Paulo V. M. Steagall

Guidelines for recognition, assessment and treatment of pain: WSAVA Global Pain Council members and co-authors of this document:.

Karol Mathews DVM DVSc DACVECC (Canada) Peter W Kronen Dr Vet Med, DVM DECVAA (Switzerland) Duncan Lascelles BSc BVSc PhD DSAS DECVS DACVS MRCVS (USA) Andrea Nolan MVB DVA PhD DECVAA DECVPT MRCVS (UK) Sheilah Robertson BVMS (Hons) PhD DACVAA DECVAA DECAWBM (WSEL) DACAW MRCVS (USA) Paulo VM Steagall MV MS PhD DACVAA (Brazil/Canada) Bonnie Wright DVM DACVAA (USA) Kazuto Yamashita DVM MS PhD DJCVS (Japan)

Antinociceptive effects of tramadol and acepromazine in cats

Effects of tramadol and acepromazine on pressure and thermal thresholds were examined in eight cats. After baseline measurements, subcutaneous (SC) tramadol 1 mg/kg, acepromazine 0.1 mg/kg, tramadol 1 mg/kg with acepromazine 0.1 mg/kg, or saline 0.3 ml were given. Serial measurements were made for 24 h. Mean thermal thresholds did not change significantly [analysis of variance (ANOVA)] from baseline. The maximum thermal threshold increase above baseline was 2.8±2.8°C at 6 h (P>0.05) after tramadol; it was above the 95% confidence interval (CI) at 0.75, 3 and 6 h. Pressure thresholds increased above baseline from 0.25 to 2 h after acepromazine (P<0.05) and from 0.5 to 3 h after the combination (P<0.05), with a maximum increase of 132±156 mmHg 0.25 h after acepromazine and 197±129 mmHg 0.5 h after the combination. Pressure thresholds were above the 95% CI from 0.25 to 2 h after acepromazine and from 0.5 to 3 h after the combination. SC tramadol at 1 mg/kg in cats had limited effect on thermal and pressure nociception, but this was enhanced by acepromazine. Acepromazine alone had pressure antinociceptive effects.

Systematic Review of Nonsteroidal Anti-Inflammatory Drug-Induced Adverse Effects in Dogs

The aim of this systematic review was to identify, assess, and critically evaluate the quality of evidence of nonsteroidal anti-inflammatory drug (NSAID)-induced adverse effects in dogs. Original prospective studies published in peer-reviewed journals in English (1990-2012) that reported data on the safety of NSAIDs administration in dogs were searched. For each study, design type (I, II, III, or IV) and assessment of quality (+, Ø, -) were rated. For each drug, quantity and consistency rating (***, **, *) and strength of evidence (high, moderate, low, or extremely low) were identified and evaluated. The strength of evidence was defined in terms of how applicable and relevant the conclusions were to the target population. Sixty-four studies met the inclusion criteria. Thirty-five (55%) research studies and 29 (45%) clinical trials were identified. A high strength of evidence existed for carprofen, firocoxib, and meloxicam; moderate for deracoxib, ketoprofen, and robenacoxib; and low for etodolac. Quality and consistency rating were as follows: carprofen (***/***), deracoxib (**/***), etodolac (*/unable to rate), firocoxib (***/**), ketoprofen (**/***), meloxicam (***/***), and robenacoxib (**/**), respectively. Adverse effects were detected in 35 studies (55%) and commonly included vomiting, diarrhea, and anorexia. Three studies (5%) reported a power analysis related to adverse effects of ≥80%. In randomized, placebo-controlled, blinded studies (n = 25, 39%), the incidence of adverse effects was not statistically different between treated and control dogs. Finally, most studies were not appropriately designed to determine the safety of NSAIDs, and involved a healthy nongeriatric population of research dogs.

Postoperative analgesic effects of intravenous, intramuscular, subcutaneous or oral transmucosal buprenorphine administered to cats undergoing ovariohysterectomy

OBJECTIVE To compare the postoperative analgesic effects of intravenous (IV), intramuscular (IM), subcutaneous (SC) or oral transmucosal (OTM) buprenorphine administered to cats undergoing ovariohysterectomy. STUDY DESIGN Randomized, prospective and blinded clinical trial. ANIMALS 100 female cats. METHODS Cats were assigned to receive 0.01 mg kg(-1) of buprenorphine administered by the IV, IM, SC or OTM route (n = 25/group). Buprenorphine was made up to 0.3 mL with 0.9% saline. DIVAS (0-100 mm) and simple descriptive scale (SDS) (from 0 to 4) pain and sedation scores were assigned to each cat before and 1, 2, 3, 4, 6, 8, 12 and 24 hours after ovariohysterectomy. Buprenorphine and carprofen were administered for rescue analgesia. Data were analyzed using anova and Fishers exact test (p < 0.05). RESULTS There were no significant differences between groups for breed, body weight, anesthetic time or surgery time (p > 0.05). There were no significant differences between groups for sedation scores at any time. SDS pain scores did not detect any differences between groups (p > 0.05). DIVAS pain scores after OTM administration were significantly higher than IV and IM administration at 1 hour and at 3, 4, 6, 8 and 12 hours, respectively (p < 0.05). DIVAS pain scores after SC administration were significantly higher than IV and IM administration at 2 hours and at 2, 3, 4, 8, 12 and 24 hours (p < 0.05), respectively. Six, four, 13 and 17 cats that received IV, IM, SC and OTM buprenorphine required rescue analgesia, respectively. There was a significantly higher incidence of treatment failure in cats that received SC and OTM buprenorphine compared with cats that received IV and IM buprenorphine (p < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE IV and IM administration of buprenorphine provided better postoperative analgesia than SC or OTM administration of the drug and these routes of administration should be preferred when buprenorphine is administered to cats.

