Levels of recommendation (Standard, Guideline, and Option) and levels of evidence (High, Moderate, Low, Very Low) are defined at the end of the "Major Recommendations" field.
Pharmacotherapy for Restless Legs Syndrome (RLS)
Non-ergot Derived Dopamine Agonist: Pramipexole
Clinicians should treat patients with RLS with pramipexole. (STANDARD)
Values and Trade-Offs: Pramipexole is upgraded to standard from the previous practice parameter based on multiple studies showing efficacy in RLS. Pramipexole is typically well tolerated and side effects are self-limited with cessation of pramipexole therapy.
Non-ergot Derived Dopamine Agonist: Ropinirole
Clinicians should treat patients with RLS with ropinirole. (STANDARD)
Values and Trade-Offs: This recommendation is upgraded to standard from the previous practice parameter based on multiple studies with randomized controlled data (RCT) data showing efficacy in RLS therapy. Ropinirole is typically well tolerated and side effects are self-limited with cessation of ropinirole therapy.
Clinicians can treat RLS patients with levodopa with dopa decarboxylase inhibitor. (GUIDELINE)
Values and Trade-Offs: This recommendation is changed from the previous practice parameter, where it was given a STANDARD level of recommendation for use. Levodopa has longstanding clinical use in RLS with concomitant concerns for daytime RLS augmentation and early morning rebound of RLS symptoms. The use of levodopa may be most advantageous for those patients with intermittent RLS symptoms that do not require daily therapy. For those that require daily therapy for RLS, the newer dopaminergic agents may be a better choice. Therapy should be tailored to the individual patient's specific circumstances and needs. Vigilance for secondary impulsive behavior as an adverse reaction is needed.
Ergot-derived Dopamine Agonists: Pergolide and Cabergoline
Clinicians should not treat RLS patients with pergolide because of the risks of heart valve damage. (STANDARD)
Values and Trade-Offs: Pergolide risks include heart valve damage and retroperitoneal fibrosis making any future use of pergolide in RLS strongly contraindicated.
Given the potential of side effects, including heart valve damage, clinicians can treat RLS patients with cabergoline only if other recommended agents have been tried first and failed, and close clinical follow-up is provided. (GUIDELINE)
Values and Trade-Offs: The risks of cabergoline are sufficient to recommend cabergoline not be used in routine clinical practice for RLS particularly since there are multiple alternative RLS dopaminergic therapies with a better side effect profile. Because the risk is unclear, it is prudent to remain cautious with respect to recommending cabergoline.
Clinicians can treat RLS patients with opioids. (GUIDELINE)
Values and Trade-Offs: Opioid data shows clinical effectiveness in treating RLS with a low level of evidence. Side effects can include an undefined potential for abuse in predisposed patients and a possible risk for the development or worsening of sleep apnea. Therefore, patients should be clinically monitored for the development of symptoms. In general, however, this medication is very well tolerated and has a lower risk of augmentation than is seen in the dopaminergic medications.
Clinicians can treat patients with RLS with gabapentin enacarbil. (GUIDELINE)
Values and Trade-Offs: This is a new recommendation from the prior practice parameter. Sufficient evidence has emerged since the last practice parameter to support gabapentin enacarbil as a guideline level for treatment in RLS therapy. Gabapentin enacarbil therapy is generally well tolerated with self-limited side effects. High level evidence is encouraging. However, this medication is relatively new, thereby warranting a conservative recommendation level of guideline at this time.
Clinicians may treat RLS patients with gabapentin. (OPTION)
Values and Trade-Offs: Low level evidence supports use of gabapentin for RLS therapy. Pain relief with gabapentin supports consideration of gabapentin in patients with both RLS and pain. There are some concerning potential side effects which makes the balance of benefits versus harms uncertain.
