Development of a lameness model in sheep for assessing efficacy of analgesics

Objective To develop a lameness model to assess the efficacy of analgesics for alleviating pain, swelling and systemic signs of inflammation in sheep. Procedures The response to subcutaneous injection of 0.1 or 0.2 mL turpentine in a forelimb pastern (n = 4 ewes per dose) was examined at 0, 3, 6, 24, 48 and 72 h. In a second experiment, responses were measured at 0, 2, 4, 6, 8, 10, 12 and 24 h in ewes receiving 0.1 mL turpentine ± meloxicam 1 mg/kg IV at 0 h (n = 6 per group). Responses measured included forceplate pressure, skin temperature, limb circumference, nociception, leucocyte count, neutrophil : lymphocyte ratio, haptoglobin and daily feed intake. Results Turpentine injection caused a decrease in weight borne on the treated limb, increased skin temperature, increased sensitivity at the injection site and leucocytosis by 2 h and increased limb circumference by 4 h. Weight borne and sensitivity of the injected limb returned to control levels after around 24 h, whereas tissue swelling, elevated skin temperature and elevated haptoglobin levels persisted for at least 72 h. Treatment with meloxicam improved weight borne by and tolerance to pressure exerted on the turpentine‐injected limb. Conclusions The local and systemic signs of inflammation and pain, temporary reduction in function of the affected limb and partial amelioration of some of these changes by the dose of meloxicam used here suggest that injection of turpentine in the lower forelimb provides a suitable model for examining the efficacy of analgesics for alleviation of pain and inflammation in sheep.     

Dose range finding study for the efficacy of meloxicam administered prior to sodium urate-induced synovitis in cats

ObjectiveTo determine the lowest efficacious dose of oral meloxicam for relieving pain in cats with a sodium urate (SU)-induced acute inflammatory synovitis.Study designRandomized, blinded, controlled, and four-way crossover study.AnimalsEight surgically neutered cats (four males, four females) paired according to sex.MethodsEach pair of cats was treated with 0 (placebo), 0.025, 0.05, or 0.075 mg kg^?1 oral meloxicam once daily for 4 days prior to injection, into alternating stifles, of 1 mL of 20 mg mL^?1 SU crystals, beginning with the right stifle. Each cat received each of the four treatments, separated by at least 21 days. Analgesic efficacy was evaluated based on objective (e.g., pressure mat data total force, contact pressure, and contact area) and subjective (e.g., scores for Analgesia Scale [AS], Lameness Scale [LS], and Visual Analog Scale [VAS]) outcome measures for pain assessment. All outcome measures were recorded before and during 30 hours after SU injection. The pre-defined primary outcome measure was the area under the response–time curve (AUC_0–30 hours) of the total force of the injected limb. Data were analyzed by analysis of variance. A sequential test procedure was applied and the test sequence stopped in case of a nonsignificant result.ResultsMeloxicam at doses of 0.05 and 0.075 mg kg^?1 day^?1 PO was significantly different from placebo for the pre-defined primary outcome measure (i.e., AUC_0–30 hours of total force). All tested meloxicam doses were lower than placebo for the subjective outcome measures (i.e., AUC_0–30 hours of AS, LS, and VAS).Conclusions and clinical relevanceThe lowest efficacious dose of meloxicam for relieving pain in cats with an SU-induced synovitis was 0.05 mg kg^?1 day^?1 PO according to the pre-defined primary outcome measure. However, lower doses may also be effective as seen in the subjective outcome measures.     

Induction of VEGF by tepoxalin does not lead to increased tumour growth in a canine osteosarcoma xenograft

The purpose of this study was to determine the impact of the non-steroidal anti-inflammatory drug tepoxalin on canine tumour cell growth and describe the changes associated with tepoxalin treatment. In vitro experiments were performed to assess tepoxalin-associated alterations in tumour cell growth. Clinically achievable tepoxalin concentrations did not significantly alter tumour cell growth in vitro. Vascular endothelial growth factor (VEGF) production and hypoxia-inducible factor-1α dose-dependently increased in vitro in the presence of tepoxalin. A canine osteosarcoma xenograft was used to determine in vivo effects of tepoxalin on tumour growth and angiogenesis. Despite increased VEGF in vitro, there was a significant growth delay associated with tepoxalin treatment. Normal dogs were administered tepoxalin to assess effects on systemic VEGF production, but not found to have significantly increased VEGF. These data suggest that tepoxalin may moderately inhibit tumour growth and may be administered as an analgesic to tumour-bearing dogs.     

