Despite minimal evidence of clinical efficacy for many conditions, gabapentin is one of the most prescribed drugs in both human and veterinary medicine. How did this happen?
Gabapentin, The Medication
Gabapentin (Neurontin®) is a synthetic drug currently approved for use in adults as an adjunct for treatment of partial onset seizures and nerve pain from shingles (post herpetic neuralgia)[1]. All other uses in humans are extralabel, including, non-neuropathic pain, restless leg syndrome, diabetic neuropathy, back and neck pain, hot flashes, alcoholism, and mood disorders such as anxiety[2]. Gabapentin is not approved for use in animals, so all use of gabapentin in animals is extralabel. Despite this, Gabapentin is routinely prescribed in veterinary medicine for pain (acute, chronic and neuropathic), anxiety, seizures, impulsivity, phobias, panic disorders, compulsive disorders, and seizures (epilepsy)[3].
Gabapentin was first conceptualized in the early 1970s, when labs were developing more effective medications for seizures. Seizures result from abnormal electrical activity in the brain. GABA (GABA-AMINOBUTYRIC ACID) is an inhibitory neurotransmitter. The idea was that if GABA is inhibited, seizures occur. Therefore, if you could “enhance” or “mimic” GABA, you could inhibit seizures.
Figure 1
Because Gabapentin cannot cross the blood brain barrier (and therefore cannot get to the brain) a lipophilic (“fat liking”) compound was added to the medication. In 1974, Parke-Davis’ German chemist Gerhard Satzinger, synthesized Gabapentin by incorporating a lipophilic cyclohexane ring so the medication can pass from blood to the brain.
In 1993, gabapentin was approved by the FDA as an adjunctive treatment for seizures; currently there are many generic versions of gabapentin available.
GABA, the Central Nervous System Inhibitory Neurotransmitter
The neurotransmitter GABA “lives in” GABAergic neurons located in the brain and spinal cord of the central nervous system. GABAergic neurons are found in the hippocampus, thalamus, basal ganglia, hypothalamus, brainstem, amygdala, prefrontal cortex, olfactory bulb, retina, and spinal cord. GABA is released from the presynaptic GABAergic neuron, travels through the synapse, and binds to GABA receptors on the postsynaptic neuron. Binding to the receptor results in decreased excitation of the postsynaptic neuron. There are (at least) three different GABA receptors including alpha, beta, and delta. Binding of GABA to the receptor results in inhibition of neurotransmission.
Figure 2a
Like all medications that affect the nervous system, it is complicated and not completely understood. The original thought was that Gabapentin, a mimic of the inhibitory neurotransmitter GABA, would bind to the GABA receptors, but, remarkably, it does not! The simplest explanation is that Gabapentin inhibits (or decreases) the release of excitatory neurotransmitters into the synapse. Although developed as a GABA analogue, Gabapentin does not affect the GABA system (it doesn’t bind to the GABA receptor), but instead binds to the alpha 2 delta 1 (α2δ1) subunit on presynaptic voltage-activated calcium ion channels in the central nervous system. Voltage gated channels are basically proteins in the cell membrane that allow (or stop) ions (calcium or sodium, for example) to enter the cell in response to changes in cell membrane voltage. Binding to the α2δ1 subunit inhibits (blocks) calcium entering the neuron, resulting in decreased release of the excitatory neurotransmitters, glutamate and monoamine neurotransmitters like dopamine, serotonin, and norepinephrine[4,5]. The theory being that by decreasing excitatory neurotransmitters, we can decrease behaviors, seizures, and pain for physiologic responses that depend on excitatory neurotransmitters. Although GABA and Gabapentin have different mechanisms of action, both result in decreased excitatory neurotransmission. We will address the peer reviewed articles on the use of Gabapentin for behavioral issues in dogs; use for pain will follow.
Use of Gabapentin for Dogs
Gabapentin is not approved for use in dogs, so all use in dogs (and other non-human animals) is extralabel, and veterinarians prescribing Gabapentin are obliged to follow the extralabel drug use rules. We will focus on the peer reviewed literature describing the use of Gabapentin for behavioral issues in dogs.
