Pregabalin produces similar effects as gabapentin for preanesthetic sedation in cats

Rahul D. Madan Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Alessia Cenani Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Elizabeth Montgomery Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Tatiana Azevedo Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Karen M. Vernau Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Robert J. Brosnan Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Abstract

OBJECTIVE

To compare the effects of oral pregabalin versus gabapentin on sedation quality and anesthesia recovery times in cats in a typical perioperative setting.

ANIMALS

50 healthy cats with > 1 kg body weight presenting for elective surgery.

METHODS

In this randomized, prospective clinical trial, cats presenting to the University of California-Davis Veterinary Medical Teaching Hospital were assigned to receive buprenorphine 0.02 mg/kg IM followed by 1 of 2 oral sedation treatments: pregabalin 4 mg/kg or gabapentin 10 mg/kg. Cats were then anesthetized using a standardized protocol. Physical examination parameters and behavioral scores were measured by 2 treatment-blinded veterinarians to compare sedation levels before and after drug administration. Inadequate sedation for handling or IV catheter placement was addressed by dexmedetomidine administration. After surgery was completed, anesthesia recovery times and quality were assessed by the same veterinarians. The effects of pregabalin versus gabapentin on body temperature, respiratory rate, and heart rate were analyzed using Student t tests; behavioral assessments were analyzed using Wilcoxon signed-rank tests; and drug treatment effects on dexmedetomidine sedation rescue and frequency of delirium during anesthetic recovery were analyzed using Fisher exact tests. A P < .05 indicated statistical significance.

RESULTS

There was no significant difference in change of physiologic parameters or sedation scores before and after sedation between groups. The need for rescue sedation for IV catheter placement and the incidence of emergence delirium were infrequent and similar for both treatments.

CLINICAL RELEVANCE

At the doses studied, oral pregabalin and gabapentin produced indistinguishable effects as adjunctive perioperative sedation agents in cats.

Abstract

OBJECTIVE

To compare the effects of oral pregabalin versus gabapentin on sedation quality and anesthesia recovery times in cats in a typical perioperative setting.

ANIMALS

50 healthy cats with > 1 kg body weight presenting for elective surgery.

METHODS

In this randomized, prospective clinical trial, cats presenting to the University of California-Davis Veterinary Medical Teaching Hospital were assigned to receive buprenorphine 0.02 mg/kg IM followed by 1 of 2 oral sedation treatments: pregabalin 4 mg/kg or gabapentin 10 mg/kg. Cats were then anesthetized using a standardized protocol. Physical examination parameters and behavioral scores were measured by 2 treatment-blinded veterinarians to compare sedation levels before and after drug administration. Inadequate sedation for handling or IV catheter placement was addressed by dexmedetomidine administration. After surgery was completed, anesthesia recovery times and quality were assessed by the same veterinarians. The effects of pregabalin versus gabapentin on body temperature, respiratory rate, and heart rate were analyzed using Student t tests; behavioral assessments were analyzed using Wilcoxon signed-rank tests; and drug treatment effects on dexmedetomidine sedation rescue and frequency of delirium during anesthetic recovery were analyzed using Fisher exact tests. A P < .05 indicated statistical significance.

RESULTS

There was no significant difference in change of physiologic parameters or sedation scores before and after sedation between groups. The need for rescue sedation for IV catheter placement and the incidence of emergence delirium were infrequent and similar for both treatments.

CLINICAL RELEVANCE

At the doses studied, oral pregabalin and gabapentin produced indistinguishable effects as adjunctive perioperative sedation agents in cats.

Introduction

The use of oral and/or parenteral sedation in cats is common practice to facilitate handling, IV catheterization, and as premedication before general anesthesia in the hospital setting to provide anxiolysis to otherwise stressed patients. Administration of sedatives through SC or IM routes requires a certain degree of experience in restraint and injection technique, which can be a limiting factor in certain clinical scenarios and in fractious and/or stressed feline patients. Oral sedation is especially advantageous due to its ease of administration compared to IM and SC injections and the ability of owners to administer these medications at home to allow for more amenable handling and an overall improved experience for patients and veterinary staff.

