Efficacy and Safety of Preoperative Etodolac and Butorphanol Administration in Dogs Undergoing Ovariohysterectomy
Eighteen dogs undergoing ovariohysterectomy were premedicated with etodolac, butorphanol, or their combination. Various parameters, such as blood pressure, isoflurane requirements, behavioral pain scores, plasma cortisol concentration, plasma glucose concentration, and mucosal bleeding time, were assessed. The integrated plasma cortisol values were significantly lower in the etodolac and etodolac with butorphanol groups. Dogs receiving etodolac and butorphanol had the lowest behavioral pain scores from extubation until the end of monitoring. Isoflurane concentration over time (area under the curve), buccal mucosal bleeding time, and indices of renal function were not significantly different among the treatment groups.
Introduction
Opioids have been commonly used to manage surgical pain in dogs.1 The consistency and efficacy of this class of drugs are difficult to dispute in the perioperative setting.1 Studies have shown that several nonsteroidal anti-inflammatory drugs (NSAIDs) are also effective in controlling postoperative pain in dogs.2–4 It has been proposed that a combination of an opioid and an NSAID may produce better analgesia than when either drug is used alone.5 Results from a previous study in dogs showed that a combination of an opioid and an NSAID resulted in a greater reduction in the minimal alveolar concentration of isoflurane than when either drug was used alone.6 Since NSAIDs may inhibit functional prostaglandins, concerns exist regarding the effects of these drugs on the kidney and the coagulation system.7 Side effects induced by prostaglandin inhibition may predispose to acute renal damage and increased intraoperative bleeding when NSAIDs are administered during the perioperative period.7
Etodolac is an NSAID commercially available in oral tablet form. It is approved in the United States for use in dogs to control osteoarthritic pain and inflammation.a Since etodolac has both analgesic and anti-inflammatory properties, it has the potential to be useful in treating other painful conditions, such as surgical pain. The side effects of etodolac in dogs when it is administered during the perioperative period have not been evaluated.
Butorphanol is an opioid commonly used for treating acute pain, and it reduces minimal alveolar concentration of isoflurane in dogs.6 Preoperative administration of butor-phanol or a combination of butorphanol with etodolac may decrease the amount of isoflurane anesthetic required for ovariohysterectomy (OHE); however, this isoflurane-sparing effect has not been previously evaluated in dogs undergoing surgery.
Plasma cortisol concentration may be used as a measurement of pain-induced distress in dogs after OHE.8–10 Measurement of cortisol is commonly utilized in research settings but is not as common in clinical settings.8,9 Plasma cortisol increases in response to stress.11 Although there is some debate regarding its ability to define true surgical stress, plasma cortisol may be a useful tool in assessing perioperative stress when opioids or NSAIDs are utilized.11 In the canine research model, plasma cortisol concentration has been considered a useful indicator of surgically induced stress.11
It was hypothesized that etodolac would have a similar analgesic effect in treating postoperative pain as butor-phanol, and that etodolac in combination with butorphanol would produce a better analgesic effect than either drug used alone. The purpose of the study was to evaluate the efficacy and safety of etodolac, butorphanol, or a combination of both agents administered preoperatively in dogs undergoing OHE. A specific objective of the study was to compare the effects of these medications on isoflurane anesthesia requirements, certain physiological parameters, behavioral pain scores, plasma cortisol and plasma glucose concentrations, mucosal bleeding time, and renal function.
Materials and Methods
This study was conducted with Institutional Animal Care and Use Committee approval. Eighteen, 1-year-old, healthy, mixed-breed hound-type dogs, weighing 18±2 kg (mean ± standard deviation), were randomly assigned to three treatment groups. One group of six dogs received etodolacb (12 to 14 mg/kg orally [PO]) 1 hour before induction of anesthesia. A second group of six dogs was given butorphanolc (0.4 mg/kg intravenously [IV]) immediately following endotracheal intubation, and a third group of six dogs was given etodolac (12 to 14 mg/kg PO) 1 hour before induction of anesthesia. These dogs later received butorphanol (0.4 mg/kg IV) immediately following endotracheal intubation.
