Comparison of the Effects of Buprenorphine, Oxymorphone Hydrochloride, and Ketoprofen for Postoperative Analgesia After Onychectomy or Onychectomy and Sterilization in Cats
In this prospective, randomized, blinded study, 68 clinically healthy cats that had onychectomy (n=20), onychectomy and castration (n=20), or onychectomy and ovariohysterectomy (n=28) were randomly assigned to one of four postoperative analgesic treatment groups: buprenorphine (0.01 mg/kg body weight, intramuscularly [IM]), oxymorphone hydrochloride (0.05 mg/kg body weight, IM), ketoprofen (2 mg/kg body weight, IM), and placebo (physiological saline). Sedation scores, visual analog pain scores, cumulative pain scores, serum cortisol concentration, and appetite were used to assess postoperative analgesic effect. Buprenorphine demonstrated the highest efficacy with the lowest cumulative pain scores and serum cortisol levels.
Introduction
Onychectomy (i.e., declawing) is commonly performed in veterinary practice in the United States. It is generally agreed that the procedure is painful.12 In recent years, there has been heightened awareness and concern about animal pain and improvement in its management. Alleviating pain in surgical patients has been shown to be beneficial.3–6
Butorphanol tartrate is a commonly used analgesic for cats undergoing surgery.12 This drug is a central-acting opiate agonist-antagonist analgesic.78 It has minimal cardiovascular effects, causes only slight respiratory depression, and has few side effects.78 However, the duration of action is short; the effects of butorphanol tartrate generally last only 2 to 4 hours.79
A drug similar to butorphanol tartrate is buprenorphine, an opioid that also acts as a partial agonist at the mu receptor.7 This drug has a duration of action of 8 to 12 hours9 and is considered to be 30 times more potent than morphine.7 Buprenorphine causes a drop in both blood pressure and cardiac rate in some cats.78
Oxymorphone hydrochloride is another commonly used analgesic in veterinary medicine. It is an opioid with a duration of action of 3 to 4 hours.9 It is considered to be approximately 10 times more potent than morphine.7 Side effects of oxymorphone include respiratory depression and bradycardia.710 High doses can cause ataxia, hyperesthesia, and behavioral changes without the effect of tranquilization.7 The drug can also cause slowed gastrointestinal motility with resultant constipation.710
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) as analgesics is common in postoperative care in human medicine, and their use in veterinary medicine is increasing. This class of drugs works by inhibiting the synthesis and release of cyclooxygenase (COX).11–14 Adverse effects of NSAIDs include gastric and duodenal ulceration, renal failure, and hemorrhage due to the inhibition of prostaglandin synthesis.12–14
The NSAID, ketoprofen, has been tested for analgesia in many animal species.12–17 It is a nonspecific COX inhibitor, which means that it inhibits both COX-1 and COX-2 receptors.121315 This inhibits the release of prostaglandins and, to some extent, the synthesis of leukotrienes, leading to a peripheral analgesic effect.12–1418 Ketoprofen also provides analgesia at a central level.1920 The duration of action of ketoprofen is 12 to 24 hours.12 Ketoprofen is recommended as a single dose after surgery and should not be repeated for 24 hours.12
Few studies on the use of analgesics in feline surgical patients have been done to determine which ones provide better effects. The purpose of this study was to compare the analgesic effects of buprenorphine, oxymorphone hydrochloride, ketoprofen, and saline in cats after onychectomy or onychectomy and castration or onychectomy and ovariohysterectomy.
Materials and Methods
Sixty-eight cats that were brought to the Pennsylvania Veterinary Specialty and Emergency Associates at Hickory Veterinary Hospital for onychectomy, onychectomy and castration, or onychectomy and ovariohysterectomy were included in the study. All cats had a physical examination and were considered healthy. Twenty cats underwent onychectomy alone, 20 cats had castration and onychectomy, and 28 cats had ovariohysterectomy and onychectomy. The owners of all cats gave informed consent. Exclusion criteria were any systemic illness, pregnancy, extreme aggression (unable to handle), and the request by the owner for other procedures to be done (e.g., mass removal, dentistry, rear declawing).
