Gabapentin in Pets

Gabapentin Use in Companion Animals: A Comprehensive Overview

PSA-DVM Paola Moreno Estanol

GABAPENTIN, an anticonvulsant, has gained popularity in Veterinary Medicine

for its potential to alleviate chronic pain, neuropathic pain, postoperative discomfort,

and anxiety in dogs, cats, and, to some extent, horses. Its mechanism

of action involves binding to voltage-gated calcium channels,

reducing excitatory neurotransmitter release.

SUMMARY:

Drug Overview:

Gabapentin is an anticonvulsant used in veterinary medicine for chronic and neuropathic pain, postoperative pain, anxiety, and seizures in dogs and cats, with uncertain efficacy in horses.

Pharmacology:

It binds to the alpha2-delta subunit of voltage-gated calcium channels, inhibiting excitatory neurotransmitter release without directly affecting GABA activity.

Anticonvulsant Use:

Effective in managing recurrent seizures in dogs and cats, possibly by binding to neurons in the cortex and inhibiting presynaptic calcium channels.

Analgesic for Chronic Neuropathic Pain:

Gabapentin alleviates chronic neuropathic pain by binding to the a28-1 subunit of voltage-gated calcium channels, modulating calcium influx and synaptic transmission.

Anxiolytic Applications:

Exhibits anxiolytic-like effects in animal models, potentially by reducing fear circuit neurotransmission, with positive outcomes in dogs and cats for conditions like storm phobia and anxiety.

Pharmacokinetics Variability:

Bioavailability and elimination half-life vary among species. In dogs, it's 80% bioavailable with a 2-4 hour half-life, while in cats, it has a 90% bioavailability with a 2.8-hour half-life. In horses, the half-life is approximately 3.4 hours.

Dosage and Administration:

Dosage recommendations are still being researched, especially for cats. Differences in metabolism and excretion across species influence dosage regimens.

Contraindications and Precautions:

Should not be used in patients hypersensitive to it. Requires dosage adjustments in cases of renal insufficiency and should be used cautiously in dogs with xylitol toxicity risks.

Adverse Effects:

Commonly causes sedation and ataxia. Abrupt discontinuation can lead to withdrawal-precipitated seizures.

Clinical Use in Animals:

Shows potential in managing various conditions in dogs and cats, like epilepsy, pain, and anxiety, but requires further research for conclusive efficacy and safety data, especially in horses. 

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INTRODUCTION:

Gabapentin, originally introduced as an anticonvulsant in human medicine, has found a place in veterinary practice. It's been found to reduce postoperative pain and the need for opioids. While its exact mechanism of action is not fully understood, it appears to bind to voltage-dependent calcium channel complexes. In veterinary medicine, gabapentin is increasingly used in dogs and cats for managing chronic and neuropathic pain, postoperative pain, and anxiety. Its efficacy in horses is less clear. 

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The mechanism of action of Gabapentin involves binding

to voltage-dependent calcium channels, reducing the release

of excitatory neurotransmitters.

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PHARMACOLOGY:

Gabapentin has analgesic and anticonvulsant properties, with the ability to prevent allodynia and hyperalgesia. Its mechanism of action involves binding to the alpha2-delta subunit of voltage-gated calcium channels, reducing calcium influx, and inhibiting the release of excitatory neurotransmitters like substance P, glutamate, and norepinephrine. Despite its structural similarity to GABA, gabapentin doesn't directly impact GABA binding, reuptake, or degradation, nor does it act as a GABA agonist in vivo.

The precise mechanism of action for gabapentin remains incompletely understood, but it's thought to selectively activate presynaptic GABA—B heteroreceptors on glutamatergic terminals without affecting GABA—B autoreceptors on GABAergic terminals. This complexity in its mechanism of action has led to various clinical applications in companion animals, including pain management and seizure control.

GABAPENTIN AS AN ANTICONVULSANT:

The current understanding of its anticonvulsant action involves its binding to neurons in the outer layer of the cortex, specifically to the a28-1 subunits of voltage-gated calcium channels (VGCCs). This binding is thought to play a role in its therapeutic effects. Gabapentin may also inhibit presynaptic calcium channels, leading to a reduction in the release of excitatory neurotransmitters, which could explain its antiseizure activity, though there is limited experimental evidence for this. It's also suggested that the a28-1 subunit may associate with N-methyl-D-aspartate receptors, contributing to gabapentin's antiseizure effects.

