Restless Legs Syndrome: Contemporary Diagnosis and Treatment

Summary

Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs while at rest, relief upon movement or getting up to walk, and worsened symptom severity at night. RLS may be primary (idiopathic) or secondary to pregnancy or a variety of systemic disorders, especially iron deficiency, and chronic renal insufficiency. Genetic predisposition with a family history is common. The pathogenesis of RLS remains unclear but is likely to involve central nervous system dopaminergic dysfunction, as well as other, undefined contributing mechanisms. Evaluation begins with a thorough history and examination, and iron measures, including ferritin and transferrin saturation, should be checked at presentation and with worsened symptoms, especially when augmentation develops. Augmentation is characterized by more intense symptom severity, earlier symptom occurrence, and often, symptom spread from the legs to the arms or other body regions. Some people with RLS have adequate symptom control with non-pharmacological measures such as massage or temperate baths. First-line management options include iron-replacement therapy in those with evidence for reduced body-iron stores or, alternatively, with prescribed gabapentin or pregabalin, and dopamine agonists such as pramipexole, ropinirole, and rotigotine. Second-line therapies include intravenous iron infusion in those who are intolerant of oral iron and/or those having augmentation with intense, severe RLS symptoms, and opioids including tramadol, oxycodone, and methadone. RLS significantly impacts patients’ quality of life and remains a therapeutic area sorely in need of innovation and a further pipeline of new, biologically informed therapies.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13311-021-01019-4.

Restless legs syndrome (RLS), also known as Willis-Ekbom disease, was first described in 1672 by Sir Thomas Willis, who noted that in those who suffer from RLS “…so great a Restlessness and Tossing of their Members ensue, that the diseased are no more able to sleep, than if they were in a Place of the greatest torture” [1]. The clinical definition of RLS has evolved further over the years, but its essential features have remained just as Willis described: an irresistible restlessness and urge to move the legs, often accompanied by unpleasant sensations. Dr. Karl Ekbom named and defined the syndrome further in the mid-twentieth century [2], and in 1995, the International Restless Legs Syndrome Study Group (IRLSSG) was formed and diagnostic features of RLS were additionally clarified [3] and recently further updated [4, 5]. While other groups such as the AASM and APA have established similar RLS criteria [6, 7], the IRLSSG group definition is the most widely accepted and thus are the main criteria addressed in this review. Also for consistency and avoidance of confusion, despite the previous effort to propose new, less stigmatizing terminology for RLS by substituting a new moniker of Willis Ekbom disease, given that this label was even less familiar and failed to gain common use and acceptance in recent years we will refer to the better known traditional terminology of RLS throughout the remainder of this article [8, 9].

Epidemiology

Dr. Ekbom wrote in 1960 “…the syndrome is so common and causes such suffering that it should be known to every physician” [2]. Epidemiological studies have emphasized the commonality of RLS, estimating that its prevalence is between 7 and 10% in the general adult European and American populations [5, 10–14]. Women are more likely to be affected than men, with increasing parity increasing risk of RLS among women [15]. There also is an increased prevalence of RLS symptoms in adults over 40 years of age, with some studies estimating prevalence to be as high as 18–23% in the elderly [16, 17]. Generally, studies have reported that there is increasing prevalence of RLS with increased age [18], although one study suggested that RLS prevalence decreases after age 64 [14]. Interestingly, studies have also indicated that RLS is relatively common in children and adolescents, affecting 1–4% of this population [19–21]. Despite its high prevalence, a majority of people with RLS experience mild to moderate RLS symptoms, while only about 1–3% of people overall have severe and frequent symptoms [13, 14, 20, 22, 23]. There is a lower prevalence in Asia (1.0–7.5%) and Africa (0.037%), although data remains limited from these regions [24, 25]. In sum, a recent meta-analysis of RLS epidemiology estimates that there is likely a 5–8% prevalence in the general population, with most patients experiencing mild RLS symptoms and with increasing prevalence of RLS symptoms with increasing age [18].

Clinical Presentation and Diagnosis

RLS has several cardinal features including an irresistible urge to move the legs, occurrence at rest, relief in part or whole by movement, and an evening predominance of symptoms. Although RLS primarily affects the legs, it has been described in other body regions such as the mouth, neck, arms, face, abdomen, and genitals [26–34]. The diagnostic criteria of RLS were updated most recently in 2014 by the IRLSSG and are composed of five key features that must be met for a diagnosis of RLS, as shown in Table 1 [5].

Table 1.

Restless leg syndrome diagnostic criteria as defined by the IRLSSG [5]

1) An irresistible urge to move the legs, usually but not always accompanied by uncomfortable and unpleasant sensations in the legs;

2) Symptoms that begin or worsen during periods of rest or inactivity, such as lying down or sitting;

3) Symptoms are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues;

4) Symptoms only occur or are worse in the evening or night than during the day; and

5) The occurrence of the above features is not solely accounted for as symptoms primary to another medical or a behavioral condition (e.g. myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping)

The varying clinical presentations of RLS have direct clinical relevance toward management including symptom frequency and severity, disease course, and response to therapy. A recent expert consensus statement outlined several different RLS diagnostic categories based on its presenting clinical features and scenarios, with suggested management strategies and approaches [35]. Intermittent RLS is defined as RLS symptoms sufficiently bothersome to require treatment and occurring, on average, less than twice weekly, for which non-pharmacologic or intermittent prescription medications are typically advised. Chronic persistent RLS constitutes moderately or severely distressing symptoms occurring at least twice weekly requiring daily treatments, most often requiring medications. Refractory RLS symptoms are unresponsive to first-line monotherapy medications due to incomplete or reduced efficacy, intolerable adverse effects, or evolution of augmentation, which is a worsening of RLS symptoms with temporally earlier, increasingly intense, and often geographically ascending characteristics (as further defined and discussed extensively later in this article). Refractory RLS symptoms are usually addressed through a revised management approach, which typically involves assessment for iron deficiency with oral or intravenous iron therapy if indicated, as well as consideration of a medication class switch, a newly added adjunctive drug, or in the setting of augmentation, reduction of dopaminergic therapies with or without substitution by non-dopaminergic medications. Complete discussion and example algorithms summarizing therapeutic approaches toward these RLS presentations are found in the RLS/WED Foundation consensus statement on RLS management [35], with a further summary discussion toward differing approaches later in this article.

