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Effects of intravenous administration of lidocaine on the thermal threshold in cats

Bruno H. PypendopDepartment of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616.

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Jan E. IlkiwDepartment of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616.

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Sheilah A. RobertsonDepartment of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610.

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Abstract

Objective—To determine the effects of IV administration of lidocaine on thermal antinociception in conscious cats. Animals—6 cats.

Procedure—2 experiments were performed in each cat (interval of at least 2 months). In experiment 1, lidocaine pharmacokinetics were determined for each conscious cat following IV administration of a bolus of lidocaine (2 mg/kg). In experiment 2, data from experiment 1 were used to calculate appropriate doses of lidocaine that would achieve predetermined plasma lidocaine concentrations in the cats; lidocaine (or an equivalent volume of saline [0.9% NaCl] solution as the control treatment) was administered IV to target pseudo–steady-state plasma concentrations of 0, 0.5, 1, 2, 5, and 8 μg/mL. Skin temperature and thermal threshold were determined at the start of the experiment (baseline) and at each concentration. Samples of venous blood were obtained at each target concentration for plasma lidocaine concentration determination.

Results—In experiment 2, actual plasma lidocaine concentrations were 0.00 ± 0.00 μg/mL, 0.25 ± 0.18 μg/mL, 0.57 ± 0.20 μg/mL, 1.39 ± 0.13 μg/mL, 2.33 ± 0.45 μg/mL, and 4.32 ± 0.66 μg/mL for target plasma concentrations of 0, 0.5, 1, 2, 5, and 8 μg/mL, respectively. Compared with baseline values, no significant change in skin temperature or thermal threshold was detected at any lidocaine plasma concentration (or saline solution equivalent). Skin temperature or thermal threshold values did not differ between lidocaine or control treatments.

Conclusions and Clinical Relevance—Results indicated that these moderate plasma concentrations of lidocaine did not affect thermal antinociception in cats.

Abstract

Objective—To determine the effects of IV administration of lidocaine on thermal antinociception in conscious cats. Animals—6 cats.

Procedure—2 experiments were performed in each cat (interval of at least 2 months). In experiment 1, lidocaine pharmacokinetics were determined for each conscious cat following IV administration of a bolus of lidocaine (2 mg/kg). In experiment 2, data from experiment 1 were used to calculate appropriate doses of lidocaine that would achieve predetermined plasma lidocaine concentrations in the cats; lidocaine (or an equivalent volume of saline [0.9% NaCl] solution as the control treatment) was administered IV to target pseudo–steady-state plasma concentrations of 0, 0.5, 1, 2, 5, and 8 μg/mL. Skin temperature and thermal threshold were determined at the start of the experiment (baseline) and at each concentration. Samples of venous blood were obtained at each target concentration for plasma lidocaine concentration determination.

Results—In experiment 2, actual plasma lidocaine concentrations were 0.00 ± 0.00 μg/mL, 0.25 ± 0.18 μg/mL, 0.57 ± 0.20 μg/mL, 1.39 ± 0.13 μg/mL, 2.33 ± 0.45 μg/mL, and 4.32 ± 0.66 μg/mL for target plasma concentrations of 0, 0.5, 1, 2, 5, and 8 μg/mL, respectively. Compared with baseline values, no significant change in skin temperature or thermal threshold was detected at any lidocaine plasma concentration (or saline solution equivalent). Skin temperature or thermal threshold values did not differ between lidocaine or control treatments.

Conclusions and Clinical Relevance—Results indicated that these moderate plasma concentrations of lidocaine did not affect thermal antinociception in cats.

Drug options for provision of analgesia in cats are limited. Although effective, opioids can produce undesirable effects, including dysphoria, especially when administered at high doses.1 Cats metabolize most nonsteroidal anti-inflammatory drugs poorly and may be especially sensitive to the toxic effects of these drugs, especially if doses and dosing intervals are not carefully selected.2–8 The α2-adrenoceptor agonists induce considerable cardiovascular depression.9 Although of potential interest, the analgesic use of ketamine in cats is limited by the paucity of scientific data.10

Lidocaine is an amide local anesthetic. When administered IV, lidocaine has been reported to provide analgesia in various painful conditions (whether experimentally induced or naturally occurring, including pain associated with surgical procedures) in several species including humans, rats, horses, and rabbits.11–21 Results of a study22 in decerebrate cats indicated that lidocaine administered IV depressed the response of nociceptive neurons to noxious thermal stimulation. However, to our knowledge, no data are available on the potential clinical use of IV administration of lidocaine as a systemic analgesic in cats.

