State of the art in restless legs syndrome therapy: Practice recommendations for treating restless legs syndrome

State of the Art in Restless Legs Syndrome Therapy: PracticeRecommendations for Treating Restless Legs Syndrome

Wolfgang H. Oertel, MD,1* Claudia Trenkwalder, MD,2 Marco Zucconi, MD,3 Heike Benes, MD,4

Diego Garcia Borreguero, MD,5 Claudio Bassetti, MD,6 Markku Partinen, MD,7

Luigi Ferini-Strambi, MD,3 and Karin Stiasny-Kolster, MD1

1Department of Neurology, Philipps-University, Marburg, Germany2Paracelsus-Elena Hospital, Center of Parkinsonism and Movement Disorders, Kassel, University of Goettingen, Germany

3Sleep Disorders Center, Vita-Salute San Raffaele University, Milan, Italy4Somni Bene Institute for Medical Research and Sleep Medicine Schwerin Ltd., Schwerin, Germany

5Fundacion Jimenez Diaz, Universidad Autonoma, Madrid, Spain6Department of Neurology, University of Zurich, Switzerland

7Skogby Sleep Clinic, Rinnekoti Research Centre, Espoo, Finland

Abstract: Dopaminergic agents are the best-studied agents andare considered first-line treatment of restless legs syndrome(RLS). Extensive data are available for levodopa, pramipexole,and ropinirole, which have approval for the indication RLS,and to a smaller extent for cabergoline, pergolide, and rotigo-tine. Apart from one recent study, comparing two active drugs(levodopa and cabergoline), no comparative studies have beenpublished. The individual treatment regimen with the mostappropriate agent concerning efficacy and side effects has to beselected by the treating physician. On the basis of these clinical

trials and expert opinion of the authors, a treatment algorithmis proposed to support the search for the optimal individualtreatment. Opioids and anticonvulsants such as gabapentine aresecond-line options in individual patients. Iron substitution isjustified in people with iron deficiency related RLS (ferritinconcentration lower than 50 �g/L). © 2007 Movement Disor-der Society

Key words: RLS; therapy; dopamine agonist; levodopa;opiod.

Restless legs syndrome (RLS) may be primary (ge-netic or idiopathic), secondary (i.e., related to other med-ical or neurological disorders), or arise from a combina-tion of factors (e.g., positive family history, irondeficiency, uremia). The most important “associations”of secondary RLS are with end-stage renal disease oriron deficiency. RLS may also develop during pregnancyor intensify or manifest during treatment with variousdrugs. Treatment recommendations based on high-levelevidence studies (Evidence Base Medicine Class I) canbe given mostly for primary RLS as reviewed in Refs.

1–3. Dopaminergic agents are the best-studied drugs todate mostly because of increasing interest of pharmaceu-tical companies in achieving approval for the indicationof RLS. However, only few and small studies have beencarried out with dopaminergic agents in uremic or iron-deficient RLS patients. No controlled studies have beenperformed in children, pregnant women, or RLS patientswith other secondary forms. In addition, only few studieshave been carried out with nondopaminergic compounds,some of which have shown promising therapeutic ef-fects, for example, with opioids and antiepileptics. Ac-cordingly, lack of controlled trials for many drug classesshould not be interpreted as negative evidence of effi-cacy. The treatment recommendations are based on evi-dence from studies published in peer-reviewed journals.When scientific data are absent, insufficient, or inconclu-sive, the recommendations are based upon a comprehen-sive review of the medical literature and by the authors’

*Correspondence to: Dr. Wolfgang H. Oertel, Department of Neu-rology, Center of Nervous Diseases, Rudolf-Bultmann-Strasse 8,D-35033 Marburg, Germany. E-mail: [email protected]

Received 17 January 2007; Revised 30 March 2007; Accepted 1April 2007

Published online 00 Month 2007 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mds.21545

Movement DisordersVol. 22, Suppl. 18, 2007, pp. S466–S475© 2007 Movement Disorder Society

S466

experiences in the treatment of RLS. The latter is ofparticular relevance, as the protocols of randomized,placebo-controlled therapeutical trials do often neitherreflect nor meet the need of most patients in real lifesituations. Those studies in general include a selectedstudy population and follow a given design. For exam-ple, intermittent use of medication, which may be rele-vant for many patients particularly in the beginning ofthe disease, has not been investigated for any drug al-though experts know that intermittent treatment is widelyused in RLS. Likewise, combination therapies are notformally studied. With the exception of cabergoline ver-sus levodopa, no adequate comparative studies of differ-ent drugs have been reported. Furthermore, no pivotalstudy has been conducted on the efficacy and safety ofnonpharmacological treatment. Finally, controlled long-term studies are rare.

