Buprenorphine, a partial μ-opioid (OP3) receptor agonist and κ-opioid (OP2) receptor antagonist, is frequently used in dogs and cats during the postoperative period to manage signs of pain of mild to moderate intensity.1 It also has the advantage of only rarely causing dysphoria or vomiting in cats.2 Butorphanol is a κ-opioid (OP2) receptor agonist and μ-opioid (OP3) receptor antagonist.3 Butorphanol induces analgesia through its κ-opioid receptor agonist activity; however, its analgesic properties have been questioned.4 Butorphanol is believed to provide adequate visceral but poor somatic analgesia.5 Notwithstanding variation in response among populations and individual cats, butorphanol has a fast onset but short duration of antinociception.5–9 Butorphanol is not suitable as a sole pain-relieving drug for the treatment of moderate to severe signs of pain following surgery.1
As a partial μ-opioid receptor agonist, buprenorphine is likely to provide greater analgesia than butorphanol, a κ-opioid receptor agonist. This is supported by the findings of Robertson et al,6 who reported that, in cats, buprenorphine administered IM increased thermal threshold in both intensity and duration (< 12 hours), compared with butorphanol (< 30 minutes). This is also in agreement with a large prospective clinical trial10 of 153 cats, which found lower postoperative pain scores in cats that received buprenorphine (0.01 to 0.02 mg/kg [0.0045 to 0.009 mg/lb], IM) as premedication prior to surgery, compared with cats premedicated with butorphanol (0.4 mg/kg [0.18 mg/lb], IM). Bortolami et al11 reported that buprenorphine provided comparable sedation and analgesia to both methadone and butorphanol when combined with acepromazine. In a recent publication,12 authors have challenged part of that study, finding that methadone provided more effective analgesia of longer duration, compared with butorphanol, in cats following ovariohysterectomy. Intravenous administration and IM administration of buprenorphine provide superior postoperative analgesia to SC or oral transmucosal administration of the drug.13 As a result of this finding, IV administration and IM administration were recommended as the preferred routes for buprenorphine in cats. In laboratory animals, buprenorphine has a bell-shaped dose-response curve, suggesting that higher doses decrease the analgesic effect.14 This has led to label restrictions on the dose and the administration interval, but clinical relevance has never been determined.2,14
Buprenorphine is registered for use in the treatment of pain in cats in Canada, the United Kingdom, and other parts of Europe, with a labeled IM dose recommendation of 0.02 mg/kg, and is available for extralabel veterinary use in the United States.15 In the United States, although butorphanol is approved for use in cats, use of buprenorphine is considered extralabel usage in veterinary patients and special regulations for its use apply.12,16
Pain expression is considered to be multidimensional, and tools that evaluate multiple dimensions of signs of pain are more accurate than those that measure only 1 dimension, such as intensity (eg, VAS, numeric rating scale, or simple descriptive scale).17,18 The purpose of the study reported here was to evaluate the analgesic effect of buprenorphine, compared with butorphanol, in cats by use of a validated multidimensional composite pain scale.12,19,20 To the authors' knowledge, no other validated pain assessment scale has been described for use in cats. The hypothesis was that buprenorphine provides greater analgesia than butorphanol in the postoperative period following ovariohysterectomy in cats.
Materials and Methods
Animals and experimental design—The study was designed as a randomized controlled masked clinical trial and was approved by the Animal Ethics Committee of the University of Melbourne Faculty of Veterinary Science, where the study was performed. During a 4-month period, domesticated female cats of ≤ 4 years of age that were admitted to the University Veterinary Hospital for elective ovariohysterectomy were included in the trial after agreement and signed consent were obtained from the owners. The cats also had to be determined healthy by use of physical examination and basic blood analysis including measurement of PCV, serum total protein concentration, BUN concentration, and blood glucose concentration.