Anesthesia was induced with propofol.d The calculated propofol dosage was 8 mg/kg IV, but the drug was administered to effect (i.e., until endotracheal intubation could be performed). Following endotracheal intubation, anesthesia was maintained by administration of isofluranee in oxygen. All dogs were mechanically ventilated to maintain end-tidal carbon dioxide (etCO2) concentrations between 35 and 45 mm Hg (reference range 35 to 45 mm Hg). End-tidal isoflurane concentration was recorded at 3 minutes following induction, at incision of the skin, at removal of the second ovary, at 5-minute intervals throughout surgery, and at extubation. The end-tidal gas concentrations were measured using a monitorf connected by a gas sampling tube to a 1.2-mm urinary catheter placed through the endotracheal tube to the approximate depth of the thoracic inlet of the trachea. The person recording the isoflurane concentrations was blinded to the treatment each dog received.
The same two experienced surgeons performed the OHE in all dogs. The total duration of anesthesia and surgery was recorded for each dog and compared between the treatment groups. A lead-II electrocardiogramg was monitored before induction and continuously throughout the experiment until the dog was moved to the recovery area. Noninvasive blood pressure was measured by an oscillometric monitorh with the cuff placed around the radial-ulnar portion of the ante-brachium. Heart and respiratory rates, rectal temperature, and systolic, diastolic, and mean arterial blood pressures were recorded at the following times: immediately prior to propofol induction (preanesthesia); at the times of the skin incision, removal of the second ovary, and extubation; and at 30, 60, 90, 120, 150, 180, and 300 minutes after extubation. A pulse oximeteri placed on the dog’s tongue monitored oxygen saturation of hemoglobin during surgery. Body temperature (via rectal measurement) was maintained during the surgery and recovery periods. Extubation was performed when the dog started coughing and/or gagging from the endotracheal tube.
Following extubation, two observers that were blinded to the treatments evaluated each dog’s behavioral response to postsurgical pain [Table 1]. Values for pain scores from both observers at each observation were determined and were averaged to yield a final score for analysis. It was predetermined that if any dog exhibited a pain score of 4 or 5, then an additional dose of butorphanol at 0.4 mg/kg IV would be provided. The number of dogs receiving additional butor-phanol was recorded and compared among treatment groups.
Plasma Cortisol Measurement
The jugular vein was used to collect blood samples for measurement of plasma cortisol concentrations. Blood samples were obtained immediately prior to propofol induction (preinduction) and at the times of the skin incision, removal of the second ovary, and extubation. Blood samples were also obtained at 30, 60, 90, 120, 150, 180, and 300 minutes after extubation. Additional blood samples were taken 1 day before surgery (day 0), the day of surgery (day 1; preanesthesia [2 hours prior to induction]), and 1 day after surgery (day 2). All blood samples were collected prior to recording the cardiorespiratory measurements. Blood samples were centrifuged, and plasma was removed and stored at −20°C until assayed 2 weeks later. Total plasma cortisol concentrations were determined by radioimmunoassayj at a clinical pathology laboratory.10 The lowest detectable concentration was 0.2 ng/mL, and the intra-assay and interassay coefficients of variation were 4.4% and 5.6%, respectively.
Other Assays
Plasma glucose concentration was also measured. Blood samples were obtained from the jugular vein immediately prior to propofol induction (preanesthesia) and at the times of the skin incision, removal of the second ovary, and extubation. Blood samples were also obtained at 30, 60, 90, 120, 150, 180, and 300 minutes after extubation. Additional blood samples were taken 1 day before surgery (day 0), the day of surgery (day 1; preanesthesia), and 1 day after surgery (day 2). All blood samples were collected prior to recording the cardiorespiratory measurements. The same clinical pathology laboratory that assessed the plasma cortisol concentrations also assessed the plasma glucose concentrations using the enzymic method.
