Effect of meloxicam or robenacoxib administration timing on renal function and postoperative analgesia in cats undergoing ovariohysterectomy: A randomized, blinded, controlled clinical trial.

We evaluated the effect of administration timing of meloxicam and robenacoxib on renal function, platelet cyclo-oxygenase and perioperative analgesia in 60 cats undergoing ovariohysterectomy, in a prospective randomized blinded controlled study. Twelve cats were randomly allocated to one subcutaneous treatment group: meloxicam (0.2 mg/kg) or robenacoxib (2 mg/kg) at admission (MA, RA), at induction (MI, RI) and robenacoxib at the end of surgery (RE). All cats received the same anaesthesia protocol. Plasma renin activity (PRA), plasma creatinine, drug concentrations and serum thromboxane (TxB2) were measured sequentially. Anaesthesia significantly increased PRA, as activity at end of the surgery was higher than 2 h later (mean ± SD: 26.6 ± 2.8 versus 10.0 ± 3.9 ng/mL/h). PRA remained higher at 2 h post-surgery in admission groups compared to induction groups (p = .01). Serum TxB2 was lower with meloxicam than robenacoxib (p = .001), and was lower in the MA than each robenacoxib group at catheter placement. Admission groups (16/24 from RA and MA groups) received earlier rescue analgesia than other groups (p = .033). In conclusion, the renin-angiotensin system was activated during anaesthesia despite cyclo-oxygenase inhibition, possibly due to hypotension or surgical stimulation. There was no effect of drug or timing on the markers of renal function but one cat receiving meloxicam at induction had suspected IRIS grade II acute kidney injury.

Pharmacology, safety, efficacy and clinical uses of the COX-2 inhibitor robenacoxib.

Robenacoxib is a veterinary-approved non-steroidal anti-inflammatory drug (NSAID) of the coxib group. It possesses anti-hyperalgesic, anti-inflammatory and anti-pyretic properties. Robenacoxib inhibits the cyclooxygenase (COX)-2 isoform of COX selectively (in vitro IC50 ratios COX-1:COX-2, 129:1 in dogs, 32:1 in cats). At registered dosages (2 mg/kg subcutaneously in dogs and cats, 1-4 mg/kg orally in dogs and 1-2.4 mg/kg orally in cats), robenacoxib produces significant inhibition of COX-2 whilst sparing COX-1. The pharmacokinetic (PK) profile of robenacoxib is characterized by a high degree of binding to plasma proteins (>98%) and moderate volume of distribution (at steady state, 240 ml/kg in dogs and 190 ml/kg in cats). In consequence, the terminal half-life in blood (<2 h) is short, despite moderate body clearance (0.81 L/kg/h) in dogs and low clearance (0.44 L/kg/h) in cats. Excretion is principally in the bile (65% in dogs and 72% in cats). Robenacoxib concentrates in inflamed tissues, and clinical efficacy is achieved with once-daily dosing, despite the short blood terminal half-life. In dogs, no relevant breed differences in robenacoxib PK have been detected. Robenacoxib has a wide safety margin; in healthy laboratory animals daily oral doses 20-fold (dog, 1 month), eight-fold (cat, 6 weeks) and five-fold (dog, 6 months) higher than recommended clinical doses were well tolerated. Clinical efficacy and safety have been demonstrated in orthopaedic and soft tissue surgery, and in musculoskeletal disorders in dogs and cats.

Evaluation of a fixed-dose combination of benazepril and pimobendan in dogs with congestive heart failure: a randomized non-inferiority clinical trial.

A fixed-dose combination tablet of benazepril and pimobendan (Fortekor Plus; Elanco Animal Health) was tested in dogs with congestive heart failure (CHF) caused by myxomatous mitral valve disease (MMVD) in a three-arm, masked, randomized, non-inferiority clinical trial in Japan. The test group (n = 34) received Fortekor Plus twice daily. Two control groups received registered formulations of benazepril (Fortekor; Elanco Animal Health) and pimobendan (Vetmedin; Boehringer Ingelheim Vetmedica) with administration of Vetmedin twice daily and Fortekor twice (Control I, n = 14) or once (Control II, n = 19) daily. Diuretics were used in 22 dogs (32.8%). Global clinical scores decreased significantly from baseline in all groups; there were no significant differences between groups, and non-inferiority of Fortekor Plus compared to Control I, Control II, and combined Control I + II groups was demonstrated. There were no significant differences between groups for relevant clinical chemistry and hematology variables or frequency of all adverse events. Frequency of emesis was significantly (p = 0.0042) lower in the Fortekor Plus (8.8%) group than in the Control I + II (39.4%) group. In conclusion, Fortekor Plus had non-inferior efficacy and was associated with significantly less emesis compared to Fortekor and Vetmedin in dogs with CHF caused by MMVD.

