Locke A. Karriker

Impact of oral meloxicam on circulating physiological biomarkers of stress and inflammation in beef steers after long distance transportation

Transportation stress can result in significant economic losses to producers due to decreased animal productivity and increased medication costs associated with sickness such as bovine respiratory disease (BRD). Meloxicam (MEL) provides pain relief and anti-inflammatory effects in cattle for several days after a single oral treatment. Our hypothesis was that MEL administration before shipping would reduce the impact of long-distance transportation on circulating physiological biomarkers of stress and inflammation in beef steers. Ninety-seven beef steers were blood sampled for baseline biomarker determination and then randomly assigned to receive either 1 mg/kg MEL (n = 49) or a placebo (CONT; n = 48) per os before a 1,316-km transportation event lasting approximately 16 h. Calves were then blood sampled on arrival and 5 d later. Changes in the hemogram, circulating plasma proteins, total carbon dioxide (TCO2), fibrinogen, substance P (SP), cortisol, haptoglobin (Hp)-matrix metalloproteinase-9 (MMP-9) complexes, and tumor necrosis factor α (TNFα) between treatments over time were compared using a mixed effects model with statistical significance designated as P < 0.05. Analysis of covariance was conducted to assess the relationship between circulating MEL concentrations and biomarker changes over time. An increase in neutrophil, platelet, monocyte, white blood cell, and red blood cell counts occurred after transportation (P < 0.0001) and a decrease in lymphocyte count were observed (P < 0.0001). Meloxicam treatment reduced the stress-induced neutrophilia (P = 0.0072) and circulating monocyte count (P = 0.013) on arrival. Mean corpuscle hemoglobin (P = 0.05), mean corpuscle volume (P = 0.05), and lymphocyte count (P = 0.05) were also greater in the CONT calves compared with MEL calves after transportation. Furthermore, Hp-MMP-9 complexes, TCO2, TNFα, plasma proteins, and SP increased and cortisol decreased after shipping (P < 0.01). Meloxicam treatment tended to reduce serum cortisol concentrations (P = 0.08) and there was evidence of a time × treatment interaction (P = 0.04). An inverse relationship between plasma MEL concentrations and circulation cortisol concentrations (P = 0.002) and neutrophil (P = 0.04) and basophil counts (P = 0.03) was also observed. The results suggest that MEL administration may reduce the impact of long-distance transportation on circulating physiological biomarkers of stress and inflammation in beef calves.

Pain Management in the Neonatal Piglet During Routine Management Procedures. Part 1: A Systematic Review of Randomized and Non-Randomized Intervention Studies

Abstract Routine procedures carried out on piglets (i.e. castration, tail docking, teeth clipping, and ear notching) are considered painful. Unfortunately the efficacy of current pain mitigation modalities is poorly understood. The aim of this systematic review was to synthesize the existing primary scientific literature regarding the effectiveness of pain management interventions used for routine procedures on piglets. The review question was, ‘In piglets under twenty-eight days old, undergoing castration, tail docking, teeth clipping, and/or methods of identification that involve cutting of the ear tissue, what is the effect of pain mitigation compared with no pain mitigation on behavioral and non-behavioral outcomes that indicate procedural pain and post-procedural pain?’ A review protocol was designed a priori. Data sources used were Agricola (EBSCO), CAB Abstracts (Thomson Reuters), PubMed, Web of Science (Thomson Reuters), BIOSIS Previews (Thomson Reuters), and ProQuest Dissertations & Theses Full Text. No restrictions on year of publication or language were placed on the search. Eligible studies assessed an intervention designed to mitigate the pain of the procedures of interest and included a comparison group that did not receive an intervention. Eligible non-English studies were translated using a translation service. Two reviewers independently screened titles and abstracts for relevance using pre-defined questions. Data were extracted from relevant articles onto pre-defined forms. From the 2203 retrieved citations forty publications, containing 52 studies met the eligibility criteria. In 40 studies, piglets underwent castration only. In seven studies, piglets underwent tail docking only. In one study, piglets underwent teeth clipping only, and in one study piglets underwent ear notching only. Three studies used multiple procedures. Thirty-two trial arms assessed general anesthesia protocols, 30 trial arms assessed local anesthetic protocols, and 28 trial arms assessed non-steroidal anti-inflammatory drugs (NSAIDs) protocols. Forty-one trial arms were controls where piglets received either placebo or no treatment. Forty-five outcomes were extracted from the studies, however only the results from studies that assessed cortisol (six studies), β-endorphins (one study), vocalisations (nine studies), and pain-related behaviors (nine studies) are reported. Other outcomes were reported in only one or two studies. Confident decision making will likely be difficult based on this body of work because lack of comprehensive reporting precludes calculation of the magnitude of pain mitigation for most outcomes.