Buccal mucosal bleeding time was assessed using a commercial testing kitk 1 day prior to etodolac administration and at the end of anesthesia prior to recovery. In addition, all used and unused gauze from the surgical pack was weighed after the surgery as a means to compare blood loss from each group. The urine gamma-glutamyltransferase (GGT) to urine creatinine ratio, blood urea nitrogen (BUN), and plasma creatinine were measured daily from 1 day before (day 0) to 3 days after surgery.
Statistical Analysis
A repeated measures, mixed-general linear model was used to analyze cortisol concentrations, heart and respiratory rates, rectal temperatures, and systolic, diastolic, and mean arterial blood pressures, with random effects of animal and time period. The trapezoidal method was used to calculate the area under the curve for the plasma cortisol concentrations over time (i.e., integrated cortisol value) and isoflurane anesthetic concentration over time. All data were analyzed using analysis of variance (ANOVA).l Multiple comparisons using the least significant difference were performed if the ANOVA was significant. The alpha value was set at 0.05.
Results
No significant differences were found between treatment groups for the induction dose of propofol used or the duration of surgery and anesthesia [Table 2]. Within each group, significantly higher (P=0.001) end-tidal isoflurane concentrations were recorded during the skin incision and removal of the second ovary when compared to 3 minutes following induction. End-tidal isoflurane concentrations during the skin incision and removal of the second ovary were similar in dogs receiving etodolac and butorphanol and in dogs receiving only butorphanol. Dogs receiving etodolac and butorphanol had significantly lower (P=0.01) end-tidal isoflurane concentrations than dogs receiving etodolac alone. The isoflurane area under the curve over the 55 minutes of anesthesia was not significantly different between treatment groups [Table 3].
All dogs maintained arterial hemoglobin oxygen saturation values between 95% and 100% during isoflurane anesthesia. Cardiorespiratory variables [Figures 1, 2, 3] fluctuated throughout the duration of monitoring. In all treatment groups, there was a tendency for heart rate, blood pressure, and respiratory rate to increase following extubation when compared with preanesthetic measurements, but none of the results were statistically significant. Among all the treatment groups, there were no significant differences noted in any of the cardiorespiratory variables over time (i.e., during anesthesia and recovery).
Pain Scores
None of the dogs reached pain scores of 4 or 5; therefore, none received additional butorphanol. The behavioral pain score [Figure 4] from extubation to the end of the study was significantly lower (P=0.01) in the etodolac with butor-phanol group. The behavioral pain scores were similar in the etodolac only and butorphanol only treatment groups.
Plasma Cortisol Concentration
In all treatment groups, plasma cortisol concentrations [Figure 5] increased after the skin incision when compared to preanesthetic values. This increase was physiologically significant but not statistically significant. In all treatment groups, plasma cortisol levels reached a statistically significant difference (P=0.01) at extubation when compared to preanesthetic levels. In the etodolac alone and the etodolac with butorphanol groups, the plasma cortisol concentrations peaked at 30 minutes after extubation and then started to decrease. In contrast, plasma cortisol concentrations in the butorphanol group peaked at 60 minutes. In the etodolac with butorphanol group, plasma cortisol concentrations began to return to preanesthetic levels 90 minutes after extubation. In the etodolac only group, plasma cortisol concentrations began to return to preanesthetic levels at 120 minutes after extubation. In the butorphanol group, plasma cortisol concentrations did not return to preanesthetic levels until 150 minutes after extubation. The integrated cortisol value (area under the cortisol curve) was significantly lower in the etodolac alone (P=0.01) and etodolac with butor-phanol (P=0.01) groups when compared with the butor-phanol only group [Table 4].
Other Assays
Plasma glucose concentrations [Figure 6] followed a trend similar to the plasma cortisol concentrations from the time of skin incision until the 300-minute measurement. In the butorphanol group, plasma glucose concentrations following skin incision were significantly (P=0.05) increased from preanesthetic values. In contrast, plasma glucose concentrations did not differ significantly from preanesthetic values until 30 minutes after extubation in either the etodolac or etodolac with butorphanol groups. Plasma glucose concentrations returned to preanesthetic levels by 90 minutes after extubation in the etodolac with butorphanol group and by 120 minutes in the etodolac only group. Plasma glucose concentrations in the butorphanol group did not return to preanesthetic values until 150 minutes after extubation.
