Background: Restless leg syndrome (RLS) is a neurologic disorder characterized by unpleasant sensations in the legs causing an uncontrollable urge to move when at rest to relieve those feelings. Between 2-15% of the general population have RLS, with a higher prevalence reported in certain serious illness such as end-stage renal disease and Parkinson’s disease (1,2). Peak incidence is between 40 and 60 years of age and females are more commonly affected (1,2). RLS is associated with disrupted sleep, depression, and a decreased quality of life. This Fast Fact will review its evaluation and management.

Causes: The etiology remains incompletely understood but there are two main hypotheses based on clinical observations: a) perturbations of the dopamine system; b) decreased intracellular iron stores in the central nervous system (3). These hypotheses may explain why dopamine agonists and iron supplementation have been associated with clinical improvement in clinical studies (4).  

Symptoms and diagnosis: RLS is a clinical diagnosis for which there is not a confirmatory diagnosis. The International RLS Study Group criteria for diagnosis include a) an urge to move the legs, b) temporary relief with movement, c) onset or worsening of symptoms with rest or inactivity, and d) worsening or onset of symptoms in the evening or night (5).  Patients may describe trouble falling asleep or “a funny/crawly feeling in the legs,” but seldom will they describe these sensations as “painful”.  Symptoms can wax and wane over time and in some cases, spontaneously remit. 

Important RLS terminology:

• Patients or their bed partners may report ‘periodic limb movements of sleep (PLMS)’, which are stereotyped, repetitive flexion movements (‘jerking’) of the limbs exacerbated when patients lie down for prolonged periods. However, PLMS has not been shown to be specific to RLS (6).
• RLS symptoms can be classified as intermittent — occurring less than 2 times per week; or persistent — occurring on average two or more times weekly. 
• RLS augmentation is a recognized phenomenon in the published literature in which patients experience a paradoxical increase in RLS symptoms from dopamine agonists used to treat RLS (7).  
• RLS should be differentiated from akathisia, a constant and generalized feeling of motor restlessness often experienced as a complication from dopamine antagonists (e.g., haloperidol, metoclopramide, prochlorperazine); akathisia is not associated with leg discomfort, rest, or circadian rhythm. 

Non-pharmacologic treatment (7,8)

• Remove exacerbating factors such as sleep deprivation, alcohol, and caffeine.
• Identify medications that may be exacerbating RLS. Common culprits include first generation antihistamines (e.g., diphenhydramine), dopamine antagonists, mirtazapine, SSRIs, and SNRIs.
• Engage in behavioral interventions such as moderate regular exercise or leg massage.
• Supplement iron if fasting serum ferritin level is < 75 ng/mL or, if the patient has a comorbid inflammatory disorder, when transferring saturation is <20%.

Pharmacologic treatment is recommended for patients who have not improved despite conservative interventions or who have recurring, distressing symptoms (7).  Experts recommend that drug options be based on whether the RLS symptoms are intermittent vs persistent (9,10).

• For intermittent symptoms, options are as needed carbidopa-levodopa (12.5 mg/50 mg or 25 mg/100 mg) and/or benzodiazepines (clonazepam 0.5-2 mg/day) taken at night (10). Carbidopa-levodopa is not recommended for persistent symptoms because of the risk of augmentation.
• For persistent symptoms, both dopamine agonists (e.g., pamiprexole) and gabapentinoids (e.g., gabapentin, pregabalin) are reasonable first-line choices (10). Since head-to-head trials have demonstrated noninferiority between pregabalin 300 mg and pamiprexole 0.5 mg (12), some advocate for using gabapentinoids first line because of the lower risk of augmentation (9).  Still, patient factors should guide this decision since gabapentinoids have a high discontinuation rate due to dizziness, somnolence, fatigue, and headache (9).  Comorbidities (e.g., diabetic neuropathy, insomnia) and cost/insurance coverage are other considerations when making this decision.  In general, if the first drug chosen is ineffective, try an alternate drug class or combination therapy (9).

Other prescribing considerations: 

• Gabapentinoids: The usual effective daily dose of pregabalin ranges from 150 to 400 mg and for gabapentin 900-2400 mg. There is no evidence suggesting superiority of pregabalin or gabapentin.  Gabapentin enacarbil is a prodrug with more consistent pharmacokinetics than gabapentin; it can be considered for patients with persistent symptomatology, but it is considerably more expensive (10).
• Dopamine agonists: once considered first-line therapy (11), it is now a patient-directed decision whether to start with dopamine agonists or gabapentinoids for persistent symptoms (14). Both pramipexole and ropinirole are oral formulations that should be taken 1.5-2 hours before usual symptom onset. The usual effective daily dose of pramipexole is 0.25-0.75 mg and ropinirole 2-4 mg.  Rotigatine is a transdermal patch changed daily, usual dose is 2-3 mg (12). Common side effects for dopamine agonists are nausea, lightheadedness, and fatigue; more serious side effects are impulse control disorders, augmentation, and anxiety/depression if withdrawn abruptly.
• Cost for 30 tabs of gabapentin is ~$11, gabapentin enacarbil $500, pregabalin $16, clonazepam $10, pramipexole $12, ropinirole $12, rotigatine patch $800 (13).
• Opioids are reserved for refractory cases. Survey data suggest that methadone (median daily dose 10 mg) and oxycodone (median daily dose 15 mg) are the most prescribed opioids for RLS symptoms in the US (14,15).
• Neurostimulation techniques are an active area of investigation. Peroneal nerve stimulation may reduce RLS symptoms by activating leg muscles in a similar way as voluntary leg movements but without interfering with sleep (16). A peroneal nerve stimulation device has been FDA approved (17).