Behavioural evaluation of analgesic efficacy for pain mitigation in lame sows

Lameness in breeding swine has a large negative economic impact and is a welfare concern. Pain-related behaviour, such as postural changes, may be used to evaluate the presence and severity of pain in animals. The objective of this work was to determine the effects of flunixin meglumine (FM) and meloxicam (M) on postural changes in lame sows. Lameness was induced in 24 mature sows (Sus scrofa) using a chemical synovitis model. Three treatments were compared: FM (2.2 mg kg; n = 24, intramuscular [IM]), M (1.0 mg kg; n = 24, by mouth [PO]) and sterile saline (equivalent volume to FM; n = 24 [IM]), administered approximately 28 and 52 h after lameness induction. Behavioural data were collected in the home pen during 12-h periods and quantified using 15-min scan sampling on the day prior to (–24 h; Day –1) through +168 h post lameness induction. Frequency of behaviour was analysed by day using generalised linear mixed model methods. The frequency of standing postures significantly decreased and lying postures increased 24–72 h post lameness induction relative to baseline day. All postures returned to baseline frequencies by +168 h. Meloxicam-treated sows demonstrated lower frequencies of lying postures +48 and +72 h after lameness induction compared to saline-treated sows. Flunixin-treated sows did not differ in lying behaviours compared to saline-treated sows. No differences were noted in standing or sitting postures between treatments. The results of this study suggest that meloxicam mitigates pain sensitivity as demonstrated by higher frequency of standing and lower frequency of lying compared to saline-treated sows.

Pain management in the neonatal piglet during routine management procedures. Part 2 :Grading the quality of evidence and the strength of recommendations

Abstract Piglets reared in swine production in the USA undergo painful procedures that include castration, tail docking, teeth clipping, and identification with ear notching or tagging. These procedures are usually performed without pain mitigation. The objective of this project was to develop recommendations for pain mitigation in 1- to 28-day-old piglets undergoing these procedures. The National Pork Board funded project to develop recommendations for pain mitigation in piglets. Recommendation development followed a defined multi-step process that included an evidence summary and estimates of the efficacies of interventions. The results of a systematic review of the interventions were reported in a companion paper. This manuscript describes the recommendation development process and the final recommendations. Recommendations were developed for three interventions (CO2/O2 general anesthesia, non-steroidal anti-inflammatory drugs (NSAIDs), and lidocaine) for use during castration. The ability to make strong recommendations was limited by low-quality evidence and strong certainty about variation in stakeholder values and preferences. The panel strongly recommended against the use of a CO2/O2 general anesthesia mixture, weakly recommended for the use of NSAIDs and weakly recommended against the use of lidocaine for pain mitigation during castration of 1- to 28-day-old piglets.

Impact of transmammary-delivered meloxicam on biomarkers of pain and distress in piglets after castration and tail docking.

To investigate a novel route for providing analgesia to processed piglets via transmammary drug delivery, meloxicam was administered orally to sows after farrowing. The objectives of the study were to demonstrate meloxicam transfer from sows to piglets via milk and to describe the analgesic effects in piglets after processing through assessment of pain biomarkers and infrared thermography (IRT). Ten sows received either meloxicam (30 mg/kg) (nu200a=u200a5) or whey protein (placebo) (nu200a=u200a5) in their daily feedings, starting four days after farrowing and continuing for three consecutive days. During this period, blood and milk samples were collected at 12-hour intervals. On Day 5 after farrowing, three boars and three gilts from each litter were castrated or sham castrated, tail docked, and administered an iron injection. Piglet blood samples were collected immediately before processing and at predetermined times over an 84-hour period. IRT images were captured at each piglet blood collection point. Plasma was tested to confirm meloxicam concentrations using a validated high-performance liquid chromatography-mass spectrometry method. Meloxicam was detected in all piglets nursing on medicated sows at each time point, and the mean (± standard error of the mean) meloxicam concentration at castration was 568.9±105.8 ng/mL. Furthermore, ex-vivo prostaglandin E2 (PGE2) synthesis inhibition was greater in piglets from treated sows compared to controls (pu200a=u200a0.0059). There was a time-by-treatment interaction for plasma cortisol (pu200a=u200a0.0009), with meloxicam-treated piglets demonstrating lower cortisol concentrations than control piglets for 10 hours after castration. No differences in mean plasma substance P concentrations between treatment groups were observed (pu200a=u200a0.67). Lower cranial skin temperatures on IRT were observed in placebo compared to meloxicam-treated piglets (pu200a=u200a0.015). This study demonstrates the successful transfer of meloxicam from sows to piglets through milk and corresponding analgesia after processing, as evidenced by a decrease in cortisol and PGE2 levels and maintenance of cranial skin temperature.

