptoms and
ment duration dependence need to be taken into con-
improving quality of life. Six more-recent studies qualify
sideration. Similarly to pramipexole and ropinirole,
for inclusion in the present review,31-34,36 including 1
further study is needed exploring the biology of aug-
comparative trial.35 These new studies range in duration
mentation and possible methods to reduce the risk
from 6 to 56 weeks (see supplementary material).
and severity of its occurrence.
Conclusions. Pramipexole (at doses of 0.25, 0.50,
Ropinirole: 2 New Studies22,23;
No New Conclusions and 0.75 mg) is considered efficacious for the treat-
ment of RLS.
Seven level I trials were included in the previous
review.24-30 These studies, varying in duration from 4 Safety. Acceptable risk with special monitoring for
to 26 weeks, found ropinirole at mean doses between augmentation.
0.78 and 4.6 mg to be effective in reducing RLS symp-
toms and improving quality of life and sleep parame- Implications for Clinical Practice. There is sufficient
ters. Two more-recent studies qualify for inclusion in evidence to conclude that pramipexole is clinically
the current review (see supplementary material).22,23 useful for the management of RLS in patients with
moderate to severe clinical symptomology. Subjective
Conclusions. Ropinirole (0.78 to 4.6 mg) is consid- reports of sleep, general RLS severity, and depressive
ered efficacious for treating RLS. and anxiety symptoms improved. Special concerns
about “sleep attacks” have not been raised.
Safety. Ropinirole is considered to pose an accept-
able risk, with special monitoring for augmentation. Implications for Clinical Research. Given the high
Only 1 study evaluated augmentation prospectively, rate of augmentation for pramipexole, further study is
reporting an incidence of 4% at 26 weeks.23 needed exploring the biology of augmentation and
From the available published clinical trials, there is no
possible methods to reduce the risk and severity of its
evidence that the incidence of adverse reactions is lower
occurrence.
or higher than with any other available dopamine ago-
nist, and there are no specific concerns about hypersom- Ergot-Derived Dopamine Agonists
nolence in RLS patients. There has been no specific
monitoring for dopamine dysregulation syndrome. The Since the previous review, no further study with an
majority of level I studies of ropinirole last 12 weeks, ergot-derived dopamine agonist in RLS has been
whereas the more recent long-term study included in published.
this current review followed patients for a total of 66
weeks (26 weeks double-blind and 40 weeks open- Cabergoline: No New Studies;
label). This recent study23 is also the first to prospec- No New Conclusions
tively evaluate the incidence of augmentation with ropi- Three randomized, controlled trials (level I) were
nirole, finding an incidence of 4% at 26 weeks. included in the earlier review,15,42,43 but only one of
6 Movement Disorders, Vol. 00, No. 00, 2018T R E A T M E N T O F R L S
these, the abovementioned comparative study by material). See the Augmentation section for details on
Trenkwalder et al,15 meets the current inclusion crite- augmentation.
ria. This study reported a statistically significant im-
provement in RLS symptoms with cabergoline (2- Conclusions. Pregabalin is efficacious for the treat-
3 mg) compared with levodopa/benserazide (300/ ment of moderate to severe idiopathic RLS when given
75 mg). at doses between 150 and 450 mg/day, 1-3 hours
before bedtime.
Conclusions. Cabergoline (2-3 mg) is considered effi-
cacious for the treatment of RLS, but special monitor- Safety. Acceptable risk without special monitoring.
ing is necessary.
Implications for Clinical Practice. Pregabalin is con-
Safety. Cabergoline is contraindicated in patients sidered clinically useful and has been shown to be
with a history of cardiac, pulmonary, or retroperito- noninferior to pramipexole. Given that pregabalin is
neal fibrosis or signs of cardiac valve abnormalities; metabolized renally, lower doses may be necessary in
therefore, the task force concludes that cabergoline is older populations, who may also experience dizziness
considered to pose an acceptable risk, with cardiopul- and somnolence. Side effects may be dose dependent.
monary monitoring for fibrosis as well as special mon- Pregabalin has been shown to improve sleep architec-
itoring for augmentation. ture. There have been suggestions that pregabalin may
be preferentially effective in patients who describe
Implications for Clinical Practice (unchanged from their sensory discomforts as pain; however, the evi-
previous review)2. There is sufficient evidence to con- dence for this is lacking.
