Effects of butorphanol and carprofen on the minimal alveolar concentration of isoflurane in dogs

Jeff C. H. Ko, DVM, MS, DACVA; Douglas N. Lange, DVM, DACVS; Ronald E. Mandsager, DVM, DACVA; Mark E. Payton, PhD; Christine Bowen, BS; Atsushi Kamata, DVM; Wei-Chen Kuo, DVM, MS
al anesthesia with a volatile anesthetic, administration of an opioid decreases the amount of volatile anesthetic that must be administered, as evidenced by a decrease in the minimal alveolar concentration (MAC) of the volatile anesthetic.2,3 In people, preoperative administration of ketorolac, an NSAID, reduces the requirement for isoflurane during surgery by an amount similar to that observed following administration of opioid analgesics.4 In rats, analgesic potencies of morphine, aspirin, and a morphine-aspirin combination were objectively compared,5 and it was found that the combination of aspirin and morphine resulted in a significantly greater reduction in the amount of isoflurane required for anesthesia than did either drug alone. Butorphanol is an opioid agonist-antagonist that can be given IV to manage pain in dogs.6 Carprofen is a recently developed NSAID that also has been shown to have analgesic effects in dogs.7 However, whether preoperative administration of butorphanol or carprofen reduces the amount of isoflurane required in dogs undergoing general anesthesia has not, to our knowledge, been determined. Furthermore, whether there is an interaction between butorphanol and carprofen in regard to the decrease in the requirement for isoflurane in dogs has not been evaluated. Therefore, the purpose of the study reported here was to evaluate the effects of butorphanol and carprofen, alone and in combination, on the MAC of isoflurane in dogs. Materials and Methods
AnimalsSix 2- to 3-year-old mixed-breed dogs (3 females and 3 males) with a mean SD body weight of 18.0 1.3 kg (39.5 2.9 lb) were used in the study. For all dogs, results of physical examinations, serum biochemical analyses, and CBC performed prior to the study were unremarkable. All dogs had received routine vaccinations and had been dewormed on a regular basis; results of an antibody heartworm test were negative. The study protocol was approved by the Oklahoma State University Animal Care and Use Committee. Study design and procedureA randomized completeblock crossover study design was used so that MAC of isoflurane was determined in each dog following administration of carprofen alone, butorphanol alone, carprofen and butorphanol, and neither drug (control). A minimum of 7 days was allowed to elapse between each treatment. For the first part of the study, food was withheld from all dogs overnight. Dogs were randomly assigned to 1 of 2 groups. Three hours prior to induction of anesthesia, dogs in the first group were given a small amount of canned food containing carprofena at a dose of 2.2 mg/kg (1 mg/lb) of body weight, and dogs in the other group were given an equivalent amount of canned food that did not contain any drugs. Anesthesia was induced by administering isoflurane in
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ObjectiveTo evaluate the effects of butorphanol and carprofen, alone and in combination, on the minimal alveolar concentration (MAC) of isoflurane in dogs. DesignRandomized complete-block crossover study. Animals6 healthy adult dogs. ProcedureMinimal alveolar concentration of isoflurane was determined following administration of carprofen alone, butorphanol alone, carprofen and butorphanol, and neither drug (control). Anesthesia was induced with isoflurane in oxygen, and MAC was determined by use of a tail clamp method. Three hours prior to induction of anesthesia, dogs were fed a small amount of canned food without any drugs (control) or with carprofen (2.2 mg/kg of body weight [1 mg/lb]). Following initial determination of MAC, butorphanol (0.4 mg/kg [0.18 mg/lb], IV) was administered, and MAC was determined again. Heart rate, respiratory rate, indirect arterial blood pressure, endtidal partial pressure of CO2, and saturation of hemoglobin with oxygen were recorded at the time MAC was determined. ResultsMean SD MAC of isoflurane following administration of butorphanol alone (1.03 0.22%) or carprofen and butorphanol (0.90 0.21%) were significantly less than the control MAC (1.28 0.14%), but MAC after administration of carprofen alone (1.20 0.13%) was not significantly different from the control value. The effects of carprofen and butorphanol on the MAC of isoflurane were additive. There were not any significant differences among treatments in regard to cardiorespiratory data. Conclusions and Clinical RelevanceResults suggest that administration of butorphanol alone or in combination with carprofen significantly reduces the MAC of isoflurane in dogs; however, the effects of butorphanol and carprofen are additive, not synergistic. (J Am Vet Med Assoc 2000;217:10251028)

pioids and nonsteroidal anti-inflammatory drugs (NSAID) have long been used to manage pain in dogs and other animals.1 In animals undergoing generFrom the Department of Veterinary Clinical Sciences, College of Veterinary Medicine (Ko, Lange, Mandsager, Bowen, Kamata, Kuo), and the Department of Statistics, College of Arts and Sciences (Payton), Oklahoma State University, Stillwater, OK 74078. Dr. Kuos present address is Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164. Supported by a grant from the College of Veterinary Medicine, Oklahoma State University. JAVMA, Vol 217 , No. 7 , October 1, 2000

oxygen, using a face mask. A cuffed endotracheal tube was A minimum of 7 days later, dogs were anesthetized placed, dogs were positioned in right lateral recumbency, and again, and MAC was determined. However, treatments were anesthesia was maintained with isoflurane administered with reversed so that 3 hours prior to anesthesia, dogs in the first oxygen (2 L/min) delivered via a circle anesthetic breathing sysgroup were given a small amount of canned food that did not tem and an out-of-circuit vaporizer. Mechanical ventilation was contain any drugs, and dogs in the other group were given an instituted to maintain end-tidal partial pressure of CO2 equivalent amount of canned food containing carprofena at a dose of 2.2 mg/kg (1 mg/lb). (PETCO2) between 35 and 45 mm Hg. Esophageal temperature was maintained between 37 and 38 C (98.6 and 100.4 F), using Statistical analysesFor each of the 3 treatments heating pads and blankets. Heart rate, cardiac rhythm, respira(carprofen alone, butorphanol alone, and carprofen and tory rate, PETCO2, indirect blood pressure, and saturation of butorphanol together), the percentage reduction in the MAC hemoglobin with oxygen were monitored. Heart rate and carb of isoflurane, compared with the control value, was deterdiac rhythm were monitored by use of electrocardiography. mined by use of the following equation: Blood pressure was measured by use of an oscillometric device.c Saturation of hemoglobin with oxygen was measured by use of percentage reduction = control MAC treatment MAC X 100/ pulse oximetry.d A commercially available adaptore modified control MAC with a catheter was placed at the Y-piece of the breathing circuit. The catheter passed through the endotracheal tube so that Values are expressed as mean SD. Cardiorespiratory its tip rested in the thoracic portion of the trachea. Samples of data and MAC were analyzed by use of ANOVA for repeated airway gases were obtained from the catheter and analyzed by measures.11 The least-significant difference test was used for use of a side-stream capnographf and anesthetic agent monitor,f multiple comparisons between treatment means. The experiwhich determined respiratory rate, PETCO2, and end-tidal mental design was a 2 X 2 factorial arrangement of treatments isoflurane concentration. The anesthetic agent monitor was calin a randomized complete-block design. The 2 factors of ibrated immediately prior to determination of MAC of isofluinterest were butorphanol and carprofen; dogs served as the g rane in each dog, using a commercial calibration kit. blocking factor. The interaction of butorphanol and carproMinimal alveolar concentration of isoflurane was deterfen was used to evaluate whether change in MAC departed 8 mined by use of the tail clamp method, with minor modififrom an additive model. If the interaction term was significations. Briefly, dogs were allowed to equilibrate for 20 to 30 cant, then the effect was synergistic (the combination of