National Sleep Foundation

Chapter 7: Sleep-Related Movement Disorders

Treatment of Restless Legs Syndrome (RLS)

Treatment of Restless Legs Syndrome (RLS)

There is currently no cure for Restless Legs Syndrome (RLS). Treatment is often individualized and includes both non-pharmacological and pharmacological modalities. (When RLS is secondary to another condition, treatment of the primary condition may decrease the severity of the RLS.)

The primary medical evaluation for RLS should include a test for iron status. Low iron status is common in the general population. If serum iron values are in the low normal or abnormal range, than iron treatment should be considered within the approved limits of safety.46

Nonnpharmacological Treatment

Milder and episodic cases of RLS may be treated behaviorally, although almost no research has been done in this area. Behavioral treatments include removal of potential aggravators of RLS from the patient’s life (e.g., alcohol, caffeine, cigarettes), and discontinuation of medications that are thought to worsen RLS (e.g., antihistamines, tricyclic antidepressants, and selective serotonin reuptake inhibitors [SSRIs]).

In addition, patients are advised to engage in moderate daytime and reduced nighttime exercise, as well as relaxation techniques (e.g., warm baths, massages). Good sleep habits and stress reduction should both be encouraged. Iron supplements have been shown to improve symptoms in patients who have low serum ferritin levels.47

Pharmacological Treatment

Pharmacologic treatment may be warranted if symptoms are not improved by the non-pharmacological strategies. Recognized treatments for RLS include Alpha-2-delta ligands (α2δ), dopamine agonists, opioids, anticonvulsants, and benzodiazepines.48

Alpha-2-delta ligands (α2δ)

These are currently recommended as first line treatment for moderate-to-severe RLS to avoid the major problem of augmentation from dopaminergic treatments.  In a large comparator trial the α2δ drug was, if anything, more effective than the dopaminergic agent and lacked the high rate of augmentation seen with the dopamine drugs.49 These drugs are also used for treatment of pain, anxiety, and some epilepsy.

Gabapentin enacarbil has been approved by the U.S. Food and Drug Administration (FDA)  for treatment of RLS.50 Two other α2δ drugs are used without FDA approval to treat RLS (pregabalin and gabapentin).  Gabapentin is available in generic form and is less expensive, but has variable uptake into the blood. 

These drugs have potentially significant adverse effects, including weight gain, dizziness, and (in some rare cases) suicidal ideation.

Dopamine agonists

Dopamine receptor agonists are recommended with caution as first-line treatment for moderate-to-severe RLS. They have a major problem of producing much worse RLS with long-term use. They must be used carefully and dose increases outside of FDA-approved ranges must be avoided.51 52 

Several dopamine receptor agonists have been approved by the Food and Drug Administration (FDA) to treat RLS: Ropinirole, pramipexole, and the rotigotine patch. They are highly effective in treating RLS, probably because of they have longer half-lives and reasonable tolerability, compared with levodopa, another dopaminergic medication.53

RLS augmentation is a major problem commonly produced by these drugs, however. The RLS becomes much worse than it was prior to the individual taking medication, and RLS symptoms begin to occur throughout the day — not just in the evening or night. These drugs can also produce impulsive behaviors such as gambling and excessive shopping. Problematically, the patient often is unaware of the behavior change until serious consequences occur as a result.

Opioids

Opioids are usually used for pain management; examples include codeine, oxycodone, morphine and methadone. They are used for severe RLS and for patients who have not responded to other treatments. Opioids should be used cautiously for patients who snore and are at-risk for sleep apnea.54

Oxycodone extended release with naloxone has been approved by the European Medicines Agency for treatment of RLS that has not responded adequately to a first line treatment. 

Benzodiazepines

Benzodiazepines are a class of drugs that are used to treat anxiety, insomnia, anxiety, seizures, and muscle spasms (among other conditions). They include clonazepam, nitrazepam, lorazepam, and temazepam. The drugs’ efficacy in treating RLS is modest, however, and they are mainly used to improve sleep continuity in those with RLS.55

References

46 Wang J, O'Reilly B, Venkataraman R, Mysliwiec V, Mysliwiec A. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study. Sleep Med 2009;10:973-5.
47 Sun ER, Chen CA, Ho G, Earley CJ, Allen RP. Iron and the restless legs syndrome. Sleep. 1998;21:371-377.
48 Allen R, Picchietti D, Hening W, et al. Restless legs syndrome. Diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101-119.
49 Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med 2014;370:621-31.
50 Montplasir J, Allen RP, Walters A, Ferini-Strambi L, “Restless Legs Syndrome and Period Limb Movements During Sleep,” in Kryger M, Roth T, Dement W (ed.), Principles and Practice of Sleep Medicine (5th Edition), St. Louis: Elsevier Saunders, 2011, pages 1026 - 1037.
51 Littner MR, Kushida C, Anderson WM, et al. Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 2004;27:557-559.
52 Montplasir J, Allen RP, Walters A, Ferini-Strambi L, “Restless Legs Syndrome and Period Limb Movements During Sleep,” in Kryger M, Roth T, Dement W (ed.), Principles and Practice of Sleep Medicine (5th Edition), St. Louis: Elsevier Saunders, 2011, pages 1032 - 1034.
53 Littner MR, Kushida C, Anderson WM, et al. Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 2004;27:557-559.
54 Montplasir J, Allen RP, Walters A, Ferini-Strambi L, “Restless Legs Syndrome and Period Limb Movements During Sleep,” in Kryger M, Roth T, Dement W (ed.), Principles and Practice of Sleep Medicine (5th Edition), St. Louis: Elsevier Saunders, 2011, pages 1026 - 1037.
55 Montplasir J, Allen RP, Walters A, Ferini-Strambi L, “Restless Legs Syndrome and Period Limb Movements During Sleep,” in Kryger M, Roth T, Dement W (ed.), Principles and Practice of Sleep Medicine (5th Edition), St. Louis: Elsevier Saunders, 2011, pages 1026 - 1037.