Presentation is loading. Please wait.

Presentation is loading. Please wait.

Treatment for Restless Legs Syndrome Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov.

Similar presentations


Presentation on theme: "Treatment for Restless Legs Syndrome Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov."— Presentation transcript:

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

2  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

3  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 Mar;4(2): PMID: Trenkwalder C, Paulus W. Nat Rev Neurol Jun;6(6): PMID: Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

4  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 Mar;4(2): PMID: García-Borreguero D, Egatz R, Winkelmann J, et al. Sleep Med Rev Jun;10(3): PMID: Trenkwalder C, Paulus W. Nature Rev Neurol Jun;6(6): PMID: Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

5  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 Jun;6(6): PMID: Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

6  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 Jul;79(7): PMID: Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

7  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 Jul;79(7): PMID: Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

8  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 May;12(5): PMID: Garcia-Borreguero D, Hogl B, Ferini-Strambi L, et al. Mov Disord Feb;27(2): PMID: Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

9 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 Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

10  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 Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

11  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) Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

12 Clinical Questions Addressed by This Comparative Effectiveness Review (2 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? Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

13  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? Clinical Questions Addressed by This Comparative Effectiveness Review (3 of 3) Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

14  The strength of evidence was classified into four broad categories: Rating the Strength of Evidence From the Comparative Effectiveness Review Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

15 Pharmacologic Therapies for Restless Legs Syndrome Assessed in This Review Treatment*Generic NameBrand Name FDA Approval for RLS Dopaminergic agents LevodopaDopar ® No RopiniroleRequip ® Yes PramipexoleMirapex ® Yes Rotigotine patchNeupro ® Yes Anticonvulsants (alpha-2-delta ligands) Gabapentin enacarbilHorizant ® Yes GabapentinNeurontin ® No PregabalinLyrica ® 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

16  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

17 Outcomes and Strength of Evidence in Placebo- Controlled Studies of Dopamine Agonists (1 of 2) Outcome With Treatment vs. PlaceboSOE RLS Treatment Compared With Placebo No. of Trialsn Summary Statistics (95% CI) Absolute Effect per 100 Patients Increase in IRLS Rating Scale Responders (>50% score reduction) HighPramipexole31,079RR 1.46 (1.22 – 1.74)21 more per 100 (10 to 34 more) Rotigotine41,139RR 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) HighPramipexole51,747RR 1.61 (1.4 – 1.86)25 more per 100 (17 to 36 more) Ropinirole61,608RR 1.37 (1.25 – 1.50)18 more per 100 (12 to 24 more) Rotigotine41,091RR 1.37 (1.22 – 1.54)19 more per 100 (12 to 28 more) Improvement in Patient-Reported RLS Quality of Life HighPramipexole3 912SMD (-0.61 to -0.25)Not reported Ropinirole2 643SMD (-0.45 to -0.25)Not reported Rotigotine4 585SMD (-0.60 to )Not reported Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

18 Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at Outcome With Treatment vs. PlaceboSOE RLS Treatment Compared With Placebo No. of Trialsn Summary Statistics (95% CI) Improvement in Patient Self- Rated Sleep Using the MOS- SPI-II Scale HighPramipexole1 356SMD (-0.60 to -0.13) Ropinirole41,237SMD (-0.24 to -0.49) Rotigotine3 459SMD (-0.24 to -0.61) Increase in Study Withdrawals Due to an Adverse Event ModeratePramipexole51,791RR 0.97 (0.69 – 1.35) Ropinirole71,698RR 1.48 (0.99 – 2.20) Rotigotine41,370RR 1.37 (1.33 – 4.70) Increase in Number of Patients With >1 Adverse Event HighPramipexole51,790RR 1.16 (1.04 – 1.29) Ropinirole71,695RR 1.20 (1.10 – 1.32) Rotigotine41,369RR 1.25 (1.00 – 1.59) Outcomes and Strength of Evidence in Placebo- Controlled Studies of Dopamine Agonists (2 of 2)

19  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. Strength of Evidence: High Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Alpha-2-Delta Ligands Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

20 Outcomes and Strength of Evidence in Placebo- Controlled Studies of Alpha-2-Delta Ligands (1 of 2) Outcome With Treatment vs. PlaceboSOE RLS Treatment Compared With Placebo No. of Trialsn Summary Statistics (95% CI) Absolute Effect per 100 Patients Increase in IRLS Rating Scale Responders (>50% score reduction) HighGabapentin enacarbil 1321RR 1.54 (1.18 – 2.01)21 more per 100 (7 to 40 more) Pregabalin2182RR 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) HighGabapentin enacarbil 2431RR 1.80 (1.51 – 2.14)33 more per 100 (21 to 48 more) Pregabalin1 44RR 1.14 (0.80 – 1.6)9 more per 100 (12 fewer to 40 more) Improvement in RLS Quality of Life LowGabapentin enacarbil 1538SMD 0.42 (0.16 to 0.69)Not reported Pregabalin1124SMD (-0.65 to -0.55)Not reported Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

21 Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at Outcome With Treatment vs. PlaceboSOE RLS Treatment Compared With Placebo No. of Trialsn Summary Statistics (95% CI) Improvement in Self-Rated Sleep Using the MOS-SPI-II Scale HighGabapentin enacarbil 2431SMD 0.53 (-0.33 to 0.72) Increase in Number of Patients With >1 Adverse Event ModerateGabapentin enacarbil 5738RR 1.09 (1.00 – 1.19) Pregabalin7195RR 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

22  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 Strength of Evidence: Low  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. Strength of Evidence: Low Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Iron Therapy Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

23  No eligible studies assessed opioids or sedative hypnotics, though these are used clinically as treatment for restless legs syndrome. Strength of Evidence: Insufficient Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at Evidence for the Benefits of Pharmacologic Interventions in Treating Restless Legs Syndrome: Opioids and Hypnotics

24  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. Strength of Evidence: Low Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at Evidence for the Benefits of Nonpharmacologic Interventions in Treating Restless Legs Syndrome (1 of 2)

25  Strength training and treadmill walking improved scores on the International Restless Legs Syndrome Rating Scale, but adherence to both types of exercise was poor. Strength of Evidence: Low  The botanical extract valerian was not effective in treating restless legs syndrome. Strength of Evidence: Low Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at Evidence for the Benefits of Nonpharmacologic Interventions in Treating Restless Legs Syndrome (2 of 2)

26  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. Strength of Evidence: Moderate  More patients randomized to dopamine agonists had at least one adverse effect when compared with those randomized to placebo. Strength of Evidence: High Evidence for the Harms of Pharmacologic Interventions in Treating Restless Legs Syndrome: Dopaminergic Agents (1 of 2) Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

27  Short-term adverse effects from dopamine agonist treatment included nausea, vomiting, somnolence, and fatigue. Strength of Evidence: High  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) Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

28  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. Strength of Evidence: High  Study withdrawals due to adverse effects was marginally greater in patients receiving alpha-2-delta ligand treatment versus placebo. Strength of Evidence: Moderate Evidence for the Harms of Pharmacologic Interventions in Treating Restless Legs Syndrome: Alpha-2-Delta Ligands Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

29  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) Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

30  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) Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

31  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) Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

32  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) Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at

33  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 and Their Caregivers Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ Comparative Effectiveness Review No. 86. Available at


Download ppt "Treatment for Restless Legs Syndrome Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov."

Similar presentations


Ads by Google