INTRODUCTION — Restless legs syndrome (RLS) refers to an urge to move the legs, usually associated with unpleasant sensations. The urge to move the legs is worse at rest and at night and is relieved by movement. RLS is commonly associated with sleep disturbance and with involuntary, jerking movements of the legs during sleep, known as periodic limb movements of sleep (PLMS). When significant sleep disturbances or impaired daytime functioning coexist with PLMS in the absence of RLS or other associated disorders, the term periodic limb movement disorder (PLMD) is used.
RLS 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 alpha-2-delta voltage-gated calcium channel ligands, dopaminergic agents, opioids, and benzodiazepines [1-4]. The treatment approach to PLMD is similar to that of RLS, 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 disorders), drug side effects, and patient preferences. The goals of therapy are to reduce or eliminate symptoms of RLS and improve daytime function, sleep, and quality of life.
This topic will review the treatment of RLS and PLMD in nonpregnant adults. The clinical features and diagnosis of RLS and PLMD in adults and treatment of these disorders in children and pregnant patients are discussed separately. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults" and "Restless legs syndrome during pregnancy and lactation" and "Restless legs syndrome and periodic limb movement disorder in children".)
IRON REPLACEMENT — Iron replacement is suggested in patients with restless legs syndrome (RLS) whose fasting serum ferritin level is ≤75 ng/mL (algorithm 1) [5-7]. As serum ferritin is an acute phase reactant, transferrin saturation (TSAT) less than 20 percent may be a more accurate measure of low iron stores in patients with acute or chronic inflammatory disorders .
Pretreatment considerations — Iron status is determined by measuring an early morning, fasting iron panel (serum ferritin, iron, total iron-binding capacity, and percentage TSAT). (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Iron studies (list of available tests)'.)
Iron therapy should not be prescribed empirically for RLS because it may result in iron overload, especially in patients with previously unsuspected hemochromatosis. Patients with evidence of iron excess (eg, TSAT ≥45 percent) should not be given a trial of iron. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)
Importantly, any adult with iron deficiency (eg, serum ferritin level <30 ng/mL) should be evaluated for the underlying cause, which may include gastrointestinal blood loss, especially for adults over 40 to 50 years, or a condition that interferes with iron absorption. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Search for source of blood and iron loss'.)
Administration of iron — Iron supplementation can be supplied orally or intravenously (IV). IV delivery has the advantage of replenishing iron stores with fewer administrations than oral therapy, but it is less convenient and carries a low risk of serious infusion reactions, including anaphylaxis with some formulations. There are no direct comparisons of IV versus oral iron supplementation in patients with RLS, and available data do not show clear superiority of one route of administration over the other.
●Oral iron – For most patients, because oral iron is easier to administer and safer, we suggest initial therapy with an oral regimen such as ferrous sulfate (325 mg orally once daily or once every second day, preferably before bed) [5,7]. In RLS trials, iron has been combined with vitamin C (100 to 200 mg with each dose of ferrous sulfate) or a small glass of orange juice . Whether vitamin C improves oral iron absorption is not known, however, and some experts do not advise patients to take vitamin C. Iron should not be taken at the same time as calcium supplements or significant amounts of dairy products. The administration of oral iron and strategies to improve tolerability, including use of every-other-day dosing, are reviewed in detail separately. (See "Treatment of iron deficiency anemia in adults", section on 'Dosing and administration (oral iron)'.)
●IV iron – IV iron therapy is generally reserved for patients with a serum ferritin ≤100 ng/mL, TSAT <45 percent, and either a malabsorption state, complete intolerance to oral iron preparations, moderate to severe symptoms despite a trial of oral iron, or the need for a more rapid response due to severity of symptoms [6,7]. Trials of IV iron suggest that it is effective in approximately 40 to 60 percent of patients selected for therapy .
A number of IV iron preparations are available, with major differences in cost, formulary/purchasing agreements, and number of visits/time required to administer the full dose. If ferric carboxymaltose is selected, trials in patients with RLS suggest that a total dose of 1000 mg, not 500 mg, should be given. We administer as a single infusion (over 10 to 15 minutes) or in two doses of 500 mg at five- to seven-day intervals . If low molecular weight iron dextran is used, a test dose of 25 mg should be administered first, followed by 975 mg infused over one hour in normal saline. (See "Treatment of iron deficiency anemia in adults", section on 'Intravenous iron'.)
For patients who respond adequately to IV iron but then have recurrent symptoms, repeated infusions can be given in at least 12-week intervals as long as serum ferritin concentration is below 300 ng/mL and TSAT is <45 percent . For patients with a questionable response, we suggest a second infusion before assuming futility, especially if the serum ferritin is still less than 100 ng/mL.
