Overview

Restless legs syndrome (RLS), or Willis-Ekbom disease, is a neurological disorder that characterized by unpleasant or painful sensations in the legs and a distressing, irresistible urge to move them.¹ RLS symptoms worsen during inactivity and at night. Partial or complete relief may result from movement such as walking, stretching, or bending of the legs. Yet, the relief is often temporary and symptoms return when movement ceases. If the disease progresses, symptoms may occur earlier in the day and intensify even further at night and/or extend beyond the legs to the arms and/or trunk. The clinical course of RLS varies, and periods of remission are common. Severe restless legs syndrome, however, may require long-term treatment.³

RLS can result in reduced quality of life and negatively impact sleep leading to daytime fatigue. However, treatment effectiveness and harms are not well established and there is little guidance on diagnosis and treatment especially determining comparative effectiveness and whether treatments vary by key patient and disease characteristics. A comprehensive review of the effectiveness and harms of treatments for RLS could lead to improved care for individuals with RLS.

RLS is defined and diagnosed based solely on clinical criteria. The essential diagnostic criteria for RLS were established by the International Restless Legs Syndrome Study Group in 1995¹ and revised in 2003.² Any RLS diagnosis requires that the all four essential criteria be met: (1) An urge to move the legs, usually accompanied by uncomfortable or unpleasant sensations in the legs; (2) Unpleasant sensations or the urge to move begin or worsen during periods of rest or inactivity such as lying or sitting; (3) Unpleasant sensations or urge to move are partly or totally relived by movement such as walking, bending, stretching, etc., at least as long as the activity continues; and (4) Unpleasant sensations or the urge to move are worse in the evening or at night than during the day, or only occur in the evening or night. In other words, to meet the four essential criteria, patients should have characteristic sensory or motor symptoms that are provoked or made worse by rest, improve with movement, and worsen or occur only in the evening or at night. These symptoms should not be solely accounted for by another condition such as leg cramps, positional discomfort, leg swelling or arthritis.

The etiology of RLS is unknown, but it may occur secondary to other conditions such as iron deficiency, end-stage renal disease, and pregnancy.² A family history of RLS is common and twin studies have shown heritability estimates of 54–83 percent. However, genome-wide association studies have shown inconsistent findings.⁵ Secondary RLS often starts later in life than does primary RLS. It is also associated with more rapid progression than and often resolves when the underlying condition is treated.² Although mechanistic relationships are yet to be established, the pathophysiology of RLS may be closely linked to abnormalities in the dopaminergic system and iron metabolism.³

The severity of RLS varies. Mild RLS may result in only minor annoyance; however, severe RLS can have a crippling impact on quality of life.⁷⁰ It can interfere with work or social activities and reduce function and emotional well-being. RLS-induced sleep disruption may lead to poor daytime functioning, anxiety, and depression. Additional long-term complications from sleep disruption could include adverse cardiovascular events though little is known on the relationship between RLS sleep disruption and cardiovascular outcomes. Sleep deprivation and daytime fatigue are the most common reasons RLS patients seek treatment.⁷⁰

Prevalence estimates for RLS range from 1.5 to 7.4 percent in adults, and are higher for women and older people.⁴ The variation reflects different approaches to diagnosing RLS and defining its frequency and severity, and the fact that many RLS questionnaires do not account for individuals who have conditions with similar symptoms. (e.g. neuropathies, pain syndromes). Also notable is that these prevalence estimates include RLS patients with a wide spectrum of disease severity; when restricted to the RLS population with clinically significant disease requiring medical attention, the prevalence estimates are much lower. For example, in a U.S. study, Allen et al.² used validated diagnostic tools and estimated that 7.4 percent of U.S. adults who responded to a telephone survey and answered questions about RLS fulfilled all four of the diagnostic criteria. Exclusion of secondary causes and mimic conditions (e.g. nocturnal leg cramps, periodic leg movements of sleep, positional discomfort, arthritis etc) resulted in a prevalence estimate of 2.4 percent for primary RLS. The prevalence estimate for “RLS sufferers,” characterized as those “having symptoms at least twice weekly with moderate to severe impact,” was 1.5 percent. In this group, 34.4 percent had moderate symptoms, 54.2 percent had severe symptoms, and 11.5 percent had very severe symptoms. Because individuals who agree to answer survey questions about RLS are likely different from adults who do not agree to respond the prevalence and severity in a true population setting are not well known though likely lower and less severe. We draw attention to these distinctions because questions related to RLS prevalence, severity and impact underlie many of the uncertainties encountered in clinical practice; accuracy in assessing RLS severity and impact is key to evaluating the need for treatment and the applicability of treatments to patients with different degrees of disease severity.

