A Comparison of Ketorolac with Flunixin, Butorphanol, and Oxymorphone in Controlling Postoperative Pain in Dogs Karol A

Home , Papaveretum, Pyrantel

A comparison of ketorolac with flunixin, butorphanol, and oxymorphone in controlling postoperative pain in dogs Karol A. Mathews, Dale M. Paley, Robert A. Foster, Anne E. Valliant, Simon S. Young

Abstract (0.4 mg/kg de poids corporel (PC), n = 21), de la Ketorolac tromethamine, a nonsteroidal anti- flunixine (1.0 mg/kg PC, n = 21) ou du ketorolac inflammatory analgesic, was compared with flu- (0.5 mg/kg PC, n = 22), le tout se deroulant 'a nixin and butorphanol for its analgesic efficacy and double insu. potential side effects after laparotomy or shoulder L'efficacite analgesique a ete determinee selon arthrotomy in dogs. Sixty-four dogs were randomly une echelle de 1 'a 4 (1 etant considere comme insuf- assigned to receive butorphanol 0.4 mg/kg body fisant et 4 comme excellent) pour chacun des chiens. weight (BW) (n = 21), flunixin 1.0 mg/kg BW (n = 21), Le resultat final apres laparotomie fut de 3,4 pour le or ketorolac 0.5 mg/kg BW (n = 22), in a double ketorolac, 2,7 pour la flunixine et 1,6 pour le butor- blind fashion. phanol. Apres arthrotomie de l'epaule, les resultats The analgesic efficacy was rated from 1 to 4 moyens etaient de 3,5 pour le ketorolac, 3,0 pour la (1 = inadequate, 4 = excellent) for each dog. The flunixine et 1,4 pour le butorphanol (5 chiens sur 11). average scores after laparotomy were ketorolac, 3.4; Comme le butorphanol ne pouvait controler ade- flunixin, 2.7; and butorphanol, 1.6. After shoulder quatement la douleur apres l'arthrotomie de l'epaule, arthrotomy, the average scores were ketorolac, 3.5; l'oxymorphone (0,05 mg/Kg PC) a par la suite ete uti- flunixin, 3.0; and butorphanol, 1.4 (5/11 dogs). As lisee chez les 6 chiens du groupe, avec un resultat de butorphanol was unable to control pain after shoul- 2,0. L'alanine amino-transferase et la creatinine der arthrotomy, oxymorphone, 0.05 mg/kg BW, seriques etaient significativement elevees par rapport replaced butorphanol in a subsequent group of dogs aux donnees de base et cela 24 heures apres la and had a score of 2.0 (6/11 dogs). Serum alanine chirurgie chez les chiens recevant de la flunixine. aminotransferase and creatinine were significantly Un chien dans chacun des groupes a montre' de elevated above baseline at 24 hours postoperatively melaena ou de l'hematochezie. Un chien recevant in dogs receiving flunixin. One dog in each group du ketorolac a presente une evidence histologique developed melena or hematochezia. One dog receiv- d'ulceration gastrique. Nous avons conclus que le ing ketorolac had histological evidence of gastric ke'torolac et un bon analgesique lors de douleurs ulceration. We concluded that ketorolac is a good post-operatoires chez le chien. analgesic for postoperative pain in dogs. (Traduit par docteur Andre Blouin) Resume Can VetJ 1996; 37: 557-567 Comparaison entre le ketorolac et la flunixine, le butorphanol et l'oxymorphone dans Introduction le controle des douleurs post-operatoires A lleviating postoperative pain is essential in the man- chez le chien agement of veterinary surgical patients because of the La tromethamine de ketorolac, un analgesique anti- deleterious physiological effects of postoperative pain inflammatoire non-steroidien, a ete comparee a la and to address humane and ethical concerns (1,2). flunixine et au butorphanol en ce qui a trait a son Narcotic analgesics are considered to be the prototype efficacite analge'sique et a ses effets secondaires agents for relief of moderate to severe pain (3,4). Opioids, potentiels apres laparotomie ou arthrotomie de such as, morphine, oxymorphone, butorphanol, and l'epaule chez le chien. Soixante-quatre chiens ont pentazocine, are effective analgesics but may be accom- ete assignes au hasard 'a recevoir du butorphanol panied by sedation, dysphoria, respiratory and cardio- vascular depression (5). Common reasons for not using Department of Clinical Studies (Mathews, Valliant), Depart- opioids are concerns with the management of controlled ment of Pathology (Foster), Ontario Veterinary College, substances and the potential for theft and abuse within University of Guelph, Guelph, Ontario N 1 G 2W1; St. John a practice setting. As pain control is a major issue in Animal Hospital, 1700 Manawagonish Road, Saint John, veterinary practice, an alternative to opioid analgesia New Brunswick E2M 3Y5 (Paley); Scientific Solutions, is desirable from both a medical and an administra- 193 Barden Street, Eden Mills, Ontario NOB lPO (Young). tive aspect. This study was supported by Pet Trust and the Department of Ketorolac tromethamine (Toradol, Syntex, Mississauga, Clinical Studies, Ontario Veterinary College, University of Ontario), a nonnarcotic, nonsteroidal, anti-inflammatory Guelph, Guelph, Ontario N 1 G 2W 1. It was presented at the analgesic (NSAIA), is currently used for alleviation of 5th International Congress of Veterinary Anesthesia, Guelph, moderate to severe postoperative pain in humans. It is Ontario, Canada 1994 and at the IV International Veterinary supplied in both parenteral and oral formulations and has Emergency Critical Care Symposium, San Antonio, Texas, a rapid onset of action, good tolerance, and no addictive USA 1994. potential (6,7). Ketorolac has similar actions to other Reprints not available. NSAIAs in that it possesses anti-inflammatory, analgesic, Can Vet J Volume 37, September 19961996557 557 DOGS (n= 64) Table 1. Assessment of behavior based on the l l~~~~~~~~~~~~~~~~~dog's activities Laparotomy (n = 32) Arthrotomy (n = 32) Assessment Activities Normal exuberant Running, playing, eating, jumping ket but flu ket but oxy flu (n=11) (n=10) (n=11) Normal Grooming; sleeping; dreaming; tail (n=11) (n=5) (n=6) (n=10) wagging with normal, nonexuberant movements when aroused or called; eating when offered food Bandaging Other laboratories class Comfortable Sleeping or sitting with normal movements with or without slight discomfort when aroused or called, sedated ket but flu but relaxed (n=11) (n=10) (n=11) Assumed painful Crying, thrashing, biting, depressed, shaking, reluctant to move, splinted 1 adopte abdomen or nonweight bearing lameness

