Treatment of Vomiting, Nausea and Inappetence in Cats with Chronic Kidney Disease

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 one of the main factors owners perceive as reducing the quality of life of these cats (Reynolds et al., 2010; Bijsmans et al., 2015). The prevalence of these signs is not well characterised in the literature as early papers did not stage cases they diagnosed. Inappetence and weight loss appear to be more common in IRIS CKD stages 3 and 4 than does vomiting, which is seen in 1 in 3 cases or fewer (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 (uraemic gastritis due to a combination of gastric hyperacidity and 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 exceeding the threshold to trigger the vomiting reflex. Human subjects 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 perceive and report on, so in animal patients we can only observe physical signs or behaviours that suggest a patient is nauseous, the most common being 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 has 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).

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 vomiting reflex and the sensation of nausea. 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. But appropriate clinical trial data to support this pharmacological approach has been lacking until recently

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 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. 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 safety of this drug in cats has not been systematically studied and there is no mirtazapine-containing formulation authorised for use in cats in the USA or Europe. The drug was administered at a rate of 1.88 mg/cat 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 and demonstrated dose-dependent kinetics suggesting saturation of clearance mechanisms may occur at higher doses in this species. In addition, kidney disease led to a 38% greater exposure of the cat to the drug as a result of reduced clearance.

The same group also published a retrospective analysis of adverse effects in cats treated with 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 doses of 3.75 mg or more and only one was reported following a dose of 1.88 mg. Although it would be more reassuring if mirtazapine had been developed for use in the cat, so that more data on its pharmacokinetics and safety would be available, the published data do provide some reassurance that short-term use of mirtazapine at a rate of 1.88 mg/cat is relatively safe.

Maropitant is a selective neurokinin-1 receptor antagonist authorised for use in dogs and cats in the EU 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 the mirtazapine trial described above and used the same entry and exclusion criteria. But 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 on 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.

In conclusion, inappetence, vomiting and weight loss are common in later stages of CKD and negatively impact quality of life in the cat. We do 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. Recent 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.

1 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. Tablets containing maropitant are available for use in dogs.

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