Gabapentin and Storm Phobia
To date, there are three peer reviewed studies that evaluate the effect of gabapentin for behavioral issues in the dog. In 2020, Bleuer-Elsner and colleagues looked at the effect of a single dose of gabapentin on storm phobia[6]. This was a double-blind, placebo-controlled study, meaning that each dog enrolled received placebo or Gabapentin prior to a naturally occurring Israeli winter storm event. Each dog was exposed to two separate storm events – receiving Gabapentin once and the placebo once. The placebo and Gabapentin capsules were prepared to look identical. Owners recorded behavioral signs of fear and “adverse effects” during each episode. The researchers provided a positive review of “storm phobia” and provide justification for their hypothesis that “a single dose of gabapentin prior to a thunderstorm will decrease fear response.”
Inclusion criteria were: between 1 and 12 years of age with a history of “excessive, long lasting (>1 min) non-spontaneously reversible fear responses to thunderstorms in the past.” In addition, these behaviors were expressed when owners were present. After the storm event, owners were sent a link to the “Thunderstorm exposure questionnaire” that contained three parts: a fear score, an adverse effect score, and a general owner’s score.
Fear was scored as 0 (no fear) to 4 (strong fear) and included body, tail, and ear position; yawning; lip licking; tongue flicking; and attempts to escape. Adverse effects included: vomiting, salivation, ataxia, muscle tremors, and anisocoria (pupils of different size), Each effect was scored as yes=0 and no=1 with a total score ranging from 0 to 5.
Owners’ score was a response to the question ”How afraid was your dog during exposure?” with 0=not fearful and 4=very fearful.
Nonparametric statistics were used to detect differences between placebo and Gabapentin. There is no explanation in the methods of why they chose to use “delta fear scores” and how they should be interpreted.
Eighteen of thirty-two dogs completed both parts of the study and were included in the final analysis. Losing almost half the number of dogs originally recruited highlights the difficulty of studying canine behavior when repeated client compliance is required. Fear scores after Gabapentin were significantly less than placebo (Gabapentin=6.61 ± 7.55 vs. placebo=15.52 ± 7.82. Delta fear scores (Gabapentin fear score minus placebo fear score) suggested that the order of medication did not affect the fear scores, however 3 dogs had greater fear scores with Gabapentin when compared with placebo. Adverse effect scores were not different between the two groups (0.39 ± 0.61 vs 0.61 ± 0.78). Owner scores after the dog received Gabapentin were significantly lower than after placebo (Gabapentin =1.16+/- 1.29 vs placebo = 3.11 ± 1.02).
The authors conclude that three scores used in this study (which were not validated or used previously) seem to “support the hypothesis that Gabapentin, given at a dosage from 25 to 30 mg/kg, 90 min before exposure to a thunderstorm, significantly decreases the intensity of fear responses in the studied dog population with minor side effects.” I might add to this conclusion “in some dogs.” It should be noted that three owners reported their dog showed increased fear with Gabapentin – highlighting the inability of researchers to control the intensity of a natural event and/or the owners’ ability to correctly interpret their dog’s behavior. The latter issue could be eliminated using video tape and professional assessment of behavior.
Many canine behavior studies use owners’ responses to surveys or questionnaires – these methods are less costly and time consuming than having trained evaluators evaluate behavior, yet allow (in general) for broader participation and larger sample size. So, what is the bottom line here – basically that Gabapentin may be useful to help alleviate thunderstorm phobic behaviors in some dogs. In addition, side effects in this study are mild and infrequent, suggesting that in general Gabapentin is safe for dogs.
Gabapentin and a Veterinary Visit
In 2022, Stollar et al. evaluated a single dose of Gabapentin on dogs during a “simulated” veterinary visit[7]. The design of this study, like the Bleuer-Elsner study, was double-blind, placebo controlled. The ”simulated” veterinary visit was similar to that described by Kim et al. in the Dazzled #10 blog post[8] and the behavior was recorded for later evaluation.
Healthy dogs of any breed between 1.5 and 12 years of age and weighing 10 to 40 kg were eligible to participate. Twenty-two dogs were randomly assigned to receive either placebo or Gabapentin for the first simulated visit (and the other for the second visit). Evaluation included a “greeting test,” infrared measurement of eye temperature, salivary cortisol measurement, and behavior recording and analysis. Ethogram behaviors included shake off, lip lick, whine, growl, jump off (exam table), sit, stand, sniff, pant. Behaviors were coded as state (duration, seconds) or event (frequency). Inter-rater reliability between two observers was 0.73, which means that in over a quarter of the behaviors there was disagreement in the interpretation of the behavior between the two observers.