minutes at an end-tidal isoflurane concentration of 1.3%. Hair butorphanol and carprofen resulted in MAC lower than was clipped from a section of the tail with a diameter approxwould have been expected if it was assumed that effects of imately equivalent to the diameter of a standard Backhaus the 2 drugs were additive) or antagonistic (the combination towel clamp. A towel clamp was then placed around the tail of butorphanol and carprofen resulted in MAC higher than and closed to the third ratchet. The clamp was left in place for would have been expected if it was assumed that effects of 60 seconds or until gross purposeful movement was evident. the 2 drugs were additive). If the interaction term was not The clamp circumscribed the tail and did not puncture the significant, then the main effects of butorphanol and carproskin of the dog, producing a blunt force on the tail.9,10 fen were examined. For all analyses, values of P < 0.05 were considered significant. If the dog exhibited any purposeful movement in response to tail clamping, the end-tidal isoflurane concentration was increased by 0.1 to 0.2%, and the dog was retested after 15 to Results 20 minutes of reequilibration. If the dog did not exhibit any There was no significant (P = 0.7) interaction purposeful movement in response to tail clamping, end-tidal between the effects of butorphanol and carprofen on isoflurane concentration was reduced by 0.1 to 0.2%, and the MAC of isoflurane, indicating that effects of butordog was retested after 15 to 20 minutes of re-equilibration. phanol and carprofen were simply additive and not Purposeful movement was defined as substantial movement of synergistic or antagonistic. Administration of butorthe head or extremities and did not include coughing, chewing, phanol or of butorphanol and carprofen significantly swallowing, or an increased respiratory effort. Testing was con(P < 0.001) decreased the MAC of isoflurane, comtinued until the lowest end-tidal isoflurane concentration at pared with the control value (Table 1). Although MAC which the dog did not demonstrate any purposeful movement in response to tail clamping was determined. The MAC was then calculated as the mean of Table 1Effects of carprofen and butorphanol, alone or in combination, on the minithe end-tidal isoflurane concentration at mal alveolar concentration (MAC) of isoflurane in dogs which the dog did not demonstrate any purTreatment poseful movement and the next lower concenCarprofen and tration tested (ie, the highest concentration at Control Carprofen Butorphanol butorphanol which the dog still demonstrated purposeful Variable movement in response to tail clamping). MAC (volume %) 1.28 0.14 1.20 0.13 1.03 0.22* 0.90 0.21* NA 6.42 3.24 20.26 12.91 29.46 15.95 For each dog, MAC was determined in Percentage reduction in MAC 114.3 27.1 111.5 19.9 94.3 25.4 92.5 20.5 triplicate. The individual determining MAC Heart rate (beats/min) 105.3 11.6 106.8 7.4 107.3 14.4 114 16.8 did not know which treatment dogs had Systolic BP (mm Hg) Mean BP (mm Hg) 72.5 6.8 74.2 6.5 73.0 9.7 76.5 11.8 received. Cardiorespiratory data were col- Diastolic BP (mm Hg) 55.3 6.2 56.3 4.5 56.7 6.4 60.2 10.2 lected at the time of MAC determination. 97.6 1.2 96.8 1.0 97.5 0.5 96.7 1.3 SpO2 (%) 14.0 7.0 12.8 6.7 12.7 4.4 14.2 7.2 After the initial MAC determination, Respiratory rate (breaths/min) 38.8 2.9 38.3 2.7 39.0 1.0 38.2 3.1 butorphanolh was administered IV at a dose PETCO2 of 0.4 mg/kg (0.18 mg/lb), and MAC was Values represent mean SD for 6 dogs. determined again. Dogs were then allowed to *Significantly (P 0.05) different from control value. Significantly (P 0.05) different from value recover from anesthesia. Determination of obtained after administration of carprofen alone. NA Not applicable. BP Blood pressure. SpO2 Saturation of hemoglobin with oxygen. PETCO2 MAC after butorphanol administration was End-tidal partial pressure of CO2. completed within 60 to 80 minutes. The Carprofen (2.2 mg/kg of body weight [1 mg/lb], PO) was administered 3 hours prior to induction of entire procedure was completed within 6 anesthesia. Butorphanol (0.4 mg/kg [0.18 mg/lb], IV) was administered after dogs were anesthetized. hours after administration of carprofen.