clude that cabergoline is efficacious for the manage-
ment of RLS in patients with moderate to severe RLS Implications for Clinical Research. Although the evi-
including patients with daytime RLS. Sleep, and RLS dence establishes pregabalin as clinically useful, long-
severity, considerably improved. Cabergoline is the term studies, studies in those with renal impairment,
only dopamine agonist to be compared with levodopa and data on withdrawal are lacking. Further studies
in a large-scale controlled trial and has been shown to are also needed to determine whether low doses may
be superior to the latter. be efficacious in certain patients—dose effect using
It is important to note that in the United States, regression showed the greatest efficacy at doses of
where the U.S. Food and Drug Administration has !150 mg.
withdrawn the ergot-dopamine agonist pergolide from
the market, cabergoline has only been approved for Gabapentin Enacarbil: 7 New Studies46-52;
hyperprolactinemic disorders. New Conclusion: Efficacious
Trials on gabapentin enacarbil were not available at
Implications for Clinical Research (unchanged from the time of the previous review. Since 2008, 7 ran-
previous review)2. Long-term trials with cabergoline domized, controlled trials (level I), which examined
need to be undertaken with better monitoring of the efficacy of gabapentin enacarbil in RLS, have been
the potential side effects such as fibrosis (especially published that qualify for inclusion.46-52 These 7 high-
heart valve fibrosis), augmentation, and compulsive quality studies,46-52 ranging in duration from 2 to 12
behaviors. weeks, indicate that gabapentin enacarbil is efficacious
up to 12 weeks at a dose of 1200 mg. A high rate of
a2d Ligands dropouts compared with placebo is striking in several
studies (see supplementary material).46-49
Pregabalin
Review of Clinical Studies: 3 New Studies35,44,45; Conclusions. Gabapentin enacarbil is efficacious at a
New Conclusion: Efficacious dose of 1200 mg. There is insufficient evidence to
Pregabalin is a new drug to appear in this review. make a conclusion about the efficacy of the 600-mg
Since the previous review, 3 randomized, controlled dose, with 1 study showing efficacy at 600 mg49 and 2
trials (level I), which examined the efficacy of pregaba- studies that did not.46,50
lin in more than 900 RLS patients over 6-52 weeks,
have been published that qualify for inclusion.35,44,45 Safety. Acceptable risk without special monitoring.
No new side effects were observed compared with
those already known from registration trials for the Implications for Clinical Practice. There are no
indications “seizure/epilepsy” and “neuropathic pain.” major safety concerns with gabapentin enacarbil.
The most frequently reported AEs were dizziness, Adverse effects are fairly common and include dizzi-
somnolence, fatigue, and headache (see supplementary ness and somnolence, which should be specifically
Movement Disorders, Vol. 00, No. 00, 2018 7W I N K E L M A N N E T A L
monitored in older patients. Side effects may be dose this combination modality should be explored further.
dependent. Gabapentin enacarbil has not been used in There has also been a suggestion in some reports that
divided doses in the abovementioned trials. No long- gabapentin may be preferentially effective in patients
term studies > 12 weeks are available, and long-term who describe their sensory discomforts as pain and
efficacy needs to be studied. that more severe RLS may not respond to gabapentin;
however, the evidence for these limitations is not con-
Implications for Clinical Research. The available evi- clusive. Another issue is whether the sedative aspect of
dence establishes the usefulness of gabapentin enacar- the drug might be especially helpful in those with RLS
bil in RLS over the short term and as a potential emergent primarily immediately before or during
initial treatment for RLS. As with all a2d ligands, sleep.
