Gamma-aminobutyric acid analogs

Generic and Brand Names

• Gabapentin — Neurontin (IR), Gralise (ER)

• Gabapentin enacarbil (prodrug of gabapentin) — Horizant (extended-release)

• Pregabalin — Lyrica (IR), Lyrica CR (ER)

• Mirogabalin — Tarlige (regional approvals)

• Related GABA-analog but different target

  • Baclofen — Lioresal (oral), Lioresal Intrathecal / Gablofen (IT pump)

Class

• Gabapentinoids (gabapentin, pregabalin, mirogabalin, gabapentin enacarbil): α2δ-1/α2δ-2 voltage-gated calcium-channel ligands (do not act on GABA receptors despite the name)

• Baclofen: GABA-B receptor agonist (included for contrast as a GABA analog with distinct pharmacology)

Mechanism of Action

• Gabapentinoids: Bind presynaptic α2δ subunit of voltage-gated Ca²⁺ channels → ↓ excitatory neurotransmitter release (glutamate, NE, substance P) → analgesic, anticonvulsant, anxiolytic effects (jurisdiction-specific)

• Baclofen: Agonizes GABA-B receptors (spinal > supraspinal) → ↓ excitatory neurotransmission → antispasticity

Indications

• Gabapentin: Adjunct for focal (partial-onset) seizures; postherpetic neuralgia (PHN)

• Gabapentin enacarbil: Restless legs syndrome (RLS); PHN (ER formulation)

• Pregabalin: Adjunct for focal seizures; neuropathic pain (PHN, diabetic peripheral neuropathy); fibromyalgia; neuropathic pain due to spinal cord injury (regions vary)

• Mirogabalin: Neuropathic pain (e.g., DPN, PHN) — regional labels

• Baclofen (contrast): Spasticity of cerebral/spinal origin (not an analgesic; not antiseizure)

Dosage and Administration (Adults)

• Gabapentin (IR): 300 mg qHS → 300 mg BID day 2 → 300 mg TID day 3; titrate to 900–3,600 mg/day in 3 doses. Take with or without food; separate from Al/Mg antacids by ≥2 h

• Gabapentin (ER, Gralise): Once-daily evening dosing; follow product-specific titration for PHN

• Gabapentin enacarbil (Horizant): RLS 600 mg once daily with food at ~5 pm; PHN 600 mg BID with food

• Pregabalin (IR): Start 75 mg BID or 50 mg TID; titrate to 150–600 mg/day in 2–3 doses based on response and renal function

  • Pregabalin CR: Once daily after evening meal (dose-equivalence per label)

• Mirogabalin: Typical 10–30 mg/day in divided doses (regional)

• Renal dose adjustment (guidance)

  • CrCl ≥60 mL/min: usual targets above

  • 30–59: gabapentin 400–1,400 mg/day; pregabalin 75–300 mg/day

  • 15–29: gabapentin 200–700 mg/day; pregabalin 25–150 mg/day

  • <15: gabapentin 100–300 mg/day; pregabalin 25–75 mg/day

  • Hemodialysis: give supplemental dose post-HD (e.g., gabapentin 100–300 mg; pregabalin 25–150 mg depending on baseline)

• Discontinuation: Taper over ≥1 week to reduce withdrawal (anxiety, insomnia, nausea, pain rebound, rare seizures)

Pharmacokinetics (Key Differences)

• Gabapentin: Nonlinear saturable intestinal uptake (L-amino-acid transporter) → bioavailability falls as dose increases (e.g., ~60% at 900 mg/day → ~35% at 3,600 mg/day). Not metabolized; renal elimination

• Gabapentin enacarbil: Prodrug with high, dose-proportional bioavailability via monocarboxylate transporters; designed for once-daily exposure

• Pregabalin: Linear PK; ≥90% oral bioavailability across doses; minimal metabolism; renal elimination

• Mirogabalin: High oral bioavailability; dual α2δ binding with slower dissociation from α2δ-1 (analgesic target) versus α2δ-2 (cerebellar adverse-effect target) — design aims to improve tolerability

Monitoring

• Pain and function scores; seizure diary if applicable

• Renal function at baseline and periodically

• Neuropsychiatric status (mood, suicidality per AED class warning)

• Weight, edema, dizziness/somnolence (falls risk), vision changes

• Misuse/diversion screening (pregabalin is Schedule V in some regions; gabapentin scheduled in some jurisdictions)

Contraindications

• Known hypersensitivity to product/components

Precautions

• CNS/respiratory depression: additive with opioids, benzodiazepines, sedatives; increased risk in COPD, elderly, and at high doses

• Peripheral edema/weight gain: caution in heart failure; monitor when combined with TZDs

• Driving/operating machinery: dizziness, somnolence, blurred vision

• Angioedema (pregabalin, rare)

• Pregnancy/lactation: risk–benefit individualized; enroll in AED pregnancy registry where available

• RLS augmentation: lower risk than dopamine agonists; still monitor symptom drift earlier in the day

