Treatment for Restless Legs Syndrome Prepared for: Agency for Healthcare Research and Quality (AHRQ)

Treatment for Restless Legs Syndrome

Prepared for:

Agency for Healthcare Research and Quality (AHRQ)

www.ahrq.gov

Introduction to restless legs syndrome (RLS) and the various therapies available for its treatment

Systematic review methods The clinical questions addressed by the comparative

effectiveness review Results of studies and evidence-based conclusions

about the relative benefits and adverse effects of currently available treatments for RLS

Gaps in knowledge and future research needs What to discuss with patients and their caregivers

Outline of Material

Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.Available at www.effectivehealthcare.ahrq.gov/restless-legs.cfm.

Restless legs syndrome* (RLS) is a neurological disorder defined and diagnosed based solely on clinical criteria.

RLS diagnosis requires that the following four essential criteria be met: There is an urge to move the legs that is usually accompanied by

uncomfortable or unpleasant sensations in the legs. Unpleasant sensations or the urge to move begin or worsen during

periods of rest or inactivity such as lying or sitting. Unpleasant sensations or 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.

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.

* Also referred to as Willis-Ekbom disease

Background: What Is Restless Legs Syndrome?

Allen RP, Picchietti D, Hening WA, et al. Sleep Med. 2003 Mar;4(2):101-19. PMID: 14592341.Trenkwalder C, Paulus W. Nat Rev Neurol. 2010 Jun;6(6):337-46. PMID: 20531433.Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.Available at www.effectivehealthcare.ahrq.gov/restless-legs.cfm.

Prevalence estimates for restless legs syndrome (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 also occurs 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.

The pathophysiology of RLS has been suggested to be closely linked to abnormalities in the dopaminergic system and iron metabolism.

Background: Prevalence and Etiology of Restless Legs Syndrome

Allen RP, Picchietti D, Hening WA, et al. Sleep Med. 2003 Mar;4(2):101-19. PMID: 14592341.García-Borreguero D, Egatz R, Winkelmann J, et al. Sleep Med Rev. 2006 Jun;10(3):153-67. PMID: 16762806.Trenkwalder C, Paulus W. Nature Rev Neurol. 2010 Jun;6(6):337-46. PMID: 20531433.Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.Available at www.effectivehealthcare.ahrq.gov/restless-legs.cfm.

Restless legs syndrome (RLS) can be defined as mild, moderate, severe, or very severe based on the International RLS (IRLS) Rating Scale. The IRLS is a 10-item scale with scores ranging from 0 (no

symptoms) to 40.

A score of ≤10 is considered mild RLS, a score of 11–20 is considered moderate RLS, a score of 21–30 is considered severe RLS, and a score >30 is considered very severe RLS.

Mild RLS may cause minor annoyance.

Severe RLS can negatively affect work, social activities, and function. It can be a chronic progressive disorder that may require long-term treatment.

RLS-induced sleep deprivation and daytime fatigue are common reasons RLS patients seek treatment.

Background: Severity and Clinical Course of Restless Legs Syndrome

Trenkwalder C, Paulus W. Nat Rev Neurol. 2010 Jun;6(6):337-46. PMID: 20531433.Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.Available at www.effectivehealthcare.ahrq.gov/restless-legs.cfm.

Treatment options for restless legs syndrome (RLS) include pharmacologic and nonpharmacologic strategies.

The major classes of pharmacologic treatments* include: Dopaminergic agents Anticonvulsant calcium channel (alpha-2-delta) ligands Iron

Pharmacologic agents approved by the U.S. Food and Drug Administration (FDA) for treating moderate to severe RLS are: Dopamine agonists: Pramipexole (Mirapex®), ropinirole

(Requip®), and rotigotine patch (Neupro®) Alpha-2-delta ligand: Gabapentin enacarbil (Horizant®)*The authors of this review did not identify any eligible studies that tested sedative

hypnotics and opioids in RLS patients. Sedative hypnotics and opioids are not approved by the FDA for treating RLS.

Background: Currently Available Treatment Options for Restless Legs Syndrome (1 of 2)

Silber MH, Ehrenberg BL, Allen RP, et al. Mayo Clin Proc. 2004 Jul;79(7):916-22. PMID: 15244390.Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.Available at www.effectivehealthcare.ahrq.gov/restless-legs.cfm.