There were no significant differences in the buccal mucosal bleeding times before and after surgery in any treatment group or between treatment groups. All bleeding times were within normal limits (43 to 145 seconds) and were <3 minutes. The weights of the surgical gauze did not differ significantly among the treatment groups. No oozing at the surgical wound was observed on any dog during the postoperative period (days 1 to 3). Blood urea nitrogen, plasma creatinine, and the urine GGT to creatinine ratio were not significantly different between or within treatment groups over time [Table 5].
Discussion
The required induction dose of propofol was similar among dogs in all of the treatment groups. As expected, etodolac did not have a propofol-sparing effect, probably because it does not possess any sedative effects. Similar results have been reported in dogs treated with ketoprofen preoperatively and induced with thiopental for OHE.12
In a previous study, a combination of butorphanol and carprofen caused the greatest reduction in the minimal alveolar concentration of isoflurane in dogs when compared to saline, carprofen, or butorphanol.6 In the present study, dogs receiving the butorphanol-etodolac combination had significantly lower end-tidal isoflurane concentrations during the skin incision and removal of the second ovary when compared to dogs treated with etodolac or butorphanol alone. However, when the isoflurane area under the curve over the 55 minutes of anesthesia was analyzed, there were no significant differences among the treatment groups. Perhaps the buffering effect of the breathing circuit on the rate of change of isoflurane concentration in the airway and its impact on the alveolar concentration of isoflurane may have obscured isoflurane concentration differences between the treatment groups. Other explanations for these differences may have been a lack of sensitivity in detecting subtle differences between treatment groups in the overall anesthetic concentration when using area-under-curve data. In addition, different noxious stimuli were used in the two studies (i.e., tail clamp versus OHE). Similar to etodolac, the lack of isoflurane-sparing effect required to maintain anesthesia in dogs undergoing OHE has been reported.12
Following extubation, heart and respiratory rates increased; however, these increases were not statistically significant, despite a corresponding increase in plasma cortisol and glucose concentrations. Results of the present study suggest that preoperative administration of etodolac, with or without butorphanol, is a safe and effective method of controlling postoperative pain following OHE for up to 5 hours (end of monitoring period). The results also indicate that etodolac combined with butorphanol is more effective than either drug alone at alleviating acute pain, based on behavioral pain scoring and integrated plasma cortisol values.
Animal behavior in response to pain can be difficult to interpret after surgery. Several types of behavioral pain scores (e.g., visual analogue and numerical rating scales) have been assessed following various types of surgeries, and these scores have been compared with objective measurements (e.g., heart rate, respiratory rate, blood pressure) and have been found to correlate poorly to very well with objective measurements.13 The pain score criteria used in this study were based on descriptive behaviors and were unable to distinguish any differences between the etodolac only and butorphanol only treatment groups, despite the difference in plasma cortisol and glucose concentrations.
It has been reported that pain-induced stress, as assessed by changes in plasma cortisol concentrations after OHE, may persist for 5 hours after surgery in dogs if effective analgesia is not administered.9 In the current study, plasma cortisol concentrations at the time of ovary removal were significantly higher than immediately prior to induction in all treatment groups. These results indicated that, despite preemptive administration of analgesic agents, plasma cortisol concentrations were still influenced by surgery and anesthesia.
It is interesting to note that plasma cortisol concentrations in the etodolac and etodolac with butorphanol groups peaked 30 minutes after extubation, while plasma cortisol in the butorphanol-treated group did not peak until 60 minutes after extubation. This delayed peak may indicate that butor-phanol alone is most likely to suppress the pain-induced stress response early in the postoperative period, and this may last for 60 minutes after extubation. It is unclear why the butorphanol-etodolac combination failed to suppress the plasma cortisol surge, as butorphanol alone was successful in doing.