Nonpharmacological Therapy

Nonpharmacological approaches performed by the pa-tients consist of sensory stimuli as cooling the extremi-ties, rubbing, and stimulating the skin, but do not suffi-ciently reduce the symptoms in most cases. Moving andwalking are the most effective approaches, but are inap-propriate for the nighttime and the tired patients. Only afew studies of nonpharmacological approaches to RLSare available. A proof-of-concept study on a psychoso-cial training4 as well as a double-blind trial on physicalexercise5 first showed favorable results and encouragefurther research activities in controlled clinical trialsinvolving nonpharmacological treatments. Frequently ig-nored by the physician is the importance of good-sleephygiene. Patients should be advised to avoid caffeine,alcohol, or heavy meals before going to bed. Bedtimehours should be regular and activity gradually reduced inthe evening. Patients should sleep in a bedroom, whichshould only be used for sleep. Daytime activities shouldinclude physical exercise and daytime sleep should beavoided. In any case, it has to be clarified by medicalhistory or polysomnographic studies if other sleep dis-orders are present and if so appropriately be treated.Secondary causes of RLS should be excluded or associ-ated disorders primarily be treated.

Therapy of RLS Related to Iron Deficiency

The most important underlying cause may be irondeficiency and a disturbed iron metabolism is supposedto play a major role in the pathophysiology of RLS assummarized in Ref. 6. Iron supplementation has beenshown to improve RLS in patients with iron deficiency7

but not in patients with normal iron levels.8 Iron levelsand storage should be measured via the indicator ferritin.

A serum ferritin concentration lower than 50 �g/L (nor-mal range 20–400 �g/L) has been associated with anincreased severity of RLS9 and an increased risk ofdeveloping augmentation with dopaminergic therapy.10

According to clinical experience, iron therapy (with vi-tamine C to enhance absorption) can be attempted inpatients with levels in this low range. Oral iron therapycan cause constipation and abdominal discomfort, andthe dose may need to be reduced in some patients. Irontablets should ideally be taken on an empty stomach toenhance absorption, but if gastrointestinal symptoms de-velop, they should be taken with food. Sufficient iron isneeded, but iron can also be toxic. It may enhanceoxidative damage, and the possibility of hemochromato-sis (iron overload) should be kept in mind. Iron shouldnot be prescribed empirically. Follow-up ferritin deter-minations are needed every 3 to 6 months and ferritinlevels ideally in the midrange should be targeted. RLSsymptoms, however, not always improved in relation toan increasing serum-ferritin concentration, even if it wasinitially low. Since iron is not very well absorbed in thegastrointestinal tract and some patients have absorptiondisturbances, the treatment of RLS with intravenous ironinfusions may be more effective and is currently underfurther investigation in patients with both low and nor-mal serum-ferritin concentrations. In a small placebo-controlled trial in RLS secondary to uremia (n � 11),RLS symptoms significantly, but transiently, improvedwith 1000-mg iron dextrane.11 In an open trial with 10patients of whom 4 patients had ferritin levels below 50�g/L, a single infusion of 1000-mg iron dextrane led toa dramatic improvement of RLS symptoms as assessedon a visual analog scale in 6 patients, whereas 4 patientsdid not respond to treatment.12 It is possible that morefrequent smaller doses are more effective than a singlelarger dose.13

Therapy of Drug-Induced RLS

Clinical experience suggests that most antidepressants(such as amitriptyline, serotonin-reuptake inhibitors, andmirtazapine) may at sometime be associated with initia-tion or worsening of RLS and several publications re-ported on antidepressant-induced RLS, as summarized inRef. 14. Whether an aggravating effect of antidepressantsubstances on RLS appears, however, cannot be pre-dicted for the individual patients. An important determi-nant of the clinical tolerability of antidepressants in RLSseems to be whether the patient has already been treatedfor RLS or not. If a patient has sufficiently been treatedfor RLS, he/she usually tolerates antidepressants,15 eventhose which are known to elicit or exacerbate RLS likemirtazapine.16 If RLS symptoms increased after the ini-

STATE OF THE ART IN RLS THERAPY S467

Movement Disorders, Vol. 22, Suppl. 18, 2007

tiation of the treatment with a specific antidepressant, itshould be discontinued. If the depressive disorder devel-oped along with severe RLS,17 the first line treatment forRLS often not only resolves RLS but also improvesdepressive symptoms.14 If (classical) neuroleptic agents,or dopamine-receptor blocking antiemetics such as met-oclopramide, lithium, or antihistaminic agents aggravateRLS, discontinuation or substitution of these drugs isrecommended.