Measuring the efficacy of flunixin meglumine and meloxicam for lame sows using nociceptive threshold tests

Lameness in breeding swine can cause severe pain leading to on-farm welfare issues and significant economic impacts. Non-steroidal anti-inflammatory drugs including meloxicam and flunixin meglumine are commonly used in veterinary medicine for their analgesic and anti-inflammatory properties. Pressure algometry and thermal sensitivity tests are non-invasive methods to quantify pain sensitivity using nociceptive thresholds to provoke withdrawal responses on lame and sound legs. The objective of this work was to determine the effects of these drugs on nociceptive thresholds in sows induced lame using pressure algometry and thermal sensitivity tests. Lameness was induced in 24 mature, mixed-parity sows using a chemical synovitis model and three treatments were compared: meloxicam (1.0 mg kg PO), flunixin meglumine (2.2 mg kg IM) and sterile saline (IM). Pressure algometry was measured on sound and lame rear legs with three replicates at three landmarks. Thermal sensitivity tests were done on sound and lame rear legs with three replicates using a thermal stimulus at one landmark. From 37 to 72 h after lameness induction, meloxicamand flunixin meglumine-treated sows tolerated higher pressure algometer nociceptive thresholds compared to saline-treated sows. Changes in thermal nociceptive thresholds were evident at the Tmax time-points for meloxicam administration and 72 and 168 h post lameness induction for flunixin meglumine-treated sows. In conclusion, flunixin meglumine and meloxicam administration mitigated pain sensitivity in lame sows post lameness induction when pain sensitivity was evaluated with pressure algometry. These analgesic drugs may be a key tool to manage pain associated with lameness.

Pharmacokinetics of meloxicam in mature swine after intravenous and oral administration

The purpose of this study was to compare the pharmacokinetics of meloxicam in mature swine after intravenous (i.v.) and oral (p.o.) administration. Six mature sows (mean bodyweight ± standard deviation = 217.3 ± 65.68 kg) were administered an i.v. or p.o. dose of meloxicam at a target dose of 0.5 mg/kg in a cross-over design. Plasma samples collected up to 48 h postadministration were analyzed by high-pressure liquid chromatography and mass spectrometry (HPLC-MS) followed by noncompartmental pharmacokinetic analysis. Mean peak plasma concentration (CMAX ) after p.o. administration was 1070 ng/mL (645-1749 ng/mL). TMAX was recorded at 2.40 h (0.50-12.00 h) after p.o. administration. Half-life (T½ λz ) for i.v. and p.o. administration was 6.15 h (4.39-7.79 h) and 6.83 h (5.18-9.63 h), respectively. The bioavailability (F) for p.o. administration was 87% (39-351%). The results of this study suggest that meloxicam is well absorbed after oral administration.

Measuring the efficacy of flunixin meglumine and meloxicam for lame sows using a GAITFour pressure mat and an embedded microcomputer-based force plate system.

