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Treatment for Restless Legs Syndrome

Clinician Summary – Aug. 30, 2013

Treatment for Restless Legs Syndrome

Formats

Table of Contents

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 can be accessed on the right side of this page. 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.

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.

Table 1. Pharmacologic Interventions Assessed in This Comparative Effectiveness Review*
Treatment Generic Name FDA Approval for RLS Brand Name
* Sedative hypnotics and opioids were included in this review; however, no eligible studies assessed these agents in patients with RLS. Sedative hypnotics and opioids have not been approved by the U.S. Food and Drug Administration (FDA) for the treatment of RLS.
Dopaminergic agents Levodopa No Dopar®
Ropinirole Yes Requip®
Pramipexole Yes Mirapex®
Rotigotine patch Yes Neupro®
Anticonvulsants (alpha-2-delta ligands) Gabapentin enacarbil Yes Horizant®
Gabapentin No Neurontin®
Pregabalin No Lyrica®
Iron Many formulations No -

† 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.

References

  1. Garcia-Borreguero D, Hogl B, Ferini-Strambi L, et al. Mov Disord. 2012;27(2):277-83. PMID: 22328464.
  2. Allen RP, Adler CH, Du W, et al. Sleep Med. 2011;12(5):431-9. PMID: 21978726

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:

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

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

Gabapentin enacarbil also improved sleep adequacy based on the sleep adequacy domain of the MOS-SPI-II Scale. evidence high

Iron therapy

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

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.** evidence low

Opioids and hypnotics

No eligible studies assessed opioids or sedative hypnotics, though these are sometimes used clinically for RLS treatment. evidence insufficient

Nonpharmacologic interventions

Evidence of Harms

Dopamine agonists (ropinirole, pramipexole, and rotigotine)

Dopamine agonists were associated with more adverse effects than placebo.

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.

* 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.

Strength of Evidence Scale

High: evidence high
High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.

Moderate: evidence medium
Moderate 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: evidence low
Low 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:evidence insufficient
Evidence is either unavailable or does not permit a conclusion.

Table 2. Individual Outcomes and Strength of Evidence in Placebo-Controlled Studies of Dopamine Agonists
Outcome for Treatment vs. Placebo, Strength of Evidence RLS Treatment That Was Compared With Placebo Number of Trials n Summary Statistics [95% CI] for Comparisons of RLS Treatment vs. Placebo Absolute Effect per 100 Patients [95% CI]
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.
Increase in IRLS Rating Scale responders (>50% score reduction) evidence high Pramipexole 3 1,079 RR 1.46 [1.22 to 1.74] 21 more per 100 [10 to 34 more]
Rotigotine 4 1,139 RR 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) evidence high Pramipexole 5 1,747 RR 1.61 [1.40 to 1.86] 25 more per 100 [17 to 36 more]
Ropinirole 6 1,608 RR 1.37 [1.25 to 1.50] 18 more per 100 [12 to 24 more]
Rotigotine 4 1,091 RR 1.37 [1.22 to 1.54] 19 more per 100 [12 to 28 more]
Improvement in RLS quality of life evidence high Pramipexole 3 912 SMD -0.43 [-0.61 to -0.25] Not reported
Ropinirole 2 643 SMD -0.30 [-0.45 to -0.14] Not reported
Rotigotine 4 585 SMD -0.37 [-0.60 to -0.13] Not reported
Improvement in patient self-rated sleep using the MOS-SPI-II Scale evidence high Pramipexole 1 356 SMD 0.36 [0.15 to 0.57] Not reported
Ropinirole 4 1,237 SMD 0.37 [0.24 to 0.49] Not reported
Rotigotine 3 459 SMD 0.43 [0.24 to 0.61] Not reported
Increase in study withdrawals due to an adverse event evidence medium Pramipexole 5 1,791 RR 0.97 [0.69 to 1.35] Not reported
Ropinirole 7 1,698 RR 1.48 [0.99 to 2.20] Not reported
Rotigotine 4 1,370 RR 2.50 [1.33 to 4.70] Not reported
Increase in number of patients with >1 adverse event evidence high Pramipexole 5 1,790 RR 1.16 [1.04 to 1.29] Not reported
Ropinirole 7 1,695 RR 1.20 [1.10 to 1.32] Not reported
Rotigotine 4 1,369 RR 1.25 [1.00 to 1.59] Not reported

Table 3. Individual Outcomes and Strength of Evidence in Placebo-Controlled Studies of Alpha-2-Delta Ligands
Outcome for Treatment vs. Placebo, Strength of Evidence RLS Treatment That Was Compared With Placebo Number of Trials n Summary Statistics [95% CI] for Comparisons of RLS Treatment vs. Placebo Absolute Effect per 100 Patients [95% CI]
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.
Increase in IRLS Rating Scale responders (>50% score reduction)evidence high Gabapentin enacarbil 1 321 RR 1.54 [1.18 to 2.01] 21 more per 100 [7 to 40 more]
Pregabalin 2 182 RR 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)evidence high Gabapentin enacarbil 2 431 RR 1.80 [1.51 to 2.14] 33 more per 100 [21 to 48 more]
Pregabalin 1 44 RR 1.14 [0.80 to 1.64] 9 more per 100 [12 fewer to 40 more]
Improvement in RLS quality of lifeevidence low Gabapentin enacarbil 1 538 SMD 0.42 [0.16 to 0.69] Not reported
Pregabalin 1 124 SMD -0.05 [-0.65 to 0.55] Not reported
Improvement in patient self-rated sleep using the MOS-SPI-II Scaleevidence high Gabapentin enacarbil 2 431 SMD 0.53 [0.33 to 0.72] Not reported
Increase in number of patients with >1 adverse eventevidence medium Gabapentin enacarbil 3 738 RR 1.09 [1.00 to 1.19] Not reported
Pregabalin 2 195 RR 1.67 [0.74 to 3.80] Not reported
 

Gaps in Knowledge

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.

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. This summary was prepared by the John M. Eisenberg Center for Clinical Decisions and Communications Science at Baylor College of Medicine, Houston, TX. It was written by Geetha Achanta, Ph.D., Joohi Jimenez-Shahed, M.D., and Michael Fordis, M.D.

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