7 Nov
Elisabetta Mancinelli
Job Title
Maropitant is a specific synthetic, non-peptide, selective NK-1 receptor antagonist that was developed for its ability to block substance P (SP) from binding within the chemoreceptor trigger zone.
SP, which binds the NK-1 receptor (NK-1R), can have effects on brain homeostasis associated with stress, anxiety and vomiting (Garcia-Recio et al, 2015; O’Connor et al, 2004). Tachykinins, such as SP, and their receptors have been detected in the nervous system, and many peripheral tissues including the cardiovascular, gastrointestinal, respiratory, urogenital systems and integument, and are involved in inflammation, nociception, smooth muscle contractility and epithelial activity.
NK-1 receptors and SP are present in brain regions involved in the vomiting reflex (the nucleus tractus solitarius and the area postrema). This anatomical localisation led to the clinical development of antagonists against NK-1R such as maropitant citrate, to treat nausea and vomiting in human patients, dogs and cats (Le, 2017). It has been postulated that these receptors may also control visceral pain (Boscan et al, 2011).
SP is involved in numerous inflammatory conditions, which prompted further investigation of maropitant citrate uses far beyond nausea control. The drug is in fact being explored in the treatment of chronic upper respiratory infections in cats, cough suppression, feline idiopathic cystitis and inflammatory bowel disease. Maropitant has also been found to significantly reduce minimum alveolar concentrations for isoflurane and sevoflurane in dogs, cats and rats, which creates additional potential for its use in balanced anaesthetic protocols in rabbits undergoing surgical procedures (Roeder et al, 2023).
Despite the evidence in dogs and cats regarding the anti-emetic properties and effects on food intake, and minimum alveolar concentration sparing effects of maropitant, no agreement exists between studies on the benefits of using maropitant as a perioperative analgesic in any species (Roeder et al, 2023).
Rabbits do not vomit. Therefore, the anti-emetic properties of maropitant are not considered clinically that important when treating this companion exotic mammal species. However, anecdotally, veterinarians have used maropitant as an anti-nausea drug in rabbits with head tilt. It is believed that maropitant may be useful for rabbits when used as an analgesic for ileus, since NK-1R antagonists have demonstrated multiple roles at gastrointestinal and spinal level.
When looking at evidence-based information, only two pharmacokinetic studies have been performed in rabbits (Ozawa et al, 2019; Sadar et al, 2021). Further to this, a single pharmacodynamics study was found in the literature (Roeder et al, 2023).
In Ozawa et al (2019), plasma concentrations of maropitant citrate were measured in rabbits 24 hours after SC and IV administration of a 1mg/kg single dose. These plasma concentrations were like those of dogs at 24 hours associated with anti-emesis.
Reactions at the SC injection site were the most common adverse effect detected. Increased faecal output may suggest an effect on gastrointestinal motility. However, as only a single dose was used in that study, additional studies were deemed necessary to evaluate higher doses and repeated administrations of maropitant to determine whether differences exist in pharmacokinetics with differing dosages in rabbits. Bioavailability, plasma concentrations and volumes of distribution in the rabbits were lower and clearance was higher than those in dogs and cats.
In this same study, bioavailability in rabbits after SC administration was only approximately 60%, which is much lower than that found in dogs (90.7%) or cats (117%). In canine and feline patients, the high bioavailability after SC administration explains the reason why equivalent doses can be used for both SC and IV administration. The cause for the low bioavailability in rabbits is not known. Because maropitant is primarily cleared by hepatic metabolism, species differences in hepatic blood flow may affect the rate of clearance.
In Sadar et al (2021), dogs’ and rabbits’ pharmacokinetic data were compared. Canine mean maximum plasma concentrations (Cmax) and area under the curve extrapolated to infinity (or AUC0→∞) were higher than rabbits. The area under the curve is a pharmacokinetic statistic used to describe the total exposure to a drug. More specifically, it is the time-averaged concentration of drug circulating in the body fluid analysed (normally plasma, blood or serum).