Nonrecovery procedures with acepromazine (Atravet, Wyeth-Ayerst, Don Mills, Postmortem Ontario), 0.2 mg/kg bodyweight (BW), IM. Anesthesia was induced with thiopental sodium (Pentothal sodium, Figure 1. Outline of groupings and procedures performed Abbott Laboratories, Mississauga, Ontario), 10 on dogs in this study. ket = ketorolac; but = butorphanol; mg/kg and maintained on flu = flunixin; oxy = oxymorphone. BW, IV, halothane (Fluothane, Wyeth-Ayerst) and 100% oxygen. A surgical plane of anesthesia was assessed standard clinical and antipyretic properties (6-9). In laboratory animals by monitoring techniques and an and humans, the analgesic potency of ketorolac is closely supervised by anesthetist sig- and anesthesia technician. The were nificantly greater than that of other NSAIAs dogs randomly (9,10). assigned (by computer) to receive butorphanol Adverse effects of the are (Torbugesic drug similar to those of other Ayerst Laboratories, St. Laurent, Quebec) 0.4 NSAIAs and include a predisposition for gastrointesti- mg/kg BW (n = 21), ketorolac 0.5 mg/kg BW (n = 22), or flu- nal irritation and ulceration, impairment of renal func- nixin tion in compromised patients, and inhibition of platelet (Banamine Solution, Schering-Plough Animal function (8,9,11,12). Health, Pointe Claire, Quebec) 1.0 mg/kg BW (n = 21) (Figure The were withdrawn into a The use of ketorolac in 1). analgesics syringe veterinary medicine has not and diluted to standardized volumes with saline been reported. The purpose of this was to by study inves- 2 technicians not involved in the laboratory. The tigate ketorolac in a perioperative setting and compare syringes were identified by a number and given to the anes- it with currently accepted analgesic agents for efficacy and adverse effects. thetist. The opioid, oxymorphone hydrochloride (Numorphan, Dupont Pharma, Mississauga, Ontario), was to be administered to effect in boluses of 0.05 to Materials and methods 0.1 mg/kg BW as a rescue protocol to any animal in This study was approved by the Animal Care Committee, which adequate analgesia could not be attained within University of Guelph and all animals were treated 15 to 20 min following 2 consecutive injections of the humanely in accordance with its guidelines. The study assigned analgesic. Initially, the test analgesics were period was from September 1992 through April 1993. administered IM prior to the skin being incised and Sixty-four dogs were used in the study. Fifty-eight bea- again at 3-hour (butorphanol) or 6-hour (ketorolac and gle dogs, purchased from a commercial breeder, and flunixin) intervals for 4 (butorphanol) or 2 (ketorolac and 6 mixed-breed dogs, weighing between 10 to 23 kg, flunixin) additional doses after the initial dose. Saline was were obtained for use in the junior surgical exercises administered in place of ketorolac and flunixin at the laboratory. Sixty-two dogs were <3 y and 2 were esti- 3-hour interval to maintain the blinded status of the mated to be between 5 and 7 y. The only abnormality study protocol. Postoperatively, if the animals appeared present in these dogs was soft stool, secondary to to be in pain prior to scheduled redosing, the appropri- Toxocara canis infection, which resolved after treat- ate drug was administered early. Because butorphanol ment with pyrantel pamoate (Pyr-A-Pam, rogar/STB, failed to provide adequate analgesia in dogs (n = London, 5) Ontario). recovering from shoulder arthrotomy in the 1 st semester, it was replaced by oxymorphone 0.05 mg/kg BW, as Surgical procedure, anesthesia and analgesia the opioid comparison, in the 2nd semester in dogs All dogs underwent either = or laparotomy (n 32) shoul- undergoing shoulder arthrotomy (n = 6) (Figure 1). der = arthrotomy (n 32). Each group of 32 subjects This dose of oxymorphone was selected, as it is the was further divided into 2 subgroups of 16, which were dose currently recommended initially for orthopedic operated on 3 mo apart (16 laparotomy and 16 shoulder pain by the anesthetists at the Ontario Veterinary College. arthrotomy procedures were conducted during the 1st and The surgical procedure was performed by 3rd year vet- 2nd semesters) (Figure 1). Each dog was premedicated erinary students with close supervision by 2 surgeons, 558 Can Vet J Volume 37, September 1996 Table 2. Overall analgesic efficacy score Table 3. Objective assessment of pain

