Skip to main content
Log in

Therapeutic Utility of Opioids for Restless Legs Syndrome

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Restless legs syndrome (RLS) is a sensorimotor neurologic disorder characterized by an unpleasant urge to move the legs, often accompanied by leg dysesthesias. Symptoms predominate in the evening or at night and often cause significant distress and disruption of sleep. Several non-opioid classes of drugs provide initial relief from the symptoms of RLS. Among these, however, the efficacy of dopamine agonists can wane over time or even paradoxically ‘augment’ the severity of symptoms during the course of long-term treatment. Opioids can alleviate RLS symptoms, even in patients who have become refractory to, or do not tolerate, other drugs. In a carefully selected group of patients with severe RLS that has not been effectively managed with other therapies, opioids may be an appropriate treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med. 2003;349(20):1943–53.

    Article  CAS  PubMed  Google Scholar 

  2. Franklin GM, American Academy of Neurology. Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology. Neurology. 2014;83(14):1277–84.

    Article  CAS  PubMed  Google Scholar 

  3. Chou R, Fanciullo GJ, Fine PG, Adler JA, Ballantyne JC, Davies P, Donovan MI, Fishbain DA, Foley KM, Fudin J, Gilson AM, Kelter A, Mauskop A, O'Connor PG, Passik SD, Pasternak GW, Portenoy RK, Rich BA, Roberts RG, Todd KH, Miaskowski C, American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Noble M, Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010;1:CD006605.

    Google Scholar 

  5. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. JAMA. 2016;315(15):1624–45.

    Article  CAS  PubMed  Google Scholar 

  6. Allen RP, Picchietti DL, García-Borreguero D, Ondo WG, Walters AS, Winkelman JW, et al. RLS/Willis–Ekbom disease diagnostic criteria: updated International RLS Study Group (IRLSSG) consensus criteria–history, rationale, description, and significance. Sleep Med. 2014;15(8):860–73.

    Article  PubMed  Google Scholar 

  7. Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, et al. RLS prevalence and impact: REST general population study. Arch Intern Med. 2005;165(11):1286–92.

    Article  PubMed  Google Scholar 

  8. Prosperetti C, Manconi M. RLS/Willis–Ekbom disease and pregnancy. Sleep Med Clin. 2015;10(3):323–9 (xiv).

    Article  PubMed  Google Scholar 

  9. Lin Z, Zhao C, Luo Q, Xia X, Yu X, Huang F. Prevalence of RLS in chronic kidney disease: a systematic review and meta-analysis of observational studies. Ren Fail. 2016;38(9):1335–46.

    Article  PubMed  Google Scholar 

  10. Allen RP, Auerbach S, Bahrain H, Auerbach M, Earley CJ. The prevalence and impact of RLS on patients with iron deficiency anemia. Am J Hematol. 2013;88(4):261–4.

    Article  PubMed  Google Scholar 

  11. Cuellar NG, Ratcliffe SJ. RLS in type 2 diabetes: implications to diabetes educators. Diabetes Educ. 2008;34(2):218–34.

    Article  PubMed  Google Scholar 

  12. Phillips B, Young T, Finn L, Asher K, Hening WA, Purvis C. Epidemiology of restless legs symptoms in adults. Arch Intern Med. 2000;160(14):2137–41.

    Article  CAS  PubMed  Google Scholar 

  13. García-Borreguero D, Kohnen R, Silber MH, Winkelman JW, Earley CJ, Högl B, et al. The long-term treatment of RLS/Willis–Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International RLS Study Group. Sleep Med. 2013;14(7):675–84.

    Article  PubMed  Google Scholar 

  14. Tzonova D, Larrosa O, Calvo E, Granizo JJ, Williams A-M, de la Llave Y, et al. Breakthrough symptoms during the daytime in patients with RLS (Willis–Ekbom disease). Sleep Med. 2012;13(2):151–5.

    Article  CAS  PubMed  Google Scholar 

  15. Zucconi M, Ferri R, Allen R, Baier PC, Bruni O, Chokroverty S, International Restless Legs Syndrome Study Group (IRLSSG), et al. The official World Association of Sleep Medicine (WASM) standards for recording and scoring periodic leg movements in sleep (PLMS) and wakefulness (PLMW) developed in collaboration with a task force from the International RLS Study Group (IRLSSG). Sleep Med. 2006;7(2):175–83.

