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Comparative Effectiveness Review Summary Guides for Clinicians [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2007-.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Comparative Effectiveness Review Summary Guides for Clinicians [Internet].

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Treatment for Restless Legs Syndrome

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Author Information and Affiliations

Issued: .

Research Focus for Clinicians

In response to a request from the public, a review was undertaken to evaluate the evidence regarding the potential benefits and adverse effects associated with various treatments for restless legs syndrome (RLS). This review did not cover other sleep disorders such as periodic limb movement disorder. The systematic review included 53 reports of randomized clinical trials and observational studies published through June 2012. The online version of this summary and the full report are available at www.effectivehealthcare.ahrq.gov/restless-legs.cfm. This summary is provided to inform discussions with patients of options and to assist in decisionmaking along with consideration of a patient’s values and preferences. However, reviews of evidence should not be construed to represent clinical recommendations or guidelines.

Background

RLS is a neurological disorder characterized by unpleasant sensations in the legs and an irresistible urge to move them. The essential diagnostic criteria for RLS were established by the International RLS (IRLS) Study Group. Any RLS diagnosis requires that all four of these 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 the urge to move are partly or totally relieved by movement such as walking, bending, stretching, et cetera, at least as long as the activity continues
  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

RLS varies in symptom severity and frequency. Mild RLS may cause minor annoyance, but severe RLS can negatively affect work, social activities, and function. RLS-induced sleep deprivation and daytime fatigue are common reasons RLS patients seek treatment. Severe RLS can be a chronic progressive disorder that may require long-term treatment.

Prevalence estimates for RLS in the United States range from 1.5 to 7.4 percent in adults. The variation reflects different approaches to diagnosing RLS and defining its frequency and severity. The etiology of primary RLS is unknown, but the disorder might occur secondary to other conditions such as iron deficiency, end-stage renal disease, and pregnancy. Insufficient sleep and sleep disorders such as sleep apnea might exacerbate symptoms of RLS.

Treatment options for RLS include nonpharmacologic and pharmacologic strategies. Nonpharmacologic treatment approaches include pneumatic compression devices, near- infrared light therapy, lower body resistance exercise, and using botanical preparations. The major classes of pharmacologic agents used are listed in Table 1. The choice of pharmacologic agent used to treat RLS depends on the frequency and severity of symptoms.

Table 1. Pharmacologic Interventions Assessed in This Comparative Effectiveness Review.

Table 1

Pharmacologic Interventions Assessed in This Comparative Effectiveness Review.

Dopaminergic agents can result in a treatment complication called augmentation. Augmentation is a drug-induced exacerbation of symptoms characterized by greater symptom intensity, onset earlier in the day, and shorter latency during inactivity. With augmentation, symptoms may also spread to the arms, trunk, and face. Recent studies suggest augmentation is more likely to occur with levodopa when compared with dopamine agonists. Augmentation can lead to poorer outcomes, a switch to other classes of medication, or treatment discontinuation.1,2 Augmentation is usually considered as resolved when the medication triggering augmentation has been discontinued or when the patient has been switched to another medication.1,2

Clinicians face uncertainty related to defining RLS, assessing disease severity, and evaluating the risks and benefits of treatment. While these challenges apply to both primary care and specialty settings, they may be more pronounced in primary care.

1.
Garcia-Borreguero D, Hogl B, Ferini-Strambi L, et al. Mov Disord. 2012;27(2):277–83. [PubMed: 22328464]
2.
Allen RP, Adler CH, Du W, et al. Sleep Med. 2011;12(5):431–9. [PubMed: 21493132]

Conclusion

When compared with placebo, dopamine agonists and alpha-2-delta ligands reduce RLS symptoms and improve patient-reported sleep outcomes and disease-specific quality of life. Moderate-level evidence suggests benefits of intravenous iron on symptoms of RLS. No eligible studies assessed opioids or sedative hypnotics as treatment for RLS. These agents also have potentially serious adverse effects. Some nonpharmacologic interventions such as compression stockings, near-infrared light, or exercise improve RLS symptoms (evidence level low to moderate). Adverse effects of pharmacologic therapies and long-term treatment withdrawals due to adverse effects or lack of efficacy are common. Evidence from observational studies suggests that augmentation is common across dopaminergic agents. The studies included in this review were conducted in adults with moderate to severe RLS. The long-term effectiveness and applicability of the assessed RLS therapies for adults with milder or less frequent RLS symptoms, individuals with secondary RLS, and children are unknown.