4 = Excellent Normal exuberant activity prior to time Vocalization Score of 2nd analgesic injection (within 3 h of None 0 recovery) that continued throughout the Intermittent 1 12-hour period. Persistent 2 Movement Score 0 3 = Good Comfortable recovery prior to 2nd anal- Normal or calm gesic injection (within 3 h of recovery) Restless I with normal activity, which was main- Thrashing 2 tained after the administration of anal- Respiratory pattern Score gesic and continued throughout the Normal 0 12-hour period. Mild abdominal component I Marked abdominal component 2 2 Acceptable Comfortable recovery prior to 2nd anal- 0 = = mild 3-4 = mod- injection, where the dog's behav- Total score: no pain; 1-2 pain; gesic erate pain; 5-6 = severe pain ior improved after the injection but only gradually recovered to normal activity throughout the 12-hour period.

= Inadequate Painful recovery where repeated analgesic injection was not effective in alle- scores (objective analgesic assessment) and the overall viating pain and oxymorphone was efficacy score (subjective analgesic assessment) were required throughout the evening analysed separately. Subjective analgesic assessment All activities were recorded in detail, and subsequently and the duration of anesthesia ranged from 3 to 4 h. All assessed as normal exuberant, normal, comfortable, or dogs recovered and IV fluid therapy was discontinued painful (Table 1). An overall subjective analgesic effi- upon completion of the surgical procedure. Analgesic cacy score was recorded, based on the assessment of each assessment began after extubation. dog's behavior relative to administration of the post- One week after surgery, the 32 dogs in the laparotomy operative analgesics and its activities throughout the group were again anesthetized, in a similar manner, study period (Table 2). The demeanor recordings for a laboratory class on bandaging techniques (Figure 1). included whether the dog was acting normally (includ- The same analgesic that had been administered in the ing sleeping), was sedated (no or minimal response to laparotomy laboratory was given after anesthetic induc- voice or tactile stimulation, presumed to be drug tion. Butorphanol administration was repeated 3 h later, induced), or was depressed or distressed. At the end of but a placebo was given instead to those that had the study period, the overall efficacy scores of the received ketorolac or flunixin. No further analgesics were 2 investigators were compared. administered. The analgesics were administered to assess behavior upon recovery as a comparison with Objective analgesic assessment the recovery behavior after the previous laparotomy The objective assessment used (Table 3) was similar to laboratory. One dog from the butorphanol study group one previously reported (13) and was based on vocal- was adopted after the bandaging laboratory. The remain- ization, abnormal respiratory pattern, and movement. The ing 31 dogs were reanesthetized 1 wk after the ban- final score was created by summing the scores of all of daging class for a nonrecovery, femur pinning proce- the parameters at each time interval for each dog (a min- dure and a 4-hour, multiple procedures laboratory, imum of 0 and maximum of 6 for each dog at each after which they were euthanized. Postmortem exami- time interval). As vocalization and weight bearing were nation was performed on these 31 dogs. Postmortem considered to be objective parameters for analgesic examination was not performed on dogs in the shoul- assessment, they were tabulated for each drug. der arthrotomy group, as they were required for other In order to assess the effects of the drugs on behavior laboratories. in the absence of pain, the behavior of each animal was assessed during and after recovery from the ban- Analgesic assessment daging laboratory held 1 wk after the laparotomy. Two of the investigators (KAM, DP), working inde- Abnornal behavior, such as vocalization and depression, pendently, assessed each dog. The students caring for after the bandaging laboratory was assumed to be drug each dog, all of whom were unaware of the drug each dog induced, so similar behavior after laparotomy could be had received, were involved from a teaching perspective. interpreted in a similar manner. However, differences in Following extubation, physiologic parameters (tem- behavior following the 2 laboratories were interpreted as perature, pulse, respiration), behavioral activities being due to pain. (Table 1), and pain scores (Table 2) were recorded hourly for 12 h after laparotomy and for 13 h after Renal and hepatic effects arthrotomy. All dogs recovered in a cage. When their Serum urea, creatinine, and alanine aminotransferase body temperature was normal, they were returned to a (ALT) concentrations were measured preoperatively run, 3 X 2.5 m, where voluntary ambulatory and play- (baseline), and at 24 h and 48 h postoperatively in each ing activity was assessed. Comparison among dogs was dog. The measurements were analyzed as change from facilitated by the close proximity of each run. The pain baseline at 24 h and 48 h for each dog. 559 Can Vet J Volume 37, September 1996 Gastrointestinal effects All feces were examined grossly for blood and melena preoperatively and for 5 d postoperatively. Examination for fecal occult blood was planned; however, due to 100 unavailability of the test product, assessment was restricted to gross evaluation. 75