In order to properly characterize and diagnose RLS, it is important to exclude other imitators that cause uncomfortable nocturnal leg sensations such as nocturnal leg cramps, painful peripheral neuropathy, myofascial pain syndromes and fibromyalgia, and motor akathisia. The exclusion of these RLS mimics is of sufficient clinical importance such that a fifth official diagnostic criterion for RLS was added in 2014, requiring assessment for these mimics [5]. These exclusionary criteria specify that RLS may not be solely caused by another motor or behavioral disorder, although other conditions may be present. Indeed, a multitude of comorbidities have been associated with RLS.

RLS symptoms often make it difficult for patients to fall asleep or rest and lead to functional impairments in mood, cognition, energy, and other daily activities. The severity of impairment from RLS is commonly measured subjectively by rating scales such as the International Restless Legs Syndrome Study Group rating scale (IRLS) or its self-administered version, the sIRLS [36, 37]. Both scales use ten questions to examine the severity of RLS symptoms in relation to the patient’s mood, normal everyday functioning, frequency, sleep quality, and overall discomfort [38].

Periodic limb movements of sleep (PLMS) are considered a supportive criterion for the diagnosis of RLS, but they are neither necessary nor sufficient for RLS diagnosis. However, PLMS are seen in 80% of patients with RLS (Fig. 1) [39]. PLMS are also very common in patients without RLS symptoms, found in 7.6–25% of the general population [40, 41] and between 1/3 and 2/3 of older adults [42, 43]. A common misconception regarding RLS is that it is synonymous with periodic limb movement disorder (PLMD); consequently, PLMD or incidental/isolated periodic limb movements of sleep (PLMS) are often misdiagnosed as RLS. A diagnosis of PLMD is restricted to patients without RLS, in whom periodic limb movements of sleep are the primary sleep disturbance and are associated with (and presumably causing) symptoms of insomnia or hypersomnia. The diagnosis of PLMD relies strictly on polysomnography (PSG) and a history of associated sleep disturbance, whereas RLS diagnosis does not require PSG. Officially, there are four criteria according to the ICSD-3 that guide the diagnosis of periodic limb movement disorder. They are as follows: (1) PSG demonstrating highly stereotyped, repetitive limb movements; (2) PLMS index ≥ 5/h for children and ≥ 15/h for adults; (3) PLMS cause a clinical sleep disturbance of any type and impaired daytime functioning; and (4) is not better explained by another medical, psychological, or substance abuse disorder [44].

Fig. 1.

Periodic leg movements (PLMS) of sleep during polysomnography PLMs are shown in channel 7 (linked anterior tibialis). Shown is a 2-min epoch during N2 sleep. This patient with a history of longstanding restless legs syndrome (RLS) had a periodic limb movement index (PLMI) that was highly elevated at 127/h

Historically, RLS has been categorized as either primary (idiopathic) or secondary. Primary RLS has a strong genetic component, with family pedigree reports indicating a predominantly autosomal dominant pattern of inheritance, often with variable expressivity [42–48]. When giving a family history, 50 to 60% of iRLS patients report a first-degree relative with RLS symptoms [36, 49] with evidence from another study indicating a heritability of 54% [50]. Genetic studies have demonstrated conflicting results on whether particular loci or genetic anticipation play a role in age of onset [44, 51−53]. The genetic complexity of RLS is highlighted by the number of loci that have been and continue to be identified. Six risk loci were first described in RLS, including MEIS1, BTBD9, PTPRD, MAP2K5, SKOR1, and TOX3, while recently 13 other risk loci have also been suggested to play a significant role in the development of RLS [54, 55]. The MEIS1 loci have the strongest genetic association with RLS [55] and are believed to play a key role in iron metabolism in the central nervous system, particularly the brain [56]. Another important genetic domain extensively studied in RLS is the BTBD9 gene, whose function is still not well understood, but is postulated to be related to dopamine metabolism and affected by MEIS1 expression [56].

Recent reviews of “secondary” RLS and its most common underlying comorbidities revealed strong evidence for increased prevalence of RLS in iron deficiency, pregnancy, and kidney disease, in addition to a likelihood of association between RLS and some cardiovascular diseases in women, diabetes, migraine, and dopaminergic treatment in PD, but weak evidence of RLS association with anemia, hypertension, multiple sclerosis, stroke, and ataxias [59–61]. Rather than a dichotomous primary/secondary classification, RLS may be better understood as a disease spectrum, with an underlying genetic predisposition combining with environmental factors and comorbidities to unveil its expression, with different relative weights of genetics and comorbidities in different individuals [62].

Iron deficiency is one of the most common comorbid conditions with RLS and of key importance given the role of iron deficiency in RLS pathophysiology and the potential for specific treatment (see subsequent sections) [60]. Pregnancy often leads to an iron-deficient state through various mechanisms, one possible reason for its association with RLS [63], although this has not been observed in all studies of pregnancy and RLS. In addition to changes in iron levels, RLS in pregnant women has also been variably demonstrated to be associated with folate supplementation [64, 65], dopaminergic insufficiency, and hormonal changes [63].

The relationship between cardiovascular disease and RLS is nuanced and inconsistent. Epidemiological studies relating the two have yielded varying results. A recent review of the literature found that 11 out of 14 cross-sectional studies indicated a significant relationship between RLS and cardiovascular diseases [66]. In addition, studies have found an increased risk of RLS following stroke [67], and RLS is associated with an increased risk of myocardial infarction [68] and cardiovascular disease mortality in women [69]. Despite these findings, a causal relationship between RLS and cardiovascular morbidity remains unclear [70–72]. It has been suggested that the pathogenesis of RLS in cardiovascular disease may be due to increased inflammation, nocturnal sympathetic activity similar to OSA, or metabolic factors [73]. The strong causal relationship between OSA and cardiovascular disease is thought to be primarily related to hypoxemia, although there may be an increased risk in cardiovascular disease inherently related to disturbance of sleep and sleep disorders in general, including RLS [73]. Future research is needed in order to clarify the relationship between RLS and cardiovascular diseases.

