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Treatment of restless legs syndrome/Willis-Ekbom disease and periodic limb movement disorder in adults
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Treatment of restless legs syndrome/Willis-Ekbom disease and periodic limb movement disorder in adults
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Sep 06, 2016.

INTRODUCTION — Restless legs syndrome/Willis-Ekbom disease (RLS/WED) refers to an overwhelming urge to move the legs, usually associated with unpleasant sensations. The urge to move the legs is worse at rest and at night and relieved by movement. RLS/WED is commonly associated with sleep disturbance and with involuntary, jerking movements of the legs during sleep, known as periodic leg movements of sleep (PLMS). When significant sleep disturbances or impaired daytime functioning coexist with PLMS in the absence of RLS/WED or other associated disorders, the term periodic limb movement disorder (PLMD) is used.

RLS/WED is a treatable condition that generally responds well to pharmacologic therapy. A variety of treatments have been studied in randomized, controlled trials; the major classes of drugs used include dopaminergic agents, alpha-2-delta calcium channel ligands, opioids, and benzodiazepines [1-4]. The treatment approach to PLMD is similar to that of RLS/WED, although supported by considerably less data. (See 'Periodic limb movement disorder' below.)

The selection of therapy depends upon a number of factors, including disease severity, patient age, comorbidities (eg, pain, depression, anxiety, history of impulse control behaviors), drug side effects, and patient preferences. The goals of therapy are to reduce or eliminate symptoms of RLS/WED and improve daytime function, sleep, and quality of life.

This topic will review the treatment of RLS/WED and PLMD in adults. The clinical features and diagnosis of RLS/WED and PLMD in adults and treatment of these disorders in children are discussed separately. (See "Clinical features and diagnosis of restless legs syndrome/Willis-Ekbom disease and periodic limb movement disorder in adults" and "Restless legs syndrome/Willis-Ekbom disease and periodic limb movement disorder in children".)

IRON REPLACEMENT — A serum ferritin concentration lower than 45 to 50 mcg/L (ng/mL) has been associated with an increased severity of restless legs syndrome/Willis-Ekbom disease (RLS/WED), and iron replacement is suggested if the serum ferritin level is lower than 75 mcg/L [5]. Iron therapy should not be prescribed empirically because it may result in iron overload, especially in patients with previously unsuspected hemochromatosis.

This recommendation is based on evidence supporting a role for iron deficiency in the pathophysiology of RLS/WED and three small randomized placebo-controlled studies showing a clinical benefit in patients receiving iron replacement therapy: one in adult patients with serum ferritin ≤75 mcg/L treated with oral iron [6], one in patients with end-stage renal disease and functional iron deficiency treated with intravenous iron dextran [7], and a third in patients with moderate to severe RLS/WED treated with intravenous ferric carboxymaltose [8].

Two other randomized studies of intravenous iron sucrose, only one of which was limited to iron-deficient patients, failed to show a benefit [9,10]. A meta-analysis that included four out of five of these studies found significant heterogeneity in the formulation of iron used, patient characteristics, and measurement of outcome variables across studies and found insufficient evidence to conclude whether iron is beneficial for treatment of RLS/WED [1].

Iron supplementation can be supplied orally or intravenously. Intravenous delivery has the advantage of replenishing iron stores more quickly than oral therapy but it is less convenient and carries a risk of serious infusion reactions, including anaphylaxis. There are no direct comparisons of intravenous versus oral iron supplementation in patients with RLS/WED, and available data do not show clear superiority of one route of administration over the other. (See "Treatment of iron deficiency anemia in adults", section on 'Allergic and infusion reactions'.)

Because oral iron is easier to administer and safer, we suggest initial therapy with an oral regimen such as ferrous sulfate (325 mg orally two to three times a day). Iron should be combined with vitamin C (100 to 200 mg with each dose of ferrous sulfate) or a glass of orange juice to enhance absorption. Iron should not be taken at the same time as calcium supplements or significant amounts of dairy products. (See "Treatment of iron deficiency anemia in adults", section on 'Dosing and administration (oral iron)'.)

Intravenous iron therapy is generally reserved for patients with low iron stores and either a malabsorption state or complete intolerance to oral iron preparations. (See "Treatment of iron deficiency anemia in adults", section on 'Oral iron'.)

Ferritin levels should be checked after three to four months of therapy and then every three to six months until the serum ferritin level is >75 mcg/L and iron saturation is greater than 20 percent. Monitoring is important to avoid the rare but serious complication of iron overload in patients with hemochromatosis genes [11]. Iron therapy can then be discontinued if an ongoing cause for iron deficiency has not been established. The etiologic evaluation of iron deficiency in adults is reviewed separately. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Search for source of blood and iron loss'.)

NONPHARMACOLOGIC THERAPY — In patients with mild symptoms, nonpharmacologic therapies may be sufficient for symptom relief. In patients with more severe symptoms, nonpharmacologic measures are worth reviewing, as they may limit medication requirements.