Pathology L- a) 50 The kidneys, stomach, pylorus, and duodenum were 0- examined grossly and histologically from all dogs, except 1 that was adopted, that underwent laparotomy 25 and were treated with ketorolac (n = 11), butorphanol (n = 9), or flunixin (n = 11). Pieces from the fundic, pyloric, and cardiac areas of the stomach and from the 0 duodenum were taken randomly from each of the 31 dogs. The kidneys were cut longitudinally in half and the tissues were placed in a large volume of 10% buffered neutral formalin for a minimum of 48 h. A thick (3 mm) wedge of kidney tissue, including capsule, 100 cortex, medulla, and pelvis, was cut from the center of the kidney and pieces of stomach and duodenum 4-, 75 were further trimmed, usually within 96 h. Tissues were ci processed routinely, embedded in paraffin, sectioned at U1 6 um and stained with hematoxylin and eosin. One sec- VL. .50 tion from each tissue was examined. Histological observations were made and recorded for each slide without 25 knowledge of the treatment the dog had received. Changes commonly seen in the stomach and duodenum of such as 0 dogs, the presence of lymphoid follicles KETOROLAC FLWNraN OXYMORPHONE BUTORPHANOL and spiral-shaped bacteria, were noted initially but not recorded as changes attributable to any drug therapy. =excellent ;good =acceptable Einadequate Statistical analysis Figure 2. Overall subjective assessment of analgesic effi- Continuous variables including urea, creatinine, ALT, cacy after laparotomy and shoulder arthrotomy for ketorolac, flunixin, oxymorphone (shoulder arthrotomy only), and temperature, respiration, and pulse were statistically butorphanol. evaluated by analysis of variance to determine if differences existed between treatments. When significant After the 8-hour dose, only 1 dog remained in the butor- differences were found, Duncan's multiple range test was phanol subgroup. Three dogs in the used to statistical laparotomy group identify significance between pairs of required rescue oxymorphone (0.15-0.2 mg/kg BW) means. Means are expressed as a number ± s. Frequency to control tables were generated for pain. All of these dogs had received butorphanol. the objective pain scores Following the bandaging laboratory, all dogs recov- (vocalization, movement, and respiratory pattern), the ered uneventfully. No dogs vocalized, scored variables of efficacy, as well developed abnor- as demeanor and mal respiratory patterns, or displayed abnormal move- weight/bearing. Fisher's exact chi-square test was ments, except for incoordination, while performed to determine significant differences in the attempting to frequencies between walk during the 1- to 3-hour recovery period. At 4 h the drug treatment groups. Through- postrecovery, all dogs ate a small meal and were out the analysis, values of P < 0.05 were deemed to con- be significant. sidered clinically normal. Analgesic efficacy Results The analgesic efficacy for each drug was analysed sep- All dogs completed the study and were included in the arately after laparotomy and shoulder arthrotomy, as analysis of analgesic efficacy. All dogs in the laparotomy visceral pain and somatic pain are different. group, excluding one that was adopted, were examined at postmortem. Four animals in the shoulder arthro- Subjective assessment tomy group that had received butorphanol were con- The overall subjective efficacy scores after laparotomy sidered to be in severe pain because of persistent were 3.4 for ketorolac, 2.7 for flunixin, and 1.6 for vocalization, clamping of jaws and feet on the cage butorphanol (Figure 2). There was a significant differ- door, or attempts to bite the caregiver after 2 doses of the ence between the scores for butorphanol and flunixin, analgesic had been administered. Each of these dogs and butorphanol and ketorolac, but not between those for received oxymorphone IV, until comfortable (approxi- ketorolac and flunixin. mately 0.15 to 0.2 mg/kg BW). From the time of oxy- The overall subjective efficacy scores after shoul- morphone administration, these dogs were not included der arthrotomy were 3.5 for ketorolac, 3.0 for flunixin, in the statistical analysis of the butorphanol subgroup. 2.0 for oxymorphone, and 1.4 for butorphanol (Figure 2).

c Ll- A 56() Can Vet J Volume 37, September 1996 100 _~ normal 4-,- c 75 - mII sedated

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0 0 1 2 3 4 5 6 7 8 9 10 11 :5siislliill~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~1 2 3 4 5 6 7 8 9 10 11 Time (hours) Time (hours)

Figure 3. Hourly postoperative assessment of dogs' demeanor after laparotomy and receiving butorphanol (n = 10), flunixin (n = ll), orketorolac (n = l1).

There was a significant difference between the scores for the ketorolac or flunixin subgroups. No difference in ketorolac and butorphanol and ketorolac and oxymor- pain score was determined between either butor- phone, and between those for flunixin and butorphanol phanol and oxymorphone or ketorolac and flunixin and flunixin and oxymorphone. There was no significant (Figure 5). difference between those for ketorolac and flunixin or The percentages of dogs bearing weight on the oper- oxymorphone and butorphanol. ated limb in the shoulder arthrotomy group throughout The 2 observers differed by 1 point (2 vs 3 or 3 vs 2) the observation period are shown in Figure 6. By 24 h, in only 3 of the 64 evaluations. all dogs were bearing weight similarly on the oper- The demeanor of the dogs assessed in the butor- ated limb. phanol subgroup was significantly different from that of The percentage of dogs in the shoulder arthrotomy those in the flunixin and ketorolac subgroups for both group that vocalized was significantly higher in the the laparotomy and arthrotomy procedures over time butorphanol and oxymorphone subgroups when com- (Figures 3 & 4). The demeanor after oxymorphone pared with the ketorolac and flunixin subgroups administration to dogs in the arthrotomy group (Figure 7). Persistent vocalization required repeated approached a significant difference over time from that or early assigned analgesic therapy, or oxymorphone to after administration of both flunixin and ketorolac. effect. None of the dogs in the laparotomy group vocalized. No significant differences in demeanor appeared The approximate duration of analgesia for each drug between oxymorphone and butorphanol or between was based on pain assessment for each dog at each flunixin and ketorolac. hour postoperatively and the change in behavior after administration of analgesia. (Table 4). As the analgesic Objective assessment was routinely given at 3 or 6 h ± 30 min (this procedure No significant differences were found between the together with the pain assessment took approximately pain scores of the dogs in the laparotomy group. For the 1 h) the duration of action beyond 6 h could not be shoulder arthrotomy, the sum of the pain scores showed evaluated in those dogs that appeared normal. Some a significant difference between the scores obtained dogs, however, appeared uncomfortable, requiring from dogs in both the butorphanol and oxymorphone repeat administration of analgesia prior to the sched- subgroups, over time, when compared with those of uled redosing.