Cats were randomly assigned to one of four treatment groups: buprenorphinea (0.01 mg/kg body weight, intramuscularly [IM]), oxymorphone hydrochlorideb (0.05 mg/kg body weight, IM), ketoprofenc (2 mg/kg body weight, IM), or placebo (preservative-free, physiological saline,d IM). The volume of saline was equal to the calculated volume of both buprenorphine and oxymorphone hydrochloride. Ketoprofen was diluted with sodium chloride so that all the drugs including the placebo were of equal volume for equal weight. One veterinarian (Dobbins) performed all surgeries and observed all the cats for the 12-hour postoperative period. This veterinarian was blinded to the drug used.
The cats were induced with ketamine (5.56 mg/kg body weight, intravenously [IV]) and diazepam (0.28 mg/kg body weight, IV) to allow for orotracheal intubation. Anesthesia was maintained with isoflurane administered with a Bain nonrebreathing system connected to a precision vaporizer. The minimum oxygen flow rate was 660 mL/kg per minute. Onychectomy was performed.e The incisions were left open, and bandages were applied to the front paws. Castration or ovariohysterectomy was performed as requested. Surgical procedure and materials used were the same for all surgeries. Recovery of deglutition reflex was used as the criterion for extubation in all cats. The selected treatment was given immediately after extubation in the lumbar muscle in all cats.
For 12 hours after surgery, cumulative pain scores were calculated on the basis of vocalization, movement, agitation, heart rate, respiration rate, and systolic blood pressure taken with a Doppler ultrasound devicef [Table 1]. Calculations were made preanesthesia, on extubation, and 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 12 hours after extubation. A visual analog pain score21 of 0 to 10, with 0 being pain free and 10 being the most painful, and a sedation score [Table 2] were also assigned at each of these times. The rectal temperature was taken at each time.
Blood for measurement of serum cortisol concentration was taken preanesthesia, immediately before extubation, and at 2 and 4 hours after extubation. Serum samples were stored at 5.5°C and analyzed within 24 hours of collection. Serum cortisol concentration was determined by solid-phase radioimmunoassayg (reference range, 1.0 to 4.5 μg/dL). Packed cell volume (PCV) and total protein were measured preanesthesia and 12 hours after extubation. The glucoseh concentration was measured at preanesthesia and 2 hours and 12 hours after extubation.
All cats were offered water free choice. All cats were offered food 4 hours after extubation, and their appetites were recorded. The food consisted of dry kibble and two choices of canned food. If a cat scored >12 on the cumulative pain score, the cat’s participation in the study was terminated so that additional analgesics could be administered.
Cumulative pain scores, visual analog pain scores, and sedation scores were each analyzed by a two-way analysis of variance (ANOVA) in repeated measures with the grouping factors of type of surgery and type of treatment. Serum cortisol concentration was compared between treatment groups and between surgical groups by evaluating the change from preanesthesia values by two-way ANOVA. Blood glucose concentration and blood pressure were compared between treatment groups by evaluating absolute numbers and change from preanesthesia values by two-way ANOVA. Packed cell volume and total protein values were compared between treatment groups and surgical groups by two-way ANOVA in repeated measures. A chi-square test was used to compare appetite between treatment groups and between surgical groups.
Cumulative pain scores and visual analog pain data were compared between treatment groups and surgical groups by two-way ANOVA in repeated measures according to procedure (i.e., onychectomy alone, onychectomy and castration, and onychectomy and ovariohysterectomy). Inasmuch as results did not vary significantly according to surgical procedure, results of statistical analysis were reported according to treatment only and not according to surgical procedure. For all analyses, a P value of <0.05 was considered significant. The data was presented as means±standard error. All analyses were performed by using a commercial statistical software program.i
Results
Sixty-eight cats were included in the study. Twenty cats underwent onychectomy alone, 20 cats underwent onychectomy and castration, and 28 cats underwent onychectomy and ovariohysterectomy. The mean age of the cats was 14 months (range, 4 months to 5 years); 47 of the 68 cats were <1 year of age. The mean body weight was 3.5±0.97 kg.