Clinical Bottom Line

Rating Scales Used To Evaluate Patient Outcomes

The International RLS (IRLS) Rating Scale is a 10-item scale where items such as intensity, frequency, and consequences of RLS are rated by patient and investigator on a 5-point scale to give a global score ranging from 0 (no RLS) to 40 (very severe RLS). Clinically meaningful responder criteria are the resolution of symptoms (score = 0); the percentage of patients with reduction of symptoms from very severe or severe to moderate or mild; and a 50-percent or greater change in the score from baseline.

The Clinical Global Impressions (CGI) or Patient Global Impressions (PGI) Scale has individual items such as disease severity, improvement from baseline, therapeutic effect, and side effects from treatment. Items are rated on a 7-point scale. Scores are not combined; often just one component of the scale (e.g., improvement) is assessed by the clinician (CGI) or the patient. Clinically meaningful responder criteria are the percentages of patients who are much improved or very much improved on the CGI Scale or the PGI Scale.

The RSL Quality of Life (RLS-QoL) Scale is an 18-item scale where items such as daily function, social activities and travel arrangements, morning activities and concentration, and sleep and sexual activity are rated on a 5-point scale to give a global score.

The Medical Outcomes Study-Sleep Problem Index II (MOS-SPI-II) Scale is a 12-item scale where several aspects of sleep such as sleep initiation, maintenance, quantity, quality, sleep adequacy, and daytime somnolence are rated by the patient.

Evidence of Benefits

Dopamine agonists (ropinirole, pramipexole, and rotigotine)

When compared with placebo, dopamine agonists:

  • Increased the percentage of patients with a clinically important response* Image clinrestlesslegfu1.jpg
  • Reduced RLS symptoms Image clinrestlesslegfu1.jpg
  • Improved RLS quality of life Image clinrestlesslegfu1.jpg
  • Improved patient-reported sleep outcomes Image clinrestlesslegfu1.jpg
Alpha-2-delta ligands (gabapentin enacarbil and pregabalin)

When compared with placebo, alpha-2-delta ligands:

  • Increased the percentage of patients with a clinically important response* Image clinrestlesslegfu1.jpg
  • Improved RLS quality of life Image clinrestlesslegfu3.jpg
  • Improved patient-reported sleep outcomes Image clinrestlesslegfu3.jpg

Gabapentin enacarbil also improved sleep adequacy based on the sleep adequacy domain of the MOS-SPI-II Scale. Image clinrestlesslegfu1.jpg

Iron therapy

Results from one small, good-quality study showed that, when compared with placebo, intravenous ferric carboxymaltose:

  • Slightly improved symptom scores on the IRLS Rating Scale Image clinrestlesslegfu2.jpg
  • Slightly improved RLS quality of life Image clinrestlesslegfu2.jpg
  • Slightly improved patient-reported sleep outcomes Image clinrestlesslegfu3.jpg

Two small randomized trials of iron therapy (one intravenous and one oral) versus placebo in adults with iron deficiency suggested that iron may improve both the percentage of adults considered IRLS responders and symptom scores on the IRLS Rating Scale.** Image clinrestlesslegfu3.jpg

Opioids and hypnotics

No eligible studies assessed opioids or sedative hypnotics, though these are sometimes used clinically for RLS treatment. Image clinrestlesslegfu4.jpg

Nonpharmacologic interventions

Pneumatic compression devices reduced IRLS Rating Scale symptom scores more than sham. Image clinrestlesslegfu2.jpg

Near-infrared light treatment improved IRLS Rating Scale symptom, scores more than sham. Image clinrestlesslegfu3.jpg

Strength training and treadmill walking improved IRLS symptoms but adherence was poor. Image clinrestlesslegfu3.jpg

The botanical extract valerian was not effective in treating RLS. Image clinrestlesslegfu3.jpg

Evidence of Harms

Dopamine agonists (ropinirole, pramipexole, and rotigotine)

Dopamine agonists were associated with more adverse effects than placebo.

  • Study withdrawals due to adverse effects were more common with dopamine agonists than with placebo. The differences were mainly due to adverse effect-related withdrawals reported in studies of transdermal rotigotine. Image clinrestlesslegfu2.jpg
  • More patients randomized to a dopamine agonist had at least one adverse effect when compared with placebo. Image clinrestlesslegfu1.jpg
  • Short-term adverse effects from dopamine agonist treatment included nausea, vomiting, somnolence, and fatigue. Image clinrestlesslegfu1.jpg

Evidence from observational studies suggests that augmentation is common across dopaminergic agents (dopamine agonists and levodopa), with prevalence estimates ranging from 2.3 to 60 percent. The reason for the wide variation in prevalence estimates across drugs is unclear. ††

Alpha-2-delta ligands (gabapentin enacarbil and pregabalin)

Alpha-2-delta ligands were associated with more adverse effects than placebo.