CanCa VetVe J VolumeVoum 37,37 SeptemberSet 1996199 56156 100 100

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Figure 4. Hourly postoperative assessment of dogs' demeanor after shoulder arthrotomy and receiving butorphanol (n = 5), oxymorphone (n = 6), flunixin (n = 10), or ketorolac (n = 11).

Vital signs was of no clinical significance. After the laparotomy, Initially, after laparotomy, there was a significant dif- there was no significant difference in respiratory rates ference in temperature between the ketorolac and butor- between drugs over time. phanol and the ketorolac and flunixin subgroups. However, this was of no clinical significance. For shoul- Gastrointestinal effects der arthrotomy, there was no significant difference There was no difference in the rate of occurrence of blood among any of the drug subgroups. in the feces or of melena in either the shoulder arthrotomy After both laparotomy and shoulder arthrotomy, there or laparotomy groups. These data were therefore pooled was a significantly lower pulse rate, over time, with the for further analysis. Blood was present in the feces opioids than with ketorolac or flunixin. However, all immediately after recovery in 4 dogs in the butorphanol, remained within normal limits. 3 in the ketorolac, 5 in the flunixin, and 2 in the oxy- After shoulder arthrotomy, there was a significant morphone subgroups. Melena was only present in 1 dog difference in respiratory rate, over time, in dogs receiv- in the ketorolac and 1 in the flunixin subgroup on the ing butorphanol compared with those receiving ketoro- 1st postoperative day and 1 dog in the butorphanol lac and with those receiving flunixin. However, this subgroup on the 2nd postoperative day. The color of the

562 Can Vet J Volume 37, September 1996 There was a significant increase of 19.14 ± 5.47 umol/L 1.75 - LAPAROTOMY in mean creatinine from the preoperative to day levels 1.50 - in the dogs receiving flunixin but not in the dogs receiv-

aI) 1.25 - ing ketorolac or oxymorphone, or to day 2 in any group. The difference in 1.00 - change from the preoperative level in creatinine was significant between flunixin and butor- 0.75 - U) phanol and flunixin and oxymorphone, but not between 0- 0.50 - flunixin and ketorolac. The difference between ketoro- 0.25 - lac and oxymorphone or butorphanol approached sig-

0.00 - nificance (Figure 9). One dog in the shoulder arthrotomy group that received flunixin had an increase in serum 0 2 4 6 8 10 12 1 4 creatinine from baseline of 89 umol/L to 211 umol/L on the 2nd postoperative which returned to 1.75 SHOULDER ARTHROTOMY 1 day, 110 umol/L by day 12 without therapy. This was 1 of the older 1.50 - dogs in the study. The creatinine level in the remaining 6L) 1.25 - dogs in all groups remained within the normal range for 0 1.00 - our laboratory. U) 0.75 - 0 Pathology a- 0.50 - Abnormalities were detected in 6 dogs treated with 0.25 - ketorolac. Four dogs had marked dilation of the lumen 0.00 of the renal medullary tubules and attenuation of the epithelium; in 2 dogs, the changes also involved the cor- 0 2 4 6 8 10 12 14 tex. Some tubules contained epithelial cells with pyknotic Time (hours) nuclei. Ulceration of the pyloric region of the stom-

0 BUTORPHANOL v OXYMORPHONE o FLUNIXIN * KETOROLAC ach was seen in 2 dogs; one had superficial loss of epithelium and attenuation of surrounding cells and

