Treatment of Restless Legs Syndrome in Adults: Practice Guideline

Restless legs syndrome (RLS) is a movement disorder characterized by an urge to move the legs or arms, commonly in response to uncomfortable dysesthesia. Clinically important RLS affects approximately 2.5% of adults in the United States and Northern Europe, with higher prevalence in women and with increasing age.1 RLS is classified as primary or secondary in origin, with secondary RLS attributed to comorbid iron deficiency, end-stage renal disease (ESRD), or pregnancy. Most patients with RLS also have periodic limb movements of sleep (PLMS).

American Academy of Neurology (AAN) has released guidelines of Evidence-based Guideline for Clinicians on Treatment of Restless Legs Syndrome in Adults in November 2016 and reaffirmed on October 22, 2022.

Following are its major recommendations:

In moderate to severe primary restless legs syndrome (RLS), clinicians should consider prescribing a pharmacologic agent to reduce RLS symptoms: 

1. Pramipexole, rotigotine, cabergoline*, and gabapentin enacarbil (Level A).

2. Ropinirole, pregabalin, and IV ferric carboxymaltose, and in patients with serum ferritin ≤ 75 mcg/l, ferrous sulfate with vitamin C (Level B).

3. Levodopa (Level C).

4. Cabergoline* instead of levodopa (Level C).

5. Preferential use of pregabalin instead of pramipexole (Level U). Gabapentin, IV iron sucrose, oxycodone, clonazepam, bupropion, clonidine, selenium, rifaximin, botulinum neurotoxin,valproic acid, carbamazepine, or valerian in the treatment of RLS (Level U).

For patients with RLS who have not responded to other treatments: 

6. Prolonged-release oxycodone/naloxone (where available) (Level C), but potential benefits need to be weighed against known opioid risks. 

For patients with primary RLS for whom clinicians want to target sleep, clinicians should consider prescribing a pharmacologic agent that improves objective or subjective sleep parameters (or both). Evidence supports agents to different extents for subjective and objective outcomes: 

7. Ropinirole, when targeting periodic limb movements of sleep (PLMS), specifically the Periodic Limb Movement Index (PLMI) as measured by polysomnography (PSG) (Level A).

8. Cabergoline* and gabapentin enacarbil, with regard to subjective sleep measures (Level A).

9. Pramipexole, rotigotine, cabergoline*, and pregabalin, when targeting PLMS, specifically the PLMI as measured by PSG (Level B).

10. Ropinirole, gabapentin enacarbil, and pregabalin, for at least some objective sleep measures (e.g., total sleep time [TST], sleep efficiency, sleep latency, and wake after sleep onset [WASO]) (Level B).

11. Pregabalin instead of pramipexole, with regard to subjective sleep outcomes (Level B).

12. Ropinirole, pramipexole, and pregabalin, with regard to subjective sleep measures (Level B).

13. Rotigotine, with regard to subjective sleep measures (Levels B and C). 

14. Levodopa, when targeting PLMS, specifically the PLMI as measured by PSG (Level C).

15. Pramipexole in preference to pregabalin, when targeting PLMS, specifically the PLMI as measured by PSG (Level C).

16 Pregabalin in preference to pramipexole, with regard to objective sleep measures other than PLMI (e.g., TST, sleep efficiency, sleep latency, and WASO) (Level C).

17. Levodopa, with regard to subjective sleep measures, with the strength of evidence varying by measure and, sometimes, dose (Level C).

18. Insufficient Evidence Gabapentin enacarbil, IV ferric carboxymaltose, or IV iron sucrose, when targeting PLMS, specifically the PLMI as measured by PSG (Level U).

19. Pramipexole, rotigotine, cabergoline*, or levodopa, with regard to other objective sleep measures (e.g., TST, sleep efficiency, sleep latency, and WASO) (Level U).

20. Ferric carboxymaltose, with regard to subjective sleep measures (Level U).

For patients with RLS for whom clinicians want to target concomitant psychiatric symptoms:

21. Ropinirole, in the context of anxiety (Level B).

22. Gabapentin enacarbil, for overall mood (Level B).

23. Ropinirole, in the context of depression (Level C).

24. Pramipexole, for depression and anxiety, in the context of moderate to severe RLS-related mood disturbance (Level C).

For patients with RLS for whom clinicians want to select an agent that improves QoL:

25. Ropinirole, pramipexole, cabergoline*, gabapentin enacarbil, or IV ferric carboxymaltose (Level B).

26.  Rotigotine or pregabalin (Level C).

27.  Levodopa, for improving QoL in RLS (Level U).

When avoidance of augmentation is a deciding factor:  

28. Pregabalin rather than pramipexole, when considering 52-week treatment in light of lower augmentation rates with pregabalin (Level C).

29. Cabergoline* rather than levodopa, when considering 30-week treatment in light of lower augmentation rates with cabergoline (Level C).

30.  Which dopaminergic agents cause the least augmentation because augmentation rates are most commonly reported in long-term open-label Class IV studies (Level U). Results of these studies are summarized in this practice guideline but cannot support formal recommendations.

For patients or clinicians wanting to use nonpharmacologic approaches to treat RLS:

31. Pneumatic compression, before usual symptom onset (Level B).

32.  Near-infrared spectroscopy (NIRS) or repetitive transcranial magnetic stimulation (rTMS) (where available) (Level C).

33. Vibrating pads, for subjective sleep concerns (Level C) but not for RLS symptoms (Level C against).

34. Transcranial direct current stimulation (tDCS), for RLS symptoms (Level C against).

35. Acupuncture, in RLS (Level U).

In patients with secondary RLS associated with end-stage renal disease/hemodialysis (ESRD/HD): 

36. Vitamin C and E supplementation (alone or in combination) (Level B).

37.  Ropinirole, levodopa, or exercise (Level C).

38. Gabapentin or IV iron dextran in RLS associated with ESRD/HD (Level U). There is also insufficient evidence to support or refute the use of gabapentin or levodopa preferentially over the other in this population (Level U).

Reference:

John W. Winkelman, Melissa J. Armstrong, Richard P. Allen, K. Ray Chaudhuri, William Ondo, Claudia Trenkwalder, Phyllis C. Zee, Gary S. Gronseth, David Gloss, Theresa Zesiewicz Neurology Dec 2016, 87 (24) 2585-2593; DOI: 10.1212/WNL.0000000000003388