  • More patients randomized to alpha-2-delta ligands had at least one adverse effect when compared with placebo. Image clinrestlesslegfu2.jpg
  • Somnolence, unsteadiness or dizziness, and dry mouth were much more common with alpha-2-delta ligands than with placebo. Image clinrestlesslegfu1.jpg
  • Study withdrawals (due to any reason) were less common with alpha-2-delta ligands than with placebo. Image clinrestlesslegfu1.jpg

Strength of Evidence Scale

High: Image clinrestlesslegfu1.jpgHigh confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.
Moderate: Image clinrestlesslegfu2.jpgModerate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.
Low: Image clinrestlesslegfu3.jpgLow confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the estimate.
Insufficient: Image clinrestlesslegfu4.jpgEvidence is either unavailable or does not permit a conclusion.
*

These are patients with a greater than 50-percent reduction in symptom scores on the IRLS Rating Scale or who were “improved” or “much improved” on the CGI Scale or the PGI Scale.

Serum ferritin levels were 26.8 mcg/L for females and 63.6 mcg/L for males among patients included in this trial.

**

In the trial evaluating intravenous iron, serum ferritin levels were reported to be 20.55 mcg/L in the included patients. Serum ferritin levels were not reported in the trial evaluating oral iron therapy.

††

This finding was not rated.

Table 2Individual Outcomes and Strength of Evidence in Placebo-Controlled Studies of Dopamine Agonists

Outcome for Treatment vs. Placebo, Strength of EvidenceRLS Treatment That Was Compared With PlaceboNumber of TrialsnSummary Statistics [95% CI] for Comparisons of RLS Treatment vs. PlaceboAbsolute Effect per 100 Patients [95% CI]
Increase in IRLS Rating Scale responders (>50% score reduction) Image clinrestlesslegfu1.jpgPramipexole31,079RR 1.46 [1.22 to 1.74]21 more per 100 [10 to 34 more]
Rotigotine41,139RR 1.76 [1.47 to 2.10]25 more per 100 [16 to 37 more]
Increase in Clinical Global Impressions Scale responders (very or much improved) Image clinrestlesslegfu1.jpgPramipexole51,747RR 1.61 [1.40 to 1.86]25 more per 100 [17 to 36 more]
Ropinirole61,608RR 1.37 [1.25 to 1.50]18 more per 100 [12 to 24 more]
Rotigotine41,091RR 1.37 [1.22 to 1.54]19 more per 100 [12 to 28 more]
Improvement in RLS quality of life Image clinrestlesslegfu1.jpgPramipexole3912SMD −0.43 [−0.61 to −0.25]Not reported
Ropinirole2643SMD −0.30 [−0.45 to −0.14]Not reported
Rotigotine4585SMD −0.37 [−0.60 to −0.13]Not reported
Improvement in patient self-rated sleep using the MOS-SPI-II Scale Image clinrestlesslegfu1.jpgPramipexole1356SMD 0.36 [0.15 to 0.57]Not reported
Ropinirole41,237SMD 0.37 [0.24 to 0.49]Not reported
Rotigotine3459SMD 0.43 [0.24 to 0.61]Not reported
Increase in study withdrawals due to an adverse event Image clinrestlesslegfu2.jpgPramipexole51,791RR 0.97 [0.69 to 1.35]Not reported
Ropinirole71,698RR 1.48 [0.99 to 2.20]Not reported
Rotigotine41,370RR 2.50 [1.33 to 4.70]Not reported
Increase in number of patients with >1 adverse event Image clinrestlesslegfu1.jpgPramipexole51,790RR 1.16 [1.04 to 1.29]Not reported
Ropinirole71,695RR 1.20 [1.10 to 1.32]Not reported
Rotigotine41,369RR 1.25 [1.00 to 1.59]Not reported

Abbreviations: 95% CI = 95-percent confidence interval; IRLS = International Restless Legs Syndrome; MOS-SPI-II = Medical Outcomes Study Sleep Problem Index II; RR = relative risk; SMD = standardized mean difference

Relative Risk: A comparison of the risk of a particular event for two different groups of people, one of which may be treated with a drug and the other with a control.

Standardized Mean Difference: A way of standardizing the “intervention effect” [the difference between treatment and control group means] that allows for making comparisons across studies.

As an example, an RR of 1.16 implies that patients on pramipexole have a 16-percent higher chance of having >1 adverse event when compared with patients on placebo.

