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Gabapentin

Pharmacology

Clinical Particulars

Regulatory Class

Gabapentin is a structural analogue of the inhibitory neurotransmitter gamma-aminobutyric acid ([GABA]) with analgesic, anticonvulsant and anxiolytic activity.

Pharmacodynamics

Pharmacokinetics

Mechanism of Action

  • Presumed MOA: The precise mechanism through which gabapentin exerts its therapeutic effects is unclear. Gabapentin binds with and inactivates presynaptic alpha2delta subunits of the voltage-gated calcium channels. Excitatory neurotransmitter release reduces through decreased calcium influx (e.g., reduction in substance P, glutamate, and norepinephrine). Gabapentin is not a GABA agonist and does not appear to alter GABA binding, reuptake, or degradation.

Clinical Applications

  • Neuralgia and Peripheral Neuropathic Pain: Adjunctive therapy in managing some forms of assumed neuropathic pain: Growing veterinary popularity for use in cats, dogs and rabbits.

  • Chronic Pain: Use usually multimodal in conjunction with other medications (typically NSAIDs or opioids).  It has been speculated that Gabapentin may also be a beneficial adjunctive treatment for OA.

  • Post-surgical Pain: When used during surgery, Gabapentin has demonstrated isoflurane MAC reduction in dogs and cats.

  • Anxiolytic: Gabapentin has been used in cats and dogs to decrease fear responses and anxiety associated with transport and veterinary examinations, often alongside additional agents such as Trazodone.

  • Anticonvulsant: Other authorised medications may be more suitable for major pet species.

Pharmacodynamics

Metabolism

  • Limited: Negligable metabolism occurs.

Elimination

  • Urinary: Gabapentin is eliminated solely in the urine as an unchanged drug.

Pharmacokinetics

Precautions

Adverse Effects

  • CNS Depression: The most commonly encountered adverse effects are mild sedation, dysphoria and ataxia. Somnolence, ptyalism and nausea are also possible.

  • Gastrointestinal Signs: Gastrointestinal irritation is occasionally reported.

  • Species-Specific Adverse Effects:  No species-specific adverse effects have been identified.

Contraindications

  • Hypersensitivity: Avoid use in animals with known hypersensitivity to the drug or its ingredients.

  • Behavioural Issues: Gabapentin should be used with caution in patients with behavioural disturbances.

  • Renal Disease: Use with caution or reduce the dose if renal function is significantly impaired (IRIS stage 2+).

Reproductive Safety

  • Pregnancy: Avoid Use; Evidence of fetotoxicity in Rodents and Rabbits (Fetal loss or delayed ossification of bones in the skull, vertebrae, forelimb and  hind  limbs)

  • Lactation: Avoid Use; Gabapentin distributes into milk following oral administration.

  • Fertility: Avoid Use. Fertility rate and other parameters concerned with fertility, sex hormones and specific biochemical profiles were significantly disturbed in male rats (Daoud et al., 2004).

Potentially Significant Interactions

  • Antacids: Absorption is reduced when concurrent antacids are used, especially those containing aluminium with magnesium. Some authors recommend that Gabapentin be taken at least 2 hours after the administration of any Antacid.

  • Cimetidine: May reduce Gabapentin clearance

  • Ketamine: Ketamine and Gabapentin may work synergistically to provide analgesia

  • Morphine: May increase Gabapentin levels

  • Tramadol: Tramadol and Gabapentin may work synergistically to provide analgesia.

Overdose

  • Prevalence:  Reported toxicity is rare within clinical settings.  Gabapentin appears clinically safe in cats, dogs and rabbits when used following the advised dosage protocols.

  • Expected Signs:  Sedation, akinesia and ataxia, lack of muscle coordination, tremors, ptyalism, diarrhoea and vomiting, lethargy, irregular or laboured breathing, loss of consciousness.

  • Mechanism: Excessive CNS depression at the various sites of gabapentin action within the brain.

  • Species Specific Information: Limited; No data located

  • Clinical Response: Active decontamination. Response to a significant oral overdose may include emesis, activated charcoal, cathartics and intravenous fluids to accelerate elimination.

  • Antidotes: None identified

  • Reversal Agents: Gabapentin appears devoid of any reversal agent. Alpha-adrenergic pressor agents (e.g., norepinephrine, phenylephrine, not epinephrine) can be considered in severe hypotension.

  • Co-administered Agents: Consider Reversal. Avoid reversal of analgesia agents and anaesthetics unless provision is made to support any critical patient.