Twenty-two dogs of various breeds, ages, and weights completed the study. No significant differences were found in greeting scores, temperature of the eye, or salivary cortisol between Gabapentin and placebo. Of all the behaviors assessed, the authors report a significant difference in the frequency of lip licking between groups (Gabapentin = 9.9 ± 10.1 vs placebo = 15.0 ± 14.7). Lip licking is considered a sign of anxiety in dogs, and the frequency may increase in response to increasing stimuli.
The authors identified “a significant decrease in stress signs (e.g., a reduction in the frequency of lip licking during a physical examination and in the total frequency of lip licking in the pre and post physical examination phases) in dogs administered Gabapentin compared to those administered a placebo.” They conclude that the significant difference in lip licking, both during the physical exam, and over the total time of the visit, supports their hypothesis that Gabapentin decreases anxiety. Like the previous study, a great deal of time and effort went into the design and execution of the study, with minimal data to support their hypothesis. This study also speaks to the safety of Gabapentin when used in dogs.
Restrospective Study of Behavioral Records
In a retrospective study of 84 owner responses, electronic records of dogs prescribed Gabapentin in a behavior-only veterinary clinic were reviewed. Data collected included: owner contact information, dog information and behavioral diagnosis. Inclusion criteria were: fear-related aggression, conflict-related aggression, aggression secondary to high arousal, generalized anxiety, separation anxiety, noise phobia, global fear, and other specific phobias. The authors provide a thorough review of the literature, abundant references, and definitions of the behavioral diagnosis.[9]
The goal of the study was to characterize the effects of Gabapentin on dogs with behavioral issues. They hypothesized that side effects, especially sedation, would be seen at higher doses and in older dogs, but that this would not “bother most owners.”
Owners who met the inclusion criteria were sent an email inviting them to fill out an on-line questionnaire (available as supplementary material). Of the 253 owners contacted, 84 filled out the questionnaire (33%), and of those 34 were rejected due to missing data, resulting in a total of 50 dogs included in the final analysis. Questions covered dose, frequency, effectiveness, and side effects of gabapentin. Because of the variability of diagnoses, and dosage, frequency, and effectiveness of gabapentin, the authors created categories.
The majority of dogs in this study were prescribed Gabapentin for fear-related aggression (n=37) and generalized anxiety (n=34). Also, specific phobias (n=22), conflict-related aggression (n=15), separation anxiety (n=8), aggression secondary to high arousal (n=7) and global fear (n=6). The number of dogs in each category suggests that each of the 50 dogs had multiple behavioral diagnoses. 
By my account, of the 50 dogs in the study, perhaps all, but at least 48, were receiving at least one other psychotropic medication. This complicates ascribing changes in behavior to Gabapentin. Most owners reported giving Gabapentin daily (n=34), while some reported only giving the drug 1-3 times (n=4), and others used it only for stressful events (n=9). Fourteen owners stopped using/giving the medication, primarily due to “lack of efficacy.” Thirty percent of owners reported no side effects; sedation (n=23) and agitation (n=12) were the most commonly reported side effects.
The authors chose to compare the “effectiveness” of Gabapentin for one behavioral diagnosis vs effectiveness of all other diagnoses – by this comparison they state “Of particular interest was that owners of dogs with a diagnosis of conflict-related aggression were more likely to rate gabapentin as being effective than were owners of dogs with other diagnoses.” Owners of 14 of 15 dogs (83.3%) with conflict-related aggression reported improvement with Gabapentin. The biological relevance of comparing the efficacy of gabapentin for one behavioral diagnosis to the “aggregate” other behavioral diagnosis is unclear. The authors conclude, “The results of this study suggest that Gabapentin may be a beneficial treatment for dogs with behavioral disorders, particularly those with aggression towards familiar humans in the household.”