Analgesia for cats after ovariohysterectomy with either buprenorphine or carprofen alone or in combination

Eighty-four female cats undergoing ovariohysterectomy in a blinded, randomised, prospective clinical study were assigned to one of three groups of 28 to receive either 0.01 mg/kg buprenorphine (group B), 4 mg/ kg carprofen (group C), or the same doses of both drugs (group BC). A dynamic and interactive visual analogue scale (DIVAS) from 0 to 100 mm, and a simple descriptive scale (SDS) from 0 to 4 were used to evaluate the cats’ degree of analgesia and sedation for 24 hours postoperatively. There was no significant difference in the cats’ sedation scores by SDS or DIVAS, and no difference in their pain scores by DIVAS. By SDS, the cats in group BC had significantly lower pain scores than the cats in group C (P<0.001) and group B (P<0.05). Nine of the cats in group B, nine in group C and five in group BC required rescue analgesia, and the cats in group C required rescue earlier than those in group B (P<0.05).

Pharmacokinetic and pharmacodynamic modelling of intravenous, intramuscular and subcutaneous buprenorphine in conscious cats

OBJECTIVE To describe simultaneous pharmacokinetics (PK) and thermal antinociception after intravenous (i.v.), intramuscular (i.m.) and subcutaneous (SC) buprenorphine in cats. STUDY DESIGN Randomized, prospective, blinded, three period crossover experiment. ANIMALS Six healthy adult cats weighing 4.1±0.5 kg. METHODS Buprenorphine (0.02 mg kg(-1)) was administered i.v., i.m. or s.c.. Thermal threshold (TT) testing and blood collection were conducted simultaneously at baseline and at predetermined time points up to 24 hours after administration. Buprenorphine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. TT was analyzed using anova (p<0.05). A pharmacokinetic-pharmacodynamic (PK-PD) model of the i.v. data was described using a model combining biophase equilibration and receptor association-dissociation kinetics. RESULTS TT increased above baseline from 15 to 480 minutes and at 30 and 60 minutes after i.v. and i.m. administration, respectively (p<0.05). Maximum increase in TT (mean±SD) was 9.3±4.9°C at 60 minutes (i.v.), 4.6±2.8°C at 45 minutes (i.m.) and 1.9±1.9°C at 60 minutes (s.c.). TT was significantly higher at 15, 60, 120 and 180 minutes, and at 15, 30, 45, 60 and 120 minutes after i.v. administration compared to i.m. and s.c., respectively. I.v. and i.m. buprenorphine concentration-time data decreased curvilinearly. S.c. PK could not be modeled due to erratic absorption and disposition. I.v. buprenorphine disposition was similar to published data. The PK-PD model showed an onset delay mainly attributable to slow biophase equilibration (t(1/2) k(e0)=47.4 minutes) and receptor binding (k(on)=0.011 mL ng(-1) minute(-1)). Persistence of thermal antinociception was due to slow receptor dissociation (t(1/2) k(off)=18.2 minutes). CONCLUSIONS AND CLINICAL RELEVANCE I.v. and i.m. data followed classical disposition and elimination in most cats. Plasma concentrations after i.v. administration were associated with antinociceptive effect in a PK-PD model including negative hysteresis. At the doses administered, the i.v. route should be preferred over the i.m. and s.c. routes when buprenorphine is administered to cats.

Evaluation of the adverse effects of oral firocoxib in healthy dogs

This study evaluated the adverse effects of oral firocoxib in dogs. Six dogs (20.2 ± 6.3 kg) were studied. Values for complete blood count (CBC), serum urea, creatinine, alanine transaminase, alanine phosphatase, γ‐glutamyl transferase, occult blood in feces, platelet aggregation, and buccal mucosal bleeding time were measured before and 7, 14, 21, and 29 days after SID treatment with firocoxib 5.3 ± 0.34 mg/kg (FG) or lactose 1 mg/kg (LG) for 28 days, in a randomized crossover study. Gastrointestinal (GI) tract endoscopy was performed before treatment began and at 29 days. Lesions were scored from grade 0 to 6. Data were analyzed using anova and paired t‐tests (P < 0.05). None of the dogs presented adverse clinical effects. There were no significant changes in CBC, biochemical profiles within groups, or differences between groups. Pretreatment mean ± SD bleeding time (LG, 70.7 ± 32.1 sec; FG, 75.8 ± 38.1 sec) and platelet aggregation (LG, 86.4 ± 10.2%; FG, 85.6 ± 9.2%) were not significantly different from readings at 29 days (LG, 95.2 ± 25 sec; FG, 91.7 ± 24 sec and LG, 73.2 ± 15.1%; FG, 84 ± 10.3%) nor the groups were different. None of the dogs had positive fecal occult blood tests, and endoscopic lesion scores were grade 0 both before treatment and at 29 days. Administration of firocoxib did not cause any adverse effects on GI, or hematological or serum biochemical variables and appears to have been well tolerated by dogs.

