AASM Clinical Practice Guideline: Treatment of RLS and PLMD (2025)
This is a condensed summary of the American Academy of Sleep Medicine (AASM) clinical practice guideline for the treatment of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) in adults and children (Winkelman et al., 2025). This CPG updates the 2012 AASM practice parameter using the GRADE methodology (Grading of Recommendations Assessment, Development, and Evaluation). Recommendations are designated as strong ("we recommend") or conditional ("we suggest"), either for or against a specific treatment. Literature search extended through September 2023.
Bottom Line: Key Recommendations
- Strong FOR: Gabapentin enacarbil, gabapentin, pregabalin, and IV ferric carboxymaltose — these are now the first-line treatments for adult RLS
- Conditional FOR: IV LMW iron dextran, IV ferumoxytol, ferrous sulfate, dipyridamole, extended-release oxycodone/other opioids, bilateral peroneal nerve stimulation
- Paradigm shift: Dopamine agonists (pramipexole, ropinirole, rotigotine) and levodopa are now recommended AGAINST as standard use due to augmentation risk
- Strong AGAINST: Cabergoline (cardiac valvulopathy risk)
- Iron assessment: All patients with clinically significant RLS should have regular serum iron studies (ferritin and transferrin saturation)
- Children: Ferrous sulfate is the only recommended treatment (conditional)
Good Practice Statements
The following are based on expert consensus and are essential for appropriate RLS management:
- Iron testing: All patients with clinically significant RLS should have regular serum iron studies (ferritin and transferrin saturation), ideally drawn in the morning after avoiding iron-containing supplements and foods for 24 hours. Supplementation thresholds:
- Adults: oral or IV iron if ferritin ≤75 ng/mL or TSAT <20%; IV iron only if ferritin 75–100 ng/mL
- Children: oral or IV iron if ferritin <50 ng/mL
- Address exacerbating factors: Alcohol, caffeine, antihistaminergic, serotonergic, and antidopaminergic medications, and untreated obstructive sleep apnea
- Pregnancy: Consider pregnancy-specific safety profile for each treatment
Adults with RLS
Strong Recommendations FOR
| Intervention | Evidence | Key Findings | Cost |
|---|---|---|---|
| Gabapentin enacarbil | 8 RCTs + 3 observational; moderate certainty | Clinically significant improvement in disease severity, sleep quality, and QoL; AEs: somnolence, dizziness (small undesirable effect); only FDA-approved drug for RLS recommended by this CPG | High |
| Gabapentin | 2 RCTs + 4 observational; moderate certainty | Clinically significant improvement in disease severity; AEs: somnolence, dizziness (small undesirable effect) | Negligible |
| Pregabalin | 3 RCTs; moderate certainty | Clinically significant improvement in disease severity and sleep quality; AEs leading to withdrawal met clinical significance; somnolence, dizziness (small undesirable effect) | Negligible |
| IV ferric carboxymaltose | 5 RCTs; moderate certainty | Clinically significant improvement in disease severity, sleep quality, and QoL; requires appropriate iron status (see good practice statement); AEs: hypophosphatemia, dizziness (small) | Moderate |
Conditional Recommendations FOR
| Intervention | Evidence | Key Findings |
|---|---|---|
| IV LMW iron dextran | 1 observational; very low certainty | Clinically significant improvement in disease severity; requires appropriate iron status; small undesirable effect |
| IV ferumoxytol | 1 RCT (prepost); very low certainty | Clinically significant improvement in disease severity; requires appropriate iron status; trivial undesirable effect |
| Ferrous sulfate | 1 RCT; moderate certainty | Clinically significant improvement in disease severity (large effect); requires appropriate iron status; oral iron poorly absorbed when ferritin >50–75 ng/mL; constipation may limit use |
| Dipyridamole | 1 RCT; low certainty | Clinically significant improvement in disease severity; increases extracellular adenosine; biologic rationale in brain-iron deficiency; AEs: dizziness |
| Oxycodone ER / other opioids | 1 RCT (oxycodone ER) + 2 RCTs; moderate certainty | Clinically significant improvement in refractory RLS; AEs met clinical significance (fatigue, somnolence, dizziness); moderate undesirable effect; risks of abuse, dependence, overdose; benefit likely a class effect (methadone, buprenorphine also used) |
| Bilateral peroneal nerve stimulation | 2 RCTs; moderate certainty | Clinically significant improvement in disease severity (small effect); noninvasive wearable device; AEs: uncomfortable sensations, skin irritation (trivial) |
Conditional Recommendations AGAINST
Dopamine Agonists: No Longer Standard Treatment
This CPG represents a continued evolution away from dopaminergic agents as first-line therapy. Although dopamine agonists have demonstrated short-term efficacy, the long-term risk of augmentation (iatrogenic worsening of RLS symptoms: earlier onset, reduced latency, extension to other body areas) led to conditional recommendations against their standard use. National data from 2017–2018 showed 60% of medication-treated RLS patients were still prescribed dopamine agonists, often at doses exceeding FDA recommendations. These agents may still be considered for individual patients who place higher value on short-term symptom reduction.