Behavioral strategies — Use of the following interventions is supported primarily on the basis of clinical experience and, in some cases, small randomized trials [5,12]:

Mental alerting activities, such as working on a computer or doing crossword puzzles, at times of rest or boredom

Avoidance of aggravating factors, including consideration of withdrawal of possibly predisposing medications (see 'Avoidance of aggravating factors' below)

Moderate regular exercise [13]

Reduced caffeine intake

For symptomatic relief – walking, bicycling, soaking the affected limbs, and leg massage, including pneumatic compression [14]

Short daily hemodialysis for patients with end-stage renal disease (see "Sleep disorders in end-stage renal disease", section on 'Treatment')

Avoidance of aggravating factors — Sleep deprivation is known to aggravate symptoms of restless legs syndrome/Willis-Ekbom disease (RLS/WED) in many patients, and general principles of sleep hygiene should be reviewed. (See "Treatment of insomnia", section on 'Sleep hygiene'.)

Antidepressants, neuroleptic agents, dopamine-blocking antiemetics such as metoclopramide, and sedating antihistamines (including those found in nonprescription medications) may contribute to emergence of RLS/WED or worsening of prior symptoms (table 1) [15]. Most antidepressant classes have been associated with RLS/WED, including tricyclics, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors [16].

Discontinuation of antidepressants, however, may not always be possible without causing patient harm. If antidepressants are necessary, the symptoms of secondary RLS/WED can usually be treated in the same way as primary RLS/WED. Bupropion is an alternative antidepressant that may be less likely to induce or worsen RLS/WED [17].

Novel devices — A device that provides vibratory stimulation to the legs (Relaxis Pad) was approved by the US Food and Drug Administration (FDA) in May 2014 for use in patients with RLS/WED. We do not find compelling evidence of benefit from the available data, however, and we suggest that patients not use this device until further studies have been performed and reported in peer reviewed publications.

According to a pooled analysis of two randomized trials (156 patients) published in a non-MEDLINE-indexed journal, patients assigned to the vibrating pad experienced improvement in Medical Outcomes Study Sleep Problems Index II (MOS-II) scores compared with those assigned to either a light-emitting or sound-producing sham pad (mean improvement from baseline for active versus sham pad: 13.2 versus 6.2 points, p = 0.02) [18]. In descriptions of the two trials available on the company website, however, the MOS-II was not a primary or secondary outcome measure and was tabulated using 9 out of 12 questions from the MOS sleep scale, which itself was listed as a secondary outcome.

Analysis of primary and secondary outcome measures revealed no differences in International Restless Legs Syndrome Study Group (IRLS) scores (improvement from baseline for active versus sham pad: 6.68 versus 6.39 points, p = 0.81) or RLS quality of life scores (improvement from baseline: 11 versus 7 points, p = 0.14). Changes in the MOS sleep scale score were not reported. The most common adverse effect of the vibratory pad was temporary worsening of RLS/WED symptoms, reported in nine patients in the active group and two patients in the control group.

CHRONIC PERSISTENT SYMPTOMS — Chronic persistent restless legs syndrome/Willis-Ekbom disease (RLS/WED) is defined as RLS/WED that is frequent and troublesome enough to require daily treatment, with symptoms usually occurring at least twice a week on average and resulting in moderate or severe distress [5].

Choice of therapy — In patients who do not respond to nonpharmacologic therapy and correction of iron deficiency, we recommend pharmacologic treatment with a dopamine agonist or an alpha-2-delta calcium channel ligand as first-line therapy (table 2). These classes of drugs have been shown to be effective compared with placebo in multiple randomized controlled trials [2-4,19-21].

Head-to-head comparisons between the two classes are limited to a single study [21], and we therefore suggest choosing initial therapy based on consideration of symptom severity, patient age and comorbidities, drug side effect profiles, and patient preferences (table 3) [5]. The long-term risk of augmentation with dopaminergic agents must be weighed against other short- and long-term risks and side effects of each agent individually and measures taken to use the lowest effective dose in all patients selected for dopaminergic therapy [22]. (See 'Augmentation' below.)

For patients with very severe RLS/WED, comorbid depression, obesity, or metabolic syndrome, a dopamine agonist is preferred over other drugs as initial therapy.

For patients with comorbid pain, anxiety, or insomnia or a history of impulse control disorder or addiction associated with use of a dopamine agonist, we suggest starting with an alpha-2-delta calcium channel ligand.

For most other patients, we initially try an alpha-2-delta calcium channel ligand because of the risk of augmentation with dopamine agonists, but other potential side effects of the various drugs should also be considered. In general, older patients are more prone to side effects of alpha-2-delta ligands. If the first drug chosen is ineffective or poorly tolerated, then a drug of the other class should be tried.

Small randomized trials and observational studies also support the use of other agents, including levodopa, benzodiazepines, and opioids, but generally these are reserved for intermittent use or in patients with more refractory symptoms. (See 'Intermittent symptoms' below and 'Refractory RLS' below.)

Drug dosages should be used at the minimum dose required to control symptoms. For dopaminergic agents, the doses required for RLS/WED are lower than those used to treat Parkinson disease and usually are given only in the evening (table 2). Ropinirole and rotigotine should be avoided in patients with hepatic failure, as they are metabolized by the liver.