Efficacy of tolfenamic acid and meloxicam in the control of postoperative pain following ovariohysterectomy in the cat

Objective The hypothesis was that Visual Analog Scale (VAS) scores would be lower, and mechanical wound thresholds (MWT) higher, in cats receiving tolfenamic acid compared to those receiving placebo in the postoperative period following elective ovariohysterectomy. Animals Sixty‐nine client‐owned cats. Methods A prospective, randomized, blinded and placebo‐controlled study was performed in cats which underwent ovariohysterectomy following preoperative tolfenamic acid, meloxicam, or placebo. A second dose of the same analgesic was administered 24 hours postoperatively. Assessments were made 1‐hour before induction and 1, 2, 4, 6, 22, and 25 hours postoperatively. Pain was assessed by a blinded observer using Numerical Rating (NRS) and VAS scales. The MWT were measured using a force‐measuring device. Group comparison was performed by using one‐way anova and chi‐squared test for qualitative and quantitative data, respectively, and a mixed model for repeated measurements (p < 0.05). Results Sixty‐five cats were included in the study. There were no differences between groups at baseline. There was a treatment effect on the NRS scores at 6, 22 and 25 hours. The meloxicam group was less painful than controls at 6 and 22 hours; both treatment groups were less painful than controls at 25 hours. There were no differences between groups in VAS for pain or sedation. The number of animals receiving rescue analgesia did not differ between groups. There was a treatment effect on MWT; thresholds in both treatment groups were significantly higher than that observed in controls at all time points. Conclusions Preoperative tolfenamic acid or meloxicam reduced wound sensitivity following ovariohysterectomy in the cat. Clinical relevance Tolfenamic acid and meloxicam administered preoperatively provided a similar analgesic effect in the postoperative period lasting 24 hours. Mechanical thresholds may be a better way of evaluating postoperative analgesia provided by nonsteroidal anti‐inflammatory drugs in cats.     

The effects of two non‐steroidal anti‐inflammatory drugs on the mobility of laying hens with keel bone fractures

ObjectiveInvestigate the effects of administration of meloxicam and carprofen on the mobility of hens with and without keel fractures.Study designWithin each of two experiments a ‘blinded’ randomised cross over design whereby birds received either the test drug (carprofen or meloxicam) or saline.AnimalsTwo groups of Lohman Brown hens with and without keel bone fractures.MethodsThe first group (n = 63) was treated with carprofen 25 mg kg⁻¹ and saline subcutaneously, twice. The second group (n = 40) was treated with meloxicam (5 mg kg⁻¹) and saline subcutaneously. The latency of birds to fly down from perches 50, 100 and 150 cm above the ground was measured after each treatment. Data from experiment 1 and 2 were analysed separately; the effects of drug treatment compared with saline on landing time for birds with and without keel bone fractures were evaluated using MLwiN.ResultsIn both experiments latency to fly down from perches was longer in hens with keel fractures and there was a significant interaction between perch height and fracture status. For carprofen, at the 50 cm, 100 cm and 150 cm perch heights, birds with fractures took (mean ± SD) 2.5 ± 2.9, 6.8 ± 9.7 and 11.5 ± 13.2 seconds respectively to fly down compared with 1.3 ± 0.5, 2.3 ± 1.2 and 4.2 ± 3.1 seconds for birds without fractures. For meloxicam, at the 50 cm, 100 cm and 150 cm perch heights, birds with fractures took 2.9 ± 2.5, 49.8 ± 85.4 and 100.3 ± 123.6 seconds respectively compared with 0.7 ± 0.5, 2.5 ± 7.1 and 3.0 ± 4.6 seconds to fly down for birds without fractures. There was no significant effect of carprofen or meloxicam treatment.Conclusion and clinical relevanceThese data provide further confirmation that keel fractures reduce the willingness of birds to move from perches.     

