Cerenia Prevents Perioperative Nausea and Vomiting and Improves Recovery in Dogs Undergoing Routine Surgery Deborah Ramsey Tim Fleck Thomas Berg Steve Nederveld Donald DeLong Jezaniah-Kira Tena Michelle Aleo Robert McCall

VMRD-Global Therapeutics Research, Zoetis, Inc. Kalamazoo, MI Corresponding Author: Robert B. McCall, [email protected]

KEY WORDS: Cerenia, Perioperative Cerenia was associated with a signifi- Nausea and Vomiting, Surgical Recovery cantly faster return to feeding compared to ABSTRACT placebo-treated dogs. Cerenia improved the quality of recovery (as measured by Cerenia is a selective neurokinin-1 receptor decreased aimless movements, vocalization, antagonist used to treat nausea and vomit- and panting) compared to placebo-treated ing in dogs. The present study investigated dogs. However, treatment with Cerenia the effects of Cerenia (maropitant) inject- able solution (1.0 mg/kg) on post-operative did not significantly change the speed with nausea and vomiting in dogs pre-medicated which dogs recovered from surgery or their with morphine or buprenorphine and under- general attitude during the recovery period, going an ovariohysterectomy or a routine or their level of sedation during recovery castration. Improvement in the quality and compared to dogs receiving placebo treat- speed of recovery were also assessed. Forty ment. Buprenorphine pre-medicated dogs eight dogs were randomized to treatment failed to display signs of nausea or vomiting. with Cerenia or placebo that were adminis- In these animals Cerenia and placebo ani- tered 45 minutes prior to the opioid pre- mals had similar surgical recoveries. This medication. Surgery was performed under study demonstrates the value of pre-opera- general anesthesia using isoflurane. Study tive Cerenia when used in conjunction with participants collecting clinical assessment morphine, but not buprenorphine, as a pre- data were masked to treatment allocation. medication to reduce nausea and vomiting, Cerenia significantly reduced both nausea to hasten return to normal food consumption and vomiting in dogs pre-medicated with post-operatively, and to improve the quality morphine. In dogs receiving morphine, of recovery from surgery.

228 Vol. 12, No.3, 2014 • Intern J Appl Res Vet Med. INTRODUCTION In the first arm of the study morphine was A large body of data indicates that brain utilized as a pre-anesthetic agent. Sixteen stem substance P acting via neurokinin-1 male and 16 female Beagles (10-30 months (NK-1) receptors is a key mediator in the of age, Marshall Farms) undergoing routine pathophysiology of emesis.1-4 CereniaTM castration or ovariohysterectomy (OHE) (maropitant) is a potent and selective NK-1 surgery were evaluated. receptor antagonist used to treat nausea and In a second series of experiments 16 vomiting in dogs.5 In laboratory studies, additional female dogs were given buprenor- Cerenia blocks emesis induced by centrally phine as a pre-anesthetic agent prior to acting emetogens (eg, apomorphine) as OHE surgery. Surgeries were staged over well as peripheral emetogens (eg, syrup of multiple days with four surgeries conducted ipecac).6 This broad spectrum of anti-emetic per day by a trained veterinarian blinded to efficacy is also noted in clinical trials.5-7 In treatment groups. Approximately 1 week this regard, Cerenia has been shown to con- prior to Study Day 0 for the first dog, an trol canine emesis resulting from a variety initial pre-study examination was conducted of etiologies in clinical trials,5 to prevent by a study veterinarian to assess suitability and treat cisplatin-induced emesis in cancer for inclusion in the study. As part of the chemotherapy8 and to prevent emesis associ- physical examination, a blood sample was ated with motion sickness.9 Cerenia has also collected for complete blood count and been shown to be effective in preventing serum chemistry analysis to insure the health emesis produced by either emetogen chal- of the animal prior to surgery. Based on the lenge or motion sickness in cats.10 physical exam findings and results of the Opioids are commonly used as pre-an- CBC/serum chemistry profile, a total of 48 esthetic agents in veterinary medicine. Full dogs were selected for the study (16 males mu agonists such as morphine and hydro- and 16 females for morphine study and 16 morphone provide dose-dependent sedation females for buprenorphine study). and analgesia and are useful in treating Animals were randomly assigned to moderate to severe pain. They are also used pen location, room, day of surgery, pre- as induction agents and as post-operative anesthetic (morphine or buprenorphine), and analgesics. Although effective, side effects treatment group (placebo or Cerenia). Dogs may include respiratory depression, seda- were transported in cages to the surgical tion, nausea, and vomiting. The reported suite where they remained for pre- and post- incidence of emesis in dogs following ad- surgical assessments. Dogs were maintained ministration of morphine or hydromorphone in the surgery suite or its recovery room given as a pre-anesthetic agent ranges from from the time of pre-medication until the 50-100%.11-13 A recent report indicates that end of the surgical recovery period (3 hours Cerenia prevents vomiting in dogs treated after the end of surgery). At the end of the with hydromorphone prior to surgery.14 The recovery period, dogs were moved back to objective of the current study was to deter- the room where they originated. mine if Cerenia is effective in preventing Cerenia Injectable Solution (1 mg/kg) nausea and vomiting in dogs pre-medicated or placebo (saline, 0.1 ml/kg) was admin- with either the full mu agonist morphine or istered subcutaneously, 60 minutes prior to the partial agonist buprenorphine prior to the induction of anesthesia with propofol. surgery and to determine if Cerenia speeds Cerenia and placebo were given chilled recovery time or improves the quality of after removal from a refrigerator in order to anesthetic recovery. minimize pain upon injection produced by 15 METHODS Cerenia. Dogs were pre-medicated with either morphine (0.5 mg/kg, s.c.) or bu- This study was approved by the Zoetis In- prenorphine (0.005 mg/kg, s.c.) 45 minutes stitutional Animal Care and Use Committee.

