Introduction

Oral gabapentin is increasingly being administered to cats before veterinary visits to decrease anxiety. Gabapentin is attractive as an anxiolytic because it is widely available, is affordable, and lacks controlled substance status. Oral gabapentin is readily absorbed with high bio-availability and rapid onset of drug effect in cats.^1,2 One recent study showed decreased fear-based responses in a feral cat colony following a single dose of ≤30 mg/kg.³ Another study revealed decreased stress and increased compliance with the use of 100 mg of gabapentin per cat.⁴ Although gabapentin dosages ≤50 mg/kg are reportedly well-tolerated in cats, effects on echocardiographic and hemodynamic parameters are uncertain.^3–5

Echocardiography is preferentially performed on unsedated animals; however, use of sedation in cats is occasionally requisite to obtain diagnostic results. The most ideal sedative drug should have minimal cardiovascular effects to provide conclusive results without altering echocardiographic parameters. Results of prior studies investigating the use of varying sedatives with cardiac function in cats emphasize the need for an oral anxiolytic drug that provides adequate sedative effects while maintaining normal hemodynamic function.^6–10

The purpose of this study was to investigate the use of oral gabapentin as an anxiolytic in healthy cats and determine its effects on non-invasive blood pressure (BP), heart rate, and echocardiographic measurements of chamber size as well as systolic and diastolic function. We hypothesized that cats receiving oral gabapentin would reliably demonstrate mild sedative effects without significant consequence on left-sided cardiac size or function.

Materials and Methods

Sedation Scoring

Level of sedation was assessed by two investigators (M.E.A. and K.F.S. or N.L.L.) at 60, 120, 180, and 240 min after the blinded capsule was administered at each visit. Sedation was assessed with varying tactile and auditory stimuli in all cats. The level of sedation was determined using a previously described sedation scoring system⁸ (Table 1).

TABLE 1 Sedation Scoring in Cats as Described by Biermann et al.

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Results

Of the 24 cats screened, 10 met inclusion criteria for enrollment in this study. Cats were excluded for various reasons including focal or diffuse concentric LV hypertrophy (n = 7), poor patient compliance (n = 2), and single instances of mild pericardial effusion, mild aortic valve insufficiency, intermittent ventricular bigeminy, bicytopenia, and vehicular trauma after screening but before study participation.

Nine enrolled cats were of mixed breed, and there was a single Siamese cat.

There were seven spayed females and three neutered males with a median age of 3 yr (range 2–13 yr). The mean weight was 4.5 ± 1.1 kg, and the mean body condition score was 5.4 ± 0.7 out of a 9-point scale. The mean dosage of gabapentin was 27.9 ± 2.6 mg/kg. Five cats received 100 mg of gabapentin, and five cats received 150 mg of gabapentin. No cats experienced an adverse drug-related event during the study.

Three cats did not exhibit any appreciable sedative effects after having received gabapentin. Of the seven cats that did exhibit sedation, five cats appeared sedate by 60 min, and all cats appeared sedate by 120 min after gabapentin administration. All sedated cats appeared modestly affected with mild ataxia (sedation score of “1”) and retained the ability to spontaneously ambulate. There was almost perfect interobserver agreement of sedation scoring ( κ = 0.84), with only two time points erroneously scored by faculty observers as a “1” on the sedation scale despite the patient having received a placebo. No significant correlation was found for gabapentin dosage, total dose, body weight, or body condition score with sedation scores at any time point (Supplementary Table I).

No significant difference was found between baseline, placebo, or gabapentin for heart rate (P = .183) or Doppler BP (P = .491). For the echocardiographic parameters (Table 2), 2D FS was significantly decreased with gabapentin (49.1 ± 9.8%) compared with baseline (53.5 ± 11.0 %, adjusted P = .047) and placebo (52.8 ± 9.2%, adjusted P = .02; Figure 1A). The M-mode LVIDs was significantly increased with gabapentin (8.2 ± 1.8 mm) compared with placebo (7.1 ± 1.3 mm, adjusted P = .037; Figure 1D) but not significant when comparing gabapentin with baseline (7.6 ± 1.8 mm, adjusted P = .061). Left atrial volumes were significantly increased with gabapentin (1.5 ± 0.4 mL) compared with baseline (1.3 ± 0.3 mL, adjusted P = .039; Figure 1E); however, it was not considered statistically significant when comparing gabapentin with placebo (1.3 ± 0.4 mL, adjusted P = .147). All three significantly affected variables by analysis of variance showed no statistical significance between placebo and baseline measurements. No significant differences were found between baseline, placebo, or gabapentin for the remaining echocardiographic parameters evaluated including linear LA size, LV wall thicknesses in diastole, LV diastolic chamber dimensions, aortic and pulmonic outflow velocities and timing intervals, mitral inflow velocities and ratios, isovolumetric relaxation time, E wave deceleration time, and tissue Doppler velocities.