Clinicians may treat patients with RLS with pregabalin. (OPTION)
Values and Trade-Offs: Preliminary data shows therapeutic efficacy in pregabalin therapy for RLS. However, long-term follow up and published experience in pregabalin therapy for RLS is lacking. Thus, other better-studied RLS therapies should be considered before prescribing pregabalin.
Clinicians may treat RLS patients with carbamazepine. (OPTION)
Values and Trade-offs: This has been downgraded from GUIDELINE in the prior practice parameter to OPTION in this practice parameter. Although carbamazepine efficacy in RLS was shown in prior studies, these data are dated with no new additional supportive work. There are other RLS therapies with comparatively more supportive evidence, risk-to-benefit ratios, and clinical experience than carbamazepine. The benefits of carbamazepine therapy are closely balanced with potential adverse side effects which include sedation, liver abnormalities and, rarely, the potential suicidal ideation and behavior, and Stevens-Johnson syndrome.
Medications Acting on the Adrenergic Systems
Clinicians may treat patients with RLS with clonidine. (OPTION)
Values and Trade-Offs: Clonidine has minimal supporting data in treating RLS and carries a considerable risk for side effects. Clonidine might be considered in treating hypertension and RLS concomitantly. The risk of side effects (such as hypotension in normotensive patients) associated with clonidine in the treatment of RLS makes the benefit-to-harm ratio unclear.
Clinicians may use supplemental iron to treat RLS patients with low ferritin levels. (OPTION)
Values and Trade-Offs: RLS therapy with iron may be effective in patients with RLS associated with low ferritin levels. Parenteral high molecular weight iron dextran therapy carries the potential for anaphylactic reaction. The parenteral infusion risk with low molecular weight iron dextran is substantially lower. Moreover, parenteral iron therapy with iron sucrose, iron gluconate, or ferumoxytol carries no anaphylactic risk. However, whenever possible, oral iron replacement is recommended. Oral supplemental iron carries fewer side effects—primarily constipation and rare cases of iron overload.
Therapies for Which No Recommendations Are Made
Refer to the original guideline document for information on those pharmacological and nonpharmacological RLS therapies for which a recommendation level could not be given secondary to either insufficient evidence to support any recommendation or because the therapy is no longer available in the U.S.
Therapies for Periodic Limb Movements of Sleep (PLMS)
There is insufficient evidence at present to comment on the use of pharmacological therapy in patients diagnosed with periodic limb movement disorder (PLMD) alone. (NO RECOMMENDATION)
Values and Trade Offs: There is insufficient evidence to comment on pharmacologic therapies in isolated PLMD. Existing data in RLS therapy does, in some cases, support some medical interventions in both RLS and PLMD. Clinical judgment must be used in any pharmacologic intervention in PLMD.
Summary of Grading of Recommendations Assessment, Development and Evaluation (GRADE) Approach to Rating Quality of Evidence*
||Initial Quality of a Body of Evidence
||Quality of a Body of Evidence
||Risk of bias
−2 Very serious
+2 Very large
|High (four plus:++++)
−2 Very serious
+1 Evidence of a gradient
|Moderate (three plus:+++O)
−2 Very serious
|All plausible residual confounding
+1 Would reduce a demonstrated effect
|Low (two plus: ++OO)
−2 Very serious
−2 Very likely
|+1 Would suggest a spurious effect if no effect was observed
||Very Low (one plus:+OOO)
Final Assessments of Level of Bodies of Evidence*
High: The guideline developers are very confident that the true effect lies close to that of the estimate of the effect.
Moderate: The guideline developers are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low: The confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
Very low: The guideline developers have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
*From Balshem H, Helfand M, Schunemann H, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401-6.
American Academy of Sleep Medicine (AASM) Levels of Recommendations
|Final Standards of Practice Recommendations
||Overall Quality of Evidence
|Assessment of benefit/harm/burden
||Benefits clearly outweigh harm/burden
|Benefits closely balanced with harm/burden
uncertainty in the estimates of benefit/harm/burden
|Harm/burden clearly outweighs benefits