Gabapentinoids (antiepileptics)
Brand names: Neurontin, Gralise, Horizant
Updated · Methodology
First line
First-line for neuropathic pain per NeuPSIG 2015 and IASP 2022. Used in diabetic polyneuropathy, post-herpetic neuralgia, and trigeminal neuralgia. Start 300 mg at bedtime, titrate to 900–3600 mg/day in three divided doses. Effect develops over 2–4 weeks. NNT for PHN – 7; for diabetic neuropathy – 6.
Sources
ICD-10: M79.2 · ICD-11: MG30.5Z
First line
First-line for post-herpetic neuralgia. Dose 1800–3600 mg/day. Alternatives: pregabalin, amitriptyline, duloxetine, topical lidocaine and capsaicin. PHN prevention: Shingrix vaccination in adults over 50.
Sources
ICD-10: B02.2 · ICD-11: 1E91.5
First line
Per the updated 2025 guideline, the first line for restless legs syndrome is the alpha-2-delta ligands (gabapentin, gabapentin enacarbil, pregabalin); they are preferred over dopamine agonists, which cause augmentation (symptom worsening) over time. Plain gabapentin is used off-label, usually 300 mg 1–2 hours before bed, titrated to 1200–1800 mg/day; gabapentin enacarbil (Horizant) has more direct trial evidence and a different regimen (600 mg once in the evening). The effect develops over 1–2 weeks. It suits patients with coexisting pain or anxiety; use caution in reduced kidney function (lower the dose) and because of sedation, dizziness, and abuse potential.
Primarily gabapentin enacarbil (Horizant), not registered in Russia. Plain gabapentin is used off-label.
Sources
ICD-10: G25.81 · ICD-11: 7A80
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
Gabapentin is an antiepileptic drug prescribed for partial epilepsy, neuropathic pain, and restless legs syndrome. It is often prescribed as a sleep aid outside an epilepsy, neuropathic pain, or RLS indication, purely because of its sedative side effect. International insomnia guidelines ( 2021, ESRS 2017, NG219) do not support this use: for primary insomnia the first line is cognitive-behavioral therapy for insomnia (CBT-I), and medication is matched to the diagnosis. Clinical trials of gabapentin for primary insomnia are few and heterogeneous. The drug has specific risks: dizziness, next-day sedation, peripheral edema, respiratory depression when combined with opioids ( warning, 2019), and potential for dependence and misuse. If gabapentin was prescribed for sleep outside an RLS or neuropathic pain indication, consider seeking a second opinion.
Sources
ICD-10: G47.0 · ICD-11: 7A00
Not recommended
Gabapentin for non-clinical anxiety or stress is not mentioned in or mental health guidelines. Off-label use is widespread but unjustified – efficacy is doubtful and dependence/abuse risks are real. Since 2018, gabapentin and pregabalin are Schedule 3 controlled substances in the UK.
Sources
ICD-10: F41.9 · ICD-11: 6B0Z
Structural analogue of GABA that does not bind GABA receptors. Binds the α2δ subunit of voltage-gated calcium channels in the CNS, reducing presynaptic calcium influx and release of excitatory neurotransmitters (glutamate, noradrenaline, substance P). Bioavailability is dose-dependent (saturation of intestinal transporter) — above 1800 mg/day, further increases produce diminishing plasma rises.
FDA categories were retired in 2015. Pregnancy safety data are limited. Use in pregnant patients with severe neuropathic pain or epilepsy is individualized with a neurologist.
Transfers into breast milk. Per LactMed, use is acceptable with monitoring for infant sedation and poor weight gain.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
4 pairs found. Sorted from critical to minor.
Mechanism
Alprazolam and gabapentin depress the central nervous system (CNS) by different pathways, and their effects add up. The alprazolam SmPC warns that combining it with antiepileptics increases CNS depression and the risk of respiratory depression, coma and death (alprazolam SmPC). The gabapentin SmPC reports cases of respiratory depression, sedation and death when gabapentin was taken with other CNS depressants (gabapentin SmPC).
Symptoms
Drowsiness, dizziness, slowed thinking and reactions, impaired coordination. With marked depression: slow, shallow breathing, confusion and loss of consciousness (alprazolam and gabapentin SmPCs). In older patients, drowsiness and dizziness increase the risk of falls (alprazolam and gabapentin SmPCs).