Treatments (nonpharmacological and pharmacological options) vary by patient age and the severity of RLS. Recommended nonpharmacological options include: exercise, avoiding potential RLS precipitants (caffeine, alcohol, antidepressants, and antihistamines); counter stimuli to sensory symptoms (hot or cold bath, limb massage, compression stockings, and counter-pulsation devices); herbal medicines and acupuncture; and cognitive behavioral therapy. Pharmacological treatment is generally reserved for patients with moderate to severe RLS. The major classes of drugs used are dopaminergic agents, sedative hypnotic agents, anticonvulsive agents, opiates, and iron. Information on these treatments is shown in Table 1. Of these drugs, two dopamine agonists (pramipexole, ropinirole, and rotigotine) and one alpha-2-delta ligand anticonvulsant drug (gabapentin enacarbil) are FDA approved for treatment of moderate to severe RLS. A significant treatment complication with long-term use of dopaminergic agents is a drug-induced worsening of symptoms known as augmentation. Augmentation is characterized by more intense symptoms with earlier onset, shorter latency, and that may spread to other body parts (usually the arms, but also the trunk and face).⁷ Impulse control disorders have also been reported in up to 9–17 percent of RLS patients using these drugs for long term.⁸

Table 1

Pharmacologic treatments for Restless Legs Syndrome.

The primary goal of RLS treatment is to manage symptoms and improve patient function, daytime fatigue and quality of life. Except for the limitations on pharmacological therapy imposed by pregnancy, and the use of iron replacement for those with iron deficiency, treatment options may not vary for primary and secondary forms of RLS.⁶ For patients with RLS secondary to pregnancy, iron deficiency, or end-stage renal disease, recommendation advise treating the associated condition first whenever possible. Clinical experience suggests that RLS associated with pregnancy resolves postpartum in most patients; however, therapy has not been evaluated this population, and very little is known about women with pregnancy-induced RLS whose symptoms persist after delivery.⁹

Methods of Assessment

Several scales are used to assess RLS severity, impact, and specific health outcomes such as patient-reported sleep outcomes, quality of life, and harms (Table 2).⁷¹ Use of these scales is limited almost exclusively to clinical research and possibly specialty settings. They are used only rarely in primary care. The International Restless Leg Syndrome Study Group (IRLS) Rating Scale is most widely reported.⁷² The IRLS is a 10-item scale with scores ranging from 0 (no symptoms) to 40. Scores >30 are considered very severe, severe (Score 21–30), moderate (scores 11–20) and ≤10, mild. The minimum change in scale score that translates to clinically significant improvement in patients has not been defined for these scales. In the absence of such definition, responder criteria that could potentially be meaningful to patients—and that have face validity and are identifiable to patients and providers—could be used. Such criteria include: (1) resolution of symptoms (IRLS scale score=0); (2) percentage of patients with reduction of symptoms from very severe (>30) or severe (21–30) to moderate (11–20) to mild (≤10); (3) 50 percent or greater change in IRLS score from baseline; or (4) percentage of patients who are much improved or very much improved on the clinician-assessed global impressions scale or patient-assessed global impressions scale.

Table 2

Methods of assessment.