TABLE 2 Hemodynamic and Echocardiographic Variables (Mean ± Standard Deviation) with Placebo and Gabapentin Compared with Baseline in Healthy Cats

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Discussion

The results of this study demonstrate that sedative doses of oral gabapentin appear hemodynamically well tolerated with minimal echocardiographic effects. Our study results supported a modest reduction in systolic function in healthy cats receiving sedative doses of gabapentin; however, all of the parameters measured remained within existing reference ranges. Not all measured indices of systolic function were significant; however, the trend is likely valid given the relatively small patient population. Importantly, no change in LV wall thickness was found, which is particularly salient for identification of cats affected with a hypertrophic phenotype. For LA size, there was no change in linear dimensions despite a mild increase in LA volume with gabapentin compared with baseline but not compared with placebo, which may reflect a statistical type 1 error given the small sample size, measurement or patient variability, or a legitimate mild increase in LA size due to increased LV filling pressures with decreased systolic performance. Furthermore, no difference in overall heart rate or BP was found, suggesting that cats are unlikely to experience deleterious hemodynamic consequence or have significant impact on echocardiographic examination with oral gabapentin. The changes seen may have been related to decreased sympathetic tone associated with gabapentin use.

Our study results also suggest that the sedative effects of gabapentin are relatively mild, with most cats exhibiting ataxia, similar to previous studies investigating gabapentin use.^3–5,12 The majority of the cats in this study were considered sedate by 120 min after gabapentin administration, which likely reflects the average peak serum concentration of gabapentin of 60–100 min.^1,2 Three cats did not exhibit overt sedation based on our sedation scale; these three cats received gabapentin dosages near the middle of the dosing range (27.2–28.9 mg/kg), suggesting no obvious dose-related effect. Additionally, no overt relationship was evident between age or body condition score of unaffected cats compared with affected cats. We suspect the lack of obvious sedation in these cats is related to the difficulties in differentiating the subtleties of mild sedation in this particular species in a hospital setting or perhaps related to differences among cats for baseline anxiety levels or individual metabolic rates. It is interesting to note that the same trend of decreased 2D FS, increased M-mode LVIDs, and increased LA volume was seen with gabapentin use even in cats that did not exhibit overt sedation. We felt owner compliance was strong because persons affiliated with the veterinary community at Oregon State University administered all capsules, and eligibility criteria included ability to administer oral medications.

The veterinary literature has documented effects of various sedative, dissociative, and analgesic drugs in cats; however, most of these drugs impact echocardiographic and hemodynamic parameters, which can confound the clinical interpretation.^6–10,13 One study assessing sedation with butorphanol and alfaxalone revealed significantly decreased indices of systolic function and a decrease in heart rate that approached significance.⁶ In that study, the affected indices of systolic function remained within established reference ranges, and there was no documented sedative effect on LV septal free wall or interventricular septal thickness.⁶ Another study comparing the effects of a combination of butorphanol and acepromazine with and without ketamine suggested that the addition of ketamine resulted in a significantly higher heart rate; higher heart rates can reduce diastolic filling with attendant changes to wall thickness echocardiographically.⁷ Sedation with butorphanol and acepromazine significantly decreased BP compared with the baseline.⁷ Additionally, several measurements of chamber size, particularly the LV free wall measurement in diastole, was increased in both protocols compared with the baseline.⁷ Although the numeric changes in LV free wall remained within established reference ranges, these sedatives could potentially lead to a misdiagnosis of abnormal wall thickening in cats that are at the upper end of the reference range. Another study in cats assessed several combinations of drugs: midazolam and butorphanol; midazolam, butorphanol, and ketamine; midazolam, butorphanol, and dexmedetomidine; and ketamine and dexmedetomidine.⁸ Results indicated that although all investigated combinations significantly reduced stroke volume and cardiac output, the use of dexmedetomidine resulted in the greatest cardiovascular depression.⁸ The study also suggested that although the combination of butorphanol and midazolam has nominal cardiovascular effects, the level of sedation may be inadequate and can lead to dysphoria.⁸ A study evaluating effects of oral trazodone revealed no clinically significant change to echocardiographic indices; however, systolic BP was significantly decreased.¹⁰ Finally, a recent study suggested that alfaxalone alone at doses of 5 mg/kg compared with combined alfaxalone and acepromazine provided good sedation with minimal change to hemodynamic parameters; however, alfaxalone alone can lead to hyperreactivity and poor recovery, so additional sedatives may be necessary.¹³ The results of these previous studies emphasize the need for an oral anxiolytic drug that provides adequate sedative effects while maintaining normal cardiovascular hemodynamics in cats. Although gabapentin generally provides milder sedation than dissociative drugs or alpha-2 agonists, the lack of substantial echocardiographic changes in our study is encouraging. For cats requiring greater sedation, the available literature suggests injectable butorphanol and alfaxalone impact cardiovascular function the least of the available sedative drugs.