there is a clinical suggestion that gabapentin enacarbil
may be preferentially effective in patients whose RLS a2d Ligands: General Implications
symptomatology is focused on sensory discomforts, for Clinical Research
and the sedative aspect of the drug might be especially This group of medications is an attractive thera-
helpful in those with RLS emergent primarily at sleep peutic alternative to dopaminergics, particularly for
onset or with an additional insomnia problem. Long- initial treatment. They have been found to have
term studies on both efficacy and safety are needed. more or equivalent efficacy to therapeutic doses of
the dopamine agonists, and they do not have the
Gabapentin: No New Studies; No New
dopaminergic problems of augmentation, compulsive
Conclusions
behaviors, or profound daytime sleepiness. Gabapen-
Four level I trials were included in the previous tin has been used for many years for pain without
review14,24,53,54; these studies varied in duration from showing any unexpected long-term complications,
4 to 12 weeks. Gabapentin has been studied in com- but similar experience is not available for RLS. The
parison with other agents: a dopamine agonist24 in the other 2 a2d ligands, gabapentin enacarbil and prega-
treatment of idiopathic RLS and a levodopa prepara- balin, are relatively new, so clinical experience for
tion in the treatment of patients with RLS and renal more than 2-4 years is limited, but so far there have
failure on dialysis.14 In patients with normal kidney been no reports of the emergence of unexpected
function, effective doses were within the range typi- adverse effects with longer-term use. The a2d ligands
cally used for seizure or pain control.54 However, have an advantage of improved sleep and no signifi-
much lower doses were used in the dialysis samples cant augmentation, but they are limited by the
because gabapentin is eliminated renally. adverse effect of dizziness, which may be a problem
for older patients. In addition, daytime sleepiness
Conclusions. Gabapentin is efficacious for the treat- may be a problem. It would be useful to provide a
ment of RLS at a dose of 800 mg, and at 200 mg for clinical case series of long-term use of these drugs
patients undergoing hemodialysis. and to have long-term clinical trials comparing these
with the longer-acting dopaminergic agents. Finally,
Safety. Acceptable risk without special monitoring. in RLS patients consuming alcohol or taking other
classes of drugs for comorbidity, the interaction and
Implications for Clinical Practice. Gabapentin is used
additive effects of anticonvulsants have to be taken
off-label in RLS patients in several countries. A combi-
into account.
nation treatment of gabapentin together with other
medications is used, but has not been investigated.
Opioids
There are no major safety concerns with gabapentin.
Oxycodone-Naloxone: One New Study55;
Side effects are fairly common, and older patients may
New Conclusion: Efficacious
experience dizziness, somnolence, and peripheral
edema. Side effects may be dose dependent. Unlike for Treatment-Resistant RLS
dopaminergic agents, gabapentin has been used in One level I study in 304 subjects qualified for inclu-
divided doses in trials. sion in the present review.55 This was a 12-week study
that sought to assess the efficacy and safety of a fixed-
Implications for Clinical Research. Although the evi- dose combination of prolonged-release oxycodone-nal-
dence establishes the usefulness of gabapentin in RLS, oxone (5.0/2.5 mg twice daily uptitrated to a maxi-
there have not yet been the large multicenter studies mum dose of 40/20 mg twice daily) in patients with
that can provide a better estimate of the range of ben- severe RLS (see supplementary material).
efits and safety issues. There is a clinical suggestion
that gabapentin may be a useful supplementary medi- Conclusions. Based on this high-quality level I
cation for those on dopaminergic therapy in RLS, and study, oxycodone-naloxone (mean dose, 21.9 mg) is
8 Movement Disorders, Vol. 00, No. 00, 2018T R E A T M E N T O F R L S
considered efficacious in patients with severe in RLS patients under opioid medication.57 This is of
treatment-resistant RLS. greater concern in those with preexisting respiratory
compromise. When treating patients with opioids, it is
Safety. Acceptable risk with special monitoring in necessary to be aware of the addiction potential, espe-
those with addictive tendencies. Possible sleep-related cially in those with preexisting addictive tendencies or
respiratory problems should be monitored. a known history of addiction. In clinical practice
opioid-opioid interactions should be a caveat in
Implications for Clinical Practice. This high-quality patients cotreated by several doctors or for those with
study has demonstrated that oxycodone-naloxone is RLS and other pain conditions.
efficacious and well tolerated in patients with severe
RLS—the mean International RLS Study Group Rat- Opioids: General Implications
ing Scale (IRLS) total score at baseline was 28.6 in the for Clinical Practice
above study—and in those who are resistant to treat- Oxycodone combined with naloxone is considered
ment with other drugs. clinically useful for the treatment of severe treatment-
resistant RLS at a mean dose of 21.9/11.0 6 7.5 mg up
Implications for Clinical Research. See Opioids: Gen-
to 12 weeks. Oxycodone alone is likely efficacious, as
eral Implications for Clinical Research, below.
concluded from the single controlled study available.