Nonpharmacologic treatment approaches for restless legs syndrome (RLS) include: Exercise Avoiding RLS precipitants such as caffeine, alcohol,

antidepressants, and antihistamines Using counter stimuli to sensory symptoms such as hot or cold

baths, limb massage, compression stockings, and counter-pulsation devices

Near-infrared light therapy Herbal medicine Acupuncture

Background: Currently Available Treatment Options for Restless Legs Syndrome (2 of 2)

Silber MH, Ehrenberg BL, Allen RP, et al. Mayo Clin Proc. 2004 Jul;79(7):916-22. PMID: 15244390.Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.Available at www.effectivehealthcare.ahrq.gov/restless-legs.cfm.

Dopaminergic agents (dopamine agonists and levodopa) used in restless legs syndrome therapy can result in a complication called augmentation in the long term.

Augmentation is a drug-induced exacerbation of symptoms characterized by greater symptom intensity, onset earlier in the day, and shorter latency during inactivity.

Incidence of augmentation may vary with type of dopaminergic agent. Augmentation is more likely to occur with levodopa than with dopamine

agonists.

Augmentation is usually considered resolved when: The medication triggering augmentation has been discontinued The patient has been switched to

Background: Restless Legs Syndrome Treatment and Augmentation

Allen RP, Adler CH, Du W, et al. Sleep Med. 2011 May;12(5):431-9. PMID: 21493132. Garcia-Borreguero D, Hogl B, Ferini-Strambi L, et al. Mov Disord. 2012 Feb;27(2):277-83. PMID: 22328464.Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.Available at www.effectivehealthcare.ahrq.gov/restless-legs.cfm.

Clinicians face uncertainty in:

Defining and diagnosing restless legs syndrome (RLS)

In primary care, standard RLS diagnostic criteria may be less consistently applied, resulting in misdiagnosis, misclassification, and unnecessary or ineffective therapy.

Measuring disease severity

The lack of well-defined measures for assessing disease severity and treatment-induced changes in disease status present challenges in clinical practice.

Assessing the risks/benefits of treatment

The relative risks/benefits of the various therapies for RLS—particularly in patients with mild disease and in older adults and children—are unclear.

Background: Uncertainties Related to the Treatment of Restless Legs Syndrome


Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others.

A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.

The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Research Summaries and the full report, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov/

Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development


Key Question 1. What is the comparative effectiveness of treatments for restless legs syndrome (RLS)?a. What are the benefits from RLS treatments when

compared with placebo or no treatment?

b. What are the benefits from RLS treatments when compared with other active treatments?

c. What are the durability and

Clinical Questions Addressed by This Comparative Effectiveness Review (1 of 3)



Key Question 2. What are the harms of restless legs syndrome (RLS) treatment?a. What are the harms from RLS treatments when

compared with placebo or no treatment?

b. What are the harms from RLS treatments when compared with other active treatments?

c. What are the long-term harms from RLS treatment?


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



The strength of evidence was classified into four broad categories:

Rating the Strength of Evidence From the Comparative Effectiveness Review


Pharmacologic Therapies for Restless Legs Syndrome Assessed in This Review

Treatment* Generic Name Brand NameFDA Approval for RLS

Dopaminergic agents

Levodopa Dopar® No

Ropinirole Requip® Yes

Pramipexole Mirapex® Yes

Rotigotine patch Neupro® Yes

Anticonvulsants (alpha-2-delta ligands)

Gabapentin enacarbil

Horizant® Yes

Gabapentin Neurontin® No

Pregabalin Lyrica® No

Iron Many formulations – No

* Sedative hypnotics and opioids were included in this review; however, no eligible studies were identified that assessed these agents in patients with restless legs syndrome (RLS). Sedative hypnotics and opioids have not been approved by the U.S. Food and Drug Administration (FDA) as treatment for RLS.

Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.Available at www.effectiveealthcare.ahrq.gov/restless-legs.cfm.

When compared with placebo, dopamine agonists (ropinirole, pramipexole, and rotigotine): Increased the percentage of patients with a clinically important

response* Reduced restless legs syndrome symptoms Improved disease-specific quality of life and patient-reported sleep

outcomes

Strength of Evidence: High

Evidence from one study suggested that cabergoline** improved symptom scores on the International Restless Legs Syndrome Rating Scale and the Restless Legs Syndrome Quality of Life Scale more than levodopa.

Strength of Evidence: Moderate

Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Dopaminergic Agents

* These are patients with a greater than 50-percent reduction in symptom scores on the International RLS Rating Scale or who were “improved” or “much improved” on the Clinical Global Impressions Scale.

** Cabergoline is not approved by the U.S. Food and Drug Administration (FDA) as treatment for RLS and is rarely used in the United States because of FDA warnings about cardiac valvular complications.Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86.

