Effect of meloxicam and butorphanol on minimum alveolar concentration of isoflurane in rabbits

Patricia V. Turner Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada

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Carolyn L. Kerr Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada

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Amanda J. Healy Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada

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W. Michael Taylor Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada

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Abstract

Objective—To determine the effects of meloxicam and butorphanol on minimum alveolar concentration of isoflurane (MACISO) in rabbits.

Animals—10 healthy young adult female rabbits.

Procedure—Rabbits were anesthetized with isoflurane on 3 occasions in a blinded, randomized complete block design to determine the MACISO associated with administration of meloxicam (0, 0.3, or 1.5 mg/kg, PO) and butorphanol (0.4 mg/kg, IV). The MACISO was determined by use of a paw clamp technique as the end-tidal concentration of isoflurane halfway between the values that allowed or inhibited purposeful movement. Rectal temperature, end-tidal CO2 concentration, heart rate, oxygen saturation, and arterial blood pressure were measured to evaluate cardiopulmonary function.

Results—Mean ± SE MACISO in saline (0.9% NaCl) solution–treated rabbits was 2.49 ± 0.07% and was not significantly different from that associated with administration of meloxicam at 0.3 mg/kg (2.56 ± 0.07%) or 1.5 mg/kg (2.66 ± 0.07%). Butorphanol significantly reduced the MACISO to 2.30 ± 0.07% when administered with saline solution alone, 2.27 ± 0.07% when administered with 0.3 mg of meloxicam/kg, and 2.33 ± 0.07% when administered with 1.5 mg of meloxicam/kg. The percentage reduction in MACISO was significantly greater for rabbits that received butorphanol and meloxicam at either dose, compared with butorphanol and saline solution.

Conclusions and Clinical Relevance—Results indicated that meloxicam does not have a direct isoflurane-sparing effect and does not interfere with the anesthetic-sparing effect of butorphanol in rabbits.

Abstract

Objective—To determine the effects of meloxicam and butorphanol on minimum alveolar concentration of isoflurane (MACISO) in rabbits.

Animals—10 healthy young adult female rabbits.

Procedure—Rabbits were anesthetized with isoflurane on 3 occasions in a blinded, randomized complete block design to determine the MACISO associated with administration of meloxicam (0, 0.3, or 1.5 mg/kg, PO) and butorphanol (0.4 mg/kg, IV). The MACISO was determined by use of a paw clamp technique as the end-tidal concentration of isoflurane halfway between the values that allowed or inhibited purposeful movement. Rectal temperature, end-tidal CO2 concentration, heart rate, oxygen saturation, and arterial blood pressure were measured to evaluate cardiopulmonary function.

Results—Mean ± SE MACISO in saline (0.9% NaCl) solution–treated rabbits was 2.49 ± 0.07% and was not significantly different from that associated with administration of meloxicam at 0.3 mg/kg (2.56 ± 0.07%) or 1.5 mg/kg (2.66 ± 0.07%). Butorphanol significantly reduced the MACISO to 2.30 ± 0.07% when administered with saline solution alone, 2.27 ± 0.07% when administered with 0.3 mg of meloxicam/kg, and 2.33 ± 0.07% when administered with 1.5 mg of meloxicam/kg. The percentage reduction in MACISO was significantly greater for rabbits that received butorphanol and meloxicam at either dose, compared with butorphanol and saline solution.

Conclusions and Clinical Relevance—Results indicated that meloxicam does not have a direct isoflurane-sparing effect and does not interfere with the anesthetic-sparing effect of butorphanol in rabbits.

Meloxicam is a novel COX-2 selective NSAID that has been used extensively as an analgesic agent in humans and, more recently, in some companion animals. Unlike many other NSAIDs, meloxicam retains high bioavailability after oral administration and has a relatively long half-life, making it an attractive analgesic for use in veterinary practice. It is used empirically as an analgesic in rabbits because there are no published pharmacokinetic or clinical data for its use in this species.

Nonsteroidal anti-inflammatory drugs are routinely used in companion animals to provide analgesia and may be combined with opioids to provide synergistically increased analgesic potency. The combination of an NSAID and an opioid such as butorphanol, a partial opioid agonist-antagonist, is commonly used with an inhalant agent such as isoflurane to optimize intra- and postoperative analgesia and reduce inflammation. For example, preemptive administration of butorphanol (0.2 mg/kg, IV) and meloxicam (0.2 mg/kg, IV) to dogs undergoing stifle joint surgery empirically provides superior postoperative analgesia, compared with 2 doses of butorphanol alone.1 In addition to providing more efficacious analgesia, use of these agents in combination allows all drugs to be used at doses less than those used when a single drug is administered, minimizing the potential for adverse effects for any 1 drug.