Many patients are treated with opioids, either as a
Oxycodone: No New Studies; No New
monotherapy or in combination with dopaminergic
Conclusions
drugs, although trials of combination therapy are not
One level I study56 was included in the previous available. It is noted, however, that other opioids such
review. No further studies of oxycodone alone (see as tramadol are often used to treat RLS. Little is
above for oxycodone-naloxone) have been published, known about the long-term efficacy in RLS. Special
and therefore the previous conclusions remain monitoring is required to avoid addiction in those
unchanged. with addictive tendencies, and possible sleep-related
respiratory problems need to be monitored.
Conclusions. Based on 1 controlled study,56 oxyco-
done is likely efficacious for the relief of the symptoms Opioids: General Implications
of RLS in those with significant daily symptoms and is for Clinical Research
widely used in various countries for pain syndromes.
The major issue with opioids is the small number of
For pain relief, oxycodone is usually prescribed in com-
controlled studies. The single randomized, controlled
bination with other nonopioid analgesics. It is also
trial of oxycodone-naloxone55 covers only one of the
available in an extended-release formulation. It has been
drugs that is commonly used in the clinical setting to
subject to abuse in its immediate-release form or when
treat RLS. Two major issues in the studies of these med-
the extended-release formulation is used improperly.
ications have been the reluctance of the manufacturers
Safety. Acceptable risk with special monitoring in to extend the range of opioid indications and the prob-
those with addictive tendencies. Possible sleep-related lems of dependence and the related controlled status of
respiratory problems should be monitored. opioids. Additional controlled and comparative studies
would be very beneficial, especially if they focused on
Implications for Clinical Practice. See Opioids: Gen- methadone and tramadol, which were excluded from
eral Implications for Clinical Practice, below. this review due to lack of new published studies, as well
as combinatory therapies with dopaminergics.
Implications for Clinical Research. See Opioids: Gen-
eral Implications For Clinical Research, below. Antidepressants
Bupropion: 1 New Study; New Conclusion58:
Opioids: General Conclusions Investigational
As stated in the previous review,2 opioids when taken Bupropion, a dopamine-enhancing substance, did not
at a sufficient analgesic dose cause a series of minor appear in the previous review. Since then, 1 randomized,
and major adverse effects. Dizziness, nausea, vomiting, controlled study (level I) 58 in patients with idiopathic
urinary retention, and constipation can all occur with RLS has been published that qualified for inclusion in
recommended doses. Respiratory depression is a major the current review (see supplementary material).
concern, especially at higher doses or with the more
potent agents. This was addressed in 1 long-term case Conclusions. This 1 small, underpowered study pro-
series that did not qualify for inclusion in the efficacy vides insufficient evidence to make a conclusion about
part of this review, but reported respiratory depression the efficacy of bupropion for the treatment of RLS.
Movement Disorders, Vol. 00, No. 00, 2018 9W I N K E L M A N N E T A L
Safety. There is insufficient evidence to make a con- previous study by Davis et al61 reported unlikely ther-
clusion on the safety of bupropion in RLS. apeutic benefit from oral iron to patients with ade-
quate iron body stores. The study by Wang et al.61 on
Implications for Clinical Practice. Bupropion is con- the other hand, reported a possible benefit to patients
sidered investigational for the treatment of RLS. with low-normal serum ferritin (see supplementary
material). So far, no level I studies have been pub-
Implications for Clinical Research. Sufficiently pow- lished in iron-deficient RLS patient groups.
ered studies are needed to establish the efficacy of
bupropion in RLS and to investigate whether adding Conclusions. There is insufficient evidence to make a
bupropion to a selective serotonin reuptake inhibitor conclusion about the efficacy of oral ferrous sulfate.
(SSRI) would improve SSRI-induced symptoms of
RLS. Safety. Oral ferrous sulfate is considered to have an
acceptable risk without the need for special monitoring.
Clonidine: Review of Clinical Studies; No New
Studies; Previous Conclusion Revised According Implications for Clinical Practice (unchanged from
to Current Criteria previous review)2. Oral ferrous sulfate is considered
One level I study59 was included in the previous possibly useful in clinical practice.
review. No further studies have been published, and There is a possibility of iron overload in those with
therefore the previous was revised from efficacious to tendencies toward iron retention, especially hemochro-
investigational in accordance with the current criteria. matosis. Therefore, iron status needs to be monitored
before and periodically during treatment. The major
Conclusions. Clonidine is investigational in RLS for adverse effects involve gastrointestinal discomfort,
those patients who are primarily bothered by symp- especially constipation, but also include nausea, reflux,
toms at bedtime. abdominal pain, and diarrhea.