No statistically significant differences in sedation scores were found between treatment (P=0.511) or surgical (P=0.847) groups. The saline-treated cats had high visual analog pain scores, but when the scores were compared with those of the other treatment groups, the differences were not statistically significant at 2 hours (P=0.665), 4 hours (P=0.105), and 12 hours (P=0.286) [Figure 1].
The buprenorphine group had a mean cumulative pain score (1.43±0.33) that was significantly lower than that of the other treatment groups at 12 hours after extubation: ketoprofen, 2.39±0.32 (P=0.04); oxymorphone, 2.66±0.31 (P=0.008); and saline, 2.73±0.33 (P=0.07). The cumulative pain scores were not statistically significantly different between treatment groups at 2 hours (P=0.21). The buprenorphine group had a significantly lower mean cumulative pain score (1.36±0.48) at 4 hours than the oxymorphone group (2.93±0.45; P=0.02) and the saline group (3.42±0.48; P=0.003) but not the ketoprofen group (2.21±0.47; P=0.205). None of the cats reached a cumulative pain score of 12, and thus additional analgesia was not administered [Figure 2].
No statistical differences were found in systolic blood pressure between treatment groups, whether comparing absolute values or values corrected based on preanesthesia values (P=0.98).
The corrected serum cortisol concentrations were obtained by subtracting the preanesthesia serum cortisol concentrations. No significant differences were found in serum cortisol concentrations between treatment groups at extubation (P=0.186). The corrected cortisol concentration of the buprenorphine group was significantly lower than that of the saline group at 2 hours (P=0.038). The corrected serum cortisol concentration of the buprenorphine group was significantly lower than that of the ketoprofen group (P=0.00002), the oxymorphone group (P=0.0001), and the saline group (P=0.0018) at 4 hours [Figure 3].
Glucose values were not significantly different between treatment groups (P=0.131). No statistical correlation was found between eating after surgery and treatment group (P=0.998). No statistical correlation was found between surgical procedure and appetite (P=0.313).
No significant difference was found between the first and last total protein values (P=0.223). The last measured PCV was significantly lower than the first measured PCV in the declaw/castration group (P=0.002) and in the declaw/ovariohysterectomy group (P=0.016).
The most common complication was bleeding from the front paws at the declaw site, which was consistently related to the removal of the bandages by the cats. Bandages were immediately replaced. This was observed more frequently in the declaw/castration and declaw/ovariohysterectomy groups than in the declaw group.
Discussion
As used in this study, buprenorphine appears to be more effective in controlling pain in cats undergoing onychectomy or onychectomy and sterilization than oxymorphone, ketoprofen, and saline. One veterinarian (Dobbins) who was blinded to the treatment assessed the pain of all the study cats from the beginning of surgery until the end of the 12-hour evaluation period to minimize variability. Variability among different observers has been proven.21
In recent years, research has been done on the need for analgesic medication in cats undergoing onychectomy.2223 Surprisingly, one study reports that over 50% of cats having onychectomy are not given pain medication.1 It has been documented, however, that surgical patients do better when given analgesics.4–6 One of the purposes of this study was to demonstrate that most cats undergoing onychectomy benefit from analgesic medication. The fact that one of the study drugs clearly provided better analgesia further supports the use of pain medication and additional study of pain management in cats.
When the authors designed this study, it was expected that all the analgesics would be highly effective and all the saline cats would have extremely high pain scores. It was expected that all the cats given saline would receive interventional analgesic. The saline group had higher pain scores than the analgesic groups. In retrospect, the pain scores needed for the cats to receive interventional analgesic should have been significantly lower. All cats were given buprenorphine at the end of the 12-hour study. This was done with the belief that the lack of extremely high pain scoring was not indicative of the lack of pain, but the lack of sensitivity of the measurement of pain.
