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Different structurally related phenylpiperidine opioids exhibit different isoflurane-sparing effects in cats. Because minimum alveolar concentration (MAC) in cats is affected only by very high plasma concentrations of some phenylpiperidine opioids, we hypothesized these effects are caused by actions on nonopioid receptors. Using a prospective, randomized, crossover design, six cats were anesthetized with isoflurane, intubated, ventilated, and instrumented. Isoflurane MAC was measured in triplicate using a tail-clamp and bracketing technique. A computer-controlled intravenous infusion using prior pharmacokinetic models targeted plasma concentrations of 60 ng/ml fentanyl, 10 ng/ml sufentanil, or 500 ng/ml alfentanil, and isoflurane MAC was measured in duplicate. Next, naltrexone 0.6 mg/kg was administered to cats hourly during the opioid infusion, and isoflurane MAC was measured in duplicate. Blood was collected during MAC determinations to measure opioid concentrations. Responses were analyzed using repeated measures ANOVA with significance at p < .05. Alfentanil and sufentanil decreased isoflurane MAC by 16.4% and 6.4%, respectively, and these effects were completely reversed by naltrexone. Fentanyl had no significant effect on isoflurane MAC. Alfentanil and sufentanil modestly reduce isoflurane MAC via agonist effects on opioid receptors. However, these effects are too small to justify clinical use of phenylpiperidine opioids as single agents to reduce MAC in cats., (© 2020 John Wiley & Sons Ltd.)

The aim of this study was to compare the pharmacokinetics of fentanyl, alfentanil, and sufentanil in isoflurane-anesthetized cats. Six adult cats were used. Anesthesia was induced and maintained with isoflurane in oxygen. End-tidal isoflurane concentration was set at 2% and adjusted as required due to spontaneous movement. Fentanyl (10 μg/kg), alfentanil (100 μg/kg), or sufentanil (1 μg/kg) was administered intravenously as a bolus, on separate days. Blood samples were collected immediately before and for 8 h following drug administration. Plasma drug concentration was determined using liquid chromatography/mass spectrometry. Compartment models were fitted to concentration-time data. A 3-compartment model best fitted the concentration-time data for all drugs, except for 1 cat in the sufentanil group (excluded from analysis). The volume of the central compartment and the volume of distribution at steady-state (L/kg) [mean ± SEM (range)], the clearance (mL/min/kg) [harmonic mean ± pseudo-SD (range)], and the terminal half-life (min) [median (range)] were 0.25 ± 0.04 (0.09-0.34), 2.18 ± 0.16 (1.79-2.83), 18.6 ± 5.0 (15-29.8), and 151 (115-211) for fentanyl; 0.10 ± 0.01 (0.07-0.14), 0.89 ± 0.16 (0.68-1.83), 11.6 ± 2.6 (9.2-15.8), and 144 (118-501) for alfentanil; and 0.06 ± 0.01 (0.04-0.10), 0.77 ± 0.07 (0.63-0.99), 17.6 ± 4.3 (13.9-24.3), and 54 (46-76) for sufentanil. Differences in clearance and volume of distribution result in similar terminal half-lives for fentanyl and alfentanil, longer than for sufentanil., (© 2013 John Wiley & Sons Ltd.)

Objective: To verify the isoflurane anesthetic minimum alveolar concentration (MAC)-sparing effect of a previously administered target plasma fentanyl concentration of 16 ng/mL and characterize an anticipated further sparing in isoflurane MAC associated with higher target plasma fentanyl concentrations., Animals: 8 horses., Procedures: Horses were assigned 2 of 3 target plasma fentanyl concentrations (16, 24, and 32 ng/mL), administered in ascending order. Following determination of baseline MAC, horses received a loading dose of fentanyl followed by a constant rate infusion; MAC determination was performed in triplicate at baseline and at each fentanyl concentration. Venous blood samples were collected throughout the study for determination of actual plasma fentanyl concentrations. Recovery from anesthesia was monitored, and behaviors were rated as excellent, good, fair, or poor., Results: Mean + or - SD fentanyl plasma concentrations were 13.9 + or - 2.6 ng/mL, 20.1 + or - 3.6 ng/mL, and 24.1 + or - 2.4 ng/mL for target concentrations of 16, 24, and 32 ng/mL, respectively. The corresponding changes in the MAC of isoflurane were -3.28%, -6.23%, and +1.14%. None of the changes were significant. Recovery behavior was variable and included highly undesirable, potentially injurious excitatory behavior., Conclusions and Clinical Relevance: Results of the study did not verify an isoflurane-sparing effect of fentanyl at a plasma target concentration of 16 ng/mL. Furthermore, a reduction in MAC was not detected at higher fentanyl concentrations. Overall, results did not support the routine use of fentanyl as an anesthetic adjuvant in adult horses.