Intern J Appl Res Vet Med • Vol. 12, No. 3, 2014. 229 following the dose of Cerenia or placebo no discharge of vomitus was observed and 15 minutes prior to anesthesia. A either because the reflex mechanism was trained blinded observer documented nausea interrupted before completion or because it and vomiting immediately prior to treatment lacked sufficient intensity to cause ejection with either Cerenia or placebo and induc- of gastric contents. Vomiting was defined tion of anesthesia with propofol. Each dog as the forceful ejection of gastric and/or underwent routine surgery under general intestinal contents (vomitus) from the mouth inhalant anesthesia with isoflurane. Follow- via forceful, sustained contractions of the ing post-surgery extubation, dogs continued abdominal muscles. to be observed for nausea and vomiting and Intensity of Nausea was determined us- also observed every 15 minutes for the first ing a visual analog scale (VAS) to assess and 30 minutes after surgery and then every 30 record the severity of nausea experienced minutes thereafter for a total of three hours by each dog during the perioperative period. for quality and attributes of surgical recov- For each nausea VAS assessment, a dog was ery as described below. Food intake was observed for 15 seconds (± 5 seconds) and a recorded for up to 26 hours post-surgery and visual analog scale measuring “no nausea” the return to feeding time (consumption of at the far left to “worst possible nausea” at a total of 100 grams of food) was recorded. the far right was marked. Signs of nausea All study participants collecting clinical as- included: sessment data (emetic events, nausea scores, • excessive salivation clinical observations of recovery, general • increased or exaggerated swallowing health observations, temperature, pulse, and respiration) were masked to treatment • licking the lips allocation. Only one study participant, the • hunched posture Treatment Administrator who prepared the • piloerection syringes of the test material, knew the al- • restlessness and. location of animal to treatment group. The • vocalization. Treatment Administrator did not perform A single observer made all of the nausea any clinical assessments during the study. assessments for all dogs for the entire study Dogs were fed Lab Diet-Certified Ca- to ensure consistency. The observer placed nine Diet #5007 (dry dog food) ad libitum a single vertical line transecting a 100 mm throughout the study except beginning at VAS scale. The distance from the far end of 18:00 on Study Day -1 when dogs were the scale (0=no nausea) to the vertical mark fasted prior to surgery. Post-operatively, was measured to obtain a numeric score. dogs were initially fasted, then offered food Quality of Surgical Recovery was as- beginning at 2 hours after the end of the sessed using numeric 0-2. For each as- surgical procedure. Water was provided ad sessment, a dog scored 0-2. The quality of libitum except on Study Day 0 when it was recovery for dogs graded 0 was considered removed just prior to induction of anesthe- smooth (dog is lying comfortably; no vocal- sia. Water was returned 3 hours after the ization or panting; minimal movement even end of the surgical procedure. when stimulated by touch; appears sleep- Primary study variables included emetic ing; relaxed posture). Dogs graded 1 were events and intensity of nausea. Quality of considered to have a moderate recovery surgical recovery and return to feeding were (dog changes position frequently; pant- secondary study variables. ing; stimulated when touched and attempts Presence of Emetic Event(s). Emetic to rise or move; hunched posture). Dogs events included retching, vomiting, and graded 2 were considered to have a rough presence of vomitus. Retching was defined recovery (dog is thrashing, paddling in as a strong involuntary effort to vomit when cage; shaking, vocalizing; touch temporar-