Therapy of Other Secondary RLS

Successful kidney transplant may lead to a completeremission in RLS patients with renal insufficiency18,19

mostly within days or weeks. The pathomechanisms areunknown. Complete remission of all RLS symptomsafter delivery-ending pregnancy is also frequently ob-served.20-22 Treatment of an underlying medical, neuro-logical, or psychiatric condition (e.g., thyroid disorders,parkinsonism, radiculopathy, myelopathy, depression,etc.) can lead to an improvement of RLS.

Pharmacological Therapy of Idiopathic RLS

Pharmacological therapy should be limited to thosepatients who suffer from clinically relevant RLS symp-toms including intermittent RLS with impaired sleepquality or quality of life. Several factors such as thefrequency and severity of symptoms, the temporal ap-pearance of symptoms, the kind and severity of sleepdisturbances, the presence or not of an excessive daytimesleepiness, and the degree to which RLS interferes withthe quality of life influence treatment strategies. Theseindividual factors are mostly ignored in controlled trialsin which treatment is given on a daily basis usually in theevening to control late evening and nighttime symptoms.All recent large-scale trials have focused their primaryoutcome measure on the IRLS (International RLS Sever-ity Scale, 10-item scale, each item with a score of 0 to 4;1 to 10 mild; 11 to 20 moderate; 21 to 30 severe; 31 to40 very severe RLS) or polysomnographic sleep param-eters. For the IRLS total score, the noninferiority marginis calculated as three points, using the reliability datafrom the IRLS validation trial.23 Only few studies haveassessed the effect of RLS-treatment over longer periodsof time.

DOPAMINERGIC AGENTS

Levodopa

Levodopa/DDCI (dopa decarboxylase inhibitor) is thesubstance most frequently studied in earlier small RLStrials and levodopa/benserazide (Restex® and Restexretard) was the first drug licensed for RLS including

uremic RLS in 2000 in single European countries.24-29

Doses of 100/25 to 200/50 mg standard levodopa/DDCIimprove RLS symptoms (as measured on visual ana-logue scales) about 1 hour after drug intake resulting inan improved quality of sleep and improved quality oflife.27 In correlation to the plasma half-life (1–2 hours),the beneficial effect decreases and RLS may persist inthe second half of the night. If so, an additional dose ofslow release levodopa/DDCI (100/25 mg) may be givenin combination with immediate release levodopa/benserazide 1 hour prior to or at bedtime).28 In a recentlarge trial, with levodopa as active comparator, 200 to300/50 to 75 mg levodopa/benserazide or 2 to 3 mgcabergoline was given in divided doses. Levodopa re-duced the IRLS by �9.6 points (no placebo arm).10

Compared to placebo, levodopa reduced the PLM indexin a polysomnography trial by �18 to 45 per hourtime-in-bed (TIB) and the PLMS arousal index by �14to 42 per hour TST during a 4-week treatment period.27

According to our current knowledge and some 10 yearsof experience with levodopa treatment, levodopa is bestused in patients with mild RLS. The immediate responseto levodopa without a long titration period is appreciatedby the patient, and a positive response to levodopa withthe first dosage strongly supports the diagnosis of RLS.30

In patients with sporadic RLS, levodopa can be given ondemand; however this treatment option is not formallystudied. The overall side-effect profile is low. The mostfrequent side effects of levodopa in a large controlledtrial were nausea (10.4%), headache (9.3%), fatigue(4.4%), and nasopharyngitis (4.4%). Augmentation ofRLS symptoms after onset of levodopa therapy appearsto be the most relevant clinical side effect and thisphenomenon is therefore described in a separate article(see article on augmentation). Prevalence rates of aug-mentation in open label trials range from 18.6 to 72%.3,31

Augmentation of RLS was reported in an early placebo-controlled trial with levodopa in 16.7 and 26.7% ofpatients with the combination of levodopa standard andsustained release.28 A recent 30-week controlled trialwith levodopa being the active comparator employed theAugmentation Severity Rating Scale (ASRS, see sepa-rate article) and revealed a prevalence of augmentationunder levodopa treatment of 9.8%10 at endpoint. Theseresults question earlier reports and indicate that the riskof augmentation with levodopa so far was over estimatedand maybe lower, when a defined treatment regimen isapplied. However, controlled long-term data on augmen-tation beyond 30 weeks of treatment are not available.

Pills are generally taken at bedtime, perhaps supple-mented by a dose earlier in the day to control evening ordaytime symptoms. For maximal absorption, levodopa

S468 W.H. OERTEL ET AL.


should not be taken with high-protein foods. Whetherlower dosages splitted for afternoon, evening, and atnight are a better regimen to reduce symptoms has notbeen studied, although some patients use this regimen.