Patients on continuous therapy should be examined regularly (eg, every 6 to 12 months) and screened for side effects and complications such as augmentation, which is a common complication of long-term dopaminergic therapy [22]. (See 'Augmentation' below.)

Dopamine agonists — Dopamine agonists belong to a class of drugs that directly stimulate dopamine receptors and have a longer half-life (four to six hours) than levodopa (90 minutes). They are generally superior to levodopa for the treatment of daily RLS/WED, because of the lower risk of complications.

In a 2011 meta-analysis of 38 trials evaluating dopamine agonists for the treatment of RLS/WED that included cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine, and sumanirole, all except sumanirole were superior to placebo [2]. In two trials, cabergoline and pramipexole were superior to levodopa for improvement in disease severity as measured by the International Restless Legs Syndrome Study Group (IRLS) rating scale [23,24].

Pramipexole and ropinirole — The non-ergot dopamine agonists, pramipexole and ropinirole, are effective in the treatment of RLS/WED and are less likely to cause side effects than other dopamine agonists (eg, cabergoline and pergolide) and levodopa. These agents, along with rotigotine, are considered to be the dopamine agonists of choice for RLS/WED [3,5].

The benefit of pramipexole was demonstrated in a meta-analysis of seven randomized placebo-controlled trials totalling over 1200 patients [3]. In all of the studies, pramipexole improved RLS/WED symptom severity, with an average improvement in the IRLS rating scale of 6.7 points over placebo (95% CI 4.9-8.5) [3]. For reference, a 6-point difference has been proposed as a clinically meaningful improvement in IRLS scores [25]. Uncontrolled studies with longer-term follow-up (26 to 52 weeks) have reported a mean improvement of 17 points on the IRLS scale [26,27].

The benefit of ropinirole was demonstrated in a meta-analysis of five randomized placebo-controlled trials totalling over 900 patients, in which the average improvement in IRLS score over placebo was 4 points (95% CI 2-6) [3].

The onset of action for pramipexole and ropinirole is typically 90 to 120 minutes after intake. Therefore, these medications should be started two hours before RLS/WED symptoms start [5]. The recommended doses are as follows (table 2) [5]:

Pramipexole 0.125 mg once daily. The dose may be increased by 0.125 mg every two to three days until relief is obtained. In a clinical trial, all three doses of pramipexole (0.25, 0.50, and 0.75 mg daily) were equally effective, and some patients responded to the initial dose of 0.125 mg daily [28]. However, side effects were more common with the 0.50 mg and 0.75 mg daily doses. Therefore, it is expected that 0.25 mg daily has the best therapeutic margin. Most patients require 0.5 mg or less, but doses up to 1 mg may be needed.

Ropinirole 0.25 mg once daily. The dose may be increased by 0.25 mg every two to three days until relief is obtained. Most patients require at least 2 mg, and doses up to 4 mg may be needed. The maximum recommended dose is 3 mg in patients with end-stage renal disease on hemodialysis. In one large randomized controlled trial, the average daily dose of ropinirole was 1.9 mg [29].

Adverse effects with pramipexole and ropinirole are usually mild, transient, and limited to nausea, lightheadedness, and fatigue; these usually resolve within 10 to 14 days. Less frequent side effects include nasal stuffiness, constipation, insomnia, and leg edema; these are reversible if the medication is stopped. Excessive daytime sleepiness can occur at higher doses and occasionally manifests as sudden, unexpected sleep attacks [30]. These may be less common than in patients with Parkinson disease on higher doses of pramipexole [31].

As first reported in patients with Parkinson disease, dopamine agonist therapy in patients with RLS/WED may be associated with an increased risk of impulse control disorders such as pathologic gambling, compulsive eating and shopping, and compulsive inappropriate hypersexuality [32,33]. (See "Pharmacologic treatment of Parkinson disease", section on 'Impulse control disorders'.)

Augmentation, which refers to a worsening of RLS/WED symptoms with increasing doses of medication, including earlier onset of symptoms, increased intensity of symptoms, shorter duration of drug action, or topographic spread of symptoms to the arms, is a common complication of long-term dopaminergic therapy in RLS/WED that is discussed in more detail below. (See 'Augmentation' below.)

Early morning rebound symptoms have also been observed in some patients and should be approached in a manner similar to augmentation. Doses of ropinirole and pramipexole should not generally exceed the limits given above to avoid or reduce the risk of augmentation.

Dopamine withdrawal syndrome can occur with abrupt discontinuation of dopamine agonist therapy. Symptoms include anxiety, panic attacks, depression, sweating, nausea, pain, fatigue, dizziness, and drug craving. (See "Pharmacologic treatment of Parkinson disease", section on 'Dopamine agonist withdrawal syndrome'.)

Rotigotine — Rotigotine is a non-ergot dopamine agonist that is formulated as a 24-hour transdermal patch. Rotigotine was withdrawn from the United States and European markets in 2008 due to problems with the delivery mechanism, but it was reintroduced in 2012.