Efficacy and safety of oral robenacoxib (tablet) for the treatment of pain associated with soft tissue surgery in client-owned dogs.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) have been proven to be effective in controlling peri-operative pain in dogs. Robenacoxib is an NSAID with high selectivity for the cyclooxygenase (COX)-2 isoform. The objective of this study was to assess the efficacy and safety of an oral tablet formulation of robenacoxib in client-owned dogs undergoing soft tissue surgery. The study was a prospective, multi-center, randomized, masked, placebo-controlled, parallel-group clinical trial. A total of 239 dogs were included and randomly allocated in a 1:1 ratio to receive either robenacoxib or placebo. Each dog received an oral tablet administration of either robenacoxib, at a target dose of 2 mg/kg, or placebo once prior to surgery and for two additional days post-operatively. All dogs also received a pre-anesthetic dose of 0.2 mg/kg butorphanol (intravenous or intramuscular). Pain assessments were performed using the short form of the Glasgow Composite Measure Pain Scale. Robenacoxib was compared to the placebo group on a success/failure basis. Treatment failure was defined as the need for rescue therapy to control post-operative pain. RESULTS: Significantly (P = 0.019) more dogs administered robenacoxib were considered treatment successes (89 of 116, 76.72%) compared to dogs given placebo (74 of 115, 64.35%). The percentage of treatment failure was therefore 23.28% in the robenacoxib and 35.65% in the placebo group. The least squares mean total pain scores were significantly different between groups and in favor of robenacoxib at 3 and 5 hours (P < 0.05) and 8 hours post-extubation (P < 0.01). Pain at the surgery sites (response to touch) was also significantly improved at 3, 5 and 8 hours post-extubation in dogs receiving robenacoxib versus placebo (P < 0.01). In addition, a significant overall improvement in posture/activity was revealed with robenacoxib having lower scores versus placebo (P < 0.01). No significant differences between the robenacoxib and placebo groups in the frequency of reported adverse events were observed. CONCLUSIONS: Robenacoxib by oral (tablet) administration was effective and well tolerated in the control of peri-operative pain and inflammation associated with soft tissue surgery in dogs.

Evaluation of injectable robenacoxib for the treatment of post-operative pain in cats: results of a randomized, masked, placebo-controlled clinical trial.

BACKGROUND: Few pharmaceuticals are registered in cats for the management of post-operative pain and inflammation. The objective of this study was to assess the field efficacy and safety of an injectable formulation of the nonsteroidal anti-inflammatory drug robenacoxib in cats undergoing surgery. The study was a multi-center, prospective, randomized, masked, parallel-group, placebo-controlled clinical trial. A total of 349 cats were enrolled and underwent surgery comprising forelimb onychectomy, as an example of orthopedic surgery, plus either ovariohysterectomy or castration. All cats received butorphanol prior to anesthesia and forelimb four-point regional nerve blocks with bupivacaine after induction of general anesthesia. Cats were randomized to receive daily subcutaneous (s.c.) injection of robenacoxib, at a target dosage of 2.0 mg/kg (n = 174), or placebo (n = 175) once prior to surgery and for an additional two days post-operatively. RESULTS: Significantly (P = 0.037) fewer cats administered robenacoxib received additional analgesia rescue therapy (34 of 173, 19.7 %) compared to cats given placebo (73 of 175, 41.7 %). The percentage of treatment success was therefore 80.3 % with robenacoxib and 58.3 % with placebo. Behavior, posture, pain on palpation of the paw and soft tissue surgery sites, and overall pain were significantly (P < 0.05) improved versus placebo at various time points within the first 8 h in cats receiving robenacoxib. The most frequently reported adverse events were incision site infection/dehiscence, bleeding, vomiting, decreased appetite and lethargy. Frequencies of reported adverse clinical signs, hematology, serum chemistry and urinalysis variables, and body weight changes were similar between groups. There were no significant changes from baseline with robenacoxib in hepatic, hematological or renal clinical pathology variables. CONCLUSIONS: Robenacoxib by s.c. injection was effective and well tolerated in the control of post-operative pain associated with orthopedic, ovariohysterectomy and castration surgery in cats.

