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[EXCERPTS]

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

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. Augmentation is usually considered as resolved when the medication triggering augmentation has been discontinued or when the patient has been switched to another medication.

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

Evidence of Benefits

Dopamine agonists (ropinirole, pramipexole, and rotigotine)

When compared with placebo, dopamine agonists:

• Increased the percentage of patients with a clinically important response* [High strength of evidence]
• Reduced RLS symptoms [High strength of evidence]
• Improved RLS quality of life [High strength of evidence]
• Improved patient-reported sleep outcomes [High strength of evidence]

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

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

• Increased the percentage of patients with a clinically important response* [High strength of evidence]
• Improved RLS quality of life [Low strength of evidence]
• Improved patient-reported sleep outcomes [Low strength of evidence]

Gabapentin enacarbil also improved sleep adequacy based on the sleep adequacy domain of the MOS-SPI-II Scale. [High strength of evidence]

Iron therapy

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

• Slightly improved symptom scores on the IRLS Rating Scale [Moderate strength of evidence]
• Slightly improved RLS quality of life [Moderate strength of evidence]
• Slightly improved patient-reported sleep outcomes [Low strength of evidence]

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.** [Low strength of evidence]

Opioids and hypnotics

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

Nonpharmacologic interventions

• Pneumatic compression devices reduced IRLS Rating Scale symptom scores more than sham. [Moderate strength of evidence]
• Near-infrared light treatment improved IRLS Rating Scale symptom, scores more than sham. [Low strength of evidence]
• Strength training and treadmill walking improved IRLS symptoms but adherence was poor. [Low strength of evidence]
• The botanical extract valerian was not effective in treating RLS. [Low strength of evidence]

Evidence of Harms

Dopamine agonists (ropinirole, pramipexole, and rotigotine)

Dopamine agonists were associated with more adverse effects than placebo.

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

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

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

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

• More patients randomized to alpha-2-delta ligands had at least one adverse effect when compared with placebo. [Moderate strength of evidence]
• Somnolence, unsteadiness or dizziness, and dry mouth were much more common with alpha-2-delta ligands than with placebo. [High strength of evidence]
• Study withdrawals (due to any reason) were less common with alpha-2-delta ligands than with placebo. [High strength of evidence]

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

Moderate: 
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: 
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 is either unavailable or does not permit a conclusion.

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