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Summary: Background: Pharmacokinetic (PK)/pharmacodynamic (PD) modelling offers new insights to design protocols for sedation and analgesia in standing horses. Objectives: To evaluate the parameters and interactions between detomidine and methadone when given alone or combined in standing horses. Study design: Randomised, placebo‐controlled, blinded, crossover. Methods: Eight adult healthy horses were given six treatments intravenously: saline (SAL); detomidine (5 μg/kg bwt; DET); methadone (0.2 mg/kg bwt; MET) alone or combined with detomidine (2.5 [MLD], 5 [MMD] or 10 [MHD] μg/kg bwt). Venous blood samples were obtained at predetermined times between 0 and 360 min after drug administration. Plasma detomidine and methadone were measured using a single, liquid/liquid extraction technique by liquid chromatography coupled with a triple quadrupole mass spectrometer (LC‐MS/MS). Sequential PK/PD modelling compared rival models, with and without PK and PD interaction between drugs, to fit the PD data including height of the head above the ground (HHAG), a visual analogue scale for sedation (VAS), electrical (ET), thermal (TT) and mechanical (MT) nociceptive thresholds and gastrointestinal motility (GIM) [1]. Results: Two and three compartment models best described the PK of detomidine and methadone, respectively. Detomidine decreased its own clearance as well as the clearance of methadone. The interaction of methadone on the effect of detomidine revealed an infra‐additive (partial antagonism) effect for HHAG (α = −1.33), VAS (α = −0.98) and GIM (α = −1.05), a positive potentiation for ET (pot = 0.0041) and TT (pot = 0.133) and a synergistic to additive effect for MT (α = 0.78). Main limitations: This is a small experimental study. Conclusions: Different PK/PD interactions were demonstrated for each PD parameter and could be modelled in vivo. The modelling of our data will allow us to simulate and predict the effect of constant rate infusions of both drugs for future investigations. [ABSTRACT FROM AUTHOR]

Reasons for performing study To investigate two protocols to provide antinociception in horses. Objectives To evaluate the antinociceptive effects of intravenous methadone combined with detomidine or acepromazine in adult horses. Study design Randomised, blinded, crossover study. Methods Mechanical, thermal and electrical stimuli were applied to the dorsal left and right metacarpus and coronary band of the left thoracic limb, respectively. A thermal stimulus was applied caudal to the withers. The horses were treated with saline (C), a combination of methadone (0.2 mg/kg bwt) and detomidine (10 μg/kg bwt) ( MD) or methadone (0.2 mg/kg bwt) and acepromazine (0.05 mg/kg bwt) ( MA) at 1 week intervals. Nociceptive thresholds were measured before and at 15 min intervals until 150 min after treatment. Wilcoxon rank-sum and Wilcoxon signed rank tests were used to compare data between groups at each time point and over time within each group, followed by the Bonferroni method to adjust the P value. Results The mechanical stimulus was the most sensitive test to differentiate the antinociceptive effects of the treatments. Mechanical thresholds were greater after MD than MA between 15 and 30 min and with both MD and MA these thresholds were greater than C from 15 to 60 min. Electrical and thermal limb thresholds were greater after MD than C at 15 and 45 min and at 15, 30, 45, 75 and 105 min, respectively. Thermal limb thresholds were greater with MA than C at 30 min. Thoracic thermal threshold in MD and MA were higher than C at 45, 75, 90 and 120 min and from 30 to 75 min, respectively. Conclusions Methadone and acepromazine produced less pronounced mechanical antinociception than MD. [ABSTRACT FROM AUTHOR]

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Reasons for performing study To validate a model for investigating the effects of analgesic drugs on mechanical, thermal and electrical stimulation testing. Objectives To investigate repeatability, sensitivity and specificity of nociceptive tests. Study design Randomised experiment with 2 observers in 2 phases. Methods Mechanical ( M), thermal ( TL) and electrical ( E) stimuli were applied to the dorsal metacarpus (M-left and TL-right) and coronary band of the left thoracic limb (E) and a thoracic thermal stimulus ( TT) was applied caudal to the withers in 8 horses (405 ± 43 kg). Stimuli intensities were increased until a clear avoidance response was detected without exceeding 20 N ( M), 60° C ( TL and TT) and 15 V ( E). For each set of tests, 3 real stimuli and one sham stimulus were applied (32 per animal) using a blinded, randomised, crossover design repeated after 6 months. A distribution frequency and, for each stimulus, Chi-square and McNemar tests compared both the proportion of positive responses detected by 2 observers and the 2 study phases. The κ coefficients estimated interobserver agreement in determining endpoints. Sensitivity (384 tests) and specificity (128 tests) were evaluated for each nociceptive stimulus to assess the evaluators' accuracy in detecting real and sham stimuli. Results Nociceptive thresholds were 3.1 ± 2 N ( M), 8.1 ± 3.8 V ( E), 51.4 ± 5.5° C ( TL) and 55.2 ± 5.3° C ( TT). The level of agreement after all tests, M, E, TL and TT, was 90, 100, 84, 98 and 75%, respectively. Sensitivity was 89, 100, 89, 98 and 70% and specificity 92, 97, 88, 91 and 94%, respectively. Conclusions The high interobserver agreement, sensitivity and specificity suggest that M, E and TL tests are valid for pain studies in horses and are suitable tools for investigating antinociceptive effects of analgesics in horses. [ABSTRACT FROM AUTHOR]