Areas of Uncertainty

Clinicians face uncertainty related to defining RLS, assessing disease severity, and evaluating the risk/benefits of treatment. While these challenges apply to both primary care and specialty settings, they may be more pronounced in primary care. Specific issues that affect clinical practice include:

• Impact of diagnostic criteria and distinguishing RLS from other disorders: RLS is diagnosed based on clinical history using standard criteria. “Mimic” conditions (e.g. nocturnal leg cramps, periodic leg movements of sleep, positional discomfort, arthritis etc) sometimes satisfy the standard RLS criteria, and must be ruled out by examination. Many patients with RLS also experience semi-rhythmic limb movements called periodic limb movements while awake or asleep. However, these movements are not RLS and they may occur among older adults, in those taking antidepressants, and as a result of certain neurological and sleep disorders (e.g., narcolepsy).⁷⁷ RLS is distinct from sleep disorders such as periodic limb movements disorder.
  The use of standard criteria is common in clinical research and possibly in specialty practice. However, in primary care, the standard criteria may be less consistently applied. As a result, patients may be misdiagnosed, misclassified, receive unnecessary or ineffective treatment, or not receive necessary care. Direct-to-consumer advertising may result in RLS patients previously unidentified receiving appropriate diagnosis and therapy, but it may also result in requests for potentially inappropriate pharmacological treatments for RLS-like symptoms.⁶⁸
• Assessing comparative risk/benefits of treatment: RLS encompasses a broad spectrum of symptom severity and impact. Because the clinical significance of RLS is due to its impact on an individual’s quality of life and function, treatments should focus on the balance of symptomatic benefits with treatment harms. Pharmacological treatments have the potential for adverse events and costs and are not curative; therefore, such therapy is generally indicated only when the disease significantly impacts quality of life-typically severe to very severe restless leg symptoms and/or associated sleep disturbance and daytime fatigue.^6,78 For the larger group of individuals with mild or moderate symptoms, determining the balance of treatment effectiveness with harms is more problematic. In addition, long-term risks and benefits of treatment are unclear. For older adults with multiple morbidities or children the benefits and risks of RLS treatments must be evaluated in the context of overall health effect and potential for adverse events or interactions with concomitant medications. Current recommendations suggest an algorithmic approach for the management of restless legs syndrome.⁶ However, little is known about the scientific validity of such an approach, the role of patient or disease characteristics in treatment selection or the comparative effectiveness and harms of currently recommended treatment options. Finally, most research has focused on pharmacologic interventions though nonpharmacologic options are widely used and recommended especially for individuals with mild symptoms, comorbid conditions or those failing pharmacologic options.
• Measuring changes in disease status and impact of treatment Lack of objective measures for assessing disease status presents a challenge in clinical practice.⁷¹ Typically, clinical interviews are used to assess disease severity and treatment-induced changes in disease status. In research settings, the same assessments are made using specific rating scales such as the IRLS Rating Scale and Clinical Global Impressions scale.⁷¹ However, the results of RLS severity scales cannot be meaningfully interpreted in the absence of clearly defined “minimum clinically important differences.”
• Long-term effectiveness, adherence, and harms of treatment. There is limited understanding of long-term outcomes of treatments for both primary and secondary RLS. RLS is often a long-term to life-long condition, yet interventions are often assessed in short-term studies. Thus, accurately assessing long-term outcomes, including the impact of leg symptoms and sleep disorders, on cardiovascular health is important. Furthermore there are little data on pharmacologic intervention adverse effects in patients older adults, those with multiple comorbidities (especially end stage kidney disease) and women either pregnant or potentially becoming pregnant as these individuals are often specifically excluded from studies.

Scope and Key Questions

Key Questions

Key Questions were developed with input from stakeholder groups representing patients, providers, and technical experts. Among the many areas of uncertainty identified, a critical issue was understanding whether treatment benefits and adherence were sustained over time (durability). Our Key Questions therefore address long-term tolerability, sustainability, and harms of treatments.

Key Question 3. What is the effect of patient characteristics (age, sex, race, comorbidities, disease severity, etiology, iron status, pregnancy, end-stage renal disease) on the benefits and harms of treatments for RLS?

The analytical framework for our Key Questions is shown in Figure 1.

Figure 1

Analytical framework. KQ = Key Question; RLS = restless legs syndrome