Clinical safety of robenacoxib in feline osteoarthritis: results of a randomized, blinded, placebo-controlled clinical trial.

OBJECTIVES: The objective of this study was to evaluate the clinical safety of the non-steroidal anti-inflammatory drug (NSAID) robenacoxib in cats with osteoarthritis. Degenerative joint disease, including osteoarthritis, is highly prevalent in cats and many cases have associated pain and impaired mobility. Although NSAIDs are used routinely to control pain and inflammation in cats with osteoarthritis, there are safety concerns because of the high concurrent prevalence of chronic kidney disease (CKD) and the paucity of data on the safety of these drugs in target clinical populations. METHODS: A total of 194 cats with osteoarthritis were recruited and randomly allocated to receive either robenacoxib at a dosage of 1.0-2.4 mg/kg (n = 95) or placebo (n = 99) tablets PO q24h for 28 days. Safety was assessed in 193 cats, including a subgroup of 40 animals with concurrent CKD, defined as serum creatinine concentration ⩾1.6 mg/dl and urine specific gravity <1.030. Safety endpoints included reports of adverse events, results of clinical examinations, including body weight, and clinical chemistry and hematology variables. RESULTS: In all 193 cats and the subgroup of 40 animals with concurrent CKD, there were no differences between groups in frequencies of reported adverse events, body weight change or results of serum or urine chemistry or hematology variables. CONCLUSIONS AND RELEVANCE: Robenacoxib was well tolerated when administered daily for 1 month in cats with osteoarthritis, including cats with evidence of concurrent CKD. There was no clinical indication of damage to the gastrointestinal tract, kidney or liver.

Robenacoxib versus meloxicam for the control of peri-operative pain and inflammation associated with orthopaedic surgery in cats: a randomised clinical trial.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in veterinary medicine. Robenacoxib is a NSAID with high selectivity for the cyclo-oxygenase-2 enzyme. In this study, the efficacy and safety of robenacoxib were evaluated in a prospective, randomised, active- and placebo-controlled masked clinical trial in 147 cats undergoing orthopaedic surgery. Cats were randomised into two treatment groups: Group 1, robenacoxib (2 mg/kg) administered via subcutaneous (s.c.) injection before surgery, followed by robenacoxib tablets (1-2.4 mg/kg) administered post-operatively for approximately 9 days (n = 101) and Group 2, meloxicam (0.3 mg/kg) administered s.c. before surgery, followed by placebo tablets administered post-operatively for approximately 9 days (n = 46). Cats were assessed using numerical rating scales (NRSs) by clinicians before surgery and at 3, 8, 22 and 28 hours after surgery and at the final visit (VF on approximately Day 10), and daily by their owners from Day 1 to the VF. RESULTS: The primary end point was the global investigator score which was the sum of clinician NRSs for posture, behaviour and pain on palpation/manipulation. The efficacy of the single robenacoxib injection, assessed during 3 to 22 hours, was statistically non-inferior to meloxicam, with a relative efficacy of 1.029 (95% confidence interval, 0.847-1.231). No significant differences were detected during the follow-up treatment with robenacoxib tablets for approximately 9 days compared with placebo via clinician assessments at 28 hours and the VF, or in owner assessments on Days 1-VF. There were no significant differences in frequencies of reported adverse events, clinical observations and haematology or clinical chemistry variables between the groups. CONCLUSIONS: Single s.c. injection of robenacoxib before surgery had non-inferior efficacy compared with meloxicam in controlling post-operative pain and inflammation in cats undergoing orthopaedic surgery. Follow-up treatment with oral robenacoxib tablets for approximately 9 days was well tolerated, but there were no differences in the efficacy scores after Day 1 compared with the group receiving meloxicam s.c. followed by placebo control.

