Jonathan Elliott, Royal Veterinary College, University of London, UK
Vomiting and inappetence are clinical signs associated with the later stages of chronic kidney disease (CKD) in cats. As cats reach IRIS CKD Stages 3 and 4 they start to lose weight, eat less and vomit. Poor appetite is the main reason owners perceive their cat's quality of life is reduced with CKD (Reynolds et al., 2010; Bijsmans et al., 2015). The prevalence of these signs is not well characterised in the literature.. Inappetence and weight loss are more common than vomiting in IRIS CKD stages 3 and 4. (Elliott & Barber 1998). Accumulation of nitrogenous waste products other than urea and creatinine affect the appetite centres in the brain and are thought to underlie the reduced appetite of cats with CKD. Vomiting might result from central effects (uraemic toxins stimulating the chemoreceptor trigger zone, for example) and peripheral mechanisms (e.g. the irritant effects of urea at high concentrations on gut mucous membranes).
Vomiting is a protective mechanism leading to the expulsion of the contents of the stomach. It occurs when multiple stimuli from the periphery and other areas of the brain stimulate the vomiting centre in the medulla and exceed the threshold to trigger the vomiting reflex. People describe waves of nausea ('feeling sick to the stomach') that precede vomiting and are relieved when the action of vomiting occurs but, if the signals to the brain do not reach the trigger threshold, the waves of nausea may continue. Nausea is a reported symptom, a sensation we can perceive and describe. However, in feline patients we can only observe physical signs or behaviours that suggest a cat is nauseous. The most common signs suggestive of nausea are salivation, lip licking and restlessness (Kenward et al., 2015), followed by excessive swallowing, abnormal body posture, lethargy and depression. In cats, it is possible that nausea may underlie the poor appetite that is associated with IRIS CKD IRIS Stages 3 and 4. The neurophysiological mechanisms underlying the sensation of nausea are not well understood and are difficult to study, but neuronal activity in the brain stem that triggers the vomiting reflex seems to radiate to higher CNS levels and give rise to the sensation of nausea. Many anti-emetic drugs licensed for human use are labelled as anti-nausea as well as anti-emetics.
It had been assumed that gastric hyperacidity and uraemic gastritis contribute to the reduced appetite, nausea and vomiting seen in cats. Hypergastrinaemia was demonstrated in feline CKD (Goldstein et al., 1998), where the prevalence of high plasma gastrin concentrations increased with the clinical stage of CKD. This paper has been used to support use of H2- receptor antagonists in the management of gastric hyperacidity contributing to uraemic gastritis and the presumed associated reduced appetite, nausea and vomiting. Anecdotally, H2 blockers have been said to be effective in cats with CKD but there are no published randomised controlled clinical trials providing evidence to support their use. Recently, the assumption that cats, like human patients, would suffer from uraemic gastritis has been called into question as a post-mortem study found no evidence of ulceration or inflammation of the gastric mucosa, identifying gastric fibrosis and mineralisation the lesions associated with CKD rather than the expected ulcerative gastritis (McLeland et al., 2014).
A recent doubled-blinded, randomised study evaluated the efficacy of once daily omeprazole (1 mg/kg) on vomiting and appetite in cats with clinical signs of hyporexia ascribed to IRIS stage 2 and 3 CKD (Spencer et al., 2021). There was a small but significant increase in the subjective assessment of food consumed (2.7%, p=0.04) in cats treated with omeprazole. However, as this observation was not associated with changes in body weight or other subjective assessments of appetite and rate of food consumption, it was considered a clinically unimportant finding. The study was small and underpowered to detect any effect of omeprazole on vomiting. Overall, given this clinical trial and the pathology study (McLeland et al., 2014), there is currently no evidence supporting omeprazole as an appropriate first line treatment for hyporexia in cats with CKD, unless there are specific reasons in individual patients to be concerned about gastrointestinal ulceration.
Thus, our understanding of the mechanisms underlying the poor appetite leading to reduced food intake and weight loss in cats with IRIS CKD Stages 3 and 4 is limited, but we assume it is related to accumulated waste products that interact centrally or peripherally with the nervous system to trigger the sensation of nausea and less often, the vomiting reflex. If so, administration of an anti-emetic drug (with associated anti-nausea effects) would be expected to inhibit these actions, reduce the feelings of nausea and increase the cat's appetite. An increasing body of short-term clinical trial data has provided evidence upon which to base initial therapeutic decision-making in inappetent cats with CKD. Longer-term clinical trial evidence is still lacking.