Response and monitoring — Symptoms of RLS usually respond slowly to oral iron, and maximal symptomatic improvement can take several months after the start of oral iron. The response to IV iron is faster, and many patients respond within several days of infusion, particularly those with iron deficiency. Clinical response may be delayed for up to six weeks, however, for reasons that are uncertain [8,9].
We repeat an iron panel after three to four months of therapy and then every three to six months until the serum ferritin level is >100 ng/mL 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 [10,11].
Iron therapy can be discontinued when target values are reached 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'.)
Patients who do not respond symptomatically to iron despite replete iron stores should be considered for pharmacotherapy. (See 'Chronic persistent symptoms' below.)
Efficacy — Iron repletion as a treatment for RLS has been studied in patients with and without iron deficiency anemia. The rationale for iron in patients without frank iron deficiency anemia is based on the theory that a deficit in central brain iron exists in RLS despite low-normal or normal peripheral iron stores. Small trials have shown that both anemic and non-anemic patients may respond to iron, and the severity of iron deficiency is not a strong predictor of response.
●Oral iron – Supportive evidence for oral iron includes results of a 12-week randomized trial in which 18 adults with RLS and a serum ferritin ≤75 ng/mL (median 37 to 41 ng/mL) were randomly assigned to receive ferrous sulfate 325 mg twice daily or placebo . At 12 weeks, mean International Restless Leg Syndrome Study Group rating scale (IRLS) scores decreased more with iron than placebo (improvement from baseline, 10.4 versus 1.1 points). An earlier trial of oral iron in 28 patients who were not selected based on serum ferritin (median 101 to 135 ng/mL) did not demonstrate a benefit .
●IV iron – A variety of IV iron formulations have been studied in RLS, including ferric carboxymaltose (FCM) [8,9,14-16], iron dextran , and iron sucrose [18,19]. Results have been inconsistent, and a 2019 meta-analysis that included four of the trials found insufficient evidence to conclude whether iron is beneficial for treatment of RLS based on significant heterogeneity in the formulation of iron used, patient characteristics, and measurement of outcome variables across studies .
Among formulations, FCM has been studied in five trials [8,9,14-16], three of which showed statistically significant improvements in RLS symptoms compared with placebo in patients with varying baseline ferritin levels [14-16]. One of the negative trials used a lower dose of FCM (500 mg), which was felt to be inadequate . A trial published subsequent to the 2019 meta-analysis was the first to restrict enrollment to patients with iron deficiency anemia; in this trial, patients randomly assigned to FCM (1500 mg total dose) had improved IRLS scores compared with placebo at six weeks (improvement from baseline, 13.5 versus 1.4 points) .
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 [7,20]:
●Mental alerting activities, such as working on a computer or doing crossword puzzles, at times of rest or boredom
●Moderate regular exercise 
●A trial of abstinence from caffeine and alcohol
●For symptomatic relief – walking, bicycling, soaking the affected limbs, and leg massage, including pneumatic compression 
●Short daily hemodialysis for patients with end-stage kidney disease (see "Sleep disorders in end-stage kidney disease", section on 'Treatment')
Avoidance of aggravating factors
●Insufficient sleep – Sleep deprivation is known to aggravate symptoms of restless legs syndrome (RLS) in many patients, and general principles of sleep hygiene should be reviewed. An approach to the evaluation and behavioral management of insufficient sleep is reviewed separately. (See "Insufficient sleep: Evaluation and management".)
Evaluation and treatment of other causes of sleep disruption and poor quality sleep, including comorbid sleep disorders such as obstructive sleep apnea (OSA), is also indicated, as treatment may possibly improve RLS symptoms . (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)
●Medication side effects – Antidepressants, neuroleptic agents, dopamine-blocking antiemetics such as metoclopramide, and sedating antihistamines (including those found in nonprescription medications) may contribute to emergence of RLS or worsening of prior symptoms (table 1) . Most antidepressant classes have been associated with RLS, including tricyclics, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors .
If antidepressants are necessary, the symptoms of secondary RLS can usually be treated in the same way as primary RLS. Bupropion is an alternative antidepressant that may be less likely to induce or worsen RLS .
Complementary and alternative therapies — A variety of complementary and alternative medical therapies have been reported to have benefits for RLS but the quality of the evidence is low and the number of trials supporting any single therapy is low . Yoga and acupuncture are low-risk strategies that may have some benefit. A variety of noninvasive neurostimulation or neuromodulation techniques are under investigation, which may eventually be an option in patients with mild symptoms or who cannot tolerate medications .
Choice of therapy — In patients with intermittent symptoms (troublesome enough to require treatment but occurring less than twice per week on average), 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 (eg, airplane or lengthy car rides, theater attendance).