Phase 1—Forty cats were randomly allocated to a butorphanol (n = 20) or buprenorphine (20) group by use of a commercially available software package.a Cats were premedicated by IM injection in the quadriceps muscle group with medetomidineb (15 μg/kg [6.8 μg/lb]) in combination with butorphanolc (0.4 mg/kg) or buprenorphined (0.02 mg/kg) with a 29-gauge, 12.7-mm insulin needle. Twenty minutes later, the effectiveness of the premedication was assessed on the basis of a published sedation scoring system.21 A 22-gauge, 25-mm over-the-needle catheter was then placed in one of the cephalic veins, and anesthetic induction commenced precisely 30 minutes after premedication with a constant rate infusion of propofole (1.5 mg/kg/min [0.68 mg/lb/min], IV) administered to effect with a calibrated syringe pumpf until orotracheal intubation was achieved. The endotracheal tube was then connected to a pediatric rebreathing system,g and isofluraneh in oxygen (2 L/min for the first 5 minutes and 1 L/min for the remainder of the procedure) was administered to effect to maintain anesthesia. All cats maintained spontaneous ventilation. A balanced crystalloid solutioni was administered IV at a rate of 10 mL/kg/h (4.5 mL/lb/h) during anesthesia. A calibrated multiparametric anesthesia monitorj displayed continuous ECG, heart rate, respiratory rate, Petco2, and pulse oximetry data. Arterial blood pressures were obtained via a veterinary-specific handheld noninvasive oscillometric blood pressure device.k
Bradycardia and hypotension were defined as a heart rate < 95 beats/min and an MAP < 60 mm Hg, respectively. Bradycardia was treated with glycopyrrolatel (0.005 mg/kg [0.0023 mg/lb], IV) as required. Hypotension was treated with IV fluid therapy (10 mL/kg for 10 minutes, repeated if required) and dopaminem infusion at 7 μg/kg/min (3.2 μg/lb/min), IV.
The same surgeon performed all the ovariohysterectomies following the surgical standards of the institution (midline approach). Anesthesia time was defined as the time from the start of anesthetic induction to the time of extubation, and surgery time was defined as the time from the primary skin incision to the placement of the last skin suture. Ten minutes following extubation, medetomidine was antagonized with atipamezolen (0.075 mg/kg [0.034 mg/lb], IM). Pain assessments were performed before administration of anesthetic premedication (baseline) and at 20, 60, 120, 180, 240, 300, and 360 minutes after extubation or until rescue analgesia was administered. If at any time point the evaluation score was ≥ 9 of 28, the cat was determined to be in moderate to severe pain and was given rescue analgesia consisting of methadoneo (0.2 mg/kg [0.09 mg/lb], IV, as needed) and meloxicamp (0.2 mg/kg, SC, q 24 h, as needed). All cats perceived as not being in pain at the 6-hour pain evaluation were administered meloxicamp (0.2 mg/kg, SC). All cats were intubated, monitored, and assessed for signs of pain by the same trained anesthetist, who was unaware of the treatment cats received. The masking was achieved by covering the graduations of the premedication syringe with a large nontransparent sticker, preventing the anesthetist from assessing the volume given.
Phase 2—The experimental design for phase 2 was similar to phase 1. By use of a commercially available software package,a in groups of 10, 40 cats were to be randomly allocated 5 at a time to butorphanol (n = 20) or buprenorphine (20) groups. During wound closure, cats received an additional dose of butorphanol (0.4 mg/kg, IM) or buprenorphine (0.02 mg/kg, IM), depending on group allocation. The syringe containing the postoperative analgesic was also covered with a large nontransparent sticker, preventing the anesthetist from assessing the volume given.
Postoperative rectal temperatures were measured immediately following discontinuation of inhalation anesthesia and prior to extubation with a digital thermometer.q Ten minutes following extubation, medetomidine was antagonized with atipamezole (0.037 mg/kg [0.017 mg/lb], IM).
Pre- and postoperative pain assessments—All pain assessments were performed by the same veterinary anesthesiologist, according to a published multidimensional composite pain scoring system validated for use in assessing postoperative pain in cats undergoing ovariohysterectomy.12,19,20 The veterinary anesthesiologist was unaware of the treatments each cat received. From the pain assessment results, 3 scores were defined. The preoperative score was the baseline pain evaluation score determined before premedication and was analyzed to detect any baseline difference between the 2 groups or any abnormal behavior that may have interfered with the scoring system. The time point evaluation score was the postoperative pain evaluation score at each time point (20, 60, 120, 180, 240, 300, and 360 minutes). The rescue analgesia score was established to assess difference of requirement in rescue analgesia between the 2 groups. A rescue analgesia score of 0 was assigned if no rescue analgesia was administered during the postoperative 360-minute period, and a score of 1 was assigned if rescue analgesia was required.
