Anesthesia & Analgesia:
Anesthetic Pharmacology: Research Reports
The Effects of Intravenous Gabapentin Administration on the Minimum Alveolar Concentration of Isoflurane in Cats
Reid, Patrick BA; Pypendop, Bruno H. DrMedVet, DrVetSci; Ilkiw, Jan E. BVSc, PhD
From the Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, California.
Supported by Merck-Merial Scholars Research Program, the School of Veterinary Medicine, University of California, Davis, the Winn Feline Foundation, the George Sydney and Phyllis Redmond Miller Trust, and the Center for Companion Animal Health, School of Veterinary Medicine, University of California, Davis.
Disclosure: The authors report no conflicts of interest.
Address correspondence and reprint requests to Bruno H. Pypendop, DrMedVet, DrVetSci, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, One Shields Ave., Davis, CA 95616. Address e-mail to email@example.com.
Accepted April 12, 2010
Published ahead of print June 14, 2010
BACKGROUND: Gabapentin is a structural analog of γ-aminobutyric acid, one of the inhibitory neurotransmitters of the mammalian central nervous system. It is increasingly being used preemptively to control postoperative pain. Therefore, its interaction with inhaled anesthetics is of clinical interest. In this study, we examined the effects of gabapentin on the minimum alveolar concentration (MAC) of isoflurane in cats. We hypothesized that gabapentin would decrease the MAC of isoflurane in a dose-dependent manner.
METHODS: Six cats were included in the study. Gabapentin was administered IV to achieve target plasma concentrations between 0 and 16 μg/mL and the MAC of isoflurane was determined at each gabapentin concentration. Gabapentin concentrations were quantitated by liquid chromatography–mass spectrometry analysis of extracted plasma samples. MAC values at the different gabapentin plasma concentrations were analyzed by a repeated-measures analysis of variance using the Huynh-Feldt correction for violation of the sphericity assumption.
RESULTS: Actual gabapentin concentrations were 0 ± 0, 1.18 ± 0.23, 2.25 ± 0.23, 4.96 ± 1.19, 10.63 ± 1.37, and 19.69 ± 3.97 μg/mL for the target concentrations of 0, 1, 2, 4, 8, and 16 μg/mL, respectively. The MAC of isoflurane in this study was 2.10%± 0.13%, 2.10% ± 0.14%, 2.13% ± 0.12%, 2.06% ± 0.11%, 2.11% ± 0.15%, and 2.09% ± 0.25% at target plasma concentrations of 0, 1, 2, 4, 8, and 16 μg/mL, respectively.
CONCLUSIONS: We conclude that gabapentin did not have a detectable effect on the MAC of isoflurane in cats.
Gabapentin is a structural analog of γ-aminobutyric acid, one of the inhibitory neurotransmitters of the mammalian central nervous system. It was first introduced as an antiepileptic drug, to reduce partial seizures.1 It was later found to be effective in treating some chronic pain syndromes such as postherpetic neuralgia, postpoliomyelitis neuropathy, and reflex sympathetic dystrophy.1 More recently, preemptive gabapentin administration has been reported to reduce postoperative pain in a number of surgical procedures including thyroid surgery,2 lumbar discoidectomy,3 and vaginal hysterectomies.4 As evidence grows that gabapentin decreases postoperative pain and analgesic consumption when administered preemptively, its use for premedication before general anesthesia is envisaged to increase. The potential interaction between gabapentin and inhaled anesthetics has not, to the authors' knowledge, been reported. Because gabapentin has been reported to have sedative5 and analgesic6 properties, it is possible that, similar to select other sedatives7,8 and analgesics,9 gabapentin decreases the immobilizing dose of inhaled anesthetics. The aim of this study was to determine the effect of gabapentin on the minimum alveolar concentration (MAC) of isoflurane, and to examine the dose dependence of the effect. We hypothesized that gabapentin decreases the MAC of isoflurane in a dose-dependent manner.
