What is the recommended treatment plan for an adult patient with moderate-to-severe restless legs syndrome (RLS) or primary periodic limb movement disorder (PLMD) using Horizant (gabapentin enacarbil)?

Horizant (Gabapentin Enacarbil) Treatment Plan for Moderate-to-Severe RLS

For adults with moderate-to-severe restless legs syndrome, initiate Horizant (gabapentin enacarbil) 600 mg once daily at approximately 5 PM with food, as this is the FDA-approved dose that provides optimal symptom control throughout the evening and night when RLS symptoms peak. 1, 2, 3

Pre-Treatment Assessment

Before starting Horizant, complete the following mandatory evaluations:

• Check morning fasting iron studies (serum ferritin and transferrin saturation) after avoiding iron supplements for at least 24 hours, as iron deficiency is a reversible cause of RLS that must be addressed first 1, 2
• Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20% using either IV ferric carboxymaltose (strong recommendation) or oral ferrous sulfate with vitamin C (conditional recommendation) 1, 2
• Review and eliminate exacerbating medications including antihistamines, SSRIs, tricyclic antidepressants, and antipsychotics (dopamine antagonists), as these can trigger or worsen RLS 1
• Screen for untreated obstructive sleep apnea, as this must be managed before initiating alpha-2-delta ligands due to respiratory depression risks 1

Dosing Protocol for Horizant

• Standard dose: 600 mg once daily at approximately 5 PM with food - this is the only FDA-approved dose for RLS and should not be titrated higher 3
• Timing is critical: Take at 5 PM to ensure peak plasma levels coincide with evening/nighttime symptom onset 3
• Food requirement: Must be taken with food to optimize absorption of this prodrug formulation 3
• Do not split, crush, or chew tablets as this destroys the extended-release mechanism 3

Why Horizant is First-Line Therapy

The American Academy of Sleep Medicine strongly recommends gabapentin enacarbil as first-line treatment over dopamine agonists because:

• No augmentation risk - unlike pramipexole, ropinirole, and rotigotine, which cause paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread in 30-70% of patients with long-term use 1, 2, 4
• Superior efficacy for RLS pain - gabapentin enacarbil significantly improves both sensory symptoms and RLS-associated pain scores 3
• Sustained response - maintains efficacy in long-term trials with lower relapse rates compared to placebo 3
• No cardiac valvulopathy risk - unlike cabergoline, which is strongly recommended against 1, 2
• No QT-interval prolongation reported in clinical trials 3

Expected Outcomes and Timeline

• Symptom improvement should be evident within 12 weeks, with significant reductions in International RLS Study Group Rating Scale (IRLS) scores 3
• Sleep quality improvements occur concurrently, with better subjective sleep measures and reduced periodic limb movements 3, 5
• Mood benefits are commonly observed as sleep improves 3

Monitoring and Side Effects

Common adverse events (mostly mild-to-moderate severity):

• Somnolence/sedation and dizziness are the most frequent side effects - warn patients about fall risk, especially in elderly populations 1, 3
• Monitor for altered mental status particularly in patients with renal impairment 1
• Reassess iron studies every 6-12 months as RLS symptoms may recur if iron stores decline 1, 2
• Evaluate for improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) 1

Critical Pitfalls to Avoid

• Do not use single nighttime dosing of regular gabapentin as a substitute for Horizant - this fails to address daytime symptoms and provides suboptimal coverage 1
• Do not start dopamine agonists first - the 2025 American Academy of Sleep Medicine guidelines explicitly recommend against standard use of pramipexole, ropinirole, and rotigotine due to augmentation risks 1, 2, 4
• Do not skip iron assessment - correcting iron deficiency can significantly improve RLS independent of pharmacotherapy 1, 2
• Do not prescribe in patients with untreated OSA without addressing the sleep apnea first, as gabapentinoids can worsen respiratory depression 1

Alternative Alpha-2-Delta Ligands

If Horizant is not tolerated or available:

• Pregabalin (strong recommendation, moderate certainty) - allows twice-daily dosing with potentially superior bioavailability 1, 2
• Regular gabapentin (strong recommendation, moderate certainty) - requires three-times-daily dosing starting at 300 mg TID, titrating by 300 mg/day every 3-7 days to maintenance dose of 1800-2400 mg/day 1, 2

Refractory Cases

For patients who fail alpha-2-delta ligands after optimizing iron status:

• Extended-release oxycodone or other low-dose opioids are conditionally recommended for moderate-to-severe refractory RLS, with evidence showing relatively low abuse risk in appropriately screened patients 1, 2
• Bilateral high-frequency peroneal nerve stimulation is a non-pharmacological option with conditional recommendation 1, 2

Special Population: End-Stage Renal Disease

• Gabapentin is preferred over gabapentin enacarbil in ESRD patients (conditional recommendation, very low certainty) 1, 2
• Start with 100 mg post-dialysis or at bedtime, with maximum doses of 200-300 mg daily due to significantly increased fall and altered mental status risk 1