Safety. The major side effects of clonidine are xero- Implications for Clinical Research (unchanged from
stomia and sedation, with some patients having men- previous review)2. The efficacy and safety of oral
tal changes and headache. iron treatment, especially in those with low iron indi-
ces, need to be further established by well-designed,
Implications for Clinical Practice. Clonidine is con- well-controlled trials. It may be useful to examine dif-
sidered investigational for the treatment of RLS. ferent oral formulations beyond ferrous sulfate, such
as ferrous fumarate or ferrous gluconate.
Implications for Clinical Research. The ability of clo-
nidine to benefit RLS patients or a subcategory of
bedtime-onset RLS patients needs to be better estab- Intravenous Ferric Carboxymaltose
lished by larger, well-designed controlled trials. It Review of Clinical Studies: 2 New Studies63,64;
remains open to discussion whether clonidine should New Conclusion: Likely Efficacious
be considered for future RLS trials with respect to its
Intravenous ferric carboxymaltose appears for the
side-effect profile.
first time in this review, as no studies were available
at the time of the previous review. Since then 2 ran-
Minerals and Vitamins
domized, controlled trials have been published.63,64
Oral Iron Preparations (Oral Ferrous Sulfate): These studies assessed the efficacy of ferric carboxy-
1 New Study60; No New Conclusions maltose (either as 2 3 500-mg infusions63 or 1 3 1000-
One randomized, controlled study61 (level I) in mg infusion64 at 4-week63 and 6-week64 end points
patients with idiopathic and secondary RLS qualified (see supplementary material).
for inclusion in the previous review, and a case
series62 (level III) examining the efficacy of oral iron Conclusions. Intravenous ferric carboxymaltose
in idiopathic RLS and not RLS secondary to iron defi- (1000 mg) is considered to be likely efficacious for the
ciency was also included. One new study has been treatment of RLS.
published in patients with idiopathic RLS.60 As an
exception to the inclusion criteria, this study is pre- Safety. Intravenous ferric carboxymaltose is consid-
sented in the supplementary material despite a low ered to present an acceptable risk without special
quality score to demonstrate the level of evidence monitoring. Some regions require intravenous iron for-
available for oral iron therapy in RLS. The 2 level I mulations to be administered in a facility with cardiac
studies available have conflicting conclusions. A resuscitation.
10 Movement Disorders, Vol. 00, No. 00, 2018T R E A T M E N T O F R L S
Implications for Clinical Practice. Intravenous ferric for the treatment of RLS secondary to end-stage renal
carboxymaltose is considered possibly useful in clinical disease. However, the waning of effectiveness at 4
practice. weeks indicates that this treatment may need to be
repeated, if that is tolerable. Two level III trials of
Implications for Clinical Research. More data are intravenous HMW iron in RLS without renal failure
required to confirm the efficacy of intravenous ferric were positive, but because of the lack of controlled tri-
carboxymaltose; in particular, larger studies are needed. als, intravenous HMW iron must remain investiga-
tional for those RLS patients with normal renal
Intravenous Iron Sucrose function with special monitoring.
Review of Clinical Studies: 2 New Studies65,66;
New Conclusion: Insufficient Evidence Safety. Because of concerns about anaphylactic reac-
Intravenous iron sucrose is a new drug to appear in tions, HMW iron dextran is considered to present an
this review, as no studies were available at the time of unacceptable risk.
the previous review. Since then 2 randomized, con-
trolled trials65,66 have been published that examined
General Conclusions on Iron
the efficacy of iron sucrose in RLS, but only one of It needs to be stressed that the iron formulations dif-
these, an 11-week study of 1000 mg iron sucrose,66 fer in bioavailability, mode of action, and route of
qualifies for inclusion (see supplementary material). application (oral versus intravenous). Therefore, they
are treated separately as different medications. The
Conclusions. There is insufficient evidence to make a only formulations for which sufficient evidence enables
conclusion about the efficacy of intravenous iron a conclusion to be drawn are intravenous ferric car-
sucrose. boxymaltose, which is considered likely to be effica-
cious for the treatment of RLS, and HMW dextran,
Safety. Intravenous iron sucrose is considered to which is considered likely to be efficacious for treat-
have an acceptable risk without the need for special ment of RLS secondary to end-stage renal disease. For
monitoring. There is a possibility of iron overload in all other formulations, both oral and intravenous,
those with tendencies toward iron retention, especially there is insufficient evidence to make any conclusions.
hemochromatosis. Therefore, iron status needs to be Further controlled trials in larger cohorts are war-
monitored before and periodically during treatment. ranted with all iron formulations.