Figure 5. The mean ± s of the hourly summed pain score of the other had an ulcer 4 mm in diameter, edema of the dogs after receiving butorphanol, oxymorphone (shoulder lamina propria, and infiltrates of macrophages and neu- arthrotomy only), flunixin, or ketorolac. For clarity, only the trophils. One foveola had neutrophils within it. negative or positive s bars are shown. Total score: 0 = no pain; Two dogs treated with butorphanol had dilation of the 1-2 = mild pain; 3-4 = moderate pain; 5-6 = severe pain. lumen of the renal medullary tubules and attenuation of the epithelium, and separation of the tubules. mucous membranes, capillary refill time, and packed cell Three dogs treated with flunixin had dilation of the volume remained within normal limits in these dogs. One tubular lumina and attenuation of the epithelium in dog that received ketorolac following shoulder arthro- radial bands that ran from the cortex to the medulla. In tomy and had melanic stool received subcutaneous 2 of these dogs, there were groups of cortical tubules sim- fluids to correct mild dehydration. ilarly affected, such that there were radial streaks of Of note, many dogs were copraphagic, which made dilated tubular lumina. One dog had dilation of the examination and assessment of each bowel movement lumen of all medullary tubules. One dog had focal difficult; however, at least one assessment per day superficial epithelial erosion and attendant neutrophils was possible. and macrophages in the stomach. Renal and hepatic effects Discussion The preoperative concentrations of serum ALT, urea, and Flunixin (14) and butorphanol (15) are currently used in creatinine were all within normal reference intervals for veterinary clinical practice for the control of pain. all dogs (ALT, 0 to 120 U/L; creatinine, 42 to 150 umol/L; Ketorolac has been reported to be as effective as morphine and urea, 2.1 to 9.7 mmol/L). There was no signifi- in managing postoperative pain in humans (16-18). cant difference between the shoulder arthrotomy and The dose and dosing interval, based on the assumed the laparotomy groups with respect to changes in duration of action of ketorolac used in this study, was serum creatinine, urea, and ALT, so the laparotomy extrapolated from human data (16-18). We chose a and shoulder arthrotomy results were combined and dosing interval of 6 h but felt that this could be longer. the effects of each drug subgroup (ketorolac n = 22, flu- A similar duration of activity was noted for flunixin. The nixin n = 21, butorphanol n = 15, and oxymorphone reported duration of activity for butorphanol is 3 to 6 h, n = 6) were assessed. oxymorphone 6 h, and flunixin 24 h (4,19), which are The only mean change of any significance in serum longer times than those found in this study. In 2 other ALT was that of 29.86 ± 9.5 U/L in the flunixin subgroup reports, the recommended dosing schedule for flunixin from baseline to day 1. This change in serum ALT over was every 24 h (15,20), with no indication as to whether time was significantly different from changes over 2 d this was based on efficacy or safety. We found that in the ketorolac, butorphanol, and oxymorphone sub- ketorolac given at 0.5 mg/kg BW was as effective an groups (Figure 8). analgesic agent as flunixin and consistently more effec- There was no significant increase in serum urea from tive than butorphanol or oxymorphone for the relief of baseline to day 1 or 2 for all 4 analgesics. the postoperative pain experienced in this study. These

Can Vet J Volume 37, September 1996 563 Figure 6. The percentages of dogs bearing weight on the operated limb each hour after recovery from shoulder arthrotomy, while receiving butorphanol (n = 5), oxymorphone (n = 6), flunixin (n = 10), or ketorolac (n = 11). No dogs receiving butorphanol were bearing weight and 4 were removed from the study during the first 8 h.

effects were particularly evident in the group of dogs that experiencing, based on a) the response of the individual underwent shoulder arthrotomy. Due to its lack of effi- dog to the analgesic administered and b) the fact that the cacy in controlling what was interpreted to be severe animal response to each analgesic appeared consistent postoperative pain, butorphanol was replaced by oxy- throughout. This is strongly supported by the fact that the morphone in this group. General demeanor, appetite, and study was blinded, with random assignment of drugs to ambulation were consistently good to excellent in the dogs of the same breed in most instances. Using the ban- ketorolac subgroup and in the flunixin subgroup. daging laboratory as a control for each dog, we assumed In this study, the lower efficacy score for oxymorphone that any difference in behavior upon recovery from the is probably due to the low dosing of 0.05 mg/kg BW. bandaging laboratory and the laparotomy procedure When no supplemental analgesic techniques, such as would be related to pain and not associated with any epidural or local anesthesia, are used, a higher dose of drugs or inhalant anesthetic used. All dogs returned to oxymorphone is necessary. their normal activities by 4 h after recovering from the Meaningful quantification of pain was based on pre- bandaging laboratory. Where similar behavior occurred viously reported methods for assessing physiologic and during this time period after recovering from the laparo- behavioral parameters in animals experiencing pain tomy procedure, we concluded that the analgesic used in (1,2,13,21-24). In addition, we assessed behavior as that particular dog prevented pain and was considered to outlined in Table 1. Recognition of a measurable pain be an excellent analgesic. Conversely, if a dog vocalized response involves physiological and behavioral obser- after recovering from the laparotomy procedure, we vations, as well as some degree of anthropomorphism assumed it was due to pain, as no dogs vocalized after the (1,2,13,21-23). We used these parameters in assess- bandaging laboratory. As there were behavioral differ- ing pain and the animals' response to analgesics admin- ences in some dogs recovering from the laparotomy istered to them. We believe the subjective assessments procedure, when compared with their recovery from accurately reflect the level of pain these dogs were the bandaging laboratory, we assessed these animals as

564 Can Vet J Volume 37, September 1996 CREATININE

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L.0) a- 50 -

60 25 - Of 0 1 2 Time (days)

* BUTORPHANOL v OXYMORPHONE o FLUNIXIN * KETOROLAC KErOROLAC FLUNIXIN OXYMORPHONE BUTORPHANOL _ none intermittent :Zpersistent Figure 9. The mean ± s levels of serum creatinine (umol/L) for dogs in each analgesic subgroup preoperatively (day 0) and at Figure 7. The percentage of dogs observed to vocalize at days I and 2 postoperatively. For clarity, only the negative or any time after recovery from shoulder arthrotomy while positive s bars are shown. receiving ketorolac, flunixin, oxymorphone, or butorphanol. gesic (lowering the score during the next hour). When II this dog's high score was analyzed with the lower 80 - ALT scores of the other dogs in the group, at that observation period, the scored average was 1-2 (mild pain). This sit- 70- uation was repeated at subsequent observation periods with different dogs having a high score. Also, an objec- 60-