All blood pressures recorded before premedication and at each pain score evaluation time point were measured with the same veterinary-specific handheld oscillometric blood pressure measurement device used during the period of general anesthesia. The width of the blood pressure cuff selected for each cat was measured to comply with manufacturer recommendations (cuff width was 42% to 50% of the limb circumference) and was placed proximal to the metacarpal region. Systolic arterial blood pressure measurements were used in the scoring system.
Evaluation of sedation level—Twenty minutes after anesthesia premedication, sedation level was assessed on the basis of a published scoring system.21 Sedation scores were ascribed according to the following criteria: no discernible effect, mild sedation (appears sleepy), moderate sedation (very sleepy, may be recumbent but could be roused), heavy sedation (recumbent, difficulty rousing), or profound sedation (lateral recumbency and not rousable).21 Sedation levels were compared between the 2 groups.
Evaluation of anesthetic-sparing effect at induction of anesthesia with buprenorphine vs butorphanol—The anesthetic-sparing effect of buprenorphine at anesthetic induction versus butorphanol was indirectly assessed 30 minutes after premedication. The propofol constant rate infusion was administered at a rate of 1.5 mg/kg/min, IV, and was discontinued once intubation without coughing was achieved. The amount of propofol used was recorded for each cat, and the mean dose of propofol required to induce anesthesia was calculated for the 2 groups. The opioid used for the group requiring less propofol was considered to have a more anesthetic-sparing effect at anesthetic induction.
Evaluation of anesthesia depth—Every 5 minutes, the depth of anesthesia was checked by means of noting the clinical signs, including degree of relaxation of the temporomandibular articulation, position of the eyes, and absence of a palpebral reflex. The isoflurane vaporizer dial setting was increased by 0.25% increments in cats that reacted to surgical stimuli. If a cat was perceived as being at a level of anesthesia that was too deep (relaxed temporomandibular articulation, eyes centrally positioned, and absence of palpebral reflexes), the isoflurane vaporizer dial setting was decreased by 0.25% increments.
Physiologic variables monitored during general anesthesia—During anesthesia, cats were assessed every 5 minutes for heart rate, respiratory rate, Petco2, oxygen saturation, and MAP. Heart rate and respiratory rate were derived from the oxygen saturation and Petco2, respectively. For each cat, the mean value for each physiologic variable was calculated for the first 20 minutes of anesthesia (or until the start of surgery) and for the first 15 minutes of surgery (or until surgery was finished if surgery time was < 20 minutes). Physiologic variables were compared between the 2 groups.
Pain reaction at injection of the premedication—Cats were minimally restrained during the anesthetic premedication injection. The anesthetist inserted the 29-gauge, 12.7-mm insulin needle into the quadriceps muscle, waited 1 to 2 seconds, and then injected the test drug. The cats were subjectively evaluated for signs of pain (abrupt movements and vocalization) at the time of injection. A score of 0 was given if no signs of pain were detected, and a score of 1 was given for signs of pain.
Statistical analysis—Data analysis was performed by use of a commercially available software package.r The Shapiro-Wilk test was used to test for normality of residuals. Comparison of weight, age, propofol requirement (propofol anesthetic induction dose), anesthesia time, surgery time, preoperative scores, and time point evaluation scores were analyzed via a 2-tailed Mann-Whitney exact test. The rescue analgesia scores were analyzed via the Fisher exact test. Heart rate, respiratory rate, Petco2, and MAP were analyzed via a 2-tailed Mann-Whitney exact test and a 2-tailed Student t test for phase 1 and phase 2, respectively. Postoperative temperatures were analyzed with a 2-tailed t test. Values of P < 0.05 were deemed significant. Results are reported as mean ± SD or median (range).