Performing a pain study on cats proved difficult. This study was designed in 1997. Since that time, several reports have been published on the methodology of measuring pain.22124 Once this study was initiated, it was not feasible to change the study design. It would have been appropriate to include a toe pinch as part of the cumulative pain score or as an individual assessment of pain. In an effort to have an informative study, the authors’ design was as inclusive as possible, by attempting to evaluate pain with as many means of observations as possible. The design included a cumulative pain score that was meant to be objective. It also included a visual analog pain score that was meant to be subjective. Serum cortisol concentrations were measured. Previous studies have favored serum cortisol as the neuroendocrine hormone to measure.222325 The serum cortisol concentration was measured preanesthesia and immediately postoperatively as a baseline, and then at 2 and 4 hours. These times were chosen because all the analgesics would have had enough time to be at full effect at 2 hours. Ketoprofen and buprenorphine should have still been at full efficacy at 4 hours. Financial constraints did not allow the authors to measure the serum cortisol concentration at each time period. The blood glucose concentration was measured knowing that stress would have an important effect on the value, and it would be of limited use. This proved correct. For analysis of study results, the 2-, 4-, and 12-hour intervals were evaluated most closely; again, this was due to financial constraints.
At the design of this study, it was decided rather than using multiple dosing of drugs (such as oxymorphone hydrochloride) when the pain score elevated, the study would be discontinued and analgesic given. This allowed the study to be blinded with only one consistent observer. Single dosing was also felt to be appropriate with the consideration that veterinarians not currently using analgesics would more readily use single-drug, single-dose analgesia. Although it seems obvious that one dose of oxymorphone hydrochloride would not be enough to maintain a cat pain free for 12 hours, it was anticipated to give good analgesic for 2 to 6 hours. Clearly, the study design was not as sensitive to feline pain as desired; however, the end result in the authors’ opinion is the demonstration that buprenorphine is an effective analgesic for use in cats undergoing onychectomy, sterilization, or both. Study cats given buprenorphine had the lowest cumulative pain scores and lowest serum cortisol concentrations. This study was a sincere attempt to encourage veterinarians to use an analgesic when performing an onychectomy.
In the authors’ study, analgesics were given postoperatively. There is a strong argument that preoperative or perioperative analgesics would be better. The administration of analgesics before the start of surgery reduces the nociceptive input that occurs during a procedure.26 In humans, it has been observed that the duration and severity of postoperative pain are much less when analgesics are given prior and during surgery than when given only after surgery.27 Today, a large number of animals still are not given an analgesic at the time of elective surgery. In the authors’ opinion, a veterinarian who rarely uses analgesics is more likely to start using them after surgery, since there is less concern about drug interactions, hypotension, and other adverse side effects once inhalant anesthesia is discontinued. Ketoprofen, a NSAID, could exacerbate renal hypoperfusion during a period of hypotension induced by anesthesia, resulting in renal damage. Another concern is that ketoprofen can decrease blood-clotting time.12–14 The manufacturer recommends that ketoprofen be given postoperatively. Oxymorphone hydrochloride can induce respiratory depression or bradycardia.710 The authors thought that by administering analgesics postoperatively, the study might have a wider impact on practicing veterinarians’ comfort levels with the use of analgesics.
It is common in veterinary practice for onychectomy to be done at the same time as sterilization. Every cat undergoing onychectomy suffers somatic pain, while cats undergoing onychectomy and sterilization experience both somatic and visceral pain. Evaluating the effect of pain medication on cats undergoing a combination of surgical procedures may not be the optimal study design; however, the results of the authors’ study are clinically relevant in helping to determine which currently available analgesics are most effective in clinical practice where onychectomy is often accompanied by sterilization. The pain scores in the cats of this study were not higher in cats undergoing ovariohysterectomy. Statistical analysis enabled the authors to compare surgical groups combined, but individual surgical groups were also evaluated.
Agitation and distress associated with recovery from anesthesia may mimic some signs of postsurgical pain. Stress and pain responses in cats have similar characteristics and, therefore, are difficult to distinguish. Visual analog pain score assessment is subjective, and in this study the authors found no significant difference in visual analog pain scores between treatment groups at 2, 4, or 12 hours, although the scores for saline-treated cats were always highest. The study design included objective measures of pain such as heart rate, respiratory rate, and blood pressure in the calculation of the cumulative pain scores; also, serum cortisol concentration was measured. Postoperative pain evokes neuroendocrine responses characterized by increased production of catecholamines and cortisol. Both serum cortisol concentration and systolic blood pressure were good indicators of postoperative pain in cats according to the study by Smith, et al.,22 and other studies have shown correlation between pain scores and serum cortisol concentration.2325 A recent article, however, questions the value of serum cortisol concentration as a measure of postoperative pain and suggests that it might be more of an indicator of the stress of recovery from anesthesia.28 Although a high serum cortisol concentration is not pathognomonic for pain,22232829 it has been documented that cortisol is an accurate means of determining analgesic efficacy.222325
The study by Smith, et al., indicates that systolic blood pressure correlates with serum cortisol concentration.22 In the authors’ study, systolic blood pressure was used as one factor in determining the cumulative pain score, although systolic blood pressure did not differ significantly between treatment groups. Serum cortisol concentration was measured at four points in time. The authors’ results were consistent whether cumulative pain scores or serum cortisol concentrations were used to compare analgesics. Buprenorphine demonstrated significantly lower values in both instances.
