Butch KuKanich

Clinical pharmacology of nonsteroidal anti-inflammatory drugs in dogs

OBJECTIVES To discuss the clinical pharmacology of currently licensed veterinary NSAIDs and to review gastrointestinal and renal adverse effects as well as drug-drug interactions that have been reported with these drugs. To review the use of NSAIDs in the peri-operative setting and their use in patients with osteoarthritis. To further review the reported effects of NSAIDs on canine articular cartilage and liver as well as the clinical relevance of a washout period. DATABASES USED PubMed, CAB abstracts and Google Scholar using dog, dogs, nonsteroidal anti-inflammatory drugs and NSAID(s) as keywords. CONCLUSIONS A good understanding of the mechanisms by which NSAIDs elicit their analgesic effect is essential in order to minimize adverse effects and drug-drug interactions. Cyclooxygenase (COX) is present in at least two active isoforms in the body and is the primary pharmacologic target of NSAIDs. Inhibition of COX is associated with the analgesic effects of NSAIDs. COX is present in the gastrointestinal tract and kidneys, along with other areas of the body, and is also the likely reason for many adverse effects including gastrointestinal and renal adverse effects. The newer veterinary approved NSAIDs have a lower frequency of gastrointestinal adverse effects in dogs compared to drugs such as aspirin, ketoprofen and flunixin, which may be due to differential effects on the COX isoforms. There are currently no published reports demonstrating that the newer NSAIDs are associated with fewer renal or hepatic adverse effects in dogs. NSAIDs remain the cornerstone of oral therapy for osteoarthritis unless contraindicated by intolerance, concurrent therapies or underlying medical conditions. NSAIDs are also effective and frequently used for the management of post-operative pain.

Pharmacokinetics and antinociceptive effects of oral tramadol hydrochloride administration in Greyhounds.

OBJECTIVE To determine the pharmacokinetics of tramadol, the active metabolite O-desmethyltrcamadol, and the metabolites N-desmethyltramadol and N,O-didesmethyltramadol after oral tramadol administration and to determine the antinociceptive effects of the drug in Greyhounds. ANIMALS 6 healthy 2- to 3-year-old Greyhounds (3 male and 3 female), weighing 25.5 to 41.1 kg. PROCEDURES A mean dose of 9.9 mg of tramadol HCl/kg was administered PO as whole tablets. Blood samples were obtained prior to and at various points after administration to measure plasma concentrations of tramadol and its metabolites via liquid chromatography with mass spectrometry. Antinociceptive effects were determined by measurement of pain-pressure thresholds with a von Frey device. RESULTS Tramadol was well tolerated, and a significant increase in pain-pressure thresholds was evident 5 and 6 hours after administration. The mean maximum plasma concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol were 215.7, 5.7, 379.1, and 2372 ng/mL, respectively. The mean area-under-the-curve values for the compounds were 592, 16, 1,536, and 1,013 h·ng/mL, respectively. The terminal half-lives of the compounds were 1.1, 1.4, 2.3, and 3.6 hours, respectively. Tramadol was detected in urine 5 days, but not 7 days, after administration. CONCLUSIONS AND CLINICAL RELEVANCE Oral tramadol administration yielded antinociceptive effects in Greyhounds, but plasma concentrations of tramadol and O-desmethyltramadol were lower than expected. Compared with the approved dose (100 mg, PO) in humans, a mean dose of 9.9 mg/kg, PO resulted in similar tramadol but lower O-desmethyltramadol plasma concentrations in Greyhounds.

Anti-inflammatory salicylate treatment alters the metabolic adaptations to lactation in dairy cattle

Adapting to the lactating state requires metabolic adjustments in multiple tissues, especially in the dairy cow, which must meet glucose demands that can exceed 5 kg/day in the face of negligible gastrointestinal glucose absorption. These challenges are met through the process of homeorhesis, the alteration of metabolic setpoints to adapt to a shift in physiological state. To investigate the role of inflammation-associated pathways in these homeorhetic adaptations, we treated cows with the nonsteroidal anti-inflammatory drug sodium salicylate (SS) for the first 7 days of lactation. Administration of SS decreased liver TNF-α mRNA and marginally decreased plasma TNF-α concentration, but plasma eicosanoids and liver NF-κB activity were unaltered during treatment. Despite the mild impact on these inflammatory markers, SS clearly altered metabolic function. Plasma glucose concentration was decreased by SS, but this was not explained by a shift in hepatic gluconeogenic gene expression or by altered milk lactose secretion. Insulin concentrations decreased in SS-treated cows on day 7 compared with controls, which was consistent with the decline in plasma glucose concentration. The revised quantitative insulin sensitivity check index (RQUICKI) was then used to assess whether altered insulin sensitivity may have influenced glucose utilization rate with SS. The RQUICKI estimate of insulin sensitivity was significantly elevated by SS on day 7, coincident with the decline in plasma glucose concentration. Salicylate prevented postpartum insulin resistance, likely causing excessive glucose utilization in peripheral tissues and hypoglycemia. These results represent the first evidence that inflammation-associated pathways are involved in homeorhetic adaptations to lactation.