For intermittent use, medication options for RLS include carbidopa-levodopa, a benzodiazepine or benzodiazepine receptor agonist, and a low-dose opioid . Among these, carbidopa-levodopa is the least sedating and therefore preferred for daytime use and when continued alertness is desired. It can also be given before bed or in the middle of the night. Bedtime use of a benzodiazepine or low-dose opioid is also an option, especially in patients with comorbid insomnia. (See 'Carbidopa-levodopa' below and 'Benzodiazepines' below and 'Opioids' below.)
Dopamine agonists are seldom used for intermittent RLS because they have a delayed onset of action (usually 90 to 120 minutes) and are less helpful once symptoms have already started.
Carbidopa-levodopa — Carbidopa-levodopa was the first drug to be formally studied in RLS, and its ability to ameliorate symptoms of RLS has long been recognized. However, use of carbidopa-levodopa for RLS 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.)
Based on its rapid onset and tolerability at low doses, however, carbidopa-levodopa remains a reasonable "on demand" treatment option for patients with intermittent RLS who do not require daily therapy [2,7,29].
●Dosing – Levodopa is given in combination with a peripheral decarboxylase inhibitor, most commonly carbidopa, to block systemic conversion of levodopa to dopamine. For best absorption, carbidopa-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 that occurs during the evening, at bedtime, or on waking during the night . This medication may be helpful for managing RLS symptoms in an "on demand" fashion, particularly when associated with specific triggers including lengthy travel by automobile or airline, or spectator events with prolonged sitting. Levodopa doses greater than 200 mg per day should be avoided to reduce the risk of augmentation.
•Carbidopa-levodopa controlled release (CR), starting at 25 mg/100 mg before bed, may be helpful for RLS symptoms that awaken the patient during the night.
●Side effects – Short-term therapy with carbidopa-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 carbidopa-levodopa include symptom rebound in the early morning (20 to 35 percent) or in the second half of the night [30,31]. Carbidopa-levodopa CR combined with standard carbidopa-levodopa may help sleep quality during the second half of the night for patients who experience recurrence .
●Efficacy – Several small, randomized studies have demonstrated that carbidopa-levodopa improves RLS symptom severity, number of periodic limb movements in sleep (PLMS), self-rated sleep quality, and quality of life compared with placebo . Most studies were performed before the International Restless Leg Syndrome Study Group rating scale (IRLS) became widely used as an outcome measure; in two studies that reported RLS symptom severity on a 10-point scale, levodopa improved symptom severity by a mean of 1.34 points compared with placebo . Carbidopa-levodopa was also effective in a double-blind study of uremic RLS .
In a small, randomized, double-blind, crossover trial, treatment with clonazepam, 1 mg daily, was superior to placebo in six patients with RLS . In an open trial, 14 of 15 patients with RLS due to uremia responded to clonazepam, 1 to 2 mg daily . 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 . However, at least one study has shown a low rate of adverse effects from clonazepam in older adult patients .
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 is generally limited to those patients that require only intermittent therapy, or as an add-on agent in patients with refractory symptoms.
Short-acting nonbenzodiazepine receptor agonists such as zolpidem can be used intermittently, especially if insomnia related to RLS is a problem. However, sleepwalking and sleep-related eating disorder have been reported with their use in the setting of RLS (as high as 80 percent in one study of 15 patients) [40-43]. This observation is important, as RLS may be misinterpreted as sleep-onset insomnia, increasing the risk for hypnotic-induced parasomnias .
CHRONIC PERSISTENT SYMPTOMS — Chronic persistent restless legs syndrome (RLS) is defined as RLS 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 .
Choice of therapy — In most patients with chronic persistent RLS despite replete iron stores and elimination of aggravating factors, we suggest initial therapy with an alpha-2-delta calcium channel ligand (ie, pregabalin, gabapentin, gabapentin enacarbil) rather than a dopamine agonist (pramipexole, ropinirole, rotigotine). Our preference for alpha-2-delta calcium channel ligands is based on the high frequency of intermediate and long-term augmentation with dopamine agonists, as well as their risk of impulse control disorders . (See 'Augmentation' below.)
A dopamine agonist is a reasonable first-line alternative in patients with increased risk for side effects from alpha-2-delta calcium channel ligand, such as those with obesity and its complications, a past or present history of moderate to severe depression, a disorder causing gait instability or respiratory failure, and a history of substance use disorder (algorithm 1).