-j tive score in an individual dog could be low (no vocal- D) 50- ization, not thrashing with minimal changes in respiratory pattern), yet that dog could be in severe pain. As an 40- example, some dogs clamped their jaws on the cage door, while others attempted to bite the caregiver, 0 // t 1 30 behavioral activities not reported to occur at any other time and only in those dogs receiving butorphanol. The 0 1 2 scoring system, however, did confirm that the dogs in the Time (Days) NSAIA subgroups were in less pain than the dogs in the opioid subgroups. * BUTORPHANOL v OXYMORPHONE o FLUNIXIN * KETOROLAC When demeanor is used to assess pain, the strength of the evaluation lies in assessing the animal as normal. Figure 8. The mean ± s levels of serum alanine aminotransferase (UAL) for dogs in each analgesic subgroup preoperatively Those animals that are sedated cannot be accurately (day 0) and at day 1 and day 2 postoperatively. For clarity, only assessed for pain and those that are categorized as depressed the negative or positive s bars are shown. or distressed are open to subjective interpretation. The heart rate data showed that the opioid agents feeling pain and administered an analgesic. The favor- resulted in a consistently lower heart rate than did the able response to the analgesic therapy confirmed that NSAIAs in both surgical procedures. This may be due to these dogs were in pain. the opioid action of lowering, or preventing, an increase At the present time, there are no validated objective in heart rate through a direct stimulation of the medullary measurements of pain in animals; however, pain assess- vagal nuclei (25). Objective pain assessment has tradi- ment based on an objective scoring system, which is pri- tionally been judged against heart rate. However, in marily physiological (heart rate, respiratory pattern, our experience and on the basis of the results in this and vocalization) has been reported (13) and was used study, heart rate (unless elevated) is an unreliable indi- in this study. The results of objective measurements cator of pain in an animal that has received opioids. here differed from those of the subjective assessment Conversely, animals in groups receiving the NSAIAs based on behavior. The objective scoring system assessed tended to have higher heart rates. This may have been that the dogs that had shoulder arthrotomy and received because they were not in pain, which allowed normal butorphanol were experiencing mild pain, whereas the activity and the associated excitement with all the atten- behavioral assessment indicated they were in severe tion they were receiving. pain. This is due to the calculation of the mean score for There was no drug-induced depression in the respi- the objective assessment at each observation time. For ratory rate of any dog. We attributed the higher respi- example, there may have been 1 dog that had a score of ratory rate of the dogs that received butorphanol after 5-6 (severe pain); this dog would then receive an anal- shoulder arthrotomy as an indication of pain. We chose