Effect of oral meloxicam on health and performance of beef steers relative to bulls castrated on arrival at the feedlot.

Castration in weaned calves is stressful and affects profitability by reducing ADG and increasing susceptibility to disease. This study evaluated the effect of meloxicam, a nonsteroidal anti-inflammatory drug (NSAID), on performance and health of calves received as steers compared with bull calves surgically castrated on arrival at the feedlot. British × Continental bulls (n = 145) and steers (n = 113; BW = 193 to 285 kg) were transported for 12 h in 3 truckloads (d 0), weighed, and randomly assigned to receive either lactose placebo (CONT; 1 mg/kg) or meloxicam (MEL; 1 mg/kg) suspended in water and administered per os, 24 h before castration. On d 1, bulls were surgically castrated (CAST) and steers were processed without castration (STR). Combinations of CONT/MEL and CAST/STR were allocated to 24 pens (6 pens per treatment) of 8 to 14 calves each. Pen was the experimental unit. Plasma meloxicam concentrations at the time of castration (d 1) were determined by HPLC-mass spectroscopy. Pen-level ADG, DMI, and G:F were estimated using BW obtained on d 0, 14, and 28 and weigh-back of feed. Individual animals were classified as sick based on a depression score of ≥2 on a 5-point scale and a rectal temperature of ≥39.8°C. On d 0, 1, and 14, calf chute temperament was evaluated using a 4-point scale. Data were analyzed using generalized linear mixed models and survival curve analyses. Castration reduced pen ADG (P < 0.001) and G:F (P < 0.001) from d 1 to 14, yet no effects (P > 0.45) were apparent by d 28. For all treatment groups, DMI increased with days on feed (P < 0.0001) but was less in CAST compared with STR calves (P < 0.016) throughout the study. From d 15 to 28, ADG increased (P = 0.0011) in CAST but not STR calves, and G:F decreased (P = 0.0004) in STR but not CAST calves. In CAST calves only, MEL treatment reduced the pen-level first pull rate (P = 0.04) and reduced bovine respiratory disease morbidity rate (P = 0.03). The frequency of chute escape behavior was greater on arrival and at castration in CAST vs. STR calves (P < 0.01) but not significantly different at d 14 (P = 0.22). Mean MEL concentrations at castration were no different between treated STR and CAST calves (P = 0.70). Meloxicam administration before castration in postweaning calves reduced the incidence of respiratory disease at the feedlot. These findings have implications for developing NSAID protocols for use in calves at castration with respect to addressing animal health and welfare concerns.

Pharmacokinetics and effect of intravenous meloxicam in weaned Holstein calves following scoop dehorning without local anesthesia.

BackgroundDehorning is a common practice involving calves on dairy operations in the United States. However, less than 20% of producers report using analgesics or anesthetics during dehorning. Administration of a systemic analgesic drug at the time of dehorning may be attractive to dairy producers since cornual nerve blocks require 10 – 15 min to take effect and only provide pain relief for a few hours. The primary objectives of this trial were to (1) describe the compartmental pharmacokinetics of meloxicam in calves after IV administration at 0.5 mg/kg and (2) to determine the effect of meloxicam (n = 6) or placebo (n = 6) treatment on serum cortisol response, plasma substance P (SP) concentrations, heart rate (HR), activity and weight gain in calves after scoop dehorning and thermocautery without local anesthesia.ResultsPlasma meloxicam concentrations were detectable for 50 h post-administration and fit a 2-compartment model with a rapid distribution phase (mean T½α = 0.22 ± 0.087 h) and a slower elimination phase (mean T½β = 21.86 ± 3.03 h). Dehorning caused a significant increase in serum cortisol concentrations and HR (P < 0.05). HR was significantly lower in the meloxicam-treated calves compared with placebo-treated calves at 8 h (P = 0.039) and 10 h (P = 0.044) after dehorning. Mean plasma SP concentrations were lower in meloxicam treated calves (71.36 ± 20.84 pg/mL) compared with control calves (114.70 ± 20.84 pg/mL) (P = 0.038). Furthermore, the change in plasma SP from baseline was inversely proportional to corresponding plasma meloxicam concentrations (P = 0.008). The effect of dehorning on lying behavior was less significant in meloxicam-treated calves (p = 0.40) compared to the placebo-treated calves (P < 0.01). Calves receiving meloxicam prior to dehorning gained on average 1.05 ± 0.13 kg bodyweight/day over 10 days post-dehorning compared with 0.40 ± 0.25 kg bodyweight/day in the placebo-treated calves (p = 0.042).ConclusionsTo our knowledge, this is the first published report examining the effects of meloxicam without local anesthesia on SP, activity and performance of calves post-dehorning. These findings suggest that administration of meloxicam alone immediately prior to dehorning does not mitigate signs of acute distress but may have long term physiological, behavior and performance effects.