Multiple agents from both of these classes of drugs have been shown to be more effective than placebo in randomized trials in patients with RLS [1-3,5,7,45-47]. Head-to-head comparisons between the two classes are limited to a single study showing approximate equivalence in effect . A network meta-analysis of 35 trials in 7333 patients with RLS found similar efficacy across all medications examined (pregabalin, gabapentin enacarbil, pramipexole, ropinirole, and rotigotine) and little evidence of inter-treatment differences . Unlike dopamine agonists, alpha-2-delta calcium channel ligands do not appear to carry risk of augmentation with long-term use. Alpha-2-delta calcium channel ligands may also be helpful for common comorbidities of RLS, such as pain, anxiety, or insomnia.
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 for RLS, including levodopa, benzodiazepines, and opioids, but generally these are reserved for intermittent use or in patients with more refractory symptoms. (See 'Intermittent symptoms' above and 'Refractory RLS' below.)
Patients on continuous therapy should be reassessed 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 . (See 'Augmentation' below.)
These recommendations are generally consistent with practice guidelines of the American Academy of Neurology , the American Academy of Sleep Medicine , and the Restless Legs Syndrome Foundation .
Alpha-2-delta calcium channel ligands — Pregabalin, gabapentin, and gabapentin enacarbil are all appropriate first-line therapies for chronic persistent RLS in many patients [7,49,50]. The mechanism of action in RLS is unknown.
●Agent selection – We choose among the three drugs based on factors that include pharmacokinetics, symptom pattern, and cost. When RLS symptoms occur predominantly in the evening or night, we start with pregabalin or gabapentin; pregabalin is preferred because of straightforward pharmacokinetics and better data on efficacy, but gabapentin is often cheaper and can be substituted if cost is a factor. For patients with RLS symptoms throughout most of the day and night, we prefer gabapentin enacarbil because it provided 24-hour coverage with the convenience of once-daily dosing.
●Comorbidities favoring use – The alpha-2-delta calcium channel ligands as a class may be particularly useful when RLS 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 symptoms . They may also be considered in the treatment of RLS 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.
●Precautions – 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. Other potential side effects, especially in older patients, include mental fogging, dizziness and unsteadiness, weight gain and leg edema. All three drugs in the class are excreted by the kidneys and require dose adjustments for renal dysfunction.
In December 2019, the US Food and Drug Administration (FDA) issued a warning about the potential for serious respiratory difficulties when alpha-2-delta calcium channel ligands are used in combination with other central nervous system depressants (eg, opioids, benzodiazepines), especially in older adults and those with respiratory disorders such as severe chronic obstructive pulmonary disease (COPD) . There is also growing awareness of the potential for misuse and abuse of these drugs .
●Dosing – We suggest starting pregabalin at a dose of 50 to 75 mg per day, taken one to two hours before the usual onset of symptoms. The usual effective dose in patients with RLS is 150 to 450 mg per day.
●Efficacy – In the largest of several randomized trials, pregabalin was compared with pramipexole and placebo in 719 patients with RLS . 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 International Restless Leg Syndrome Study Group rating scale (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). By 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.
●Dosing – We suggest beginning gabapentin at 100 to 300 mg in the evening (eg, one to two hours before the usual onset of symptoms) and titrating slowly upwards based on response and tolerability, particularly in older adults. The usual effective dose is 900 to 2400 mg daily given in a single dose or divided as one-third an hour before symptoms commence and two-thirds before bed. Especially in doses above 1200 mg, the administered dose may not correlate well with serum levels because of nonlinear kinetics.
●Side effects – Common dose-related side effects of gabapentin include somnolence, dizziness, and ataxia. These effects can be minimized by starting with a low dose and titrating slowly. As with other drugs in this class, clinicians should be aware of risks and safety concerns related to suicidality, respiratory depression, and misuse and abuse. (See 'Alpha-2-delta calcium channel ligands' above.)
●Efficacy – Gabapentin, mean dose 733 mg/day, was effective in a four-week, open-label study of nine patients with idiopathic RLS , and at a much higher mean dose (1855 mg) in a randomized, placebo-controlled trial of 22 patients . Although this trial suggested that mean gabapentin doses of 1800 mg a day are needed for maximal symptom benefit, many patients appear to benefit from a lower dose. 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 .
Gabapentin enacarbil — Gabapentin enacarbil is a prodrug of gabapentin that is converted to gabapentin after absorption and enables more consistent single daily dose administration. For the purposes of RLS, which tends to peak in the evenings, the dose is typically timed at about 5 PM to achieve target therapeutic levels at bedtime . It is preferred over other alpha-2-delta agonists in patients with symptoms during the day and night based on consistent pharmacokinetic properties.
●Dosing – The suggested starting dose of gabapentin enacarbil for RLS is 600 mg, taken in the early evening (eg, at 5 PM). A lower starting dose (300 mg) is recommended in older adults. Although regulatory approval is only for the 600 mg dose, trials and clinical experience support titration up to 1200 mg as needed .