Because of these findings, the authors sought to evaluate the pharmacokinetics of maropitant in rabbits using a higher dose (10mg/kg SC) than previously evaluated in three healthy, five-month-old female intact New Zealand white rabbits. Rabbits received maropitant 10mg/kg SC interscapularly. Blood samples were collected at several intervals post-administration.
The Cmax was reached at 30 to 60 minutes (231.7ng/ml plus or minus 39.64ng/ml). The concentration decreased to 24.4ng/ml plus or minus 4.7ng/ml at 24 hours. The half-life was 12.6 plus-minus 2.3 hours and the clearance of the drug from plasma was 6.74L/h/kg plus or minus 0.17L/h/kg. One rabbit experienced a localised dermal reaction after injection.
When comparing results of previous studies to this pilot study, the mean Cmax for 1mg/kg IV were 1,920ng/ml and 247ng/ml in canine studies showing antiemetic and minimum alveolar concentration sparing effects, compared to 101.8ng/mL in rabbits (Ozawa et al, 2019).
After SC administration, the mean Cmax for 1mg/kg was 92ng/ml in dogs, while for rabbits the mean Cmax was 14.4ng/ml (Ozawa et al, 2019). The Cmax after 10mg/kg SC was higher than dogs and rabbits after 1mg/kg SC, and dogs after 2mg/kg SC. Based on the results of this pilot study, maropitant 10mg/kg SC in three rabbits achieved plasma concentrations similar or higher to those found in dogs at 1mg/kg and 2mg/kg SC. Plasma levels were measurable at 24 hours after administration. Some accumulation of maropitant was expected, although it was estimated at 20% to 50% based on the half-lives.
Further studies with more rabbits, multiple doses, and pharmacodynamic studies are needed.
“It is believed that maropitant may be useful for rabbits when used as an analgesic for ileus, since [NK-1 receptor] antagonists have demonstrated multiple roles at gastrointestinal and spinal level.”
Finally, in Roeder et al (2023), the authors aimed to evaluate the pharmacodynamic effects of maropitant by utilising a visceral pain model in the form of either an orchiectomy or ovariohysterectomy procedure.
This study evaluated maropitant as an adjunct analgesic modality in protocols for rabbits undergoing orchiectomy or ovariohysterectomy. Differently from the other studies, this was a multi-institutional prospective study and the inclusion criteria for the study were apparently healthy rabbits based on clinical history and preoperative physical exam, and presentation for elective orchiectomy or ovariohysterectomy.
Rabbits were either client-owned or from rescue groups. Rabbits were excluded from the study if they had complications during the anaesthetic and surgical procedures that were considered moderate or major in nature. Rabbits were randomly assigned to one of three treatment groups: low-dose maropitant (2mg/kg SC once), high-dose maropitant (10mg/kg SC once), and control (1ml/kg saline SC once).
At completion of surgery, all rabbits, regardless of treatment group and anaesthetic protocol, received buprenorphine hydrochloride (0.06mg/kg IM every eight hours) and meloxicam (1mg/kg IM every 24 hours) for postoperative analgesia.
In dogs and cats, reported side effects include hypersalivation, pre-travel vomiting, injection site pain, depression, lethargy, anorexia, diarrhoea, ataxia, tremors, fever, dyspnoea, collapse/loss of consciousness, sedation and, in worst cases, convulsions or anaphylactic reactions. These were monitored during the study.
After surgery, rabbits were monitored using a video camera placed outside of each kennel, which recorded continuously for the remainder of their time in the hospital. This was for 24 hours after surgery or until hospital discharge, whichever came soonest, as rabbits from the general practice were not hospitalised overnight. Three blinded observers independently reviewed the video clips to assess pain scores (using a combination of the grimace scale and pain-related behavioural assessment scale), behaviour scores and activity scores. Food intake and faecal output were measured to evaluate appetite and gastrointestinal function postoperatively.