The benefit of rotigotine for RLS/WED was demonstrated in a meta-analysis of five randomized controlled trials totalling over 600 patients, in which the average improvement in IRLS score over placebo was 7 points (95% CI 5.6-8.4) [3]. Two long-term follow-up studies (52 to 104 weeks) have reported a mean improvement of 15 to 17 points on the IRLS scale [34,35].

Transdermal rotigotine is a once-daily patch that is typically started at 1 mg/24 hours and titrated upwards to a maximum dose of 3 mg/24 hours. Application site reaction is the most common adverse effect of the patch formulation (not related to rotigotine itself per se), reported by 40 to 50 percent of patients. To decrease the risk of skin reactions, the manufacturer recommends rotating application sites, avoidance of direct sun exposure, and removal of the patch during magnetic resonance imaging. Other side effects are similar to those seen with oral dopamine agonists, including augmentation. (See 'Augmentation' below.)

Long-acting oral formations of pramipexole and ropinirole exist but have not yet been studied in RLS/WED.

Alpha-2-delta calcium channel ligands — Gabapentin enacarbil, gabapentin, and pregabalin are alternatives to dopaminergic therapy for patients with chronic persistent RLS [5,36,37].

The alpha-2-delta calcium channel ligands may be particularly useful when RLS/WED occurs in the setting of a painful peripheral neuropathy or an unrelated chronic pain syndrome and in patients with comorbid insomnia or sleep disturbance that is disproportionate to other RLS/WED symptoms [20]. They are preferred over dopamine agonists in patients with impulse control disorders and are probably more helpful than dopamine agonists in patients with comorbid anxiety (table 3).

They may also be considered in the treatment of RLS/WED in association with Parkinson disease, since these patients may already be receiving dopaminergic therapy, or as an add-on therapy in patients with a partial response to dopamine agonist therapy but intolerance to higher doses. Unlike the dopamine agonists, they are not associated with augmentation.

As with other antiepileptic drugs (AEDs), the alpha-2-delta calcium channel ligands may be associated with an increased risk of suicidal thoughts and behavior, and patients should be monitored for emergent suicidality and depression. (See "Overview of the management of epilepsy in adults", section on 'Specific adverse reactions'.)

Gabapentin enacarbil — Several randomized, placebo-controlled studies have demonstrated that gabapentin enacarbil is effective in reducing RLS/WED symptom severity [3,38]. In the largest study of 325 patients, gabapentin enacarbil at a dose of 600 or 1200 mg/day was associated with a 3- to 4-point improvement in IRLS scores compared with placebo [39]. In another randomized study, gabapentin enacarbil also showed efficacy in decreasing the polysomnographic parameters of wake time during sleep and number of periodic limb movements with arousals per hour of sleep [40].

The recommended dose of gabapentin enacarbil for RLS/WED is 600 mg, taken in the early evening (eg, at 5 pm). Common adverse effects associated with gabapentin enacarbil include somnolence and dizziness; these are generally mild to moderate and remit with time. In a 52-week open-label study, two-thirds of patients reported mild to moderate side effects, leading to treatment discontinuation in 10 percent [41]. Somnolence, dizziness and weight gain were among the most common reasons for discontinuation. Although not formally assessed with rating scales, augmentation was not recognized in any patients based on retrospective review of adverse events.

Gabapentin — More limited data also suggest that gabapentin may be effective in RLS/WED. Gabapentin, mean dose 733 mg/day, was effective in a four-week open-label study of nine patients with idiopathic RLS [42], and at a much higher mean dose (1855 mg) in a randomized, placebo-controlled trial of 22 patients [43]. Although this trial suggested that mean gabapentin doses of 1800 mg a day are needed, many patients appear to benefit from a lower dose.

We suggest beginning treatment at 100 to 300 mg per dose because of the tendency of the drug to cause somnolence and gait unsteadiness [5]. Among dialysis patients, low-dose gabapentin (200 to 300 mg three times weekly after hemodialysis) was effective in a 12-week, double-blind crossover study [44].

Pregabalin — In a small randomized trial of 58 patients, pregabalin (starting dose 150 mg daily, mean dose 337 mg daily) was superior to placebo for improving symptoms of RLS/WED [45].

In a subsequent larger randomized trial, pregabalin was compared with pramipexole and placebo in 719 patients with RLS/WED [21]. After 12 weeks of therapy, both pregabalin (300 mg daily) and pramipexole (0.5 mg daily) were associated with a significant 3- to 4-point improvement in IRLS scores compared with placebo. Over 40 to 52 weeks of treatment, pregabalin was noninferior to pramipexole on measures of efficacy and was associated with a significantly lower augmentation rate (2.1 percent) compared with pramipexole at a dose of 0.25 mg (5.3 percent) or 0.5 mg (7.7 percent). In contrast, pregabalin was associated with a slightly higher rate of treatment discontinuation due to side effects (28 percent, versus 19 and 24 percent for pramipexole 0.25 mg and 0.5 mg daily, respectively). Suicidal ideation was reported in six patients taking pregabalin and in five patients taking pramipexole.

Similar to gabapentin enacarbil, pregabalin may also improve subjective and objective measures of sleep maintenance and total sleep time in patients with RLS and comorbid insomnia [46].