Management
The alprazolam SmPC requires limiting the dose and duration of co-administration with antiepileptics, which include gabapentin (alprazolam SmPC; alprazolam label of the US Food and Drug Administration, ). Use alprazolam at the lowest effective dose for the shortest time, no longer than 2–4 weeks; in older patients, start with 0.25 mg two or three times a day and use caution because of sedation, muscle weakness and the risk of falls (alprazolam SmPC). Watch the patient closely for drowsiness, sedation and respiratory depression, and reduce the dose of gabapentin or of the other CNS depressant accordingly (gabapentin SmPC). The risk of severe respiratory depression is higher in older patients and in those with lung disease, neurological disease or renal impairment (gabapentin SmPC). Advise the patient not to drive or operate machinery while taking alprazolam (alprazolam FDA label).
Sources
Mechanism
Morphine and gabapentin both depress the central nervous system, and the effects add up: the risk of profound sedation, respiratory depression, coma and death rises. The kinetic effect goes one way: controlled-release morphine taken 2 hours before gabapentin raised gabapentin AUC by 44%, while gabapentin did not change morphine pharmacokinetics. In December 2019 the warned about serious breathing problems when gabapentinoids are combined with opioids.
Symptoms
Drowsiness, slowed breathing (rate below 12/min), cyanosis of lips. Severe cases include respiratory arrest. Older patients: fall risk.
Management
The US morphine label reserves the combination for patients whose alternative treatment options are inadequate, and the Spanish label requires limiting the dose and duration of concomitant use. Start gabapentin at a low dose. If drowsiness or slowed breathing appears, reduce the gabapentin or morphine dose per the label. Monitor respiratory rate, oxygen saturation and level of consciousness, with extra care in older adults and in patients with lung disease or renal impairment. Prescribe naloxone and teach the patient and family the signs of overdose.
Sources
Mechanism
Additive CNS depression. Gabapentin does not lower the seizure threshold, but opioid-gabapentinoid combinations are associated with respiratory depression risk, especially in older patients.
Symptoms
Drowsiness, slowed breathing (rate below 12/min), cyanosis of lips. Severe cases include respiratory arrest. Older patients: fall risk.
Management
The combination is possible in neuropathic pain. Keep doses minimal, start low. Warn the patient about drowsiness and ataxia. Older patients: enhanced fall monitoring.
Sources
Mechanism
Additive CNS depression via different mechanisms. Sedation, dizziness, and fall risk amplify, especially in older patients.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk.
Management
For neuropathic pain (diabetic neuropathy, post-herpetic neuralgia), start both at minimum doses: amitriptyline 10 mg at bedtime, gabapentin 100 mg three times daily. Up-titrate every 1–2 weeks as tolerated. Avoid in older patients — fall risk. Alternatives: duloxetine with topicals (capsaicin, lidocaine patch).
Sources
Verbatim lines from the interaction sections, in the language of the label
«Uso concomitante con opioides: Los pacientes que requieran un tratamiento concomitante con opioides deberán ser cuidadosamente observados para ver si presentan signos de depresión del sistema…»AEMPS, section 4.4 · Open on CIMA
«Uso concomitante con opioides: Los pacientes que requieran un tratamiento concomitante con opioides deberán ser cuidadosamente observados para ver si presentan signos de depresión del sistema…»AEMPS, section 4.4 · Open on CIMA
«Maalox ® (aluminum hydroxide, magnesium hydroxide): Concentrations increased by morphine; may need dose adjustment ( 5.4 , 7.2 )»FDA, section 7 · Open on DailyMed
«Opioids: Hydrocodone Coadministration of gabapentin with hydrocodone decreases hydrocodone exposure [ see Clinical Pharmacology (12.3 )]. The potential for alteration in hydrocodone exposure and…»FDA, section 7 · Open on DailyMed
«Maalox ® (aluminum hydroxide, magnesium hydroxide): The mean bioavailability of gabapentin was reduced by about 20% with concomitant use of an antacid (Maalox ® ) containing magnesium and aluminum…»FDA, section 7 · Open on DailyMed
«La co-administración de gabapentina con antiácidos que contengan aluminio o magnesio reduce la biodisponibilidad de gabapentina hasta un 24%. Se recomienda tomar gabapentina dos horas después de la…»AEMPS, section 4.5 · Open on CIMA