This study was approved by the Institutional Animal Care and Use Committee of the University of California, Davis. Six healthy domestic shorthair cats, 1 to 2 years old, weighing 4.8 ± 0.6 kg (mean ± SD) were used. Food but not water was withheld from each cat for 12 hours before performance of the experiments.
Anesthesia was induced with isoflurane in oxygen using an induction box and a facemask. The trachea was then intubated with a cuffed endotracheal tube (internal diameter, 4.5 mm), and anesthesia was maintained with isoflurane, initially at 2%, in oxygen via a Bain circuit using a fresh gas flow rate of 2 L/min. All the cats were allowed to breathe spontaneously throughout the study.
A catheter was passed through the lumen of the endotracheal tube so that its tip was positioned at the distal end of the tube. This catheter was connected to a Raman spectrometer (Rascal II; Ohmeda, Salt Lake City, UT) for continuous measurement of inspired and end-tidal (ET) oxygen, carbon dioxide, and isoflurane concentrations. The spectrometer was calibrated with 3 calibration gases of known isoflurane concentrations (0.5%, 1.5%, and 2.5%) every 80 minutes, corresponding to its internal calibration interval. A 22-gauge, 2.5-cm catheter was inserted in a cephalic vein, and lactated Ringer solution was administered at 3 mL/kg/h. A 20-gauge catheter was inserted in a medial saphenous vein for blood sampling. A Doppler crystal and occluding cuff were placed over a median artery for systolic blood pressure determination. A pulse oximeter probe was placed on the tongue for arterial hemoglobin oxygen saturation (SpO2) measurement. A thermistor, calibrated against a certified thermometer, was placed in the esophagus at the level of the midthorax and connected to a physiograph for continuous temperature monitoring. External heat (warm water and/or forced air blankets) was supplied as needed to maintain body temperature between 38.5°C and 39.5°C.
For each MAC determination, ET isoflurane concentration was kept constant for a minimum of 15 minutes. To improve accuracy of ET isoflurane concentration determinations, ET gas samples (20 mL) were obtained by manual collection in a glass syringe over 5 to 10 breaths. ET isoflurane concentrations were determined using an infrared analyzer calibrated every 80 minutes with 3 calibration gases of known isoflurane concentrations (0.5%, 1.5%, and 2.5%). Carbon dioxide concentrations were determined using the Raman spectrometer. These samples were collected in triplicate, and the results were averaged. Heart rate, respiratory rate, esophageal temperature, systolic blood pressure, and SpO2 were all recorded.
MAC was determined using the bracketing method and tail clamping. A maximal nociceptive stimulus was applied using a 20-cm Martin forceps positioned on the tail and closed to the first ratchet. The forceps was maintained in place until gross purposeful movement was observed or 1 minute had elapsed, whichever occurred first. Isoflurane concentration was either increased or decreased by 10% after a positive (gross purposeful movement) or negative response to tail clamping, respectively. The new concentration was kept constant for at least 15 minutes, and the measurements were repeated. Isoflurane MAC was defined as the average of 2 successive isoflurane concentrations, 1 allowing and 1 preventing gross purposeful movement in response to tail clamping. MAC was determined in triplicate (i.e., a minimum 4 tail clampings per MAC determination), and the average is reported.