The potency of an inhalant anesthetic agent can be determined objectively by measurement of the amount of anesthetic required to prevent movement in 50% of individuals in response to a noxious stimulus and is termed MAC.2 This standard technique can also be used to study the relative analgesic effects of various drugs on anesthetic requirements.2 The MACISO in rabbits is 2.08% as measured by use of the paw-clamp technique.3 Butorphanol is commonly added to the anesthetic regimen of rabbits to provide intraoperative analgesia; however, butorphanol-sparing effects on MACISO in rabbits have not been reported. In cats, butorphanol given at either 0.08 or 0.8 mg/kg, IV, induces an 18% to 19% reduction in MACISO. This is somewhat less than the maximal reduction in MACISO of 28% induced in cats by treatment with morphine at 1 mg/kg, IV, and the difference was attributed to the partial opioid agonist-antagonist activity of butorphanol, compared with the pure μ-agonist activity of morphine.4 Whether a COX-2 preferential inhibitor, such as meloxicam, can potentiate the anesthetic-sparing effects of butorphanol on MACISO is important information for providing optimal intraoperative anesthesia and analgesia for rabbits and other species, including humans. Determining whether meloxicam and butorphanol can reduce MACISO has other important implications for all species because decreasing the amount of inhalant anesthetic agent required for patients decreases dose-related adverse effects of cardiorespiratory suppression, anesthetic costs, and pollution from waste gases.

The purpose of the study reported here was to determine the effects of meloxicam and butorphanol on MACISO in rabbits.

Materials and Methods

Rabbits—Ten 3-month-old female New Zealand White rabbitsa that weighed approximately 3 kg were group housed in floor pens on kiln-dried pine shavings on a 12:12-hour light-to-dark cycle at 20 ± 4°C and relative humidity of 30% to 70%. Rabbits were fed twice daily and provided with fresh water ad libitum. Vendor surveillance reports indicated that rabbits were free of known bacterial, viral, and parasitic pathogens. Rabbits were acclimated extensively prior to study initiation. The facilities and procedures were in compliance with the Animals for Research Act of Ontario and the Guidelines of the Canadian Council on Animal Care. The University of Guelph Animal Care and Use Committee approved the study protocol.

Experimental design—The study design was a complete-block crossover design randomized on rabbit and treatment order to account for period and carryover effects. The investigators were unaware of treatments administered to each rabbit prior to induction of anesthesia. Each rabbit was anesthetized 3 times, and each period of anesthesia was preceded by 1 of 3 oral administrations (meloxicam,b 0.3 mg/kg; meloxicam, 1.5 mg/kg; or an equivalent volume of saline [0.9% NaCl] solution). After initial MACISO determination, butorphanol tartratec (0.4 mg/kg, IV) was administered, and MACISO was measured again after a 30-minute equilibration period. A 14-day washout period was used between subsequent anesthetic periods. Rabbits were euthanatized at completion of the third trial.

Anesthesia—Each rabbit received the assigned oral administration 1 hour prior to anesthetic induction with isofluraned in oxygen by facemask. The trachea was intubated, and anesthesia was maintained by use of a Bain breathing circuit at an oxygen flow rate of 2 L/min.

During a 30-minute anesthetic equilibration period in which rabbits were maintained at a stable end-tidal isoflurane concentration, rabbits were instrumented with a rectal temperature probe,e an arterial blood oxygen saturation sensor,f and a direct arterial blood pressure catheter in the auricular artery.g Intratracheal end-tidal concentrations of isoflurane and CO2 were monitored by use of an infrared absorption spectrophotometerh that was calibrated prior to the start of each experiment with a standardized calibration gas mixture designed for the analyzer.i Rabbits were mechanically ventilated, and end-tidal CO2 concentration was maintained from 30 to 40 mm Hg. Rectal temperature was maintained at normothermia by use of a circulating water blanket. A catheter was inserted into the auricular vein, and lactated Ringer's solution was administered at a rate of 10 mL/kg/h. Just prior to each MACISO determination, arterial blood pressurej and heart rate were recorded.

