Restless Legs Syndrome Medication
- Author: Ali M Bozorg, MD; Chief Editor: Selim R Benbadis, MD more...
Medications used in the treatment of restless legs syndrome (RLS) include the following:
Alpha 2 -adrenergic agonists
Antiparkinson Agents, Dopamine Agonists
Dopamine agonists may improve sensory symptoms associated with RLS. Agents such as pramipexole, ropinirole, and bromocriptine are less likely to produce augmentation or rebound than the combination of levodopa and carbidopa is. These agents can be used alone or along with levodopa.
Pramipexole is a dopamine D2- and D3-receptor agonist that has been approved by the US Food and Drug Administration (FDA) for the treatment of Parkinson disease. It is also used effectively in patients with RLS.
Ropinirole is a dopamine D2-receptor agonist that has been approved by the FDA for the treatment of Parkinson disease. It has also has been used in patients with RLS. Ropinirole is a nonergoline, nonphenolic indolone derivative.
Levodopa with carbidopa can improve sensory symptoms and periodic leg movements of sleep (PLMS) in primary RLS and in secondary RLS due to uremia. Most patients experience benefits with doses of 25/100 mg (in mild cases), with a maximum dosage of 50/200 mg/day.
Dosages higher than 50/200 mg/day are accompanied by marked augmentation of symptoms in 85% of patients. Adjunctive therapy with reduction of levodopa dose or discontinuance of levodopa and substitution with a dopamine agonist drug may help. Sinemet is preferred for patients with occasional and mild symptoms.
Bromocriptine mesylate is a dopamine D2-receptor agonist that has been found to be effective in RLS. However, it is usually poorly tolerated because of nausea and orthostatic hypotension. Other dopamine agonists, such pramipexole, are preferred.
Rotigotine is a dopamine agonist stimulating D3, D2, and D1 receptors. It is indicated for treatment of moderate-to-severe primary RLS. It is available as a transdermal patch that provides continuous delivery for 24 hours.
A benzodiazepine may be used as monotherapy in patients with mild or intermittent symptoms of RLS or as a component of combination therapy in severe cases. Clonazepam has been shown to ease sensory symptoms and PLMS in RLS. Other benzodiazepines, such as temazepam and alprazolam, also can be effective.
No controlled trials have demonstrated that clonazepam or any other gamma-aminobutyric acid (GABA)-ergic sedative hypnotic actually reduces the symptoms of RLS. Clonazepam's therapeutic benefit appears to arise from sleep-promoting properties that allow the patient to continue to sleep despite disturbances from RLS symptoms.
Low-potency opioids (eg, codeine) can benefit patients with mild and intermittent symptoms; higher-potency agents (eg, oxycodone hydrochloride, methadone hydrochloride, and levorphanol tartrate), may have a role in refractory cases. Because of the risk of addiction, these drugs should be used with caution; their use usually is recommended only in refractory cases, especially in ones with a prominent pain component.
Codeine and other opioids can be helpful in decreasing the symptoms of RLS, serving as a treatment of second choice when other treatments have failed or have caused augmentation problems.
Anticonvulsants are being used more frequently for the treatment of moderate-to-severe RLS. They are particularly helpful in patients with a strong neuropathic symptom component or with comorbid neuropathy.
A prodrug of gabapentin, gabapentin enacarbil, has been approved by the FDA. In a randomized, placebo-controlled study, 600 mg orally, taken once daily at 5 PM, provided sustained gabapentin exposure and maintained improvements in RLS symptoms in comparison with placebo.
Gabapentin is indicated for patients whose symptoms include pain, neuropathy, or both. It may be used as a single treatment or with other treatments.
Pregabalin binds with high affinity to the alpha2-delta site (a calcium channel subunit). Its mechanism of action is unknown. In vitro, pregabalin reduces the calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. This agent is FDA-approved for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures. It is not FDA-approved for the treatment of RLS.
Presynaptic alpha2 -adrenergic agents stimulate alpha2 adrenoreceptors in the brainstem, activating an inhibitory neuron, which in turn results in reduced sympathetic outflow.
Clonidine hydrochloride may be effective in primary RLS, as well as in RLS associated with uremia. However, it has no effect on PLMS.
Iron salt is used to correct iron deficiency resulting from chronic hemodialysis.
Iron sucrose is used to treat iron deficiency (in conjunction with erythropoietin) due to chronic hemodialysis. Iron sucrose has shown a lower incidence of anaphylaxis than other parenteral iron products. Parenteral iron sucrose has also been shown to improve symptoms of RLS in patients with RLS and low ferritin levels. Parenteral iron sucrose is not FDA-approved for the treatment of RLS.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. 5th. Arlington, VA: American Psychiatric Association; 2013. 410-3.
Krueger BR. Restless legs syndrome and periodic movements of sleep. Mayo Clin Proc. 1990 Jul. 65(7):999-1006. [Medline].
Gamaldo CE, Earley CJ. Restless legs syndrome: a clinical update. Chest. 2006 Nov. 130(5):1596-604. [Medline].
Hening WA. Restless Legs Syndrome. Curr Treat Options Neurol. 1999 Sep. 1(4):309-319. [Medline].
Ferreri F, Rossini PM. Neurophysiological investigations in restless legs syndrome and other disorders of movement during sleep. Sleep Med. 2004 Jul. 5(4):397-9. [Medline].
Restless legs syndrome. detection and management in primary care. National Heart, Lung, and Blood Institute Working Group on Restless Legs Syndrome. Am Fam Phys. 2000 Jul 1. 62(1):108-14. [Medline].
Evidente VG, Adler CH. How to help patients with restless legs syndrome. Discerning the indescribable and relaxing the restless. Postgrad Med. 1999 Mar. 105(3):59-61, 65-6, 73-4. [Medline].
