Comparing paracetamol/codeine and meloxicam for postoperative analgesia in dogs: a non-inferiority trial.

BACKGROUND: There are limited published data on the analgesic efficacy of paracetamol/codeine in dogs. METHODS: Prospective, randomised, blinded, positive-controlled clinical trial with 70 dogs (paracetamol/codeine, n=46; meloxicam, n=24) undergoing surgery. Drugs were administered orally 2 hours before and for 48 hours after surgery at the licensed dose. Anaesthesia was standardised. Dogs received buprenorphine 6 hourly for the first 24 hours after surgery. Outcome assessments were made pretrial and at regular intervals up to 48 hours after extubation and comprised the Glasgow Composite Measure Pain Score-Short Form, visual analogue scale for sedation and inflammation and mechanical nociceptive threshold (MNT). Non-inferiority of paracetamol/codeine compared with meloxicam was defined using a non-inferiority margin (Δ) against the 95 per cent confidence interval of the difference between the treatment means. RESULTS: Pain scores were low in both treatment groups. With the exception of MNT all upper 95 per cent confidence intervals for the differences between outcome variable treatment means were within +Δ for each variable, establishing non-inferiority for each outcome variable. CONCLUSIONS: Paracetamol/codeine is a useful perioperative analgesic that within the context of the perioperative analgesia regimen studied (methadone premedication, buprenorphine for the first 24 hours after surgery) shows non-inferiority to the NSAID meloxicam.

Effect of intramuscular methadone on pharmacokinetic data and thermal and mechanical nociceptive thresholds in the cat.

Objectives The aim of the study was to assess simultaneous pharmacokinetics and thermal and mechanical antinociception after intramuscular methadone (0.6 mg/kg) in 10 cats. Methods Thermal and mechanical threshold (TT and MT, respectively) testing and blood collection were conducted at baseline and up to 24 h after administration. Methadone plasma concentrations were determined by liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were estimated by a non-compartmental method. TT and MT were analysed using ANOVA ( P <0.05). Time of maximum plasma concentration (Tmax), time of onset of antinociception and time of reaching cut-out threshold (TT 55°C; MT 30 Newtons [N]) were determined. Results TT and MT increased above baseline from 20-240 mins and 5-40 mins, respectively, after intramuscular (IM) administration ( P <0.005). Mean maximum delta T (measured as TT minus baseline threshold) was 7.9°C (95% confidence interval [CI] 4.3-11.6) at 60 mins and mean maximum delta F (measured as MT minus baseline threshold) was 4.2 (95% CI 1.6-6.7) N at 45 mins. IM methadone concentration-time data decreased curvilinearly, and gave a clearance estimate of mean 9.1 ml/kg/min (range 5.2-15.7) with median Tmax at 20 mins (range 5-360 mins). Conclusions and relevance IM data followed classical disposition and elimination in all cats. Plasma concentrations after IM administration were associated with an antinociceptive effect, including negative hysteresis. These data can be used for devising dosing schedules for methadone in clinical feline practice.

Methadone in combination with medetomidine as premedication prior to ovariohysterectomy and castration in the cat.

OBJECTIVES: The aim of the study was to evaluate the tolerability, sedative and analgesic effects of methadone in combination with medetomidine for premedication prior to neutering in healthy cats. METHODS: This was an assessor-blinded, randomised, clinical research study. Forty-five cats were recruited and divided into three treatment groups of 15. Following premedication with medetomidine (20 µg/kg) and one of the three test drugs - methadone 0.5 mg/kg, buprenorphine 20 µg/kg or butorphanol 0.4 mg/kg intramuscularly - anaesthesia was induced with propofol and maintained with isoflurane, and neutering was carried out. Sedation and physiological parameters were assessed before premedication, after premedication before induction of anaesthesia, and at 90 mins and 2, 3, 4, 6, 7, 8 and 24 h after premedication. Pain and mechanical nociceptive threshold were assessed at similar time points. RESULTS: There were no differences between groups with respect to age, sex, duration of anaesthesia or surgery. Most cats had low pain scores in the postoperative period, with small differences in pain scores between groups at individual time points only. Five, two and no cats required additional rescue analgesia in the postoperative period in the butorphanol, methadone and buprenorphine groups, respectively, representing no significant difference between groups. CONCLUSIONS AND RELEVANCE: Medetomidine combined with methadone for premedication prior to neutering in healthy cats provided adequate analgesia for the first 6 h after administration with no adverse effects; effects overall were comparable with medetomidine combined with buprenorphine or butorphanol. Administration of further analgesia with methadone at 6 h and a non-steroidal anti-inflammatory drug at 8 h provided adequate analgesia for the first 24 h after surgery.

The effects of an intravenous bolus of dexmedetomidine following extubation in a mixed population of dogs undergoing general anaesthesia and surgery.