The MACISO value was determined according to established techniques in rabbits by use of a paw clamp as the nociceptive stimulus and a bracketing technique for verifying MACISO.2,3 Briefly, after the anesthesia equilibration period, a paw of the hind limb was clamped with sponge forceps, 24 cm in length, with protective plastic tubing on each jaw and held until gross purposeful movement occurred or 15 seconds had elapsed. If no response occurred, end-tidal isoflurane concentration was decreased by 0.1%, the anesthetic plane was stabilized for at least 20 minutes, and the MACISO was retested. If the response was positive, the endtidal isoflurane concentration was increased by 0.1%, the anesthetic plane was stabilized for at least 20 minutes, and the MACISO retested. The MACISO was taken as the value midway between the highest value at which purposeful movement was detected and the lowest value that prevented purposeful movement and was determined in duplicate.

Statistical analysis—All results are expressed as mean ± SE. Percentage reduction of baseline MACISO after treatment with butorphanol was calculated as follows: (MACISO baseline − MACISO + butorphanol)/MACISO baseline × 100. Statistical analysis was performed by use of a general linear mixed model with rabbit and treatment as whole-plot variables and pre- and posttreatment with butorphanol as splitplot variables, respectively.k A Shapiro-Wilk test was conducted on the residuals to confirm normal distribution of the data. Significance was set at a value of P < 0.05.

Results

Mean MACISO in saline solution–treated rabbits was 2.49 ± 0.07%. Treatment with meloxicam alone at either 0.3 or 1.5 mg/kg, PO, resulted in MACISO of 2.56 ± 0.07% and 2.66 ± 0.07%, respectively; however, these values were not significantly different from the MACISO value determined for saline solution alone (P = 0.38 and 0.06, respectively).

Addition of butorphanol (0.4 mg/kg, IV) resulted in a consistent and significant (P = 0.002) reduction in MACISO from baseline (saline solution alone) for all 3 groups (Figure 1). The absolute mean MACISO values determined after administration of butorphanol were not significantly different for all groups (approx 2.3 ± 0.07%). The absolute reductions from baseline associated with administration of butorphanol and meloxicam at 0.3 and 1.5 mg/kg were 0.29% and 0.33%, respectively, and were significantly different from the 0.19% reduction detected with butorphanol in saline solution–treated rabbits (P = 0.005 and P < 0.001, respectively); differences between the 2 meloxicam groups were not significant (P = 0.271). Addition of butorphanol induced percentage reductions from values obtained after administration of saline solution or both doses of meloxicam alone of 7.63%, 11.33%, and 12.41%, respectively. Mean ± SE time required for MAC determinations after the initial equilibration period was 82 ± 5 minutes.

Figure 1—
Figure 1—

Mean ± SE MACISO after administration of saline (0.9% NaCl) solution (SAL), meloxicam (MXC; 0.3 or 1.5 mg/kg), and butorphanol (BUP) in 10 rabbits. *Significant (P < 0.05) difference from value in saline solution group. †Significant (P < 0.05) difference from the saline and meloxicam pre-treatment groups, following addition of butorphanol.

Citation: American Journal of Veterinary Research 67, 5; 10.2460/ajvr.67.5.770

Administration of meloxicam led to nonsignificant, dose-dependent decreases in heart rate and increases in blood pressure at MACISO (Table 1). Butorphanol injection resulted in further decreases in heart rate at the time of MACISO determination in rabbits pretreated with saline solution or meloxicam at 0.3 mg/kg and decreases in blood pressure of all rabbits, regardless of pretreatment.

Table 1—

Mean ± SE values for heart rate (beats per minute [bpm]) and arterial blood pressure (MAP; mm Hg) at MACISO in 10 rabbits treated with saline solution or meloxicam (0.3 or 1.5 mg/kg) that did or did not receive butorphanol (BUT; 0.4 mg/kg, IV).

GroupSaline0.3 mg/kg1.5 mg/kg
No BUT
 Heart rate241 ± 4.3234 ± 4.3221 ± 10.3
 MAP41 ± 346 ± 354 ± 5
BUT
 Heart rate223 ± 5*221 ± 2228 ± 5.7
 MAP37 ± 2.339 ± 339 ± 1.7

Significantly (P = 0.028) different from value without BUT.

Significantly (P = 0.039) different from value without BUT.

