Procedures—Gabapentin was administered IV (4 mg/kg) or orally (10 mg/kg) in a crossover randomized design. Blood samples were obtained immediately before gabapentin administration and at various times up to 960 minutes after IV administration or up to 1,440 minutes after oral administration. Blood samples were immediately transferred to tubes that contained EDTA and were centrifuged at 4°C. Plasma was harvested and stored at −20°C until analysis. Plasma concentrations of gabapentin were determined by use of liquid chromatography-mass spectrometry. Gabapentin concentration-time data were fit to compartment models.
Results—A 3-compartment model with elimination from the central compartment best described the disposition of gabapentin administered IV to cats, but a 1-compartment model best described the disposition of gabapentin administered orally to cats. After IV administration, the mean ± SEM apparent volume of the central compartment, apparent volume of distribution at steady state, and clearance and the harmonic mean ± jackknife pseudo-SD for terminal half-life were 90.4 ± 11.3 mL/kg, 650 ± 14 mL/kg, 3 ± 0.2 mL/min/kg, and 170 ± 21 minutes, respectively. Mean ± SD systemic availability and harmonic mean ± jackknife pseudo-SD terminal half-life after oral administration were 88.7 ± 11.1% and 177 ± 25 minutes, respectively.
Conclusions and Clinical Relevance—The disposition of gabapentin in cats was characterized by a small volume of distribution and a low clearance.
Objective—To determine the thermal antinociceptive effect of oral administration of tramadol hydrochloride at doses between 0.5 and 4 mg/kg in cats.
Animals—6 healthy adult domestic shorthair cats.
Procedures—Baseline (before drug administration; time 0) thermal threshold was determined by applying a thermal probe to the thorax of each cat. Tramadol (0.5, 1, 2, 3, or 4 mg/kg) or a placebo was then administered orally in accordance with a Latin square design. Thermal threshold was determined by an observer who was unaware of treatment at various times until thermal threshold returned to baseline values or 6 hours had elapsed. Plasma tramadol and O-desmethyl-tramadol concentrations were measured prior to drug administration and at 1-hour intervals thereafter. Effect-concentration data were fitted to effect maximum models.
Results—Highest plasma tramadol and O-desmethyl-tramadol concentrations increased with increasing tramadol dose. Significant effects of dose and time on thermal threshold were detected. Thermal threshold was significantly higher than the baseline value at 80 and 120 minutes for the 0.5 mg/kg dose, at 80 and from 120 to 360 minutes for the 2 mg/kg dose, from 40 to 360 minutes for the 3 mg/kg dose, and from 60 to 360 minutes for the 4 mg/kg dose.
Conclusions and Clinical Relevance—Tramadol induced thermal antinociception in cats. Doses of 2 to 4 mg/kg appeared necessary for induction of significant and sustained analgesic effects. Simulations predicted that 4 mg/kg every 6 hours would maintain analgesia close to the maximum effect of tramadol.
Objective—To determine the thermal antinociceptive effect of various single doses of gabapentin administered orally in cats.
Animals—6 healthy adult domestic shorthair cats.
Procedures—Baseline skin temperature and baseline thermal threshold were determined via application of a thermal probe to the thorax of each cat prior to oral administration (in random order) of an empty capsule (placebo) or a capsule containing 5, 10, or 30 mg of gabapentin/kg (4 experiments/cat). After each treatment, thermal threshold was determined at intervals during an 8-hour period. Plasma gabapentin concentration was measured prior to and at 1-hour intervals after drug administration. Dose and time effects were analyzed by use of a repeated-measures ANOVA.
Results—Peak plasma gabapentin concentration increased with increasing gabapentin dose. After administration of the 5, 10, and 30 mg/kg doses, median interval until the greatest gabapentin concentration was detected was 60, 120, and 90 minutes, respectively (interval ranges were 60 to 120 minutes, 60 to 120 minutes, and 60 to 180 minutes, respectively). In the experiments involving administration of the placebo or increasing doses of gabapentin, mean ± SD baseline skin temperature and thermal threshold were 36.8 ± 1.21°C and 45.8 ± 4.4°C, 36.9 ± 1.1°C and 43.1 ± 2.4°C, 37.0 ± 0.7°C and 44.0 ± 1.5°C, and 36.1 ± 1.7°C and 43.3 ± 3.3°C, respectively. There was no significant effect of treatment on thermal threshold.
