Inhalation anesthesia is widely used in veterinary practice and is characterized by quick onset, rapid recovery, and adjustability of anesthetic depth. However, using high concentrations of inhaled anesthetics, such as isoflurane, can cause adverse cardiovascular and pulmonary effects in cats (1). Minimum alveolar concentration (MAC) is the most commonly used measure of potency for inhaled anesthetics (2, 3). A decrease in MAC may decrease the concentration of inhaled anesthetics required to maintain adequate depth of anesthesia, which may reduce adverse cardiovascular and pulmonary effects (4, 5).

Gabapentin, 1-(aminomethyl) cyclohexane acetic acid, is a structural analog of gamma-aminobutyric acid (GABA). Although GABA is one of the inhibitory neurotransmitters of the mammalian central nervous system (6), gabapentin does not act on GABA receptors but selectively inhibits voltage-gated calcium channels containing the α2δ-1 subunit (7). Originally, gabapentin was used as antiepileptic therapy to reduce partial seizures (8). In later studies, the effect of gabapentin in treating chronic pain in cats has been revealed (9). More recently, due to its ease of administration and availability, gabapentin is widely used as an anxiolytic in the clinical setting for cats. In addition, oral gabapentin has been described to attenuate fear responses in community cats (10), stimulate appetite for post-ovariectomy (11), contribute to reducing stress during transportation as well as improve compliance in veterinary examination (12). Commonly used oral single doses of gabapentin are 50, 100, and 150 mg cat⁻¹, or ~10–30 mg kg⁻¹, which caused sedative effects for most cats (10, 12, 13). Pharmacokinetic studies of oral gabapentin in cats have shown that the time to reach maximum plasma concentration was ~1–2 h after a single oral dose of gabapentin (10 mg kg⁻¹) (14, 15); the time from oral administration to achieve mild sedative effect was also within this time frame (12, 13).

Perorally administered gabapentin (20 mg kg⁻¹) 2 h before general anesthesia maintained with isoflurane was shown to have a MAC-sparing effect in dogs (16). However, intravenous gabapentin administration was reported to have no detectable effects on MAC_ISO in cats (17). To the authors' knowledge, no clinical studies have been published assessing the effect of perorally administered gabapentin on the MAC_ISO in cats.

The objective of this study was to determine the effect of prior perorally administered 100 mg gabapentin on MAC_ISO in cats. We hypothesized that prior perorally administered gabapentin would decrease MAC_ISO in cats.

Six cats weighing 3.31 ± 0.26 kg were perorally administered 100 mg gabapentin, resulting in a dosage of 30.36 ± 2.46 mg kg⁻¹ in the gabapentin treatment. The MAC_ISO of the gabapentin treatment was 1.02 ± 0.11%, which was significantly (p < 0.001) lower than in the placebo treatment (1.49 ± 0.12%; Figure 2). The MAC_ISO decreased by 31.58 ± 6.94% with prior administration of gabapentin.

When equilibration of FE′Iso was reached throughout anesthesia regardless of responses to tail clamping, SBP was 118 ± 24 mmHg for all measurements. T (all measurements pooled) was 38.8 ± 0.2°C. PE′CO₂ (all measurements pooled) was 34 ± 4 mmHg. After equilibration at the lowest FE′Iso, when cats did not respond to tail clamping, no significant differences were found between the gabapentin treatment and the placebo treatment in cardiovascular and other vital variables (Table 1). The FE′Iso at extubation in gabapentin treatment was 0.25 ± 0.05%, which was significantly (p = 0.005) lower than that in the placebo treatment (0.48 ± 0.10%). No significant differences in the time from discontinuation of isoflurane to extubation were found between gabapentin and placebo treatments.

The time from gabapentin/placebo administration to starting MAC determination was 122 ± 2 min in gabapentin and placebo treatments, with no significant differences found between treatments. The duration of anesthesia and the time from gabapentin/placebo administration to the first and second MAC determination were significantly less in the placebo treatment than those in the gabapentin treatment (p = 0.012, p < 0.001, p = 0.018, respectively; Table 2).

This study supports our hypothesis that prior perorally administered gabapentin would decrease MAC_ISO in cats. Gabapentin (100 mg cat⁻¹) perorally administered 2 h before starting MAC determination maintained with isoflurane significantly reduced MAC_ISO by 31.58 ± 6.94% compared with the placebo treatment. This finding is in agreement with a previous study in dogs that oral gabapentin (20 mg kg⁻¹) had a 20 ± 14% MAC-sparing effect (16). The MAC_ISO range for cats was reported to be between 1.20 ± 0.13% and 2.22 ± 0.35%, while the mean MAC_ISO in cats was 1.71 ± 0.07% (28). In this study, the MAC_ISO for the placebo treatment (1.49 ± 0.12%) is within the reported range, but slightly lower than the reported mean MAC_ISO. The FE′Iso at extubation in gabapentin treatment was significantly lower than that in the placebo treatment. Possibly due to the MAC-sparing effect of gabapentin, cats were allowed to tolerate the endotracheal tube at a lower FE′Iso in the gabapentin treatment. But the significance of FE′Iso at extubation is difficult to interpret because it was obtained without equilibration, therefore not representative of the partial pressure in the central nervous system. PE′CO₂ and body temperature were both kept within the target range. Although there was no significant difference in cardiovascular variables between gabapentin and placebo treatments, implying that gabapentin may not bring significant hemodynamic benefits in anesthetized cats, the results should be interpreted with caution due to the small sample size. A recent study examined the effects of oral gabapentin (27.9 ± 2.6 mg kg⁻¹) within 2 h of administration on sedation, hemodynamic and echocardiographic variables in awake cats. Heart rate and blood pressure did not differ significantly between the baseline, placebo, and gabapentin treatments, while most cats exhibited signs of sedation with mild ataxia and had a reduction in echocardiographic systolic function albeit they remained within the reference range (13). Gabapentin may have limited effects on hemodynamic variables in either anesthetized or awake cats, but further investigations are warranted for verification.