An observer blinded, placebo controlled study evaluated the effects of 62.5 µg/m(2) dexmedetomidine administered IV on recovery from isoflurane anaesthesia in dogs. Forty-four healthy dogs, weighing 1.8-19.95 kg, presented for surgery that was expected to cause mild to moderate pain were studied. All were premedicated with 125 µg/m(2) dexmedetomidine and 20 µg/kg buprenorphine IM. Anaesthesia was induced with propofol and maintained with isoflurane. Non-steroidal anti-inflammatory drugs and local anaesthetics were administered as appropriate. Immediately prior to extubation dogs were treated with dexmedetomidine 62.5 µg/m(2) (group D) or an equivalent volume of heparinised saline (S). Assessments of heart rate, respiratory rate, pain (short form Glasgow composite pain scale [SF-GCPS], dynamic interactive visual analogue scale [DIVAS]), sedation (simple descriptive scale [SDS], DIVAS) and mechanical nociceptive threshold (MNT) were performed immediately before premedication, 20 min later, at the time of test drug administration (T0) and at 15-30 min intervals for four hours (T240 min). Recovery quality was scored 0 - 3 (SDS). Data were analysed with Student's t and Mann-Whitney U tests, two-way ANOVA and Fisher's exact test. Significantly fewer poor quality recoveries were observed in group D (D 2 [1-3]; S 2 [0-3]; P=0.02), however, sedation was increased in group D compared to group S from T15 to T150 min (P=0.0001). Pain scores were lower in group D compared to group S from T15 to T120 min (P=0.001), but the requirement for additional analgesia in the first 4h following extubation was not different between groups. Dexmedetomidine may decrease the incidence of poor quality anaesthetic recoveries in dogs.

Methadone in combination with acepromazine as premedication prior to neutering in the cat.

OBJECTIVE: To investigate the safety, sedative and analgesic properties of methadone in combination with acepromazine prior to neutering in cats. STUDY DESIGN: Controlled clinical, block randomized, prospective, blinded study designed for regulatory purposes. ANIMALS: 24 female and 21 male healthy cats. METHODS: Cats received one of three opioids combined with acepromazine (0.05 mg kg(-1) ) intramuscularly (IM) for premedication: Group 1: buprenorphine (0.02 mg kg(-1) ), group 2: methadone (0.5 mg kg(-1) ), group 3 butorphanol (0.4 mg kg(-1) ). Sedation was assessed 30 minutes after premedication using a visual analogue scale (VAS) and simple descriptive scale. Anaesthesia was induced with alfaxalone and maintained with isoflurane in oxygen. Surgical ovariohysterectomy or castration was performed. Pain was assessed using an interactive VAS (IVAS) and mechanical nociceptive threshold (MNT) with a pressure rate onset device. Methadone (0.5 mg kg(-1) IM) and meloxicam (0.2 mg kg(-1) subcutaneously) were provided 6 and 8 hours after premedication respectively, or together as rescue analgesia (IVAS above 50). RESULTS: Sedation scores, induction agent dose, pain scores at all time points and rescue analgesia were not statistically different between groups. In methadone treated cats there was no significant variation in MNT over time, suggesting a possible anti-hyperalgesic action, whereas in the other two groups lower thresholds were recorded at various time points after surgery compared to baseline. No cats required rescue analgesia after the second dose of methadone. No perioperative adverse effects occurred. CONCLUSION AND CLINICAL RELEVANCE: Methadone provided comparable sedation and analgesia to both buprenorphine and butorphanol when combined with acepromazine. Differences in analgesic efficacy between opioids might have been undetectable because of the surgical model and surgeon competency. Nevertheless, methadone is an effective analgesic in cats and its administration prior to feline neutering may be advantageous.

A study to evaluate buprenorphine at 40 µg kg(-1) compared to 20 µg kg(-1) as a post-operative analgesic in the dog.

OBJECTIVE: Comparison of the analgesic effect of buprenorphine at 20 or 40 µg kg(-1) . STUDY DESIGN: An investigator 'blinded', randomised study. ANIMALS: Twenty six dogs presented for ovariohysterectomy. METHODS: Dogs were premedicated intramuscularly with acepromazine 0.03 mg kg(-1) and buprenorphine at either 20 (B20, n = 12) or 40 µg kg(-1) (B40, n = 14) followed by anaesthetic induction with propofol and maintenance with isoflurane. During anaesthesia non invasive blood pressure, heart rate, respiratory rate, blood oxygen saturation, inspired and expired volatile agent, end-tidal carbon dioxide and ECG were recorded. Pain and sedation were assessed using interactive VAS scores; mechanical nociceptive thresholds were measured at the wound and hindlimb--all were assessed before and up to 22 hours after administration. Carprofen was used for rescue analgesia. RESULTS: There were no significant differences between the two groups for any of the parameters examined. Rescue analgesia was required around 5 hours after administration of buprenorphine in a significant number of animals. Sedation was good preoperatively and scores decreased over time postoperatively. Hock thresholds did not change over time; wound thresholds decreased significantly compared to the baseline value from 3 hours onwards. CONCLUSIONS: Administration of buprenorphine at either 20 or 40 µg kg(-1) IM with acepromazine provided good pre-operative sedation. Cardiovascular and respiratory values remained within clinically acceptable limits during anaesthesia. There was no evidence that increasing dose increased adverse events that may be associated with opioid administration (e.g. bradycardia and respiratory depression). CLINICAL RELEVANCE: Increasing the dose of buprenorphine from 20 to 40 µg kg(-1) did not provide any benefits with respect to analgesia after ovariohysterectomy as assessed using the VAS scoring system.