●Side effects – 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 . Somnolence, dizziness, and weight gain were among the most common reasons for discontinuation.
●Efficacy – Several randomized, placebo-controlled studies have demonstrated that gabapentin enacarbil is effective in reducing RLS symptom severity [2,49,50,59-61]. 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 . 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 .
Dopamine agonists — The non-ergot dopamine agonists, pramipexole, ropinirole, and rotigotine, are effective in the treatment of RLS at low doses and are all considered reasonable first-line therapies for chronic persistent RLS in patients with an increased risk for side effects from alpha-2-delta calcium channel ligands . Efficacy is similar among the three agents, and selection of a specific drug is typically based on patient preference with regard to route of administration (oral versus transdermal delivery), cost and formulary considerations, and whether or not daytime symptoms are present.
Among dopaminergic therapies, the non-ergot dopamine agonists have a longer half-life and lower risk of augmentation compared with levodopa [62,63]. The older ergot dopamine agonists (bromocriptine, cabergoline, pergolide) have short-term efficacy but are no longer used to treat RLS due to risks of cardiac valvular disease and other fibrotic reactions [1,7].
Administration and efficacy — The clinical effects of the three dopamine agonists are similar. Ropinirole and rotigotine should be avoided in patients with hepatic failure, as they are metabolized by the liver, and all three are renally excreted and require caution and/or dose modifications in patients with moderate to severe renal impairment.
All dopamine agonists should be used at the minimum dose required to control symptoms and not exceeding dose ranges in the table in order to reduce the risk of augmentation (table 2). Doses required for RLS are lower than those used to treat Parkinson disease. Side effects common to all three agents are discussed below. (See 'Side effects and monitoring' below.)
●Pramipexole – Pramipexole immediate release (IR) is one of two oral dopamine agonists used in the treatment of RLS. A long-acting formulation exists but is not well studied in RLS.
•Dosing – The recommended starting dose of pramipexole IR is 0.125 mg once daily (table 2). Time to peak blood level is 120 minutes, and therefore the dose should be taken about two hours before the usual start of symptoms . The dose can be increased by 0.125 mg every two to three days depending on response and tolerability. Most patients require 0.5 mg or less for clinical benefit [46,64].
•Efficacy – The benefit of pramipexole IR was demonstrated in a meta-analysis of seven randomized placebo-controlled trials totaling over 1200 patients . In all of the studies, pramipexole improved RLS symptom severity, with an average improvement in the IRLS score of 6.7 points over placebo (95% CI 4.9-8.5) . For reference, a 6-point difference has been proposed as a clinically meaningful improvement in IRLS scores .
Uncontrolled studies with longer-term follow-up (26 to 52 weeks) have reported a mean improvement of 17 points on the IRLS [66,67]. In a large multicenter trial of two doses of pramipexole compared with pregabalin and placebo, 0.25 mg pramipexole was no more effective than placebo but 0.5 mg reduced the IRLS score more than placebo and had an equivalent effect to that of pregabalin .
•Dosing – The recommended starting dose of ropinirole IR is 0.25 mg once daily (table 2). Time to peak blood level is 90 minutes, and therefore the dose should be taken about 90 minutes before the usual start of symptoms . 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 kidney disease on hemodialysis. In one large randomized controlled trial, the average daily dose of ropinirole was 1.9 mg .
•Efficacy – The benefit of ropinirole was demonstrated in a meta-analysis of five randomized placebo-controlled trials totaling over 900 patients, in which the average improvement in IRLS score over placebo was 4 points (95% CI 2-6) .
●Rotigotine – Rotigotine is a non-ergot dopamine agonist that is formulated as a 24-hour transdermal patch. It is typically reserved for use in patients with symptoms throughout the day, for whom 24-hour coverage would be beneficial, or for patients with augmentation on oral dopamine agonists. (See 'Management' below.)
•Dosing – Transdermal rotigotine 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.
•Efficacy – The benefit of rotigotine for RLS was demonstrated in a meta-analysis of five randomized controlled trials totaling over 600 patients, in which the average improvement in IRLS score over placebo was 7 points (95% CI 5.6-8.4) . Two long-term follow-up studies (52 to 104 weeks) have reported a mean improvement of 15 to 17 points on the IRLS [69-71].
Side effects and monitoring — The most common initial side effects of dopamine agonists are nausea, lightheadedness, and fatigue; these are usually mild and resolve within 10 to 14 days. Less frequent side effects include nasal stuffiness, constipation, insomnia, leg edema, and mental status changes (confusion, psychosis); these are reversible if the medication is stopped. Excessive daytime sleepiness can occur at higher doses and occasionally manifests as sudden, unexpected sleep attacks . These may be less common than in patients with Parkinson disease on higher doses of pramipexole .