Mirtazapine:
Mirtazapine is a an antidepressant drug that acts by antagonizing pre-synaptic alpha2-adrenoceptors (autoreceptors), thereby, increasing norepinephrine release and presynaptic alpha2-heteroreceptors enhancing serotoninergic neurotransmission. Because mirtazapine also blocks 5-HT2 and 5-HT3 receptors, this presynaptic action enhances serotoninergic transmission involving 5-HT1A receptors. Finally, mirtazapine also has a high affinity for histamine H1 receptors and lower affinity for multiple other amine receptors in the central nervous system and so has a very complex pharmacology (Anttila & Leinonen 2001)..
Mirtazapine has been shown to improve appetite, reduce vomiting and increase weight gain in cats with naturally occurring CKD (Quimby and Lunn 2013). This study, a well-designed randomised controlled masked clinical trial with clear inclusion and exclusion criteria, provided level 1 evidence of efficacy. Importantly, cats were only included if their owners felt appetite was reduced, so beneficial effects of orally administered mirtazapine cannot be extrapolated to cats where appetites are considered normal. In addition, cats that had undergone a uraemic crisis or were considered at risk of developing a uraemic crisis were excluded. The study only recruited cats with plasma creatinine values of 2 to 5 mg/dl (177 to 440 µmol/l), encompassing the upper part of Stage 2 and all of Stage 3. The authors screened 172 cats to identify 16 to randomise for entry into the study and the analysis was done of 11 cats that completed the study. This was a crossover study with treatment periods of 3 weeks and a 4-day washout period between placebo or mirtazapine (1.88 mg per cat every second day). Ten of the 11 cats gained some weight (mean weight gain of 0.18 kg) while treated with mirtazapine whereas 9 of 11 lost weight (mean weight loss of 0.07 kg) whilst receiving placebo. The study was conducted over a short time frame and longer studies are required to determine safety and efficacy of mirtazapine for longer-term management of CKD.
Five cats enrolled in the study were excluded from data analysis: three never received the medication (all randomised to the placebo first) and two suffered uraemic crises during the study (both when taking placebo). The only adverse effect of mirtazapine reported was a substantial increase in ALT in one cat that normalised when mirtazapine was stopped. The owner elected to start the drug again and similar increases in ALT occurred, but with no associated clinical signs. Consequently, it is recommended that plasma ALT be monitored in cats treated with mirtazapine.
The dose of mirtazapine was based on studies where 1.88 mg/cat was administered in capsules formulated by the University Pharmacy. This dose rate was selected following earlier single dose pharmacokinetic studies in healthy older cats and cats suffering from CKD and in young healthy cats (Quimby et al., 2011a,b). The young cats were given low (1.88 mg) and high (3.75 mg) doses. Mirtazapine is extensively metabolised in the liver. Pharmacokinetics studies suggest that the clearance mechanisms of mirtazapine in cats may become saturated at higher doses. In addition, kidney disease led to a 38% greater exposure of the cat to the drug as a result of reduced clearance.
This study has been extended to include mirtazapine administered by the transcutaneous route in cats with CKD (Quimby et al., 2020). Two separate double blinded placebo controlled cross-over studies were undertaken in cats with IRIS stage 2 or 3 CKD where weight loss was reported. The first involved 3.75 mg of mirtazapine (or placebo) administered every other day for 3 weeks and the second had the same design but used a lower dose of 1.88 mg/cat every other day. Mirtazapine was formulated by a University Pharmacy into a gel formulation (from tablets) suitable for transdermal administration. In the first study, 81 cats were screened to find 12 cats suitable to enter into the trial and 9 of the 12 completed the study, with two of the cats failing to complete the mirtazapine arm of the study.
In the second study, 53 cats were screened to find 12 suitable cats to randomise, 10 of which completed both arms of the study with two cats failing to complete the mirtazapine arm. In both studies, mirtazapine administration led to significant weight gain (in 100% and 90% of cats respectively), whereas when the same cats received the placebo, 66 and 70% lost weight. Weight gain was accompanied by significantly increased appetite, speed of food consumption and body condition score.