    Article  PubMed  Google Scholar 

  16. Montplaisir J, Boucher S, Poirier G, Lavigne G, Lapierre O, Lespérance P. Clinical, polysomnographic, and genetic characteristics of RLS: a study of 133 patients diagnosed with new standard criteria. Mov Disord. 1997;12(1):61–5.

    Article  CAS  PubMed  Google Scholar 

  17. Fulda S. The role of periodic limb movements during sleep in RLS: a selective update. Sleep Med Clin. 2015;10(3):241–8 (xii).

    Article  PubMed  Google Scholar 

  18. Lipford MC, Silber MH. Long-term use of pramipexole in the management of RLS. Sleep Med. 2012;13(10):1280–5.

    Article  PubMed  Google Scholar 

  19. García-Borreguero D, Allen RP, Kohnen R, Högl B, Trenkwalder C, Oertel W, et al. Diagnostic standards for dopaminergic augmentation of RLS: report from a World Association of Sleep Medicine-International RLS Study Group consensus conference at the Max Planck Institute. Sleep Med. 2007;8(5):520–30.

    Article  PubMed  Google Scholar 

  20. von Spiczak S, Whone AL, Hammers A, Asselin M-C, Turkheimer F, Tings T, et al. The role of opioids in RLS: an [11C]diprenorphine PET study. Brain. 2005;128(Pt 4):906–17.

    Article  Google Scholar 

  21. Walters AS, Ondo WG, Zhu W, Le W. Does the endogenous opiate system play a role in the RLS? A pilot post-mortem study. J Neurol Sci. 2009;279(1–2):62–5.

    Article  CAS  PubMed  Google Scholar 

  22. Hening WA, Walters A, Kavey N, Gidro-Frank S, Côté L, Fahn S. Dyskinesias while awake and periodic movements in sleep in RLS: treatment with opioids. Neurology. 1986;36(10):1363–6.

    Article  CAS  PubMed  Google Scholar 

  23. Hagelberg N, Kajander JK, Någren K, Hinkka S, Hietala J, Scheinin H. Mu-receptor agonism with alfentanil increases striatal dopamine D2 receptor binding in man. Synapse. 2002;45(1):25–30.

    Article  CAS  PubMed  Google Scholar 

  24. Di Chiara G, Imperato A. Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats. J Pharmacol Exp Ther. 1988;244(3):1067–80.

    PubMed  Google Scholar 

  25. Mackie SE, McHugh RK, McDermott K, Griffin ML, Winkelman JW, Weiss RD. Prevalence of RLS during detoxification from alcohol and opioids. J Subst Abuse Treat. 2017;73:35–9.

    Article  PubMed  Google Scholar 

  26. Ekbom KA. RLS. Neurology. 1960;10:868–73.

    Article  CAS  PubMed  Google Scholar 

  27. Trzepacz PT, Violette EJ, Sateia MJ. Response to opioids in three patients with RLS. Am J Psychiatry. 1984;141(8):993–5.

    Article  CAS  PubMed  Google Scholar 

  28. Kaplan PW, Allen RP, Buchholz DW, Walters JK. A double-blind, placebo-controlled study of the treatment of periodic limb movements in sleep using carbidopa/levodopa and propoxyphene. Sleep. 1993;16(8):717–23.

    Article  CAS  PubMed  Google Scholar 

  29. Walters AS, Wagner ML, Hening WA, Grasing K, Mills R, Chokroverty S, et al. Successful treatment of the idiopathic RLS in a randomized double-blind trial of oxycodone versus placebo. Sleep. 1993;16(4):327–32.

    Article  CAS  PubMed  Google Scholar 

  30. Becker PM. Efficacy of different opioids in the treatment of restless legs syndrome (RLS): a naturalistic study. Sleep. 2001;24(031.N):A19.

  31. Trenkwalder C, Beneš H, Grote L, García-Borreguero D, Högl B, Hopp M, et al. Prolonged release oxycodone-naloxone for treatment of severe RLS after failure of previous treatment: a double-blind, randomised, placebo-controlled trial with an open-label extension. Lancet Neurol. 2013;12(12):1141–50.