The plasma cortisol concentrations in the etodolac and etodolac with butorphanol treatment groups returned to preinduction values earlier than the butorphanol treatment group. In order for NSAIDs to induce analgesia, they must block the synthesis of prostaglandins from arachidonic acid by inhibiting the cyclooxygenase enzyme that is induced by noxious stimuli.14 Perhaps when these inflammatory mediators were produced following OHE, etodolac was able to rapidly modulate the nociceptive input and suppress the plasma cortisol concentrations in the treated dogs.
The mean integrated cortisol value (i.e., area under the cortisol curve) was significantly lower in the etodolac and etodolac with butorphanol groups compared to the butor-phanol only group; this indicated that the total amount of cortisol induced by stress was less in these two treatment groups. It has been reported that preoperative administration of meloxicam is more effective than butorphanol in controlling postoperative pain in dogs undergoing abdominal surgery.14 The results of the current study also support the idea that a potent NSAID, like etodolac, may provide better analgesia than butorphanol in the first few hours of the postoperative period. It should be noted that the lower mean integrated plasma cortisol concentration observed in this study was a direct result of an early and rapid decline of plasma cortisol concentrations in dogs of the etodolac and etodolac-butorphanol groups.
It has been shown that plasma glucose concentrations, unlike plasma cortisol concentrations, did not change significantly in dogs when the stress response was assessed during open or laparoscopic surgery.11 In the current study, however, plasma glucose concentrations had similar trends to the plasma cortisol concentrations, and they were clearly different among the treatment groups over time. The discrepancy between these studies may have arisen because of the different surgical procedures and drugs tested.
It has been reported that the stress response induced by OHE, although significant, is of short duration in dogs.13 Measurement of the stress response following OHE in dogs has clearly shown that catecholamine, adrenocorticotropic hormone, cortisol, and insulin increase during the surgical procedure, peak near the end of surgery or shortly after recovery from anesthesia, and return to preoperative levels by 300 minutes after completion of surgery.15 Results of the study reported here support these findings. Most of the stress-induced variables (e.g., plasma cortisol and glucose concentrations) measured in the present study returned to preanesthetic levels by 150 minutes after extubation.
Using NSAIDs as preoperative analgesic agents has raised concerns of enhanced intraoperative bleeding and impaired renal perfusion.16 Buccal mucosal bleeding time has been used to detect the dynamic interactions of the primary hemostasis system, including the vessel walls, vascular endothelium, and platelets.17 An increase in the buccal mucosal bleeding time may indicate abnormalities in primary hemostasis, including platelet dysfunction.17 The buccal mucosal bleeding times measured in the dogs of this study were all within the normal ranges. In addition, there was minimal bleeding observed during surgery, and the weights of the surgical gauze following surgery were not significantly different between treatment groups. These results indicate that etodolac does not enhance bleeding in dogs undergoing OHE. Because a small number of dogs were used in this study, caution is still needed in monitoring the dog postoperatively for potential bleeding.
The urine GGT to urine creatinine ratio has recently been reported as a sensitive indicator of early nephrotoxicity.18,19 This ratio has been used previously to evaluate the renal effects of carprofen in anesthetized dogs.16 In the current study, the indices of renal function monitored before and for three consecutive days after surgery were all within the normal ranges and were comparable between treatment groups. No detectable adverse effects on renal function were found in any of the dogs.
Conclusion
Eighteen dogs undergoing OHE were premedicated with etodolac, with or without butorphanol, and were induced with propofol and maintained on isoflurane during general anesthesia. No differences were detected between treatment groups in several cardiorespiratory variables. Integrated plasma cortisol values were significantly lower in the etodolac only and the etodolac with butorphanol groups. Dogs receiving etodolac with butorphanol had the lowest behavioral pain scores. Isoflurane concentration over time, buccal mucosal bleeding times, and indices of renal function were not significantly different between treatment groups. The results of this study show that etodolac pre-medication, with or without butorphanol, in dogs induced with propofol and maintained on isoflurane is a relatively safe and effective method in treating postoperative pain from OHE.