We suggest starting pregabalin at a dose of 50 to 75 mg per day. The usual effective dose is 150 to 450 mg. The most common side effects reported with pregabalin include dizziness, somnolence, fatigue, headache, peripheral edema, and weight gain [21,45].

Duration of therapy — RLS/WED is often a lifelong disease, but the optimal and safe duration of pharmacologic therapy has not been well established [20]. Most of the supporting data are based on relatively short (≤12-week) randomized trials, with fewer long-term extension studies supporting efficacy for 6 to 12 months of therapy with either a dopamine agonist or gabapentin enacarbil.

In clinical practice, the most common problems that arise with long-term therapy are loss of efficacy and augmentation. (See 'Augmentation' below and 'Refractory RLS' below.)

INTERMITTENT SYMPTOMS

Choice of therapy — In patients with mild or intermittent symptoms, nonpharmacologic therapies may be sufficient for symptom relief. In other patients, clinically significant symptoms do not occur frequently enough to require daily treatment but are nonetheless disabling when they do occur. For such patients, we suggest use of levodopa or a dopamine agonist on an as-needed basis. While this approach has not been systematically studied in clinical trials, clinical experience suggests that it is a reasonable strategy.

The use of dopamine agonists in restless legs syndrome/Willis-Ekbom disease (RLS/WED) is discussed in more detail above (see 'Dopamine agonists' above). Other treatment options include intermittent use of levodopa, a benzodiazepine, or a low-potency opioid [5]. (See 'Levodopa' below and 'Benzodiazepines' below and 'Opioids' below.)

Levodopa — Levodopa was the first drug to be formally studied in RLS/WED, and its ability to ameliorate symptoms of RLS/WED has long been recognized. However, use of levodopa for RLS/WED has waned over time as the risk for augmentation has been better characterized, and as other dopaminergic agents that have a lower risk for augmentation have become available. (See 'Augmentation' below.)

Levodopa remains a reasonable "on demand" treatment option for patients with intermittent RLS who do not require daily therapy [3,5,22].

Several small randomized studies have demonstrated that levodopa improves RLS/WED symptom severity, number of periodic limb movements in sleep (PLMS), self-rated sleep quality, and quality of life compared with placebo [47]. Most studies were performed before the International Restless Leg Syndrome Study Group (IRLS) rating scale became widely used as an outcome measure; in two studies that reported RLS/WED symptom severity on a 10-point scale, levodopa improved symptom severity by a mean of 1.34 points compared with placebo [47]. Levodopa was also effective in a double-blind study of uremic RLS/WED [48].

Short-term therapy with levodopa is generally well tolerated; common adverse effects such as nausea, dizziness, and somnolence are usually mild and improve over time. Other problems that may occur in patients on levodopa include symptom rebound in the early morning (20 to 35 percent) or in the second half of the night [49,50]. Controlled release (CR) carbidopa-levodopa combined with standard carbidopa-levodopa may help sleep quality during the second half of the night for patients who experience recurrence [51].

For best absorption, levodopa should not be taken with high protein foods. Suggested agents include:

Carbidopa-levodopa 25 mg/100 mg, one-half or one tablet, can be used as a starting dose for intermittent RLS/WED that occurs during the evening, at bedtime, or on waking during the night. Additionally, this medication may be helpful for RLS/WED associated with specific triggers including lengthy travel by auto or airline, or spectator events with prolonged sitting. Levodopa doses greater than 200 mg per day should be avoided.

Carbidopa-levodopa CR, starting at 25 mg/100 mg before bed, may be helpful for RLS/WED symptoms that awaken the patient during the night.

Benzodiazepines — Benzodiazepines can be useful in mild cases of RLS/WED, particularly in younger patients [52,53]. The best-studied benzodiazepine in RLS/WED is clonazepam.

In a small randomized, double-blind, crossover trial, treatment with clonazepam, 1 mg daily, was superior to placebo in six patients with RLS/WED [54]. In an open trial, 14 of 15 patients with RLS/WED due to uremia responded to clonazepam, 1 to 2 mg daily [55]. Clinical experience suggests that clonazepam is useful in some patients at 0.5 mg daily.

Although most trials have been performed with clonazepam, its long duration of action may result in more adverse effects, such as nocturnal unsteadiness, drowsiness or cognitive impairment in the morning, impotence, and exacerbation of sleep apnea [56]. However, at least one study has shown a low rate of adverse effects from clonazepam in older adult patients [52].

Long-term maintenance treatment with benzodiazepines is limited by tolerance in many patients, but abuse appears to be low in this disorder. Because of tolerance and the potential for side effects, use of benzodiazepines for RLS/WED is generally limited to those patients that require only intermittent therapy, or as an add-on agent in patients with refractory symptoms.

Short-acting benzodiazepine receptor agonists such as zolpidem should generally be avoided, as a high frequency of sleepwalking and sleep-related eating disorder has been reported with their use in the setting of RLS/WED (as high as 80 percent in one study of 15 patients) [57-59].

