Veterinary Anaesthesia and Analgesia, 2013, 40,

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1 Veterinary Anaesthesia and Analgesia, 2013, 40, doi: /vaa RESEARCH PAPER Effect of maropitant, a neurokinin-1 receptor antagonist, on the minimum alveolar concentration of sevoflurane during stimulation of the ovarian ligament in cats Sirirat Niyom*, Pedro Boscan*, David C Twedt*, Eric Monnet* & Jens C Eickhoff* *Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA Correspondence: Dr. Sirirat Niyom, Veterinary Teaching Hospital, Colorado State University, 300 W. Drake Rd., Fort Collins, CO 80523, USA. srniyom@colostate.edu Abstract Objective Determine if maropitant decreases the minimum alveolar concentration (MAC) of sevoflurane during stimulation of the ovarian ligament in cats. Study design Prospective study. Animals Fifteen, female cats weighing kg (mean SD). Methods Anesthesia was induced and maintained with sevoflurane. The right ovary was accessed via laparoscopy. A suture around the ovary and ovarian ligament was exteriorized through the abdominal wall for stimulation. A stimulus response curve was created to identify the optimal force for MAC comparisons. In 10 cats, MAC was determined with only sevoflurane (baseline) then after 1 and 5mgkg 1 intravenous maropitant administration. The stimulation tension force used was 4.9 N. Repeated measures ANOVA was used to compare the groups. MAC was defined as the average of the crossover concentrations and reported MAC is adjusted to sea-level and depicted as mean SD. Results The stimulus-response curve was hyperbolic and plateaued at N. The optimal tension force chosen to compare MAC was 4.9 N. The baseline sevoflurane MAC was %. Maropitant, 1 mg kg 1, decreased the MAC to % (15%, p < 0.01). The higher maropitant dose of 5 mg kg 1 did not change MAC further when compared to the low dose ( %, p = 0.33). Conclusion and clinical relevance The ovarian ligament stimulation model is suitable to determine MAC during visceral stimulation in cats. Maropitant decreased the anesthetic requirements during visceral ovarian and ovarian ligament stimulation in cats. Maropitant (1 mg kg 1 ) decreases MAC by 15%; a higher dose had no additional effect. Keywords maropitant, minimum alveolar concentration, neurokinin-1 receptor, sevoflurane. Introduction A study in cats demonstrated the release of substance P in spinal cord after pain stimulations by thermal and capsaicin application (Go & Yaksh 1987). These results suggest a role for substance P in regulating pain transmission. Similar studies in other species have shown that by antagonizing the neurokinin-1 (NK-1) receptor and its neurotransmitter, substance P, the nociceptive response to visceral noxious stimuli was suppressed. Administration of an NK-1 receptor antagonist and deleting the gene encoding for NK-1 receptor in mice increased pain thresholds significantly after intraperitoneal injection of acetic acid 425

2 and intracolonic administration of capsaicin, respectively (Nagahisa et al. 1992; Laird et al. 2000). Maropitant (Cerenia; Pfizer Animal Health, NY) is an NK-1 receptor antagonist approved for use in dogs to treat emesis and motion sickness. In dogs, the drug has high efficacy and safety preventing and treating emesis caused by different factors such as, motion sickness (Benchaoui et al. 2007; Conder et al. 2008), cisplatin administration (Vail et al. 2007), emetogens such as apomorphine and syrup of ipecac (Sedlacek et al. 2008), and various other acute vomiting etiologies (De la Puente-Redondo et al. 2007; Ramsey et al. 2008). In cats, maropitant is well tolerated and safe, and has antiemetic properties against emesis induced with xylazine and motion sickness (Hickman et al. 2008). A previous study in dogs demonstrated that maropitant decreased the minimum alveolar concentration (MAC) of sevoflurane during ovarian ligament stimulation, demonstrating an anesthesia sparing effect in dogs (Boscan et al. 2011a). In the present study, the aim was to investigate the anesthetic sparing effect of maropitant during visceral noxious stimulus of the ovarian ligament in cats using the technique previously described for dogs (Boscan et al. 2011b). Materials and methods Animals The study was approved by the University Animal Care and Use Committee, Protocol ID: A. Fifteen client-owned, domestic, healthy, female cats, older than 12 weeks of age, weighing kg (mean SD) were enrolled in the study. Water was available at all times, food was withheld overnight for the study. Experimental protocol The ovarian ligament stimulation model was used to induce visceral noxious stimuli to determine MAC (Boscan et al. 2011a,b). The study was divided in two phases. Phase 1 was designed to create and validate the ovarian ligament stimulation model in cats and to determine the optimal ovarian tension force necessary, by constructing a stimulus response