Discussion

Use of MAC values to study potential analgesic interactions between an NSAID and an opioid provides a relevant objective assessment of analgesic efficacy and minimizes subjective error that may occur when assessing postoperative pain scores in animals. In rabbits, meloxicam given PO alone at either 0.3 or 1.5 mg/kg had no effect on MACISO. Despite this, the values obtained for MACISO associated with either dose of meloxicam plus butorphanol were almost identical to those obtained with saline solution and butorphanol alone (approx 2.30%), and this indicated that there was no disadvantage in terms of inhalant requirements in giving these 2 drugs together for perioperative analgesic management of rabbits. Significant dose-related differences were detected in the magnitude of the relative reductions of MACISO obtained when rabbits had been pretreated with meloxicam. With saline solution alone, butorphanol induced a percentage reduction of MACISO of 7.63%, whereas pretreatment with meloxicam at 0.3 or 1.5 mg/kg induced significantly greater reductions of 11.33% and 12.41%, respectively. Because meloxicam did not have any effect on its own, this may be suggestive of a beneficial pharmacologic interaction between meloxicam and butorphanol.

A recent study5 of the effects of meloxicam on reduction of MACISO by morphine in outbred rats determined that meloxicam did not potentiate the anesthetic-sparing effects of morphine. In the rat study, there were no differences in the percentage reductions in MACISO associated with administration of meloxicam plus morphine versus morphine alone. The reasons for these differences are unclear but may be because of species-specific variations in drug response; sex or strain-related differences in metabolism of meloxicam or MACISO; analgesic potency of morphine, compared with butorphanol; or issues related to study design.6–8 In the rat study reported by Santos et al,5 study design issues may have reduced statistical power and influenced results because different groups of rats were evaluated for each drug treatment. Morphine induces a profound reduction in MACISO, compared with butorphanol, which may obscure more subtle pharmacologic interactions, as has been reported in cats.4 A study of the effect of another NSAID, flunixin meglumine, on morphine-induced reductions in MACISO in goats also did not find any additional effect when flunixin meglumine was given, potentially because of the 30% reduction in MACISO obtained with morphine alone.9 Among animals of a species, there may be as much as 20% variation in MAC values but variation is generally < 10% in an individual animal.10 Variation in MAC values may be controlled to some extent by conducting repeated measures within the same animals, as in our study.

Others have reported additive or synergistic effects on reduction of MACISO when NSAIDs have been combined with opioids. A mild additive reduction of MACISO by carprofen and butorphanol has been reported in dogs, and a synergistic reduction was detected with aspirin and morphine in rats.11,12 In the dog study,11 carprofen induced a direct mild isoflurane-sparing effect. The percentage reduction in MACISO values from untreated controls was 6.4% with 2.2 mg of carprofen/kg, 20.3% with 0.4 mg of butorphanol/kg IV, and 29.5% with both carprofen and butorphanol.11 In the rat study,12 the effects of aspirin on morphine-induced reduction of MACISO were synergistic and similar to the present study; aspirin did not alter MACISO when used alone. Morphine alone (1 mg/kg) induced a 17% reduction in MACISO, and the addition of 30 mg of aspirin/kg resulted in a 32% reduction.12 The pharmacologic features of these 2 NSAIDs are quite different from meloxicam because carprofen yields equipotent inhibition of COX-1 and COX-2 in vitro, whereas aspirin primarily inhibits COX-1 isozymes.13,14

Mean MACISO value for saline solution–treated rabbits in our study was approximately 20% higher than that reported for rabbits by use of a similar supra-maximal stimulus (paw-clamp [2.08%] or tail-clamp technique [2.07%]).3,15 This is within the expected variation for a given species and may be related to variations in sex, age, source, and health status of the rabbits used in the different studies.10 In the present study, all anesthetic procedures were carried out at the same time of day to minimize circadian rhythm effects; however, this information is rarely reported and may also affect response to anesthesia.16

The isoflurane-sparing effect of butorphanol has not been reported previously in rabbits. The effect was small but significant and represented only a 7.5% reduction in MACISO from baseline (saline solution treatment only). Marked species differences have been reported for opiate-induced reductions of inhalant anesthetic requirements. Intravenous administration of morphine (2 mg/kg) induces mean MACISO reductions from controls of 55% in rhesus monkeys, 50% in dogs, and 13% in swine, whereas administration of butorphanol (0.05 mg/kg, IV) does not have any effect on MAC of halothane in ponies.17,18 In dogs, administration of butorphanol (0.4 mg/kg, IV) results in a 20% reduction in isoflurane requirements, whereas butorphanol at either 0.08 or 0.8 mg/kg, IV in cats led to an 18% to 19% reduction in MACISO.4,11 The smaller magnitude of reduction in MACISO after butorphanol administration in rabbits may be attributable to species-specific butorphanol pharmacokinetics.