Results
Phase 1—Because of a high requirement for rescue analgesia, phase 1 of the study was discontinued for ethical reasons. Only 10 female cats (domestic shorthair, domestic medium-hair, or domestic longhair) underwent testing and were included in phase 1 (4 were allocated to the buprenorphine group and 6 to the butorphanol group). Weight was not significantly (P = 0.32) different between the cats that received buprenorphine (median, 2.4 kg [5.3 lb]; range, 2.2 to 2.6 kg [4.8 to 5.7 lb]) and butorphanol (median, 3.0 kg [6.6 lb]; range, 2.1 to 3.8 kg [4.6 to 8.4 lb]). Age was not significantly (P = 0.41) different between the cats that received buprenorphine (median, 6.5 months; range, 5 to 17 months) and butorphanol (median, 11.5 months; range, 6 to 48 months). Anesthesia time was not significantly (P = 0.86) different between the cats that received buprenorphine (median, 45 minutes; range, 45 to 55 minutes) and butorphanol (median, 47.5 minutes; range, 40 to 60 minutes). Surgery time was not significantly (P = 0.27) different between the cats that received buprenorphine (median, 20 minutes; range, 15 to 20 minutes) and butorphanol (median, 20 minutes; range, 20 to 30 minutes). No cats were removed from the study after enrollment, and no cats died or were euthanized during the study.
Median preoperative pain scores were 0 (range, 0 to 1) and 0 (range, 0 to 1) for buprenorphine and butorphanol groups, respectively (P = 0.999). The median 20-minute pain scores were 13.5 (range, 13 to 18) and 14.5 (range, 8 to 19) for the buprenorphine and butorphanol groups, respectively (P = 0.999; Figure 1). Nine of 10 cats required rescue analgesia at the first (20 minutes after extubation) postoperative pain assessment. One cat from the butorphanol group required rescue analgesia at the third pain evaluation, 120 minutes after extubation. Subsequent pain score comparisons were inapplicable. Median sedation scores were 3 (range, 3 to 3) and 3 (range, 2 to 5) for the buprenorphine and butorphanol groups, respectively (P = 0.999).
Anesthetic-sparing effect at induction of anesthesia was not significantly different with buprenorphine versus butorphanol. The median dose of propofol needed to induce general anesthesia was 5.3 mg/kg (2.4 mg/lb; range, 5.1 to 5.5 mg/kg [2.3 to 2.5 mg/lb]) and 4.4 mg/kg (2.0 mg/lb; range, 3.5 to 6.2 mg/kg [1.6 to 2.8 mg/lb]) for the buprenorphine and butorphanol groups, respectively (P = 0.11).
Box-and-whisker plots of pain scores at 20 minutes after extubation (A [phase 1] and B [phase 2]), sedation scores (C), and propofol requirement (D) in 39 cats undergoing ovariohysterctomy receiving buprenorphine (4 in phase 1; 14 in phase 2) or butorphanol (6 in phase 1; 15 in phase 2) for perioperative analgesia. The box indicates the interquartile range (25th to 75th percentile), the black line in the box indicates the median, and the whiskers indicate the range. Pain scores and sedation scores were obtained by use of a validated multidimensional composite scale and a published simple descriptive scale, respectively. During phases 1 and 2, cats were premedicated with buprenorphine (0.02 mg/kg [0.009 mg/lb], IM) or butorphanol (0.4 mg/kg [0.18 mg/lb], IM), in combination with medetomidine (0.015 mg/kg [0.007 mg/lb]). In phase 2, cats from the butorphanol and buprenorphine groups also received butorphanol (0.4 mg/kg, IM) or buprenorphine (0.02 mg/kg, IM), respectively, during wound closure. Pain score at which cats were perceived as being in moderate to severe pain and when rescue analgesia was given (dotted line) and outliers > 1. 5 times the interquartile range (circles) and > 3 times the interquartile range (asterisks) are indicated.