• Baclofen (contrast): risk of life-threatening withdrawal with abrupt stop (especially intrathecal)

Adverse Effects

• Common: dizziness, somnolence, ataxia, fatigue, tremor, blurred vision, peripheral edema, weight gain, dry mouth

• GI: constipation or diarrhea, nausea

• Neuropsychiatric: euphoria, mood change, irritability (dose-related)

• Hypersensitivity/angioedema (rare; pregabalin > gabapentin)

• Withdrawal with abrupt cessation (anxiety, insomnia, diaphoresis, pain rebound; seizures in susceptible patients)

Drug Interactions (Clinically Relevant)

• Opioids/benzodiazepines/other CNS depressants: additive sedation, respiratory depression

• Antacids (Al/Mg): ↓ gabapentin absorption — separate by ≥2 h

• No meaningful CYP interactions (class advantage)

• Thiazolidinediones: additive edema/weight gain with pregabalin (monitor)

Overdose

• Symptoms: profound somnolence, dizziness/ataxia, agitation, GI upset; seizures are uncommon but possible

• Management: airway/ventilatory support, activated charcoal if appropriate, hemodialysis enhances clearance (especially in renal failure)

Patient Counselling

• Take as prescribed; do not stop suddenly — taper with clinician

• Expect early dizziness/sleepiness; avoid alcohol/sedatives; caution with driving

• Report leg swelling, sudden weight gain, rash, or facial swelling

• For gabapentin IR, separate from antacids by ≥2 hours

• For RLS (gabapentin enacarbil), take with food in the early evening

• If on opioids or with lung disease, alert clinician due to breathing-risk synergy

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Comparison Table 1 — Gabapentinoids

Attribute	Gabapentin (IR/ER)	Gabapentin enacarbil (ER)	Pregabalin (IR/CR)	Mirogabalin
Primary indications	Focal seizures (adjunct), PHN	RLS, PHN	Focal seizures (adjunct), DPN, PHN, fibromyalgia, neuropathic pain (SCI)	Neuropathic pain (regional)
PK/bioavailability	Nonlinear, ↓ with dose	Prodrug, high, dose-proportional	Linear, ≥90%	High; designed for α2δ-1 selectivity
Dosing frequency	TID (IR); once-daily evening (ER Gralise for PHN)	Once daily (RLS) or BID (PHN) with food	BID/TID (IR) or QD (CR)	BID (typical regional)
Renal adjustment	Required	Required	Required	Required
Common AEs	Dizziness, somnolence, ataxia, edema, weight gain	Similar to gabapentin; somnolence, dizziness	Somnolence, dizziness, edema, weight gain, blurred vision	Dizziness, somnolence; aim of improved tolerability
Abuse/misuse	Emerging reports; jurisdictional scheduling	As gabapentin	Schedule V (many regions)	Regional controls vary
Practical pearls	Separate from antacids; absorption saturates at high doses	Evening dosing improves RLS symptoms	Faster titration; consistent exposure	Availability limited to certain countries

Comparison Table 2 — GABA Analogs by Pharmacologic Target

Feature	Gabapentinoids (Gabapentin, Pregabalin, Mirogabalin, Gabapentin enacarbil)	Baclofen (contrast)
Primary target	α2δ subunit of voltage-gated Ca²⁺ channels	GABA-B receptor agonist
Principal clinical use	Neuropathic pain, focal-seizure adjunct; RLS (enacarbil); fibromyalgia (pregabalin)	Spasticity (spinal/cerebral)
Onset/titration	Days; titrate over 1–2 weeks	Days; titrate cautiously
CNS adverse profile	Dizziness, somnolence, ataxia, edema	Sedation, weakness, dizziness
Withdrawal risk if abrupt stop	Yes (milder; anxiety, insomnia, pain rebound)	High (delirium, hyperthermia, rhabdomyolysis; especially intrathecal)
Respiratory-depressant synergy	Yes with opioids/benzos	Yes with other CNS depressants
Drug interactions	Minimal CYP; antacids ↓ gabapentin absorption	Minimal CYP; additive CNS depression

Renal Dosing Quick-Guide (Adults)

CrCl (mL/min)	Gabapentin total daily	Pregabalin total daily	Supplement after HD
≥60	900–3,600 mg (TID)	150–600 mg	Gabapentin 100–300 mg; Pregabalin 25–150 mg
30–59	400–1,400 mg (divided)	75–300 mg	As above
15–29	200–700 mg (divided)	25–150 mg	As above
<15	100–300 mg (QD)	25–75 mg	As above

Practical Positioning

• Prefer pregabalin when predictable PK, faster titration, and broader labeled pain indications are desired.

• Prefer gabapentin when cost is critical and slower titration is acceptable; consider ER or enacarbil for PHN/RLS adherence.

• Reserve mirogabalin where available when neuropathic pain and tolerability balance is prioritized.

• Screen for sedation/fall risk, concurrent opioids, and renal impairment before choosing and dosing.