curve while measuring the sevoflurane MAC. Phase 2 was designed to identify the maropitant MAC sparing effects during ovarian stimulation. Phase 1 Anesthesia was induced and maintained with sevoflurane in five cats. Anesthesia was induced by placing the cat in an acrylic chamber and once the cat had lost its righting reflex it was removed from the chamber and a face mask was used until the animal was anesthetized. An endotracheal tube (internal diameter, mm) was placed in the trachea to administer O 2 and maintain anesthesia with sevoflurane. The cats were mechanically ventilated to maintain an end-tidal CO 2 (PE CO 2 ) between 25 and 35 mmhg ( kpa). A 22- gauge catheter was inserted into a cephalic vein and lactated Ringer s solution (Baxter, IL) was administered at 5 ml kg 1 hour 1. The cats were monitored with an ECG to assess heart rate and rhythm, a Doppler over a digital artery to measure blood pressure, an esophageal thermometer to measure core temperature (Power Lab amplifiers from ADInstruments) and an end-tidal gas analyzer (Biochem 9100; BCI International, WI) to measure respiratory rate, inspired and expired O 2,CO 2 and sevoflurane concentration. The samples for the endtidal gas analyzer were obtained at the level of the tracheal carina with a catheter placed through the endotracheal tube. Core temperature was maintained between 37 and 39 C using active heating blankets during the study. In order to access the right ovarian ligament, laparoscopic surgery was performed with two 5 mm cannulas placed along the midline after all the monitoring equipment was in place. The abdomen was insufflated with CO 2 to pressures between 4 and 8 cmh 2 O for better visualization. A 3-0 byosin suture (MWI Veterinary Supply, CO) was placed around and through the ovarian ligament for stimulation. The loose ends of the suture were exteriorized through the abdominal wall and connected to a pre-calibrated force transducer. The force transducer has a force displacement range of kgmm 1 ( N) and maximum load of 10 kg (FT03; ADInstruments, CO). The technique used followed a similar protocol to a published study in dogs (Boscan et al. 2011b). To create the stimulus response curve and identify the optimal force for further MAC comparisons, four stimulation forces were tested randomly in each cat (1.96, 3.92, 5.88 and 7.85 N) and the MAC of sevoflurane was determined for each tension force in each cat in duplicate. MAC was determined by applying the desired tension force for 1 minute (if no Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 40,

3 response was observed) or until purposeful movement was observed. If purposeful movement was observed, the end-tidal sevoflurane was increased by 10% of the setting for the following test. On the contrary, if no movement occurred, the end-tidal sevoflurane was decreased by 10% of the setting for the following test. MAC was defined as the average of the two concentrations where movement and no movement occurred. In this phase, MAC was determined in duplicate and at least 15 minutes were allowed between tests. The final value was the average of these two concentrations. MAC is depicted as mean SD, adjusted for calibration values and to sea-level. Phase 2 To evaluate the anesthetic sparing effect of maropitant, ten cats were anesthetized with sevoflurane and monitored as described above. Laparoscopic surgery to access the right ovary and ovarian ligament was performed as described during phase 1. For phase 2, MAC determinations were performed in triplicate for each cat and the two maropitant doses tested. First, a baseline MAC determination was performed between 1 and 2 hours after the induction of anesthesia. To compare MAC, a force of 4.9 N was used to stimulate the ovarian ligament during phase 2. This force was chosen from phase 1 as being above the start of the plateau in the force response curve (supramaximal) but being unlikely to cause tissue damage. Following MAC determination in each cat for the baseline data, a maropitant dose of 1 mg kg 1 was administered intravenously over 5 minutes and MAC was measured in triplicate. This was followed by a maropitant dose of 5 mg kg 1 IV over 5 minutes and MAC was measured again in triplicate. At the end of the studies (both phase 1 and 2), all cats were spayed laparoscopically. Cefazolin 20 mg kg 1 was administered intravenously to prevent infection. For pain management, ketoprofen 1mgkg 1 and buprenorphine 20 lg kg 1 were administered subcutaneously minutes before recovery. All cats recovered and went home without complications. Statistical methods The software used to construct the stimulus response curve in phase 1 and determine the optimal stimulation force to study MAC was SAS statistical software, version 9.2. (SAS institute, Inc., NC). To construct the stimulus response curve, various nonlinear growth curve models were considered to describe the dose