In more severely affected patients, RLS symptomsmay not be adequately controlled for the whole nighteven with the combination of standard and sustainedrelease preparations. These patients benefit from alterna-tive medication (Fig. 1). If levodopa therapy is compli-cated by augmentation based on clinical experience,levodopa should be completely substituted by a dopa-mine agonist or opioid. Since augmentation seems to bemore frequent in patients with higher levodopa dosages,maximum dosages of 300 to 400 mg should not beexceeded.31 It is also possible that augmentation may betriggered if patients are treated with higher levodopadosages than are needed or if daily levodopa therapy isrecommended although symptoms only appear intermit-

tently. Therefore, in some patients with mild symptoms,50-mg levodopa perhaps on demand may be sufficient.

Levodopa/DDCI preparations can also be combinedwith catechol-O-methyl transferase (COMT) inhibitorsuch as entacapone or tolcapone. Levodopa/DDCI is alsoavailable in a triple combination together with theCOMT inhibitor entacapone. COMT inhibitors increasethe availability of levodopa in plasma and therefore canprolong the central action of this compound. One recentpolysomnographic study (n � 28) investigated the effectof levodopa/carbidopa/entacapone (LCE) in an active(versus levodopa/carbidopa; LC) and placebo-controlledcrossover trial. Patients had a mean PLMS index of 23.7at baseline, 25.7 under placebo, and 9.5 when receivingLC (P � 0.005). With LCE, the PLMS index signifi-cantly improved: LCE 150 (levodopa 150/carbidopa37.5/entacapone 200 mg) period: 3.5 PLMS per hourtotal sleep time (P � 0.001), LCE 100 (100/25/200 mg;

Dopamine Agonist

Ropinirole

Pramipexole

Cabergoline

Pergolide

Rotigotine patch

Dopamine Agonist

Ropinirole (Adartrel®, Requip®)*

Cabergoline

Pergolide

Rotigotine patch

Idiopathic RLS Secondary RLS

primary diseaseSleep hygiene

Pharmacotherapy necessary ?

Moderate tosevereRLS

(IRLS >15)

Mild to moderate RLS

SevereRLS

Dopaminergictherapy

Opioidergictherapy

L-Dopa + DDCI Opioids with short half life

e.g.Tilidine

Opioids with long half life

e.g.Tilidine ret.

Oxycodone

Augmentation Augmentation

Other treatments

Gabapentine

Valproate

Other anticonvulsants

Opioidsc.i.?DA

c.i.?

NoNo

Yes

Yes

c.i.= contra indication

Mild to moderate RLS

(Restex®*)

* = licenced for RLS

ClonazepamPramipexole (Sifrol®, Mirapex®, Mirapexin®)*

Treatment of the

FIG. 1. Treatment algorithm: Recommendation how to use dopamimetics is based on clinical trials phase II, III, and approval by EMEA and FDA.For off-label use of dopamimetics, refer the text.



P � 0.001): 6.4 PLMS per hour total sleep time, LCE 50(50/12.5/200 mg; P � 0.05): 12.6 PLMS per hour totalsleep time. In addition, there was an overall dose-depen-dent treatment response in PLMS arousal per hour TST(all P � 0.05).32 These data however do not showwhether the triple combination is superior to the samedose of a slow release preparation of LC. This compar-ison should be particularly investigated in respect to thesecond part of the night.

Dopamine Agonists

Because of their longer half-life (Table I) and a pre-sumably low augmentation rate (at least according topresent clinical observations), dopamine agonists arepreferred especially in patients with moderate to severeRLS. Several experts tend to use dopamine agonists asfirst line therapy also in mild RLS (off-label use) basedon the assumption that dopamine agonists may induce alower prevalence of augmentation. Given once in theearly evening—in dosages that are usually lower thanthose required in the therapy of Parkinson’s disease(PD)—dopamine agonists cover sensory and motorsymptoms of RLS throughout the night. As a conse-quence, sleep and quality of life markedly improves inmost patients.

Convincing data from double-blind trials are availablefor the ergot-dopamine agonists cabergoline,33-35 pergol-ide,36-38 and the nonergot DA ropinirole,38-42

pramipexole,43-46 and the nonergot DA patch rotigo-tine.46,47 There is yet insufficient evidence to make arecommendation about �-dihydroergocriptine, bro-mocriptine, and lisuride. Apart from general consider-ations several factors will determine the physician’s de-