References

1. Ohayon, M. M., O’Hara, R., & Vitiello, M. V. (2012). Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep medicine reviews, 16(4), 283–295.
2. Tuna Oran, N., Yuksel, E., & Ruzgar, S. (2021). Prevalence of restless leg syndrome and effects on quality of life during pregnancy. Sleep & breathing = Schlaf & Atmung, 25(4), 2127–2134.
3. Zucconi M, Ferini-Strambi L. Epidemiology and clinical findings of restless legs syndrome. Sleep Med. 2004; 5:293-299.
4. Trotti, L. M., & Becker, L. A. (2019). Iron for the treatment of restless legs syndrome. The Cochrane database of systematic reviews, 1(1), CD007834.
5. Allen RP, Picchietti D, Hening WA, 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.
6. Coleman, R. M., Miles, L. E., Guilleminault, C. C., Zarcone, V. P., Jr, van den Hoed, J., & Dement, W. C. (1981). Sleep-wake disorders in the elderly: polysomnographic analysis. Journal of the American Geriatrics Society, 29(7), 289–29.
7. Silber MH, Ehrenberg BL, Allen RP, et al. An algorithm for the management of restless legs syndrome. Mayo Clin Proc. 2004; 79(7):916-22.
8. Aurora RN, Kristo DA, et al.  The treatment of restless legs syndrome and periodic limb movement disorder in adults – an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses. Sleep 2012; 35:1039-1062.
9. Silber, M. H., Buchfuhrer, M. J., Earley, C. J., Koo, B. B., Manconi, M., Winkelman, J. W., & Scientific and Medical Advisory Board of the Restless Legs Syndrome Foundation (2021). The Management of Restless Legs Syndrome: An Updated Algorithm. Mayo Clinic proceedings, 96(7), 1921–1937.
10. Silber, M.H. (2023). Management of restless legs syndrome and periodic limb movement disorder in adults. UpToDate. Retrieved November 7, 2023 from https://www.uptodate.com/contents/management-of-restless-legs-syndrome-and-periodic-limb-movement-disorder-in-adults?search=restless%20leg%20syndrome&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H2700116398 
11. Aurora RN, Kristo DA, et al.  The treatment of restless legs syndrome and periodic limb movement disorder in adults – an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses. Sleep 2012; 35:1039-1062.
12. Allen, R. P., Chen, C., Garcia-Borreguero, D., Polo, O., DuBrava, S., Miceli, J., Knapp, L., & Winkelman, J. W. (2014). Comparison of pregabalin with pramipexole for restless legs syndrome. The New England journal of medicine, 370(7), 621–631.
13. https://www.goodrx.com.  Last accessed November 27, 2023.
14. Winkelman, J. (2023). RLS Registry 3-Year Update. [Powerpoint presentation]. National RLS Opioid Registry. https://www.massgeneral.org/assets/mgh/pdf/rls-registry/registry-3y-update.pdf
15. Ferré S, García-Borreguero D, Allen RP, Earley CJ. New Insights into the Neurobiology of Restless Legs Syndrome. Neuroscientist. 2019 Apr;25(2):113-125
16. Charlesworth, J. D., Adlou, B., Singh, H., & Buchfuhrer, M. J. (2023). Bilateral high-frequency noninvasive peroneal nerve stimulation evokes tonic leg muscle activation for sleep-compatible reduction of restless legs syndrome symptoms. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 19(7), 1199–1209. https://doi.org/10.5664/jcsm.10536
17. Bogan, R. K., Roy, A., Kram, J., Ojile, J., Rosenberg, R., Hudson, J. D., Scheuller, H. S., Winkelman, J. W., & Charlesworth, J. D. (2023). Efficacy and safety of tonic motor activation (TOMAC) for medication-refractory restless legs syndrome: a randomized clinical trial. Sleep, 46(10), zsad190.

Author Affiliations:  University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Version History: Originally electronically published in July 2009; copy-re-edited by Sean Marks MD in August 2015; major revision occurred in December 2023 by Kendall Downer MD.