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Treatment Options for Restless Legs Syndrome

By: Svetlana Akbasheva, Staff Editor

      Restless Legs Syndrome (RLS or Willis-Ekbom disease) is a condition that affects an estimated 2 to 3% of adults in the United States.1 Patients with RLS experience a strong urge to move the legs, which is more prevalent at rest and is usually alleviated by physical movement. Symptoms commonly occur in the evening, although patients with more severe disease may experience daytime symptoms as well.2 RLS has been seen in all age groups and it appears to affect women more than men.1

RLS can be primary or secondary in nature. Primary, or idiopathic, RLS has no known cause or comorbidities that may be contributing to the patient’s symptoms. On the other hand, secondary RLS is linked to certain medical conditions, such as iron deficiency, pregnancy, or chronic renal failure.3 Over half of RLS patients have a family history of the condition, which suggests a genetic basis in some cases. Although it is hypothesized that transmission may be autosomal dominant, the genetics are very complex and a clear mode of inheritance has not yet been established.2 The definite pathology of RLS is unclear but is thought to involve the dopaminergic system as well as CNS iron levels.3 Recent research has also shown the possibility of a link between RLS and vitamin D deficiency, and there was a case in which correcting vitamin B12 deficiency in an elderly patient led to complete relief from RLS symptoms.3,4

All patients experiencing RLS symptoms should be screened for iron deficiency, and those who exhibit low ferritin levels should be treated with oral or parenteral iron supplementation. Oral iron replacement consists of 50 to 60 mg of elemental iron (as a ferrous salt) twice daily, administered with vitamin C to increase absorption.2 However, unpleasant gastrointestinal side effects of oral supplementation, including nausea, constipation, and abdominal pain, are a limitation of this route.2 If parenteral iron replacement is chosen instead, the lower molecular weight formulation of iron dextran should be chosen to avoid hypersensitivity reactions.5

Up to 25% of pregnant women may experience symptoms of RLS, particularly in the third trimester, but these symptoms should abate soon after delivery.6 Chronic renal failure patients on dialysis have also been shown to be more likely to develop RLS. The ideal way to treat RLS in these cases is through a kidney transplant; however, until this is feasible, patients are treated similarly to primary RLS patients.2

There are also certain medications that can cause or exacerbate RLS. The major class is the antidepressants, including tricyclic antidepressants, SSRIs, and SNRIs.2 Physicians whose patients are experiencing RLS symptoms are encouraged to discontinue these medications and try bupropion instead, which has not been associated with RLS.2 Other medications to avoid include dopamine antagonists such as metoclopramide, as the dopaminergic system is implicated in the pathology of RLS.2 Antihistamines and antiemetics have also been shown to contribute to RLS and should be avoided.5

Patients presenting with RLS should be screened for the presence of secondary causes, including medication-induced RLS.2 Patients with minimal intermittent symptoms may be controlled with non-pharmacologic therapy alone. Mild RLS may be alleviated with physical activity, since symptoms typically appear at rest.5 There is limited evidence that avoiding alcohol, nicotine, and caffeine may help as well.5

For patients with moderate to severe primary RLS, the first line of treatment is usually a dopamine agonist. The three dopamine agonists that are currently FDA-approved for RLS are pramipexole, ropinirole, and rotigotine.2 Factors to consider when choosing between pramipexole and ropinirole are differences in half-lives and metabolism. Pramipexole has a shorter duration of action, with a half-life of 6 hours compared to up to 12 hours for ropinirole. In addition, pramipexole is renally eliminated, while ropinirole undergoes hepatic metabolism.5 Rotigotine is unique in that it comes as a 24-hour transdermal patch that delivers a constant plasma level of the medication.7 Thus, it is especially beneficial for patients who experience daytime or unpredictable RLS symptoms. As expected, the most common adverse effect with the patch is application-site reactions.7 Adverse effects for with all of the dopaminergic agents are daytime drowsiness and behaviors associated with the loss of impulse control, such as gambling and hypersexuality.2

A report from the International Restless Legs Syndrome Study Group stated that there was evidence for the efficacy of the dopamine agonists, lasting for six months, in RLS.8 In addition, pramipexole and ropinirole are probably effective for up to one year, while rotigotine may be efficacious for up to five years.8 However, a major problem with the dopamine agonists is the development of augmentation with chronic use. Augmentation is a phenomenon that was first observed with the use of levodopa for Parkinson’s disease and which has since become associated with dopamine agonists as a class. After long-term use of these agents, not only do the medications lose efficacy, but patients’ symptoms can actually become more severe than they were prior to dopamine agonist therapy.7 To avoid or at least delay this phenomenon, dopamine agonists should be used at the lowest effective dose.7