cision for a certain substance and its dosage, forexample, the half-life, the duration of uptitration, thestructure (nonergot or ergot), individual efficacy andtolerability, the risk to develop heart valve fibrosis, andof course the physician’s experience with a particulardopamine agonist. For selection of a dopaminergic drug,it may be of utmost importance regarding legal andeconomic reasons, if a drug is licensed for RLS therapyin a certain country or not (Fig. 1). Shorter-acting dopa-mine agonists may require twice-daily doses with anearlier dose in the late afternoon and a second dose in theevening. With longer-acting dopamine agonists, a singleevening dose (2–3 hours before bedtime) is sufficient.Dopamine agonist patches, which are currently underinvestigation may extend the beneficial effect because ofits 24-hour control and may be preferred in severelyaffected patients. If RLS symptoms are not adequatelycontrolled with one dopamine agonist or intolerable sideeffects occur the switch to another dopamine agonist isrecommended. Like in PD, no evidence-based recom-mendation on equivalent doses of different dopamineagonists can be given since RLS patients may responddifferently to different dopamine agonists. If insomniaremains a considerable problem when sensorimotor RLSsymptoms are well controlled by the dopaminergic drug,an additional sleep inducing treatment option has to beconsidered.

Sudden onset of sleep (SOS) was reported in patientswith PD under dopaminergic treatment. Although aknown side effect reported also in single patients withRLS,48 dopaminergic drugs may in general, in contrast toPD, reduce the risk of SOS in RLS possibly due to their

TABLE 1. Characteristics of dopamine agonists in the treatment of RLS

Half-life (hr) Initial dosage Titration Dosage in RLS Max. dosage

�-Dihydroergocriptine 10–15 5 mg 5 mg/3 d 10–40 mg 80 mgBromocriptine 3–8 1.25 mg 1.25 mg/week 2.5–5 mg 7.5 mgCabergoline 65 0.5 mg 0.5 mg/week 0.5–2 mg 4 mgLisuride 2–3 0.1 mg 0.1 mg/week 0.1–2 mg 4 mgPergolide 7–16 0.05 mg 0.05 mg/3 d 0.1–0.75 mg 1.5Pramipexole-HCl*

(nonergot)8–12 0.125 mg 0.125 mg/4 d 0.125–0.5 mg 0.75 mg**

Ropinirole (nonergot) 6 0.25 mg Day 3: 0.5 mg 0.5–4 mg 4 mg**Week 2: 1 mgWeek 3: 1.5 mgWeek 4: 2 mg0.5 mg/week

Rotigotine CDS(nonergot)

(5 hr) Constant plasmalevels because ofpatch application

0.5 mg/24 hr (2.5cm2) or 1 mg/24 hr (5 cm2)

1 mg/wk 0.5–3 mg/24 hr(2.5–15 cm2)

4 mg/24 hr (20cm2)

Bold, at least two randomized, placebo-controlled clinical trials with a sufficient number of patients.*In some European countries declared as free base 0.088 mg pramipexole � 0.125 mg pramipexole-HCl.**According to package leaflet.CDS, constant delivery system.



beneficial effect on sleep.49 Characteristics of variousdopamine agonists are given in Table I.

Nonergot Dopamine Agonists

In 2006, the nonergot dopamine agonists pramipexoleand ropinirole received EMEA and FDA approval formoderate to severe RLS with a score on the IRLS � 15points.

Pramipexole

In four large placebo-controlled trials pramipexoledemonstrated significant improvement in RLS severityas assessed by the IRLS, by a modified form of theRLS-6, and the CGI with corresponding improvementsin sleep and quality of life.44-46,50 About 0.125 mg of acidcorresponds to 0.88-mg pramipexole base and respec-tively 0.75 mg acid corresponds to 0.54 mg base. In thisreview, we refer always to the acid form. Using anindividually optimized dose design (0.125–0.75 mgpramipexole), a mean daily dose of 0.35 mg pramipexolereduced the IRLS score by �12.3 to 12.3 points (placebo�5.7 points; P � 0.0001; n � 345).46 In a fixed dosedesign, pramipexole lead to the following IRLS improve-ments: 0.125 mg, �11.9 points; 0.25 mg, �15.2 points;0.5 mg, �17.0 points; 0.75 mg, �15.9 points (placebo�6.1 points, n � 109).45 A similar study performed inthe US showed a significant reduction of the IRLS aftera 12-week parallel trial with 0.25, 0.5, and 0.75-mgpramipexole (all P � 0.01) in 344 patients with RLS.50

In addition, in a placebo-controlled withdrawal trial (n �150), patients were first treated with pramipexole in anopen 6-month trial. When patients were switched toplacebo, they reached a predefined worsening on both theCGI-I and the IRLS significantly more often (85.5%)than those who continued to receive pramipexole 0.125to 0.75 mg (20.5%).44