Background: Pain is the leading cause of animal suffering, hence the importance of validated tools to ensure its appropriate evaluation and treatment. We aimed to test the psychometric properties of the short form of the Unesp-Botucatu Feline Pain Scale (UFEPS-SF) in eight languages., Methods: The original scale was condensed from ten to four items. The content validation was performed by five specialists in veterinary anesthesia and analgesia. The English version of the scale was translated and back-translated into Chinese, French, German, Italian, Japanese, Portuguese and Spanish by fluent English and native speaker translators. Videos of the perioperative period of 30 cats submitted to ovariohysterectomy (preoperative, after surgery, after rescue analgesia and 24 h after surgery) were randomly evaluated twice (one-month interval) by one evaluator for each language unaware of the pain condition. After watching each video, the evaluators scored the unidimensional, UFEPS-SF and Glasgow composite multidimensional feline pain scales. Statistical analyses were carried out using R software for intra and interobserver reliability, principal component analysis, criteria concurrent and predictive validities, construct validity, item-total correlation, internal consistency, specificity, sensitivity, the definition of the intervention score for rescue analgesia and diagnostic uncertainty zone, according to the receiver operating characteristic (ROC) curve., Results: UFEPS-SF intra- and inter-observer reliability were ≥0.92 and 0.84, respectively, for all observers. According to the principal component analysis, UFEPS-SF is a unidimensional scale. Concurrent criterion validity was confirmed by the high correlation between UFEPS-SF and all other scales (≥0.9). The total score and all items of UFEPS-SF increased after surgery (pain), decreased to baseline after analgesia and were intermediate at 24 h after surgery (moderate pain), confirming responsiveness and construct validity. Item total correlation of each item (0.68-0.83) confirmed that the items contributed homogeneously to the total score. Internal consistency was excellent (≥0.9) for all items. Both specificity (baseline) and sensitivity (after surgery) based on the Youden index was 99% (97-100%). The suggestive cut-off score for the administration of analgesia according to the ROC curve was ≥4 out of 12. The diagnostic uncertainty zone ranged from 3 to 4. The area under the curve of 0.99 indicated excellent discriminatory capacity of UFEPS-SF., Conclusions: The UFEPS-SF and its items, assessed by experienced evaluators, demonstrated very good repeatability and reproducibility, content, criterion and construct validities, item-total correlation, internal consistency, excellent sensitivity and specificity and a cut-off point indicating the need for rescue analgesia in Chinese, French, English, German, Italian, Japanese, Portuguese and Spanish., Competing Interests: The authors declare there are no competing interests., (©2022 Luna et al.)

The purpose of this study was to evaluate the pharmacokinetics of oral amitriptyline in horses. Oral amitriptyline (1 mg/kg) was administered to six horses. Blood samples were collected from jugular and lateral thoracic vein at predetermined times from 0 to 24 hr after administration. Plasma concentrations were determined by high-performance liquid chromatography and analyzed using noncompartmental methods. Pharmacodynamic parameters including heart rate, respiration rate, and intestinal motility were evaluated, and electrocardiographic examinations were performed in all subjects. The mean maximum plasma concentration (C max ) of amitriptyline was 30.7 ng/ml, time to maximum plasma concentration (T max ) 1-2 hr, elimination half-life (t 1/2 ) 17.2 hr, area under plasma concentration-time curve (AUC) 487.4 ng ml -1  hr -1 , apparent clearance (Cl/F) 2.6 L hr -1  kg -1 , and apparent volume of distribution (Vd/F) 60.1 L/kg. Jugular vein sampling overestimated the amount of amitriptyline absorbed and should not be used to study uptake following oral administration. Heart rate and intestinal motility showed significant variation (p < .05). Electrocardiography did not provide conclusive results. Further studies are required to discern if multiple dose treatment would take the drug to steady state as expected, consequently increasing plasma concentrations., (© 2020 John Wiley & Sons Ltd.)

