Treatment for Restless Legs Syndrome

1
Treatment for Restless Legs Syndrome

• Prepared for
• Agency for Healthcare Research and Quality (AHRQ)
• www.ahrq.gov

2
Outline of Material

• 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

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

3
Background What Is Restless Legs Syndrome?

• 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

• Allen RP, Picchietti D, Hening WA, et al. Sleep
  Med. 2003 Mar4(2)101-19. PMID 14592341.
• Trenkwalder C, Paulus W. Nat Rev Neurol. 2010
  Jun6(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/rest
  less-legs.cfm.

4
Background Prevalence and Etiology of Restless
Legs Syndrome

• 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.

• Allen RP, Picchietti D, Hening WA, et al. Sleep
  Med. 2003 Mar4(2)101-19. PMID 14592341.
• García-Borreguero D, Egatz R, Winkelmann J, et
  al. Sleep Med Rev. 2006 Jun10(3)153-67. PMID
  16762806.
• Trenkwalder C, Paulus W. Nature Rev Neurol. 2010
  Jun6(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/rest
  less-legs.cfm.

5
Background Severity and Clinical Course of
Restless Legs Syndrome

• 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
  1120 is considered moderate RLS, a score of
  2130 is considered severe RLS, and a score gt30
  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.

• Trenkwalder C, Paulus W. Nat Rev Neurol. 2010
  Jun6(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/rest
  less-legs.cfm.

6
Background Currently Available Treatment Options
for Restless Legs Syndrome (1 of 2)

• 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.

• Silber MH, Ehrenberg BL, Allen RP, et al. Mayo
  Clin Proc. 2004 Jul79(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/rest
  less-legs.cfm.

7
Background Currently Available Treatment Options
for Restless Legs Syndrome (2 of 2)

• 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

• Silber MH, Ehrenberg BL, Allen RP, et al. Mayo
  Clin Proc. 2004 Jul79(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/rest
  less-legs.cfm.

8
Background Restless Legs Syndrome Treatment and
Augmentation

• 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

• Allen RP, Adler CH, Du W, et al. Sleep Med. 2011
  May12(5)431-9. PMID 21493132.
• Garcia-Borreguero D, Hogl B, Ferini-Strambi L, et
  al. Mov Disord. 2012 Feb27(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/rest
  less-legs.cfm.

9
Background Uncertainties Related to the
Treatment of Restless Legs Syndrome

• 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 RLSparticularly in patients with
  mild disease and in older adults and childrenare
  unclear.

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

10
Agency for Healthcare Research and Quality (AHRQ)
Comparative Effectiveness Review (CER) Development

• 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/

Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ
Comparative Effectiveness Review No.
86. Available at www.effectivehealthcare.ahrq.gov/
restless-legs.cfm.
11
Clinical Questions Addressed by This Comparative
Effectiveness Review (1 of 3)

• Key Question 1. What is the comparative
  effectiveness of treatments for restless legs
  syndrome (RLS)?
• What are the benefits from RLS treatments when
  compared with placebo or no treatment?
• What are the benefits from RLS treatments when
  compared with other active treatments?
• What are the durability and

Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ
Comparative Effectiveness Review No.
86. Available at www.effectivehealthcare.ahrq.gov/
restless-legs.cfm.
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?
• What are the harms from RLS treatments when
  compared with placebo or no treatment?
• What are the harms from RLS treatments when
  compared with other active treatments?
• 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 www.effectivehealthcare.ahrq.gov/
restless-legs.cfm.
13
Clinical Questions Addressed by This Comparative
Effectiveness Review (3 of 3)

• 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?

Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ
Comparative Effectiveness Review No.
86. Available at www.effectivehealthcare.ahrq.gov/
restless-legs.cfm.
14
Rating the Strength of Evidence From the
Comparative Effectiveness Review

• The strength of evidence was classified into four
  broad categories

High Further research is very unlikely to change the confidence in the estimate of effect.
Moderate Further research may change the confidence in the estimate of effect and may change the estimate.
Low Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.
Insufficient Evidence either is unavailable or does not permit a conclusion.
Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ
Comparative Effectiveness Review No.
86. Available at www.effectivehealthcare.ahrq.gov/
restless-legs.cfm.
15
Pharmacologic Therapies for Restless Legs
Syndrome Assessed in This Review
Treatment Generic Name Brand Name FDA Approval for RLS
Dopaminergic agents Levodopa Dopar No
Dopaminergic agents Ropinirole Requip Yes
Dopaminergic agents Pramipexole Mirapex Yes
Dopaminergic agents Rotigotine patch Neupro Yes
Anticonvulsants (alpha-2-delta ligands) Gabapentin enacarbil Horizant Yes
Anticonvulsants (alpha-2-delta ligands) Gabapentin Neurontin No
Anticonvulsants (alpha-2-delta ligands) 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. 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. 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. 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/restl
  ess-legs.cfm.

16
Evidence for the Benefits of Pharmacologic
Interventions in Treating Restless Legs Syndrome
Dopaminergic Agents

• 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

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.
17
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 (gt50 score reduction) High Pramipexole 3 1,079 RR 1.46 (1.221.74) 21 more per 100 (10 to 34 more)
Increase in IRLS Rating Scale Responders (gt50 score reduction) High Rotigotine 4 1,139 RR 1.76 (1.472.100) 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 RR 1.61 (1.41.86) 25 more per 100 (17 to 36 more)
Increase in Clinical Global Impressions Scale Responders (much or very much improved) High Ropinirole 6 1,608 RR 1.37 (1.251.50) 18 more per 100 (12 to 24 more)
Increase in Clinical Global Impressions Scale Responders (much or very much improved) High Rotigotine 4 1,091 RR 1.37 (1.221.54) 19 more per 100 (12 to 28 more)
Improvement in Patient-Reported RLS Quality of Life High Pramipexole 3 912 SMD -0.43 (-0.61 to -0.25) Not reported
Improvement in Patient-Reported RLS Quality of Life High Ropinirole 2 643 SMD -0.30 (-0.45 to -0.25) Not reported
Improvement in Patient-Reported RLS Quality of Life High Rotigotine 4 585 SMD -0.37 (-0.60 to - 0.13) Not reported

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

18
Outcomes and Strength of Evidence in
Placebo-Controlled Studies of Dopamine Agonists
(2 of 2)
Outcome With Treatment vs. Placebo SOE RLS Treatment Compared With Placebo No. 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)
Improvement in Patient Self-Rated Sleep Using the MOS-SPI-II Scale High Ropinirole 4 1,237 SMD -0.37 (-0.24 to -0.49)
Improvement in Patient Self-Rated Sleep Using the MOS-SPI-II Scale High 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 (0.691.35)
Increase in Study Withdrawals Due to an Adverse Event Moderate Ropinirole 7 1,698 RR 1.48 (0.992.20)
Increase in Study Withdrawals Due to an Adverse Event Moderate Rotigotine 4 1,370 RR 1.37 (1.334.70)
Increase in Number of Patients With gt1 Adverse Event High Pramipexole 5 1,790 RR 1.16 (1.041.29)
Increase in Number of Patients With gt1 Adverse Event High Ropinirole 7 1,695 RR 1.20 (1.101.32)
Increase in Number of Patients With gt1 Adverse Event High Rotigotine 4 1,369 RR 1.25 (1.001.59)