A total of 28 female and 23 male domestic rabbits from three institutions were included. The low-dose maropitant group included 17 rabbits, the high-dose maropitant included 19 and the saline control group included 15. Ages for 18 rabbits ranged from four to 24 months (mean 9.5 plus or minus 6.16 months). The remaining 33 were of unknown age. A variety of breeds were included.
Female rabbits underwent a ventral approach ovariohysterectomy (n=28). Male rabbits had an open scrotal (n=8), closed scrotal (n=14) or closed pre-scrotal (n=1) approach performed. None of the previously noted adverse effects in dogs or cats, or new adverse effects of maropitant, were clinically appreciable in any of the rabbits.
Overall, authors found that maropitant at 2mg/kg SC and at 10mg/kg SC failed to significantly reduce pain when compared to the control group. A difference between rabbits that received high-dose and low-dose maropitant was expected, as in a previous pharmacokinetic study, rabbits achieved plasma concentrations shown to be effective in dogs at 10mg/kg SC. In contrast, results of this study suggested that maropitant may not have adequate analgesic effects in this species.
A limitation of this study was the fact that interpretation of pain scales and ethograms creates opportunity for human error each time a subjective observation is translated to an objective numerical measurement. Therefore, serial studies utilising maropitant at intermediate dosages (more than 2mg/kg and less than 10mg/kg) within analgesic protocols are warranted to evaluate if results of this study are reproducible.
Buprenorphine has been found to decrease gastrointestinal motility in rabbits, and it is possible that maropitant could not overcome the negative motility effects of the adjunctive opioid within the analgesic protocol, or does not have analgesic properties of its own in this species.
Pain was also evaluated in this study utilising the facial grimace scale. Given the clinical utility of validated facial grimace scores, the lack of statistical significance identified in this study was unexpected. However, facial grimace scores that have been validated in rabbits are not specific to visceral pain, and previous studies have noted that focusing on evaluating the face alone was insufficient to identify rabbits in pain. Additionally, due to limitations associated with video capabilities, the entire scale could not be utilised, which may limit the conclusions made by using this scoring technique. As stated previously, the lack of statistical significance may have also been due to lack of analgesic properties with use of maropitant.
The authors advise that, when developing future studies, ensuring video capabilities, and applying multiple methods for pain assessment and pain scales that have been developed since these data were collected, may be more accurate than facial grimace scores alone and may confirm or invalidate these results. Further to this, in this study, food intake and faecal output trended down with administration of higher maropitant dosages.
Hyporexia and hypomotility – especially at maropitant 10mg/kg SC – are negative clinical aspects of this drug that would preclude its use at this dose. However, the wide standard deviation for both food intake and faecal output also suggests that a larger sample size is necessary in future studies to elucidate the impact of maropitant and dose on the gastrointestinal tract of rabbits.
The described trend may be clinically significant and suggests that higher doses of maropitant could potentiate risk of gastrointestinal hypomotility through undetermined mechanisms. This may be analogous to findings in dogs and cats, where doses at which visceral nociception was thought to be controlled based on decreasing minimum alveolar concentration requirements also concluded no difference between groups for postoperative nausea and vomiting (Swallow et al, 2017).
Results may have also been skewed by earlier discharge times in a proportion of the individuals included and a lack of food and faecal data reported from the general practice.
Ozawa et al (2019) found that maropitant use in rabbits may increase faecal output in some individuals. This had suggested the opportunity to also mitigate gastrointestinal hypomotility while utilising this medication. However, the last reported study found that detrimental effects on gastrointestinal transit may be associated with addition of this medication when used at higher dosage. An intermediate dose could be considered to appropriately control visceral pain, while avoiding the possible negative gastrointestinal effects that may have been appreciated here.
It is very hard to make relevant and practical conclusions where the available evidence is contrasting. The authors have since increased the dose to maropitant to 4mg/kg once daily SC. However, as this drug is often given concurrently to many other analgesics and alongside fluid therapy and supportive care, it remains difficult to evaluate its real clinical benefits for each patient.
Clinical judgement and practical considerations may be required in practice on a case-by-case situation. Off-licence consent should always be obtained. Please refer to the literature provided for more detailed information.