Precautions

Availability

Formulations

  • Gabapentin Oral Capsules and Tablets: 100, 300, and 400 mg capsules; 600 and 800 mg tablets

  • Gabapentin Oral Solution: 250 mg/5 ml (50 mg/ml) ( ensure products are devoid of additional active ingredients)

Availability

Identifiers

  • Systematic IUPAC  Name: 2-[1-(aminomethyl)cyclohexyl]acetic acid

  • Chemical Formula: C9-H17-NO2

  • Pharmacotherapeutic Group: Nervous system; Analgesic

  • ATC vet code: N02BF01

Identifiers

Evidence Base

  1. Benarroch, E.E., 2021. What Is the Mechanism of Therapeutic and Adverse Effects of Gabapentinoids? Neurology 96, 318–321. https://doi.org/10.1212/WNL.0000000000011424

  2. Berg, K., 2018. Therapeutic Review: GABAPENTIN. Journal of Exotic Pet Medicine 27, 78–81. https://doi.org/10.1053/j.jepm.2018.07.002

  3. Beydoun, A., Uthman, B.M., Sackellares, J.C., 1995. Gabapentin: pharmacokinetics, efficacy, and safety. Clin Neuropharmacol 18, 469–481.

  4. Blum, R.A., Comstock, T.J., Sica, D.A., Schultz, R.W., Keller, E., Reetze, P., Bockbrader, H., Tuerck, D., Busch, J.A., Reece, P.A., 1994. Pharmacokinetics of gabapentin in subjects with various degrees of renal function. Clin Pharmacol Ther 56, 154–159. https://doi.org/10.1038/clpt.1994.118

  5. Bockbrader, H.N., Wesche, D., Miller, R., Chapel, S., Janiczek, N., Burger, P., 2010. A Comparison of the Pharmacokinetics and Pharmacodynamics of Pregabalin and Gabapentin. Clin Pharmacokinet 49, 661–669. https://doi.org/10.2165/11536200-000000000-00000

  6. Brodie, M.J., 2010. Antiepileptic drug therapy the story so far. Seizure 19, 650–655. https://doi.org/10.1016/j.seizure.2010.10.027

  7. Cheng, J.-K., Chiou, L.-C., 2006. Mechanisms of the Antinociceptive Action of Gabapentin. J Pharmacol Sci 100, 471–486. https://doi.org/10.1254/jphs.CR0050020

  8. Chincholkar, M., 2020. Gabapentinoids: pharmacokinetics, pharmacodynamics and considerations for clinical practice. Br J Pain 14, 104–114. https://doi.org/10.1177/2049463720912496

  9. Costa, A.C.C., Yamamoto, P.A., Lauretti, G.R., de Lima Benzi, J.R., Zanelli, C.F., Barz, V., Ciarimboli, G., de Moraes, N.V., 2020. Cetirizine Reduces Gabapentin Plasma Concentrations and Effect: Role of Renal Drug Transporters for Organic Cations. J Clin Pharmacol 60, 1076–1086. https://doi.org/10.1002/jcph.1603

  10. Court, M.H., 2013. Feline Drug Metabolism and Disposition: Pharmacokinetic Evidence for Species Differences and Molecular Mechanisms. Veterinary Clinics of North America: Small Animal Practice, Clinical Pharmacology and Therapeutics 43, 1039–1054. https://doi.org/10.1016/j.cvsm.2013.05.002

  11. Daoud, A.S., Bataineh, H., Otoom, S., Abdul-Zahra, E., 2004. The effect of Vigabatrin, Lamotrigine and Gabapentin on the fertility, weights, sex hormones and biochemical profiles of male rats. Neuro Endocrinol Lett 25, 178–183.

  12. Epstein, M.E., 2014. Adjunctive, Pain-Modifying, Analgesic Drugs. Topics in Companion Animal Medicine, Approaches to Pain Management 29, 30–34. https://doi.org/10.1053/j.tcam.2014.07.001

  13. Fornasari, D., 2017. Pharmacotherapy for Neuropathic Pain: A Review. Pain Ther 6, 25–33. https://doi.org/10.1007/s40122-017-0091-4

  14. Garrone, B., di Matteo, A., Amato, A., Pistillo, L., Durando, L., Milanese, C., Di Giorgio, F.P., Tongiani, S., 2021. Synergistic interaction between trazodone and gabapentin in rodent models of neuropathic pain. PLoS One 16, e0244649. https://doi.org/10.1371/journal.pone.0244649

  15. Gee, N.S., Brown, J.P., Dissanayake, V.U., Offord, J., Thurlow, R., Woodruff, G.N., 1996. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem 271, 5768–5776. https://doi.org/10.1074/jbc.271.10.5768

  16. Gochenauer, A.E., Holmes, E.R., Barber, K.E., Forsythe, L.R., 2019. The Current Landscape of Veterinary Compounding in the Pharmacy Setting. Int J Pharm Compd 23, 422–427.