Patients on continuous dopamine agonist therapy are also at risk for the following:
●Impulse control disorders – As first reported in patients with Parkinson disease, dopamine agonist therapy in patients with RLS may be associated with an increased risk of impulse control disorders such as pathologic gambling, compulsive eating and shopping, and compulsive inappropriate hypersexuality [74,75]. The risk in patients with RLS is estimated to range from 6 to 17 percent . (See "Initial pharmacologic treatment of Parkinson disease", section on 'Impulse control disorders'.)
●Augmentation – Augmentation, which refers to a worsening of RLS 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 that is discussed in more detail below. Patients on daily dopaminergic therapy should be reassessed 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 . (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.
●Withdrawal syndrome – Dopamine agonist withdrawal syndrome can occur with abrupt discontinuation of dopamine agonist therapy. Symptoms, including anxiety, panic attacks, depression, sweating, nausea, pain, fatigue, dizziness, and drug craving, may last many months . (See "Initial pharmacologic treatment of Parkinson disease", section on 'Dopamine agonist withdrawal syndrome'.)
Duration of therapy — RLS is often a lifelong disease, but the optimal and safe duration of pharmacologic therapy has not been well established . 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.
AUGMENTATION — Augmentation is the main complication of long-term dopaminergic therapy for restless legs syndrome (RLS) . It refers to an overall increase in RLS symptom severity with increasing doses of medication, including earlier onset of symptoms, increased intensity of symptoms, shorter duration of drug action, or topographic (geographic) spread of symptoms to previously unaffected body parts, including the trunk and arms.
Identification — Augmentation should be considered a possibility in the following circumstances [29,77]:
●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 spread 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
The differential diagnosis of augmentation includes end-of-dose rebound, tolerance, natural disease progression, and exacerbating factors (table 4). Symptom characteristics and response to dose changes can be used to distinguish among them. For example, 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 (table 4).
Risk factors — Augmentation was first recognized in patients taking carbidopa-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 . 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 , about one-third of patients taking pramipexole for two years , and 42 to 68 percent of patients taking pramipexole for 8 to 10 years [72,80]. 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 [70,81,82] and 38 percent of those using rotigotine for five years (only clinically significant in 13 percent) . 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 [46,84]. 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 and in those who had no evidence of neuropathy on electromyography or nerve conduction studies .
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, despite the high risk of augmentation with continuous use. (See 'Carbidopa-levodopa' above.)
●Re-evaluate iron – Iron stores should be re-evaluated and iron replacement initiated if stores are low. Ferritin is the most useful test of iron stores but is an acute phase reactant and can be elevated independent of iron stores. Alternative studies to evaluate for iron deficiency in the setting of acute illness, inflammation, or malignancy are reviewed separately. (See 'Iron replacement' above and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)
●Review concomitant medications and sleep – Patients should be asked about lifestyle changes or new medications that may be exacerbating symptoms. (See 'Nonpharmacologic therapy' above.)
●Adjust dosing – For mild augmentation, the dose of a dopamine agonist can be split between a nighttime dose and a dose earlier in the day (algorithm 2). 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.
●Change formulation – For more severe augmentation, switching from pramipexole or ropinirole to the extended-release transdermal preparation, rotigotine, can sometimes help, as the rate of significant augmentation may be less with rotigotine. Extended-release formulations of oral pramipexole and oral ropinirole also exist but have not yet been well studied in RLS .
●Discontinue dopamine agonist – Alternatively, dopamine agonists can be discontinued and replaced with alpha-2-delta calcium channel ligands (algorithm 2). 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 symptoms and profound insomnia during the wash-out period.
●Add adjunctive therapy – 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.)
Definition and general approach — Refractory restless legs syndrome (RLS) 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.
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. Additional sleep disorders, such as obstructive sleep apnea, should be considered, especially for patients living alone or who present with a disproportionate degree of sleep fragmentation, insomnia, or excessive sleepiness. Augmentation should be considered in patients on dopamine agonist therapy, particularly in patients requiring high daily doses. (See 'Iron replacement' above and 'Avoidance of aggravating factors' above and 'Augmentation' above.)
Referral to a specialist for RLS management should be considered for these patients . 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 opioid. (See 'Opioids' below.)
Opioids — Opioids can be effective in the treatment of chronic and refractory RLS, particularly for patients who have not responded to other therapies. The mechanism of action is not known, but an interaction between spinal opioid and dopamine receptors has been speculated . Although low-potency opioids such as tramadol and codeine can be tried, most patients with refractory symptoms will require a high-potency agent such as oxycodone or methadone .