In a fixed dose polysomnographic trial, 0.125 to 0.75mg pramipexole dose-independently significantly re-duced the PLM index by up to �53 per hour TIB(placebo �3 per hour TIB), the PLMS index by up to�27 per hour TST (placebo �3 per hour TST), and thePLMS arousal index by �3 per hour TST (placebo �2per hour TST). Sleep efficiency nonsignificantly in-creased with pramipexole by a maximum of 8% (placebo�6%).45

The most common side effects in the two largestdouble-blind studies were headache (up to 13%), nausea(up to 12%), fatigue (up to 9%), nasopharyngitis (up to4%), abdominal pain (up to 4%), diarrhea (up to 4%),and dizziness (up to 4%). Queried explicitly about SOS,patients reported no such episodes.44,46

Augmentation with pramipexole was reported in opentrials in 8.5 to 39%.51-53 In placebo-controlled trials, aug-mentation was not specifically asked for and also not un-solicitedly reported by the patients.44,46 Within the 12-weekstudies, no patient was classified as presenting with aug-mentation, as rated by experienced investigators.44

Ropinirole

In several placebo-controlled trials, ropinirole demon-strated significant improvement in RLS severity as as-sessed by the IRLS, a modified form of the RLS-6 andthe CGI with corresponding improvements in sleep andquality of life.38-40,42

In a flexible 12-week titration study, a median dose of1.5 mg ropinirole (range 0.5–4 mg) given 1 to 3 hoursprior to bedtime reduced the IRLS score by 11.2 points(placebo �8.7 points, P � 0.0197, n � 267).39 In twoother large placebo-controlled 12-week trials with thesame study design (n � 284/381), the IRLS reductionwas very similar with �11.0/�13.5 for ropinirole (meandose 1.9/2.1 mg) and �8.0/�9.8 for placebo (P �0.0034/P � 0.00138,40). A significant reduction of theIRLS by �6.8 points was already noted at day 3 oftreatment when patients received 0.25 mg ropinirole(placebo �4.6 points).40 One placebo-controlled poly-somnographic trial with 59 patients showed no signifi-cant reduction in the IRLS with a mean dose of 1.8 mgropinirole compared to placebo (adjusted treatment dif-ference �1.2 points).42 In contrast, a small (n � 22)placebo-controlled crossover trial showed that IRLSscores with higher dosages of ropinirole (up to 6 mg,mean dosage 4.6 mg) were lower (13.0 points) comparedwith those under placebo treatment (24.7 points, P �0.001).54 A placebo-controlled trial with randomizationafter a single blind ropinirole run-in period (maximumdosage 4 mg) showed a significant lower percentage ofrelapsing patients (defined as an increase of at least sixpoints in the IRLS or withdrawal because of lack ofefficacy) in 32.6% with ropinirole (same dose establishedduring the single-blind phase) and in 57.8% with placebo(P � 0.0156).41

In a flexible dose-titration polysomnographic trial, amean dose of 1.8 mg ropinirole significantly reduced thePLMW index by �32.9 to 23.6 per hour TIB (placebo�9.5 per hour TIB), the PLMS index by �36.7 to 11.8per hour TST (placebo �1.5 per hour TST), and thePLMS arousal index by �4.5 to 2.5 per hour TST(placebo �1.8 per hour TST). Sleep efficiency nonsig-nificantly increased by 5.2% under ropinirole (placebo�1.0%).42 In an actigraphic placebo-controlled trial, 2.1mg ropinirole reduced the PLM index by �24.2 to 15.6per hour TIB (placebo �5.3 to 27.5 per hour TIB).40



The most common side effects in double-blind studieswere nausea (up to 43%), headache (up to 34%), vom-iting (up to 16%), abdominal pain (12%), somnolence(up to 16%), nasopharyngitis (11%), and dizziness (up to19%).38-40,42 There were no reports of augmentation butaugmentation was not systematically assessed.

Rotigotine

In two placebo-controlled trials, rotigotine demon-strated significant improvement in RLS severity as as-sessed by the IRLS, the RLS-6, and the CGI with cor-responding improvements in sleep and quality of lifeparticularly with higher dosages.47,55 Using a fixed doseregimen, rotigotine reduced the IRLS dose-dependently:0.5 mg/24 hours, �10.5 points; 1 mg/24 hours, �12.3points; 2 mg/24 hours, �15.7 points (P � 0.01 for 2 mg),and �8.0 points for placebo in a 1-week pilot study (n �63).47 A recent placebo-controlled fixed-dose trial (n �341) showed that higher dosages may be more efficientin individual patients but overall with a ceiling effect: 0.5mg/24 hours, �10.5 points (P � 0.2338); 1 mg/24 hours,�15.3 points (P � 0.0004); 2 mg/24 hours, �15.7points; 3 mg/24 hours, �17.5 points (P � 0.0001); 4mg/24 hours, �14.8 points (P � 0.0013) (placebo �9.3points.55 The most common side effects were applicationside-reactions, which can be minimized when changingthe application site continuously (depending on the dos-age up to 38.5%,47 up to 25% with 4 mg/24 hours).55

Other side effects were headache (up to 38.5/12.5%),pruritus (up to 15.4/10.8%), nausea (up to 7.7/24.6%),and fatigue (up to 10.5/10.8%).47,55 Dose-response rela-tionship was only observed for application side-reactionsand nausea. Augmentation was not specifically investi-gated in either trial.