Gabapentin was administered IV via the cephalic vein catheter using a target-controlled infusion pump and computer system (Rugloop I; Demed, Temse, Belgium). Gabapentin (Spectrum Chemical, Gardena, CA) was dissolved in water for injection to a concentration of 10 mg/mL, and filtered through a 0.2-μm filter. Fresh solution was prepared for each target gabapentin concentration. Individual pharmacokinetic data corresponding to a 3-compartment model, obtained during a previous study,10 were used. With this system, the central compartment was rapidly loaded to the desired concentration. The infusion rate was then updated every 10 seconds as needed to maintain pseudo steady-state plasma concentration, according to the following equation: r = CT × V1(k10 + k12e−k21t + k13e−k31t), where r is the infusion rate, CT is the target plasma concentration, V1 is the volume of the central compartment, and k10, k12, k21, k13, and k31 are the microrate constants. Target plasma concentrations were 0, 1, 2, 4, 8, and 16 μg/mL. During this experiment, each cat was anesthetized twice with at least 2 weeks separating successive studies. For each cat, 3 concentrations were randomly selected and arranged in an ascending order to decrease experimental time. The 3 remaining concentrations were arranged in an ascending order and administered during the second study (Table 1). At least 15 minutes were allowed after each change in target gabapentin concentration, before MAC determination, for conditions to equilibrate. Isoflurane MAC was determined in triplicate at each gabapentin concentration using the bracketing method in each animal (Fig. 1). At the end of the equilibration time after each change in target gabapentin concentration, and immediately after each MAC determination, a blood sample (1.5 mL) was collected from the medial saphenous catheter (i.e., total of 4 samples for each target gabapentin concentration). Blood was immediately transferred to a tube containing EDTA, centrifuged for 10 minutes at 4°C, and the plasma was collected and frozen for later gabapentin plasma concentration determination.
Gabapentin was quantitated in feline plasma by liquid chromatography–mass spectrometry analysis of extracted plasma samples, according to a modification of the methods reported elsewhere.11–13 The calibration standards were prepared as follows. Stock solutions were made by dissolving 10.0 mg gabapentin standard in 10.0 mL acetonitrile (ACN). Working solutions were prepared by dilution of the gabapentin stock solution with ACN to concentrations of 10.0, 1.0, and 0.1 mg/mL. Plasma calibrators were prepared by dilution of the working gabapentin solutions with drug-free plasma to concentrations of 0.5, 2.0, 5.0, 10, 25, 50, 100, 500, 1000, 2000, 5000, 10,000, 20,000, 30,000, and 40,000 ng/mL. Calibration curves and negative control samples were prepared fresh for each quantitative assay. In addition, quality control samples (plasma fortified with analytes at concentrations midpoint of the standard curve) were routinely included as an additional check of accuracy. The concentration of gabapentin in each sample was determined by the internal standard (baclofen) method using the peak area ratio and linear regression analysis.
Quantitative analyses were performed on a TSQ Quantum Ultra triple quadrupole mass spectrometer (Thermo Scientific, San Jose, CA) coupled with an 1100 series liquid chromatography system (Agilent Technologies, Palo Alto, CA). Chromatography consisted of a Discovery C-18, 50 × 2.1 mm, 3-μm, column (Supelco, State College, PA) and a linear gradient of ACN in water with a constant 0.2% formic acid at a flow rate of 0.4 mL/min. The ACN concentration was held at 2% for 0.3 minute, ramped up to 98% over 2.0 minutes. Before analysis, all plasma samples were extracted by solid phase extraction. The solid phase extraction cartridges used were Clean Screen (United Chemical Technologies, Inc., Bristol, PA), 200 mg, 3-mL cartridges, sorbent type CEC18 (octadecyl, endcapped). Aliquots of 0.4 mL of plasma were treated with 2.0 mL of pH 7.0 phosphate buffer, fortified with 4 ng of internal standard, to an extraction procedure developed to elute gabapentin and baclofen in a single fraction. The injection volumes were 30.0 μL.
Detection and quantification consisted of full-scan liquid chromatography–tandem mass spectrometry transitions of initial product ions for gabapentin (mass-to-charge ratio 172.1). The responses for the major product ion, for gabapentin (mass-to-charge ratio 154.1), were plotted and peaks at the proper retention time integrated using LCQuan software (Thermo Scientific). LCQuan software was used to generate calibration curves and quantitate these analytes in all samples.