The exact mechanism by which gabapentin reduces MAC remains to be determined. Studies have shown that gabapentin provides an antinociceptive effect by binding to the alpha2-delta subunit of voltage-gated calcium channels, which reduces the release of glutamate, norepinephrine (noradrenaline), and substance P (29). However, it remains unknown whether the MAC-sparing effect of gabapentin is due to its antinociceptive effect (30).

The effect of gabapentin on MAC differs based on animal species and routes of administration. In a study evaluating the effects of intraperitoneal gabapentin treatment on MAC_ISO in adult male rats, only high dosages of intraperitoneal gabapentin were shown to significantly reduce MAC (31). When gabapentin was administered intraperitoneally at concentrations of 300 and 1,000 mg kg⁻¹, MAC_ISO was significantly reduced by 19 and 18%, respectively (31). The effects of intravenous gabapentin administration on the MAC_ISO in cats have been investigated, but no significant differences were identified at any of the target plasma concentrations (17). This finding contradicts our findings and previous studies in dogs and rats (16, 31). The cause for the difference in MAC-sparing effect between oral and intravenous administration of gabapentin is unclear, and additional study is warranted to investigate the effect and mechanism of different gabapentin administration routes on MAC in cats.

There are certain limitations in the current study. Lidocaine was used prior to tracheal intubation and may have been systemically absorbed to reduce MAC (32). However, due to the low dose as well as the long duration between lidocaine administration and MAC determination, the effect of lidocaine on MAC may be marginal. The statistical power for detecting effects on cardiovascular and other vital variables is unknown, but it is probably low because the sample size was chosen according to the power analysis to identify changes in MAC_ISO. Besides, the cardiovascular effects of gabapentin in anesthetized cats were not designed to explore in detail, so the cardiovascular effects of gabapentin warrant additional investigation. Positive pressure ventilation was used during anesthesia which might decrease cardiac output (33), and affect blood pressure. Due to the invasiveness and technical challenges, non-invasive blood pressure (Doppler) rather than arterial blood pressure measurement was employed in this study. Doppler has been shown to underestimate systolic blood pressure in anesthetized cats (34), therefore, SBP reported in this study may not represent its true systolic blood pressure. Based on study timeline, the equilibration time before the first noxious stimulation was longer than in other similar studies (21, 23). Owing to fewer adjustments of isoflurane concentration in the placebo treatment, the duration of anesthesia and the time from gabapentin/placebo administration to the first and second MAC determination were less in the placebo treatment than in the gabapentin treatment. However, the duration of anesthesia is not known to affect MAC_ISO (35). In this study, a single-point calibration was used which might affect the accuracy and reliability of the MAC determinations (36). Gabapentin plasma concentrations were not measured concurrently, making it difficult to evaluate the relationship between plasma concentrations and MAC determinations. Two pharmacokinetic studies of single oral administration of gabapentin in cats agreed that a 1-compartment model with lag time fitted best for the decrease in the plasma concentration of gabapentin after oral administration, and peak plasma concentrations of single oral doses of gabapentin (10 mg kg⁻¹) were 7.982 ± 1.053 and 12.42 (8.31–18.35) μg mL⁻¹ after 100 ± 22 and 63 (44.4–126.6) min of administration, respectively (14, 15). However, the mean time from drug administration to MAC determination was about 240 min, at which time gabapentin plasma concentrations had declined from peak concentrations. In future studies, simultaneous analysis of gabapentin plasma concentration is still needed, although plasma concentrations may or may not represent target tissue concentration (central nervous system in this case).

In conclusion, this study found that oral administration of 100 mg gabapentin 2 h before starting MAC determination reduced MAC_ISO with no observed hemodynamic benefit. Further studies of other formulations of gabapentin and variable dosing regimens and their correlation with plasma concentration and MAC_ISO in cats are warranted.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The animal study was reviewed and approved by Institutional Animal Care and Use Committee of Nanjing Agricultural University.

HC: study design, statistical analysis, and preparation of manuscript. HY: study design, data acquisition, and preparation of manuscript. MengqL: study design and statistical analysis. HP: study design and data acquisition. WG: study design and preparation of manuscript. MengL: study design, data management, and preparation of manuscript. All authors approved the final version of the manuscript.