Citation: Journal of the American Veterinary Medical Association 245, 2; 10.2460/javma.245.2.195
No significant differences between treatment groups were detected for physiologic variables monitored during anesthesia. Median heart rate, respiratory rate, Petco2, and MAP were, respectively, 122 beats/min (range, 84 to 162 beats/min), 17 respirations/min (range, 10 to 31 respirations/min), 37.5 mm Hg (range, 27 to 44 mm Hg), and 90.5 mm Hg (range, 60 to 177 mm Hg) for the buprenorphine group and were 115 beats/min (range, 96 to 166 beats/min), 18 respirations/min (range, 8 to 34 respirations/min), 38 mm Hg (range, 26 to 48 mm Hg), and 79.5 mm Hg (60 to 142 mm Hg) for the butorphanol group. Oxygen saturation of hemoglobin as measured by pulse oximetry remained > 95% in all cats. No cats from either group developed hypotension throughout the period of anesthesia. No cardiac anomalies were detected via ECG in any cats.
None of the cats in either group had signs of pain at injection of the premedication. In addition, at the time of the last evaluation, no cat had signs of subcutaneous or cutaneous reactions at the site of the injection.
Phase 2—Because of the difficulty in recruiting cases, only 30 cats were enrolled in phase 2 of the study (15 in the buprenorphine group and 15 in the butorphanol group). One cat allocated to the buprenorphine group was excluded from the study prior to surgery because the presence of an abdominal scar and faint ear tattoo suggested it had previously been neutered. Median weight of the cats was 2.6 kg (5.7 lb; range, 1.8 to 3.2 kg [4.0 to 7.0 lb]) and 2.65 kg (5.8 lb; range, 2.0 to 4.7 kg [4.4 to 10.3 lb]) for the buprenorphine and butorphanol groups, respectively (P = 0.52). Median age was 8 months (range, 5 to 24 months) and 10 months (range, 5 to 24 months) for the buprenorphine and butorphanol groups, respectively (P = 0.35). Twenty-eight cats were domestic shorthair, domestic medium-hair, or domestic longhair, and 1 was a purebred Persian. No cats died or were euthanized during the study. Median anesthesia times were 42.5 minutes (range, 30 to 50 minutes) and 45 minutes (range, 35 to 80 minutes) for the buprenorphine and butorphanol groups, respectively (P = 0.053). Median surgery times were 20 minutes (range, 15 to 25 minutes) and 20 minutes (range, 15 to 60 minutes) for the buprenorphine and butorphanol groups, respectively (P = 0.11). One cat from the butorphanol group had a surgery time > 25 minutes owing to difficulties in locating the ovaries; no other complications were observed in this cat. Mean ± SD postoperative rectal temperatures of the cats were 36.1 ± 0.4°C (97.0 ± 0.7°F) and 35.8 ± 0.9°C (96.5 ± 1.6°F) for the buprenorphine and butorphanol groups, respectively (P = 0.36).
Median preoperative pain scores were 0 (range, 0 to 1) and 0 (range, 0 to 0) for the buprenorphine and butorphanol groups, respectively (P = 0.48). The median 20-minute pain scores were 3.5 (range, 1 to 7) and 11 (range, 9 to 16) for the buprenorphine and butorphanol groups, respectively (P < 0.001; Figure 1). Subsequent time point pain assessment scores were not statistically analyzed because all cats in the butorphanol group had received rescue analgesia and were not evaluated further. All cats from the butorphanol group required rescue analgesia at the first postoperative pain assessment (20 minutes after extubation), and none of the cats from the buprenorphine group required rescue analgesia at any time point. Subsequent pain score comparisons were inapplicable. The median time point evaluation scores in the buprenorphine group at 20, 60, 120, 180, 240, 300, and 360 minutes were 3.5 (range, 1 to 7), 2.0 (range, 1 to 7), 2.0 (range, 1 to 7), 1.5 (range, 1 to 6), 1 (range, 1 to 5), 1 (range, 1 to 4), and 1 (range, 1 to 4), respectively. Median sedation scores were 3.5 (range, 1 to 4) and 4 (range, 2 to 4) for the buprenorphine and butorphanol groups, respectively (P = 0.013).