The association of RLS with peripheral neuropathy is complex, as neuropathy with dysesthesias or pain may be one of the mimics of RLS, while on the other hand, RLS can be perceived as painful by patients due to altered central somatosensory processing, accentuating this diagnostic confusion [74]. However, some patients manifest clear clinical features of RLS, with neurological examination features of concurrent neuropathy or polyradiculopathy from compressive lumbar spine disease, and these patients may have some of the most recalcitrant and difficult to treat RLS symptoms.

RLS may have a relationship with Parkinson disease (PD), but it may be driven by dopaminergic treatments rather than neurodegenerative changes in the brain [75]. Studies have demonstrated that RLS prevalence is similar to the general population at the time of PD diagnosis, but RLS prevalence progressively increases over time in PD cohorts [75, 76]. Pathophysiologically, PD symptoms are a result of a hypo-dopaminergic state, while RLS has been postulated to be a result of dopaminergic dysfunction—yet, they have some overlap in symptoms and treatment [77]. This counterintuitive association between these entities emphasizes the complexity of the dopaminergic hypothesis, as further described in the following section.

As RLS symptoms occur predominantly in the evening, the relationship between RLS and circadian rhythms has been well studied. Melatonin levels have been correlated with the worsening of RLS symptoms in the evening [78]. There may be differences in the cortical excitability of neurons controlling motor pathways. In one study, there was loss of subcortical inhibition of corticospinal pathways during the nighttime, increasing propensity for RLS symptoms [79]. Circadian changes in dopamine levels may also play a role in RLS symptom generation, as discussed further below. Rotational shift work has also been suggested to be a risk factor for RLS [80].

There have also been reported cases of “phantom” RLS, where patients with an amputated limb reported perceiving sensations of RLS in the location of the absent phantom limb, suggesting that the central nervous system may be responsible for RLS symptom generation and perception [81, 82]. In many of these atypical RLS cases, usual RLS treatments may still be beneficial for relief of symptoms.

Pathophysiology

Iron Deficiency Hypothesis

Ekbom and Nordlander both examined the role of iron in RLS in the early stages of the disease [2, 83]. Several imaging studies have established a strong relationship between iron metabolism and RLS, particularly in the brain [77]. It has remained somewhat unclear whether RLS is more related to low iron levels in the periphery or in the central nervous system. Early evidence indicated a possible association with peripheral iron levels, as indicated by RLS severity increasing with decreased peripheral iron [84], and a higher prevalence of RLS has been found in patients with peripheral iron deficiency [85]. However, recent works have brought these findings into question, with one population-based study determining that RLS was unrelated to plasma ferritin levels [86] and another arguing that the prevalence of RLS in iron-deficient patients has not been confirmed in population-based, cross-sectional studies [60]. Currently, the prevailing theory is that brain iron deficiency is a key biological driver in RLS, likely resulting from various factors including low peripheral iron and/or genetics [87]. R. P. Allen noted in 2015 that the “pathophysiology (of RLS) seems to involve a regional brain iron deficiency present in most RLS patients despite normal iron status” [77].

A proposed pathway by which CNS iron levels mediate RLS pathophysiology is through activation of hypoxic-state pathways. Elevated levels of hypoxia-inducible factor 1-alpha in substantia nigra neurons as well as elevated hypoxia-inducible factor 2-alpha and vascular endothelial growth factor (VEGF) were seen in the microvasculature of RLS patients [88]. Hypoxic conditions in the peripheral tissues have also been postulated to cause RLS symptoms [87, 89, 90]. Iron deficiency may cause activation of the hypoxia pathway, and since oxygen transport requires iron to be effective [77], hypoxic pathway activation could affect the regulatory transport mechanisms of iron across the blood-brain barrier [70]. However, the peripheral hypoxic state pathways have also been implicated in RLS pathophysiology and symptom generation, as one study showed that cutaneous measurements of peripheral tissue hypoxemia strongly correlated with RLS symptom severity, and symptoms and hypoxemia were both partially reversed by dopaminergic therapy [91, 92]. An exact causal relationship between decreased CNS iron and hypoxic states remains unclear; a bidirectional relationship may be most likely [70, 87].

Iron-deficient states and genetic factors both have a role in the activation of hypoxic pathways, and additionally, adenosine has also been implicated in RLS pathophysiology. Low iron may activate the hypoxic cascade by inducing a hypo-adenosinergic state [93]. As adenosine is an inhibitor of ascending arousal systems, low levels of adenosine may promote hyperarousal and increased activation of the limbs, while also activating other pathways implicated in RLS such as the dopaminergic and hypoxic systems [94]. Future research is necessary to further elucidate this recently discovered association between adenosine and RLS [93].

Dopamine Hypothesis

The dopamine hypothesis of RLS pathophysiology was initially driven by the dramatic effects of dopamine agonists on relieving symptoms of RLS. However, the mechanisms in which these drugs exert their effects in patients with RLS are not well understood. Brain iron deficiency is one of the biological hallmarks of RLS, and there are close relationships between iron and dopamine, with a leading theory postulating that low cellular iron directly or indirectly changes aspects of the dopaminergic system [95, 96]. However, it is more complex than the relative amount of these molecules. Since dopamine agonists relieve RLS symptoms, it may be reasonably anticipated that brain dopamine levels should be low in RLS patients. However, to date, studies have not found this to be the case. There is no difference in CSF levels of dopamine in patients with RLS compared with healthy controls [77]. Brain imaging studies have confirmed alterations of the dopamine system in people with RLS, particularly within the striatum [96]. However, these results are more consistent with increased, rather than decreased, synaptic dopamine [96–98]. These findings suggest that dopamine deficiency per se is not the predominant mechanism underlying RLS, but rather dopamine dysregulation leads to RLS symptoms. Animal models have indicated that an altered D3 dopaminergic system leads to increased sensory excitability (restlessness, paresthesia), while increased D1 activation may lead to increased motor activity [99]. The reduced drive by hypothalamic A11 dopaminergic cell group, which sub-serves spinal dopaminergic input, may also play a role in RLS symptom generation, since D3 knockout mice demonstrate a dopamine facilitation of spinal reflexes, reversal of circadian timing of tyrosine hydroxylase functioning, and excessive locomotor activity that mirrors the human RLS phenotype [100]. However, this hypothetical underpinning to RLS has not been proven to exist directly in humans, since a human autopsy study of RLS patients showed no abnormalities in the A11 dopaminergic system [101].