This study was reported in abstract form in 2017, prior to FDA approval in 2018 of a commercial formulation of mirtazapine in the USA for transdermal administration. A pivotal multi-centre field safety and efficacy clinical trial involved 230 cats (>1 year old) experiencing unintended weight loss (various causes) randomised to either placebo (n=111 in the intention to treat population with 94 in the per protocol population) or mirtazapine (n=113 in the intention to treat population with 83 in the per protocol population) at 2 mg/cat once daily for 14 days (Poole et al., 2018). Mirtazapine treated cats (per protocol population) gained 3.9 ±5.4 % body weight which was significantly greater than placebo where the weight change was +0.4 ±3.3%. The main adverse effect reported was mild erythema at the site of administration which was seen in both test and placebo groups. Kidney disease (diagnosed at the investigator's discretion) was the underlying cause of the unintended weight loss in 36.5% of the cats entered into this study. Cats with range of other reasons for the unintended weight loss were included in the trial on the basis of which the product was also granted a product authorisation by EMA in 2019 (EMA 2019).
The same group also published a retrospective analysis of adverse effects in cats treated with oral mirtazapine (Ferguson et al., 2016). This involved analysis of records from the American Society for the Prevention of Cruelty to Animals' Animal Poison Control Centre where exposure to mirtazapine was reported between 2006 and 2011. Of the 84 cases involved, 59 were reported as 'accidental' exposure. The adverse clinical signs reported included vocalization, agitation, vomiting, abnormal gait/ataxia, restlessness, tremors/trembling, hypersalivation, tachypnoea, tachydardia and lethargy. Signs of toxicity were almost invariably associated with oral doses of 3.75 mg or more and only one was reported following a dose of 1.88 mg. The authorised transdermal product has a stipulated duration of use of 14 days in both the USA and EU. The safety and efficacy of the product beyond this period of time has not been established under field conditions.
While mirtazapine is registered in the USA, UK and the EU as a transdermal ointment for the management of weight loss in cats, elsewhere, prescribing mirtazapine requires splitting larger tablets (registered for use in people), which are bitter, or use of compounding pharmacies, both of which have practical limitations.
Maropitant
Maropitant is a selective neurokinin-1 receptor antagonist authorised for use in dogs and cats in the EU, UK and USA. in cats it is indicated for prevention and treatment of vomiting and reduction of nausea. Quimby et al. (2015) reported a randomised double masked placebo controlled clinical trial of maropitant in cats with CKD. The design had some similarities to their mirtazapine trial described above (Quimby & Lunn 2013) and used the same entry and exclusion criteria. However, rather than a cross-over study, this was a parallel group design where cats were stratified according to stage to ensure an even distribution of cats in IRIS CKD Stages 2 and 3 CKD before being randomised to the two groups. Eighty-four cats were screened for entry and 44 were randomised: 21 cats completed the two weeks of maropitant treatment (dosed orally at 4 mg/cat daily) and 12 cats completed two weeks of placebo. Maropitant significantly reduced the frequency of vomiting seen when compared to placebo but had no effect on appetite score, activity score or body weight. This study only followed cats for 2 weeks before assessing the response to treatment. The placebo group did not lose body weight whereas the cats in the mirtazapine study did lose weight when they dosed for 3 weeks with placebo. No adverse events were attributed to maropitant. The larger number of cats that ended up receiving maropitant compared to the placebo group may have influenced the outcome of the study.
The registered dose rate of maropitant in cats in Europe is 1 mg/kg once daily for up to 5 days by subcutaneous injection so this is off-label use (both in terms of the oral formulation and the duration of treatment). Tablets containing maropitant are available for use in dogs.
Conclusion:
In conclusion, inappetence, vomiting and weight loss are common in later stages of CKD and negatively impact quality of life in the cat. We need more information to allow concrete treatment recommendations to be made, but two pharmacological agents now have Level 1 evidence for safety and efficacy in managing vomiting (maropitant and mirtazapine) and inappetence (mirtazapine only) in the short-term. Published pathology data also cast doubt on the importance of hyperacidity and uraemic gastritis, previously used as a rationale for use of H2-receptor blocking drugs in cats with CKD. Nausea, like pain, is difficult to assess in veterinary practice, so identification of biomarkers for nausea would be very useful in helping show which cats with CKD might benefit from anti-nausea treatment.
The registration of transdermal mirtazapine for use in cats provides a consistent quality product for the short-term management of inappetence in cats of proven efficacy and safety in the feline CKD patient and is a significant advance.
Summary:
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