Available at www.effectivehealthcare.ahrq.gov/restless-legs.cfm.

Outcomes and Strength of Evidence in Placebo-Controlled Studies of Dopamine Agonists (1 of 2)

Outcome With

Treatment vs. Placebo

SOE

RLS Treatment Compared

With Placebo

No. of Trials n

Summary Statistics(95% CI)

Absolute Effect per 100

Patients

Increase in IRLS Rating Scale Responders (>50% score reduction)

High

Pramipexole

3 1,079

RR 1.46 (1.22–1.74) 21 more per 100 (10 to 34 more)

Rotigotine 4 1,139

RR 1.76 (1.47–2.100)

25 more per 100 (16 to 37 more)

Increase in Clinical Global Impressions Scale Responders (much or very much improved)

High

Pramipexole

5 1,747


Ropinirole 6 1,608


Rotigotine 4 1,091


Improvement in Patient-Reported RLS Qualityof Life

High

Pramipexole

3 912

SMD -0.43 (-0.61 to -0.25)

Not reported

Ropinirole 2 643

SMD -0.30 (-0.45 to -0.25)

Not reported

Rotigotine 4 585

SMD -0.37 (-0.60 to - 0.13)

Not reported



Outcome With


SOE


With PlaceboNo. of Trials n

Summary Statistics (95% CI)

Improvement in Patient Self-Rated Sleep Using the MOS-SPI-II Scale

High Pramipexole 1 356 SMD -0.36 (-0.60 to -0.13)

Ropinirole 4 1,237 SMD -0.37 (-0.24 to -0.49)

Rotigotine 3 459 SMD -0.43 (-0.24 to -0.61)

Increase in Study Withdrawals Due to an Adverse Event

Moderate

Pramipexole 5 1,791 RR 0.97 (0.69–1.35)

Ropinirole 7 1,698 RR 1.48 (0.99–2.20)

Rotigotine 4 1,370 RR 1.37 (1.33–4.70)

Increase in Number of Patients With >1 Adverse Event

High Pramipexole 5 1,790 RR 1.16 (1.04–1.29)

Ropinirole 7 1,695 RR 1.20 (1.10–1.32)

Rotigotine 4 1,369 RR 1.25 (1.00–1.59)

Outcomes and Strength of Evidence in Placebo-Controlled Studies of Dopamine Agonists (2 of 2)

When compared with placebo, alpha-2-delta ligands (gabapentin enacarbil and pregabalin): Increased the percentage of patients with a clinically important

response

Strength of Evidence: High Improved disease-specific quality of life and patient-reported sleep

outcomes

Strength of Evidence: Low

Gabapentin enacarbil improved sleep adequacy based on the sleep adequacy domain of the Medical Outcomes Study.


Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Alpha-2-Delta Ligands


Outcomes and Strength of Evidence in Placebo-Controlled Studies of Alpha-2-Delta Ligands (1 of 2)

Outcome With


SOE


With Placebo

No. of Trials n

Summary Statistics(95% CI)

Absolute Effect per

100 Patients

Increase in IRLS Rating Scale Responders (>50% score reduction)

High


1 321 RR 1.54 (1.18–2.01) 21 more per 100 (7 to 40 more)

Pregabalin 2 182 RR 2.03 (1.33–3.11) 34 more per 100 (11 to 69 more)

Increase in Clinical Global Impressions Scale Responders (much–very much improved)

High


2 431 RR 1.80 (1.51–2.14) 33 more per 100 (21 to 48 more)

Pregabalin 1 44 RR 1.14 (0.80–1.6) 9 more per 100 (12 fewer to 40 more)

Improvement in RLS Qualityof Life

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



Outcome With

Treatment vs. Placebo SOE


With Placebo

No. of

Trialsn

Summary Statistics (95% CI)

Improvement in Self-Rated Sleep Using the MOS-SPI-II Scale

High Gabapentin enacarbil

2 431 SMD 0.53 (-0.33 to 0.72)

Increase in Number of Patients With >1 Adverse Event

Moderate


5 738 RR 1.09 (1.00–1.19)

Pregabalin 7 195 RR 1.67 (0.74–3.80)

Outcomes and Strength of Evidence in Placebo-Controlled Studies of Alpha-2-Delta Ligands (2 of 2)

Abbreviations: 95% CI = 95-percent confidence interval; MOS-SPI-II = Medical Outcomes Scale–Sleep Problems Index II; RR = relative risk; SMD = standardized mean difference; SOE = strength of evidence

Results from a small, good-quality study showed that when compared with placebo, intravenous ferric carboxymaltose: Improved symptom scores on the International Restless Legs

(IRLS) Syndrome Rating Scale and the Restless Legs Syndrome Quality of Life Scale

Strength of Evidence: Moderate Improved patient-reported sleep outcomes


Two small trials of iron therapy versus placebo in adults with iron deficiency suggested that iron may improve the percentage of adults considered IRLS Rating Scale responders and symptom scores on the IRLS Rating Scale.


Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Iron Therapy


No eligible studies assessed opioids or sedative hypnotics, though these are used clinically as treatment for restless legs syndrome.

Strength of Evidence: Insufficient


Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Opioids and Hypnotics

When compared with sham treatment, pneumatic compression devices: Improved symptom scores on the International Restless Legs

Syndrome (IRLS) Rating Scale Improved quality of life Reduced daytime somnolence Achieved better symptom resolution

Strength of Evidence: Moderate Near-infrared light treatment improved symptom scores on

the IRLS Rating Scale more than sham treatment.



Evidence for the Benefits of Nonpharmacologic Interventions in Treating Restless Legs Syndrome (1 of 2)

Strength training and treadmill walking improved scores on the International Restless Legs Syndrome Rating Scale, but adherence to both types of exercise was poor.


The botanical extract valerian was not effective in treating restless legs syndrome.



Evidence for the Benefits of Nonpharmacologic Interventions in Treating Restless Legs Syndrome (2 of 2)

Study withdrawals due to adverse effects were more common with dopamine agonist treatments than with placebo. The differences were mainly due to an increase in withdrawals

related to adverse effects reported in studies of transdermal rotigotine.


More patients randomized to dopamine agonists had at least one adverse effect when compared with those randomized to placebo.


Evidence for the Harms of Pharmacologic Interventions in Treating Restless Legs Syndrome: Dopaminergic Agents (1 of 2)


Short-term adverse effects from dopamine agonist treatment included nausea, vomiting, somnolence, and fatigue.


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 prevalence estimates of augmentation were higher in

studies of levodopa when compared with studies of dopamine agonists.

The reason for the wide variation in prevalence estimates across drugs is unclear.

* This finding was not rated.

Evidence for the Harms of Pharmacologic Interventions in Treating Restless Legs Syndrome: Dopaminergic Agents (2 of 2)


Short-term adverse effects such as somnolence, unsteadiness or dizziness, and dry mouth were much more common with alpha-2-delta ligands than with placebo.


Study withdrawals due to adverse effects was marginally greater in patients receiving alpha-2-delta ligand treatment versus placebo.


Evidence for the Harms of Pharmacologic Interventions in Treating Restless Legs Syndrome: Alpha-2-Delta Ligands


When compared with placebo, dopamine agonists and alpha-2-delta ligands reduce restless legs syndrome (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 for the treatment of RLS.

Some nonpharmacologic interventions such as compression stockings, near-infrared light, and exercise improve RLS symptoms (evidence quality low to moderate).

Conclusions (1 of 2)


Adverse effects of pharmacologic therapies for restless legs syndrome (RLS) and 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 idiopathic RLS. The 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.

Conclusions (2 of 2)


Most studies included in this review were efficacy studies. The included studies did not permit reliable indirect comparisons about comparative benefits and harms.

The current evidence base consists almost exclusively of pharmacologic treatments. The effectiveness of several nonpharmacologic treatments for restless legs syndrome (RLS) is not known. Additionally, the effectiveness of over-the-counter iron supplements is not known.

No evidence was found from eligible studies about the effectiveness of therapies in specific subgroups such as children, older adults with multiple comorbidities, or individuals with secondary RLS.

Gaps in Knowledge (1 of 2)


The long-term durability of benefits from treatment of restless legs syndrome (RLS) remains unknown.

Augmentation is a significant harm with dopaminergic therapy; yet, little is known about patient characteristics or other risk factors 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.

Gaps in Knowledge (2 of 2)


What restless legs syndrome (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 available pharmacologic and nonpharmacologic therapies for RLS The available evidence for the various treatments for RLS* with

regard to: Disease symptoms Quality of life and sleep outcomes Adverse effects

The possibility that the patient might develop augmentation if he/she is taking levodopa or dopamine agonists

* However, it should be emphasized that the evidence is based on studies in patients with moderate to severe RLS, and its applicability to patients with mild RLS or with RLS due to other causes is unknown. Data on long-term benefits and harms of treatments are lacking.

What To Discuss With Your Patients andTheir Caregivers


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Treatment for Restless Legs Syndrome Prepared for: Agency for Healthcare Research and Quality (AHRQ)