The use of a device for determination of thermal threshold in cats has recently been reported.23–25 In those studies, the thermal threshold in cats increased in response to various opioids, proving the usefulness of this technique in investigations of analgesic drugs. Accordingly, the purpose of the study reported here was to determine the effects of IV administration of lidocaine on thermal antinociception in conscious cats. Our intent was to evaluate the effects of 6 plasma lidocaine concentrations on thermal threshold in cats, compared with the effect of a control treatment. We hypothesized that lidocaine would increase thermal threshold in a dose-dependent manner in cats.

Materials and Methods

Animals—Six healthy adult domestic shorthair cats (mean ± SD weight, 5.20 ± 0.52 kg) were used in the study. Food, but not water, was withheld from cats for 12 hours before experiments were initiated. The study was approved by the Animal Care and Use Committee of the University of California, Davis.

Experiments—Two experiments were undertaken in each cat with an interval of at least 2 months between each experiment. In experiment 1, the lidocaine pharmacokinetics were determined for each conscious cat. In experiment 2, data from experiment 1 were used to calculate appropriate doses of lidocaine that would achieve predetermined plasma lidocaine concentrations in the cats; the thermal threshold was then evaluated at each concentration. For comparison, an equivalent volume of saline (0.9% NaCl) solution was administered to each cat on another day and thermal threshold was determined at the same time intervals as those applied when lidocaine was administered.

Preparation—The day before experiment 1 or 2, cats were anesthetized with isoflurane in oxygen by use of an induction box. Induction of anesthesia was completed by use of a face mask; each cat was then intubated with a cuffed endotracheal tube, and anesthesia was maintained by administration of isoflurane in oxygen via a Bain circuit with an oxygen flow rate of 500 mL/kg/min. A 24-gauge, 9-cm cathetera was inserted in a jugular vein. A 22-gauge, 2.5-cm catheterb was inserted in a medial saphenous vein. Light bandages were placed over the catheters. For experiment 2, hair on the lateral aspect of the thorax was clipped. Following these preparations, cats were allowed to recover from anesthesia.

Lidocaine pharmacokinetics (experiment 1)—Twenty-four hours after catheter placement, 2 mg of lidocainec/kg was administered IV via the medial saphenous catheter (duration of injection, 5 seconds). Blood samples (1.5 mL) were collected from a jugular catheter prior to and at 1, 2, 3, 4, 6, 8, 16, 30, 60, 90, 120, 150, 180, 210, and 240 minutes after lidocaine administration. Each sample was transferred to a tube containing EDTA and immediately centrifuged for 10 minutes; plasma was collected and frozen for later determinations of lidocaine and MEGX concentrations. The total volume of blood withdrawn (24 mL) was < 10% of each cat's blood volume. Intravenous fluids were not administered during this experiment, but cats had free access to water. Cefazolind (22 mg/kg, IV) was administered at the end of the experiment, and catheters were removed.