Unfortunately, while treatment with dopaminergic agonists initially provides relief from RLS symptoms, these drugs may not be a long-term solution, given the frequency of augmentation syndrome. Augmentation syndrome is often seen in RLS patients who have been chronically treated by dopamine agonists, and it presents as worsened RLS symptoms oftentimes in relation to increased dosages of dopamine agonists. Augmentation has been postulated to result from compensatory mechanisms of the dopaminergic system (i.e., receptor downregulation), which may lower the tolerance of dopaminergic effects, particularly in relation to the circadian system [96]. The diagnostic criteria for augmentation syndrome are addressed in Table 2 [4].

Table 2.

Augmentation syndrome diagnostic criteria as defined by the IRLSSG [4]

1) An increased overall intensity of the urge to move or sensation is temporally related to an increase in the daily medication dosage

2) A decreased overall intensity of the urge to move or sensations is temporally related to a decrease in the daily medication dosage

3) The latency to RLS symptoms at rest is shorter than the latency with initial therapeutic response or before treatment was instituted

4) The urge to move or sensations are extended to previously unaffected limbs or body parts

5) The duration of treatment effect is shorter than the duration with initial therapeutic response

6) Periodic limb movements while awake either occur for the first time or are worse than with initial therapeutic response or before treatment was instituted

Diagnostic Testing

The diagnostic approach to a patient with RLS should include measurement of serum ferritin, transferrin-percent saturation, and, in selected cases, a soluble transferrin-receptor assay to assess for possible iron deficiency or lower body iron stores likely to compound or aggravate RLS symptoms. Serum ferritin may be considered to be marginal or low normal at the threshold of 75 µg/liter or lower, and transferrin saturation is a marker of insufficient body iron stores when below the 20–25% level. Serum ferritin is a marker for tissue iron-load status in the body, and low serum-ferritin levels (< 75 µg/L) serve as a rationale for starting iron-replacement therapy in a patient with restless leg syndrome, particularly when symptoms have worsened (i.e., at time of initial diagnosis, when symptoms progress, or in the setting of augmentation syndrome).

However, one must be wary about interpretation of normal or even high levels of ferritin; ferritin values can be misleading in states of acute or chronic inflammation, since ferritin is an acute-phase reactant. In such cases, transferrin saturation should also be evaluated; our practice is to check both values in RLS patients. We consider offering iron-replacement therapy when the transferrin-saturation level is below 20 to 25%, even when ferritin levels are normal or high. When these results are in conflict, the soluble transferrin receptor (STR) assay may be of additional value, since elevated STR values are a more reliable and specific indicator of low body iron stores. More research to determine the value of these iron markers is needed in patients with RLS, to enable greater understanding of the relationship between iron homeostasis and RLS severity and to inform timely application of iron-replacement therapy in patients most likely to benefit from it.

In select cases with concurrent clinical symptoms or exam features of polyneuropathy, electromyography (EMG) and nerve conduction studies may also be considered. Polysomnography is not required to diagnose RLS but can be a helpful adjunct to diagnosis in cases where the clinical history is not clear, with findings of periodic limb movements of wakefulness representing an objective marker to confirm the diagnosis (and/or frequent periodic leg movements of sleep, although these are not specific for RLS nor required for diagnosis).

Therapeutics

Overall Management Principles and Approaches

For patients with intermittent or mild RLS symptoms, the use of nonpharmacological approaches as a first-line approach is often helpful and sometimes may be  the only treatment necessary. However, for other RLS patients, non-pharmacologic measures should also be considered and suggested as complementary therapeutic approaches to prescription medication treatment. Non-pharmacological measures that are helpful for RLS include massage, stretching, walking, cognitive distraction (such as playing games or working puzzles), or taking temperate warm or cool baths. Patient education can provide specific advice concerning proper “sleep hygiene,” with behavioral modification as appropriate to assure a regular sleep-wake cycle, and obtaining the proper amount of sleep should also be advised. While these measures are generally tolerable and safe for all RLS patients, the benefit of these non-pharmacologic approaches tends to be transient and lacks solid evidence despite anecdotal reports of benefit. There are low-level evidence trials for measures such as exercise [102–104], yoga [105], and lavender-oil massage [106]. These nonpharmacological approaches may also be beneficial to recommend as ancillary therapy that may help avoid higher doses of pharmacological treatments.

Additionally, a general principle of the initial RLS therapeutic approach, especially those with intermittent or mild symptoms, is choice of an appropriate monotherapy (single drug at a time) strategy for treatment of RLS, which may help in avoiding adverse effects and reducing the possibility for drug-drug interactions. Details regarding specific pharmacotherapies for RLS and their clinical pharmacology are shown in Table 3, and each drug is discussed in further detail in following sections of this article. Oftentimes, drug selection is aided by consideration of a medication that also effectively treats a co-morbid disorder. For example, gabapentin is preferential for treatment of patients with painful RLS or patients with a co-morbid chronic pain disorder such as painful diabetic small fiber neuropathy, while a dopaminergic therapy might be preferable to provide additional benefit for tremor or motor symptoms in a patient with Parkinson disease. Another important overarching therapeutic principle is to consider the possibility of iron deficiency early and often in the care of RLS patients; thus, practitioners should consider obtaining iron measures at presentation and periodically in the course of RLS management as discussed below.

Table 3.