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 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 and who maintain regular follow-up to monitor for response and toxicity. Potential side effects include constipation, nausea, fatigue, itchiness, sweating, unsteadiness, depression, and exacerbation of sleep apnea.
In order to promote appropriate and safe use of opioids in patients with refractory RLS, an expert consensus panel endorses the following guidelines :
●Before initiating opioid therapy, assess patients for the risk of opioid use disorder. State prescription drug monitoring programs should be queried, and a urine drug screen should be performed. (See "Use of opioids in the management of chronic non-cancer pain", section on 'Evaluation of risk prior to initiating therapy'.)
●Inform patients about expectations of treatment, the goals of therapy, and the risks of opioids . (See "Use of opioids in the management of chronic non-cancer pain", section on 'Setting patient responsibilities, expectations, and treatment goals'.)
●Consider use of a written opioid agreement or contract. (See "Use of opioids in the management of chronic non-cancer pain", section on 'Opioid agreement/consent form'.)
●Schedule regular follow-up to assess effectiveness of therapy, side effects, and evidence for development of opioid use disorder. Review state prescription drug monitoring programs regularly and consider urine drug screening at least annually, especially in high-risk patients.
When opioid therapy is selected, the choice of a specific agent should be individualized based on patient factors, physician preference, and cost. An initial trial of a low-potency opioid is often reasonable, although many patients will require a high-potency agent. Importantly, the usual effective doses of high-potency opioids for RLS are far lower than those used for treatment of chronic pain, and high doses should raise concern for misuse or diversion.
In patients with RLS, longer-acting and controlled-release formulations may be preferred at night, as short-acting opioids may not give adequate length of coverage and may be associated with end-of-dose rebound of RLS symptoms, which may further disturb sleep . The Centers for Disease Control and Prevention (CDC) advises that opioid-naïve patients should not be started on extended-release/long-acting opioids as initial therapy for chronic pain, and extended-release/long-acting opioids should only be started in patients who have been taking opioids for at least one week . This practice may also be reasonable in patients with RLS. Treatment should begin at the lowest dose provided below, with the usual effective dose ranges for RLS provided in parentheses [39,88].
●Low-potency opioids or opioid agonists:
•Codeine 30 mg (60 to 180 mg)
•Tramadol (immediate release) 50 mg (50 to 100 mg)
•Tramadol (extended release) 100 mg (100 to 200 mg)
•Morphine controlled release 10 or 15 mg (15 to 45 mg)
•Oxycodone (immediate or extended release) 5 mg (10 to 30 mg)
•Hydrocodone (immediate or extended release) 10 mg (20 to 45 mg)
•Methadone 2.5 mg (5 to 20 mg)
Evidence to support the efficacy of opioids for RLS consists of case series and a small number of randomized trials . The quality of the evidence is limited by short-term follow-up in many studies, heterogeneous outcome assessment, and loss to follow-up.
●In a double-blind, multicenter trial of 304 patients with refractory RLS, controlled-release oxycodone-naloxone (not available in the United States) was 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 rating scale [IRLS] scores: 8.15; 95% CI 5.5-10.8) . 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.
●A blinded, four-week crossover study of 11 patients with refractory RLS found that oxycodone (mean dose 16 mg/day) was superior to placebo with regard to number of sleep arousals, periodic leg movement frequency, and sleep efficiency .
●A long-term retrospective study of 113 patients treated with opioids demonstrated persistent benefit, but a small number of patients developed sleep apnea . In a 10-year, open-label study of methadone for RLS, 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.
In the United States, a National RLS Opioid Registry has been created to help assess the long-term safety and efficacy of opioids for RLS. Information for patients and prescribers is available on the website . In the first report of 500 participants (median age 65 years, 57 percent female), methadone was the most commonly reported opioid (46 percent), followed by oxycodone (24 percent) and hydrocodone (14 percent) . The median total daily dose of opioid was 30 morphine milligram equivalents, and approximately one-third of the cohort reported an increase in opioid dose over the first year of registry follow-up.
Other drugs — Other drugs that may be useful in RLS but have been reported in only a small number of (mainly open-label) studies include carbamazepine (mean dose 236 mg/day) , clonidine (0.05 mg/day) , and amantadine (up to 300 mg/day) . Cannabis has been described as beneficial for RLS in case reports but has not been studied systematically . There is inadequate evidence to suggest that magnesium supplementation is an effective treatment for RLS . Dipyridamole, a nucleoside transporter inhibitor with antiplatelet and pro-adenosine effects, may be useful based on a two-week placebo-controlled cross-over study in 29 patients with previously untreated RLS, but longer studies in a more varied patient population are needed .
Vitamin D deficiency has been associated with an increased risk of RLS in several observational studies [102,103]. It is not yet known, however, whether vitamin D supplementation improves symptoms.
