What is the indicated treatment for a patient with a 2-month history of nocturnal crawling sensations in the calves, thighs, and arms, relieved by stretching and movement?

Initial Management of Restless Legs Syndrome

Check serum ferritin and transferrin saturation immediately, and if ferritin ≤75 ng/mL or transferrin saturation <20%, initiate iron supplementation while simultaneously starting first-line pharmacological therapy with gabapentin, gabapentin enacarbil, or pregabalin. 1, 2

Diagnostic Confirmation

This patient meets all four essential diagnostic criteria for Restless Legs Syndrome (RLS):

• Urge to move with uncomfortable sensations (crawling sensation in calves, thighs, arms) 1
• Symptoms worsen at rest (occurs nightly when lying down) 1
• Relief with movement (stretching and getting up provides temporary relief) 1
• Circadian pattern (symptoms occur nightly, consistent with evening/nighttime worsening) 1

The 2-month duration and involvement of upper extremities indicate this is clinically significant RLS requiring treatment. 3

Immediate Workup Required

Obtain morning fasting iron studies (ferritin and transferrin saturation) after avoiding iron-containing supplements for at least 24 hours. 1, 2 This is critical because:

• Iron deficiency plays a central role in RLS pathophysiology through impaired dopamine transport in the substantia nigra 1
• RLS-specific iron thresholds differ from general population guidelines 1, 2
• Ferritin ≤75 ng/mL or transferrin saturation <20% warrants supplementation even if considered "normal" for general health 1, 2

Perform thorough neurologic examination to exclude secondary causes including peripheral neuropathy, radiculopathy, vascular disease, or spinal cord lesions. 1, 3

Review current medications for RLS-exacerbating agents including tricyclic antidepressants, SSRIs, lithium, antihistamines, and dopamine antagonists (antipsychotics). 1

First-Line Pharmacological Treatment

The 2025 American Academy of Sleep Medicine guidelines represent a major paradigm shift away from dopamine agonists due to augmentation risk. 1

Alpha-2-delta ligands are now strongly recommended as first-line therapy:

• Gabapentin enacarbil (strong recommendation, moderate certainty) 1, 2
• Gabapentin (strong recommendation, moderate certainty) 1, 2
• Pregabalin (strong recommendation, moderate certainty) 1, 2

These agents avoid the augmentation phenomenon—a paradoxical worsening of symptoms with earlier onset, increased intensity, and spread to other body regions—that occurs with long-term dopaminergic therapy. 1, 4

Iron Supplementation Strategy

If ferritin ≤75 ng/mL or transferrin saturation <20%:

• Oral ferrous sulfate is conditionally recommended as initial therapy (moderate certainty) 1, 2
• IV ferric carboxymaltose is strongly recommended for patients with appropriate iron parameters who don't respond to oral therapy or have severe symptoms (moderate certainty) 1, 2
• IV low molecular weight iron dextran or ferumoxytol are conditional alternatives (very low certainty) 1

The higher ferritin threshold for RLS (75 ng/mL vs. 50 ng/mL for general population) reflects that brain iron deficiency drives RLS pathophysiology even when serum iron appears adequate. 1, 2

Treatments to Avoid

Dopamine agonists (pramipexole, ropinirole, rotigotine) are now recommended AGAINST for standard use due to high augmentation rates with long-term therapy. 1, 5 This represents a substantial change from older 2009 guidelines that recommended these as first-line. 1, 5

Levodopa is specifically recommended against (conditional recommendation, very low certainty) due to even higher augmentation risk. 1, 2

Cabergoline is strongly recommended against (strong recommendation, moderate certainty). 1, 2

Critical Pitfall to Avoid

Do not start dopaminergic agents as initial therapy despite their FDA approval and historical use. 1 Augmentation develops in a substantial proportion of patients on long-term dopamine agonist therapy, leading to progressively worsening symptoms that can become around-the-clock and nearly untreatable. 1, 4 Once augmentation develops, management requires complex strategies including dopamine agonist taper, addition of opioids, and IV iron therapy. 1, 2

Second-Line Options for Refractory Cases

If symptoms persist despite alpha-2-delta ligands and iron optimization:

• Extended-release oxycodone or other low-dose opioids (conditional recommendation, moderate certainty) 1, 2
• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 1, 2
• Dipyridamole (conditional recommendation, low certainty) 1

Addressing Exacerbating Factors

Before or concurrent with pharmacological treatment, address modifiable factors:

• Reduce or eliminate alcohol, caffeine intake 1, 2
• Screen for and treat obstructive sleep apnea if present 1, 2
• Discontinue or substitute RLS-worsening medications when possible 1, 2
• Address lifestyle factors including sedentary behavior, elevated BMI, tobacco use 1