Therapeutics

Drug (An asterisk (*) indicates FDA approval for treatment of RLS)	Initial dosage	Target dose range	Adverse effects	Special consideration
Iron (oral)	Depends on formulation	Depends on formulation	Gastric upset, nausea, constipation	Vitamin C improves absorption
Iron (intravenous)	Depends on formulation	Depends on formulation	Cost, anaphylactic reaction	Some formulations require pretreatment
Gabapentin	100–300 mg	600–1800 mg	Drowsiness, dizziness, peripheral edema, weight gain	Renal metabolism
Gabapentin Enacarbil *	600 mg	600–1200 mg	Cost, drowsiness, dizziness, peripheral edema, weight gain
Pregabalin	75 mg	150–450 mg	Drowsiness, sleepiness dizziness, peripheral edema, weight gain	No dose-limited absorption
Pramipexole*	0.125 mg	0.375–0.5 mg	Nausea, headache, augmentation syndrome, impulse control disorder spectrum symptoms
Ropinirole*	0.25 mg	3.0–4.0 mg	Nausea, headache, augmentation syndrome, impulse control disorder spectrum symptoms
Rotigotine*	1.0 mg	2.0–3.0 mg	Nausea, headache, augmentation syndrome, impulse control disorder spectrum symptoms cutaneous reactions
Tramadol	25–200 mg	200–300 mg	Sleepiness, drowsiness, dizziness, nausea, gastric upset	Reserved for refractory RLS and/or augmentation; concern for abuse potential/respiratory depression
Oxycodone	5–10 mg	10–40 mg	Nausea, constipation, gastric upset	Reserved for refractory RLS and/or augmentation; concern for abuse potential/respiratory depression
Methadone	5 mg	10–30 mg	Nausea, constipation, gastric upset, hyperhidrosis, QT prolongation	Reserved for refractory RLS and/or augmentation, typically when other lower potency opioid agents (i.e., tramadol, oxycodone) have failed; concern for abuse potential/respiratory depression

For patients with chronic persistent RLS symptoms, a daily prescription medication is indicated, with drug selection aided by considering co-morbidities and symptom intensity; medications are generally prescribed about 1 to 2 h in advance of onset of the patient’s habitual RLS  symptoms. Generally, once-daily dosing suffices, but some patients need split dosing with earlier daytime dosing as well to adequately cover bothersome daytime symptoms. This is more common in the later course of patients with chronic persistent RLS and especially in those whose symptoms evolve to an earlier timeframe in the setting of augmentation. In such cases, dividing the daily prescribed dose in half and giving half the dose earlier in the day and the remainder at night suffices, although further titration of doses may be necessary to address symptoms adequately. As in other therapeutic areas, such as chronic pain disorders or epilepsy management, individualizing treatment by thoughtful tailoring of prescribed medications is necessary to optimize efficacy and tolerability in RLS management.

Patients with sufficiently mild symptoms are usually managed effectively by alpha-2-delta ligand medications (e.g., gabapentin, pregabalin), while those with moderate or severe symptoms may instead require a dopaminergic therapy or consideration of an opioid medication. In the setting of refractory RLS, sequentially rotating monotherapies using different medication classes (e.g., alpha-2-delta ligand, dopaminergic, opioids, and other mechanisms) should be trialed, and in the setting of augmentation, dose reduction and/or complete tapering of dopaminergic medications can be helpful but difficult to achieve without an added adjunctive “rescue” or bridging therapy from an alternative drug class, such as alpha-2-delta ligand medications or opioids. In patients who seem to have developed tolerance to a medication, an anecdotal concept to consider is a “drug holiday,” with an attempted tapering of the current medication therapy to which apparent tolerance has developed and efficacy for relief of RLS symptoms has waned, with or without substitution with another class of medication, followed by later restoration or rechallenging with the previously effective drug. However, no evidence is available to guide this practice to our knowledge. Further detailed management approaches and algorithms are found in the RLS/WED Foundation consensus statement on RLS management [35].

Iron-Replacement Therapy

The iron-deficiency hypothesis remains paramount in RLS pathophysiology, although oral or intravenous iron-replacement therapy has variable efficacy in treatment of RLS. Peripheral iron stores (ferritin, transferrin saturation) should be assessed at the time of initial RLS diagnosis, and later during the course of chronic management, whenever there is a change in symptom control, especially when there are features of augmentation or overall clinical worsening of symptom frequency or severity, and/or when there is a waning response to previously effective therapy. If iron stores are low, iron-replacement therapy should generally be pursued, either as monotherapy (if symptoms are relatively mild) or in combination with another RLS treatment.

If iron-replacement therapy is indicated for an RLS patient, the first-line approach is typically oral iron-replacement therapy. Various oral iron-replacement therapies are available, most commonly ferrous sulfate. Adjunctive vitamin C aids the absorption of elemental iron from the GI tract, often minimizing adverse effects. Alternatively, a formulation of ferrous fumarate (Vitron C) may be considered, with dosing of 65 mg of elemental iron taken approximately 1 h before mealtimes to facilitate optimal absorption. Some patients are unable to tolerate oral iron due to gastric upset, nausea, or constipation or are unable to absorb it effectively, particularly when there is concomitant proton-pump inhibitor use for gastroesophageal reflux (which lowers gastric acid, thereby often decreasing iron absorption), or in patients with a history of prior bariatric or other bowel surgeries leading to limited small-bowel iron absorption. Oral iron supplementation may be insufficient for RLS patients presenting with severe symptoms, with or without augmentation, since it often takes a prolonged timeframe of weeks or months for resulting efficacy.

In cases when oral iron is not tolerated or effectively absorbed and in patients with severe RLS symptoms, the use of intravenous iron-replacement therapy may be considered. Several formulations are available, with best evidence supporting the use of ferric carboxymaltose (FCM) in single or divided infused total doses of 1000–1500 mg (i.e., either 1000 mg × one infused dose, or two infused doses of 500–750 mg) [107–110]. Of note, iron deficiency was not a requirement for some of the clinical trials of FCM for RLS. Thus, this therapy may be beneficial for people with RLS without low iron (as long as there is no iron overload), although in practice, use is often limited to those with evidence of iron deficiency. FCM is expensive and may be difficult to obtain; in these instances, an alternative formulation to consider is low-molecular weight iron dextran (INFeD), with a 1000 mg total dose infused over 1 h [111]. Pre-treatment with acetaminophen, 1 g, and Solu-Medrol, 125–250 mg, can be considered to limit the possibility of anaphylactic reaction. INFeD 25 mg may be administered as a test dose over 15 min, followed by the remaining 975 mg infusion over 45 min to complete a total 1000 mg infused dose. IV iron infusion typically leads to improvement in clinical restless leg symptoms severity within 2 to 4 weeks. Assessment of the serum ferritin after 1 and 3 months to ensure adequate replacement is prudent. If insufficient (i.e., the patient remains with a ferritin < 75 µg/L and/or transferrin saturation < 20–25%), repeat infusion may be considered.