Pibarot, et al. compared ketoprofen, oxymorphone hydrochloride, and butorphanol in the treatment of postoperative pain in dogs undergoing orthopedic surgery of the hind limb.29 Dogs given ketoprofen alone after elective orthopedic surgery had a greater level and longer lasting analgesia than dogs given oxymorphone or butorphanol alone.29 Slingby and Waterman-Pearson compared the postoperative analgesic effects of pethidine, buprenorphine, and ketoprofen in cats undergoing ovariohysterectomy.30 Cats given ketoprofen required the least interventional analgesia and had the best overall clinical assessment, followed by those given buprenorphine and then pethidine.30 The dose of buprenorphine was lower (0.006 mg/kg body weight) than that used in this study, and ketoprofen was given at the same dose (2 mg/kg body weight) but subcutaneously rather than IM. Possibly, the lower dose of buprenorphine accounted for the different results, or the difference could have been due to the difference in the surgical procedure performed.
Conclusion
Results of this study indicate that buprenophrine is a more effective analgesic in cats undergoing onychectomy and sterilization compared with ketoprofen or oxymorphone; ketoprofen was more effective than oxymorphone. These elective procedures do induce pain, and this study does support the use of postoperative analgesia. It is difficult to assess pain in cats, but it is better to provide analgesia in anticipation of a painful response to surgery than not to provide relief from pain. This is especially true in young, healthy animals in which the risk of side effects is small. The authors did not observe any side effects from the analgesics that deemed special treatment or monitoring of the cats in this study. Depending on the analgesic and its duration, multiple doses may be warranted. Research is needed to determine whether a combination of drugs, such as a nonsteroidal analgesic in combination with an opioid, would provide a better alternative for analgesia than single-drug therapy.
Buprenex; Norwich Easton, Reckitt & Colman Products, Hull, England. Distributed by Reckitt & Colman Pharmaceuticals, Inc., Richmond, VA
Numorphan; Endo Pharmaceutical Inc., Chadds Ford, PA
Ketofen; Fort Dodge Animal Health, Fort Dodge, IA
Sodium chloride, physiological saline solution, preservative free; Phoenix Scientific, Inc., St. Joseph, MO
White declaw scissor; Jorvet, Loveland, CO
Ultrasonic Doppler flow, Detector Model 811-B; Parks Medical Electronics, Inc., Aloha, OR
AnTech diagnostic laboratories, Irvine, CA
Accu-chek Advantage, glucometer model no. 768; Boehringer Mannheim Corporation, Indianapolis, IN
SAS statistical software, Version 6.12; SAS Institute, Cary, NC
Acknowledgment
The authors thank Christine MacMurray for all her editorial advice.
Citation: Journal of the American Animal Hospital Association 38, 6; 10.5326/0380507
Citation: Journal of the American Animal Hospital Association 38, 6; 10.5326/0380507
Citation: Journal of the American Animal Hospital Association 38, 6; 10.5326/0380507
Bar graph demonstrating the mean visual analog pain score for each treatment group at each time a score was determined. All surgical groups are included. All values are mean values plus standard error bars.
Bar graph demonstrating the mean cumulative pain score for each treatment group at each time a score was determined. All surgical groups are included. All values are mean values plus standard error bars.
Bar graph demonstrating the mean cortisol concentration after correction based on the preanesthesia value. All surgical groups are included. All values are mean values plus standard error bars.