AUGMENTATION — Augmentation is the main complication of long-term dopaminergic therapy for restless legs syndrome/Willis-Ekbom disease (RLS/WED) [22]. It refers to an overall increase in RLS/WED symptom severity with increasing doses of medication, including earlier onset of symptoms, increased intensity of symptoms, shorter duration of drug action, or topographic spread of symptoms to other body parts, including the trunk and arms.

Identification — Augmentation should be considered a possibility in the following circumstances [22,60]:

A maintained increase in symptom severity despite appropriate treatment

A maintained increase in symptom severity following a dose increase, particularly if a dose reduction leads to an improvement in symptoms

Earlier onset of symptoms in the afternoon/evening

Topographic spreading of symptoms to previously unaffected body parts (eg, arms)

Shorter latency to symptom onset during the day when at rest

Shorter duration of action of the drug

Four screening questions have been proposed to help identify augmentation in patients on dopaminergic therapy for RLS/WED (table 4) [22]. Augmentation should be distinguished from end-of-dose rebound, which can cause worsening symptoms in the early morning but does not generally involve spread to the arms, and natural progression of disease or exacerbating factors, which can cause worsening of symptoms and topographic spread that do not improve by reducing the dopaminergic load.

Risk factors — Augmentation was first recognized in patients taking levodopa. In a multicenter open-label study using flexible dosing of levodopa (mean maximum daily dose, 311 mg), 60 percent of patients developed augmentation at a median time of 71 days into therapy, leading to treatment discontinuation in 12 percent [61]. Augmentation was significantly more common in patients taking greater than or equal to 300 mg of levodopa daily (70 versus 35 percent).

The risk of augmentation with dopamine agonists appears to be lower but not insignificant; it has been reported in 3 to 9 percent of patients taking pramipexole for one year [21], about one-third of patients taking pramipexole for two years [62], and 42 to 68 percent of patients taking pramipexole for 8 to 10 years [30,63]. Fewer studies have been performed on ropinirole, but it appears that the short-term augmentation rate is similar to that of pramipexole. Augmentation has been reported in 2 to 9 percent of patients taking rotigotine for one year [35,64,65] and 38 percent of those using rotigotine for five years (only clinically significant in 13 percent) [66]. The definition of augmentation and the method of assessment (ie, retrospective or prospective) have varied across studies, and therefore direct comparisons are difficult.

The risk of augmentation increases with higher daily doses, longer duration of use, and lower iron stores [21,67]. Other risk factors for augmentation are not well known; in one study, augmentation was significantly more common in patients with a family history of RLS/WED and in those who had no evidence of neuropathy on electromyography or nerve conduction studies [68].

Using dopaminergic drugs on an intermittent basis rather than continuously may lower the risk of augmentation, although this has not been well studied. This is the rationale for use of levodopa in patients with intermittent RLS/WED, despite the high risk of augmentation with continuous use. (See 'Levodopa' above.)

Alpha-2-delta calcium channel ligands have not been associated with augmentation.

Management — Consensus-based guidelines for the management of augmentation when it is recognized in patients on dopamine agonists include the following [5,22]:

Iron stores should be re-evaluated and iron replacement initiated if stores are low. Patients should be asked about lifestyle changes or new medications that may be exacerbating symptoms. (See 'Iron replacement' above and 'Nonpharmacologic therapy' above.)

For mild augmentation, the dose of a dopamine agonist can be split between a nighttime dose and a dose earlier in the day. If this is ineffective, the dose can be modestly increased, but caution should be used not to exceed the maximum recommended total daily dosage (table 2). In addition, the patient should be carefully followed to ensure that augmentation is not worsening.

For more severe augmentation, switching from pramipexole or ropinirole to the extended release preparation, rotigotine, can sometimes help, as the rate of significant augmentation may be less with rotigotine.

Alternatively, dopamine agonists can be discontinued and replaced with alpha-2-delta calcium channel ligands. We typically introduce the new drug and increase the dose to an effective level before slowly reducing the dopamine agonist and discontinuing if at all possible. Some experts advocate a 10-day wash-out period before introducing the alpha-2-delta ligand in order to establish a baseline measure of disease severity, but this can result in increased RLS/WED symptoms and profound insomnia during the wash-out period.

For severe, continuous symptoms despite these measures, a low dose of a long-acting opioid may be an option in selected patients. (See 'Opioids' below.)

REFRACTORY RLS — Refractory restless legs syndrome/Willis-Ekbom disease (RLS/WED) is defined as restless legs unresponsive to monotherapy with tolerable doses of a dopamine agonist or alpha-2-delta ligand due to reduced efficacy, augmentation, or adverse effects [5].

In patients with refractory symptoms, iron stores should be re-evaluated and iron replacement initiated if stores are low. Lifestyle practices, concomitant medications, and treatment adherence should also be reviewed. (See 'Iron replacement' above and 'Avoidance of aggravating factors' above.)

Referral to a specialist for RLS/WED management should be considered for these patients [56]. The main pharmacologic treatment options are:

Use a combination of agents, such as a dopamine agonist, alpha-2 delta ligand, and/or a benzodiazepine. (See 'Dopamine agonists' above and 'Alpha-2-delta calcium channel ligands' above and 'Benzodiazepines' above.)

Change to a low-dose, high-potency opioid. (See 'Opioids' below.)