230 Vol. 12, No.3, 2014 • Intern J Appl Res Vet Med. ily calms but movement and sound resumes recovery was summarized by treatment when stimulation is withdrawn). A single and sex. Whether or not an animal had an observer made all of the surgical recovery emetic event was analyzed using Fisher’s assessments for all dogs for the entire study Exact Test as the generalized linear mixed to ensure consistency. model with a logit link function and a Attributes of Surgical Recovery included binomial error distribution did not converge. assessments of attitude, level of sedation, VAS scores were analyzed with a general and speed of recovery from anesthesia. At- linear mixed model for repeated measures. tributes were scored on a 0-3 scale, and the The fixed effects in the model were sex, percent of dogs in each attribute category treatment, sex by treatment interaction, time was compared across treatment groups. point, sex by time point interaction, treat- Level of sedation was recorded according to ment by time point interaction, and sex by methods published by Young16 in which a treatment by time point interaction. The score of 0-3 was provided for each of three random effects in the model were room, sedation parameters: spontaneous posture, block within room, block within room by response to noise, and relaxation of jaw sex interaction, block within room by sex by and tongue. The times of key elements of treatment interaction (animal term), and re- recovery were recorded and compared to sidual. If any interactions involving sex and when the vaporizer was turned off to derive treatment were significant, then treatments an elapsed time to extubation, time to sternal were compared at each time point for each recumbency, time to standing posture, and sex. Otherwise, treatments were compared time to return to feeding. Since dogs were at each time point across sex. Treatment not observed continuously once extubated, least squares means (LSM), standard errors, the recorded times were approximate and 95% confidence intervals, minimums, and recorded when first observed. For example, maximums were calculated at the same level if at 30 minutes into the recovery period, that the treatment comparisons were made. the dog was in lateral recumbency but at RESULTS 45 minutes was sternal, the time of sternal In the first series of experiments, morphine recumbency was the time of the 45 minute was used as a pre-anesthetic agent in 16 observation. male and female dogs. These animals Return to Feeding was assessed directly received either Cerenia Injectable Solution by weighing food consumed at 2, 3, 6, 20, (1 mg/kg, sc) or placebo (saline) 45 minutes and hours post surgery. In addition, bu- prior to morphine administration. One prenorphine dogs were assessed at 26 hours Cerenia dog was removed from the statisti- as this group had a delayed return to feed- cal analysis as it was not correctly dosed. ing. At each time point dogs were offered Morphine induced emesis in 15 of 16 dogs 100 grams of their normal chow and given treated with placebo. Nine of these 15 dogs 10 minutes to consume the food. A dog’s vomited more than one time. Emesis was time of return to feeding was defined as the noted within 5 minutes of morphine treat- time when a cumulative total of 100 grams ment and continued for 10 minutes until of feed had been consumed. propofol was administered. All hypothesis tests were conducted at In contrast, none of the 15 Cerenia the 0.05 level of significance (two-tailed). treated dogs vomited during the pre-anes- The primary variables were presence of thetic period. There were no emetic events emetic events and intensity of nausea. All observed during the 150 minute post-oper- other variables were secondary. Presence of ative period in any dog in either treatment emetic events was summarized by treatment group. The ability of Cerenia to prevent and time point. Whether or not an animal emesis pre-operatively in dogs treated with had an emetic event up to 150 minutes into morphine compared to that of the placebo

