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Restless Legs Syndrome

VERSION: 1.0 CREATED: January 29, 2026 REVISED: January 29, 2026 STATUS: Approved

DIAGNOSIS: Restless Legs Syndrome (RLS) / Willis-Ekbom Disease

ICD-10: G25.81 (Restless legs syndrome), G25.89 (Other specified extrapyramidal and movement disorders), G47.61 (Periodic limb movement disorder)

CPT CODES: 82728 (Serum ferritin), 83540 (Serum iron), 83550 (TIBC), 84466 (Transferrin saturation), 85025 (CBC), 80053 (CMP), 84443 (TSH), 82947 (Glucose), 82607 (Vitamin B12), 82746 (Folate), 83735 (Magnesium), 95907-95913 (Nerve conduction studies), 86235 (ANA), 95810 (Polysomnography (PSG)), 72141 (MRI spine), 96365 (IV iron (ferric carboxymaltose))

SYNONYMS: Restless legs syndrome, RLS, Willis-Ekbom disease, WED, restless leg syndrome, Ekbom syndrome, anxietas tibiarum, leg jitters, nocturnal leg cramps (often confused with), periodic limb movement disorder, PLMD, akathisia (related)

SCOPE: Diagnosis and management of restless legs syndrome in adults. Covers diagnostic criteria, workup for secondary causes, pharmacologic and non-pharmacologic treatment, and prevention of augmentation. Excludes periodic limb movement disorder as separate entity, akathisia, and leg cramps.

DEFINITIONS: - Restless Legs Syndrome (RLS): Neurological sensorimotor disorder characterized by urge to move legs, usually accompanied by uncomfortable sensations, with circadian pattern and relief with movement - Augmentation: Paradoxical worsening of RLS with dopaminergic treatment: earlier onset, spread to arms, shorter latency, increased intensity - Periodic Limb Movements of Sleep (PLMS): Repetitive limb movements during sleep, often associated with RLS (but can occur independently) - Refractory RLS: RLS not adequately controlled by standard treatments

DIAGNOSTIC CRITERIA (IRLSSG 2014):

All 5 essential criteria must be met:

  1. Urge to move the legs usually accompanied by uncomfortable sensations in the legs (may occur without)
  2. Symptoms worsen during rest or inactivity (lying, sitting)
  3. Symptoms partially or totally relieved by movement (walking, stretching) at least as long as activity continues
  4. Symptoms occur exclusively or predominantly in evening/night (worse at night than day)
  5. Not solely accounted for by another condition (leg cramps, positional discomfort, myalgia, venous stasis, leg edema, arthritis, habitual foot tapping, akathisia)

Supportive Features: - Family history of RLS - Response to dopaminergic therapy - Periodic limb movements (on PSG or actigraphy)

Severity (IRLS Rating Scale): - Mild: 0-10 - Moderate: 11-20 - Severe: 21-30 - Very severe: 31-40

PRIORITY KEY: STAT = Immediate | URGENT = Within hours | ROUTINE = Standard | EXT = Extended/atypical cases | - = Not applicable to this setting

1. LABORATORY WORKUP

1A. Essential/Core Labs (All Patients)

Test ED HOSP OPD ICU Rationale Target Finding
Serum ferritin (CPT 82728) - ROUTINE ROUTINE - Iron deficiency is treatable cause; target >75 ng/mL >75 ng/mL (>100 preferred)
Serum iron (CPT 83540) - ROUTINE ROUTINE - Iron deficiency assessment Normal
TIBC (CPT 83550) - ROUTINE ROUTINE - Iron deficiency assessment Normal
Transferrin saturation (CPT 84466) - ROUTINE ROUTINE - Target >20% >20%
CBC (CPT 85025) - ROUTINE ROUTINE - Anemia workup Normal
CMP (CPT 80053) - ROUTINE ROUTINE - Renal function (uremia can cause RLS), electrolytes Normal
TSH (CPT 84443) - ROUTINE ROUTINE - Thyroid dysfunction Normal
Glucose (CPT 82947) / HbA1c (CPT 83036) - ROUTINE ROUTINE - Diabetes can cause neuropathy mimicking RLS Normal

1B. Extended Workup (Second-line)

Test ED HOSP OPD ICU Rationale Target Finding
Vitamin B12 (CPT 82607) - ROUTINE ROUTINE - Deficiency can cause neuropathy >400 pg/mL
Folate (CPT 82746) - ROUTINE ROUTINE - Deficiency Normal
Magnesium (CPT 83735) - ROUTINE ROUTINE - Deficiency can contribute Normal
BUN/Creatinine - ROUTINE ROUTINE - Uremic RLS Normal
Pregnancy test - ROUTINE ROUTINE - RLS common in pregnancy; affects treatment Document

