What medication is appropriate for an adult with restless legs syndrome and insomnia, assuming normal renal function and no history of severe depression or suicidal ideation?

Gabapentin or pregabalin is the best medication for restless legs syndrome with insomnia

For an adult with restless legs syndrome (RLS) and insomnia, start with gabapentin enacarbil, gabapentin, or pregabalin as first-line therapy—these are the only medications with strong recommendations from the most recent 2025 AASM guidelines and they address both RLS symptoms and sleep quality without the risk of augmentation that plagues dopamine agonists. 1

Why Alpha-2-Delta Ligands Are First-Line

The 2025 AASM clinical practice guideline represents a major shift in RLS treatment, now prioritizing alpha-2-delta calcium channel ligands over dopamine agonists. The three medications with strong recommendations (the highest level) are:

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

These medications directly improve both RLS symptoms and subjective sleep quality 1, making them ideal for your patient presenting with both complaints.

The Dopamine Agonist Problem

The guidelines now suggest against standard use of all dopamine agonists including pramipexole, ropinirole, and rotigotine 1. While these drugs work short-term, they carry significant risk of augmentation—a progressive iatrogenic worsening where RLS symptoms become more severe, occur earlier in the day, and spread to other body parts 2. This long-term complication affects quality of life substantially and is difficult to reverse.

The guidelines only permit dopamine agonist use "in patients who place a higher value on reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use" 1—essentially relegating them to second-line or rescue therapy.

Practical Prescribing Algorithm

Step 1: Check iron status first

• Obtain serum ferritin and transferrin saturation
• If ferritin ≤75 μg/L, start ferrous sulfate with vitamin C 1
• If appropriate iron parameters exist, consider IV ferric carboxymaltose (strong recommendation) 1

Step 2: Start an alpha-2-delta ligand

• Gabapentin enacarbil: 600 mg once daily (extended-release formulation, best bioavailability)
• Gabapentin: Start 300 mg at bedtime, titrate up to 1200-1800 mg/day divided
• Pregabalin: Start 75 mg at bedtime, titrate to 150-300 mg/day

All three have equivalent strong recommendations, so choose based on:

• Renal function (dose-adjust all three in renal impairment)
• Cost/insurance coverage (gabapentin enacarbil is branded and expensive)
• Dosing convenience (gabapentin enacarbil is once-daily)

Step 3: If inadequate response after 4-6 weeks at therapeutic doses

• Add low-dose opioid (extended-release oxycodone/naloxone) 1
• Consider combination therapy with a different alpha-2-delta ligand
• Bilateral peroneal nerve stimulation is an emerging option 1

Critical Pitfalls to Avoid

Do not use benzodiazepines for RLS-related insomnia. The guidelines specifically recommend against clonazepam 1, and while the 2016 ACP insomnia guideline discusses benzodiazepines for chronic insomnia 3, they don't address RLS symptoms and carry dependency risks.

Avoid medications that worsen RLS: Many antidepressants (especially SSRIs, SNRIs, mirtazapine) and antihistamines (diphenhydramine, doxylamine) can exacerbate RLS symptoms. If your patient is on these for depression or sleep, consider switching to bupropion (though note the guidelines suggest against bupropion specifically for RLS treatment 1).

Don't start with dopamine agonists despite their historical use—the 2025 guidelines represent an evidence-based paradigm shift away from these agents due to augmentation risks that compromise long-term quality of life 4.

Special Considerations

If your patient has end-stage renal disease, gabapentin remains appropriate (conditional recommendation) 1, though dose adjustment is essential. IV iron sucrose is also recommended in dialysis patients with ferritin <200 ng/mL and transferrin saturation <20% 1.

The alpha-2-delta ligands improve both objective RLS symptom scores and subjective sleep quality measures 1, making them uniquely suited for patients presenting with both complaints. They also have favorable long-term safety profiles without the augmentation phenomenon that plagues dopaminergic therapy 4.