Silber MH. Restless legs syndrome. Mayo Clin Proc. 1997 Mar. 72(3):261-4. [Medline].
Takaki J, Nishi T, Nangaku M, et al. Clinical and psychological aspects of restless legs syndrome in uremic patients on hemodialysis. Am J Kidney Dis. 2003 Apr. 41(4):833-9. [Medline].
Walters AS, LeBrocq C, Dhar A, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 2003 Mar. 4(2):121-32. [Medline].
Weinstock LB, Walters AS, Paueksakon P. Restless legs syndrome - Theoretical roles of inflammatory and immune mechanisms. Sleep Med Rev. 2012 Jan 16. [Medline].
Winkelman JW. Considering the causes of RLS. Eur J Neurol. 2006 Oct. 13 Suppl 3:8-14. [Medline].
Allen RP, Earley CJ. Restless legs syndrome: a review of clinical and pathophysiologic features. J Clin Neurophysiol. 2001 Mar. 18(2):128-47. [Medline].
Jhoo JH, Yoon IY, Kim YK, Chung S, Kim JM, Lee SB. Availability of brain serotonin transporters in patients with restless legs syndrome. Neurology. 2010 Feb 9. 74(6):513-8. [Medline].
Trenkwalder C, Hogl B, Winkelmann J. Recent advances in the diagnosis, genetics and treatment of restless legs syndrome. J Neurol. 2009 Apr. 256(4):539-53. [Medline].
Cesnik E, Casetta I, Turri M, Govoni V, Granieri E, Strambi LF, et al. Transient RLS during pregnancy is a risk factor for the chronic idiopathic form. Neurology. 2010 Dec 7. 75(23):2117-20. [Medline].
Berger K, Luedemann J, Trenkwalder C, et al. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med. 2004 Jan 26. 164(2):196-202. [Medline].
Kutner NG, Zhang R, Huang Y, Bliwise DL. Racial differences in restless legs symptoms and serum ferritin in an incident dialysis patient cohort. Int Urol Nephrol. 2012 Jan 5. [Medline].
Abetz L, Allen R, Follet A, et al. Evaluating the quality of life of patients with restless legs syndrome. Clin Ther. 2004 Jun. 26(6):925-35. [Medline].
Ekbom K, Ulfberg J. Restless legs syndrome. J Intern Med. 2009 Nov. 266(5):419-31. [Medline].
Simakajornboon N, Kheirandish-Gozal L, Gozal D. Diagnosis and management of restless legs syndrome in children. Sleep Med Rev. 2009 Apr. 13(2):149-56. [Medline].
Kotagal S, Silber MH. Childhood-onset restless legs syndrome. Ann Neurol. 2004 Dec. 56(6):803-7. [Medline].
Lane RM. SSRI-induced extrapyramidal side-effects and akathisia: implications for treatment. J Psychopharmacol. 1998. 12(2):192-214. [Medline].
Hattan E, Chalk C, Postuma RB. Is there a higher risk of restless legs syndrome in peripheral neuropathy?. Neurology. 2009 Mar 17. 72(11):955-60. [Medline].
Montplaisir J, Nicolas A, Denesle R. Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology. 1999 Mar 23. 52(5):938-43. [Medline].
Ondo W. Ropinirole for restless legs syndrome. Mov Disord. 1999 Jan. 14(1):138-40. [Medline].
Giorgi L, Asgharian A, Hunter B. Ropinirole in Patients With Restless Legs Syndrome and Baseline IRLS Total Scores =24: Efficacy and Tolerability in a 26-Week, Double-Blind, Parallel-Group, Placebo-Controlled Study Followed by a 40-Week Open-Label Extension. Clin Ther. 2013 Aug 9. [Medline].
Baldwin CM, Keating GM. Rotigotine transdermal patch: in restless legs syndrome. CNS Drugs. 2008. 22(10):797-806. [Medline].
Bogan RK, Bornemann MA, Kushida CA, Trân PV, Barrett RW. Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study. Mayo Clin Proc. 2010 Jun. 85(6):512-21. [Medline]. [Full Text].
Garcia-Borreguero D, Kohnen R, Silber MH, Winkelman JW, Earley CJ, Högl B, et al. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Med. 2013 Jul. 14(7):675-84. [Medline].
Grote L, Leissner L, Hedner J, Ulfberg J. A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Mov Disord. 2009 Jul 30. 24(10):1445-52. [Medline].
Shinno H, Yamanaka M, Ishikawa I, Danjo S, Nakamura Y, Inami Y. Successful treatment of restless legs syndrome with the herbal prescription Yokukansan. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Feb 1. 34(1):252-3. [Medline].
Oscroft NS, Smith IE. Oral glucocorticosteroids: effective in a case of restless legs syndrome resistant to other therapies. Sleep Med. 2010 Jun. 11(6):596. [Medline].
Giannaki CD, Hadjigeorgiou GM, Karatzaferi C, Maridaki MD, Koutedakis Y, Founta P, et al. A single-blind randomized controlled trial to evaluate the effect of 6 months of progressive aerobic exercise training in patients with uraemic restless legs syndrome. Nephrol Dial Transplant. 2013 Aug 8. [Medline].
Anderson P. Restless Legs Syndrome Linked to Higher Mortality. Available at http://www.medscape.com/viewarticle/805712. Accessed: Jun 19 2013.
Li Y, Wang W, Winkelman JW, Malhotra A, Ma J, Gao X. Prospective study of restless legs syndrome and mortality among men. Neurology. 2013 Jun 12. [Medline].
Jeffrey S. FDA Okays First Device for Restless Legs Syndrome. Medscape Medical News. May 30 2014. [Full Text].