The concentration of gabapentin in each sample (e.g., calibrators, quality control, and unknowns) was determined by an internal standard method using the peak area ratio and linear regression analysis. The response for gabapentin was linear and gave correlation coefficients (R2) of 0.99 or better. The technique was optimized to provide a limit of detection at 0.5 ng/mL and limit of quantitation at 2.0 ng/mL. Intraday accuracy (percentage of nominal concentration) was 91% and 93% for 20 and 100 ng/mL, respectively. Interday accuracy (percentage of nominal concentration) was 90% and 92% for 20 and 100 ng/mL. Intraday precision (percentage relative standard deviation) was 8.2% and 3.8% for 20 and 100 ng/mL. Interday precision (percentage of nominal concentration) was 10.4% and 7.5% for 20 and 100 ng/mL.
Power analysis based on previous MAC studies conducted in our laboratory suggested that 6 cats would provide a power of 0.9 to detect a 20% effect on MAC, with an α level set at 0.05.14,15 MAC values at the different gabapentin plasma concentrations were analyzed by a repeated-measures analysis of variance using the Huynh-Feldt correction for violation of the sphericity assumption. The analysis was repeated on the third (last) MAC determination at each gabapentin concentration. Coefficient of variation was calculated for the 4 plasma concentration determinations at each target gabapentin concentration in each individual. Significance was set at P < 0.05. Data are reported as mean ± SD, except where specified otherwise.
Systolic blood pressure, SpO2, body temperature, and ET CO2 were 83.6 ± 15.0 mm Hg, 97.7% ± 1.0%, 39.0°C ± 0.1°C, and 30.1 ± 5.8 mm Hg, respectively, for all cats at all times. Four to eight adjustments in isoflurane concentration were necessary for the triplicate isoflurane MAC determination in each cat at each target gabapentin concentration.
Actual gabapentin concentrations achieved were 0 ± 0, 1.175 ± 0.225, 2.249 ± 0.231, 4.957 ± 1.186, 10.63 ± 1.372, and 19.685 ± 3.972 μg/mL for target concentrations of 0, 1, 2, 4, 8, and 16 μg/mL, respectively. MAC values for each of the triplicate measurements and overall MAC values at each plasma gabapentin concentration are presented in Table 2. The MAC values are not significantly different. Similarly, the analysis of the last MAC value for each plasma gabapentin concentration did not reach significance. The median (range) coefficient of variation for the 4 plasma concentration determinations at each target concentration was 4.8% (1.4%–15.7%). The mean infusion duration at each gabapentin concentration was 160 ± 34 minutes.
In this study, gabapentin at plasma concentrations ranging from 1 to 20 μg/mL had no detectable effect on the MAC of isoflurane in cats. The method of measuring MAC used in this study has been described before.14–17 Published values of the MAC of isoflurane in cats have ranged from 1.2% to 2.2%18–21 and the control value determined in this study (2.11%) is within this range. MAC was determined in triplicate at each gabapentin concentration to ensure repeatability. The mean time at each gabapentin concentration was 160 ± 34 minutes, or almost 3 hours. To our knowledge, there have been no comparable studies of the effect of gabapentin on the MAC of isoflurane in any other mammalian species.