response relationship between traction force and sevoflurane requirements. The Akaike s information criterion (AIC) was used to compare the model fit between the growth curve models, and to identify a model with the best fit. Maximum likelihood estimates of the model parameters were obtained using the Quasi-Newton Raphson algorithm. The parametric bootstrap technique was used to calculate the standard error of the estimated traction force required for the curve to reach plateau, and to construct the corresponding 95% confidence intervals (Davison & Hinkley 1997). Specifically, the observed means and standard deviations of the anesthetic requirements (%) for the traction forces 1.96, 3.92, 5.88 and 7.85 N were used to generate Monte Carlo samples of size m = 1000 which were drawn from a multivariate normal distribution. The standard deviations of the estimated plateau levels from the fitted growth curve models across the 1000 simulated data were then used to estimate the standard errors of the estimated traction force required for the curve to reach plateau. The three-parameter logistic growth curve formula used for the calculation of the estimated traction force to reach the plateau level of the curve with a 95% confidence interval is depicted. y ij ¼ c 1 þ expð ða þ b x ij ÞÞ þ s i þ e ij ; y ij is the sevoflurane requirements (%) for subject i at measurement point j, s i is the random subject effect, ɛ ij is the overall error, x ij is the traction force (N) for subject i at measurement point j, a is the intercept parameter, b is the slope parameter, and c is the plateau of the growth curve. Data obtained from phase 2 are presented as mean SD and the groups were compared using a repeated measures ANOVA followed by post hoc Bonferroni test (GraphPad Prism,version 4.03; Graph- Pad Software Inc, CA). The repeated-measures factor was time and the between-subject factor was treatment. Pair wise comparisons between treatments at each time point were examined using t-tests. Residuals from ANOVA were approximately normal and independent. Statistical significance was considered at a p value < Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 40,

4 Results Phase 1 The stimulation-response curve using traction forces of 1.96, 3.92, 5.88 and 7.85 N is depicted in (Fig. 1). The MAC obtained ranged between 2.69 and 4.17% with a hyperbolic presentation. The three-parameter logistic growth curve model provided the best model fit. Hence, this model was used to describe the dose response relationship between traction force and sevoflurane requirements. The estimated traction force to reach the plateau level of the curve with a 95% confidence interval was N. The three-parameter logistic growth curve formula used for the calculation is depicted above in the statistical methods. Phase 2 The average anesthesia time during phase 2 was minutes. The times spent to determine MAC for baseline, 1 mg kg 1 maropitant and 5mgkg 1 maropitant groups were 51 4, 53 6 and 45 6 minutes, respectively. The MAC of sevoflurane in the control group was %. Maropitant at 1 mg kg 1 decreased MAC to % (15%, p < 0.01). At 5mgkg 1 there was no further change in MAC ( %; p = 0.33). The Doppler blood pressure, body temperature, heart rate, respiratory rate and PE CO 2 were not different between groups (Table 1). However, intravenous administration of maropitant transiently decreased the blood pressure. When 1 and 5mgkg 1 were administered, the Doppler blood pressure decreased from 88 to 61 mmhg (p < 0.001), and 86 to 50 mmhg (p < 0.001) respectively for 6 minutes or less. At this time, the blood pressure returned to pre-administration values. Discussion The present study demonstrates that intravenous administration of maropitant, a specific NK-1 receptor antagonist, reduces the anesthetic requirements in cats during ovarian ligament noxious stimulation but it is not dose dependent for the two doses tested. The results are similar to the previous study reported in dogs where maropitant reduced the anesthetic requirements (Boscan et al. 2011a). The study in dogs showed that maropitant at 1 and 5 mg kg 1 decreased the MAC of sevoflurane by 24% and 30%, respectively. The anesthetic sparing effect observed in dogs was greater than that in cats (15% and 17% sevoflurane MAC sparing, respectively). In neither species did the 5 mg kg 1 dose of maropitant decrease the sevoflurane MAC further. It is unknown why the anesthetic sparing effect does not appear to be dose-dependent at the doses tested. It is possible that the maximal maropitant effect occurs at 1mgkg 1, therefore, a higher dose would not change MAC further. Previous studies have shown that NK1 antagonists may have differences in receptor affinity between species so perhaps the drug has very high affinity in dogs and cats, resulting in receptor saturation at lower doses (< 1mgkg 1 ; Beresford et al. 1991; Gitter et al. 1991; Barr & Watson 1993). Another possibility is Figure 1 The stimulus-response curve for sevoflurane MAC when stimulation traction forces ranging from 1.96, 3.92, 5.88 and 7.85 N were applied to the right ovarian ligament in five cats. The mean SD of sevoflurane MAC was measured using the end-tidal sevoflurane concentration. The stimulation force was recorded using a force transducer. The arrow indicates a stimulation force of 4.9 N chosen to determine MAC during phase Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 40,