Intern J Appl Res Vet Med • Vol. 12, No. 3, 2014. 231 was statistically significant (p<0.05). In the standing posture. No significant difference second series of experiments, buprenorphine between Cerenia and placebo dogs was was used as a pre-anesthetic agent in an ad- noted in any of these measures whether the ditional 16 female dogs treated either with animals were pretreated with morphine or Cerenia or placebo. None of the buprenor- buprenorphine. Similarly there was no dif- phine dogs had an emetic event in the pre- ference in sedation during recovery between or post-operative period. Cerenia and placebo dogs pre-medicated Intensity of nausea was evaluated using with morphine or buprenorphine. a VAS scale over the 15 minutes (in 5-min- The quality of recovery from anesthesia ute intervals) between the administration of for each dog was graded on a 0-2 scale. In morphine or buprenorphine until induction animals pre-medicated with morphine, none of anesthesia and again post-operatively of the 15 Cerenia-treated dogs were con- for 3 hours. In animals pre-treated with sidered to have a rough recovery while two morphine, the sex by treatment by time placebo-treated dog were scored as having point interaction was significant so treatment a rough recovery; one at the 15-minute and comparisons were made at each time-point one at the 30-minute observation times. At for each sex. For both males and females, 60 minutes into recovery, all Cerenia-treated the intensity of nausea was significantly dogs were considered to be recovering greater in the placebo-treated dogs at 5 and smoothly (score =0) and continued with 10 minutes after morphine administration a smooth recovery to the last observation pre-operatively. For females, intensity of 3 hours after surgery. In contrast, at 60 nausea was significantly different between minutes into recovery, 25% of placebo- treatment groups post-operatively at extuba- treated dogs were considered to be having a tion and at 30, 45, 60, 90, 120, and, 150 moderate recovery (changing position, pant- minutes after extubation. The least squares ing, hunched posture) and a similar number mean (LSM) VAS score for intensity of continued through the 3-hour evaluation nausea five minutes after morphine admin- period. In animals pre-medicated with bu- istration was 54.7 (female) and 57.4 (male) prenorphine, Cerenia improved the quality in placebo-treated dogs and 7.5 (female) of recovery at 15 minutes, but was similar and 15.8 (male) in Cerenia-treated dogs. At to placebo throughout the remaining 3-hour 45 minutes into the post-operative recov- observation period. ery period, the LSM nausea VAS was 26.4 Twelve dogs pre-treated with morphine (female) and 5.2 (male) for placebo-treated returned to feeding (100 grams of food dogs and 10.5 (female) and 1.9 (male) for consumed) by 6 hours post-operation (Table the Cerenia-treated dogs. 1). Of the 12 dogs that returned to feeding Buprenorphine treated dogs displayed by 6 hours into recovery, 4/12 (33.3%) had few signs of nausea. For example, the received placebo treatment and 8/12 (66.7%) mean VAS nausea score 45 minutes post- had been treated with Cerenia pre-opera- operation was 8.0 for placebo dogs and 4.0 tively. Seven of 13 placebo-treated dogs for Cerenia treated dogs. This compares (53.8%) had not eaten at least 100 grams of to a nausea score of 26.4 in placebo dogs food 20 hours after surgery while only one treated with morphine. As such, there were Cerenia-treated dog (6.7%) still had not eat- no significant differences in nausea intensity en a total of 100 grams of food at 20 hours. in Cerenia versus placebo dogs treated with The difference in the proportion of dogs that buprenorphine. returned to feeding during the study between Speed of surgical recovery was quanti- treatment groups was significant (P=0.0272). tated from the time the anesthetic vaporizer Total food consumption during the 20 hour was turned off to the time of extubation, post operative period was measured. Table time to sternal recumbency, and time to 2 shows that Cerenia dogs ate significantly