As in phase 1, anesthetic-sparing effect at induction of anesthesia was not significantly different with buprenorphine versus butorphanol (Figure 1). The median dose of propofol needed to induce general anesthesia was 4.7 mg/kg (2.1 mg/lb; 3.6 to 6.8 mg/kg [1.6 to 3.1 mg/lb]) and 4.0 mg/kg (1.8 mg/lb; 3.1 to 9.5 mg/kg [1.4 to 4.3 mg/lb]) for the buprenorphine and butorphanol groups, respectively (P = 0.14).
No significant differences between treatment groups were detected at any time point of anesthesia during the preparation time or surgery time for physiologic variables monitored during anesthesia. Oxygen saturation of hemoglobin remained > 95% in all cats. No cat from either group developed hypotension throughout the period of anesthesia.
None of the cats in either group had signs of pain at injection of the premedication. In addition, at the time of the last evaluation, no cat had signs of subcutaneous or cutaneous reactions at the site of the injection.
Discussion
The present study was designed to assess the analgesic efficacy of buprenorphine for regulatory purposes to obtain registration for administration of buprenorphine as a perioperative analgesic in cats in Australia. During phase 1, the dose used for butorphanol was the registered dose in Australia, and the dose used for buprenorphine was the registered dose in Europe. With this regimen, the initial hypothesis (that buprenorphine provides greater analgesia than butorphanol in the postoperative period following ovariohysterectomy) could not be confirmed. Indeed, both drugs provided inadequate postoperative analgesia, and additional analgesic drugs needed to be administered. As a consequence, during phase 2, the authors had the option of either doubling the preoperative doses of the tested drugs or administering an additional dose after surgery. For buprenorphine, the margin of safety was reported for a 0.02 mg/kg dose administered IM in cats; therefore, it was decided to choose the latter option and administer an additional dose of butorphanol (0.4 mg/kg, IM) or buprenorphine (0.02 mg/kg, IM) at the commencement of wound closure for the butorphanol and the buprenorphine groups, respectively. These changes allowed the initial hypothesis to be confirmed in phase 2.
In an attempt to minimize stress, all cats were premedicated prior to catheter placement. Premedication drugs were injected IM, as this route affords superior drug absorption, compared with SC administration.22
Because ovariohysterectomy is known to be a painful procedure requiring analgesia, a negative control group was not included in the study design for ethical reasons.23 All cats involved in this study were client owned and representative of the domestic population. Most cats were young domestic crossbreeds; however, 1 purebred Persian was included in phase 2. There were no outstanding differences in temperament.
The sedation scoring system used in this study was unmodified from a previous scale used to assess sedation in dogs.21 This scale was deemed suitable, as it was similar to scales previously applied to assess sedation in cats with the additional advantage of more precise differentiation of sedation levels in recumbent animals.24,25 In phase 1, sedation scores were not significantly different for cats in the buprenorphine or butorphanol groups. This finding was potentially due to the small number of cats sampled. Indeed, in phase 2, which involved the same protocol for anesthetic premedication but a higher number of cats, the sedation level was significantly different. The degree of sedation was greater for cats receiving butorphanol; however, buprenorphine still provided an overall moderate level of sedation. The medetomidine component of the premedication likely contributed to the degree of sedation reported in the buprenorphine group.26 It is plausible that the dose of medetomidine administered in phase 2 could have been reduced when combined with butorphanol to avoid the heavy degree of sedation observed in most cats from this group. These findings were expected because butorphanol has been reported to provide mild sedation when administered alone in cats27; however, others have reported butorphanol to cause central stimulation.7