| Intervention | Recommendation | Key Concern |
|---|---|---|
| Levodopa | Conditional against standard use | No clinically significant improvement in severity or sleep quality; substantial augmentation risk; may be used short-term (e.g., travel) with monitoring |
| Pramipexole | Conditional against standard use | 17 RCTs showed short-term efficacy; clinically significant augmentation in long-term studies; impulse control disorders; moderate undesirable effect |
| Rotigotine (transdermal) | Conditional against standard use | Short-term efficacy demonstrated; significant augmentation with long-term use; application site reactions; high cost |
| Ropinirole | Conditional against standard use | 13 RCTs showed short-term efficacy; clinically significant augmentation in observational studies; moderate undesirable effect |
| Bupropion | Conditional against | No clinically significant improvement in disease severity; trivial undesirable effect |
| Carbamazepine | Conditional against | No clinically significant improvement; AEs met clinical significance; hepatotoxicity and hematopoietic risks |
| Clonazepam | Conditional against | Insufficient evidence for benefit; risks of cognitive impairment and chemical dependence |
| Valerian | Conditional against | No clinically significant improvement; AEs met clinical significance |
| Valproic acid | Conditional against | No clinically significant improvement; hepatotoxicity and teratogenicity risks |
Strong Recommendation AGAINST
- Cabergoline: Despite large effect on disease severity, QoL, and sleep, the risk of cardiac valvulopathy and clinically significant augmentation led to a strong recommendation against use
No Recommendation (Insufficient Evidence)
- Acupuncture, botulinum toxin, CBT, clonidine, IV iron sucrose (general RLS), near infrared light therapy, perampanel, tramadol, transcranial magnetic stimulation, transcutaneous spinal direct current stimulation, vitamin D, yoga
Special Adult Populations: RLS with ESRD
| Intervention | Recommendation | Notes |
|---|---|---|
| Gabapentin | Conditional FOR | Clinically significant improvement in severity and sleep quality (large effect); very low certainty |
| IV iron sucrose | Conditional FOR | For ferritin <200 ng/mL and TSAT <20%; moderate certainty; pharmacology differs from slow-release formulations |
| Vitamin C | Conditional FOR | Clinically significant improvement in severity; low certainty |
| Levodopa | Conditional AGAINST | Short-term efficacy but substantial augmentation risk |
| Rotigotine | Conditional AGAINST | Augmentation risk with long-term use; high cost |
Adults with PLMD
- Triazolam: Conditional against (very low certainty; marginal benefit vs. side effects)
- Valproic acid: Conditional against (very low certainty; hepatotoxicity, teratogenicity)
- PLMD remains a controversial diagnosis; causality of PLMS with sleep disturbance is debated
- No treatment studies for PLMD in the past two decades
Children with RLS
- Ferrous sulfate: Conditional FOR in patients with appropriate iron status (ferritin <50 ng/mL); very low certainty
- No evidence to support treating children with medications commonly used in adults
- Regular monitoring of symptoms, QoL, sleep, and academic performance is necessary
Practical Treatment Algorithm (AASM 2025)
- All patients: Check serum iron studies (ferritin, TSAT); address exacerbating factors (alcohol, caffeine, medications, OSA)
- Step 1 — Iron deficient (ferritin ≤75 or TSAT <20%): Oral iron (ferrous sulfate) or IV iron (ferric carboxymaltose preferred); IV iron only if ferritin 75–100
- Step 2 — First-line pharmacotherapy: Alpha-2-delta ligand (gabapentin, gabapentin enacarbil, or pregabalin) — strong recommendation
- Step 3 — Second-line: Dipyridamole, or bilateral peroneal nerve stimulation (noninvasive)
- Step 4 — Refractory RLS: Low-dose opioids (extended-release oxycodone, methadone, buprenorphine) with appropriate screening and monitoring
- Limited circumstances for dopamine agonists: Short-term use (e.g., travel), poor tolerability of other options, or patient preference with understanding of augmentation risk; regular monitoring of augmentation and impulse control disorders
- ESRD patients: Gabapentin, IV iron sucrose (ferritin <200, TSAT <20%), vitamin C
- Children: Ferrous sulfate if ferritin <50 ng/mL
Key Changes from 2012 AASM Practice Parameter
- Dopamine agonists downgraded: Pramipexole, ropinirole, and rotigotine changed from STANDARD/GUIDELINE level to conditional against standard use, due to long-term augmentation risk
- Alpha-2-delta ligands promoted: Gabapentin, gabapentin enacarbil, and pregabalin are now strongly recommended (previously GUIDELINE/OPTION level)
- IV iron added: Ferric carboxymaltose is a new strong recommendation based on multiple recent RCTs
- New treatments: Dipyridamole (adenosine pathway) and peroneal nerve stimulation (noninvasive device) receive conditional recommendations
- Cabergoline: Now strongly recommended against (previously GUIDELINE with caveats) due to cardiac valvulopathy
- Methodology: Changed from 3-tier system (STANDARD/GUIDELINE/OPTION) to 2-tier GRADE methodology (strong/conditional)
- Augmentation emphasis: Augmentation treated as a critical outcome with special weight in risk-benefit assessment
Reference
Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2025;21(1):137–152. doi: 10.5664/jcsm.11390