Gabapentin

(gabapentin)

Brands

Neurontin

Availability

  • Tablets: 100 mg, 300 mg, and 400 mg
  • Capsules: 600 mg and 800 mg
  • Oral solution: 50 mg/mL

*Note: Some human liquid oral formulations may contain xylitol, a sugar substitute. While this is toxic to dogs, it does not show the same response in rats at sub-acute levels.1,2,3,4

Pharmacology

Gabapentin, is an analog of GABA (gamma-aminobutyric acid). While structurally related to GABA, it is not metabolically converted to GABA, and does not interact with GABAergic, glutamatergic, or other common neurotransmitter receptor sites.5 Although its mechanism of action is unknown, it exhibits anticonvulsant activity. It also exhibits analgesic effects against neuropathic pain e.g., hyperesthesia which is an amplified reaction to pain and allodynia which is a painful response to normal harmless stimuli.

Gabapentin is well absorbed and widely distributed into tissue. In rats gabapentin has been shown, in studies, to reach maximum blood levels within 1-3 hours following oral administration.6 Gabapentin is not appreciably metabolized in the liver. Less than 5% is metabolized to N-methylgabapentin in the rat. It is not an inducer of hepatic cytochrome P450 7, nor does it inhibit metabolism of other antiepileptic drugs.

Gabapentin is nearly exclusively eliminated unchanged by way of the kidneys in urine. Approximately 99.8% of renal elimination, in rats, occurred following oral administration.6 It is recommended to use caution when administering in rats having renal impairment.

Gabapentin has shown to be non-toxic at therapeutic dosing. Although one study of developmental toxicity showed no adverse maternal or fetal effects in pregnant rats given doses ranging from 60-1500 mg/kg, it also noted that a small incidence of visceral variations was observed in rat fetuses at the higher range of 1500 mg/kg as a result of a slight incidence of dilated renal pelvis.8 The drug also shows presence in maternal milk; however, the percentage of drug appears to be well below therapeutic dosing levels. While it is unlikely to be of significant concern in the nursing rat, use in nursing and pregnant rats should still be based on benefit versus risk.

In addition, a 2-year tumor bioassay study showed an increase of pancreatic acinar neoplasia in male Wistar rats fed doses from 250 mg-2000 mg/kg over several weeks. There were no other tumor types observed, and no tumor increase in female rats. Also, the tumors were not invasive and did not metastasize. Life expectancy was not shortened. Although the study showed that gabapentin was carcinogenic in the male Wister rats used in the study, the development of the tumors required very high doses to be given, and the tumor development was limited to the pancreas in a single species and sex of rodent.9

In conclusion, gabapentin is shown to be safe at therapeutic dosing and exhibits beneficial effects with regard to neuropathic pain, and while not considered a first-choice treatment of seizures in the pet rat, it has shown to be useful as an additive therapy where seizures are refractory to the use of conventional seizure medications.

Indications

  • Used in the treatment of neuropathic pain where opioids do not provide pain relief.10,11
  • Also used as an add-on therapy in the management of seizure activity, it can significantly reduce frequency of partial and secondary generalized tonic-clonic seizures that are refractory to the use of conventional seizure medications such as phenobarbital.

Drug Interactions or Contraindications

  • Antacids containing aluminum with magnesium can decrease gabapentin absorption. When having to give antacids allow for 2 hours before or after administration of gabapentin.
  • Gabapentin is fairly short acting, but effects may last longer in rats with renal impairment.

Adverse Reactions

CNS: Mild sedation (sleepiness), ataxia (poor coordination)

CV: Vasodilation

GI: inappetence, constipation, diarrhea

GU: Drug may cause a false positive reading on urinary protein tests.