The lack of effect of gabapentin on MAC in this study could be related to several factors. First, the plasma concentration achieved may have been insufficient and not reflective of concentrations achieved when the drug is used for preemptive analgesia in clinical patients. The pharmacokinetics of gabapentin in humans have been studied using an 800-mg oral dose,22 whereas a 1200-mg dose has been used in several studies of gabapentin as a preoperative analgesic.2,4 In 1 study,23 a 600-mg dose was found to be the optimal preemptive dose for postoperative pain relief after lumbar diskectomy. Using the data on the pharmacokinetics of gabapentin in humans, we estimated that peak concentrations at the 1200-mg dose would be approximately 13 μg/mL in a human weighing 70 kg. In our study, plasma concentrations of up to 20 μg/mL were achieved in cats with no detectable effect on the MAC of isoflurane. Second, although the plasma concentrations explored covered the range of relevant plasma concentrations in humans, uncertainty remains about the relative potency of gabapentin in humans and cats. However, it is frequently assumed that, contrary to pharmacokinetics, pharmacodynamic parameters such as 50% effective concentration are independent of species and size.24 This suggests that the doses frequently reported for preemptive analgesic use in humans may be unlikely to affect anesthetic requirements. Third, it is possible that gabapentin's effect on MAC has a delayed onset, and would not have been observed. However, in most clinical studies examining the effect of preoperative gabapentin, the drug is administered shortly, i.e., 1 to 2 hours, before induction of anesthesia.2,3,23,25,26 Moreover, because it is given orally, absorption delays the exposure to the drug, and peak concentrations have been reported to be observed 1 to 3 hours after administration.22 In this study, MAC was determined in triplicate at each concentration. Gabapentin was infused for a mean time of >2.5 hours for each individual plasma concentration. When only the last isoflurane determination, obtained toward the end of the infusion time, is compared with the control MAC, no significance is observed, confirming that within that time frame, no significant effect was produced. Moreover, contrary to single, oral administration, target-controlled infusion maintains stable plasma concentrations for the duration of the infusion at that target, as illustrated by the low coefficients of variation between the concentrations measured during infusion at a target, resulting in a larger exposure to the drug during that time than would occur after oral administration. Although it is possible that gabapentin exerts an effect on MAC after longer exposure, we believe that the duration of exposure in this study is representative of many clinical situations, with surgery times of 2 to 2.5 hours. Finally, the lack of significant effect could be attributable to a type II statistical error. Prospective power analysis showed this study to be adequately powered (i.e., power of 0.9); however, although adequate power limits the risk of type II errors, it does not eliminate it. The fact that no trend toward decreasing MAC values with increasing plasma gabapentin concentrations was observed is suggestive of a true lack of effect. However, the small number of subjects in the study makes it difficult to draw definitive conclusions.
Because the preoperative use of gabapentin has been proposed, it is important to know if it influences anesthetic requirements. Many analgesic and sedative drugs have been shown to decrease MAC,7–9 and gabapentin produces both analgesia and sedation.5,6 It could therefore be postulated that gabapentin may be expected to affect MAC. However, it is unclear how analgesic drugs actually decrease MAC. In a recent study, it was shown that the analgesic effect of nitrous oxide could be ablated without influencing its MAC.27 In another study in cats, we showed that remifentanil produced analgesia in a dose-dependent manner in a model of thermal pain, but had no effect on MAC.28 Taken together, these results may suggest that analgesia is not necessarily the mechanism by which some analgesic drugs decrease MAC. Moreover, some effects of gabapentin in cats at the dose range studied may differ from those in humans. In another study in our laboratory,29 we did not observe significant sedation of cats at oral doses of gabapentin up to 30 mg/kg, yet sedation is a frequently noted side effect in humans.4,5
It is unclear why actual plasma concentrations achieved in this study exceeded target concentrations. The 3-compartment pharmacokinetic model used was based on data obtained from a previous study in awake cats. It is likely that the disposition of gabapentin is altered by isoflurane anesthesia, as has been reported for other drugs.30,31 Isoflurane anesthesia would be expected to decrease the volume of distribution and clearance because of its effect on cardiac output,32 possibly resulting in the differences between target and actual gabapentin concentrations in this study. Whereas the target-controlled infusion produced concentrations higher than targeted, the relationship between target and actual concentrations remained linear. Because no observable effect on MAC was seen at concentrations higher than targeted, the underestimation of actual concentrations did not affect the findings of the study.
In conclusion, we tested the hypothesis that gabapentin would decrease the MAC for isoflurane in cats in a dose-dependent manner. Our results did not prove this hypothesis. In this study, gabapentin did not have a detectable effect on the MAC of isoflurane in cats at plasma concentrations similar to or larger than therapeutic concentrations used in preoperative human analgesic doses. This suggests that gabapentin can be used without influencing the concentration of inhaled anesthetics required to produce immobility in response to an acute noxious stimulus. However, further studies are warranted to determine whether the same is true in humans or other mammalian species.
The authors are grateful to Scott D. Stanley, California Animal Health and Food Safety Laboratory System, for the gabapentin plasma concentration determinations and to Kristine Siao for her technical assistance.
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