Opioids — Opioids can be effective in the treatment of chronic and refractory RLS/WED, particularly for patients who have not responded to other therapies. A variety of opioids, including oxycodone, codeine, propoxyphene, methadone, and tramadol, have been reported to be helpful for RLS/WED, primarily in uncontrolled trials [3,69].

In a double-blind, four-week crossover study of 11 patients, oxycodone (mean dose 16 mg/day) was superior to placebo with regard to number of sleep arousals, periodic leg movement frequency, and sleep efficiency [70]. One long-term retrospective study of 113 patients treated with opioids demonstrated persistent benefit, but a small number of patients developed sleep apnea [71].

In a double-blind, multicenter trial of 304 patients with refractory RLS/WED, controlled release oxycodone-naloxone was significantly more effective than placebo at 12 weeks in the 204 patients who completed the 12-week efficacy period (mean difference in International Restless Legs Syndrome Study Group [IRLS] scores: 8.15) [72]. The mean daily dose of oxycodone was 22 mg. Benefit was preserved over a 40-week, open-label extension period that included 197 patients. Fatigue and constipation were the most common side effects; two patients developed ileus or sub-ileus. No augmentation was seen. Thirteen percent of patients taking oxycodone-naloxone during the randomized phase discontinued the study due to side effects.

In a 10-year, open-label study of methadone for RLS/WED, 15 percent of 76 patients discontinued methadone treatment in the first year, but the remainder continued to use it with benefit. The mean daily dose after six months was 10 mg, with subsequent increases of no more than 10 mg [63].

Low potency opioids or opioid agonists can be used for intermittent RLS [56]. These drugs are usually taken before bed and include:

Codeine 30 to 60 mg.

Tramadol 50 to 100 mg before bed or during the night. Of note, tramadol has also been reported to cause augmentation in some patients [15].

Similar to benzodiazepines, tolerance to high potency opioids can develop with long-term maintenance therapy, but opioid abuse potential appears to be low in patients with RLS/WED in the absence of a history of substance abuse. Nevertheless, we typically restrict use to patients with more severe symptoms who fail to respond to other agents. Potential side effects include constipation, nausea, fatigue, itchiness, unsteadiness, and exacerbation of sleep apnea. Agents include [56]:

Oxycodone 5 to 30 mg

Hydrocodone 5 to 30 mg

Methadone 2.5 to 20 mg

Other drugs — Other drugs that may be useful in RLS/WED but have been reported in only a small number of (mainly open-label) studies include carbamazepine (mean dose 236 mg/day) [73], clonidine (0.05 mg/day) [74], and amantadine (up to 300 mg/day) [75]. There is inadequate evidence to suggest that magnesium supplementation is an effective treatment for RLS/WED.

SPECIAL POPULATIONS

Pregnancy and lactation — Management of restless legs syndrome/Willis-Ekbom disease (RLS/WED) during pregnancy should be individualized based on symptom severity, comorbidities such as depression or anxiety, and patient preferences.

Many patients can be managed successfully with education, reassurance, iron supplementation if indicated, and nonpharmacologic strategies. Pharmacologic therapies such as clonazepam or carbidopa-levodopa may be considered for severe symptoms in women who wish to try medication. (See "Restless legs syndrome/Willis-Ekbom disease during pregnancy and lactation".)

End-stage renal disease — The management of RLS/WED in patients with end-stage renal disease is similar to that in patients with normal renal function. However, medication doses may need to be adjusted, especially if the patient is not yet receiving dialysis, as dopamine agonists and alpha-2-delta ligands are all excreted by the kidneys. Careful attention to iron status is especially important in this group [76]. (See "Sleep disorders in end-stage renal disease", section on 'Treatment'.)

PERIODIC LIMB MOVEMENT DISORDER — Periodic limb movements of sleep (PLMS) accompany many sleep and neurologic disorders, including restless legs syndrome/Willis-Ekbom disease (RLS/WED), obstructive sleep apnea, rapid eye movement (REM) sleep behavior disorder, narcolepsy, and Parkinson disease. PLMS increase in frequency with age. (See "Clinical features and diagnosis of restless legs syndrome/Willis-Ekbom disease and periodic limb movement disorder in adults", section on 'Periodic limb movements of sleep'.)

PLMS do not have a consistent relationship with symptoms (eg, insomnia, excessive daytime sleepiness) or with polysomnographic variables of sleep disruption. They are generally considered to be an age-related phenomenon, a response to arousals, or an epiphenomenon of other disorders. However, occasionally they occur abundantly with frequent electroencephalographic arousals in the absence of other disorders, leading the clinician to suspect that they are directly responsible for complaints of excessive sleepiness or insomnia. The term periodic limb movement disorder (PLMD) should be restricted to this subgroup.

For patients with PLMS associated with RLS/WED, treatment should concentrate on the symptoms of RLS/WED rather than on the leg movements. For PLMS associated with other sleep disorders, independent treatment of PLMS is rarely required.