This study evaluated the validity of measuring fentanyl concentrations in equine plasma using radioimmunoassay (RIA) by comparing it to the established technique of liquid chromatography-mass spectrometry (LC-MS). Equine plasma samples were analyzed using a solid-phase Coat-A-Count fentanyl RIA and a validated LC-MS method. The fentanyl concentrations derived by both methods were compared by linear regression and pharmacokinetic analysis. The cross-reactivity of the primary equine fentanyl metabolite, N-[1-(2-phenethyl-4-piperidinyl)]maloanilinic acid (PMA), with the RIA was determined. The binding potency of fentanyl and PMA were compared at three opioid receptor subtypes in equine cerebral cortex using a radioligand binding technique. Fentanyl concentrations determined by RIA and LC-MS correlated, but the RIA overestimated low fentanyl concentrations and underestimated high fentanyl concentrations. The overestimation of low fentanyl concentrations is most likely due to the 29% cross-reactivity of PMA with the RIA. As a result, pharmacokinetic variables determined from an intravenous fentanyl bolus to four anesthetized horses differed depending on the analytical method. Although fentanyl bound with nanomolar potency to the three receptor subtypes, PMA exhibited no binding activity even at micromolar concentrations. In conclusion, when compared with LC-MS, fentanyl concentrations determined by RIA in equine plasma are misleading, especially for the calculation of fentanyl pharmacokinetics.

Objective: To characterize the pharmacokinetics of fentanyl and the tolerance of foals to the drug following a single application of a commercially available transdermal system (TS)., Study Design: Prospective experimental study., Animals: Six (two male, four female) foals aged 4-8 days, weighing 56-74 kg., Methods: After placement of a jugular sampling catheter, one fentanyl TS (FTS) containing 10.2 mg fentanyl, released at 100 microg hour(-1), was applied for 72 hours. Blood samples were withdrawn over the course of 90 hours for fentanyl plasma analysis. Before and after the study, weight, complete blood count and blood chemistry values were obtained. During the study, tolerance and safety were monitored by physical examination and assessment of behavior., Results: Fentanyl was detected as early as 20 minutes after FTS placement. Peak plasma concentrations were variable (0.1-28.7 ng mL(-1)), were reached after 14.3 +/- 7.6 hours (mean +/- SD), and returned to baseline concentrations 12 hours after FTS removal. All foals satisfactorily tolerated the FTS application and no significant adverse effects were observed. Rectal temperature increased above 38.5 degrees C (max. 39.0 degrees C) in all foals, although this did not correlate with fentanyl plasma concentrations. Results of hematological and biochemical analyses were within reference ranges., Conclusion and Clinical Relevance: Our data show that 100 microg hour(-1) fentanyl administered by an FTS results in time-related but variable plasma concentrations in foals. The FTS was easy to apply and was well tolerated.

Reasons for Performing Study: In order to evaluate its potential as an adjunct to inhalant anaesthesia in horses, the pharmacokinetics of fentanyl must first be determined., Objectives: To describe the pharmacokinetics of fentanyl and its metabolite, N-[1-(2-phenethyl-4-piperidinyl)maloanilinic acid (PMA), after i.v. administration of a single dose to horses that were awake in Treatment 1 and anaesthetised with isoflurane in Treatment 2., Methods: A balanced crossover design was used (n = 4/group). During Treatment 1, horses received a single dose of fentanyl (4 microg/kg bwt, i.v.) and during Treatment 2, they were anaesthetised with isoflurane and maintained at 1.2 x minimum alveolar anaesthetic concentration. After a 30 min equilibration period, a single dose of fentanyl (4 microg/kg bwt, i.v.) was administered to each horse. Plasma fentanyl and PMA concentrations were measured at various time points using liquid chromatography-mass spectrometry., Results: Anaesthesia with isoflurane significantly decreased mean fentanyl clearance (P < 0.05). The fentanyl elimination half-life, in awake and anaesthetised horses, was 1 h and volume of distribution at steady state was 0.37 and 0.26 l/kg bwt, respectively. Anaesthesia with isoflurane also significantly decreased PMA apparent clearance and volume of distribution. The elimination half-life of PMA was 2 and 1.5 h in awake and anaesthetised horses, respectively., Conclusions and Potential Relevance: Pharmacokinetics of fentanyl and PMA in horses were substantially altered in horses anaesthetised with isoflurane. These pharmacokinetic parameters provide information necessary for determination of suitable fentanyl loading and infusion doses in awake and isoflurane-anaesthetised horses.

Background: Fentanyl decreases the minimum alveolar concentration (MAC) of inhaled anaesthetics and has been used clinically to reduce the requirements of other anaesthetic drugs in humans and small animals. We hypothesized that i.v. fentanyl would decrease the MAC of isoflurane in horses in a dose-dependent manner., Methods: Following determination of baseline MAC of isoflurane, fentanyl was administered i.v. to target plasma concentrations of 1, 8 and 16 ng ml(-1). Each horse was randomly assigned two of three target concentrations administered in ascending order. Loading and infusion doses for each horse were determined from previously derived individual pharmacokinetic values. Isoflurane MAC determination began 45 min after fentanyl administration at each target fentanyl concentration. Venous blood was collected at fixed intervals during the infusion for measurement of plasma fentanyl concentrations., Results: Mean actual fentanyl plasma concentrations were 0 (baseline), and 0.72 (SD 0.26), 8.43 (3.22), and 13.31 (6.66) ng ml(-1) for the target concentrations of 1, 8 and 16 ng ml(-1), respectively. The corresponding isoflurane MAC values were a baseline of 1.57 (0.23), and 1.51 (0.24), 1.41 (0.23) and 1.37 (0.09)%, respectively. The fentanyl concentrations of 0.72 and 8.43 ng ml(-1) did not significantly alter the MAC of isoflurane, but an 18 (7)% ISO-MAC reduction was observed at the 13.31 ng ml(-1) concentration., Conclusions: These results cautiously encourage further study of fentanyl as an opioid anaesthetic adjunct to inhalant anaesthesia in horses.