Etogesic package insert; Fort Dodge Animal Health, Fort Dodge, IA 50501
Etogesic; Fort Dodge Animal Health, Fort Dodge, IA 50501
Torbugesic; Fort Dodge Animal Health, Fort Dodge, IA 50501
PropoFlo; Abbott Laboratories, North Chicago, IL 60064
IsoFlo; Abbott Laboratories, North Chicago, IL 60064
Passport Datascope, Gas Module; Passport Corp., Paramus, NJ 07652
Passport Datascope; Passport Corp., Paramus, NJ 07652
Cardell-9300; Sharn Veterinary, Inc., Tampa, FL 33624
Pulse oximeter; Nellcor- N-20PA, Pleasanton, CA 94588
Cortisol-RIA; Diagnostic Products Corp., Los Angeles, CA 91342
Simplate; Organon Teknika Corp., Durham, NC 27703
SAS-9; SAS Institute Inc., Cary, NC 27513-2414
Citation: Journal of the American Animal Hospital Association 42, 3; 10.5326/0420178
Citation: Journal of the American Animal Hospital Association 42, 3; 10.5326/0420178
Citation: Journal of the American Animal Hospital Association 42, 3; 10.5326/0420178
Citation: Journal of the American Animal Hospital Association 42, 3; 10.5326/0420178
Citation: Journal of the American Animal Hospital Association 42, 3; 10.5326/0420178
Citation: Journal of the American Animal Hospital Association 42, 3; 10.5326/0420178
Heart rates (mean ± standard deviation) in dogs treated with butor-phanol (n=6), etodolac (n=6), or butorphanol plus etodolac (n=6) before, during, and after anesthesia for ovariohysterectomy.
Measurements were taken at various times, including immediately prior to induction (Induction), at time of skin incision (Incision), at removal of second ovary (Ovary), and up to 300 minutes after extubation (E).
Respiratory rates (mean ± standard deviation) in dogs treated with butor-phanol (n=6), etodolac (n=6), or butorphanol plus etodolac (n=6) before, during, and after anesthesia for ovariohysterectomy.
Measurements were taken at various times, including immediately prior to induction (Induction), at time of skin incision (Incision), at removal of second ovary (Ovary), and up to 300 minutes after extubation (E).
Blood pressures (mean ± standard deviation) in dogs treated with butorphanol (n=6), etodolac (n=6), or butorphanol plus etodolac (n=6) before, during, and after anesthesia for ovariohysterectomy. Measurements were taken at various times, including immediately prior to induction (Induction), at time of skin incision (Incision), at removal of second ovary (Ovary), and up to 300 minutes after extubation (E).
Behavioral pain scores in dogs treated with butorphanol (n=6), etodolac (n=6), or butorphanol plus etodolac (n=6) after an ovariohysterectomy.
Measurements were taken at various times, from extubation (E) to 300 minutes after extubation.
* Values significantly different between treatment groups.
+ Values significantly different from etodolac group.
Plasma cortisol concentrations (mean ± standard deviation) in dogs treated with butorphanol (n=6), etodolac (n=6), or butorphanol plus etodolac (n=6) before, during, and after anesthesia for ovariohysterectomy. Values were determined at various times, including 1 day prior to anesthesia (Day 0), preanesthesia (Day 1, 2 hours prior to anesthesia induction), immediately prior to induction (Induction), at time of skin incision (Incision), at removal of second ovary (Ovary), and up to 300 minutes after extubation (E).
* Values significantly (P=0.05) different from preanesthetic values within the same group.
+ Values significantly different between treatment groups.
Plasma glucose concentrations (mean ± standard deviation) in dogs treated with butorphanol (n=6), etodolac (n=6), or butorphanol plus etodolac (n=6) before, during, and after anesthesia for ovariohysterectomy. Values were determined at various times, including 1 day prior to anesthesia (Day 0), preanesthesia (Day 1, 2 hours prior to anesthesia induction), immediately prior to induction (Induction), at time of skin incision (Incision), at removal of second ovary (Ovary), and up to 300 minutes after extubation (E).
* Values significantly (P=0.05) different from induction within the same group.
+ Values significantly different between treatment groups.