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was lower after administration of carprofen, compared with the control value, the P value (P = 0.069) was not less than the cutoff for significance. There were not any significant differences among treatments in regard to cardiorespiratory data. Discussion In the present study, administration of butorphanol alone and butorphanol in combination with carprofen significantly reduced the MAC of isoflurane in dogs; however, the effects of butorphanol and carprofen were additive, not synergistic. Mean SD MAC of isoflurane when dogs were not given butorphanol or carprofen (ie, control value) was 1.28 0.14%. This is similar to the MAC of isoflurane reported by Steffey and Howland12 for a larger group of dogs (n = 17). It has been reported that preoperative administration of carprofen has a greater analgesic effect in the early postoperative period in dogs undergoing ovariohysterectomy than does postoperative administration.13 However, it is not currently known whether preoperative administration of carprofen has an analgesic effect during surgery. In the present study, we tested the hypothesis that preoperative administration of carprofen would reduce the amount of isoflurane, as reflected by the MAC, needed for anesthesia of dogs. We found that preoperative administration of carprofen reduced the MAC of isoflurane by a mean of 6.24 3.42%, compared with the control value. Even though this difference was not significant (P = 0.069), we believe the data provided a strong indication that carprofen may in fact have an effect on the MAC of isoflurane in dogs. There are several reasons why we did not detect a significant reduction in the MAC of isoflurane following administration of carprofen in the present study. Most importantly, carprofen may be a weak analgesic agent; therefore, it has only a weak ability to decrease the amount of isoflurane that must be administered to prevent the dogs from feeling noxious stimuli in this study. Other possible reasons for our inability to detect a significant decrease in MAC are the small sample size used and the limitations of the tail clamp method for determining MAC. The stimulus provided by tail clamping may not adequately mimic the pain and inflammatory responses induced by surgery, and the tail clamp method may, therefore, have failed to detect important beneficial effects of carprofen. This may also help to explain the findings of Alibhai and Clarke,14 who reported that carprofen minimally influenced the MAC of halothane in dogs and used electrical stimulation as the noxious stimulus for determining MAC. Although carprofen only minimally reduced the MAC of isoflurane in the present study, the beneficial effects that preoperative administration of carprofen in dogs has during the early recovery period have been well-demonstrated.7,13 In contrast to carprofen, butorphanol induced a 20.26 12.91% reduction in MAC of isoflurane in the present study. The reduction in MAC may have been a result of greater analgesia, greater hypnosis, better hyporeflexia, or some combination of these, and our results suggest that butorphanol has a stronger action
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on these activities than does carprofen. There is conflicting information in the literature regarding the effect of butorphanol on the MAC of inhalant anesthetics in dogs. In 1 study,15 administration of butorphanol at doses up to 0.8 mg/kg (0.36 mg/lb) did not affect the MAC of halothane, whereas in another study,2 administration of butorphanol at a dose of 0.3 mg/kg (0.14 mg/lb) reduced the MAC of enflurane by 15 4%. Differences among the results of previous studies and the present study are likely attributable to differences in the method used to determine MAC and differences in the dose of butorphanol used in each study. Combinations of analgesic agents have long been used in human patients.1 The most important consideration when formulating analgesic combinations is to combine 2 or more analgesics with different mechanisms of action to enhance analgesia and reduce the risk of adverse effects.1 In the present study, we found the reduction in MAC of isoflurane associated with administration of butorphanol was approximately 3 times and the reduction associated with administration of a combination of butorphanol and carprofen was approximately 5 times the reduction associated with administration of carprofen alone. This was attributed to the additive effects of carprofen and butorphanol on the MAC of isoflurane in dogs. The potential benefits of decreasing the amount of inhalant anesthetic required for anesthesia include decreases in dose-related cardiorespiratory depressant effects, anesthetic waste gas pollution, and the cost of inhalation anesthesia.16 Isoflurane has dose-dependent depressant effects on respiratory function, blood pressure, and cardiac output in dogs12; however, in healthy dogs, the cardiorespiratory effects of isoflurane at the MAC are modest. In the present study, we did not detect any significant differences in cardiopulmonary function among treatments. This failure to observe any beneficial effects on cardiopulmonary function in association with a reduction in isoflurane concentration may have been a result of the small sample size, the lack of sophisticated cardiorespiratory measurement devices, the minimal effect of low doses of isoflurane (1 X MAC) in healthy dogs, or a combination of these factors. Improvements in cardiopulmonary function associated with the isoflurane-sparing effect of the combination of carprofen and butorphanol may be apparent in dogs in a surgical plane of anesthesia (1.2 to 1.5 X MAC)17 and in debilitated patients. It has been reported that the isoflurane-sparing effects of aspirin and morphine are synergistic in rats,5 and NSAID such as ketorolac have been found to potentiate the antinociceptive effect of morphine in rats.18 Nonsteroidal anti-inflammatory drugs increase the availability of arachidonic acid, which is converted to 12-lipoxygenase, and 12-lipoxygenase presensitizes mu-opioid receptors to the action of mu-opioid agonists.19 In the present study, the effects of carprofen and butorphanol in combination on the MAC of isoflurane were simply additive rather than synergistic. Possible explanations for the lack of a synergistic effect include species variations between dogs and rats and the fact that morphine is a mu-opioid agonist, whereas butorphanol is a kappa-opioid agonist.20
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Rimadyl, Pfizer Animal Health, Exton, Pa. Passport-XG Datascope, Passport Corp, Paramus, NJ. c Dinamap, Critikon, Tampa, Fla. d Nellcor N-20PA, Nellcor-Puritan Bennett, Pleasanton, Calif. e Disposable airway adaptor, Datex, Wilmington, Mass. f Passport-Gas Module-II Datascope, Passport Corp, Paramus, NJ. g Calibration gas, Passport Corp, Paramus, NJ. h Torbugesic, Fort Dodge Animal Health, Overland Park, Kan.