Mild, transient increases in either diastolic or systolic blood pressure have been recorded in conscious rats and anesthetized cats treated with meloxicam parenterally as in this study; however, these changes were minimal, transient, and not interpreted to be of clinical importance.19 Similarly, butorphanol administration to halothane-anesthetized dogs induces transient decreases in arterial pressure, which is not thought to be clinically important.20 In general, blood pressure values obtained for rabbits in this study were low; however, mean ± SE arterial pressure recorded from the auricular artery of rabbits at MACISO have been reported to be similarly low (46.8 ± 7.2 mm Hg) by others.15 Isoflurane decreases mean arterial pressure; however, the exaggerated hypotensive response seen in rabbits may be species-specific, and no postanesthetic-related adverse events have been reported.21 Blood pressures in the present study may have been marginally lower than those reported by Imai et al15 in rabbits because our rabbits were mechanically ventilated and not spontaneously breathing as in that study. Rabbits, like human pediatric patients, have high basal sympathetic tone and may be sensitive to vagal overstimulation and arteriolar vasodilatation after initiation of positive-pressure ventilation.22 We do not believe that the combination of meloxicam with butorphanol induces clinically important risk of adverse cardiovascular events in isoflurane-anesthetized rabbits.

In all species examined to date, meloxicam administration results in marked preferential inhibition of COX-2, compared with COX-1.13,23 Similar to other NSAIDs, meloxicam has potent anti-inflammatory and analgesic activity in rat arthritis models because of COX-2 inhibition.24,25 Meloxicam also has direct analgesic activity in inflamed tissues that is hypothesized to be attributable to a peripheral antinociceptive mechanism that is as yet undetermined.25 This particular mechanism of action differs considerably from that of butorphanol, a mixed-opioid agonist-antagonist with primary agonistic activity at the [.kappa]-opiate receptor.26 In recent reports,27,28 it is suggested that NSAIDs may also have indirect agonistic effects at central opioid μ receptors, which are potent analgesic targets. It is intriguing to speculate that the increased magnitude of MACISO reduction detected when rabbits were cotreated with meloxicam and butorphanol is attributable to partial reversal of direct antagonistic effects of butorphanol at central μ receptors by meloxicam. This serves to emphasize the rationale for combining the 2 drugs, which have dissimilar mechanisms of action, to optimize analgesic effects while minimizing the potential for important adverse effects.

Results of this study indicated that meloxicam administration alone does not reduce MACISO of rabbits at 0.3 mg/kg. Meloxicam pretreatment does not interfere with the anesthetic-sparing effect of butorphanol in rabbits and has minimal effects on cardiorespiratory variables. Because of this, use of meloxicam alone before surgery is unlikely to induce a clinically important reduction in MACISO. If the time to peak plasma concentration of meloxicam in rabbits after oral administration is as long as for other species such as dogs, there may be an advantage to giving the drug before surgery to ensure appropriate postoperative analgesic blood concentration of the drug. Further research is required to determine the pharmacokinetics of meloxicam in rabbits.

ABBREVIATIONS

COX

Cyclooxygenase

NSAID

Nonsteroidal anti-inflammatory drug

MAC

Minimum alveolar concentration

MACISO

MAC of isoflurane

a.

Charles River Canada, St Constant, QC, Canada.

b.

Metacam, Boehringer-Ingelheim, Burlington, ON, Canada.

c.

Torbugesic, Ayerst Laboratories, St Laurent, QC, Canada.

d.

Isoflurane, Bimeda-MTC Animal Health Inc, Cambridge, ON, Canada.

e.

Tele-thermometer, Yellow Springs Instrument Co, Yellow Springs, Ohio.

f.

Nonin Medical Inc, Minneapolis, Minn.

g.

Angiocath, Becton-Dickinson, Sandy, Utah.

h.

Criticare 1100 patient monitor, Criticare Systems, Wankeska, Wis.

i.

Standardized calibration gas, Scott Medical Products, Plumsteadville, Calif.

j.

Becton-Dickinson Infusion Therapy Systems, Sandy, Utah.

k.

SAS, version 8.2, SAS Institute Inc, Cary, NC.

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