The requirement for post-operative analgesia after ovariohysterectomy (OH) versus orchiectomy in dogs and cats was compared. Twelve male and 12 female cats and 12 male and 12 female dogs received meloxicam, 0.1 mg/kg body weight, PO, 2 h before surgery. Eleven female cats and 3 female dogs received rescue analgesia ( P = 0.002). No male of either species required rescue analgesia. The number of cats receiving rescue analgesia was greater in females than in males ( P < 0.0001). One should not rely solely on preoperative short-acting opioid and preemptive use of NSAIDs to control postoperative pain following OH, in dogs or cats. Postoperative pain after OH should be assessed for at least 2 h for cats and 4 h for dogs, using species-specific validated tools, to ensure proper postoperative pain diagnosis and management. Male dogs and cats subjected to orchiectomy required less postoperative analgesia intervention than female dogs and cats submitted to OH., Competing Interests: Use of this article is limited to a single copy for personal study. Anyone interested in obtaining reprints should contact the CVMA office (hbroughton@cvma-acmv.org) for additional copies or permission to use this material elsewhere.

Objective: To evaluate intravenous (IV) detomidine with methadone in horses to identify a combination which provides sedation and antinociception without adverse effects., Study Design: Randomized, placebo-controlled, blinded, crossover., Animals: A group of eight adult healthy horses aged (mean ± standard deviation) 7 ± 2 years and 372 ± 27 kg., Methods: A total of six treatments were administered IV: saline (SAL); detomidine (5 μg kg -1 ; DET); methadone (0.2 mg kg -1 ; MET) alone or combined with detomidine [2.5 (MLD), 5 (MMD) or 10 (MHD) μg kg -1 ]. Thermal, mechanical and electrical nociceptive thresholds were measured, and sedation, head height above ground (HHAG), cardiopulmonary variables and intestinal motility were evaluated at 5, 15, 30, 45, 60, 75, 90, 120 and 180 minutes. Normal data were analyzed by mixed-model analysis of variance and non-normal by Kruskal-Wallis (p < 0.05)., Results: Nociceptive thresholds in horses administered methadone with the higher doses of detomidine (MMD, MHD) were increased above baseline to a greater degree and for longer duration (MMD: 15-30 minutes, MHD: 30-60 minutes) than in horses administered low dose with methadone or detomidine alone (MLD, DET: 5-15 minutes). No increases in nociceptive thresholds were recorded in SAL or MET. Compared with baseline, HHAG was lower for 30 minutes in MMD and DET, and for 45 minutes in MHD. No significant sedation was observed in SAL, MET or MLD. Intestinal motility was reduced for 75 minutes in MHD and for 30 minutes in all other treatments., Conclusions: Methadone (0.2 mg kg -1 ) potentiated the antinociception produced by detomidine (5 μg kg -1 ), with minimal sedative effects., Clinical Relevance: Detomidine (5 μg kg -1 ) with methadone (0.2 mg kg -1 ) produced antinociception without the adverse effects of higher doses of detomidine., (Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Objective: To examine the relationship between probe tip size and force readings of mechanical nociceptive thresholds (MTs) to identify appropriate probes for horses., Study Design: Randomized, crossover study., Animals: Eight adult, mixed-breed horses aged 5-10 years, weighing 268-460 kg., Methods: Four probe configurations (PCs) were used in random sequence: 1.0 mm diameter (SHARP); 3.2 mm (BLUNT); spring-mounted 1.0 mm (SPRING), and 3 × 2.5 mm (3PIN). A remote-controlled unit on the horse increased force (1.2 N second(-1)) in a pneumatic actuator on the metacarpus. Mean MT for each PC was calculated from 10 readings for each horse. Data were log-transformed for analysis using mixed-effects anova/linear regression (p < 0.05). Variability of data for each PC was assessed using the coefficient of variation (CV)., Results: Mean ± standard deviation MTs were: SHARP, 5.6 ± 2.3 N; BLUNT, 11.4 ± 3.4 N; 3PIN, 9.6 ± 4.6 N, and SPRING 6.4 ± 1.8 N. Mean MT for SHARP was significantly lower than for BLUNT (p < 0.001) and 3PIN (p < 0.001), but not different from SPRING (p > 0.05). Mean MT was significantly higher for BLUNT than for 3PIN (p < 0.05) and SPRING (p < 0.001). Mean MT for 3PIN was significantly higher than for SPRING (p < 0.001). Larger contact area PCs produced higher MTs than smaller PCs, but the relationship was not linear. BLUNT (area: 10-fold greater) gave a MT two-fold higher than SHARP. 3PIN (area: 20-fold greater) produced more variable MTs, less than two-fold higher than SHARP. SPRING was similar to SHARP. CVs were: SHARP, 22.9%; BLUNT, 72.3%; 3PIN, 44.2%, and SPRING, 28.7%., Conclusions and Clinical Relevance: The PC has nonlinear effects on MT. Therefore, it is important to define PC when measuring MT. Smaller probe tips may be preferable as MT data are less variable., (© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.)