Comparison of high-definition oscillometry -- a non-invasive technology for arterial blood pressure measurement -- with a direct invasive method using radio-telemetry in awake healthy cats.

This study compared indirect blood pressure measurements using a non-invasive method, high-definition oscillometry (HDO), with direct measurements using a radio-telemetry device in awake cats. Paired measurements partitioned to five sub-ranges were collected in six cats using both methods. The results were analysed for assessment of correlation and agreement between the two methods, taking into account all pressure ranges, and with data separated in three sub-groups, low, normal and high ranges of systolic (SBP) and diastolic (DBP) blood pressure. SBP data displayed a mean correlation coefficient of 0.92 ± 0.02 that was reduced for low SBP. The agreement level evaluated from the whole data set was high and slightly reduced for low SBP values. The mean correlation coefficient of DBP was lower than for SBP (ie, 0.81 ± 0.02). The bias for DBP between the two methods was 22.3 ± 1.6 mmHg, suggesting that HDO produced lower values than telemetry. These results suggest that HDO met the validation criteria defined by the American College of Veterinary Internal Medicine consensus panel and provided a faithful measurement of SBP in conscious cats. For DBP, results suggest that HDO tended to underestimate DBP. This finding is clearly inconsistent with the good agreement reported in dogs, but is similar to outcomes achieved in marmosets and cynomolgus monkeys, suggesting that this is not related to HDO but is species related. The data support that the HDO is the first and only validated non-invasive blood pressure device and, as such, it is the only non-invasive reference technique that should be used in future validation studies.

Robenacoxib versus meloxicam for the management of pain and inflammation associated with soft tissue surgery in dogs: a randomized, non-inferiority clinical trial.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are used routinely to control pain and inflammation after surgery in dogs. Robenacoxib is a new NSAID with high selectivity for the cyclo-oxygenase (COX)-2 isoform of COX. The objective of this study was to evaluate the efficacy and tolerability of robenacoxib for the management of peri-operative pain and inflammation associated with soft tissue surgery in dogs. The study was a prospective, randomized, blinded, positive-controlled, non-inferiority, multi-center clinical trial. A total of 174 dogs undergoing major soft tissue surgery were included and randomly allocated in a 2:1 ratio to receive either robenacoxib (n = 118) or the positive control, meloxicam (n = 56). Each dog received an initial dose subcutaneously prior to surgery (robenacoxib 2 mg/kg, meloxicam 0.2 mg/kg), followed by daily oral doses (robenacoxib 1-2 mg/kg, meloxicam 0.1 mg/kg) for 12 days (range 10-14) after surgery. Pain and inflammation were assessed subjectively using the Glasgow Composite Pain Scale (GCPS) by clinicians as the primary end point and additional evaluations by the clinicians and animal owners as secondary endpoints. RESULTS: Both treatments provided similar pain control, with no significant differences between groups for any efficacy variable using non-parametric analyses (Mann-Whitney U test). In no dog was analgesic rescue therapy administered. Non-inferior efficacy of robenacoxib compared to meloxicam was demonstrated statistically for the primary and all secondary endpoints using parametric analysis of variance, although the data were not normally distributed even after log transformation. For the primary endpoint (reciprocal of the modified GCPS score), the relative efficacy of robenacoxib/meloxicam was 1.12 with a 95% confidence interval of 0.97-1.29. CONCLUSION: A treatment regimen of robenacoxib by subcutaneous injection followed by oral tablets had good tolerability and non-inferior efficacy compared to meloxicam for the management of peri-operative pain and inflammation associated with soft tissue surgery in dogs.

Comparison of injectable robenacoxib versus meloxicam for peri-operative use in cats: results of a randomised clinical trial.