Thermal threshold determination (experiment 2)— Twenty-four hours after catheter placement, each cat was placed in an individual cage (80 × 80 × 65 cm) that had a transparent acrylic door and mirrors on each sidewall. A probe containing a heater element and an adjacent temperature sensor, both embedded in epoxy, was attached to a pressure cuff and held in place over the lateral aspect of the thorax by an elastic band. Thermal probes were calibrated prior to the experiment in each cat. For calibration, the probe was securely attached on top of a 9.0 × 9.0 × 0.5-cm aluminium plate. A thermocouple was placed in a previously drilled horizontal hole so that the tip was directly below the probe and was connected to a digital thermometer.e The aluminium block was placed on a standard laboratory hot plate that was heated to 85°C and then allowed to cool to room temperature (22°C). Readings from the probe and thermocouple were recorded at each 2.0°C drop in hot plate temperature. If required, adjustments were made to the zero position and gain on the thermal threshold unit so that the probe reading was within 0.1°C of the thermocouple reading. For several months prior to the experiment, each cat was brought to the laboratory and placed in the cage with the probe and cuff in place to acclimate it to study conditions. Before the experiment began, the probe was connected to a control unit by use of a flexible cable; the cat was allowed to move freely in the cage during testing. Skin temperature was measured, the heater was activated, and the cat was observed for a reaction. The rate of temperature rise was 0.6°C/s, and a cutout temperature was set at 55°C. When a reaction was observed (jumping, turning the head toward the probe, or licking or biting the probe area or cable), the temperature was recorded and the heater was turned off. Thermal threshold was defined as the probe temperature at which the reaction occurred. Thermal thresholds were always determined by the same investigator (SAR), who was unaware of the cats' treatments.

Before treatment with lidocaine or physiologic saline solution, 4 baseline thermal thresholds were determined at 15-minute intervals in each cat and the mean baseline value was calculated. Lidocainec or an equivalent volume of saline solution was then administered IV via the catheter in the medial saphenous vein by use of a target-controlled infusion system to achieve target pseudo–steady-state plasma concentrations of 0.5, 1, 2, 5, and 8 μg of lidocaine/mL. Treatment with lidocaine or saline solution was assigned in a randomized crossover design. An interval of 2 weeks was allowed between successive experiments. All target plasma concentrations (or equivalent volume of saline solution) were administered during the same experiment in an incremental manner. Total experimental time was 5 hours.

The target-controlled infusion system consisted of a syringe pumpf and computer software.g 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 concentrations, according to the following equation:

article image

where R is the infusion rate; CT is the target plasma concentration; V1 is the volume of the central compartment; t is the time; and k10, k12, k21, k13, and k31 are the microrate constants. Individual pharmacokinetic data obtained from experiment 1 were used. After each change of target plasma lidocaine concentration, an interval of 15 minutes was allowed to elapse to permit conditions to equilibrate. At each target plasma lidocaine concentration, 2 thermal threshold determinations were performed at an interval of 20 minutes and the mean value was calculated. On a separate day, similar determinations were made after each administration of an equivalent volume of saline solution. Blood samples (1.5 mL each) were collected via the jugular catheter prior to administration of lidocaine or saline solution and at 25 minutes after each change of plasma lidocaine concentration or, in the case of the saline solution treatment, at 25 minutes after the change of infusion rate. Each blood sample was transferred to a tube containing EDTA and immediately centrifuged for 10 minutes; plasma was collected and frozen for later determinations of lidocaine and MEGX concentrations. Only blood samples from cats treated with lidocaine were actually analyzed. At the conclusion of the experiment, cefazolind (22 mg/kg, IV) was administered to each cat and the probe and catheters were removed.

Determination of lidocaine and MEGX plasma concentrations—Lidocaine and MEGX plasma concentrations were determined by use of a triple quadruple mass spectrometerh that was equipped with a liquid chromatographyi system, according to methods reported elsewhere.26

Pharmacokinetic modeling—Nonlinear least squares regression analysis was performed on plasma lidocaine concentration values obtained after IV bolus administration of the drug by use of computer software.j Data were fitted to 2 and 3-compartment models, and the appropriate model was selected by use of the Akaike information criterion. Standard compartmental equations were used to estimate pharmacokinetic parameters for each cat.27

Statistical analysis—Data are presented as mean ± SD. The effect of lidocaine dose on thermal threshold was analyzed by use of a mixed-model ANOVA, in which subject-related effects were treated as random effects. The effect on skin temperature and the difference between thermal threshold and skin temperature (excursion) were also assessed by use of a mixed-model ANOVA. Significance level was set at a value of P < 0.05.