Gabapentinoid/Alpha-2-Delta Ligand Drugs

Gabapentin and related medications (gabapentin enacarbil, pregabalin [Lyrica]) have recently become preferred first-line medications for RLS management [35, 112, 113]. Alpha-2-delta medications have a mechanism of action mediated by binding to the alpha-2-delta calcium-channel receptor on presynaptic neurons, influencing the release of neurotransmitters. Gabapentin was so named due to the structural resemblance of gabapentin to the GABA neurotransmitter, although there is no direct action of gabapentin or related compounds on GABA-receptor modulation and little evidence that gabapentin-related medications have a GABAergic-modulating influence overall. Gabapentin was first developed to treat epilepsy and seizures and received FDA approval for drug-resistant, focal epilepsy in 1991. However, it was rapidly adopted for a variety of other indications, particularly the treatment of neuropathic pain, given its broad safety, tolerability, and minimal potential for interactions with other medications. Gabapentin was later implemented for treatment of RLS, although it is not approved by the FDA for this indication, and relatively few trials have been performed specifically testing gabapentin in RLS, although small-scale randomized trials have demonstrated its efficacy [114–117].

Subsequently, the compound gabapentin enacarbil, a gabapentin prodrug with more favorable gastrointestinal absorption, was developed and shown to be effective in the treatment of RLS. Gabapentin enacarbil (marketed as Horizant) carries an FDA indication for the treatment of restless legs syndrome at a dose of 600 mg in the early evening, although FDA-approved doses of 1200 mg are permitted for other indications and used in some of the RLS clinical trials. While there are no head-to-head trials between gabapentin and gabapentin enacarbil, our clinical experience has been that gabapentin has equally favorable results in clinical practice for symptomatic control of restless leg syndrome, is considerably less expensive for patients, and may particularly be desirable for use in some patients for whom greater dosing flexibility or higher doses (i.e., > 1200 mg/day) to achieve efficacy for RLS symptom relief are necessary. Gabapentin also can be administered in lower starting doses for patients who may be more sensitive to adverse effects and is more affordable in higher dosages, which are often required for managing difficult RLS symptoms. Given its affordability and lower propensity for augmentation, gabapentin has become a first-line therapy for RLS management by expert consensus.

Gabapentin may be started at doses of 100 to 300 mg, 1 to 2 h in advance of evening symptoms, and can be given in divided doses throughout the daytime depending on whether patients have late-afternoon or early-evening symptoms (i.e., given BID, TID, or QID, individualizing to the patients symptoms and perceived duration of action). The doses are then advanced by 100- to 300-mg increments as needed and tolerated, typically every 3 to 7 days, toward a broad target dosage of 600 to 2400 mg nightly, which was rigorously analyzed in an early proof of concept, randomized, double-blind, placebo-controlled crossover trial which showed a mean effective gabapentin dose of 1855 mg/day and the effective dose ranging from 1391 to 2400 mg/day [114].

The extended time needed for titration to high doses can be challenging for patients with severe symptoms, and in these cases, gabapentin enacarbil or pregabalin may be considered. Another limitation of gabapentin is that higher range doses (i.e., above 1800 mg/day) are poorly absorbed, since the drug is absorbed by a saturable intestinal L-amino acid transporter. Therefore, smaller, more frequent doses must be given to permit adequate absorption, through the dose range of 1800 to 3600 mg daily, although dosages substantially above 2400 mg are even more poorly absorbed despite multiple daily doses.

For patients responsive to and able to tolerate gabapentin but requiring higher doses to achieve efficacy, pregabalin (Lyrica) may be especially valuable to consider, since there is no dose-limited absorption of this medication and it works mechanistically similarly to gabapentin. Sound evidence exists for efficacy of pregabalin in RLS. A pivotal, randomized, controlled trial compared the efficacy of pregabalin to pramipexole and found that doses of pregabalin in the range of 300 mg daily offered comparable or superior efficacy to pramipexole but with a lower incidence of augmentation syndrome.

Typical adverse effects of gabapentin, gabapentin enacarbil, and pregabalin include sleepiness, drowsiness, dizziness, and unsteadiness, so caution must be taken in elderly patients to avoid the risk of instability and falls. Driving impairment may occur. Providers also must use prudence with patients with chronic renal insufficiency, since these medications can accumulate due to reduced renal clearance. In such patients, starting with lower-end doses and titrating toward a lower target dose is advised. Other typical adverse effects with gabapentin include peripheral edema and weight gain. A similar range of adverse effects are seen in gabapentin enacarbil and pregabalin.

Dopaminergic Therapies

Dopamine agonists (pramipexole, ropinirole, rotigotine) have been the traditional mainstays of therapy for RLS. The initial discovery that carbidopa/levodopa (Sinemet) was highly efficacious for relief of subjective restless legs symptoms inspired the dopamine hypothesis for RLS, and a later dedicated clinical development program with a series of randomized controlled trials consequentially led to the FDA labeling and indications for dopamine agonists in the treatment of RLS [118–123].