232 Vol. 12, No.3, 2014 • Intern J Appl Res Vet Med. Table 1. Summary of Morphine Premedicated Dogs Returning to Feeding By Time Into Recov- ery Treatment Time Into Recovery (After End of Procedure) Group 3 hours 6 hours 20 hours Did not return to feeding n % n % n % n % Placebo (T01) 1 6.7 3 20.0 1 6.7 7 46.7 Cerenia (T02) 0 0 8 53.3 2 13.3 1 6.7 Total 1 6.5 11 36.7 3 10.0 8 26.7

(p = 0.0419) more grams of food (190 + associated with the use of morphine. None 47.8) than placebo dogs (39.1 + 27.5) . No of the 15 Cerenia-treated dogs vomited buprenorphine pre-treated dogs returned to after receiving morphine. Fourteen of 15 feeding during by 6 hours following surgery. placebo-treated dogs vomited post-morphine Since buprenorphine pre-medication delayed administration, and of those 14 vomiting the return to feeding we evaluated these dogs, NINE vomited more than one time. dogs 26 hours post surgery. Only 57% of These data indicate that Cerenia blocks placebo dogs and 37% of Cerenia dogs had morphine-induced emesis and supports a re- returned to feeding by 26 hours. At 26 hours cent case report in which Cerenia prevented post recovery placebo dogs ate a LSM total vomiting induced by epidural administration of 82.6 + 36.2 grams of food compared to of morphine in the dog.17 Similarly, Cerenia 127.6 + 33.9 grams in the Cerenia dogs has been demonstrated to prevent emesis in- (Table 3). duced by hydromorphone, a potent analog of 14, 18 DISCUSSION morphine. In contrast to morphine, no emesis was noted in 16 dogs pre-medicated The purpose of the present study was to de- with buprenorphine prior to surgery. The termine if Cerenia is effective in preventing decrease incidence of emesis in buprenor- nausea and vomiting in dogs pre-medicated phine treated dogs compared to morphine with either the full opioid agonist morphine treated dogs has been documented and likely or the partial opioid agonist buprenorphine results from the partial agonist activity of prior to surgery, and to determine if Cerenia buprenorphine at the mu receptor.19 speeds recovery time as well as the quality The dorsal motor nucleus of the vagus, of anesthetic recovery. We found that in the the nucleus tractus solitarius (NTS) and the 30 analyzable dogs receiving morphine as a area postrema (AP) integrate emetic signal- pre-medication prior to general anesthesia ing and are often referred to collectively for routine surgery, Cerenia, at a dosage as the emetic center.20 Lacking a blood of 1.0 mg/kg was significantly better than brain barrier, the AP detects emetogens in placebo (p<0.05) in preventing vomiting

Table 2. Analysis of Food Consumption Least Squares Means (LSM) and Confidence Inter- vals (CI) in Morphine Pre-Medicated Dogs Treatment Number of LSM Standard Lower Upper Minimum Maximum Animals Error 95% CI 95% CI Saline 8 39.1 27.5 -106.9 185 0 111 (T01) Cerenia 8 190.0 47.8 58.7 321.2 3.6 337.8 (T02)

Intern J Appl Res Vet Med • Vol. 12, No. 3, 2014. 233 Table 3. Analysis of Food Consumption Least Squares Mean (LSM) and Confidence Intervals (CI) in Buprenorphine Pre-medicated Dogs