Can Vet J Volume 37, September 1996 565 to use respiratory pattern as an objective assessment of mals had the same lesions. The most likely inciting pain, based on the 1st author's previous observations that cause in our dogs was hypotension during the surgical animals in pain had higher than normal rates with the period, possibly a direct effect of the anesthetic agent and abdomen noticeably rising on inspiration followed by an high dose acepromazine. Both halothane (31) and ace- exaggerated push on expiration. The abdominal com- promazine (25) can cause hypotension. Nonsteroidal ponent appears to be associated with attempts at crying anti-inflammatory analgesics may have exacerbated with minimal or no vocalization. A similar description the lesions. to this has been reported (19). This exaggerated pattern, The occurrence of melena was low but happened which is quite different from the respiratory pattern with each drug. Blood was present in the feces imme- during restful sleep, smooth and slow, is abolished diately upon recovery in dogs of all treatment groups. after administration of an appropriate analgesic. This can be explained by several factors associated The body temperature of dogs after laparotomy was with possible acepromazine and halothane hypoten- significantly reduced immediately postoperatively, sion or perioperative stress. During periods of low cir- probably as a result of heat loss associated with the culating blood volume (hypotension) and subsequent long duration of anesthesia and an open abdomen. The increase in sympathetic nervous system stimulation, significant decrease in body temperature in the dogs vasoconstriction occurs, with possible persistence of receiving ketorolac compared with the other dogs may venoconstriction (32-34). A stress induced endocrine have been due to a more potent antipyretic effect of response (35) may also have caused splanchnic vaso- ketorolac, although this has not been noted in our clin- constriction perioperatively. Examination for fecal ical cases (unpublished observations) nor was it seen in occult blood would have been more informative than the dogs after shoulder arthrotomy. gross examination alone; however, due to the unavail- A major pharmacological activity of NSAIAs is ability of the test product, assessment was restricted thought to be the inhibition of the enzyme cyclo-oxygenase to gross evaluation. The use of NSAIAs has been asso- and a reduction of prostaglandin synthesis (26). Under ciated with gastrointestinal ulceration and bleeding, conditions of reduced renal blood flow, such as, anes- and the likelihood of this adverse effect occurring thesia and surgery, hypovolemia, hypotension, dehy- increases when additional risk factors, such as, stress of dration, and renal insufficiency, the local synthesis of surgery, geriatric status, the concomitant use of corti- vasodilating prostaglandins is important in maintaining costeroids, dehydration and hypotension are present renal medullary blood flow (26). Impairment of renal (7,36,37). Gastric erosion or ulceration was noted in function has been reported with the use of NSAIAs, 3 dogs that had been given NSAIAs. The most severe the prevalence of which increases in geriatric, hypoten- lesion was seen in 1 dog given ketorolac. sive, and dehydrated patients, and in those with renal The serum ALT remained unchanged in all dogs, insufficiency (26). In this study, serum creatinine and except those receiving flunixin. Increases in ALT can be urea remained within normal limits in all dogs except one associated with many NSAIAs (38). receiving flunixin. Five of 8 dogs receiving flunixin, 2 of In conclusion, we believe that ketorolac is an excel- 8 dogs receiving ketorolac, and 1 of 8 dogs receiving lent analgesic and appears to have minimal side effects butorphanol experienced a greater than 30 umol/L when used perioperatively in young to middle-aged, increase in serum creatinine from baseline. We found well-hydrated dogs, provided that halothane or isoflurane there was a recovery to pretreatment concentrations is used for maintenance anesthesia. Flunixin produces after discontinuance of the NSAIA therapy. This obser- nephrotoxicity if used with methoxyflurane anesthe- vation has been described previously in humans (27). A sia (39). While ketorolac and flunixin were administered possible cause for the increase in creatinine and urea in preoperatively to dogs in this study to fully assess their those dogs receiving NSAIAs may be due to a period of potential side effects, this practice is not recommended. intraoperative hypotension. A recent study in humans, When contemplating the use of NSAIAs, one must specifically assessing renal function in postoperative consider the potential side effects of these drugs. We can- patients receiving parenteral ketorolac or placebo peri- not recommend the use of NSAIAs in any patient with- operatively, found no difference between the groups out giving serious consideration to renal function, the (28). Renal failure has been reported in dogs given a sin- potential for gastrointestinal ulceration, and coagulation gle parenteral dose of flunixin (29,30). We found that status (not examined in this study, but NSAIAs are dogs subjected to prolonged anesthesia and surgery (8 h) known to interfere with platelet function). Hepatic immediately prior to euthanasia and treated with NSAIAs function should also be considered prior to use of during the previous 2 wk were more likely to have NSAIAs, especially flunixin. microscopic lesions of acute renal medullary degener- As there is very little, if any, sedative effect associated ation than did those dogs treated with butorphanol. The with NSAIAs, the addition of low dose butorphanol lesions were acute, because there was only dilation of (0.02-0.04 mg/kg BW) or oxymorphone (0.05 mg/kg tubules and, in some cases, single cell necrosis of tubu- BW) prior to, or upon, extubation may be required in the lar epithelial cells. They could have been the result of young boisterous dog. The combination of ketorolac medullary or regional ischemia or hypoxia. Dilation 0.3 mg/kg BW and oxymorphone or butorphanol, at of tubular lumina can occur because of necrosis of single the above dose, upon completion of a surgical procedure cells and subsequent migration and thinning of residual where IV fluids have been administered, provides excel- cells to cover the deficit. While it is tempting to conclude lent analgesia in dogs with moderate to severe pain. that previous use of NSAIAs may have caused the Ketorolac can be repeated only once more in 8 to 12 h medullary degeneration, some butorphanol-treated ani- (Mathews, unpublished observations).

566 Can Vet J Volume 37, September 1996 Acknowledgements 25. Soma LR. Preanesthetic medication. In: Soma LR, ed. Textbook of Veterinary Anesthesia. Baltimore, Maryland: Williams The authors thank OVC '94 students for their assis- & Wilkins, 1977: 121-155. tance and care given to the dogs, and to Felicia Uriarte 26. Hamisk. The role of prostaglandins in the control of renal function. for data entry. cvi Br J Anaesth 1992: 233-235. 27 Pearce CJ, Gonzalez FM, Wallin D. Renal failure and hyper- kalemia associated with ketorolac tromethamine. Arch Intern References Med 1993; 153: 100-1002. 1. Kitchen H, Aronson, AL, Bittle JL, et al. Panel report on the 28. Aitken HA, Burns JW, McArdle CS, Kenny GNC. Effects of colloquim on recognition and alleviation of animal pain and ketorolac trometamol on renal function. Br J Anaesth 1992; 68: stress. J Am Vet Med Assoc 1987; 191: 1186-1191. 481-485. 2. Crane SW. Perioperative analgesia: A surgeon's perspective. J Am 29. McNeil P. 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Buckley MT, Brogden RN. Ketorolac: A review of its pharma- A, eds. Animal Pain. New York: Churchill Livingstone, 1992: codynamics and pharmacokinetic properties, and therapeutic 63-69. potential. Drugs 1990; 39: 86-109. 36. McKellar QA, May SA, Lees P. Pharmacology and therapeutics of 10. Forbes, JA, Butterworth GA, Burchfield WH, Beaver WT. non-steroidal anti-inflammatory drugs in the dog and cat: 2 indi- Evaluation of ketorolac, aspirin, and acetaminophen-codeine vidual agents. J Small Anim Pract 1991: 225-235. combination in post-operative oral surgery pain. Pharmacotherapy 37. Vonderhaar MA, Salisbury K. Gastroduodenal ulceration associated 1990: 775-935. with flunixin meglumine administration in three dogs. J Am Vet 11. Syntex Laboratories Incorporated. Toradol IM (Ketorolac Med Assoc 1993: 92-95. Tromethamine) Prescribing Information. Palo Alto, California: 38. Canadian Pharmaceutical Association [CPA]. Compendium of Syntex Laboratories Incorporated; 1990. 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