Outpatient oral analgesics in dogs and cats beyond nonsteroidal antiinflammatory drugs: an evidence-based approach.

This article evaluates the current literature on oral analgesics and analgesic adjuncts in dogs and cats. An overview of how dosing recommendations are made covering controlled clinical trials, experimental study design, and pharmacokinetic studies is included. The weight of evidence for each drug is reviewed and compared with the gold standard, controlled clinical trials. Other evidence such as experimental studies, extrapolation of pharmacokinetic studies, and case reports/series is also considered. It important to know from what data dosing recommendations are derived and how much evidence supports the use of oral analgesics and analgesic adjuncts in dogs and cats.

Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine‐6‐glucuronide in healthy Greyhound dogs

The purpose of this study was to determine the pharmacokinetics of codeine and the active metabolites morphine and codeine-6-glucuronide after i.v. codeine administration and the pharmacokinetics of acetaminophen (APAP), codeine, morphine, and codeine-6-glucuronide after oral administration of combination product containing acetaminophen and codeine to dogs. Six healthy Greyhound dogs were administered 0.734 mg/kg codeine i.v. and acetaminophen (10.46 mg/kg mean dose) with codeine (1.43 mg/kg mean dose) orally. Blood samples were collected at predetermined time points for the determination of codeine, morphine, and codeine-6-glucuronide plasma concentrations by LC/MS and acetaminophen by HPLC with UV detection. Codeine was rapidly eliminated after i.v. administration (T(1/2) = 1.22 h; clearance = 29.94 mL/min/kg; volume of distribution = 3.17 L/kg) with negligible amounts of morphine present, but large amounts of codeine-6-glucuronide (C(max) = 735.75 ng/mL) were detected. The oral bioavailability of codeine was 4%, morphine concentrations were negligible, but large amounts of codeine-6-glucuronide (C(max) = 1952.86 ng/mL) were detected suggesting substantial first pass metabolism. Acetaminophen was rapidly absorbed (C(max) = 6.74 microg/mL; T(max) = 0.85 h) and eliminated (T(1/2) = 0.96 h). In conclusion, the pharmacokinetics of codeine was similar to other opioids in dogs with a short half-life, rapid clearance, large volume of distribution, and poor oral bioavailability. High concentrations of codeine-6-glucuronide were detected after i.v. and oral administration.

Pharmacokinetics of oral gabapentin alone or co-administered with meloxicam in ruminant beef calves

Gabapentin is a γ-aminobutyric acid (GABA) analogue indicated for treatment of neuropathic pain. This study determined the pharmacokinetics of oral (PO) gabapentin alone or in combination with meloxicam in ruminant calves. Gabapentin capsules at 10mg/kg or gabapentin powder (from capsules at 15mg/kg) and meloxicam tablets (0.5mg/kg) were administered PO to six beef calves. Plasma drug concentrations were determined over 48h post-administration by liquid chromatography/mass spectrometry followed by non-compartmental pharmacokinetic analysis. The mean (± standard deviation, SD) C(max), T(max) and elimination half-life (t(½)λz) for gabapentin (10mg/kg) alone was 2.97 ± 0.40μg/mL, 9.33 ± 2.73h and 11.02 ± 3.68h, respectively. The mean (± SD) C(max), T(max) and t(½)λz for gabapentin (15mg/kg) co-administered with meloxicam was 3.57±1.04μg/mL, 7.33 ± 1.63h and 8.12±2.11h, respectively. The mean (±SD) C(max), T(max) and t(½)λz for meloxicam was 2.11± 0.19μg/mL, 11.67 ± 3.44h and 20.47 ± 9.22h, respectively. Plasma gabapentin concentrations >2μg/mL were maintained for up to 15h and meloxicam concentrations >0.2μg/mL for up to 48h. The pharmacokinetic profile of oral gabapentin and meloxicam supported clinical evaluation of these compounds for management of neuropathic pain in cattle.