Treatment Number of Least Standard Lower Upper Minimum Maximum Animals Squares Error 95% CI 95% CI Mean T01 (SALINE) 7 82.6 36.2 4.3 160.8 0 171 T02 (CERENIA) 8 127.6 33.9 54.4 200.8 0 332 the blood and sends projections to the NTS the prevention of nausea as well as vomit- which contains neurons controlling swal- ing and several studies indicate that Cerenia lowing, respiration and stomach and lower prevents nausea associated with emetogens esophageal sphincter tone. These neurons and motion sickness.5-10 In the present coordinate the physical and autonomic activ- study we assessed nausea from the time of ity associated with nausea and vomiting. injection of morphine or buprenorphine to The emetic center receives input from four intubation and again following surgery for major locations: the chemoreceptor trigger 3 hours. Nausea was measured by a blinded zone, the GI tract, the vestibular appara- observer using VAS and nausea signs tus and the cerebral cortex. Opioids exert included excessive salivation, increased or emetogenic effects via direct stimulation of exaggerated swallowing, licking the lips, the chemoreceptor trigger zone, inhibition of hunched posture, piloerection, restlessness gut motility, and stimulation of the vestibu- and vocalization. Cerenia significantly lar apparatus by activation of mu, kappa and reduced nausea in both male and female delta opioid receptors.21 dogs pre-medicated with morphine during In addition, acute administration of the preoperative period compared to placebo morphine causes an increase in expression treated animals. Following surgery, male of substance P in the central nervous system dogs pre-medicated with morphine did not and up-regulates NK1 receptors.22,23 In this exhibit nausea whether treated with Cerenia regard, a large body of evidence indicates or placebo. In contrast, female dogs given that substance P mediates emesis via NK1 morphine and placebo were nauseous for receptors in the brainstem emetic center.20 150 minutes following surgery. Cerenia Cerenia is a NK1 receptor antagonist and blocked the nausea in female dogs during effectively controls emesis produced by cen- this time period. Female dogs likely exhib- tral and peripheral acting emetogenic agents ited prolonged nausea compared to males as in both dogs and cats.6 Cerenia is thought a result of abdominal surgery in combination to act at the level of the brainstem emetic with the morphine pretreatment. Animals center to inhibit the final site of integration premedicated with buprenorphine did not of emetic stimuli. Thus, Cerenia has been exhibit signs of nausea. shown to block emesis induced by a wide The quality of surgical recovery from range of emetogens including as demonstrat- anesthesia was also evaluated in this study ed in the present study, morphine. using a three point scale signifying smooth, The neural pathways for nausea are moderate, and rough recovery. The surgical distinct from those associated with vomit- recovery of the 15 dogs pre-medicated with ing24 Indeed, vomiting is not always as- morphine and given Cerenia was judged sociated with nausea,25 although a common to be smooth by a blinded observed at all pathway for nausea and vomiting may apply time points during the recovery period. In for stimuli acting via vagal afferents and contrast, recovery of two placebo dogs was the AP. Cerenia is registered in Europe for considered rough during the first 30 min- utes of anesthesia recovery and 25% of the