Table 3Individual Outcomes and Strength of Evidence in Placebo-Controlled Studies of Alpha-2-Delta Ligands

Outcome for Treatment vs. Placebo, Strength of EvidenceRLS Treatment That Was Compared With PlaceboNumber of TrialsnSummary Statistics [95% CI] for Comparisons of RLS Treatment vs. PlaceboAbsolute Effect per 100 Patients [95% CI]
Increase in IRLS Rating Scale responders (>50% score reduction) Image clinrestlesslegfu1.jpgGabapentin enacarbil1321RR 1.54 [1.18 to 2.01]21 more per 100 [7 to 40 more]
Pregabalin2182RR 2.03 [1.33 to 3.11]34 more per 100 [11 to 69 more]
Increase in Clinical Global Impressions Scale responders (much or very much improved) Image clinrestlesslegfu1.jpgGabapentin enacarbil2431RR 1.80 [1.51 to 2.14]33 more per 100 [21 to 48 more]
Pregabalin144RR 1.14 [0.80 to 1.64]9 more per 100 [12 fewer to 40 more]
Improvement in RLS quality of life Image clinrestlesslegfu3.jpgGabapentin enacarbil1538SMD 0.42 [0.16 to 0.69]Not reported
Pregabalin1124SMD −0.05 [−0.65 to 0.55]Not reported
Improvement in patient self-rated sleep using the MOS-SPI-II Scale Image clinrestlesslegfu1.jpgGabapentin enacarbil2431SMD 0.53 [0.33 to 0.72]Not reported
Increase in number of patients with >1 adverse event Image clinrestlesslegfu2.jpgGabapentin enacarbil3738RR 1.09 [1.00 to 1.19]Not reported
Pregabalin2195RR 1.67 [0.74 to 3.80]Not reported

See the legend under Table 2.

Gaps in Knowledge

  • Most studies included in this review were efficacy studies. No studies making head-to-head comparison between RLS medications were identified. The included studies did not permit reliable conclusions about comparative benefits and harms.
  • The current evidence base consists almost exclusively of pharmacologic treatments. The effectiveness of nonpharmacologic treatments including herbal therapy, mind-body medicine, and manipulative treatments is not known. Additionally, the effectiveness of over-the-counter iron supplements is not known.
  • Most of the studies included in this review were conducted in patients with moderate to severe RLS. The effectiveness of the assessed treatments in patients with mild RLS is unknown.
  • No evidence was found about the effectiveness of therapies in specific subgroups such as children, older adults with multiple comorbidities, or individuals with secondary RLS (including those with iron deficiency or end-stage renal disease and pregnant women).
  • The long-term durability of treatment benefits remains unknown.
  • Little is known about patient characteristics that may lead to augmentation.
  • The included studies do not consistently report on the use of objective criteria for sleep assessment.
  • There is a paucity of information on the effects of environmental factors on RLS and their impact on treatment outcomes.

What To Discuss With Your Patients and Their Caregivers

  • What RLS is, and that it is a treatable condition
  • That RLS can become a chronic condition that requires treatment in moderate to severe cases
  • The currently available pharmacologic and nonpharmacologic therapies for RLS
  • The available evidence for the effectiveness of the various treatments for RLS with regard to disease symptoms, quality of life, and sleep outcomes
  • The available evidence for the harms of the various treatments for RLS
  • The possibility that the patient might develop augmentation if he/she is taking levodopa or dopamine agonists

    Ask the patient at each visit if he/she is experiencing symptoms of augmentation.

Resource for Patients

Options for Treating Restless Legs Syndrome, A Review of the Research for Adults, is a free companion to this clinician research summary. It can help patients talk with their health care professionals about the many options for treating RLS.

Ordering Information

For electronic copies of Options for Treating Restless Legs Syndrome, A Review of the Research for Adults, this clinician research summary, and the full systematic review, visit www.effectivehealthcare.ahrq.gov/restless-legs.cfm. To order free print copies of this clinician research summary, call the AHRQ Publications Clearinghouse at 800-358-9295.

Source

The information in this summary is based on Treatment for Restless Legs Syndrome, Comparative Effectiveness Review No. 86, prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-2007-10064-I for the Agency for Healthcare Research and Quality, November 2012. Available at www.effectivehealthcare.ahrq.gov/restless-legs.cfm. This summary was prepared by the John M. Eisenberg Center for Clinical Decisions and Communications Science at Baylor College of Medicine, Houston, TX.

Footnotes

Also referred to as Willis-Ekbom disease

RLS can be defined as mild, moderate, severe, or very severe based on the IRLS Rating Scale. The IRLS is a 10-item scale with scores ranging from 0 (no symptoms) to 40. Scores ≤10 are considered as mild, scores 11–20 as moderate, scores 21–30 as severe, and scores >30 as very severe RLS.

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