Wintertime pharmacokinetics of intravenously and orally administered meloxicam in semi-domesticated reindeer (Rangifer tarandus tarandus)

ObjectiveTo investigate the pharmacokinetics of orally and intravenously (IV) administered meloxicam in semi-domesticated reindeer (Rangifer tarandus tarandus).Study designA crossover design with an 11 day washout period.AnimalsA total of eight young male reindeer, aged 1.5–2.5 years and weighing 74.3 ± 6.3 kg, mean ± standard deviation.MethodsThe reindeer were administered meloxicam (0.5 mg kg^–1 IV or orally). Blood samples were repeatedly collected from the jugular vein for up to 72 hours post administration. Plasma samples were analysed for meloxicam concentrations with ultraperformance liquid chromatography combined with triple quadrupole mass spectrometry. Noncompartmental analysis for determination of pharmacokinetic variables was performed.ResultsThe pharmacokinetic values, median (range), were determined. Elimination half-life (t_½) with the IV route (n = 4) was 15.2 (13.2–16.8) hours, the volume of distribution at steady state was 133 (113–151) mL kg^?1 and clearance was 3.98 (2.63–5.29) mL hour^–1 kg^–1. After oral administration (n = 7), the peak plasma concentration (C_max) was detected at 6 hours, t_½ was 19.3 (16.7–20.5) hours, C_max 1.82 (1.17–2.78) μg mL^–1 and bioavailability (n = 3) 49 (46–73)%. No evident adverse effects were detected after either administration route.Conclusions and clinical relevanceA single dose of meloxicam (0.5 mg kg^–1 IV or orally) has the potential to maintain the therapeutic concentration determined in other species for up to 3 days in reindeer plasma.     

Effect of meloxicam administration after calving on milk production,acute phase proteins,and behavior in dairy cows

Calving is an intrinsically risky process that can cause welfare and economic problems. The objective of this study was to assess the effect of the nonsteroidal anti-inflammatory drug meloxicam on various physiological and behavioral measures which can be related to pain in cattle. Sixty Friesian dairy cows from first to sixth parity were studied around calving and were randomly allocated into 2 homogeneous groups relative to parity and treated with either meloxicam or a placebo after calving. Treatments were administered on average 3.4 hours after calving, within a maximum of 6 hours. Calf positions at calving and calving assistance (unassisted or easy manual pull) were recorded. Milk production, rectal temperature, and activity (calculated as the number of steps per hour) were measured on each cow. From a subsample of 20 cows, haptoglobin (Hp) and serum amyloid A (SAA) concentrations were also obtained. The following behaviors were observed on video recordings: posture, changing posture, location of cow in pen, feeding, and tail up behaviors 2 days before and after calving. Statistical analysis was carried out with the SAS software using MIXED or GENMOD procedures. Most variables showed a parity and/or time effect around calving. This study did not demonstrate any significant effect of meloxicam on milk production or on acute phase responses of Hp and SAA. However, postcalving activity was significantly increased in meloxicam-treated heifers.     

Evaluating a novel analgesic strategy for ring castration of ram lambs

Objective To evaluate the analgesic efficacy of the NSAIDs flunixin and meloxicam administered locally to the scrotum before ring castration. Study design Randomised, controlled, prospective study. Animals Forty eight single born male Merino lambs. Methods Lambs, aged approximately 4 weeks, were allocated to four groups for castration. Groups were: sham control; castration + saline; castration + flunixin; castration + meloxicam. Drugs (5 mL) were administered subcutaneously around the circumference of the scrotum immediately before castration. Cortisol, rectal temperature, haematology and plasma haptoglobin were measured before and up to 48 hours after treatment. Behaviour recorded by video for 12 hours after treatment was classified as pain avoidance behaviours in the first hour and postural behaviours in three 4 hour intervals. Results Ring castration (saline group) induced a bi‐phasic increase in cortisol with peaks at 90 minutes and 24 hours but no significant changes in haematology, haptoglobin or rectal temperature. Pain avoidance behaviours were increased and teat seeking decreased. Normal lying and normal standing postures were decreased and abnormal ventral lying, statue standing, abnormal standing and total abnormal postures increased. Flunixin decreased cortisol at 90 minutes (60.3 versus 117.3 nmol L^?1) and cortisol AUC (0–6 hours), decreased elevated leg movement (2.5 versus 5.4 events) and sum of pain avoidance behaviours (8.5 versus 16.7 events), improved time spent in normal ventral lying and decreased abnormal ventral lying and total abnormal postures compared to saline treated lambs. In a similar contrast, meloxicam caused non‐significant decreases in cortisol at 90 minutes, cortisol AUC (0–6 hours) and pain avoidance behaviours, and significantly improved the postural behaviours normal ventral lying (26.7 versus 15.4%) and normal standing (13.9 versus 7.5%), and reduced abnormal standing and total abnormal postures. Physiological and behavioural responses associated with ring castration for both NSAID treatment groups were generally greater than sham controls. Conclusions and clinical relevance Locally administered NSAIDs provided partial analgesia for ring castration.     