Gabapentin and pregabalin are structural analogs to the inhibitory neurotransmitter GABA. Members of this drug class, known as gabapentinoids, do not affect the GABA-A receptor but instead bind to the α-2-delta subunit of voltage-gated calcium channels in the CNS, decreasing the release of excitatory neurotransmitters.1,2 Gabapentinoids were traditionally used as antiepileptic and neuropathic pain medications, but more recently they are being utilized for their sedative properties. Gabapentin is widely used in veterinary practices as an anxiolytic in cats with the advantage of having minimal undesirable effects.3 In humans, pregabalin has been shown to have greater potency and lipid solubility compared to gabapentin and cause greater degrees of sedation.4,5

While previous studies have separately evaluated clinical effects of gabapentin or pregabalin in cats, there are currently no published data comparing sedative effects of these 2 drugs in this species in a hospital setting.2,3 The objective of this study was to compare the degree and quality of sedation between gabapentin and pregabalin in cats when used as an adjunct oral premedication prior to general anesthesia and surgery. We hypothesized that behavioral responses to the gabapentinoids would not be the same since oral pregabalin might produce deeper sedation when compared to oral gabapentin due to its more favorable pharmacokinetic properties.

Methods

This prospective, randomized clinical study was approved by both the Clinical Trials Review Board and the IACUC of the University of California-Davis (Protocols No. 23503 and 23540), and informed consent was obtained from owners or shelter representatives prior to enrollment for all cats. Fifty cats weighing 1.9 ± 0.7 kg and aged 4.6 ± 3 months presenting to the University of California-Davis Gourley Veterinary Teaching Center between July and August 2023 for general anesthesia and surgery were studied. Summary demographic information is provided (Table 1). Inclusion criteria for the study were cats > 1 kg body weight and American Society of Anesthesiologists status of I or II based on clinical examination and preanesthetic blood work. Cats with painful preexisting conditions that may affect their general response to sedation were excluded from the study.

Table 1

Summary of demographics and surgical and anesthetic events in 50 cats administered buprenorphine 0.02 mg/kg IM followed by either pregabalin (4 mg/kg) or gabapentin (10 mg/kg) PO; cats were then administered general anesthesia for a clinical surgical procedure. Averages are presented as mean ± SD or median (25th to 75th percentile). P values for treatment group differences were calculated using Student t tests (ketamine) and Mann-Whitney U tests (anesthesia and surgery times and cat age).

Demographics Pregabalin (n = 25) Gabapentin (n = 25) P value
Age (mo) 4 ± 1.9 5.3 ± 3.6 .3
Sex
  Male 12 13
  Male castrated 2 1
  Female 10 11
  Female spayed 1 0
Breed
  Domestic shorthair 19 23
  Domestic medium hair 2 0
  Domestic longhair 2 1
  Siamese 2 1
Surgical procedure
  Spay 10 11
  Neuter 10 12
  Enucleation 4 1
  Wound revision 1 1
Total anesthesia time (min) 92 (15–125) 62 (13–119) .6
Total surgery time (min) 55 (6–67) 36 (4–77) .4
Total ketamine IV dose (mg/kg) 4.7 ± 0.9 4.8 ± 0.6 .9
Anesthetic complications
  Hypotension 3 6
  Hypoventilation 0 1
  Hypothermia 1 3
  Bradycardia 1 2

Cats were admitted to the hospital 2 to 48 hours prior to their scheduled surgical procedure and allowed an acclimatization period of at least 30 minutes in the preoperative induction area before being handled. Prior to premedication, all cats were assessed by the same observers (RDM, TA) who were masked to the oral sedation treatment. Heart rate (HR), respiratory rate (RR), rectal temperature, body weight (kg), and body condition score were recorded. Temperament was assessed using a previously described simple descriptive scale, with 1 being the most relaxed and 4 being very fractious.6 Sedation level was graded using a previously validated feline multiparametric sedation scale (FMSS) that evaluated the animal’s posture, behavior, response to sound, and response to restraint for IM injection or IV catheter (IVC) placement on a scale of 0 to 3 for each parameter.7 The final score ranged from 0 to 12, with 0 representing no sedation and 12 representing maximum sedation. The second component of the FMSS involved the use of a simple qualitative scale to describe the level of sedation: none, mild, moderate, or profound.