Dosage Recommendations

30 mg/kg, PO, q8hr  41, 42

Considerations

  • Gabapentin may be combined with tramadol (an opioid) where nerve pain is not controlled by an opioid alone and can be helpful.12 It is important to follow the advice of the veterinarian, when prescribed, as the combination can increase risk of sedation.
  • When incorporating gabapentin in the treatment of seizures, avoid abrupt withdrawal of gabapentin to reduce the risk of increased seizure frequency and status epilepticus. It is important for the pet owner to keep record of any seizure activity, in the event medication efficacy needs to be reviewed by the veterinarian, such as: increased frequency, duration, or type of seizure activity.
  • Gabapentin may be given with or without food. It is suggested to give right before feeding or with food as it may cause stomach upset.
  • Store tablets and capsules at room temperature away from light and moisture. For compounded liquid or suspension medication follow directions on label.

Consultants

Nathalie Baldwin, DVM
Adele Wharton, MRCVS, CertGP (F&L) Veterinary Surgeon

References
  1. Truhaut, R., Coquet, B., Fouillet, X., Galland, L., Guyot, D., Rouaud, J. L., & Long, D. W. (1977). Sub-acute toxicity of xylitol in rats; absence of hepatotoxicity. Toxicology, 8(1), 79–85. https://doi.org/10.1016/0300-483x(77)90025-7
  2. Kay, N. (2021, August 24). Popular xylitol products that can poison your dog. Retrieved October 5, 2021, from https://www.pethealthnetwork.com/dog-health/dog-toxins-poisons/popular-xylitol-products-can-poison-your-dog
  3. Islam, Md. S. (2011). Effects of xylitol as a sugar substitute on diabetes-related parameters in nondiabetic rats. Journal of Medicinal Food, 14(5), 505–511. https://doi.org/10.1089/jmf.2010.0015
  4. Schmid, R. D., & Hovda, L. R. (2015). Acute hepatic failure in a dog after xylitol ingestion. Journal of Medical Toxicology, 12(2), 201–205. https://doi.org/10.1007/s13181-015-0531-7
  5. Plumb, D. (2008). Gabapentin. In Plumb’s Veterinary Drug Handbook (6th ed., pp. 415-417).
  6. Vollmer, K. O., von Hodenberg, A., & Kölle, E. U. (1986). Pharmacokinetics and metabolism of gabapentin in rat, dog and man. Arzneimittel-Forschung, 36(5), 830–839. https://pubmed.ncbi.nlm.nih.gov/3730018/
  7. Radulovic, L. L., Türck, D., von Hodenberg, A., Vollmer, K. O., McNally, W. P., DeHart, P. D., Hanson, B. J., Bockbrader, H. N., & Chang, T. (1995). Disposition of gabapentin (neurontin) in mice, rats, dogs, and monkeys. Drug metabolism and disposition: the biological fate of chemicals, 23(4), 441–448. https://pubmed.ncbi.nlm.nih.gov/7600909/
  8. Petrere, J. (1994). Developmental toxicity studies in mice, rats, and rabbits with the anticonvulsant gabapentin. Fundamental and Applied Toxicology, 23(4), 585–589. https://doi.org/10.1006/faat.1994.1144
  9. Sigler, R. (1995). Pancreatic acinar cell neoplasia in male Wistar rats following 2 years of gabapentin exposure. Toxicology, 98(1–3), 73–82. https://doi.org/10.1016/0300-483x(94)02966-x
  10. Ibrahim, M. A., Abdelzaher, W. Y., Rofaeil, R. R., & Abdelwahab, S. (2018). Efficacy and safety of combined low doses of either diclofenac or celecoxib with gabapentin versus their single high dose in treatment of neuropathic pain in rats. Biomedicine & Pharmacotherapy, 100, 267–274. https://doi.org/10.1016/j.biopha.2018.01.102
  11. Field, M. J., Gonzalez, M. I., Tallarida, R. J., & Singh, L. (2002). Gabapentin and the Neurokinin1 receptor antagonist CI-1021 act synergistically in two rat models of neuropathic pain. Journal of Pharmacology and Experimental Therapeutics, 303(2), 730–735. https://doi.org/10.1124/jpet.102.033134
  12. Granados-Soto, V., & Argüelles, C. F. (2005). Synergic antinociceptive interaction between tramadol and gabapentin after local, spinal and systemic administration. Pharmacology, 74(4), 200–208. https://doi.org/10.1159/000085700

 

 

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