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

19
Evidence for the Benefits of Pharmacologic
Interventions in Treating Restless Legs Syndrome
Alpha-2-Delta Ligands

• 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

Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ
Comparative Effectiveness Review No.
86. Available at www.effectivehealthcare.ahrq.gov/
restless-legs.cfm.
20
Outcomes and Strength of Evidence in
Placebo-Controlled Studies of Alpha-2-Delta
Ligands (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 (gt50 score reduction) High Gabapentin enacarbil 1 321 RR 1.54 (1.182.01) 21 more per 100 (7 to 40 more)
Increase in IRLS Rating Scale Responders (gt50 score reduction) High Pregabalin 2 182 RR 2.03 (1.333.11) 34 more per 100 (11 to 69 more)
Increase in Clinical Global Impressions Scale Responders (muchvery much improved) High Gabapentin enacarbil 2 431 RR 1.80 (1.512.14) 33 more per 100 (21 to 48 more)
Increase in Clinical Global Impressions Scale Responders (muchvery much improved) High Pregabalin 1 44 RR 1.14 (0.801.6) 9 more per 100 (12 fewer to 40 more)
Improvement in RLS Quality of Life Low Gabapentin enacarbil 1 538 SMD 0.42 (0.16 to 0.69) Not reported
Improvement in RLS Quality of Life Low Pregabalin 1 124 SMD -0.05 (-0.65 to -0.55) Not reported

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

21
Outcomes and Strength of Evidence in
Placebo-Controlled Studies of Alpha-2-Delta
Ligands (2 of 2)
Outcome With Treatment vs. Placebo SOE RLS Treatment Compared With Placebo No. of Trials n 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 gt1 Adverse Event Moderate Gabapentin enacarbil 5 738 RR 1.09 (1.001.19)
Increase in Number of Patients With gt1 Adverse Event Moderate Pregabalin 7 195 RR 1.67 (0.743.80)
Abbreviations 95 CI 95-percent confidence
interval MOS-SPI-II Medical Outcomes
ScaleSleep Problems Index II RR relative
risk SMD standardized mean difference SOE
strength of evidence

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

22
Evidence for the Benefits of Pharmacologic
Interventions in Treating Restless Legs Syndrome
Iron Therapy

• 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

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

23
Evidence for the Benefits of Pharmacologic
Interventions in Treating Restless Legs Syndrome
Opioids and Hypnotics

• 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 www.effectivehealthcare.ahrq.gov/rest
  less-legs.cfm.

24
Evidence for the Benefits of Nonpharmacologic
Interventions in Treating Restless Legs Syndrome
(1 of 2)

• 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 www.effectivehealthcare.ahrq.gov/rest
  less-legs.cfm.

25
Evidence for the Benefits of Nonpharmacologic
Interventions in Treating Restless Legs Syndrome
(2 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.
• 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 www.effectivehealthcare.ahrq.gov/rest
  less-legs.cfm.

26
Evidence for the Harms of Pharmacologic
Interventions in Treating Restless Legs Syndrome
Dopaminergic Agents (1 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.
• 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

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

27
Evidence for the Harms of Pharmacologic
Interventions in Treating Restless Legs
Syndrome Dopaminergic Agents (2 of 2)

• 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.

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

28
Evidence for the Harms of Pharmacologic
Interventions in Treating Restless Legs Syndrome
Alpha-2-Delta Ligands

• 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

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

29
Conclusions (1 of 2)

• 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).

Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ
Comparative Effectiveness Review No.
86. Available at www.effectivehealthcare.ahrq.gov/
restless-legs.cfm.
30
Conclusions (2 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.

Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ
Comparative Effectiveness Review No.
86. Available at www.effectivehealthcare.ahrq.gov/
restless-legs.cfm.
31
Gaps in Knowledge (1 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.

Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ
Comparative Effectiveness Review No.
86. Available at www.effectivehealthcare.ahrq.gov/
restless-legs.cfm.
32
Gaps in Knowledge (2 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.

Wilt TJ, MacDonald R, Ouellette J, et al. AHRQ
Comparative Effectiveness Review No.
86. Available at www.effectivehealthcare.ahrq.gov/
restless-legs.cfm.
33
What To Discuss With Your Patients andTheir
Caregivers

• 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.

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