gabapentin enacarbil

General Information

Gabapentin enacarbil (brand Horizant) is an extended-release prodrug of gabapentin indicated for moderate-to-severe primary RLS and for postherpetic neuralgia (label).

It is an alpha-2-delta ligand (via conversion to gabapentin). In RLS, alpha-2-delta ligands are often positioned when painful symptoms and insomnia are prominent or when avoiding long-term dopaminergic risks (including augmentation) is a priority (guideline/clinical).

The main tolerability issues are somnolence and dizziness; next-day impairment and fall risk are important follow-up topics, especially when combined with other sedatives (label/clinical).

Gabapentin enacarbil and released gabapentin are not CYP substrates, inhibitors, or inducers; interaction management focuses on additive sedation and kidney-function-based dosing (label).

The gabapentin enacarbil compare view, evidence feed, and print page support review of RLS options and monitoring topics.

Gabapentin enacarbil is often positioned as a non-dopaminergic option for RLS when sedation is acceptable or helpful and when avoiding dopamine-agonist long-term risks is important; tolerability depends on next-day function, fall risk, and total sedative burden (guideline/clinical).

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Prodrug converted to gabapentin, an alpha-2-delta ligand that modulates voltage-gated calcium channels and reduces excitatory neurotransmitter release (class/mechanism).

It does not act through dopamine receptors and is not a dopamine agonist.

In RLS care frameworks, alpha-2-delta ligands are often used when painful sensations, insomnia, or risk of dopaminergic augmentation are key constraints (guideline/clinical).

• Alpha-2-delta ligand (via gabapentin).

Metabolism and Pharmacokinetics

• After oral administration, gabapentin enacarbil undergoes extensive first-pass hydrolysis by non-specific carboxylesterases (primarily in enterocytes) to form gabapentin; levels of gabapentin enacarbil are low and transient (label).
• Released gabapentin is not appreciably metabolized and is excreted unchanged in urine; clearance tracks renal function (label).
• Elimination half-life (gabapentin) is ~5.1 to 6.0 hours (label).

Dosing and Administration

• RLS: 600 mg once daily taken at about 5 PM with food (label).
• Postherpetic neuralgia: 600 mg in the morning for 3 days, then 600 mg twice daily with food (label).
• Tablets are taken whole; crushing or chewing can alter the extended-release profile and increase adverse effects (label).
• Dose adjustment is required in renal impairment; dosing is tied to creatinine clearance (label).

Monitoring & Labs

• Next-day sedation and driving/falls risk monitoring (label/clinical).
• Kidney function and renal-dose adjustment review (label).
• Mood and suicidality monitoring when baseline risk is elevated (label/class).
• Edema and weight monitoring during longer courses (label/clinical).
• Review of concurrent sedatives/substances (alcohol, opioids, benzodiazepines) to reduce additive CNS depression risk (label/clinical).

Adverse Effects

Interactions

• Gabapentin enacarbil and released gabapentin are not CYP substrates, inhibitors, or inducers; interactions are primarily driven by additive sedation and renal clearance rather than CYP-mediated effects (label).
• CNS depressants (including alcohol) increase impairment risk; combined use increases sedation/falls risk and may require closer follow-up (label/clinical).

Other Useful Information

• RLS frameworks emphasize screening for contributors (iron deficiency, sleep apnea, medication triggers) and reassessing treatment when symptoms shift earlier in the day or intensify (guideline/clinical).
• The AASM guideline and updated algorithms provide practical framing for choosing between alpha-2-delta ligands and dopamine agonists, including monitoring for augmentation and impulse-control symptoms (guideline).
• Gabapentin enacarbil is not interchangeable with immediate-release gabapentin on a mg-for-mg basis. Switching between formulations is typically done deliberately with ongoing monitoring for efficacy, daytime sedation, and renal-dose appropriateness (label/clinical).

References

1. Horizant (gabapentin Enacarbil) Extended Release Tablets Prescribing Information — DailyMed (2025)
2. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline — Journal of Clinical Sleep Medicine (2025)
3. The Management of Restless Legs Syndrome: An Updated Algorithm — Mayo Clinic Proceedings (2021)
4. Gabapentin Enacarbil IN Japanese Patients With Restless Legs Syndrome: A 12 Week, Randomized, Double Blind, Placebo Controlled, Parallel Group Study — Current Medical Research and Opinion (2012)