Ergot Dopamine Agonists

Cabergoline

A single-evening dosage of 0.5, 1.0, or 2.0 mg caber-goline given about 3 hours before bedtime markedlyreduced RLS symptoms during the night and the follow-ing day as rated on the RLS-6 scales and the CGI.34,35

The IRLS score significantly improved dose-dependentlyby �13.1 to 15.7 points (placebo �3.3 points).34 A fixedevening dose of 2 mg and 2 to 3 mg cabergoline reducedthe IRLS by 23.7 points (placebo �7.9 points, base-line � 31 points, P � 0.0002)35 and by 16.1 points(levodopa/benserazide �9.6 points, P � 0.001),10 re-spectively. Results of an open 1 year long-term treatmentperiod showed that the beneficial effects of low dosecabergoline (mean dosage 2.2 mg, highest dosage 6 mg)

on RLS symptoms, in particular on daytime symptoms,persist throughout a follow-up period up to 1 year.34

A fixed dosage of 2 mg cabergoline reduced the PLMindex by �42 to 12 per hour TIB (placebo �19 per hourTIB), the PLMS index by �43 to 9 per hour TST(placebo �10 per hour TST), and the PLMS arousalindex by �18 to 3 per hour TST (placebo �5 per hourTST) in a 5-week polysomnographic trial (n � 40). Sleepefficiency increased significantly by a mean of 6.2% withcabergoline compared with 3.3% with placebo.35

The most common side effects in double-blind studieswere nausea (up to 35%), constipation (up to 20%),headache (up to 20%), dizziness (up to 13%), somno-lence (up to 11%), fatigue (up to 14%), abdominal pain(up to 8%), vomiting (9%), and vertigo (8%),10,34,35

which were less frequent in open trials.56,57 Augmenta-tion was reported in 3 to 9.5%.34,56 A recent active-controlled trial using the ASRS showed a frequency ofaugmentation of 4.0%.10 In a single-blind study in asmall number of RLS patients (n � 12), cabergolineshowed no augmentation in a 1-year follow-up.58

Pergolide

In general, pergolide is no longer estimated as a firstline treatment of RLS because of potential valvular fi-brosis observed in patients with PD. Using an individu-ally optimized dose design, a mean daily dose of 0.4 mgpergolide (possibly divided in 4 and 2 hours beforebedtime) reduced the IRLS score by �12.2 to 11.5 points(placebo �1.8 points).59

In a multicenter 1-year controlled study with 100patients, a mean dosage of 0.4 mg pergolide was com-pared to placebo and significantly reduced the PLMindex and the PLMS arousal index. The 1 year results ofthis study showed that pergolide maintained its efficacyin particular on sleep measures.59 Previous studies withpergolide showed similar results with significant im-provements of pergolide on sleep and subjective RLSsymptoms.36,60

The most common side effects in double-blind stud-ies were nausea (up to 59%), headache (up to 32%),asthenia (18%), rhinitis (up to 21%), vomiting (up to18%), dizziness (up to 22%), postural hypotension(13%), abdominal pain (10%), and pharyngitis (10%).In open trials, augmentation was reported in 15 to 27%of patients.37,61,62

Ergot-derived compounds can cause pleural, pericar-dial, and retroperitoneal fibrosis.63 In RLS pleuropul-monary disease due to pergolide treament has been re-ported.64 A possible association between ergot derivativedopamine agonists and valvular heart disease particularlyafter treatment with a high cumulative dose in PD has



been reported for pergolide and cabergoline.65-68 Tworecent studies confirm this increased risk of cardiac-valve regurgitation and of valvular heart disease by echo-cardiography, in PD with cabergoline and pergolidecompared to nonergot compounds and to the generalpopulation.69,70 This side effect was not reported in con-trolled RLS trials but cardiologic investigations have notbeen performed regularly in RLS studies. Therefore,transthoracic echocardiography and heart auscultationfor heart murmurs have to be regularly performed.68,71

Until now, there are few case reports about the occur-rence of gambling during therapy with dopamine ago-nists in RLS.72 It has to be verified in the future ifimpulsive behaviors are a clinically relevant adverseevent in low dose dopamine agonist therapy in RLS.