A large body of evidence indicates that dopamine agonists are highly effective for relieving RLS symptoms, at least in the short term [118–123]. Unfortunately, a growing body of evidence over the last decade has indicated several shortcomings of dopaminergic therapies due to their adverse event potential. Most significantly, a large proportion of RLS patients treated with excessive doses of dopaminergic therapies develop augmentation syndrome, at a rate of approximately 8% per year for pramipexole [124–126]. As discussed previously, augmentation syndrome represents both a temporal and spatial progression of RLS symptoms to an earlier time-of-day of symptom onset (often daylong persistence), with growing intensity of symptoms that have a shorter latency to occur following briefer period of daytime and evening rest, becoming highly sleep-disturbing, and involving variable spread of symptoms from the legs to other body regions, especially the arms. A second further significant concern of dopaminergic medications is the approximately 15% frequency of impulse-control disorder symptoms (compared with 6–8% in sleep disorder patients not treated with dopamine agonists) including a spectrum of undesired behaviors such as compulsive and financially destructive shopping, gambling, punding (repetitive aimless hand movements, such as assembly and reassembly of watches or other gadgets), and other quasi-addictive behaviors [127]. A common theme of impulse control disorder spectrum behaviors is an inability to control impulses toward undesirable behaviors, often leading to socially destructive consequences.

In addition, dose-related adverse effects, such as dizziness, drowsiness, nausea, or headache, may be seen with dopamine agonists, often alleviated by reducing the dose or stopping the medication. A rare but additional potentially serious adverse effect of dopamine agonists is excessive daytime sleepiness with sleep attacks, leading to harmful consequences such as drowsy driving and motor vehicle collisions. This is a particular caution in patients with co-morbid parkinsonism, but there have been rare reports of this occurring in RLS patients without a history of parkinsonism as well [128–130]. Before entertaining use of a dopaminergic therapy, these potential adverse consequences should be discussed with patients to facilitate awareness of these side effects and to enable prompt intervention to change therapy should these adverse events occur.

Pramipexole (Mirapex) is started at a dose of 0.125 mg administered approximately 1 to 2 h prior to bedtime (or typical symptom onset, if symptoms begin before bed). Pramipexole may then be further titrated by 0.125 mg every 3 to 7 days, toward a target dose in the range of 0.375 to 0.5 mg at maximum for the day, using the lowest effective dosage for symptom control. Some patients require divided doses, in the afternoon and prior to bedtime, if symptoms begin earlier in the afternoon. The maximal pramipexole dose range of 0.5 mg/day should only rarely be exceeded, due to the increased risk of augmentation syndrome at higher doses [131]. However, some experts advise further titration over the dose range of 0.5 to 1.0 mg total daily dose with careful serial observation and repeated counseling to instruct patients to immediately report earlier or more intense symptoms [131].

An alternative is ropinirole (Requip), with initial doses of 0.25 mg, increasing by 0.25 to 0.5 mg increments to the dose range of 3.0 to 4.0 mg maximal daily dose. However, some experts will consider more aggressive dosing in the daily dose range of 4.0 to 6.0 mg with similar careful observation and adequate counseling of the patient.

The rotigotine (Neupro) patch can provide daylong symptom control for the patient, given its continual gradual daylong release [126, 132–135]. This prolonged duration of action and more continual release of dopamine into the bloodstream may minimize dopamine fluctuation at receptors and may be associated with a lower tendency toward evolving augmentation syndrome [134]. Rotigotine dosing may be started at a 1.0 mg patch strength and titrated weekly to either 2 or 3 mg maximal daily dose [131]. The clinical trials of rotigotine suggested that further dose increases to 4.0 mg daily may be considered, but there may be greater augmentation risk at this higher dose [126]. Rotigotine as a transdermal patch may cause cutaneous reactions such as excessive itching or redness of the skin underlying the site of patch application. However, this may be avoided or minimized by rotation of the patch location on a daily basis. Optimal places for patch location include sites along the upper outer arms, upper legs, the scapula, or upper back. Otherwise, the range of adverse effects is similar to the other dopaminergic therapies. Expense has been a limiting factor in the more widespread application of this dopaminergic therapy.

Carbidopa levodopa (Sinemet) may still be useful in the occasional patient with infrequent symptoms for which intermittent medication treatment can be considered. Sinemet should be avoided in patients with daily disturbing RLS symptoms; approximately 60% of patients will experience augmentation syndrome within 6 months of treatment when carbidopa levodopa is given daily [136]. However, it can be useful in treating RLS in the patient with occasional symptoms, such as those who experience symptoms during flights or long car rides. If patients find this medication to be sedating, they should be counseled not to use it prior to driving.

Opioid Therapies

Evidence-based use of opioid therapies for the treatment of restless legs syndrome is solid, particularly for prolonged-release oxycodone–naloxone, which is a combination medication not currently available in the USA. Opioids are typically reserved for patients who have failed other pharmacologic agents [137, 138]. With carefully supervised use and appropriate counseling, chronic opioid therapy is appropriate for select patients with restless legs syndrome.

Initial use of lower-potency opioid agents and later escalation toward higher-potency opioids is the preferred approach in chronic severe RLS symptom management unless the patient has particularly severe symptoms or advanced augmentation syndrome, which may necessitate escalation to higher-potency opioids. Tramadol, 50 to 200 mg nightly, rarely exceeding and titrating further to 300 or 400 mg as the maximal daily dosage, is often the initial lower-potency opioid used for treating RLS. When symptoms begin earlier in the daytime (i.e., in the early evening, afternoon hours, or earlier), a strategy of split multiple daily doses divided between a 6- and 8-h dosing interval may be employed. Typical adverse effects include sleepiness, drowsiness, or dizziness. Nausea or gastric upset may also occur. Tramadol may be especially useful in patients with concurrent chronic neuropathic pain.

The next intermediate-potency opioid agent to treat RLS is oxycodone, in initial doses of 5 to 10 mg, titrating by 5- to 10-mg increments in nightly doses 1 h before symptom onset. Alternatively, patients with earlier daytime symptoms may divide the doses 2 or 3 times daily on a schedule of every 6 to 12 h. The range of adverse effects is similar to those outlined above, with more prominent nausea, gastric upset, and constipation occurring with oxycodone.