Pain associated with lameness on farm is a negative affective state and has a detrimental impact on individual farm animal welfare. Animal pain can be managed utilizing husbandry tools and through pharmacological approaches. Nonsteroidal anti-inflammatory drugs including meloxicam and flunixin meglumine are compounds used in many species for pain management because they are easy to administer, long lasting, and cost-effective. Assessing an animals biomechanical parameters using such tools as the embedded microcomputer-based force plate system and GAITFour pressure mat gait analysis walkway system provides an objective, sensitive, and precise means to detect animals in lame states. The objectives of this study were to determine the efficacy of meloxicam and flunixin meglumine for pain mitigation in lame sows using the embedded microcomputer-based force plate system and GAITFour pressure mat gait analysis walkway system. Lameness was induced in 24 mature mixed-parity sows using a chemical synovitis model and compared 3 treatments: meloxicam (1.0 mg/kg per os), flunixin meglumine (2.2 mg/kg intramuscular) and sterile saline (intramuscular). Weight distribution (kg) for each foot was collected twice per second for a total of 5 min for each time point using the embedded microcomputer-based force plate system. Stride time, stride length, maximum pressure, activated sensors, and stance time were collected using 3 quality walks (readings) for each time point using the GAITFour pressure mat gait analysis walkway system. Sows administered flunixin meglumine or meloxicam tolerated more weight on their lame leg compared with saline sows (P < 0.005). Sows administered flunixin meglumine or meloxicam had smaller differences in stance time, maximum pressure, and activated sensors between the sound and lame legs compared with saline-treated sows between 37 and 60 h after lameness induction (P < 0.03). In conclusion, flunixin meglumine and meloxicam administration mitigated pain sensitivity in sows after lameness induction when pain sensitivity was evaluated with the embedded microcomputer-based force plate system and GAITFour pressure mat gait analysis walkway system. Analgesic drugs may be a key tool to manage negative pain affective states associated with lameness.

Review: Assessment of completeness of reporting in intervention studies using livestock: an example from pain mitigation interventions in neonatal piglets.

Accurate and complete reporting of study methods, results and interpretation are essential components for any scientific process, allowing end-users to evaluate the internal and external validity of a study. When animals are used in research, excellence in reporting is expected as a matter of continued ethical acceptability of animal use in the sciences. Our primary objective was to assess completeness of reporting for a series of studies relevant to mitigation of pain in neonatal piglets undergoing routine management procedures. Our second objective was to illustrate how authors can report the items in the Reporting guidElines For randomized controLled trials for livEstoCk and food safety (REFLECT) statement using examples from the animal welfare science literature. A total of 52 studies from 40 articles were evaluated using a modified REFLECT statement. No single study reported all REFLECT checklist items. Seven studies reported specific objectives with testable hypotheses. Six studies identified primary or secondary outcomes. Randomization and blinding were considered to be partially reported in 21 and 18 studies, respectively. No studies reported the rationale for sample sizes. Several studies failed to report key design features such as units for measurement, means, standard deviations, standard errors for continuous outcomes or comparative characteristics for categorical outcomes expressed as either rates or proportions. In the discipline of animal welfare science, authors, reviewers and editors are encouraged to use available reporting guidelines to ensure that scientific methods and results are adequately described and free of misrepresentations and inaccuracies. Complete and accurate reporting increases the ability to apply the results of studies to the decision-making process and prevent wastage of financial and animal resources.

Are severely depressed suckling pigs resistant to gas euthanasia

Severely depressed pigs exhibit differences in a number of important parameters that may affect gas euthanasia, including decreased respiration rate and tidal volume. Hence, the objectives of this study were to assess the efficacy and animal welfare implications of gas euthanasia of suckling pigs with varied disease severity (severely depressed [DP] vs other [OT]). A 2 × 2 factorial design was utilised with two gas types (carbon dioxide [CO2]; argon [Ar]) and two flow rates (G = gradual, 35% box volume exchange per min [BVE min]; P = prefill + 20% BVE min). Sixty-two pigs were enrolled and tested as DP/OT pairs in each gas treatment combination. Pigs identified for euthanasia were assigned a subjective depression score (0 = normal to 3 = severely depressed). Pigs scored 3 and ≤ 1 were categorised as DP and OT, respectively. Significantly lower respiration, rectal temperature, pulse and weight were observed for the DP pigs relative to OT. Pigs were assessed for behavioural indicators of efficacy and welfare. No differences were observed between DP and OT when using P-CO2 or G-CO2. However in P-Ar, DP had greater latency to loss of consciousness relative to OT (212 [± 22] vs 77 [± 22] s), decreased latency to last limb movement (511 [± 72] vs 816 [± 72] s), greater duration of open-mouth breathing (151 [± 21] vs 69 [± 21] s), decreased duration ataxia (101 [± 42] vs 188 [± 42] s) and decreased righting response (27 [± 11] vs 63 [± 11] s). The G-Ar treatment was removed due to ethical concerns associated with prolonged induction. In conclusion, depression score did not affect pig responses to euthanasia with CO2 gas, but did affect responses to Ar. Furthermore, Ar was associated with a prolonged euthanasia process, including frequencies and durations of distress behaviours.