What is the first line therapy for restless legs syndrome (RLS)?

First-Line Therapy for Restless Legs Syndrome

Alpha-2-delta ligands, such as pregabalin or gabapentin, are the recommended first-line treatments for restless legs syndrome (RLS) due to their efficacy and favorable long-term safety profile. 1

Diagnosis Confirmation

RLS is characterized by:

• Uncomfortable urge to move the legs
• Symptoms that begin or worsen during periods of rest
• Relief with movement
• Worsening of symptoms in the evening or night

Treatment Algorithm

First-Line Treatment Options

1. Alpha-2-delta ligands:

   • Pregabalin or gabapentin
   • Preferred over dopamine agonists due to lower risk of augmentation (paradoxical worsening of symptoms)
   • Particularly beneficial in patients with comorbid chronic kidney disease (CKD) or end-stage renal disease (ESRD) 1

2. Iron supplementation:

   • Should be initiated concurrently if ferritin levels <50 ng/mL
   • For ESRD patients: IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 1

Second-Line Treatment Options

1. Dopamine agonists:

   • Ropinirole: Starting dose 0.25 mg orally 1-3 hours before bedtime
   • Pramipexole: Starting dose 0.125 mg orally 2-3 hours before bedtime
   • Rotigotine patch
   • Important caution: Use only for short-term management due to risk of augmentation 1, 2
   • Clinical trials showed significant improvement in RLS symptoms with ropinirole compared to placebo 2

2. Low-dose opioids:

   • For moderate to severe RLS that has failed other therapies
   • Can facilitate tapering of dopamine agonists
   • Use with caution due to risk of central sleep apnea and respiratory depression 1

Non-Pharmacological Approaches

These should be implemented alongside pharmacological treatment:

• Regular aerobic and resistance exercise 1, 3
• Smoking cessation
• Alcohol avoidance
• Caffeine reduction or elimination
• Compression devices 3
• Repetitive transcranial magnetic stimulation (emerging evidence) 3

Monitoring and Follow-up

1. Regular assessment for medication side effects:

   • Particularly important for patients on dopamine agonists (monitor for augmentation)
   • Symptoms of augmentation include earlier onset of symptoms during the day and spread to other body parts

2. Laboratory monitoring:

   • Complete blood count
   • Basic metabolic panel
   • Liver function tests
   • Serum ferritin (primary laboratory test)
   • Thyroid function tests, HbA1c, and urine albumin:creatinine ratio as indicated 1

Special Considerations

1. Patients with CKD or ESRD:

   • Gabapentin is first-line
   • Consider vitamin C supplementation
   • Cool dialysate for patients on hemodialysis 1

2. Severe to very severe RLS:

   • Consider extended-release oxycodone as second-line therapy 1

Common Pitfalls to Avoid

1. Long-term use of dopamine agonists without monitoring for augmentation

   • Despite their efficacy (shown in clinical trials with ropinirole demonstrating 16.8-19.9% higher response rates compared to placebo 2), the risk of augmentation limits their long-term utility

2. Failure to evaluate and treat iron deficiency

   • Iron supplementation is essential for patients with low ferritin levels

3. Overlooking mimics of RLS

   • Leg cramps, venous stasis, positional discomfort, and arthritis can present similarly 1

The evidence strongly supports alpha-2-delta ligands as first-line therapy for RLS, representing a shift from earlier practices that favored dopamine agonists. This change is based on the recognition of augmentation as a significant long-term complication of dopamine agonist therapy, while alpha-2-delta ligands maintain efficacy with a more favorable safety profile.