The study participants were allocated randomly using a random number table into 1 of 2 oral premedication treatments: gabapentin (50 mg/mL oral solution; Amneal Pharmaceuticals) 10 mg/kg PO or pregabalin (20 mg/mL oral solution; Ascend Laboratories) 4 mg/kg PO.8 The concentration of each drug and selected doses were based on previous studies suggesting similar potency, and these doses resulted in equal drug volumes for both treatments.2,3,5 Vials were premade containing either gabapentin or pregabalin and numbered according to the randomized list. Following the initial assessment, cats were restrained with a towel for IM premedication with buprenorphine (Buprenex), 0.02 mg/kg, to assess response to restraint prior to gabapentinoid sedation used as part of the calculation of the total FMSS score. The cats were then administered 0.2 mL/kg of unlabeled study drug directly in the mouth with a syringe by one of the primary investigators (RDM). The time of administration of buprenorphine and the study drug were recorded. Interactions with patients per FMSS, restraint, and medication administration technique were standardized. Approximately 1 hour after buprenorphine and gabapentin or pregabalin administration, HR, RR, body temperature, and sedation level of the cats using the FMSS were assessed. For the postsedation evaluation, response to restraint was assessed with IVC placement in a cephalic vein for which cats were restrained by wrapping in a towel and extending one of the forelimbs, after shaving and sterile prepping. If a catheter was deemed unnecessary due to the short nature of the procedure, IVC placement was simulated by restraining the patients in the same fashion, shaving and aseptically preparing a patch of skin on the antebrachium, and making a small skin incision with a 22-gauge needle in the region of the cephalic vein. IVC placement was performed by final-year veterinary students, anesthesia technicians, or anesthesia residents. If patients were resistant to restraint and IV cannulation, dexmedetomidine (Dexdomitor) 5 µg/kg was administered IM prior to IVC placement. If there was no response to restraint for cannulation, this same dose of dexmedetomidine was administered IM after IVC placement to ensure standardization of the anesthetic protocol. A note was made whether dexmedetomidine was given before (sedation rescue) or after IV cannulation. General anesthesia was induced with ketamine (Zetamine) IV titrated to effect and midazolam (Akorn Pharmaceuticals) 0.3 mg/kg IV after 1 to 3 minutes of preoxygenation via face mask. Lidocaine 2% 0.1 mL was administered topically onto the arytenoid cartilage to desensitize the larynx prior to endotracheal intubation. Intubation was performed by veterinary students under supervision by anesthesia clinicians or technicians. Time of induction and induction drug doses were recorded.

Anesthesia was maintained with isoflurane in 100% oxygen with spontaneous ventilation. Anesthetic monitoring included measurement of HR, RR, esophageal or rectal temperature, capnography, pulse oximetry, and noninvasive blood pressure. Lactated Ringer solution was administered at 5 mL/kg/h in cats that underwent IVC placement, and a forced warmer was used to support body temperature. Cats underwent routine castration (n = 22), ovariohysterectomy (21), or enucleation (5) procedures performed by veterinary students under faculty supervision. Two cats underwent wound revision surgery to address incisional dehiscence or defect from a previous surgery. Total surgery time measured from the initial incision to final suture was recorded. Anesthesia time was recorded starting from time of induction and ending at the time the inhalant vaporizer was turned off. The time when patients arrived in the postanesthetic recovery room and the time from end of anesthesia to extubation (when applicable), time to lift head, and time to sternal recumbency were also recorded. Heart rate, RR, and rectal temperature were obtained at the time of extubation. Patients were assigned a subjective recovery score (0 to 3), with 0 and 3 being a very excitable and/or dysphoric recovery and a calm recovery, respectively.9 Following extubation, the cats were administered a dose of either meloxicam (0.1 mg/kg, IV) or robenacoxib (2 mg/kg, IV or SC).