Higher-potency opioids, particularly methadone, have been utilized with good success as a “last resort” in the treatment of particularly severe and intense RLS symptoms, often in the setting of augmentation syndrome caused by high dosage dopaminergic medications [139]. In such settings, rapid weaning of the dopaminergic drug and replacing it with methadone may be the best strategy for select patients with severe RLS symptoms, with careful oversight. Patients require significant counseling regarding the stigma of methadone, as it is often used in the setting of heroin detoxification and advanced cancer pain. Methadone has the advantage of a particularly long duration of action, but this also carries an inherent risk for overdose [140]. Initial doses of 5 mg daily, titrating by 2.5- to 5-mg increments as needed and tolerated toward a total daily dosage of 20 to 30 mg daily is the usual strategy [138, 141]. As above, doses may be divided, typically in 12-h intervals as a twice-daily dose strategy for patients with daylong severe RLS symptoms. After augmentation symptoms have been controlled for a few weeks to months, the methadone dose can be lowered to the lowest effective dosing level. In addition to usual adverse effects of sedation, nausea or constipation, distinctive adverse effects seen with methadone include hyperhidrosis, which is sometimes intolerable, and the potential for QTc prolongation and severe ventricular cardiac arrhythmias including ventricular tachycardia, torsade de pointe, or fibrillation [142]. Therefore, baseline ECG and serial monitoring of electrocardiograms are recommended both during titration and once the patient has reached an effective target dose to assure safety of continued treatment. If the patient is receiving other QTc-prolonging medications, there may be a particular danger of precipitating cardiac arrhythmias, so discontinuation of other QTc-prolonging drugs is recommended prior to initiating methadone. The concomitant use of benzodiazepines with opioids also should be avoided. Discontinuation of benzodiazepine medications should occur prior to opioid use to avoid respiratory depression. Treatment of co-morbid sleep-disordered breathing with nasal positive airway-pressure therapies is also essential when opioids are used to prevent worsening of obstructive or central sleep apnea. In particular, chronic opioid use has been associated with central sleep apnea and ataxic breathing [143, 144]. For this reason, patients receiving opioid medications should be evaluated for possible sleep-disordered breathing and undergo a polysomnogram (PSG) or home sleep apnea test study if there is a concern for co-morbid sleep apnea.

With all opioids, institutional practices for opioid prescription must be thoughtfully followed, such as an opioid contract with the patient, advanced use of the opioid-risk tool to screen for abuse potential, and completion of a urine drug screen to ensure there is no concomitant misuse or abuse of street or prescription medications. Periodic drug screens and review of opioid-prescribing guidelines are recommended, alongside careful oversight and monitoring with serial clinical visits to oversee continued safety of treatment.

Investigational/Emerging Therapies

There is a therapeutic void for the management of severe and refractory RLS patients given the relatively narrow slate of traditional medication therapies available as therapeutic mainstays, and unfortunately, few novel therapies have been advanced. Recently, two novel pharmacologic approaches have shown promise in small-scale but rigorous open-label trials that provide proof of concept for their efficacy, including perampanel (Fycompa), a selective AMPA antagonist of glutamatergic neurotransmission that may contribute to RLS pathophysiology, and dipyridamole, a non-selective ENT1/ENT2 adenosine transporter antagonist that may increase extracellular adenosine and thereby counteract the postulated hypoadenosinergic state thought to accompany brain iron deficiency in RLS [145, 146]. However, confirmation of efficacy, safety, and tolerability of these novel pharmacologic approaches will require future adequately powered, large-scale, randomized controlled trials.

While not applied in standard clinical practice, a variety of neuro-stimulation approaches for RLS remain in development at the time of this writing. There has been a low-level evidence trial for a vibratory counter-stimulus device (Relaxis) [147]; however, the Relaxis device is no longer clinically available for prescription given failure to obtain CMS reimbursement [113], and our experience with the device suggested only very limited efficacy for symptom relief in most patients who tried it. A foot-binding device known as Restific is marketed for RLS therapy, based on a low-level evidence open trial [148]. Additionally, there has been a randomized sham-controlled trial showing RLS symptom improvement using pneumatic-compression devices [149]. Other neurostimulation approaches include noninvasive application of surface electrodes over peripheral-nerve territories to apply counter stimulation [150]. An approach under development is the application of near-infrared spectrum-light therapy, which putatively may influence the peripheral vasculature to nerve and/or muscle tissues to relieve RLS symptoms [151]. There has been a single open-label trial of a marketed FDA-approved device known as the Scrambler, an electrical stimulator that presumably offers counter stimulation to effectively reduce neuropathic pain symptoms, which demonstrated possible efficacy [152]. Neuro-stimulation of the central nervous system has also been tried, particularly spinal cord stimulation and transcranial magnetic stimulation, but there is currently no solid evidence basis for applying any of these methods. In addition, experience with treatment effects of deep brain stimulation (DBS) in the setting of its indication for advanced Parkinson disease has suggested conflicting effects on RLS symptoms, with one study reporting an emergence of RLS after DBS surgery [153], while another found RLS symptom resolution in 3 of 6 patients with PD and co-morbid RLS [154]. Currently, DBS treatment primarily for treatment of RLS is not recommended [155], although further evidence is needed to determine its effect on RLS in patients who receive DBS surgery for treatment of their parkinsonism, which may provide clearer evidence of whether DBS relieves or exacerbates co-morbid RLS symptoms. Further prospective clinical research trials will be needed to establish the safety, tolerability, and efficacy of these novel approaches [156].

Conclusions

RLS is a common disorder that significantly impacts quality of life and sleep quality. The initial management approach should include measuring serum ferritin and transferrin-percent saturation, with iron-replacement therapy indicated when these measures are below the low-to-normal range thresholds of ferritin < 75 µg/L and/or transferrin-percent saturation < 20–25%. In patients with normal peripheral-iron levels, gabapentinoid medications are now often first-line therapies, but dopaminergic therapies are still highly effective when necessary, with appropriate advanced patient counseling, surveillance, and use of the lowest-effective dose. Opioids should be reserved for patients who have failed those options and, when utilized with cautious oversight, are appropriate rescue therapies. Emerging investigational approaches include neuro-stimulation and near-infrared spectroscopy. RLS remains a challenging and therapeutically impoverished disease in sore need of more rationale and biologically informed and directed treatments.

Supplementary Information

Below is the link to the electronic supplementary material.

Funding

This publication was supported by NIH/NCRR/NCATS CCaTS Grant Number UL1 TR002377 and by NIH/NIA R34AG056639 (NAPS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.