5 Table 1 Mean SD values for Doppler obtained systolic arterial pressure (SAP), body temperature, heart rate, respiratory rate and PE CO 2 in the cats prior to (baseline) and after 1 and 5 mg kg 1 of maropitant IV. Values were averaged from the MAC determination period. Baseline Maropitant 1mgkg 1 Maropitant 5mgkg 1 SAP (mmhg) Temperature ( C) Heart rate (beats minute 1 ) Respiratory rate (breaths minute 1 ) PE CO 2 (mmhg) that other drugs such as sevoflurane could be occupying and inhibiting NK-1 receptors and reducing the population of receptors available for inhibition. Finally, it could be that neurokinin-1 receptors have limited ability to modulate immobility produced by the inhaled agent. However, further studies are necessary to identify the dose effect relationship in dogs and cats. The explanation for maropitant s effect in decreasing the anesthetic requirements during visceral noxious stimulation remains unknown. Both NK1 receptors and substance P are located at the level of nerve terminals, dorsal root ganglia, spinal cord, ascending projections and higher brain structures (Duggan et al. 1988; Mantyh et al. 1995; Quartara & Maggi 1998); most of them involved in nociception or the nociceptive response. In this study, maropitant was administered intravenously and since we allowed enough time for the drug to reach all body compartments where NK1 receptors may be located we cannot differentiate the action site for maropitant. High concentrations of NK1 receptors have been found in spinal cord regions where visceral afferents terminate in laminae I and X (Brown et al. 1995; Laird et al. 2000) making a spinal cord effect plausible. A previous study showed that epidural administration of maropitant to dogs did not decrease the MAC during somatic stimulation (tail clamp) (Alvillar et al. 2012). The study did not use visceral stimulation and the pharmacokinetics of epidural maropitant have not been described. Thus, the spinal cord role in the anesthetic sparing effect of maropitant remains to be elucidated. It is reported that over 80% of the visceral nerve afferents to the spinal cord dorsal horn contain substance P, whereas only 21% of cutaneous afferents express this peptide (Perry & Lawson 1998). It is therefore possible that NK1 receptor antagonists may have a greater effect during visceral nociceptive processing than that for cutaneous nociceptive processing. In addition to the anesthetic sparing effect reported, we present a new approach to measure MAC in cats during visceral stimulation of the ovarian ligament. The model was adapted from a previous dog study (Boscan et al. 2011a). The application of the model to cats appeared to work well inducing predictable visceral noxious stimuli. There was no evidence of visual tissue damage to the ovary or ovarian ligament and the response was consistent and repeatable within and between animals. This model may be of clinical interest because of its similarities to the pain response observed during ovariectomy or ovariohysterectomy surgeries. For phase 2, after constructing a three-parameter logistic growth curve model for the stimulusresponse curve, the optimal ovarian tension force we chose to test and compare was 4.9 N. This is the force considered to be a supramaximal force for the model. Stronger tension forces should not influence the MAC and the stimulation force is soft enough to prevent tissue damage, desensitization or hyperalgesia. A potential caveat in the study is that the end tidal gas samples were measured via an automated sidestream collection system. The sidestream collection systems may have produced a larger sevoflurane variability due to the higher respiratory rate and lower tidal volumes observed in cats. An interesting observation was that intravenous administration of maropitant decreased blood pressure significantly for a short period of time. Previous NK1 antagonists tested have shown diverging results. Five different pure antagonist drugs tested did not show any cardiovascular adverse effects in rodents (Iyengar et al. 1997; Cellier et al. 1999; Wang et al. 2008), ferrets (Watson et al. 1995) or dogs (Watson et al. 1995). On the contrary, the NK1 antagonist (CP-96,345) decreased blood pressure in mice (Sakamoto et al. 1993). We do not know if there could be a direct cardiovascular effect from maropitant or the vehicles (metacresol and sulphobutylether-beta-cyclodextrin) in Cerenia. We did notice in dogs that intravenous administration of 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 40,