Combination of dexmedetomidine with buprenorphine enhances the antinociceptive effect to a thermal stimulus in the cat compared with either agent alone.

OBJECTIVE: To evaluate the sedative and antinociceptive effects of combinations of dexmedetomidine and buprenorphine in cats. STUDY DESIGN: Experimental randomized study. ANIMALS: Twelve purpose-bred neutered domestic short-hair cats (4 male and 8 female) weighing 4.6 kg (range 3.7-5.5 kg) aged from 2 to 5 years. METHODS: Six cats per group were administered buprenorphine (B) at 10 (B10) or 20 microg kg(-1) (B20) or dexmedetomidine (D) at 20 (D20) or 40 microg kg(-1) (D40) or a combination of B10/D20. A feline thermal nociceptive threshold testing device was used to evaluate the antinociceptive effects of the drugs before and up to 24 hours after drug treatment. Sedation was scored using a 100 mm visual analogue scale (VAS). RESULTS: Thermal thresholds increased significantly after administration of all but D20. Area under the curve (AUC, hours degrees C) for the first 6 hours (mean +/- SD) for B20 (281 +/- 17.8) was significantly greater than B10 (260 +/- 11.4), D20 (250 +/- 7.9) and D40 (255 +/- 11.4). The AUC for B10/D20 (273 +/- 12.2) was significantly greater than D20 but not the other treatments. No sedation was seen after administration of B10 or B20 and maximal sedation was seen for all animals in the D40 and B10/D20 groups and most animals in the D20 group. CONCLUSIONS: D20 alone had the smallest analgesic effect; B10 alone provided no sedation but their combination gave good sedation with analgesia comparable with B20. CLINICAL RELEVANCE: This combination could be a useful multimodal sedative/analgesic regimen in cats.

Thermal antinociception after dexmedetomidine administration in cats: a comparison between intramuscular and oral transmucosal administration.

Dexmedetomidine 40microg/kg was administered either intramuscularly (IM) or oral transmucosally (OTM) to 12 cats in a randomised cross-over study. Thermal nociceptive thresholds and visual analogue scale (VAS) sedation scores were obtained before and at regular intervals up to 24h after test drug administration. The summary measures of overall mean threshold, overall mean VAS sedation plus onset, offset and duration of analgesia were investigated using a univariate general linear model. There were no significant differences between treatment groups. Data are presented as mean+/-standard deviation: delta T mean increase over time (IM 6 degrees C+/-3 degrees C, OTM 6 degrees C+/-2 degrees C); overall mean VAS (IM 43+/-9 OTM 39+/-1); onset (IM 35+/-32 and OTM 30+/-40min); offset (IM 96+/-56 and OTM 138+/-135min); duration (IM 61+/-47 OTM 99+/-124min). Dexmedetomidine is well absorbed through the oral mucosa in cats since OTM and IM administration of dexmedetomidine 40microg/kg produced similar overall sedative and antinociceptive effects.

A comparison between pre-operative carprofen and a long-acting sufentanil formulation for analgesia after ovariohysterectomy in dogs.

OBJECTIVE: To assess the analgesic efficacy and adverse effects of a novel, long-acting sufentanil preparation in dogs undergoing ovariohysterectomy (OHE). STUDY DESIGN: Blinded, positively controlled, randomized field trial with four parallel treatment groups. ANIMALS: Eighty client owned dogs undergoing elective OHE randomly allocated into four treatment groups (each n = 20). MATERIALS AND METHODS: Three groups received intramuscular (IM) sufentanil (at 10, 15 and 25 microg kg(-1), respectively) and the control group received subcutaneous (SC) carprofen 4 mg kg(-1) SC plus acepromazine 0.05 mg kg(-1) IM as pre-anaesthetic medication. OHE was performed under thiopental/halothane anaesthesia. Visual Analogue Scale (VAS) scores for pain and sedation were awarded and mechanical nociceptive thresholds were measured at the wound and hock before surgery and up to 24 hours after tracheal extubation. Serum cortisol was measured before surgery, during surgery and up to 24 hours after tracheal extubation. Animals with inadequate post-operative analgesia were given rescue medication. RESULTS: In the carprofen group, VAS pain scores were significantly higher, wound tenderness was greater and requirement for rescue analgesia was more than in the sufentanil-treated groups. Sufentanil produced dose dependent analgesia and sedation. All treatment groups showed similar patterns of change for cortisol concentrations. Use of the sufentanil preparation was associated with a relatively high incidence of adverse events. CONCLUSIONS: The long-acting preparation of sufentanil provided excellent post-operative analgesia that was significantly better than that provided by carprofen. However, use of this formulation, in the anaesthetic technique used in the study, resulted in a relatively high incidence of adverse effects. CLINICAL RELEVANCE: Full mu (MOP) opioid agonists provide significantly better post-operative analgesia than nonsteroidal anti-inflammatory drugs after moderately painful surgery. However, the widely recognized adverse effects of opioids may preclude the use of these agents.