    Article  CAS  PubMed  Google Scholar 

  32. Ondo WG. Methadone for refractory RLS. Mov Disord. 2005;20(3):345–8.

    Article  PubMed  Google Scholar 

  33. Silver N, Allen RP, Senerth J, Earley CJ. A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of RLS. Sleep Med. 2011;12(5):440–4.

    Article  PubMed  Google Scholar 

  34. Walters AS, Winkelmann J, Trenkwalder C, Fry JM, Kataria V, Wagner M, et al. Long-term follow-up on RLS patients treated with opioids. Mov Disord. 2001;16(6):1105–9.

    Article  CAS  PubMed  Google Scholar 

  35. Vetrugno R, La Morgia C, D’Angelo R, Loi D, Provini F, Plazzi G, et al. Augmentation of RLS with long-term tramadol treatment. Mov Disord. 2007;22(3):424–7.

    Article  PubMed  Google Scholar 

  36. Chokroverty S. Opioid-induced hyperalgesia and dopamine-induced augmentation in an intractable and refractory case of RLS. Sleep Med. 2015;16(10):1304.

    Article  PubMed  Google Scholar 

  37. Katz N, Mazer NA. The impact of opioids on the endocrine system. Clin J Pain. 2009;25(2):170–5.

    Article  PubMed  Google Scholar 

  38. Bliesener N, Albrecht S, Schwager A, Weckbecker K, Lichtermann D, Klingmüller D. Plasma testosterone and sexual function in men receiving buprenorphine maintenance for opioid dependence. J Clin Endocrinol Metab. 2005;90(1):203–6.

    Article  CAS  PubMed  Google Scholar 

  39. Cushman P, Kreek MJ. Methadone-maintained patients. Effect of methadone on plasma testosterone, FSH, LH, and prolactin. N Y State J Med. 1974;74(11):1970–3.

    PubMed  Google Scholar 

  40. Bawor M, Bami H, Dennis BB, Plater C, Worster A, Varenbut M, et al. Testosterone suppression in opioid users: a systematic review and meta-analysis. Drug Alcohol Depend. 2015;1(149):1–9.

    Article  Google Scholar 

  41. Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence and clinical relevance of corrected QT interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction. 2009;104(6):993–9.

    Article  PubMed  Google Scholar 

  42. Roy M, de Zwaan M, Tuin I, Philipsen A, Brähler E, Müller A. Association Between RLS and adult ADHD in a German community-based sample. J Atten Disord. 2005. doi:10.1177/1087054714561291.

  43. Rose AR, Catcheside PG, McEvoy RD, Paul D, Kapur D, Peak E, et al. Sleep disordered breathing and chronic respiratory failure in patients with chronic pain on long term opioid therapy. J Clin Sleep Med. 2014;10(8):847–52.

    PubMed  PubMed Central  Google Scholar 

  44. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool. Pain Med. 2005;6(6):432–42.

    Article  PubMed  Google Scholar 

  45. Aurora RN, Kristo DA, Bista SR, Rowley JA, Zak RS, Casey KR, et al. The treatment of RLS and periodic limb movement disorder in adults-an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline. Sleep. 2012;35(8):1039–62.

    Article  PubMed  PubMed Central  Google Scholar 

  46. García-Borreguero D, Silber MH, Winkelman JW, Högl B, Bainbridge J, Buchfuhrer M, et al. Guidelines for the first-line treatment of RLS/Willis–Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016;21:1–11.

    Article  PubMed  Google Scholar 

  47. Winkelman JW, Armstrong MJ, Allen RP, Chaudhuri KR, Ondo W, Trenkwalder C, et al. Practice guideline summary: treatment of RLS in adults: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016;87(24):2585–93.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Susan E. Mackie.

Ethics declarations

Funding

No funding was received for publication of this manuscript.

Conflicts of interest

Dr. Mackie has no conflicts to declare. Dr. Winkelman is a consultant for Merck and Flex Pharma; receives royalties from UpToDate; has received research grants from UCB Pharma, NeuroMetrix, NIMH, and Luitpold Pharma; and has received speaker fees and travel support from Otsuka.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mackie, S.E., Winkelman, J.W. Therapeutic Utility of Opioids for Restless Legs Syndrome. Drugs 77, 1337–1344 (2017). https://doi.org/10.1007/s40265-017-0773-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-017-0773-6

Navigation