6 Cerenia decreased blood pressure transiently as well (Boscan et al. 2011a). The clinical implication from this finding is unknown but we advise caution if the intravenous route is used. In summary, maropitant 1 mg kg 1 reduced the MAC of sevoflurane by 15% in cats and this did not increase with a higher dose. The ovarian ligament appears to be a good model for visceral noxious stimulation in cats. Acknowledgements The study was performed with the support from a Winn Feline Foundation Grant. References Alvillar BM, Boscan P, Mama KR et al. (2012) Effect of epidural and intravenous use of the neurokinin-1 (NK-1) receptor antagonist maropitant on the sevoflurane minimum alveolar concentration (MAC) in dogs. Vet Anaesth Analg 39, Barr AJ, Watson SP (1993) Non-peptide antagonists, CP- 96,345 and RP 67580, distinguish species variants in tachykinin NK1 receptors. Br J Pharmacol 108, Benchaoui HA, Siedek EM, De La Puente-Redondo VA et al. (2007) Efficacy of maropitant for preventing vomiting associated with motion sickness in dogs. Vet Rec 161, Beresford IJ, Birch PJ, Hagan RM et al. (1991) Investigation into species variants in tachykinin NK1 receptors by use of the non-peptide antagonist, CP- 96,345. Br J Pharmacol 104, Boscan P, Monnet E, Mama K et al. (2011a) Effect of maropitant, a neurokinin 1 receptor antagonist, on anesthetic requirements during noxious visceral stimulation of the ovary in dogs. Am J Vet Res 72, Boscan P, Monnet E, Mama K et al. (2011b) A dog model to study ovary, ovarian ligament and visceral pain. Vet Anaesth Analg 38, Brown JL, Liu H, Maggio JE et al. (1995) Morphological characterization of substance P receptor-immunoreactive neurons in the rat spinal cord and trigeminal nucleus caudalis. J Comp Neurol 356, Cellier E, Barbot L, Iyengar S et al. (1999) Characterization of central and peripheral effects of septide with the use of five tachykinin NK1 receptor antagonists in the rat. Br J Pharmacol 127, Conder GA, Sedlacek HS, Bouncher JF et al. (2008) Efficacy and safety of maropitant, a selective neurokinin 1 receptor antagonist, in two randomized clinical trials for prevention of vomiting due to motion sickness in dogs. J Vet Pharmacol Ther 51, Davison AC, Hinkley DV (1997) Bootstrap Methods and their Application (Cambridge Series in Statistical and Probabilistic Mathematics). Cambridge University Press, Cambridge, UK. De la Puente-Redondo VA, Siedek EM, Benchaoui HA et al. (2007) The anti-emetic efficacy of maropitant (Cerenia) in the treatment of ongoing emesis caused by a wide range of underlying clinical aetiologies in canine patients in Europe. J Small Anim Pract 48, Duggan AW, Hendry IA, Morton CR et al. (1988) Cutaneous stimuli releasing immunoreactive substance P in the dorsal horn of the cat. Brain Res 451, Gitter BD, Waters DC, Bruns RF et al. (1991) Species differences in affinities of non-peptide antagonists for substance P receptors. Eur J Pharmacol 197, Go VL, Yaksh TL (1987) Release of substance P from the cat spinal cord. J Physiol 391, Hickman MA, Cox SR, Mahabir S et al. (2008) Safety, pharmacokinetics and use of the novel NK-1 receptor antagonist maropitant (Cerenia) for the prevention of emesis and motion sickness in cats. J Vet Pharmacol Ther 31, Iyengar S, Hipskind PA, Gehlert DR et al. (1997) LY303870, a centrally active neurokinin-1 antagonist with a long duration of action. J Pharmacol Exp Ther 280, Laird JM, Olivar T, Roza C et al. (2000) Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene. Neuroscience 98, Mantyh PW, DeMaster E, Malhotra A et al. (1995) Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation. Science 68, Nagahisa A, Kanai Y, Suga O et al. (1992) Antiinflammatory and analgesic activity of a nonpeptide substance P receptor antagonist. Eur J Pharmacol 217, Perry MJ, Lawson SN (1998) Differences in expression of oligosaccharides, neuropeptides, carbonic anhydrase and neurofilament in rat primary afferent neurons retrogradely labelled via skin, muscle or visceral nerves. Neuroscience 85, Quartara L, Maggi CA (1998) The tachykinin NK1 receptor. Part II: distribution and pathophysiological roles. Neuropeptides 32, Ramsey DS, Kincaid K, Watkins JA et al. (2008) Safety and efficacy of injectable and oral maropitant, a selective neurokinin1 receptor antagonist, in a randomized clinical trial for treatment of vomiting in dogs. J Vet Pharmacol Ther 31, Sakamoto T, Barnes PJ, Chung KF (1993) Effect of CP- 96,345, a non-peptide NK1 receptor antagonist, against substance P-, bradykinin- and allergen-induced airway microvascular leakage and bronchoconstriction in the guinea pig. Eur J Pharmacol 231, Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 40,

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