Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline.

Introduction: This guideline establishes clinical practice recommendations for Treatment of Restless Legs Syndrome (RLS) and Periodic Limb Movement Disorder (PLMD) in adults and pediatric patients.

Methods: The American Academy of Sleep Medicine (AASM) commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths based on a systematic review of the literature and an assessment of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. The task force provided a summary of the relevant literature and the certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations.

Good practice statement: The following good practice statement is based on expert consensus, and its implementation is necessary for the appropriate and effective management of patients with RLS.

1. In all patients with clinically significant RLS, clinicians should regularly test serum iron studies including ferritin and transferrin saturation (calculated from iron and total iron binding capacity, TIBC). The test should ideally be administered in the morning avoiding all iron-containing supplements and foods at least 24 hours prior to blood draw. Analysis of iron studies greatly influences the decision to use oral or intravenous (IV) iron treatment. Consensus guidelines, which have not been empirically tested, suggest that supplementation of iron in adults with RLS should be instituted with oral or IV iron if serum ferritin ≤75 ng/mL or transferrin saturation < 20%, and only with IV iron if serum ferritin is between 75 ng/mL and 100 ng/mL. In children, supplementation of iron should be instituted for serum ferritin < 50 ng/mL with oral or IV formulations. These iron supplementation guidelines are different than for the general population.

2. The first step in the management of RLS should be addressing exacerbating factors, such as alcohol, caffeine, antihistaminergic, serotonergic, anti-dopaminergic medications, and untreated obstructive sleep apnea (OSA).

3. RLS is common in pregnancy; prescribers should consider the pregnancy-specific safety profile of each treatment being considered.

Recommendations: The following recommendations are intended as a guide for clinicians in choosing a specific treatment for RLS and PLMD in adults and children. Each recommendation statement is assigned a strength ("Strong" or "Conditional"). A "Strong" recommendation (i.e., "We recommend…") is one that clinicians should follow under most circumstances. The recommendations listed below are ranked in the order of strength of recommendations and grouped by class of treatments within each PICO question. Some recommendations include remarks that provide additional context to guide clinicians with implementation of this recommendation.

Adults with RLS.

1. In adults with RLS, the AASM recommends the use of gabapentin enacarbil over no gabapentin enacarbil (Strong recommendation, moderate certainty of evidence).

2. In adults with RLS, the AASM recommends the use of gabapentin over no gabapentin (Strong recommendation, moderate certainty of evidence).

3. In adults with RLS, the AASM recommends the use of pregabalin over no pregabalin (Strong recommendation, moderate certainty of evidence).

4. In adults with RLS, the AASM recommends the use of IV ferric carboxymaltose over no IV ferric carboxymaltose in patients with appropriate iron status (see good practice statement for iron parameters) (Strong recommendation, moderate certainty of evidence).

5. In adults with RLS, the AASM suggests the use of IV low molecular weight (LMW) iron dextran over no IV LMW iron dextran in patients with appropriate iron status (see good practice statement for iron parameters) (Conditional recommendation, very low certainty of evidence).

6. Recommendation 6: In adults with RLS, the AASM suggests the use of IV ferumoxytol over no IV ferumoxytol in patients with appropriate iron status (see good practice statement for iron parameters) (Conditional recommendation, very low certainty of evidence).

7. In adults with RLS, the AASM suggests the use of ferrous sulfate over no ferrous sulfate in patients with appropriate iron status (see good practice statement for iron parameters) (Conditional recommendation, moderate certainty of evidence).

8. In adults with RLS, the AASM suggests the use of dipyridamole over no dipyridamole (Conditional recommendation, low certainty of evidence).

9. In adults with RLS, the AASM suggests the use of extended-release oxycodone and other opioids over no opioids (Conditional recommendation, moderate certainty of evidence).

10. In adults with RLS, the AASM suggests the use of bilateral high-frequency peroneal nerve stimulation over no peroneal nerve stimulation (Conditional recommendation, low certainty of evidence).

11. In adults with RLS, the AASM suggests against the standard use of levodopa (Conditional recommendation, very low certainty of evidence).

Remarks: Levodopa may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).

12. In adults with RLS, the AASM suggests against the standard use of pramipexole (Conditional recommendation, moderate certainty of evidence).

Remarks: Pramipexole may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).

13. In adults with RLS, the AASM suggests against the standard use of transdermal rotigotine (Conditional recommendation, low certainty of evidence).

Remarks: Transdermal Rotigotine may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).

14. In adults with RLS, the AASM suggests against the standard use of ropinirole (Conditional recommendation, moderate certainty of evidence).

Remarks: Ropinirole may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).

15. In adults with RLS, the AASM suggests against the use of bupropion for the treatment of RLS (Conditional recommendation, moderate certainty of evidence).

16. In adults with RLS, the AASM suggests against the use of carbamazepine (Conditional recommendation, low certainty of evidence).

17. In adults with RLS, the AASM suggests against the use of clonazepam (Conditional recommendation, very low certainty of evidence).

18. In adults with RLS, the AASM suggests against the use of valerian (Conditional recommendation, low certainty of evidence).

19. In adults with RLS, the AASM suggests against the use of valproic acid (Conditional recommendation, low certainty of evidence).

20. In adults with RLS, the AASM recommends against the use of cabergoline (Strong recommendation, moderate certainty of evidence).

Special adult populations with RLS.

21. In adults with RLS and end-stage renal disease (ESRD), the AASM suggests the use of gabapentin over no gabapentin (conditional recommendation, very low certainty of evidence).

22. In adults with RLS and ESRD, the AASM suggests the use of IV iron sucrose over no IV iron sucrose in patients with ferritin < 200 ng/mL and transferrin saturation < 20% (Conditional recommendation, moderate certainty of evidence).

23. In adults with RLS and ESRD, the AASM suggests the use of vitamin C over no vitamin C (conditional recommendation, low certainty of evidence).

24. In adults with RLS and ESRD, the AASM suggests against the standard use of levodopa (Conditional recommendation, low certainty of evidence).

Remarks: Levodopa may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).

25. In adults with RLS and ESRD, the AASM suggests against the standard use of rotigotine (Conditional recommendation, very low certainty of evidence).

Remarks: Rotigotine may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).

Adults with PLMD.

26. In adults with PLMD, the AASM suggests against the use of triazolam (Conditional recommendation, very low certainty of evidence).

27. In adults with PLMD, the AASM suggests against the use of valproic acid (Conditional recommendation, very low certainty of evidence).

Children with RLS.

28. In children with RLS, the AASM suggests the use of ferrous sulfate over no ferrous sulfate in patients with appropriate iron status (see good practice statement for iron parameters) (Conditional recommendation, very low certainty of evidence).