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The anticonvulsant action of Gabapentin is due to its binding to neurons,

specifically to the a28-1 subunits of voltage-dependent calcium channels,

inhibiting the release of excitatory neurotransmitters.

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GABAPENTIN AS AN ANALGESIC:

Gabapentin's analgesic properties likely result from its specific binding to the a28-1 auxiliary subunit of voltage-gated calcium channels. This binding indirectly influences calcium influx, modulating synaptic transmission and providing an antiallodynic effect, particularly in cases of CNP associated with upregulated a28-1 subunits, often found in damaged sensitive nerve fibers.

Research has shown that gabapentin operates at both presynaptic and supraspinal sites of action, involving neurotransmission modulation in the spinal cord and interaction with noradrenaline (NA) and GABA brain release. Recent studies propose a dual action: gabapentin interacts in the locus coeruleus (LC) to reduce pre-synaptic GABA release while activating mechanisms to induce glutamate release from LC astrocytes. This increased glutamate contributes to activating the descending noradrenergic system, ultimately reducing the transmission of nociceptive information in the spinal cord.

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Gabapentin, through its selective binding to the

a28-1 auxiliary subunit of voltage-dependent calcium channels,

exerts an analgesic effect by modulating synaptic transmission in the spinal cord.

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GABAPENTIN AS AN ANXIOLYTIC:

In human medicine, gabapentin has been beneficial in controlling anxiety, as well as treating conditions like bipolar disorder and post-traumatic stress. However, the exact mechanism behind gabapentin's anxiolytic effects remains unclear.

The speculated mechanism for its effectiveness in animal models involves binding to the a28 subunits of voltage-gated calcium channels (VGCCs), potentially reducing fear circuits' neurotransmission, which is pathologically activated in anxiety disorders. Notably, while there is limited evidence for gabapentin's efficacy in anxiety disorders in human medicine, it has shown positive outcomes in dogs and cats, particularly in addressing storm phobia, anxiety, and reducing fear before veterinary visits.

The precise mechanism of gabapentin's anxiolytic effect remains uncertain, necessitating further investigation, especially in the context of its use in dogs and cats.

PHARMACOKINETICS:

Gabapentin's pharmacokinetics vary across species:

In dogs, oral bioavailability is around 80% at a dose of 50 mg/kg, with peak plasma levels occurring approximately 2 hours after dosing. Elimination is primarily through renal routes, and the elimination half-life is about 2-4 hours.

Cats show well-absorbed gabapentin after oral dosing with an average bioavailability of 90%, although there is significant interpatient variation (ranging from 50% to 120%). Peak levels are observed around 100 minutes after dosing, with a low volume of distribution and an elimination half-life of about 2.8 hours.

In horses, after a single oral dose of 5 mg/kg, gabapentin is rapidly absorbed, with peak levels noted within 2 hours (mean 1.4 hours). Plasma elimination half-life is approximately 3.4 hours.

For humans absorption is minimally affected by the presence of food. Gabapentin is minimally bound to plasma proteins, and it's excreted mostly unchanged in urine. The elimination half-lives are approximately 5-7 hours.

In animals the drug's bioavailability can vary across species and is influenced by feeding behaviors and other factors, like the presence and saturation capacity of intestinal transporters for the drug.

PHARMACOKINETICS IN DOGS:

Gabapentin's pharmacokinetics in dogs have been partially explored. It is rapidly absorbed, metabolized to N-methyl-gabapentin, and eliminated unchanged in urine. Oral bioavailability at a dose of 50 mg/kg has been reported to be 80%. In a recent study, gabapentin was administered at 10 mg/kg on day 1 and 20 mg/kg on day 2 to healthy greyhound dogs. The results revealed varying maximum concentrations (Cmax) and terminal half-lives. The efficacy of the drug was not evaluated, but it was suggested that 10-20 mg/kg every 8 hours could maintain a therapeutic plasma concentration.

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In dogs, the oral bioavailability is approximately 80%

at a dose of 50 mg/kg, and peak plasma levels

occur approximately 2 hours after administration.

Elimination primarily occurs through the kidneys,

and the elimination half-life is approximately 2-4 hours.

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PHARMACOKINETICS IN CATS:

Gabapentin's pharmacokinetics in cats are still poorly understood. Limited studies have yielded different results. In recent research, transdermal gabapentin showed promise in permeating feline skin, encouraging further exploration. The optimum plasma concentration for gabapentin in cats remains unknown, but it is hypothesized to be around 8 mg/kg four times a day.