  17. Grubb, T., 2010a. Chronic Neuropathic Pain in Veterinary Patients. Topics in Companion Animal Medicine, Chronic Pain 25, 45–52. https://doi.org/10.1053/j.tcam.2009.10.007

  18. Grubb, T., 2010b. What Do We Really Know About the Drugs We Use to Treat Chronic Pain? Topics in Companion Animal Medicine, Chronic Pain 25, 10–19. https://doi.org/10.1053/j.tcam.2009.10.001

  19. Guttuso, T., Shaman, M., Thornburg, L.L., 2014. Potential maternal symptomatic benefit of gabapentin and review of its safety in pregnancy. Eur J Obstet Gynecol Reprod Biol 181, 280–283. https://doi.org/10.1016/j.ejogrb.2014.08.013

  20. Johannessen Landmark, C., Patsalos, P.N., 2010. Drug interactions involving the new second- and third-generation antiepileptic drugs. Expert Rev Neurother 10, 119–140. https://doi.org/10.1586/ern.09.136

  21. Lal, R., Sukbuntherng, J., Luo, W., Vicente, V., Blumenthal, R., Ho, J., Cundy, K.C., 2010. Clinical pharmacokinetic drug interaction studies of gabapentin enacarbil, a novel transported prodrug of gabapentin, with naproxen and cimetidine. Br J Clin Pharmacol 69, 498–507. https://doi.org/10.1111/j.1365-2125.2010.03616.x

  22. Morris, G.L., 1995. Efficacy and tolerability of gabapentin in clinical practice. Clin Ther 17, 891–900. https://doi.org/10.1016/0149-2918(95)80067-0

  23. Patorno, E., Hernandez-Diaz, S., Huybrechts, K.F., Desai, R.J., Cohen, J.M., Mogun, H., Bateman, B.T., 2020. Gabapentin in pregnancy and the risk of adverse neonatal and maternal outcomes: A population-based cohort study nested in the US Medicaid Analytic eXtract dataset. PLoS Med 17, e1003322. https://doi.org/10.1371/journal.pmed.1003322

  24. Patsalos, P.N., 2013. Drug interactions with the newer antiepileptic drugs (AEDs)--part 1: pharmacokinetic and pharmacodynamic interactions between AEDs. Clin Pharmacokinet 52, 927–966. https://doi.org/10.1007/s40262-013-0087-0

  25. Prakash,  null, Prabhu, L.V., Rai, R., Pai, M.M., Yadav, S.K., Madhyastha, S., Goel, R.K., Singh, G., Nasar, M.A., 2008. Teratogenic effects of the anticonvulsant gabapentin in mice. Singapore Med J 49, 47–53.

  26. Rentsch, C.T., Morford, K.L., Fiellin, D.A., Bryant, K.J., Justice, A.C., Tate, J.P., 2020. Safety of Gabapentin Prescribed for Any Indication in a Large Clinical Cohort of 571,718 US Veterans with and without Alcohol Use Disorder. Alcohol Clin Exp Res 44, 1807–1815. https://doi.org/10.1111/acer.14408

  27. Sarac, B.A., Schoenbrunner, A.R., Brower, K.I., Joshi, G.P., Janis, J.E., 2022. Analysis of Adverse Effects of Multimodal Gabapentin in Abdominal Wall Reconstruction. Plast Reconstr Surg 149, 733–739. https://doi.org/10.1097/PRS.0000000000008836

  28. Sills, G.J., 2006. The mechanisms of action of gabapentin and pregabalin. Current Opinion in Pharmacology, Neurosciences 6, 108–113. https://doi.org/10.1016/j.coph.2005.11.003

  29. Timmerman, W., Bouma, M., De Vries, J.B., Davis, M., Westerink, B.H., 2000. A microdialysis study on the mechanism of action of gabapentin. Eur J Pharmacol 398, 53–57. https://doi.org/10.1016/s0014-2999(00)00309-5

  30. Wesche, D., Bockbrader, H., 2005. A pharmacokinetic comparison of pregabalin and gabapentin. The Journal of Pain 6, S29. https://doi.org/10.1016/j.jpain.2005.01.114

Evidence

Monograph Details

Mono Details
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