Another class of medications that is considered first-line therapy for RLS is the alpha-2-delta ligands, which include gabapentin, gabapentin enacarbil, and pregabalin. Of the three, only gabapentin enacarbil (Horizant®) is FDA-approved for RLS.2 A disadvantage of gabapentin is its unpredictable kinetics; the active drug has saturable absorption and levels of the drug transporter are inconsistent among the population, which causes the same dose to exhibit different plasma levels among individuals.1 To remedy this issue, the prodrug gabapentin enacarbil was developed, which is well absorbed and produces consistent plasma gabapentin levels. It is important to note that due to these pharmacokinetic differences, gabapentin and gabapentin enacarbil are not interchangeable, as the same dose of each may not produce equivalent plasma levels.1

The increased popularity of pregabalin for RLS may be due to its efficacy in improving sleep in RLS patients. A major complaint among RLS patients is the inability to sleep well at night, which can impinge on other aspects of their lives as well.9 A double-blinded, randomized crossover study comparing the effects of pregabalin versus pramipexole on sleep length and quality in RLS patients found that although the occurrence of periodic limb movements (PLM) was reduced with pramipexole, this did not necessarily translate to improved sleep quality, as patients experienced greater subjective total sleep time and fewer awakenings with pregabalin than pramipexole.9 Pramipexole and pregabalin also differ in their side effect profile, which can influence treatment decisions. Pramipexole is associated with more headache, nausea, and vomiting, while pregabalin may cause somnolence, weight gain, and suicidal ideation.10

When one agent is not effective, a combination of a dopaminergic agent and an alpha-2-delta ligand may be used.5 Additional medications are also an option for patients refractive to the first-line therapies or who need add-on agents for their symptoms. Opioid compounds can be used as needed for breakthrough symptoms throughout the day; however, these medications are not routinely used due to the risk of addiction.2,5 Clonazepam may also be useful for patients who have trouble sleeping.2 However, its long half-life may lead to next-day sedation; shorter-acting zolpidem or eszopiclone may be a better option.5

It is important to remember that Restless Legs Syndrome is a condition that has a profound impact on patients’ quality of life. When the 36-Item Short Form health survey (SF-36) was used to assess the subjective impact of RLS, these patients’ scores were significantly worse than the general population’s in the assessment of general health, physical functioning, and bodily pain; mental health scores were also lower.6 Despite the currently available therapies, not all patients experience relief and there is still ongoing research into the best treatment options for these patients. Newer therapies may be available in the coming years as the underlying cause of RLS is better understood.



  1. Kume A. Gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (Willis-Ekbom disease): 600 or 1,200 mg dose? Neuropsychiatr Dis Treat. 2014;10:249-62.
  2. Comella CL. Treatment of restless legs syndrome. Neurotherapeutics. 2014;11(1):177-87.
  3. Oran M, Unsal C, Albayrak Y, et al. Possible association between vitamin D deficiency and restless legs syndrome. Neuropsychiatr Dis Treat. 2014;21(10):953-8.
  4. O’Keeffe ST, Noel J, Lavan JN. Restless legs syndrome in the elderly. Postgrad Med J. 1993;69(815):701-703. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2399773/. Accessed January 24, 2015.
  5. Buchfuhrer MJ. Strategies for the treatment of restless legs syndrome. Neurotherapeutics. 2012;9(4):776-90.
  6. Sethi KD, Mehta SH. A clinical primer on restless legs syndrome: what we know, and what we don’t know. Am J Manag Care. 2012;18(5 Suppl):S83-8. http://www.ncbi.nlm.nih.gov.jerome.stjohns.edu:81/pubmed/23009275. Accessed January 24, 2015.
  7. Bogan RK. From bench to bedside: An overview of rotigotine for the treatment of restless legs syndrome. Clin Ther. 2014;36(3):436-55.
  8. Garcia-Borreguero D, Kohnen R, Silber MH, et al. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidelines: a report from the International Restless Legs Syndrome Study Group. Sleep Medicine. 2013;14(7):675-684.
  9. Garcia-Borreguero D, Patrick J, DuBrava S, Becker PM, et al. Pregabalin Versus Pramipexole: Effects on Sleep Disturbance in Restless Legs Syndrome. Sleep. 2014;37(4):635-43.
  10. Allen, RP, Chen C, Garcia-Borreguero, D, et al. Comparison of Pregabalin with Pramipexole for Restless Legs Syndrome. N Engl J Med. 2014;370(7):621-31.

[pubmed_related keyword1=”restless” keyword2=”legs” keyword3=”syndrome”]

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