b

References
1. Beaver WT. Combination analgesics. Am J Med 1984;77: 3853. 2. Murphy MR, Hug CC. The enflurane sparing effect of morphine, butorphanol, and nalbuphine. Anesthesiology 1982;57: 489492. 3. Steffey EP, Baggot JD, Eisele JH, et al. Morphine-isoflurane interaction in dogs, swine, and Rhesus monkeys. J Vet Pharmcol Ther 1994;17:202210. 4. Moss JT, Baysinger CL, Boswell GW, et al. Possible intraoperative anesthetic-sparing effect of parenteral ketorolac. Ann Pharmacother 1992;26:922924. 5. Gomez de Sequra LA, Criado AB, Santos M, et al. Aspirin synergistically potentiates isoflurane minimal alveolar concentration reduction produced by morphine in the rat. Anesthesiology 1998;89:14891494. 6. Hosgood G. Pharmacologic features of butorphanol in dogs and cats. J Am Vet Med Assoc 1990;196:135136. 7. Welsh EM, Reid AMN. Beneficial effects of administering carprofen before surgery in dogs. Vet Rec 1997;141:251253. 8. Eger EI II, Saidman LJ, Brandstater B. Minimal alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 1965;26:756763.

9. Ko JCH, Nicklin CF , Melendaz M, et al. Effects of a microdose of medetomidine on diazepam-ketamine induced anesthesia in dogs. J Am Vet Med Assoc 1998;213:215219. 10. Ko JCH, Bailey JE, Pablo LS, et al. Comparison of sedative and cardiorespiratory effects of medetomidine and a medetomidinebutorphanol combination in dogs. Am J Vet Res 1996;57:535540. 11. SAS/IML software usage and reference: version 7. 2nd ed. Cary, NC: SAS Institute Inc, 1998;140180. 12. Steffey EP, Howland D Jr. Isoflurane potency in the dog and cat. Am J Vet Res 1977;38:18331836. 13. Lascelles BD, Cripps PJ, Jones A, et al. Efficacy and kinetics of carprofen, administered preoperatively or postoperatively, for the prevention of pain in dogs undergoing ovariohysterectomy. Vet Surg 1998;27:568582. 14. Alibhai HIK, Clarke KW. Influence of carprofen on minimum alveolar concentration of halothane in dogs. J Vet Pharmacol Ther 1996;19:320321. 15. Quandt JE, Raffe MR, Robinson EP. Butorphanol does not reduce the minimal alveolar concentration of halothane in dogs. Vet Surg 1994;23:156159. 16. Heard DJ, Webb AI, Daniels RT. Effect of acepromazine on the anesthetic requirement of halothane in the dog. Am J Vet Res 1986;47:21132115. 17. Muir WW III, Hubble JAE. Inhalation anesthesia. In: Muir WW III, Hubble JAE, eds. Handbook of veterinary anesthesia. St Louis: CV Mosby Co, 1989;8794. 18. Maves TJ, Pechman PS, Meller ST, et al. Ketorolac potentiates morphine antinociception during visceral nociception in the rat. Anesthesiology 1994;80:10941101. 19. Vaughan CW, Ingram SL, Connor MA, et al. How opioids inhibit GABA-medicated neurotransmission. Nature 1997;390:611614. 20. Williams JT. The painless synergism of aspirin and opium. Nature 1997;390:557558.

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