What are the next steps for a patient with restless legs syndrome (RLS) that has not responded to Cymbalta (duloxetine) or Requip (ropinirole)?

Treatment Options for Restless Legs Syndrome After Failed Therapy with Cymbalta and Requip

For patients with restless legs syndrome (RLS) who have failed treatment with duloxetine (Cymbalta) and ropinirole (Requip), the most effective next step is to switch to alpha-2-delta ligands such as gabapentin, gabapentin enacarbil, or pregabalin, which are strongly recommended as first-line treatments by current guidelines. 1

Assessment of Iron Status

Before initiating new medication:

1. Check serum iron studies including:

   • Ferritin level
   • Transferrin saturation (calculated from iron and total iron binding capacity)

2. Iron parameters requiring treatment:

   • If ferritin ≤ 75 ng/mL or transferrin saturation < 20%: Consider oral iron supplementation
   • If ferritin between 75-100 ng/mL: Consider IV iron therapy 1

Treatment Algorithm

First-line options (after dopamine agonist failure):

1. Alpha-2-delta ligands (strong recommendation, moderate certainty):

   • Gabapentin: 300-1200 mg daily (start low, titrate up)
   • Gabapentin enacarbil: 600 mg daily
   • Pregabalin: 150-300 mg daily 1

2. IV iron therapy (if iron deficient):

   • IV ferric carboxymaltose (strong recommendation)
   • IV low molecular weight iron dextran (conditional recommendation)
   • IV ferumoxytol (conditional recommendation) 1

Second-line options:

1. Dipyridamole (conditional recommendation, low certainty)

   • Acts through adenosine pathways 1, 2

2. Opioids (conditional recommendation, moderate certainty):

   • Extended-release oxycodone or other opioids
   • Reserve for refractory cases due to addiction potential 1

3. Non-pharmacological interventions:

   • Bilateral high-frequency peroneal nerve stimulation (conditional recommendation) 1
   • Exercise programs 3
   • Compression devices 3

Addressing Exacerbating Factors

Eliminate potential RLS triggers:

• Alcohol consumption
• Caffeine intake
• Antihistamines
• Serotonergic medications
• Antidopaminergic medications
• Untreated obstructive sleep apnea 1

Important Considerations

• Avoid dopamine agonists as next step: The American Academy of Sleep Medicine suggests against standard use of dopamine agonists like ropinirole due to risk of augmentation with long-term use 1

• Augmentation risk: This phenomenon causes symptoms to occur earlier in the day, with greater intensity, and spreading to other body parts - a common reason for dopamine agonist failure 1

• Avoid bupropion: Despite its pro-dopaminergic properties, the AASM specifically recommends against bupropion for RLS treatment 1, 2

• Antidepressant consideration: Duloxetine (Cymbalta) may actually worsen RLS symptoms in some patients due to its serotonergic properties 1

Special Situations

• End-stage renal disease: Consider gabapentin (dose-adjusted), IV iron sucrose (if ferritin <200 ng/mL), or vitamin C 1

• Pregnancy: Consider iron supplementation and non-pharmacological approaches first 1

The evidence strongly supports alpha-2-delta ligands as the most effective next step after dopamine agonist failure, with gabapentin showing similar efficacy to dopamine agonists but with better long-term tolerability and lower risk of augmentation 1, 4.