Results

Experiment 1—A 3-compartment model best described the decrease in plasma lidocaine concentrations over time for all cats. Values of V1, k21, k31, k10, k12, and k13 were 0.57 ± 0.15 L/kg, 0.23 ± 0.16/min, 0.01 ± 0.00/min, 0.05 ± 0.01/min, 0.17 ± 0.11/min, and 0.02 ± 0.01/min, respectively. The pharmacokinetics of lidocaine and MEGX in conscious cats are reported in detail elsewhere.28

Table 1—

Skin temperature and thermal threshold after IV administration of lidocaine to achieve various plasma lidocaine concentrations or after administration of a corresponding equivalent volume of saline (0.9% NaCl) solution in 6 cats.

Actual plasma lidocaine concentration (μg/mL)Treatment groupSkin temperature (°C)Thermal threshold (°C)
0Lidocaine37.3 ± 0.542.6 ± 1.2
Saline37.3 ± 0.442.3 ± 1.3
0.25Lidocaine37.5 ± 0.442.4 ± 1.8
Saline37.2 ± 0.542.6 ± 2.5
0.57Lidocaine37.5 ± 0.443.6 ± 3.6
Saline37.3 ± 0.842.3 ± 2.3
1.39Lidocaine37.4 ± 0.441.6 ± 1.6
Saline37.3 ± 0.743.8 ± 2.9
2.33Lidocaine37.0 ± 0.644.2 ± 3.3
Saline36.7 ± 3.242.8 ± 2.2
4.32Lidocaine37.2 ± 0.545.0 ± 3.8
Saline37.5 ± 0.543.1 ± 1.5

Experiment 2—Actual mean plasma lidocaine concentrations were 0.00 ± 0.00 μg/mL, 0.25 ± 0.18 μg/mL, 0.57 ± 0.20 μg/mL, 1.39 ± 0.13 μg/mL, 2.33 ± 0.45 μg/mL, and 4.32 ± 0.66 μg/mL for target plasma lidocaine concentrations of 0, 0.5, 1, 2, 5, and 8 μg/mL, respectively. No significant difference in skin temperature or thermal threshold value, or in the difference between skin temperature and thermal threshold, was detected over time in the cats at any plasma lidocaine concentration, compared with baseline values (Table 1). No significant difference in skin temperature or thermal threshold value, or in the difference between skin temperature and thermal threshold, was detected over time in the cats after administration of saline solution, compared with baseline values. Skin temperature and thermal threshold values did not differ between treatments at baseline or any plasma lidocaine concentration.

Discussion

In the study reported here, moderate plasma lidocaine concentrations (ie, 0.25 to 4.32 μg/mL) did not affect the thermal threshold of cats. Our study has 2 main limitations. Lidocaine is reported to provide analgesia in a variety of species at plasma concentrations ranging from 0.62 to 5.7 μg/mL.13,19,21,22,29–31 Therefore, the target plasma lidocaine concentrations used in the study reported here were selected to include this range. However, target plasma lidocaine concentrations were not established in the study cats, and the maximal mean plasma lidocaine concentration was only 4.32 μg/mL. Although most previous studies13,21,22,29–31 revealed an analgesic effect at concentrations <4 μg/mL, it is possible that lidocaine would significantly affect thermal threshold at higher plasma concentrations than those achieved in the study reported here. The second limitation is related to the small number of cats involved in our study. It is possible that analysis of data from a larger number of cats would result in the detection of a significant effect. A posteriori power analysis revealed that our sample of 6 cats in each treatment group was sufficient to detect a difference in thermal threshold of 3.75°C between groups, with a power of 0.8 and a significance level set at a value of P < 0.05. This difference represents a <10% change in thermal threshold and is lower than differences in thermal threshold detected after administration of opioids.23–25 It is nevertheless possible that lidocaine causes an increase in thermal threshold of smaller magnitude than that associated with opioids and that this effect was not detected because of the small number of animals in our study.