The objective of this study was to evaluate the efficacy and tolerability of robenacoxib, a selective cyclooxygenase-2 inhibitor, for the treatment of post-operative pain and inflammation in cats. The study was a prospective, multi-centre, randomised, blinded, non-inferiority design clinical study to compare robenacoxib to meloxicam. Ninety-six cats undergoing surgery at eight centres in Japan were allocated randomly to receive a single s.c. injection of robenacoxib (2 mg/kg, n=67) or meloxicam (0.3 mg/kg, n=29) shortly before induction of anaesthesia. Most cats underwent soft tissue surgery (n=87), mainly ovariectomy (n=68). Post-operative pain and inflammation were assessed at 3, 8 and 22 h after recovery from anaesthesia using numerical rating scales. For the primary efficacy endpoint (total clinician score), robenacoxib had significantly better efficacy than meloxicam, the relative efficacy ratio being 1.47 (95% confidence interval 1.19-1.78, P=0.0003). For the secondary efficacy endpoints, robenacoxib was superior to meloxicam when assessed on the basis of posture, behaviour, pain on palpation and overall pain control, while meloxicam was superior with respect to wound heat. No cat in either group required rescue analgesia therapy. In tolerability assessments, pain during injection and pain and inflammation at the injection site 22 h after recovery from anaesthesia were rated significantly less with robenacoxib compared to meloxicam. Both treatments were well tolerated on the basis of clinical observations and blood tests, with no significant differences between groups. In conclusion, single pre-operative administration of robenacoxib was well tolerated and had superior efficacy to meloxicam in reducing post-operative pain in cats.

Evaluation of oral robenacoxib for the treatment of postoperative pain and inflammation in cats: results of a randomized clinical trial.

The efficacy and safety of robenacoxib were assessed for the control of postoperative pain and inflammation in cats. The study was a multicenter, prospective, randomized, blinded, and parallel group clinical trial. A total of 249 client-owned cats scheduled for forelimb onychectomy plus either ovariohysterectomy or castration surgeries were included. All cats received butorphanol prior to anesthesia and forelimb four-point regional nerve blocks with bupivacaine after induction of general anesthesia. Cats were randomized to receive daily oral tablet robenacoxib, at a mean (range) dosage of 1.84 (1.03-2.40) mg/kg (n = 167), or placebo (n = 82), once prior to surgery and for two days postoperatively. Significantly (P < 0.05) fewer robenacoxib cats received additional analgesia rescue therapy (16.5%) than placebo cats (46.3%). Pain elicited on palpation of the soft tissue incision site, behavior following social interaction, and posture assessed during the first 8 hours after extubation were significantly (P < 0.05) improved in cats receiving robenacoxib. Frequency of reported adverse clinical signs, hematology, serum chemistry and urinalysis variables, and body weight changes weresimilar between groups. In conclusion, robenacoxib was effective and well tolerated in the control of postoperative pain and inflammation in cats undergoing onychectomy with ovariohysterectomy or castration.

Evaluation of subcutaneous and oral administration of robenacoxib and meloxicam for the treatment of acute pain and inflammation associated with orthopedic surgery in dogs.

OBJECTIVE: To assess efficacy and tolerability of robenacoxib for control of pain and inflammation in dogs undergoing orthopedic surgery. ANIMALS: 140 client-owned dogs. PROCEDURES: A multicenter, prospective, randomized, blinded field trial was conducted to compare robenacoxib (97 dogs) and meloxicam (43 dogs). After randomization, each dog received an initial dose (robenacoxib, 2 mg/kg; meloxicam, 0.2 mg/kg) via SC injection before surgery and daily doses (robenacoxib, 1 to 2 mg/kg; meloxicam, 0.1 mg/kg) administered orally for up to 15 days after surgery. Efficacy was assessed by veterinarians and owners via numeric rating scales and visual analogue scales. Safety was assessed on the basis of reported adverse events, clinical signs, results of hematologic and biochemical analyses, and buccal mucosa bleeding times. RESULTS: Treatment groups were balanced with respect to baseline and demographic data. Both treatments provided similar adequate pain control, as assessed with a modified Glasgow pain scale as the primary end point and supported by secondary end points in evaluations conducted by veterinarians and owners. For the primary end point, the ratio of the reciprocal of the scores for robenacoxib to meloxicam was 1.16 (95% confidence interval, 0.98 to 1.37). No dogs required rescue analgesia. Both treatments were associated with only minor adverse events, which were not necessarily related to the administered treatments and did not affect mucosal bleeding times. CONCLUSIONS AND CLINICAL RELEVANCE: Robenacoxib provided efficacy and tolerability similar to those of meloxicam for the management of perioperative pain and inflammation in dogs undergoing orthopedic surgery.