Dose-related antinociceptive effects of intravenous buprenorphine in cats.

The dose-related antinociceptive effects of intravenous (IV) buprenorphine were evaluated in cats. Thermal (TT) and mechanical threshold (MT) devices were used for nociceptive stimulation. After baseline threshold recordings, buprenorphine was administered IV (0.01, 0.02 or 0.04 mg/kg; B1, B2 and B4, respectively) in a randomised, blinded and cross-over study. Data were analysed by ANOVA (P<0.05) using 95% confidence intervals (CI). TT increased 15, 30, 45 min and 1 (5.2+/-2.7 degrees C), 2, 3 and 4 h after B1; 15, 30, 45 min and 1 (5.1+/-3.9 degrees C) and 2 h after B2, and 15, 30, 45 min and 1 (5.4+/-3.3 degrees C), 2, 3, 6 and 8 h after B4. MT increased 15 and 45 min after B2 (260+/-171 mmHg), and 30 (209+/-116 mmHg) and 45 min and 1 and 2 h after B4. At 45 min, MT values were significantly higher after B2 compared to B1 (P<0.05). With MT, B2 and B4 produced more antinociception and longer duration of action than B1, respectively. No dose response to thermal stimulation was detected.

A Review of the Studies Using Buprenorphine in Cats

Pain management is a crucial component of feline medicine and surgery. This review critically evaluates studies using buprenorphine in cats and highlights the clinical application of the opioid in this species. The pharmacokinetic‐pharmacodynamic (PK‐PD) modeling of IV buprenorphine has been best described by a combined effect compartmental/receptor association‐dissociation model with negative hysteresis. Therefore, plasma concentrations of the drug are not correlated with analgesia, and clinicians should not expect to observe pain relief immediately after drug administration. In addition, a ceiling effect has not been demonstrated after administration of clinical doses of buprenorphine in cats; dosages of up to 0.04 mg/kg have been reported. The route of administration influences the onset, duration, and magnitude of antinociception and analgesia when using this drug in cats. At clinical dosages, the SC route of administration does not appear to provide adequate antinociception and analgesia whereas the buccal route has produced inconsistent results. Intravenous or IM administration at a dosage of 0.02–0.04 mg/kg is the preferred for treatment of pain in the acute setting. A literature search found 14 clinical trials evaluating buprenorphine sedation, analgesia, or both in cats. There were 22 original research studies reporting the antinociceptive effects of buprenorphine by means of thermal threshold, mechanical threshold, or both, minimal alveolar concentration, or PK‐PD. Individual variability in response to buprenorphine administration has been reported, indicating that buprenorphine may not provide sufficient analgesia in some cats. Pain assessment is important when evaluating the efficacy of buprenorphine and determining whether additional analgesic treatment is needed.

Effect of remifentanil hydrochloride administered via constant rate infusion on the minimum alveolar concentration of isoflurane in cats

OBJECTIVE To evaluate the effects of increasing doses of remifentanil hydrochloride administered via constant rate infusion (CRI) on the minimum alveolar concentration (MAC) of isoflurane in cats. ANIMALS 6 healthy adult cats. PROCEDURES For each cat, 2 experiments were performed (2-week interval). On each study day, anesthesia was induced and maintained with isoflurane; a catheter was placed in a cephalic vein for the administration of lactated Ringers solution or remifentanil CRIs, and a catheter was placed in the jugular vein for collection of blood samples for blood gas analyses. On the first study day, individual basal MAC (MAC(Basal)) was determined for each cat. On the second study day, 3 remifentanil CRIs (0.25, 0.5, and 1.0 microg/kg/min) were administered (in ascending order); for each infusion, at least 30 minutes elapsed before determination of MAC (designated as MAC(R0.25), MAC(R0.5), and MAC(R1.0), respectively). A 15-minute washout period was allowed between CRIs. A control MAC (MAC(Control)) was determined after the last remifentanil infusion. RESULTS Mean +/- SD MAC(Basal) and MAC(Control) values at sea level did not differ significantly (1.66 +/- 0.08% and 1.52 +/- 0.21%, respectively). The MAC values determined for each remifentanil CRI did not differ significantly. However, MAC(R0.25), MAC(R0.5), and MAC(R1.0) were significantly decreased, compared with MAC(Basal), by 23.4 +/- 7.9%, 29.8 +/- 8.3%, and 26.0 +/- 9.4%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE The 3 doses of remifentanil administered via CRI resulted in a similar degree of isoflurane MAC reduction in adult cats, indicating that a ceiling effect was achieved following administration of the lowest dose.