«La coadministración de gabapentina con anticonceptivos orales que contengan noretindrona y/AEMPS, section 4.5 · Open on CIMA
«No se ha observado interacción entre gabapentina y fenobarbital, fenitoína, ácido valproico o carbamazepina.»AEMPS, section 4.5 · Open on CIMA
«La coadministración de gabapentina con anticonceptivos orales que contengan noretindrona y/AEMPS, section 4.5 · Open on CIMA
«Opioids: Respiratory depression and sedation, sometimes resulting in death, have been reported following coadministration of gabapentin with opioids (e.g., morphine, hydrocodone, oxycodone…»FDA, section 7 · Open on DailyMed
«No se ha observado interacción entre gabapentina y fenobarbital, fenitoína, ácido valproico o carbamazepina.»AEMPS, section 4.5 · Open on CIMA
«No se ha observado interacción entre gabapentina y fenobarbital, fenitoína, ácido valproico o carbamazepina.»AEMPS, section 4.5 · Open on CIMA
«No se ha observado interacción entre gabapentina y fenobarbital, fenitoína, ácido valproico o carbamazepina.»AEMPS, section 4.5 · Open on CIMA
«El empleo concomitante de Fentanilo Matrix Normon con otros depresores del sistema nervioso central (incluidos benzodiazepinas y otros sedantes/AEMPS, section 4.5 · Open on CIMA
«La administración concomitante de Petidina Basi con gabapentinoides (gabapentina y pregabalina) puede provocar depresión respiratoria, hipotensión, sedación profunda, coma o la muerte (véase la…»AEMPS, section 4.5 · Open on CIMA
«- la morfina debe utilizarse con precaución en pacientes que estén recibiendo simultáneamente otros depresores del sistema nervioso central, incluidos sedantes o hipnóticos, anestésicos generales…»AEMPS, section 4.5 · Open on CIMA
«El uso concomitante de tramadol con gabapentinoides (gabapentina y pregabalina) puede provocar depresión respiratoria, hipotensión, sedación profunda, coma o muerte.»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Examples: Benzodiazepines and other sedatives/FDA, section 7 · Open on DailyMed
«Fármacos que tienen poco o ningún efecto en la concentración de lamotrigina: Gabapentina»AEMPS, section 4.5 · Open on CIMA
«Medicamentos antiepilépticos: Los datos de los estudios clínicos, realizados en adultos antes de la comercialización, indican que levetiracetam no influye en las concentraciones séricas de los…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Examples: Benzodiazepines and other sedatives/FDA, section 7 · Open on DailyMed
«El uso concomitante de opioides y gabapentinoides (gabapentina y pregabalina) aumenta el riesgo de sobredosis de opioides, depresión respiratoria y muerte.»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Examples: Benzodiazepines and other sedatives/FDA, section 7 · Open on DailyMed
«DRUG INTERACTIONS: Examples: Benzodiazepines and other sedatives/FDA, section 7 · Open on DailyMed
«Estudios in vivo y análisis farmacocinético de la población: En consecuencia, en los estudios in vivo , no se observaron interacciones farmacocinéticas relevantes desde el punto de vista clínico…»AEMPS, section 4.5 · Open on CIMA
«El uso concomitante de opioides y gabapentinoides (gabapentina y pregabalina) aumenta el riesgo de sobredosis de opioides, depresión respiratoria y muerte.»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Examples: Benzodiazepines and other sedatives/FDA, section 7 · Open on DailyMed
«DRUG INTERACTIONS: Examples: Benzodiazepines and other sedatives/FDA, section 7 · Open on DailyMed
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Gabapentin is evaluated for the following indications with varying evidence strength: Neuropathic pain (evidence tier A), Restless legs syndrome (evidence tier A), Postherpetic neuralgia (evidence tier A). See the full indication matrix with dosing and citations above on this page.
Common side effects of Gabapentin (≥ 1 in 100): Somnolence, sedation (especially first weeks), Dizziness, Ataxia, gait disturbance, Peripheral edema, Weight gain, Dry mouth. See the Safety section for uncommon and serious reactions.
FDA categories were retired in 2015. Pregnancy safety data are limited. Use in pregnant patients with severe neuropathic pain or epilepsy is individualized with a neurologist.
Transfers into breast milk. Per LactMed, use is acceptable with monitoring for infant sedation and poor weight gain.
Gabapentin is contraindicated in: Hypersensitivity; Age under 3 (in epilepsy). Full list in the Safety section.
Direct links to regulator labels. Open in a new tab.
Lacosamide, Lamotrigine, Levetiracetam, Phenobarbital, Topiramate, Zonisamide, Phenytoin, Pregabalin