Evaluation and Management of Restless Legs Syndrome
Alpha-2-delta ligands (such as pregabalin and gabapentin) are strongly recommended as first-line pharmacologic therapy for restless legs syndrome (RLS) due to their strong evidence of efficacy and favorable long-term safety profile compared to dopaminergic agents. 1, 2
Diagnosis and Assessment
Diagnostic criteria for RLS include:
- Urge to move the legs with or without uncomfortable sensations
- Worsening of symptoms during periods of rest or inactivity
- Relief of symptoms with movement
- Symptoms worsen in the evening or at night
Essential laboratory evaluation:
- Serum ferritin
- Transferrin saturation
- Complete blood count
- Renal function tests
- Consider additional testing based on clinical suspicion of secondary causes
Treatment Algorithm
Step 1: Iron Therapy
- Check iron studies for all RLS patients
- Initiate iron therapy if ferritin ≤75 ng/mL or transferrin saturation <20% 2
- Oral ferrous sulfate for most patients
- IV ferric carboxymaltose for inadequate response to oral iron
- IV iron sucrose for ESRD patients with ferritin <200 ng/mL and transferrin saturation <20%
Step 2: Non-Pharmacological Approaches
- Regular aerobic and resistance exercise
- Good sleep hygiene practices
- Avoidance of substances that may worsen RLS:
- Caffeine, alcohol
- Antihistamines
- Most antidepressants (especially SSRIs)
- Dopamine antagonists
Step 3: First-Line Pharmacological Therapy
- Alpha-2-delta ligands 1, 2
- Pregabalin or gabapentin
- Advantages: No risk of augmentation, effective for long-term use
- Dose adjustment needed for patients with CKD or ESRD
- Monitor for side effects: dizziness, somnolence
- Caution in patients with risk factors for substance misuse
Step 4: Second-Line Therapy
- Dopamine agonists (short-term use only) 1, 2, 3
- Ropinirole, pramipexole, or rotigotine patch
- Mean effective dose of pramipexole ~0.3 mg
- Major limitation: Risk of augmentation (paradoxical worsening of symptoms)
- No longer recommended as first-line therapy due to augmentation risk
- Monitor closely for augmentation signs:
- Earlier symptom onset
- Increased intensity of symptoms
- Spread of symptoms to other body parts
Step 5: Refractory RLS
- Opioids for moderate to severe RLS 1, 2
- Extended-release oxycodone is conditionally recommended
- Particularly useful for patients who have failed other therapies
- Effective for managing augmentation during dopamine agonist withdrawal
- Monitor for respiratory depression and central sleep apnea
Special Populations
End-Stage Renal Disease
- Gabapentin with dose adjustment
- IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20%
- Consider cool dialysate during hemodialysis
Pregnancy
- Prioritize non-pharmacological approaches
- Iron supplementation if deficient
- Medication use requires careful risk-benefit assessment
Children
- Iron therapy as first-line for those with low iron stores
- Limited evidence for medications in children
- No FDA-approved options for pediatric RLS
Management of Augmentation
- If augmentation occurs with dopamine agonists:
- Gradually taper and discontinue the dopamine agonist
- Transition to alpha-2-delta ligands or opioids
- Consider IV iron therapy
- Maintain high serum ferritin levels to help prevent augmentation
Monitoring
- Regular assessment of symptom severity and medication side effects
- Periodic reassessment of iron status
- Vigilance for signs of augmentation in patients on dopamine agonists
- Careful monitoring for misuse potential with alpha-2-delta ligands and opioids
The paradigm shift away from dopamine agonists as first-line therapy represents a significant change in RLS management, based on growing evidence of the risks of augmentation with long-term dopaminergic therapy 1. While dopamine agonists remain effective for symptom control, their long-term use is limited by this potentially treatment-limiting complication.