In human medicine, gabapentin is used for ailments such as epilepsy, chronic neuropathic pain, and a variety of psychoses.¹⁴ Although the number of randomized, controlled trials evaluating the anxiolytic effect of gabapentin is limited, several studies have demonstrated its benefits as a perioperative anxiolytic with postoperative pain modulation in human patients.^15,16 Similar to the above-mentioned reports, the benefits of using gabapentin for treating chronic pain in cats have also been demonstrated.^12,17 Originally developed to be an analog of gamma-aminobutyric acid, the gabapentinoid drugs gabapentin and pregabalin were found to have no action on gamma-aminobutyric acid receptors.¹⁸ Instead, gabapentin binds to α2δ auxiliary subunit of voltage-gated calcium channels and has an inhibitory effect on these channels by decreasing channel trafficking and plasma membrane expression.^19,20 There is conflicting evidence about the impact gabapentin has on voltage-gated calcium channels regarding calcium conduction or myocardial function. Deletion of the α2δ-1 subunit in knockout mice demonstrated decreased myocardial contractility and relaxation, in addition to decreased L-type calcium current amplitude.²¹ Additionally, mutations in the gene encoding the α2δ-1 subunit have been associated with malignant arrhythmias such as Brugada syndrome and short QT syndrome in people.^21,22 Gabapentin appears generally well tolerated by human patients, yet there are rare case reports of decompensated congestive heart failure associated with gabapentinoid use.^23,24 This has led to caution in the use of pregabalin with New York Heart Association class III–IV heart failure by the American Heart Association, and the need for cautious gabapentin use in milder cases of heart disease is less clear.^24,25 Of note, there was also a single case report of suspected third-degree atrioventricular block secondary to pregabalin use, as well as an association seen between gabapentinoid use and development of atrial fibrillation in older patients.^26,27 To date, there have been no reports of decompensated heart failure or cardiovascular complications with use of gabapentinoids in companion animals. These findings suggest that it would be prudent to exhibit caution with gabapentinoid use in animals with significant underlying structural or electrical heart disease; however, further studies are warranted to determine the extent of this concern.

Our study had several limitations. Although few echocardiographic indices were significantly affected by gabapentin administration, the study’s sample size was small, and a larger-scale study may further elucidate the importance of these echocardiographic changes. True to the spirit of this study, cats can be difficult to handle, and one limitation of our study was necessitating the use of friendly cats. This makes it difficult to extrapolate the benefits of gabapentin for excessively anxious or fractious cats; the lack of overt sedation in three cats despite adequate dosing suggests that gabapentin alone may be inadequate for some cats. Additionally, finding qualifying cats was a challenge for our study, and almost half (11/24, 46%) of the reportedly healthy screened patients had unexpected findings echocardiographically, electrocardiographically, or on baseline bloodwork. This highlights the preponderance of incidental abnormalities in purportedly healthy cats and underscores the questionable importance of equivocal focal septal hypertrophy as a pathologic entity in cats. In relation to this, data were collected using only healthy cats, and therefore the outcomes of this study may not be adequately extrapolated to cats that have overt cardiac disease. Lastly, a limitation of our study was the ability to adequately assess mild sedation in cats. Cats as a species can vary significantly in their behavior in the clinic setting; nuances in the varying degrees of mild sedation can be difficult to ascertain in cats attempting to hide or those that are unwilling to ambulate.

Conclusion

The results of this study suggest that a single, oral dose of gabapentin produces mild sedative effects in most cats within 120 min of administration and causes clinically insignificant changes to echocardiographic measurements. Despite statistically significant echocardiographic differences between gabapentin and baseline, affected measurements remained within established reference ranges. A single dose of oral gabapentin may produce a modest decrease in systolic function in healthy cats; however, these data should be validated by a larger study. The safety of long-term gabapentin administration cannot be extrapolated from our study, and further studies are warranted to assess the safety and efficacy of oral gabapentin in patients with concurrent cardiac disease.