Statistical analysis

Differences between pre- and postsedation responses were calculated for physiologic and behavioral variables. Pre- and postsedation differences for HR, RR, and body temperature were deemed normally distributed using Shapiro-Wilk tests, and drug treatment effects on pre- versus postsedation measurements were analyzed using Student t tests. The need for dexmedetomidine rescue sedation prior to IVC placement and the incidence of emergence delirium were analyzed using Fisher exact tests. Mann-Whitney U tests were used to assess pre- versus postsedation behavioral changes in temperament, sedation, and recovery scores. Recovery times were tested for normality by Shapiro-Wilk tests and were found to be not normally distributed, and these data were also analyzed using Mann-Whitney U tests. A P < .05 was required for statistical significance (SPSS Statistics version 28; IBM Corp). A post hoc sample size calculation for detection of significant differences in FMSS scores was performed assuming a Mann-Whitney U test (G*Power version 3.1.9.6; Heinrich-Heine-Universität Düsseldorf).

Results

Normally distributed continuous data were summarized as mean ± SD (SD), and nonnormally distributed data and ordinal data were summarized using median and IQR (25th to 75th quartile). Cats were equally divided between treatment groups. Demographic data is displayed (Table 1). There were no significant differences in the pre- to postsedation change in rectal temperature, HR, or RR between treatment groups (Table 2).

Table 2

Mean ± SD changes in physiologic parameters in 50 study cats (postsedation minus presedation) administered buprenorphine 0.02 mg/kg IM followed by either pregabalin (4 mg/kg) or gabapentin (10 mg/kg) PO.

Pregabalin (n = 25) Gabapentin (n = 25) P value
Temperature (°C) 0.15 ± 0.13 0.04 ± 0.10 .2
Heart rate (beats/min) –2 ± 6 –3 ± 8 1
Respiratory rate (breaths/min) –3 ± 3 1 ± 3 .3

The median and IQR for pre- and postsedation temperament scores were 1.5 (1 to 2) and 1.5 (1 to 1.5), respectively, and the change was not significantly different between gabapentin versus pregabalin administration (P = .3). The median values and IQR for the change (post- minus presedation) in scores for posture, behavior, response to sound, and response to restraint are summarized (Table 3). None of these behavioral changes were significantly different between treatment groups (P = .3 to .9). The median total FMSS score was 3 (2 to 4) presedation and 5.5 (4.5 to 6.5) postsedation, and there was no significant change seen in FMSS score between the 2 groups (P = 1.0). A post hoc sample size calculation showed that 1,126 cats would have been required to detect a significant difference in FMSS scores between treatment groups, assuming the treatment effect size and response variability was unchanged from the 50 cats studied here.

Table 3

Summary of changes in sedation parameters (postsedation minus presedation) in 50 study cats administered buprenorphine 0.02 mg/kg IM followed by either pregabalin (4 mg/kg) or gabapentin (10 mg/kg) PO. Averages are presented as median (IQR).

Gabapentin Pregabalin P value
Temperament 0 (–0.5–0.5) 0 (0–0) .3
Posture 0 (0–0.5) 0 (0–0.5) .9
Behavior 1 (0.5–1) 0.5 (0.5–1) .4
Response to sound 1 (0.5–1.5) 1 (0.5–1.5) .9
Response to restraint 0.5 (0–1) 0.5 (0–1) .9
Total FMSS score 2.5 (1.5–3.5) 2.5 (2–3.5) 1

FMSS = Feline multiparametric sedation scale.

The median recovery score was 2.25 (1.5 to 3), and there was no significant difference between treatments (P = .4). The median times to lifting of head and to sternal recumbency were 8 minutes (5 to 13 minutes) and 9 minutes (6 to 13 minutes), respectively, and there was no significant difference between groups for either time (P = .6 to .7).

Six cats in the study required rescue sedation with dexmedetomidine to allow IVC restraint and placement: 2 (8%) in the gabapentin group and 4 (16%) in the pregabalin group, and the incidence was similar between groups (P = .7). Among the cats that received gabapentin, 7 (28%) exhibited emergence delirium, and in those that received pregabalin, delirium was noted in 5 (20%) cats. There was no difference in frequency of emergence delirium (P = .7) between groups.