It is unclear why target plasma lidocaine concentrations were not achieved in the cats used in the study reported here. On the basis of individual pharmacokinetic data obtained in conditions similar to those used in experiment 2 (ie, in awake cats), lidocaine was administered by use of a target-controlled infusion system. Although pharmacokinetic data in each cat were obtained after a single bolus injection rather than an infusion of lidocaine, this would generally result in an overestimation of the volume of the central compartment.32 Through experimental application of those pharmacokinetic data, actual plasma lidocaine concentrations above, rather than below, target concentrations would therefore be predicted. The use of venous, rather than arterial, plasma concentration determination in the pharmacokinetic study may have resulted in decreased accuracy of the target-controlled infusion system. However, in 2 recent studies26,33 in which the same system was used to administer lidocaine in cats, the actual plasma lidocaine concentrations achieved were very close to the target concentrations. In those investigations, the cats were anesthetized, unlike the cats used in our study; thus, different pharmacokinetic data were used, but those data were also derived from a single bolus injection of lidocaine and venous plasma concentration determinations. Although unlikely, the lidocaine administered during pharmacokinetic data collection (experiment 1) in our study might have induced changes in hepatic function and altered the metabolism of the subsequently administered drug in the cats, resulting in a higher clearance during the thermal threshold investigation (experiment 2) than that determined during experiment 1. It is also possible that prolonged administration of lidocaine resulted in changes in its disposition, for example, by altering hepatic blood flow in the cats.

In various species, lidocaine has been shown to provide relief from pain associated with acute injury, chronic headache, cancer, and burns and relief from visceral and neuropathic pain.11,13,15,18,19,22,30,34–36 In addition, lidocaine has been reported to decrease pain severity and opioid consumption after major abdominal surgery and radical prostatectomy.12,14,17 Of interest, IV administration of lidocaine has been shown to depress the response of dorsal horn neurons to noxious thermal stimulation in cats,22 whereas results of another study29 indicated that IV administration of the drug was associated with an increase in hot pain threshold in humans with neuropathic pain. To the contrary, other studies37–42 did not reveal a significant effect of lidocaine on thermal pain, although some of those studies reported an effect on other pain modalities, such as mechanical pain. In a study21 in horses involving the same thermal threshold method used in the study reported here, mean plasma lidocaine concentrations of 0.9 to 1 μg/mL significantly depressed thermal nociception. It is possible that horses are particularly sensitive to the effects of lidocaine. This is illustrated by the fact that, compared with other species, toxic effects on the CNS and muscle tremors are detected in horses at lower plasma lidocaine concentra-tions.43 It could be speculated that the plasma lidocaine concentration at which nerve conduction (including the transmission of noxious thermal information) is affected is lower in horses than it is in cats. Muscle tremors or CNS toxicosis was not observed in any cat in our study at any of the plasma lidocaine concentrations. The effects of systemically administered lidocaine on thermal pain appear to be variable and species-specific, and the selection of thermal threshold determination alone may not have been optimal for investigation of possible analgesic effects of this drug in cats. However, thermal threshold determination is a minimally invasive, ethically acceptable, objective pain assessment method that has been validated in cats; its sensitivity has been confirmed in several studies23–25 in which various opioids significantly increased thermal thresholds in cats. Moreover, repeated determinations did not significantly affect the threshold.

Overall, the plasma lidocaine concentrations used in the study of this report did not affect thermal thresholds in cats. However, further studies involving different types of pain are warranted to assess whether lidocaine could be a useful analgesic in cats.

MEGX

Monoethylglycylxylidide

a

Central venous catheterization kit, Arrow International, Reading, Pa.

b

Insyte catheter, Becton-Dickinson, Sandy, Utah.

c

Xylocaine 20 mg/mL, AstraZeneca LP, Wilmington, Del.

d

Cefazolin, Apothecon, Princeton, NJ.

e

RS Components, Corby, Northamptonshire, UK.

f

PHD 2000 Programmable, Harvard Apparatus, Holliston, Mass.

g

Rugloop I, Demed, Temse, Belgium.

h

Thermo TSQ Quantum, Thermo Electron Corp, San Jose, Calif.

i

Agilent model 1100, Agilent, Palo Alto, Calif.

j

WinNonlin Professional, Pharsight Inc, Mountain View, Calif.

References

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Contributor Notes

Address correspondence to Dr. Pypendop.

Supported by the Winn Feline Foundation, affiliated with The Cat Fanciers' Association Incorporated.

The authors thank Scott D. Stanley for plasma lidocaine concentration determinations, Sara Thomasy for pharmacokinetic modeling, and Cristina Moreno for technical assistance.