All intravenous iron formulations, similarly to oral
Implications for Clinical Practice. Intravenous iron iron formulations, require long-term monitoring for
sucrose is considered investigational for clinical practice. the development of iron overload and/or toxicity, with
careful attention to the possibility that patients may
Implications for Clinical Research. More random- have a tendency toward hemochromatosis.
ized, controlled studies are needed to examine the effi-
cacy of intravenous iron sucrose in RLS, both with Implications for Clinical Practice — Oral Versus
and without iron deficiency. In addition, long-term Intravenous Iron Administration (unchanged from
studies of intravenous iron sucrose are needed with previous review)2
special emphasis on the possibilities of iron overload The gastrointestinal side effects so prominent with
and respective adverse events. oral iron do not occur with intravenous iron therapy.
However, there is the same, if not greater concern
Intravenous High-Molecular-Weight Iron about a toxic iron overload. In addition, with the
Dextran (note that this formulation has been HMW dextran formulation, the risk of an anaphylac-
removed from the market in most of the world tic reaction has been reported. The risk is higher in
and is only listed here for exhaustivity) those with preexisting autoimmune or rheumatoid dis-
Review of Clinical Studies: No New Studies, No orders and can occur in as many as 3% of those given
New Conclusions this formulation. Fortunately, this formulation has
One randomized, controlled study67 and 2 level III been taken off the market. Anaphylactic reactions are
studies were included in the previous review. No fur- very rare for low-molecular-weight iron dextran and
ther studies have been published, and therefore the other nondextran intravenous iron formulations.
previous conclusions remain.
Implications for Clinical Research
2
Conclusions (unchanged from previous review) . One The efficacy and safety of intravenous iron need to be
level I study has shown intravenous high-molecular- established with larger, well-designed controlled trials.
weight (HMW) iron dextran to likely be efficacious A particular issue is how long the treatment effects last
Movement Disorders, Vol. 00, No. 00, 2018 11W I N K E L M A N N E T A L
and whether repeated doses will lead to adverse effects controlled trial assessing 3 weekly intradialytic cycling
of iron accumulation. Intravenous iron formulations sessions has been published since then that meets
that do not contain polymerized dextran, for example, inclusion criteria.69
ferric carboxymaltose, sodium ferric gluconate, and
iron sucrose, to date have not been associated with ana- Conclusions. An exercise regimen, as provided (see
phylaxis. Moreover, it may be important to note the rel- supplementary material), is considered likely effica-
ative lack of efficacy of the intravenous iron cious in reducing RLS symptoms in uremic patients.
formulations that release iron rapidly into the blood
(eg, iron sucrose) compared with those that release the Implications for Clinical Practice (unchanged from
iron very slowly over many hours (eg, ferric carboxy- previous review)2. An exercise regimen, as provided
maltose). This may reflect the issues of iron manage- (see supplementary material), is possibly useful in clin-
ment and transport to the brain. It will be important to ical practice. Exercise can cause difficulty in those in a
investigate these matters further. In general, we need to deconditioned state and may be the cause of various
know more about how iron is handled in RLS, which injuries. Therefore, all individuals entering an exercise
may be a primary abnormality in many patients, and program should be screened to be sure they were not
the causal role of iron deficiency for some RLS patients. at greater risk for injury or strain.
Moreover, as RLS is a heterogeneous disorder, there
may be subgroups of patients who tend to respond dif- Implications for Clinical Research (unchanged from
previous review)2. Because exercise has many com-
ferently to iron, and they need to be identified.
ponents and can be done at various times of the day,
it may be important to define just which aspects of
Vitamins C and E
exercise contribute to alleviating RLS and when is the
Review of Clinical Studies; 1 New Study68; optimal time of day to exercise.