Pregnancy and lactation — Management of restless legs syndrome (RLS) 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 during pregnancy and lactation".)
End-stage kidney disease — The management of RLS in patients with end-stage kidney disease is similar to that in patients with normal kidney function. However, medication doses may need to be adjusted, especially if the patient is not yet receiving dialysis, as most dopamine agonists and alpha-2-delta ligands are excreted by the kidneys (table 2). Transdermal rotigotine is a notable exception. Careful attention to iron status is especially important in patients with end-stage kidney disease . (See "Sleep disorders in end-stage kidney disease", section on 'Treatment'.)
PERIODIC LIMB MOVEMENT DISORDER — Periodic limb movements of sleep (PLMS) accompany many sleep and neurologic disorders, including restless legs syndrome (RLS), obstructive sleep apnea (OSA), 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 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, treatment should concentrate on the symptoms of RLS 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 have shown reduction in the periodic limb movement index with pramipexole, ropinirole, rotigotine, gabapentin, gabapentin enacarbil, and pregabalin [2,61,105]. A comparison study suggested greater reduction with pramipexole compared with pregabalin .
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. (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 "Evaluation and diagnosis of insomnia in adults" and "Approach to the patient with excessive daytime sleepiness".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Restless legs syndrome".)
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.)
SUMMARY AND RECOMMENDATIONS
●Goals of therapy – Restless legs syndrome (RLS) is a treatable condition that generally responds well to pharmacologic therapy. The goals of therapy are to reduce or eliminate symptoms of RLS and improve daytime function, sleep, and quality of life.
●Check iron stores – Iron stores should be evaluated in all patients with RLS (algorithm 1). We suggest a trial of oral iron therapy for patients with iron deficiency or low-normal ferritin levels (ie, serum ferritin level <75 ng/mL) (Grade 2C). Intravenous iron is generally reserved for patients with a serum ferritin ≤100 ng/mL and either a malabsorption state, complete intolerance to oral iron preparations, or moderate to severe symptoms despite a trial of oral iron, or the need for a more rapid response due to severity of symptoms. (See 'Iron replacement' above.)
Any adult with iron deficiency (eg, serum ferritin level <30 ng/mL) should be evaluated for the underlying cause, which may include gastrointestinal blood loss, especially for adults over 40 to 50 years, or a condition that interferes with iron absorption. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Search for source of blood and iron loss'.)
●Behavioral strategies – Patients should be counseled to avoid aggravating drugs and substances such as caffeine (table 1). Mental alerting activities, exercise, leg massage, and applied heat often help RLS. In patients with mild and/or intermittent symptoms, these therapies may be sufficient for symptom relief. (See 'Nonpharmacologic therapy' above.)
●First-line daily medication – In most patients with chronic persistent RLS, we suggest initial therapy with an alpha-2-delta calcium channel ligand (pregabalin, gabapentin, or gabapentin enacarbil) rather than a dopamine agonist (Grade 2B). While both classes of medications are more effective than placebo, we prefer to start with an alpha-2-delta calcium channel ligand to avoid the risk of augmentation and impulse control disorders with dopamine agonists. Doses are provided in the table (table 2). (See 'Choice of therapy' above and 'Alpha-2-delta calcium channel ligands' above.)
A dopamine agonist (pramipexole, ropinirole, or rotigotine) is a reasonable first-line alternative in patients at increased risk for side effects from an alpha-2-delta calcium channel ligand, such as those with obesity and its complications, a past or present history of moderate or severe depression, disorders causing gait instability or respiratory failure, and a history of substance use disorder (algorithm 1). (See 'Dopamine agonists' above.)
If the first drug chosen is ineffective or poorly tolerated, then a drug of the other class should be tried.
●Options for intermittent (not daily) symptoms – 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 carbidopa-levodopa on an as-needed basis (Grade 2C). Other less attractive treatment options for intermittent symptoms include benzodiazepines and opioids. (See 'Intermittent symptoms' above.)
●Options for refractory RLS – When RLS symptoms are refractory to first-line therapy with an alpha-2-delta calcium channel ligand or a dopamine agonist, treatment options include combination therapy and opioids. (See 'Refractory RLS' above.)
●Management of augmentation – Augmentation, which refers to an overall worsening of RLS 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 3 and table 4). Anecdotal evidence suggests that alterations in drug dosing or formulation and/or switching drug class may be helpful (algorithm 2). (See 'Augmentation' above.)
●Periodic limb movement disorder – Treatment of periodic limb movement disorder (PLMD) as an entity distinct from RLS is not well studied, but the approach is similar to that of RLS. 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, and Daniel Tarsy, MD, who contributed to earlier versions of this topic review.