Other Substances

Opioids have shown to be effective in RLS and theiranalgesic or sedative effect may be of advantage inindividual patients but data from placebo-controlled tri-als are very limited and only available for oxycodone.73

A mean dose of 11.4 mg oxycodone resulted in a 52%improvement in subjective RLS rating scales. In thisstudy, oxycodone also significantly reduced the PLMSindex from 38.8 to 18.4 per hour sleep and the PLMSarousal index from 39.1 to 26.6 per hour sleep. Sleepefficiency was significantly improved (P � 0.006). Ad-verse events were minimal with constipation in two anddaytime lethargy in one of 11 patients.74 In an openlong-term study, various opioids mild sedation and rarenocturnal respiratory disturbances were observed.

Opioids may be a highly effective therapy particularlyin the advanced and severe forms of RLS and should notbe withheld from patients because of a potential devel-opment of tolerance or dependence. Escalation of dosesis rare, and dependence is infrequent in the absence of ahistory of substance abuse.73 If opioids are used, treat-ment regimens like in chronic pain syndromes should beapplied. Severely affected patients may particularly ben-efit from opioid patch applications. No studies with thisapplication form in RLS are available. To avoid consti-pation lactulose should be added from the beginning.However, since there is insufficient evidence we cannotmake a firm recommendation about specific substancesand dosages.

Gabapentine may be an alternative choice, particularlyif first line treatment is not tolerated or fails. In addition,gabapentine may be given in RLS perceived as painful,RLS in combination with a painful peripheral neuropathyor an additional unrelated chronic pain syndrome. Gaba-pentine should be used as once- or twice-daily doses inthe late afternoon or evening (one-third of the dose) or

before sleep (two-thirds of the dose). Treatment shouldcommence with 300 mg/dose or even less because of thepossible tendency to cause somnolence and gait un-steadiness, especially in elderly patients. A controlledtrial (n � 24) of 6 weeks has shown that mean doses of1800 mg/d are needed for efficacy.75 We do not thinkthat this is an adequate treatment for mild RLS. It is,however, stated that gabapentine is an alternative ther-apy, if dopaminergic drugs cannot be tolerated or fail.

The anticonvulsants carbamazepin76 and valproic ac-id77 seem to be less effective in RLS than gabapentine.Other anticonvulsants with antinociceptive effect arecurrently under investigation in RLS patients.

Benzodiazepines are sometimes employed for residualinsomnia but should be used with caution in particular inolder patients. Better alternatives, also indicated only forshort-term use, are zaleplon (5–10 mg), zolpidem (5–10mg), or zopiclone (3.25–7.5 mg).

In some patients, combination therapies with dopami-nergic agents, opioids, anticonvulsants, or benzodiaz-epines may be a necessary but not formally studiedoption. In clinical practice, up to about 20% of patientsmay need a combination of two or more drugs to controlRLS.78

Magnesium supplements may be beneficial in patientswith mild RLS. 12.4-mmol magnesium in the eveninghave been shown to be beneficial in an open trial79 butthese promising results could not be replicated in asubsequent placebo-controlled trial of the same investi-gators.80 There are no controlled studies that have showna beneficial effect of other supplements such as zinc,vitamin B1, vitamin B12, vitamin E, or vitamin C. Treat-ment of associated psychiatric symptoms such as anxietyand depression may be necessary in some patients evenwhen RLS-symptoms are sufficiently controlled withdopaminergic agents.

CONCLUSION AND PERSPECTIVE

To date, extensive data are available for levodopa anddopamine agonists, especially for pramipexole and ropi-nirole and to a smaller extent for cabergoline, pergolide,and rotigotine. As apart from one study comparing caber-goline with levodopa, no comparative studies have beenperformed. The individual treatment regimen with themost appropriate agent concerning efficacy and side ef-fects has to be selected by the treating physician. On thebasis of the clinical trials and expert opinion of theauthors, a treatment algorithm is proposed to support thesearch for the optimal individual treatment (Fig. 1). Al-though intermittent therapy of RLS has not been inves-tigated in clinical trials, a treatment on demand is aclinical need in mostly mild and moderate RLS symp-



toms. According to clinical experience and in line withpharmacological data, we would recommend a short-acting dopaminergic agent, that is, levodopa 100 mg forintermittent therapy during daytime or at sleep onset.Short-acting opioids may be given as alternative treat-ment when dopaminergic agents cannot be used. Furtherstudies on intermittent therapy of RLS symptoms andcombination therapies are urgently needed, to guide cli-nicians in this field.

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State of the art in restless legs syndrome therapy: Practice recommendations for treating restless legs syndrome