The average dose of IV ketamine used for induction, median anesthesia and surgery times, and incidence of anesthetic complications for each treatment group are listed (Table 1). Anesthetic complications included hypotension (n = 7), hypothermia (4), bradycardia (4), and hypoventilation (1). Hypotension was defined as a systolic blood pressure < 80 mm Hg or mean arterial pressure < 60 mm Hg, hypoventilation was defined as an end-tidal CO2 > 45 mm Hg, and hypothermia was defined as rectal temperature < 36.1 °C. These were addressed using standard management techniques by the overseeing anesthesia clinician. There were no reported surgical complications.

Discussion

The present study did not show oral pregabalin to be superior to gabapentin in its effects on sedation or recovery when used in conjunction with buprenorphine IM for premedication in cats undergoing general anesthesia. As gabapentin has been shown to be significantly sedating in cats, the lack of difference in effect between the treatment groups in this study supports similar efficacy of pregabalin.2,3,10 The doses of gabapentin and pregabalin chosen in this study were both extrapolated from previous studies of dogs, in which these doses appeared to have relatively comparable analgesic properties, and also based on dosages that are typically used clinically for sedation and analgesia in dogs and cats.2,3,11,12 In our study, the similarity in sedation scores found between treatment groups supports that pregabalin 4 mg/kg PO and gabapentin 10 mg/kg PO are equipotent doses for sedation in cats. Buprenorphine, a partial µ-opioid receptor agonist, is a commonly used analgesic for routine surgical procedures in the authors’ institution as well as many small animal practices and was needed to provide perioperative analgesia in this study.1315 As buprenorphine does not have profound sedative properties in healthy cats, this likely had minimal impact on the degree of sedation in this study.16,17 For the present research study, the IM buprenorphine injection was administered before the oral sedative to compare the response of the cats to physical restraint and a mildly noxious stimulus before and after sedation. However, for routine clinical use, it may be advantageous to administer the oral sedative prior to other parenteral analgesic injections.

One limitation of this study may have been that there was insufficient time between administration of the oral gabapentinoids and the postsedation assessment. The postsedation evaluation at 60 minutes was decided on the basis of previous studies that demonstrated a time to maximum concentration (tmax) of 0.5 to 1 hour for oral pregabalin at a dose of 5 mg/kg in cats and to reflect a realistic clinical scenario.18 Although tmax for pregabalin is reported to be approximately 1 hour, other pharmacokinetic studies indicate that it may take longer to reach tmax for gabapentin and the peak concentrations for gabapentin typically occur well after 60 minutes.5,1820 It is thus possible that, at the time of assessment, cats in this study had not yet reached the maximum plasma concentration and/or peak effect for gabapentin or pregabalin.

The need for dexmedetomidine rescue sedation was similar between treatment groups, and sedation quality when using either gabapentin or pregabalin with buprenorphine as a premedication was sufficient for general handling and IVC placement for most cats. This further supports that pregabalin does not provide superior sedation in cats compared to gabapentin, but either drug can be used to achieve an adequate plane of sedation for IVC placement in most cases. It should be noted that a population of relatively docile animals with low temperament behavioral scores may have made treatment differences more difficult to detect, and a study using a population of less well-handled animals could yield different results.

Dexmedetomidine has been shown to increase sedation scores for up to 60 minutes following extubation in cats.21 As such, it is possible that dexmedetomidine obscured treatment group effects on recovery times. Although ketamine used for anesthetic induction can affect recovery times for short surgical cases, the doses and anesthesia times were similar between treatment groups. Therefore, ketamine dose and anesthesia/surgery times were not included as covariants in the statistical analysis.

The present study used a sample size similar to previously published studies that successfully detected clinically relevant sedation effects in cats.2224 The absence of a significant difference in recovery times or behaviors between gabapentin or pregabalin treatments is consistent with no clinically meaningful difference in sedative effects between gabapentin and pregabalin within this population of cats using similar anesthetic and analgesic techniques. Results from the present study support the efficacy and use of either agent as adjunct oral sedation for cats in the perianesthetic setting.

Acknowledgments

None reported.

Disclosures

The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.

Funding

The authors have nothing to disclose.

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