Similar to the evaluation of sedation scores, the small sample size in phase 1 did not permit statistical comparisons to be made between treatment groups regarding propofol requirement at anesthetic induction. In phase 2, although the median propofol requirement to induce general anesthesia was lower for the butorphanol group, the difference was not significant (P = 0.14). However, 2 cats from the butorphanol group had a much higher propofol requirement than the other group members. Those 2 cats could likely be representatives of the small population of cats that have central stimulation in response to butorphanol.7 Given that the degree of sedation was greater for the butorphanol group, it seems intuitive that this would confer a greater anesthetic-sparing effect at anesthetic induction, compared with buprenorphine. The reported anesthetic induction dose for propofol in nonpremedicated cats is 6 mg/kg (2.7 mg/lb), IV. The propofol anesthetic induction dose requirements observed in this study were lower than this, which was to be expected given the degree of sedation seen in cats from both groups. The slow rate of propofol administration used to achieve anesthetic induction has been discussed in a previous publication.12
To the authors' knowledge, the present study used the only published validated multidimensional composite pain scale for assessing postoperative signs of pain in cats undergoing ovariohysterectomy.12,19,20 This composite scale evaluates 4 dimensions of pain (psychomotor change, protection of wound area, physiologic variables, and vocal expression of pain) and evaluates pain more accurately than those scales measuring only a single dimension (eg, a VAS, numeric rating scale, or simple descriptive scale).17,18
During phase 1, although the insufficient analgesic effect of preoperative administration of butorphanol confirmed the findings of a previous study,12 the insufficient analgesic effect of preoperative administration of buprenorphine was unexpected. Indeed, results of the present study conflict with those of previous studies10,11,23,28 in which the analgesic effects of buprenorphine were evaluated after neutering in cats. Slingsby and Waterman-Pearson23 and Bortolami et al11 used a VAS and a mechanical nociceptive threshold testing device. The use of the VAS calls those results into question because such methods of pain evaluation are unreliable in assessing acute or perioperative pain in a hospital setting.18,29 In addition, the study by Bortolami et al11 failed to detect the analgesic effect of buprenorphine by use of the mechanical nociceptive threshold–testing device because the postoperative pressure was not greater than the preoperative pressure. A multicenter prospective trial by Taylor et al10 found that approximately 75% of cats undergoing surgery (predominantly for neutering procedures) were assessed as being without pain or in mild pain when administered buprenorphine at doses ranging between 0.01 and 0.02 mg/kg, IM. It is possible that the simple descriptive scale used by Taylor et al10 lacked sensitivity or that the multidimensional composite scale used in the present study lacked specificity. Taking into account that the scale used by Brondani et al20 is validated and that multidimensional pain scoring systems are known to be a more accurate instrument for assessing postoperative signs of pain than the simple descriptive scale, and together with the fact that we have successfully used this scale previously without encountering problems of specificity, it seems reasonable to assume the findings of the present study are representative.12 In addition, although Staffieri et al28 found low 1-hour postovariohysterectomy pain scores in cats given buprenorphine (0.02 mg/kg, SC) with a simple descriptive scale, 9 of 10 cats given buprenorphine did receive rescue analgesia over the 8-hour evaluation period.
In phase 2, buprenorphine had net analgesic superiority to butorphanol. This was to be expected, given that buprenorphine, a partial μ-opioid receptor agonist, is thought to provide better analgesia than butorphanol, which is a μ-opioid receptor antagonist and κ-opioid receptor agonist.1,4,30 Although administration of a second dose of butorphanol did decrease pain scores, they were not decreased to < 9 of 28 (ie, cats had moderate to severe pain). In contrast, the 2 doses of buprenorphine provided acceptable postoperative analgesia in all cats. There are 2 potential explanations for the difference in the analgesic efficacy of buprenorphine reported in phase 1 and 2. It could be that the duration of action of buprenorphine is shorter than required to provide an adequate analgesic effect in the postoperative period when only given before surgery. Alternatively, it could be that a single administration of buprenorphine at a dose rate of 0.02 mg/kg, IM, was subanalgesic and that a second dose had a cumulative effect, which allowed buprenorphine (and potential active metabolites) to achieve therapeutic plasma concentrations sufficient to provide adequate and longer-lasting postoperative analgesia. A study by Robertson et al6 supports the notion of longer duration of action of buprenorphine, reinforcing the idea of the second hypothesis. Consequently, it is possible that a higher single dose of 40 μg/kg (18 μg/lb), IM, may have provided sufficient analgesia.6 It is important to recognize that substantial variation in individual response to opioids has been reported in cats, and as a consequence, cats should be assessed and treated on an individual basis rather than under the assumption that a generic opioid dosage will be effective for all cats.9,12