There are limited data regarding management of PLMD. Polysomnographic studies of PLMS in RLS/WED have shown reduction in the periodic limb movement index with pramipexole, ropinirole, rotigotine, gabapentin, gabapentin enacarbil, and pregabalin [3,40,77]. A comparison study suggested greater reduction with pramipexole compared with pregabalin [46].

Extrapolating from this data, we suggest a trial of dopamine agonist therapy in suspected cases of PLMD. If there are contraindications to dopamine agonist therapy, an alpha-2-delta ligand can be tried. Dosing and safety considerations are the same as for use in RLS/WED. (See 'Dopamine agonists' above and 'Alpha-2-delta calcium channel ligands' above.)

If the primary symptoms of insomnia or sleepiness do not respond to adequate doses of the selected drug, then the patient should be re-evaluated for other causes of insomnia or excessive daytime sleepiness. (See "Clinical features and diagnosis of insomnia" and "Approach to the patient with excessive daytime sleepiness".)

Clonazepam, valproate, and selegiline have been reported to help PLMD in small, uncontrolled studies [3]. It would appear, however, that clonazepam reduces arousals rather than eliminates PLMS.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Restless legs syndrome (Willis-Ekbom disease) (The Basics)" and "Patient education: Nocturnal (nighttime) leg cramps (The Basics)")

Online information and support is available for patients with RLS/WED through The Restless Legs Syndrome Foundation and the American Academy of Sleep Medicine (yoursleep.aasmnet.org).

SUMMARY AND RECOMMENDATIONS — Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is a treatable condition that generally responds well to pharmacologic therapy. A variety of treatments for RLS/WED have been studied in randomized controlled trials. The goals of therapy are to reduce or eliminate symptoms of RLS/WED and improve daytime function, sleep, and quality of life.

Iron stores should be evaluated in all patients with suspected or established RLS/WED. We suggest a trial of oral iron therapy for patients with iron deficiency or low-normal ferritin levels (ie, serum ferritin level <75 mcg/mL) (Grade 2C). (See 'Iron replacement' above.)

Nonpharmacologic therapy options include avoidance of aggravating drugs and substances such as caffeine (table 1), mental alerting activities, short daily hemodialysis for patients in renal failure, exercise, leg massage, and applied heat. In patients with mild and/or intermittent symptoms, these therapies may be sufficient for symptom relief. (See 'Nonpharmacologic therapy' above.)

In patients with chronic persistent RLS/WED despite nonpharmacologic therapies, we recommend pharmacologic therapy with a non-ergot dopamine agonist or an alpha-2-delta calcium channel ligand (Grade 1B). The choice between the two classes of drugs is based on symptom severity, patient age and comorbidities, drug side effect profiles, and patient preferences (table 3 and table 2). (See 'Choice of therapy' above.)

For patients with very severe RLS/WED, comorbid depression, or obesity/metabolic syndrome, we suggest initial therapy with a dopamine agonist (pramipexole, ropinirole, or rotigotine) rather than an alpha-2-delta calcium channel ligand (Grade 2C). (See 'Dopamine agonists' above.)

For patients with comorbid pain, anxiety, or insomnia or a history of impulse control disorder or addiction associated with use of a dopamine agonist, we suggest starting with an alpha-2-delta calcium channel ligand (gabapentin enacarbil, gabapentin, or pregabalin) (Grade 2C). (See 'Alpha-2-delta calcium channel ligands' above.)

For most other patients, we initially try an alpha-2-delta calcium channel ligand because of the risk of augmentation with dopamine agonists, but other potential side effects of the various drugs should also be considered. In general, older patients are more prone to side effects of alpha-2-delta ligands. If the first drug chosen is ineffective or poorly tolerated, then a drug of the other class should be tried.

In patients with intermittent symptoms that are not frequent enough to require daily therapy but are nonetheless disabling when they do occur, we suggest a trial of a dopamine agonist or levodopa on an as-needed basis (Grade 2C). Other treatment options for intermittent symptoms include benzodiazepines and opioids. (See 'Intermittent symptoms' above.)

When RLS/WED symptoms are refractory to first-line therapy with a dopamine agonist or an alpha-2-delta calcium channel ligand, treatment options include combination therapy and opioids. (See 'Refractory RLS' above.)

Augmentation, which refers to an overall worsening of RLS/WED symptom severity, with earlier onset of symptoms, shorter symptom latency with rest, shorter duration of action of drugs, or spread of symptoms to trunk or arms, is the most common complication of long-term dopaminergic therapy (table 4). Augmentation may be managed by alteration in the treatment regimen. (See 'Augmentation' above.)

RLS/WED is common during pregnancy. Many patients can be managed successfully with education, reassurance, iron supplementation if indicated, and nonpharmacologic strategies. Pharmacologic therapies such as clonazepam and carbidopa-levodopa may be considered for severe symptoms. (See "Restless legs syndrome/Willis-Ekbom disease during pregnancy and lactation".)

Treatment of periodic limb movement disorder (PLMD) as an entity distinct from RLS/WED is not well studied, but the approach is similar to that of RLS/WED. Periodic limb movements of sleep (PLMS) in the absence of insomnia or excessive daytime sleepiness do not require treatment. (See 'Periodic limb movement disorder' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Robert Sheon, MD, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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