1C. Rare/Specialized

Test ED HOSP OPD ICU Rationale Target Finding
Nerve conduction studies (CPT 95907-95913) / EMG (CPT 95885) - - EXT - If neuropathy suspected Rule out neuropathy mimics
ANA (CPT 86235), anti-SSA/SSB - - EXT - If autoimmune neuropathy suspected Negative

2. DIAGNOSTIC IMAGING & STUDIES

2A. Essential/First-line

Study ED HOSP OPD ICU Timing Target Finding Contraindications
Clinical diagnosis - ROUTINE ROUTINE - At evaluation All 5 diagnostic criteria met None

2B. Extended

Study ED HOSP OPD ICU Timing Target Finding Contraindications
Polysomnography (PSG) (CPT 95810) - - EXT - If PLMD suspected or other sleep disorder PLMS >15/hour supports diagnosis Not required for diagnosis
Actigraphy - - EXT - Objective movement assessment Document periodic movements None
MRI spine (CPT 72141) - - EXT - If radiculopathy suspected Rule out structural cause Per MRI
Doppler ultrasound (legs) - - EXT - If venous insufficiency suspected Rule out venous disease None

3. TREATMENT

3A. Non-Pharmacologic Treatment (All Patients)

Treatment Route Indication Dosing Contraindications Monitoring ED HOSP OPD ICU
Sleep hygiene - - N/A :: - :: daily :: Regular sleep schedule, cool room, limit screen time None Foundation of treatment - ROUTINE ROUTINE -
Avoid triggers - - N/A :: - :: N/A :: Avoid alcohol, caffeine, nicotine (especially evening) None Critical - ROUTINE ROUTINE -
Moderate exercise - - N/A :: - :: QHS :: Regular exercise, but avoid intense exercise close to bedtime None Helps symptoms - - ROUTINE -
Leg massage/stretching - - N/A :: - :: daily :: Gentle stretching, massage before bed None May provide relief - ROUTINE ROUTINE -
Hot bath - - N/A :: - :: QHS :: Warm bath before bedtime None Relaxation - - ROUTINE -
Mental alerting activities - - N/A :: - :: per protocol :: Crosswords, video games can distract during symptoms None Useful for mild cases - - ROUTINE -
Pneumatic compression devices - - N/A :: - :: continuous :: Sequential compression 1 hour before bed DVT, arterial disease Limited evidence - - EXT -

3B. Iron Replacement (If Ferritin <75 ng/mL)

Treatment Route Indication Dosing Contraindications Monitoring ED HOSP OPD ICU
Ferrous sulfate - - 325 mg :: - :: daily :: 325 mg (65 mg elemental iron) with vitamin C 100 mg, on empty stomach, daily or every other day Iron overload, hemochromatosis Ferritin q3 months; GI side effects - ROUTINE ROUTINE -
Ferrous gluconate PO - 324 mg :: PO :: daily :: 324 mg (36 mg elemental iron) daily; better tolerated Same Same - ROUTINE ROUTINE -
IV iron (ferric carboxymaltose) (CPT 96365) IV - 1000 mg :: IV :: once :: 1000 mg IV once (if oral intolerant or severe deficiency); may repeat Iron overload, infection Ferritin in 8 weeks; faster response - ROUTINE ROUTINE -
IV iron sucrose (CPT 96365) IV - 200 mg :: IV :: - :: 200 mg IV × 5 doses over 2 weeks Same Same - ROUTINE ROUTINE -

3C. First-Line Pharmacologic Treatment - Alpha-2-Delta Ligands (PREFERRED)

Note: Alpha-2-delta ligands (gabapentinoids) are now FIRST-LINE due to lower augmentation risk than dopamine agonists.

Treatment Route Indication Dosing Contraindications Monitoring ED HOSP OPD ICU
Gabapentin PO - 300 mg :: PO :: QHS :: Start 300 mg QHS; titrate by 300 mg every few days to 900-1800 mg QHS Renal impairment (adjust) Sedation, dizziness, edema - ROUTINE ROUTINE -
Gabapentin enacarbil (Horizant) PO - 600 mg :: PO :: daily :: 600 mg daily at ~5 PM; FDA approved for RLS Renal impairment (adjust) Sedation, dizziness - - ROUTINE -
Pregabalin PO - 75 mg :: PO :: QHS :: Start 75 mg QHS; titrate to 150-300 mg QHS Renal impairment (adjust) Sedation, dizziness, weight gain - ROUTINE ROUTINE -

3D. Second-Line Pharmacologic Treatment - Dopamine Agonists

AUGMENTATION WARNING: Dopamine agonists have significant augmentation risk (up to 70% over 10 years). Use lowest effective dose. Monitor closely.