Conclusions and Clinical Relevance—At the doses evaluated, orally administered gabapentin did not affect the thermal threshold in healthy cats and therefore did not appear to provide thermal antinociception. (Am J Vet Res 2010;71:1027–1032)
Objective—To evaluate effects of various doses of remifentanil on measures of analgesia in anesthetized cats.
Animals—6 healthy adult cats.
Procedures—Minimum alveolar concentration (MAC) for isoflurane and thermal threshold responses were evaluated in anesthetized cats. Remifentanil infusions of 0 (baseline), 0.0625, 0.125, 0.25, 0.5, 1, 2, 4, 8, and 16 μg/kg/min were administered; after a 45-minute equilibration period, isoflurane MAC and responses were determined. Isoflurane MAC was determined in anesthetized cats once for each remifentanil infusion rate by use of a standard tail clamp technique. Thermal threshold was measured in awake cats by use of a commercially available analgesiometric probe placed on the lateral portion of the thorax; remifentanil infusions were administered in randomized order to anesthetized cats, and thermal threshold determinations were made by an investigator who was unaware of the infusion rate.
Results—Mean ± SEM median effective concentration (EC50) for remifentanil and its active metabolite, GR90291, for the thermal threshold test was 1.00 ± 0.35 ng/mL and 307 ± 28 ng/mL of blood, respectively. Dysphoria was detected in all awake cats at the 2 highest remifentanil infusion rates. However, isoflurane MAC during remifentanil infusions was unchanged from baseline values, even at blood opioid concentrations approximately 75 times the analgesic EC50.
Conclusions and Clinical Relevance—Immobility and analgesia as reflected by thermal threshold testing were independent anesthetic end points in the cats. Results of MAC-sparing evaluations should not be used to infer analgesic potency without prior validation of an MAC-analgesia relationship for specific drugs and species.
Objective—To characterize the pharmacokinetics of remifentanil in conscious cats and cats anesthetized with isoflurane.
Procedures—Remifentanil (1 μg/kg/min for 5 minutes) was administered IV in conscious cats or cats anesthetized with 1.63% isoflurane in oxygen in a randomized crossover design. Blood samples were obtained immediately prior to remifentanil administration and every minute for 10 minutes, every 2 minutes for 10 minutes, and every 5 minutes for 10 minutes after the beginning of the infusion. Blood was immediately transferred to tubes containing citric acid, flash frozen in liquid nitrogen, and stored at −80°C until analysis. Blood remifentanil concentration was determined by use of liquid chromatography–mass spectrometry. Remifentanil concentration-time data were fitted to compartment models.
Results—A 2-compartment model (with zero-order input because of study design) best described the disposition of remifentanil in awake and isoflurane-anesthetized cats. The apparent volume of distribution of the central compartment, the apparent volume of distribution at steady state, the clearance, and the terminal half-life (median [range]) were 1,596 (1,164 to 2,111) and 567 (278 to 641) mL/kg, 7,632 (2,284 to 76,039) and 1,651 (446 to 29,229) mL/kg, 766 (408 to 1,473) and 371 (197 to 472) mL/min/kg, and 17.4 (5.5 to 920.3) and 15.7 (3.8 to 410.3) minutes in conscious and anesthetized cats, respectively.
Conclusions and Clinical Relevance—The disposition of remifentanil in cats was characterized by a high clearance. Isoflurane anesthesia significantly decreased the volume of the central compartment, likely by decreasing blood flow to vessel-rich organs.
Objective—To determine the antinociceptive effects of epidural administration of morphine or buprenorphine in cats by use of a thermal threshold model.
Animals—6 healthy adult cats.