Gabapentin: The Takeaway
These studies highlight some of the difficulties encountered when trying to assess efficacy of human medications used extralabel in dogs. FDA approval requires that studies be performed to assess safety and efficacy of the medication. The number of participants required is generally determined statistically (called “power analysis”) so that we need so many dogs to identify safety issues at X%. Including a larger number of animals improves the ability to detect low frequency events. In the studies used for FDA approval of Reconcile® and Clomicalm® over 200 dogs were in each group (drug vs. placebo[10]). In the Gabapentin studies the largest number of participants was 50 and the variability in diagnoses and medications, plus client observations make it difficult to “ferret out” the impact of Gabapentin on behavioral issues in the dog. But what we do know from these studies is that Gabapentin is generally safe and may provide improvement for dogs with behavioral issues.
Thanks to Rene Smith CBDC, Kerrie Hoar MS, CDBC, CPDT-KA, Michael Shikashio CDBC, and CC Bourgeois CPDT-KA, CSAT, PMCT for careful review of this article. This article covers the peer reviewed case controlled and retrospective studies as of 8/1/2024.
References
[1] https://tinyurl.com/7bz47bj7
[2] https://www.health.harvard.edu/staying-healthy/gabapentin-uses-side-effects-and-what-you-should-know-if-youve-been-prescribed-this-medication
[3] Landsberg GM, Hunthausen W, Ackerman L. Pharmacologic intervention in behavior therapy. In: Behavior Problems of the Dog and Cat. 3rd ed. Philadelphia: Saunders, 2013:113-138.
[4] Chincholkar M. Gabapentinoids: pharmacokinetics, pharmacodynamics and considerations for clinical practice. Br J Pain. 14(2):104–114, 2020 https://pmc.ncbi.nlm.nih.gov/articles/PMC7265598/
[5] Crowell-Davis SL, Murray TF, de Souza Dantas LM. Veterinary Psychopharmacology. Wiley & Sons, Inc. 2019.
[6] Bleuer-Elsner S, Medam T, Masson S. Effects of a single oral dose of gabapentin on storm phobia in dogs: A double-blind, placebo-controlled crossover trial. Vet Rec. 2021;e453. https://doi.org/10.1002/vetr.453
[7] Stollar OO, et al. Effects of a single dose of orally administered gabapentin in dogs during a veterinary visit: a double-blinded, placebo-controlled study. JAVMA 260:1031-1040, 2022. https://tinyurl.com/ym8fmsmt
[8] https://aggressivedog.com/2024/10/15/dazzled-by-science-part-10-game-changer-behavior-meds-lets-start-with-trazodone/
[9] Kirbey-Madden T, et al. Effects of Gabapentin on the Treatment of Behavioral Disorders in Dogs: A Retrospective Evaluation. animals 14:1462-1476, 2024 https://doi.org/10.3390/ani14101462
[10] https://aggressivedog.com/2024/01/25/fluoxetine/ https://aggressivedog.com/2024/08/01/dazzled-by-science-part-9-behavior-medications-ssris-and-a-few-tcas/
For more information on the approval, regulatory issues, and extra label use of medications for dogs see Dazzled blog posts #6 & #7. https://aggressivedog.com/page/2/?s=dazzled
Lana Kaiser, MD, DVM
Lana Kaiser, born in Buffalo, NY, received a BA in English from SUNY at Buffalo with plans to be a poet. She is a graduate of Michigan State College of Human Medicine and College of Veterinary Medicine. She is a Board-Certified (human Internist), a cattle veterinarian, and a Michigan State University Emeritus Professor.
Trained as a biomedical researcher with a research focus on cardiovascular pathophysiology and parasitology, she is also interested in scientifically studying the interaction between humans and animals, and has published in both scientific disciplines. She resides on a farm in Mason, MI where she raises Maine-Anjou and Red Angus cattle.
She has a mobile beef cattle practice, consults for several national agricultural entities, and has written and lectured about animal welfare, animal health, genetic defects, human-livestock interactions, and animal behavior at the state and national levels. She is involved in issues of animal behavior and welfare at the county, state and national level. Although she has a long history of training dogs, she “stumbled into” the “contemporary dog industry” by attending the first Aggression in Dogs Conference, which was followed by the master course, and innumerable other dog behavior and training webinars and conferences. When she started her dog behavior journey she had six dogs, an ancient Belgian Tervuren), an almost ancient Pyrenees, a very very ancient OCD deaf Beagle and three puppies - two Pyrenees and a Tervuren. She currently shares her life with an adult Belgian Tervuren, an adult Pyrenees, a Pyrenees puppy, a herd of cows and one horse. kaisercattle@gmail.com