234 Vol. 12, No.3, 2014 • Intern J Appl Res Vet Med. dogs had a moderately difficult recovery as was not statistically significant. At 26 hours judged by frequent position changes, pant- post-recovery placebo dogs ate a LSM total ing, stimulation when touched, and hunched of 82.6 + 36.2 grams of food compared to posture throughout the 3-hour recovery 127.6 + 33.9 grams in the Cerenia dogs. observation period. Dogs pre-medicated The difference in return to feeding in mor- with buprenorphine and given placebo phine versus buprenorphine medicated dogs seemed to have a better quality of recovery is unknown, but may be related to either bet- than did their morphine counterparts treated ter pain control in morphine dogs or perhaps with placebo. Cerenia treated dogs did re- a direct hyperphagic effect produced by cover significantly better than placebo at 15 morphine.27 In contrast buprenorphine has minutes post-recovery in animals pretreated been shown to decrease food intake follow- with buprenorphine. All dogs pre-medicated ing surgery in rats.28 with buprenorphine had a smooth recovery The present study demonstrates that at 30 minutes and later during the recovery Cerenia provides benefit when morphine period. These data indicate that Cerenia is used as a pre-anesthetic agent prior to increased the quality of surgical recovery surgery in dogs. First, Cerenia prevented from anesthesia in animals pre-medicated emesis induced by the morphine. Cerenia with morphine. Cerenia has been shown to has been shown to block the emesis of a decrease the anesthetic requirements during second full mu agonist hydromorphone in visceral surgery.26 This finding may be re- the dog.1. Second, Cerenia prevented nausea lated to the increase in the quality of surgical associated with morphine administration recovery in Cerenia treated animals in the prior to and following surgery. Similarly, current study. Cerenia blocks nausea produced by hydro- Cerenia significantly hastened the return morphone.14 Satisfaction with anesthesia is to feeding following surgery in morphine most closely tied to avoidance of vomiting pre-medicated dogs. At 6 hours post-surgery and nausea in humans.29 Thus avoiding 66.7% of Cerenia dogs had returned to nausea and vomiting by use of Cerenia when feeding (consuming a total of 100 grams of morphine or hydromorphone is given prior food compared to 33.3% of placebo dogs). to surgery in dogs should be considered. At 20 hours post-surgery all but one Cerenia This may be especially important for dog (93%) had returned to feeding while abdominal surgery as the level of nausea only 46% of placebo dogs had consumed in this study was more prolonged in fe- >100 grams of food. At 20 hours Cerenia male dogs undergoing ovariohysterectomy dogs had consumed a mean of 190 grams compared to male dogs undergoing routine of food while placebo dogs had consumed castration. Third, Cerenia provided ad- 39 grams of chow. Thus Cerenia decreased ditional benefits in the post surgery period the time to feeding return and increased the in animals pre-medicated with morphine. amount of food consumed in the hours fol- All dogs treated with Cerenia had a smooth lowing surgery compared to placebo treated recovery from anesthesia. In contrast, 25% dogs. Although Cerenia increased feeding of placebo dogs experienced moderate and post-surgery in morphine dogs this effect difficult recovery from anesthesia based on was not evident in animals pre-medicated behavioral observation. with buprenorphine. Pre-medication with In addition, dogs pre-medicated with buprenorphine delayed the return to feeding morphine and given Cerenia returned to following surgery independent of Cerenia feeding faster and ate greater amounts than or placebo treatment. No buprenorphine did placebo dogs. Improved feeding and pre-treated dogs returned to feeding during smooth recovery from anesthesia may allow by 6 hours following surgery. Only 57% earlier discharge from the clinic and thus of placebo dogs and 37% of Cerenia dogs decrease related expenses and may improve had returned to feeding by 26 hours. This