In cats with chronic kidney disease, is suggested the need for dose adjustments due to impaired renal excretion of the drug. While there is no definitive data on the optimum plasma concentration for gabapentin in cats, it has been hypothesized that an effective dose could be around 8 mg/kg given four times a day,

CONTRAINDICATIONS / PRECAUTIONS:

Gabapentin is contraindicated in patients hypersensitive to it. Caution should be exercised in patients with renal insufficiency, and dosage adjustments might be necessary. The commercially available human oral solution, Neurontin, may contain xylitol, which can be harmful to dogs. Adverse effects in small animals may include sedation or ataxia. There have been reports of xylitol toxicity in dogs, albeit at relatively high doses. In cats, xylitol toxicity does not appear to be a significant concern with gabapentin.

ADVERSE EFFECTS:

Common adverse effects in dogs and cats are sedation and ataxia. Starting at a lower dose and gradually increasing it can help alleviate these effects. In humans, common adverse effects are dizziness, somnolence, and peripheral edema. Gabapentin was associated with an increased rate of pancreatic adenocarcinoma in male rats, but it is unknown if this effect extends to other species. Abrupt discontinuation of the drug can lead to withdrawal-precipitated seizures in humans.

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Gabapentin can cause sedation and ataxia

in dogs and cats, caution should be exercised

in patients with renal insufficiency.

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REPRODUCTIVE / NURSING SAFETY:

In humans, gabapentin is categorized as a category C drug for use during pregnancy, which means that animal studies have shown adverse effects on the fetus, but there are no adequate studies in humans. In veterinary patients, the exposure of nursing cat infants to gabapentin is unlikely to be of significant clinical concern.

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OVERDOSE / ACUTE TOXICITY:

In humans, high doses have been reported without fatalities. However, the commercially available oral solution contains xylitol, which can be toxic to dogs. There have been cases of exposure reported to the ASPCA Animal Poison Control Center. Treatment for gabapentin overdose is generally supportive. Drug interactions should be considered, such as the possible interaction with antacids, hydrocodone, and morphine.

GABAPENTIN IN DOGS:

Gabapentin has been used in dogs to control epilepsy, chronic pain, neuropathic pain, post-operative pain, and anxiety. Notably, it is often used in combination with other treatments, and there is limited data on its use as monotherapy. Some studies show promising results in reducing seizures and managing pain, while others suggest no significant benefit. Gabapentin has been tested for use in other conditions, such as controlling scratching activity or anxiety. Occasionally, ataxia and sedation have been observed as side effects.

GABAPENTIN IN CATS:

In cats, gabapentin is used for post-operative pain management and anxiety. It has shown positive results in controlling hyperalgesia and allodynia, especially when opioid and NSAID therapy has failed. Its safety and efficacy are yet to be fully explored for various applications. Studies have also indicated its potential to reduce stress during transport to veterinary clinics. Some reports suggest that gabapentin might be a useful appetite stimulant for cats in the postoperative period. Side effects may include ataxia and sedation.

GABAPENTIN IN HORSES:

In horses, gabapentin has been considered for managing neuropathic and chronic pain, associated with conditions like laminitis, arthritis, headshaking, and navicular syndrome. Some cases have reported success in mitigating intractable pain following colic surgery and in reducing violent head-shaking behavior. Gabapentin, either alone or in combination with firocoxib, has shown promise for managing pain. However, its effectiveness, especially as monotherapy, requires further investigation.

CONCLUSIONS:

In conclusion, gabapentin has been recently utilized in companion animal medicine to manage different medical conditions. While promising results have been reported in dogs, cats, and horses, further research is essential to understand its full potential. Combining pharmacokinetic studies with efficacy evaluations can lead to rational dosing recommendations for different animal species. Proper randomized, placebo-controlled trials are warranted to assess the drug's efficacy. In veterinary practice, gabapentin's role holds promise but demands additional scientific scrutiny for its thoughtful inclusion in the armamentarium of veterinary drugs.

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​REFERENCES:

• Plumb, DC. Plumb’s Veterinary Drug Handbook. 7th edition. Pharmacology Vet Inc. 

• Siao, KT. Pharmacokinetics of Gabapentin in Cats. Am J Vet Res 2010;71:817–821

• Cesare, FD. Gabapentin, Clinical use and Pharmacokinetics in Dogs Cats and Horses. Animals. 2023, 13, 2045.​