Comparison of milk and plasma pharmacokinetics of meloxicam in postpartum versus mid‐lactation Holstein cows

The objective of this study reported here was determine whether differences occurred in meloxicam pharmacokinetics between postpartum cows and mid‐lactation cows. Preliminary data from a separate study (P. J. Gorden, unpublished data) in postpartum cows demonstrated elevated plasma and milk concentration profiles compared to previously published data (Malreddy, Coetzee, KuKanich, & Gehring, 2013 ). Two different groups were enrolled, each with 10 cows. The treatment group (TRT) was postpartum cows treated with meloxicam, and the positive control (PC) group was cows in mid‐lactation treated with meloxicam. Plasma and milk meloxicam concentrations between the TRT and PC group were compared. Significant differences in meloxicam concentration in plasma were determined at all time points from 8 hr to 120 hr post‐treatment. In milk, there was a treatment (p = .003), time (p < .001), and treatment by time interaction (p < .001). Significant differences in milk meloxicam concentration were determined at all time points from 8 hr to 96 hr post‐treatment, except for the 16‐hr time point. The time needed for meloxicam to no longer be detected in milk of the TRT group was longer compared to the PC group, indicating that a longer milk withdrawal is needed. These data suggest higher bioavailability as the underlying mechanism. Further research is needed to determine the mechanisms underlying differences this outcome.     

Effects of tramadol alone,in combination with meloxicam or dipyrone,on postoperative pain and the analgesic requirement in dogs undergoing unilateral mastectomy with or without ovariohysterectomy

ObjectiveTo compare the effects of tramadol alone, or in combination with dipyrone or meloxicam, on postoperative pain and analgesia requirement after unilateral mastectomy with or without ovariohysterectomy in dogs.Study designProspective, randomized, clinical study.AnimalsTwenty seven bitches undergoing unilateral mastectomy with or without ovariohysterectomy.MethodsAnesthesia was induced with propofol and maintained with isoflurane and a constant rate infusion of morphine. Before the end of surgery, dogs were randomly assigned to receive intravenous tramadol alone (3 mg kg^?1, group T), combined with dipyrone (30 mg kg^?1, group TD) or meloxicam (0.2 mg kg^?1, group TM). Dogs received additional doses of tramadol (groups T and TM) or tramadol with dipyrone (group TD) at 8 and 16 hours after extubation. Postoperative pain was assessed by a blinded observer before anesthesia (baseline) and at 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours after extubation using a visual analog scale (VAS) and a modified Glasgow scale. Rescue analgesia (morphine, 0.5 mg kg^?1) was administered if the Glasgow pain score was >3.5.ResultsThere were no significant differences among groups in pain scores evaluated by the VAS or the Glasgow scale. In groups T, TD and TM, pain scores were significantly higher than at baseline for 6, 8 and 2 hours, respectively. Rescue analgesia was administered to 3/9, 2/9 and 1/9 dogs in groups T, TD and TM, respectively (p > 0.05) [Correction added on 15 August 2013, after first online publication: ‘T, TM and TD’ was changed to ‘T, TD and TM’.].Conclusions and clinical relevanceUnder the conditions of this study, tramadol alone or in combination with dypyrone or meloxicam provided effective analgesia for 24 hours in most dogs after unilateral mastectomy with or without ovariohysterectomy. Further evaluation of combination therapies is needed in larger groups of dogs.     

Pharmacokinetics and relative bioavailability of meloxicam oil suspension in pigs after intramuscular administration

This study aimed to develop one novel meloxicam (MEL) oil suspension for sustained-release and compare the pharmacokinetic characteristics of it with MEL conventional formulation in pigs after a single intramuscular administration. Six healthy pigs were used for the study by a crossover design in two periods with a withdrawal interval of 14 days. Plasma concentrations of MEL were measured by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Pharmacokinetic parameters were calculated by noncompartmental methods. The difference was statistically significant (p < .05) between MEL oil suspension and MEL conventional formulation in pharmacokinetic parameters of mean residence time (6.16 ± 4.04) hr versus (2.66 ± 0.55) hr, peak plasma concentration (C_max) (0.82 ± 0.12) µg/ml versus (1.12 ± 0.22) µg/ml, time needed to reach C_max (T_max) (2.33 ± 0.82) hr versus (0.59 ± 0.18) hr, and terminal elimination half-life (t_1/2λz) (3.74 ± 2.66) hr versus (1.55 ± 0.37) hr. The mean area under the concentration–time curve (AUC_0–∝) of MEL oil suspension and MEL conventional formulation was 5.35 and 3.43 hr µg/ml, respectively, with a relative bioavailability of 155.98%. Results of the present study demonstrated that the MEL oil suspension could prolong the effective time of drugs in blood, thereby reducing the frequency of administration on a course of treatment. Therefore, the novel MEL oil suspension seems to be of great value in veterinary clinical application.     