In the United States, atipamezole is registered for use in dogs but not in cats. The registered dose of atipamezole for use in dogs is 5 times the dose of medetomidine that was administered. This dose of atipamezole (0.075 mg/kg, IM) was administered to cats in phase 1. The Australian registered dose for atipamezole in cats (2.5 times the medetomidine dose) was administered in phase 2 (0.038 mg/kg [0.017 mg/lb], IM). Although the higher dose of phase 1 was chosen to eliminate any possible residual analgesic effects of medetomidine, the dosage was reduced for phase 2 in an attempt to rule out potential factors contributing to the high proportion of cats that had high pain scores. Atipamezole has been documented as causing excessive alertness and excitatory-like effects in cats; however, the doses at which these adverse effects have been reported were much higher (0.2 to 0.6 mg/kg [0.09 to 0.27 mg/lb], IM) than those used in the present study. In addition, the prevalence of such effects was relatively low (6.6%),31 whereas all cats required rescue analgesia in the present study. The potential interaction of atipamezole with opioid receptors has also been postulated, but studies have failed to detect affinity for the μ- or κ-opioid receptors. As a result, the authors believe atipamezole is unlikely to be the main factor for the phase 1 findings that all cats had inadequate postoperative analgesia, although further molecular research is required to exclude the possibility that α2-adrenergic receptors located on the same cells as opioid receptors do not influence each other's cellular mechanisms.32
Physiologic data collected during anesthesia in the present study indicated that variables remained within established reference ranges, indicating that neither opioid had deleterious effects on vital functions and that both could be used safely for premedication prior to general anesthesia.
Within the conditions of the present study, buprenorphine administered as a premedication at 0.02 mg/kg, IM, with repeated administration of the same dose at the time of surgical wound closure, provided effective postoperative analgesia for at least 6 hours following ovariohysterectomy in cats. Buprenorphine appeared superior to butorphanol in providing an adequate period of effective postoperative analgesia.
ABBREVIATIONS
| MAP | Mean arterial blood pressure |
| Petco2 | End-tidal partial pressure of carbon dioxide |
| VAS | Visual analogue scale |
Microsoft Excel for Mac 2011, version 14.1.0, Microsoft Corp, Redmond, Wash.
Domitor, medetomidine hydrochloride (1 mg/mL), Pfizer Animal Health, West Ryde, NSW, Australia.
Butormidor injection, butorphanol tartrate (10 mg/mL), Ausrichter Pty Ltd, Camperdown, NSW, Australia.
Ilium buprenorphine injection, buprenorphine hydrochloride (10 mg/mL), Troy Laboratories Australia Pty Ltd, Glendenning, NSW, Australia.
Provine 1%, propofol emulsion injection (10 mg/mL), Claris Lifesciences Ltd, Burwood, NSW, Australia.
Graseby 3300 PCA Pump, SIMS Graseby Ltd, Walfort, Hertfordshire, England.
SurgiVet small animal anesthesia machine V701001, Smiths Medical PM Inc, Waukesha, Wis.
Isorrane, isoflurane USP (100%), Baxter Healthcare Pty Ltd, Old Toongabbie, NSW, Australia.
Hartmann's Solution for Injection, Fresenius Kabi Pty Ltd, Pymble, NSW, Australia.
SurgiVet Advisor vital signs monitor V9203, Smiths Medical PM Inc, Waukesha, Wis.
petMAP graphic, Ramsey Medical Inc, Tampa, Fla.
Glycosate Vet Injection, glycopyrrolate (0.28 mg/mL), Nature Vet Pty Ltd, Glenorie, NSW, Australia.
DBL sterile dopamine concentrate (40 mg/mL), Hospira Australia Pty Ltd, Melbourne, VIC, Australia.
Antisedan, atipamezole hydrochloride (5 mg/mL), Pfizer Animal Health, West Ryde, NSW, Australia.
Ilium methadone injection, methadone hydrochloride (10 mg/mL), Troy Laboratories Australia Pty Ltd, Glendenning, NSW, Australia.
Metacam, meloxicam (5 mg/mL), Boehringer Ingelheim Pty Ltd, North Ryde, NSW, Australia.
Health Team digital thermometer, Graham-Field Health Products, Atlanta, Ga.
IBM SPSS Statistics, version 20, IBM Corp, Armonk, NY.
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