Intern J Appl Res Vet Med • Vol. 12, No. 3, 2014. 235 owner satisfaction of the surgical experi- Anaesth Analg 2007; 34: 15-22. ence. Finally, it should be noted that these 13. KuKanich B, Hogan B, Krugner-Highby L et al. Pharmacokinetics of hydromorphone in healthy benefits of Cerenia apply only when full mu dogs. Vet Anaesth Analg 2008; 35: 256-264. agonists are given as a medication during 14. Kraus B. Efficacy of maropitant in preventing vom- surgery. iting in dogs premedicated with hydromorphone. REFERENCES Vet Anaesth Analg 2013; 40: 28-34. 15. Narishetty S. et al. Effect of refrigeration of the an- 1. Arumi H, Saito R, Nago S, et al. The role of tachyki- tiemetic Cerenia (maropitant) on pain on injection. nin NK1 receptors in the area postrema of ferrets in Vet Therapeutics 2009; 10: 93-102,. emesis. Neurosci Lett 2000; 286: 123-126. 16. Young L, Brearley J, Richards D et al. Medetomi- 2. Hargreaves R. Imaging substance P receptors (NK-1) dine as a premedicant in dogs and its reversal by in the living human brain using positron emission atipamezole. J Small Animal Practice 1990; 31: tomography. J Clin Psychiatry 2002; 63 (Suppl. 554-559. 11): 18-24. 17. Mathis A, Lee K, Alibhai H. The use of maropitant 3. Gardner CJ, Twissell DJ, Dale TJ, et al. The broad to prevent vomiting induced by epidural adminis- spectrum anti-emetic activity of the novel non- tration of preservative free morphine through an peptide tachykinin NK1 receptor antagonist epidural catheter in a dog. Vet Anaesth Analg 2011; GR203040. Br J Pharmacol 1995; 116: 3158-3163. 38: 516-517. 4. Diemunsch P, Grelot L. Potential of substance P an- 18. Kraus B. Efficacy of orally administered maropitant tagonists as antiemetics. Drugs 2000; 60: 533-546. citrate in preventing vomiting associated with 5. De La Puente-Redondo V, Siedek E., Benchaoui, hydromorphone administration in dogs. JAVMA H., Tilt N, Rowan T, Clemence R. The anti-emetic 2014; 244: 1164-1169. efficacy of maropitant (CereniaTM) in the treat- 19. Dum J, Herz A. In vivo receptor binding of the ment of ongoing emesis caused by a wide range of opiate partial agonist, buprenorphine, correlated underlying clinical aetiologies in canine patients in with its agonistic and antagonistic actions. Br J Europe. J Small Animal Practice 2007; 48: 93-98. Pharmac 1981; 74: 627-633. 6. Sedlacek H, Ramsey D, Boucher J, Eagleson J, 20. Hornby P. Central neurocircuitry associated with Conder G, Clemence R. Comparative efficacy emesis. Am J Med 2001; 111 (Suppl 8A): 106S- of maropitant and selected drugs in preventing 112S. emesis induced by centrally or peripherally acting emetogens in dogs. J Vet Pharmacol Therap 2008; 21. Holden J, Jeong Y, Forrest J. the endogenous opioid 31: 533-537. system and clinical pain management. AACN Clin Issues 2005;16: 291-301. 7. Ramsey D, Kincaid K, Watkins J, Boucher J, Conder G, Eagleson J, Clemence R. Safety and efficacy 22. Cantarella P, Chahl L. Acute effects of morphine of injectable and oral maropitant, a selective on substance P concentrations in microdissected neurokinin1 receptor antagonist, in a randomized regions of guinea-pig brain. Behav Pharmacol clinical trial for treatment of vomiting in dogs. J 1996; 7: 470-476. Vet Pharmacol Therap 2008; 31: 538-543. 23. Wan Q, Douglas S, Wang X, et al. Morphine 8. Vail D, Rodabaugh H, Conder G, Boucher J, Mathur upregulates functional expression of neurokinin-1 S. Efficacy of injectable maropitant (CereniaTM) receptor in neurons. J Neurosci Res 2006; 84: in a randomized clinical trial for prevention and 1588-1596. treatment of cisplatin-induced emesis in dogs 24. Andrews P, Horn C. Signals for nausea and emesis: presented as veterinary patients. Veterinary and implications for models of upper gastrointestinal Comparative Oncology 2007; 5: 38-46. diseases. Auton Neurosci 2006; 125: 100-115. 9. Conder G, Sedlacek H, Boucher J, Clemence R. 25. Lee M, Feldman M. Nausea and vomiting. In: Slei- Efficacy and safety of maropitant, a selective senger MH, Fordtran JS, editors. Gastrointestinal neurokinin 1 receptor antagonist, in two random- Disease. Philadelphia, USA: W.B. Saunders Co.; ized clinical trials for prevention of vomiting due 1993. pp. 509–523. to motion sickness in dogs. J Vet Pharmacol Ther 26. Boscan P, Monnet E, Mama K, et. al. Effect of 2008; 31: 528-532. maropitant, a neurokinin 1 receptor antagonist, on 10. Hickman M, Cox S, Mahabir S, Miskell C, Lin J, anesthetic requirements during noxious visceral Bunger A, McCall R. Safety, pharmacokinetics stimulation of the ovary in dogs. Am J Vet Res and use of the novel NK-1 receptor antagonist 2011; 72: 1576-1579. maropitant (Cerenia) for the prevention of emesis 27. Gulati K, Ray A, Sharma K. Effect of acute and and motion sickness in cats. J Vet Pharmacol Ther chronic morphine on food intake in rats: modula- 2008; 3: 220-229. tion by oxytocin and vasopressin. Pharmacol 11. Valverde A, Cantwell S, Hernandez J et al. Effects Biochem Behav 1991; 40: 27-32. of acepromazine on the incidence of vomiting 28. Liles J, Flecknell P. The effects of buprenorphine, associated with opioid administration in dogs. Vet malbuphine and butorphanol alone or following Anaesth Analg 2004; 31: 40-45. halothane anesthesia on food and water consump- 12. Wison D, Evans A Mauer W. Pre-anesthetic meperi- tion and locomotor movements in rats. Laboratory dine: associated vomiting and gastroesophageal Animals 1992; 26: 180-189. reflux during the subsequent anesthetic in dogs.Vet

236 Vol. 12, No.3, 2014 • Intern J Appl Res Vet Med. 29. Lehmann M, Monte K, Barach P, et al. Postopera- tive patient complaints: a prospective interview study of 12,276 patients. J Clin Anesth. 2010; 22:13-21.

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