What is the preferred initial treatment for a patient with neuropathic pain or restless legs syndrome, without significant impaired renal function or a history of substance abuse, between Horizant (gabapentin enacarbil) and gabapentin?

Gabapentin vs Horizant (Gabapentin Enacarbil): Treatment Selection

For both neuropathic pain and restless legs syndrome, standard gabapentin is the preferred initial treatment over Horizant (gabapentin enacarbil) due to stronger guideline support, extensive clinical experience, lower cost, and equivalent efficacy when properly dosed.

For Neuropathic Pain

First-Line Recommendation

• Gabapentin is strongly recommended as first-line oral pharmacological treatment for neuropathic pain, with the most robust evidence in HIV-associated neuropathy (strong recommendation, moderate certainty) and cancer-related neuropathic pain 1, 2
• Standard gabapentin should be initiated at 100-300 mg at bedtime or three times daily, with gradual titration to a target maintenance dose of 900-1800 mg/day in divided doses, allowing 3-8 weeks for titration plus 2 weeks at maximum tolerated dose for adequate trial 2, 3
• Horizant (gabapentin enacarbil) has FDA approval for postherpetic neuralgia but lacks the extensive guideline support and clinical evidence base that standard gabapentin has accumulated across multiple neuropathic pain conditions 4, 5

Key Pharmacokinetic Differences

• Gabapentin has nonlinear, saturable absorption that becomes less efficient at higher doses, requiring divided dosing (typically three times daily) and gradual titration 2, 6
• Horizant provides more predictable absorption through its prodrug formulation, allowing once or twice daily dosing, but this pharmacokinetic advantage does not translate to superior clinical outcomes in head-to-head comparisons 4, 5
• Both medications are eliminated unchanged by the kidneys and require mandatory dose reduction in renal impairment 2, 7

Practical Dosing Algorithm for Gabapentin

• Start with 100-300 mg at bedtime on day 1, then increase to 100-300 mg three times daily by day 3 3
• Titrate gradually by 100-300 mg every 3-7 days as tolerated, targeting 1800-3600 mg/day in three divided doses 2, 3
• Allow adequate trial duration: 3-8 weeks for titration plus 2 weeks at maximum tolerated dose before declaring treatment failure 2, 3
• Maximum dose is 3600 mg/day, with doses above 2400 mg/day used cautiously, especially in older adults 3

Cost Considerations

• Generic gabapentin is substantially less expensive than branded Horizant, making it the more cost-effective first-line choice without sacrificing efficacy 2

For Restless Legs Syndrome

Updated Guideline Recommendations (2025)

• The American Academy of Sleep Medicine (AASM) 2025 guidelines recommend gabapentin enacarbil as first-line treatment for RLS (strong recommendation, moderate certainty of evidence), representing a significant shift from dopamine agonists due to augmentation concerns 1
• Alpha-2-delta ligands (gabapentin enacarbil and pregabalin) are now preferred over dopamine agonists for standard use, as the AASM suggests against standard use of pramipexole, ropinirole, and rotigotine due to long-term augmentation risk 1
• Standard gabapentin is conditionally recommended for RLS patients with end-stage renal disease (ESRD), though the evidence quality is very low 1

Horizant-Specific Advantages for RLS

• Horizant (gabapentin enacarbil) has FDA approval specifically for moderate-to-severe RLS, with demonstrated efficacy in reducing RLS symptoms and improving sleep quality 4, 5
• Bioavailability is significantly greater with gabapentin enacarbil compared to standard gabapentin, providing more consistent drug levels with once or twice daily dosing 5
• Augmentation has not been associated with gabapentin or gabapentin enacarbil, unlike dopamine agonists where augmentation rates can be substantial 5

Standard Gabapentin for RLS

• Standard gabapentin (300 mg initial dose with up-titration) has demonstrated significant improvement in subjective RLS symptoms and reduction in periodic leg movements during sleep (PLMS) in clinical studies 8
• Gabapentin provides well-tolerated and effective treatment for idiopathic RLS, though dosing may require individual titration 8

Clinical Decision Algorithm for RLS

If patient has moderate-to-severe RLS requiring medication:

1. First choice: Gabapentin enacarbil (Horizant) based on 2025 AASM strong recommendation and FDA approval for this specific indication 1, 5
2. Alternative: Standard gabapentin if cost is prohibitive or insurance does not cover Horizant, using gradual titration starting at 300 mg 1, 8
3. Avoid dopamine agonists as first-line unless patient places higher value on short-term symptom reduction and lower value on long-term augmentation risk 1

If patient has RLS with end-stage renal disease:

• Use standard gabapentin with mandatory dose reduction based on creatinine clearance 1, 7
• Start at 100-200 mg once daily with maximum dose of 200-700 mg/day as single daily dose in severe renal impairment (CrCl 15-29 mL/min) 3

Critical Safety Considerations

Adverse Effects (Common to Both Formulations)

• Dizziness (19-46%), somnolence (14-25%), peripheral edema (7-10%), and gait disturbance (9%) are the most common dose-dependent adverse effects 2, 6, 3
• These effects are typically mild to moderate and often transient, usually subsiding within approximately 10 days 3
• In hemodialysis patients, gabapentin and pregabalin are associated with 50% higher hazards of altered mental status, 55% higher hazards of falls, and 38% higher hazards of fractures at highest doses, with even lower doses showing elevated risk 7

Special Population Warnings

• Elderly patients require lower starting doses and slower titration due to increased risk of falls, confusion, and sedation 2, 6, 3
• Mandatory renal function assessment before initiating therapy using Cockcroft-Gault equation, as elderly patients invariably have reduced renal function 3
• Never start at high doses without gradual titration, as this dramatically increases risk of intolerable adverse effects 3

Discontinuation Protocol

• Never abruptly discontinue either medication—taper gradually over minimum of 1 week to avoid withdrawal symptoms 2, 6

Common Pitfalls to Avoid

• Do not assume Horizant is superior to gabapentin for neuropathic pain simply because it has better bioavailability—the extensive guideline support and clinical evidence favor standard gabapentin as first-line 1, 2
• Do not fail to allow adequate trial duration with gabapentin (2+ months including titration) before switching to alternative agents 2, 3
• Do not use standard doses in renal impairment—both formulations require mandatory dose reduction based on creatinine clearance 2, 3, 7
• Do not overlook the 2025 AASM guideline shift favoring alpha-2-delta ligands over dopamine agonists for RLS due to augmentation concerns 1