Procedures—Baseline thermal threshold was determined in duplicate. Cats were anesthetized with isoflurane in oxygen. Morphine (100 μg/kg diluted with saline [0.9% NaCl] solution to a total volume of 0.3 mL/kg), buprenorphine (12.5 μg/kg diluted with saline solution to a total volume of 0.3 mL/kg), or saline solution (0.3 mL/kg) was administered into the epidural space according to a Latin square design. Thermal threshold was determined at various times up to 24 hours after epidural injection.
Results—Epidural administration of saline solution did not affect thermal threshold. Thermal threshold was significantly higher after epidural administration of morphine and buprenorphine, compared with the effect of saline solution, from 1 to 16 hours and 1 to 10 hours, respectively. Maximum (cutout) temperature was reached without the cat reacting in 0, 74, and 11 occasions in the saline solution, morphine, and buprenorphine groups, respectively.
Conclusions and Clinical Relevance—Epidural administration of morphine and buprenorphine induced thermal antinociception in cats. At the doses used in this study, the effect of morphine lasted longer and was more intense than that of buprenorphine.
Objective—To determine fluid retention, glomerular filtration rate, and urine output in dogs anesthetized for a surgical orthopedic procedure.
Animals—23 dogs treated with a tibial plateau leveling osteotomy.
Procedures—12 dogs were used as a control group. Cardiac output was measured in 5 dogs, and 6 dogs received carprofen for at least 14 days. Dogs received oxymorphone, atropine, propofol, and isoflurane for anesthesia (duration, 4 hours). Urine and blood samples were obtained for analysis every 30 minutes. Lactated Ringer's solution was administered at 10 mL/kg/h. Urine output was measured and glomerular filtration rate was estimated. Fluid retention was measured by use of body weight, fluid balance, and bioimpedance spectroscopy.
Results—No difference was found among control, cardiac output, or carprofen groups, so data were combined. Median urine output and glomerular filtration rate were 0.46 mL/kg/h and 1.84 mL/kg/min. Dogs retained a large amount of fluids during anesthesia, as indicated by increased body weight, positive fluid balance, increased total body water volume, and increased extracellular fluid volume. The PCV, total protein concentration, and esophageal temperature decreased in a linear manner.
Conclusions and Clinical Relevance—Dogs anesthetized for a tibial plateau leveling osteotomy retained a large amount of fluids, had low urinary output, and had decreased PCV, total protein concentration, and esophageal temperature. Evaluation of urine output alone in anesthetized dogs may not be an adequate indicator of fluid balance.
Objective—To determine the pharmacokinetics of dexmedetomidine administered as a short-duration IV infusion in isoflurane-anesthetized cats.
Animals—6 healthy adult domestic female cats.
Procedures—Dexmedetomidine hydrochloride was injected IV (10 μg/kg over 5 minutes [rate, 2 μg/kg/min]) in isoflurane-anesthetized cats. Blood samples were obtained immediately prior to and at 1, 2, 5, 6, 7, 10, 15, 30, 60, 90, 120, 240, and 480 minutes following the start of the IV infusion. Collected blood samples were transferred to tubes containing EDTA, immediately placed on ice, and then centrifuged at 3,901 × g for 10 minutes at 4°C. The plasma was harvested and stored at −20°C until analyzed. Plasma dexmedetomidine concentrations were determined by means of liquid chromatography–mass spectrometry. Dexmedetomidine plasma concentration-time data were fitted to compartmental models.
Results—A 2-compartment model with input in and elimination from the central compartment best described the disposition of dexmedetomidine administered via short-duration IV infusion in isoflurane-anesthetized cats. Weighted mean ± SEM apparent volume of distribution of the central compartment and apparent volume of distribution at steady-state were 402 ± 47 mL/kg and 1,701 ± 200 mL/kg, respectively; clearance and terminal half-life (harmonic mean ± jackknife pseudo-SD) were 6.3 ± 2.8 mL/min/kg and 198 ± 75 minutes, respectively. The area under the plasma concentration curve and maximal plasma concentration were 1,061 ± 292 min•ng/mL and 17.6 ± 1.8 ng/mL, respectively.
Conclusions and Clinical Relevance—Disposition of dexmedetomidine administered via short-duration IV infusion in isoflurane-anesthetized cats was characterized by a moderate clearance and a long terminal half-life.