Pharmacokinetics and physiologic effects of intramuscularly administered xylazine hydrochloride-ketamine hydrochloride- butorphanol tartrate alone or in combination with orally administered sodium salicylate on biomarkers of pain in Holstein calves following castration and dehorning

OBJECTIVE To determine the pharmacokinetic parameters of xylazine, ketamine, and butorphanol (XKB) administered IM and sodium salicylate (SAL) administered PO to calves and to compare drug effects on biomarkers of pain and distress following sham and actual castration and dehorning. ANIMALS 40 Holstein bull calves from 3 farms. PROCEDURES Calves weighing 108 to 235 kg (n = 10 calves/group) received one of the following treatments prior to sham (period 1) and actual (period 2) castration and dehorning: saline (0.9% NaCl) solution IM (placebo); SAL administered PO through drinking water at concentrations from 2.5 to 5 mg/mL from 24 hours prior to period 1 to 48 hours after period 2; butorphanol (0.025 mg/kg), xylazine (0.05 mg/kg), and ketamine (0.1 mg/kg) coadministered IM immediately prior to both periods; and a combination of SAL and XKB (SAL+XKB). Plasma drug concentrations, average daily gain (ADG), chute exit velocity, serum cortisol concentrations, and electrodermal activity were evaluated. RESULTS ADG (days 0 to 13) was significantly greater in the SAL and SAL+XKB groups than in the other 2 groups. Calves receiving XKB had reduced chute exit velocity in both periods. Serum cortisol concentrations increased in all groups from period 1 to period 2. However, XKB attenuated the cortisol response for the first hour after castration and dehorning and oral SAL administration reduced the response from 1 to 6 hours. Administration of XKB decreased electrodermal activity scores in both periods. CONCLUSIONS AND CLINICAL RELEVANCE SAL administered PO through drinking water decreased cortisol concentrations and reduced the decrease in ADG associated with castration and dehorning in calves.

Analgesic efficacy of sodium salicylate in an amphotericin B-induced bovine synovitis-arthritis model

This study examined the efficacy of sodium salicylate for providing analgesia in an amphotericin B-induced bovine synovitis-arthritis model using 10 male Holstein calves, 4 to 6 mo old and weighing approximately 250 kg. The study used a repeated measures partial crossover design with 2 phases, consisting of 3 treatment periods within each phase. Calves were blocked by body weight and randomly assigned to the sodium salicylate (50 mg/kg i.v.) or placebo group for phase 1. In period 1, lameness induction was simulated with a needle prick of the coronary band, followed by drug or placebo administration. At predetermined time points, serial blood samples for cortisol and salicylate concentrations, electrodermal activity measurements, heart rates, and pressure mat data were collected. Visual lameness scores were recorded by an observer blinded to treatments. In period 2, lameness was induced with injection of amphotericin B into the distal interphalangeal joint, followed by drug or placebo administration, with sample collection as described previously. In period 3, the drug or placebo was administered to the respective calves with sample collection. After a 10-d washout period, phase 2 was conducted with treatments crossed over between groups. Cortisol and salicylate samples were analyzed by competitive chemiluminescent immunoassay and fluorescence polarization immunoassay, respectively. The pharmacokinetic data were analyzed using compartmental analysis. Mean intravenous salicylate apparent volume of distribution was 0.2 +/- 0.005 L/kg, total body clearance was 4.3 +/- 0.2 mL/min.kg, and elimination half-life was 36.9 +/- 1.2 min. The repeated measures data were analyzed based on a univariate split-plot approach with a random effects-mixed model. Differences in stance phase duration and serum cortisol concentration values were seen both between periods and between treatment group x periods; differences in heart rate, contact surface area, and contact pressure values were seen between periods, suggesting that our lameness model was effective. No differences were seen between treatment groups. When analyzed by visual lameness score, differences were seen in heart rate, contact surface area, contact pressure, and cortisol concentrations. Area under the time-effect curves, determined by using the trapezoidal rule, had results similar to the repeated measures data, except for a difference in period for electrodermal activity. This amphotericin B-induced synovitis-arthritis model is a useful tool for studying changes associated with lameness in cattle. Sodium salicylate was not effective in providing analgesia after lameness.