Dose-response relationship for the antipyretic effect of meloxicam in an endotoxin model in cats

The antipyretic efficacy of meloxicam was evaluated in a feline endotoxin model using a replicated change-over design. Twelve adult cats of both sexes were allocated at random to three experimental groups. At 30 min prior to the intravenous (i.v.) endotoxin challenge (0.5 µg/kg body weight(b.w.)), 2 animals in each group received an i.v. injection of 0.1, 0.3 or 0.5 mg meloxicam/kg b.w. and the two remaining animals in each group received physiological saline. In a second phase, 21 days later, the meloxicam/placebo treatment was exchanged within each group. The rectal temperature and scores for general demeanour were determined at 30-min intervals from before dosing to 300 min after the endotoxin challenge. Haematological parameters were analysed before and 60 min after administration of endotoxin. The results indicated a significant dose-dependent antipyretic response to meloxicam after endotoxin challenge. The antipyretic response in the medium- and high-dose meloxicam groups did not differ significantly, but both were significantly different from the low-dosage group. The individual effects of endotoxin on general demeanour were rather variable but meloxicam tended to have a beneficial effect. Endotoxin induced a reduction in the white blood cell count but this was not influenced by meloxicam. It was concluded that the pyretic endotoxin model is very suitable for studying new NSAIDs in cats and that the optimum single dose of meloxicam in this model was 0.3 mg/kg b.w.Abbreviations AUC area under the curve - b.w. body weight - i.v. intravenous - LPS lipopolysaccharide - MCV mean corpuscular volume - NSAID non-steroidal anti-inflammatory drug - WBC white blood cell count     

Behavioral and performance response associated with administration of intravenous flunixin meglumine or oral meloxicam immediately prior to surgical castration in bull calves

The objective of this study was to determine the effects of flunixin meglumine or meloxicam on behavioral response and performance characteristics associated with surgical castration in crossbred bulls. Intact male Bos taurus calves (n = 252; averaging 176 kg) were randomly allocated into one of three treatment groups within pen: control (CON), flunixin meglumine (FLU; 2.2 mg/kg intravenous injection), or meloxicam (MEL; 2.0 mg/kg per os). The individual animal was the experimental unit. Calves were individually weighed on days 0 and 14 of the trial to evaluate performance outcomes. On study day 0, treatments were administered, according to their random allocation, immediately prior to surgical castration using the Henderson tool method. Visual analog scale (VAS) assessment and categorical attitude score (CAS) were collected on days −1, 0 (6 h post-castration), 1, 2, 3, and 4 in the study. The VAS was assigned using a 100 mm horizontal line with “normal” labeled at one end of the line and “moribund” at the other end of the horizontal line. The masked observer assigned a mark on the horizontal line based upon the observed severity of pain exhibited by that individual animal. The CAS was assigned by the same observer using five different categories with a score of 0 being “normal”. Average daily gain tended (P = 0.09) to be associated with the treatment group, and MEL had a greater (P = 0.04) average daily gain through day 14 compared with CON. A significant (P < 0.01) treatment by day interaction was indicated for VAS score, and MEL had lower VAS scores on days 0, 1, 2, and 3 post-castration compared with CON; FLU had lower VAS scores on days 0 and 1 compared with CON. A significant treatment by day interaction was not present (P = 0.25) for CAS. The FLU had lesser percent CAS ≥1 (17.5%; P = 0.05) compared with CON (29.4%); MEL has lesser percent CAS ≥1 observations (14.9%; P = 0.01) compared with CON. The median VAS increased as CAS was more severe. Results indicated MEL and FLU calves temporally improved behavioral responses following surgical castration with positive numerical trends for a 14 d average daily gain (ADG). The VAS system appeared to be an effective method of subjective evaluation of pain in beef calves in this study. Route of administration, duration of therapy, and low relative cost make oral meloxicam a reasonable analgesic treatment in calves when administered at the time of surgical castration.