New Conclusion: Likely Efficacious for the
Treatment of RLS in Uremic Patients Pneumatic Compression Devices
Vitamins C and E did not appear in the previous Review of Clinical Studies: 1 New Study; New
review. Since then 1 randomized, controlled study in Conclusion: Likely Efficacious
uremic RLS has been published, which meets the cur-
The previous review included no studies on pneu-
rent inclusion criteria.68 This single-center trial re- matic compression devices (PCDs). Since then 1 ran-
ported the efficacy of vitamins C and E in improving domized, sham-controlled trial has been published
RLS symptoms over the short term in uremic patients that meets the inclusion criteria of the present review
(see supplementary material). (see supplementary material).71
Conclusions. Vitamins C (200 mg) and E (400 mg) Conclusions. PCDs are considered likely efficacious
treatment are likely efficacious in uremic patients. in RLS.
Safety. Vitamins C and E pose an acceptable risk Safety. PCDs are considered to pose an acceptable
without special monitoring. risk without the need for special monitoring.
Implications for Clinical Practice. Vitamins C and E Implications for Clinical Practice. PCDs are consid-
are considered possibly useful for the treatment of ered possibly useful in clinical practice and may be an
RLS in patients undergoing hemodialysis. effective adjunctive therapy for RLS treatment.
Implications for Clinical Research. Further studies Implications for Clinical Research. Additional sham-
with larger samples are required to evaluate the long- controlled studies should be performed to confirm the
term efficacy and possible mechanisms of action of efficacy of this treatment for RLS and determine its
vitamins C and E in the treatment of uremic RLS. mechanism of action so that other, more practical solu-
tions addressing the same mechanism can be developed.
Other
Excluded From the Current Review
Exercise
Trials investigating the efficacy of carbamazepine,
Review of Clinical Studies: 1 New Study69; New valproic acid, topiramate, methadone, tramadol, clo-
Conclusion: Likely Efficacious for the Treatment nazepam, zolpidem, amantadine, folic acid, magne-
of RLS in Uremic Patients sium, and external counterpulsation were included in
One randomized, controlled trial70 was included in the previous review. None of these studies meet cur-
the previous review, and 1 new randomized, rent inclusion criteria, and no further trials have been
12 Movement Disorders, Vol. 00, No. 00, 2018T R E A T M E N T O F R L S
published, and therefore, according to the current They highlight the difficulties encountered when diag-
evaluation criteria, these drugs and interventions are nosing augmentation and at the same time the lack of
all considered investigational for RLS treatment. existing data on the treatment of augmentation.
Finally, the group was able to conclude that the likeli-
Augmentation hood of augmentation increases with duration of
Augmentation, an iatrogenic worsening of RLS treatment with dopaminergic agents. Future research
symptoms following treatment with dopaminergic on the basic mechanisms of augmentation in RLS is
agents, has been recognized as an important issue in urgently needed to understand this phenomenon. In
the management of RLS. Consequently, in addition to the future, treatment recommendations should be
evaluating the efficacy of drugs in treating RLS, the revised to address the prevention as well as the man-
task force reviewed each study for data on augmenta- agement of augmentation.
tion. Despite the number of quality studies reviewed, The identification of genetic risk variants and the
only 6 studies23,32,35,55,69,72 assessed augmentation functional follow-up of these variants have enabled
prospectively (see supplementary material). Given the the establishment of new concepts for the pathophysi-
sparse data and the variable durations and methods ology of RLS. Future studies should take the genomic
for evaluating augmentation in the abovementioned profile of patients into account to provide a more tai-
studies, it is impossible to make any evidence-based lored therapy for specific subgroups of RLS. Finally,
recommendations on augmentation. we want to emphasize that this article provides a com-
prehensive evidence-based review of existing treatment
studies but not guidelines for treating RLS. However,
Discussion this document can be used as a base to set up treat-
Since the first evidence-based review, the RLS field ment guidelines, which can be adjusted for different
has made important strides by developing new drugs. countries by taking local regulations and the availabil-
The new data accrued in the last 10 years in high- ity of medications into account.
quality trials have enabled updated conclusions on Acknowledgments: Wolfgang H. Oertel is Hertie Senior Research
treatment options already studied in the previous Professor, supported by the Charitable Hertie Foundation, Frankfurt/
review, but more important are the inclusion of prega- Main, Germany. The authors thank Anne-Marie Williams for her edito-
rial assistance.
balin, gabapentin enacarbil, and oxycodone/naloxone,
which were not mentioned in the previous review, and
their classification as efficacious for the treatment of
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