Treatment Route Indication Dosing Pre-Treatment Requirements Contraindications Monitoring ED HOSP OPD ICU
Pramipexole (Mirapex) PO - 0.125 mg :: PO :: - :: Start 0.125 mg 2-3h before bedtime; titrate by 0.125 mg q4-7 days; max 0.5 mg (keep dose LOW) - Severe renal impairment AUGMENTATION, ICDs, sleepiness - ROUTINE ROUTINE -
Ropinirole (Requip) PO - 0.25 mg :: PO :: - :: Start 0.25 mg 1-3h before bedtime; titrate by 0.25 mg q4-7 days; max 4 mg (keep dose LOW) - Severe hepatic impairment AUGMENTATION, ICDs, sleepiness - ROUTINE ROUTINE -
Rotigotine patch (Neupro) Transdermal - 1 mg :: PO :: - :: Start 1 mg/24h patch; titrate by 1 mg/week; max 3 mg/24h - Sulfite allergy AUGMENTATION, ICDs, skin reactions - ROUTINE ROUTINE -

3E. Third-Line / Refractory Treatment

Treatment Route Indication Dosing Contraindications Monitoring ED HOSP OPD ICU
Low-dose opioids PO - 5-15 mg :: PO :: QHS :: Oxycodone 5-15 mg QHS or tramadol 50-100 mg QHS; RESERVE for refractory cases Addiction risk, respiratory depression, apnea Dependence, respiratory - - EXT -
Extended-release oxycodone PO - 10-20 mg :: PO :: QHS :: 10-20 mg QHS; for severe refractory RLS Same Same - - EXT -
Methadone (specialist use) PO - 5-10 mg :: PO :: QHS :: 5-10 mg QHS; specialist prescribing only Same; QT prolongation QTc, respiratory - - EXT -
Buprenorphine (specialist use) - - 0.2-0.8 mg :: - :: QHS :: 0.2-0.8 mg SL QHS; may have lower abuse potential Same Same - - EXT -

3F. Managing Augmentation

Treatment Route Indication Dosing Contraindications Monitoring ED HOSP OPD ICU
Recognize augmentation - - - - Key to management - ROUTINE ROUTINE -
Discontinue dopamine agonist - - - - "Washout" period difficult - ROUTINE ROUTINE -
Bridge with opioid - - - - Temporary use - ROUTINE ROUTINE -
Switch to alpha-2-delta ligand - - - - New first-line - ROUTINE ROUTINE -
IV iron IV - - - Helpful during transition - ROUTINE ROUTINE -

4. OTHER RECOMMENDATIONS

4A. Referrals & Consults

Recommendation ED HOSP OPD ICU Indication
Sleep medicine specialist - - ROUTINE - Refractory RLS, PLMD evaluation, PSG needed
Neurology - ROUTINE ROUTINE - Diagnostic uncertainty, refractory cases
Hematology - - ROUTINE - Significant iron deficiency, iron infusion
Nephrology - ROUTINE ROUTINE - Uremic RLS (ESRD patients)
Psychiatry - - ROUTINE - Impulse control disorders on dopamine agonists
Pain management - - EXT - Opioid management in refractory cases

4B. Patient/Family Instructions

Recommendation ED HOSP OPD
RLS is a real neurological condition, not psychological - ROUTINE ROUTINE
Iron levels should be optimized (ferritin >75) - ROUTINE ROUTINE
Avoid caffeine, alcohol, and nicotine, especially in evening - ROUTINE ROUTINE
Maintain regular sleep schedule - ROUTINE ROUTINE
Report symptoms of augmentation: earlier onset, spreading to arms - ROUTINE ROUTINE
Report impulse control changes if on dopamine agonists (gambling, shopping) - ROUTINE ROUTINE
Exercise regularly but not close to bedtime - ROUTINE ROUTINE
Many medications can worsen RLS - check with doctor before starting new meds - ROUTINE ROUTINE
RLS Foundation (rls.org) for resources and support - - ROUTINE

4C. Medications That May Worsen RLS (Avoid/Minimize)

Recommendation ED HOSP OPD
Antihistamines (diphenhydramine, hydroxyzine) ROUTINE ROUTINE ROUTINE
Antidopaminergic antiemetics (metoclopramide, prochlorperazine) ROUTINE ROUTINE ROUTINE
Antipsychotics (especially typical; atypical less so) ROUTINE ROUTINE ROUTINE
SSRIs/SNRIs (may worsen in some patients) - ROUTINE ROUTINE
TCAs (may worsen in some patients) - ROUTINE ROUTINE
Lithium - ROUTINE ROUTINE

5. DIFFERENTIAL DIAGNOSIS

Alternative Diagnosis Key Distinguishing Features Tests to Differentiate
Nocturnal leg cramps Painful muscle contraction, sudden onset, relieved by stretching Clinical; no urge to move
Peripheral neuropathy Numbness/tingling, burning, not worse at rest, not circadian EMG/NCS; different symptom pattern
Akathisia Inner restlessness, not limb-specific, medication-induced (antipsychotics) Medication history; involves whole body
Positional discomfort Relieved by position change; not circadian Clinical
Varicose veins/venous stasis Visible veins, edema, worse with standing Doppler ultrasound
Arthritis Joint pain, stiffness, not circadian Clinical; imaging
Peripheral artery disease Claudication, worse with activity, cool extremities ABI, vascular studies
Radiculopathy Dermatomal distribution, back pain MRI spine; EMG
Growing pains (children) Bilateral, no urge to move, different demographics Clinical
Habitual foot tapping/leg bouncing Voluntary, not uncomfortable, no urge Clinical
Periodic limb movement disorder Movements during sleep; no awake symptoms PSG; RLS is awake symptom

6. MONITORING PARAMETERS

Parameter ED HOSP OPD ICU Frequency Target/Threshold Action if Abnormal
IRLS severity scale - ROUTINE ROUTINE - Each visit Improving score Adjust treatment
Ferritin - ROUTINE ROUTINE - q3-6 months until stable >75-100 ng/mL Iron supplementation
Transferrin saturation - ROUTINE ROUTINE - With ferritin >20% Iron supplementation
Augmentation screening - ROUTINE ROUTINE - Each visit (if on DA) Absent Stop/switch dopamine agonist
Impulse control screening - ROUTINE ROUTINE - Each visit (if on DA) Absent Stop dopamine agonist
Sleep quality - ROUTINE ROUTINE - Each visit Improved Adjust treatment
Renal function (if uremic) - ROUTINE ROUTINE - Per nephrology Stable Dialysis optimization

7. DISPOSITION CRITERIA

Disposition Criteria
Outpatient management Most patients; mild-moderate RLS
Sleep medicine referral Refractory RLS, PLMD suspected, PSG needed
Hematology referral Significant iron deficiency, IV iron needed
Neurology referral Diagnostic uncertainty, refractory cases, augmentation management
Follow-up frequency q1-3 months initially; less frequent once stable

8. EVIDENCE & REFERENCES

Recommendation Evidence Level Source
IRLSSG diagnostic criteria Class I Allen et al., Sleep Med 2014
Iron supplementation if ferritin <75 Class I, Level A Multiple RCTs; AASM Guidelines
Alpha-2-delta ligands first-line Class I, Level A Updated guidelines 2016; lower augmentation risk
Gabapentin enacarbil FDA approved Class I, Level A FDA approval; multiple RCTs
Pregabalin effective Class I, Level A Multiple RCTs
Dopamine agonists effective but augmentation risk Class I, Level A Multiple RCTs; 70% augmentation at 10 years
Low-dose opioids for refractory RLS Class II, Level B Limited RCTs
Avoid antihistamines, antidopaminergics Class II, Level B Observational data

NOTES

  • RLS is primarily a clinical diagnosis based on 5 essential criteria
  • Iron deficiency is the most important reversible cause - check ferritin in ALL patients
  • Target ferritin >75 ng/mL (many experts prefer >100)
  • Alpha-2-delta ligands (gabapentin, pregabalin) are now FIRST-LINE due to lower augmentation risk
  • Dopamine agonists cause augmentation in up to 70% of patients over 10 years
  • If using dopamine agonists, use LOWEST effective dose
  • Augmentation = earlier onset, spread to arms, shorter latency, higher intensity
  • Many common medications worsen RLS (antihistamines, metoclopramide, antipsychotics)
  • RLS is common in pregnancy (~25%); iron deficiency is often the cause
  • RLS is common in ESRD (~30%); optimizing dialysis and treating iron deficiency helps
  • Opioids are reserved for refractory cases; effective but addiction concern

CHANGE LOG

v1.0 (January 29, 2026) - Initial template creation - IRLSSG 2014 diagnostic criteria - Alpha-2-delta ligands positioned as first-line (per updated guidelines) - Augmentation management section - Medications to avoid listed - Iron supplementation emphasized