Dr. Rosie DVM

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

Adapted from the IRIS education article by Jonathan Elliott, Royal Veterinary College, University of London, UK.

Why Cats With CKD Stop Eating

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 feel their cat's quality of life is reduced by CKD (Reynolds et al., 2010; Bijsmans et al., 2016). The prevalence of these signs is not well described in the literature, but inappetence and weight loss are more common than vomiting in IRIS CKD Stages 3 and 4 (Elliott and Barber, 1998). The accumulation of nitrogenous waste products other than urea and creatinine affects the appetite centers in the brain and is thought to underlie the reduced appetite of cats with CKD. Vomiting may result from central effects, such as uremic toxins stimulating the chemoreceptor trigger zone, and from peripheral mechanisms, such as the irritant effect of high concentrations of urea on the lining of the gut.

Vomiting and Nausea

Vomiting is a protective mechanism that expels the contents of the stomach. It occurs when multiple stimuli from the periphery and from other areas of the brain stimulate the vomiting center in the medulla and exceed the threshold that triggers the vomiting reflex. People describe waves of nausea ("feeling sick to the stomach") that precede vomiting and are relieved by vomiting, but if the signals to the brain do not reach the trigger threshold, the waves of nausea may continue.

Nausea is a symptom, a sensation we can perceive and describe. In cats, we can only observe physical signs or behaviors 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, nausea may underlie the poor appetite associated with IRIS CKD Stages 3 and 4. The neurophysiological mechanisms of nausea are not well understood and are difficult to study, but activity in the brain stem that triggers the vomiting reflex seems to spread to higher levels of the central nervous system and give rise to the sensation of nausea. Many antiemetic drugs licensed for human use are labeled as anti-nausea drugs as well as antiemetics.

Stomach Acid and Uremic Gastritis

It had been assumed that excess stomach acid and uremic gastritis contribute to the reduced appetite, nausea, and vomiting seen in cats with CKD. High blood gastrin concentrations (hypergastrinemia) were demonstrated in feline CKD, with the prevalence of high plasma gastrin increasing with the clinical stage of disease (Goldstein et al., 1998). This paper has been used to support the use of H2-receptor antagonists to manage excess stomach acid thought to contribute to uremic gastritis and the associated reduced appetite, nausea, and vomiting. Anecdotally, H2 blockers have been said to be effective in cats with CKD, but there are no published randomized controlled clinical trials to support their use. More recently, the assumption that cats, like human patients, suffer from uremic gastritis has been called into question. A post-mortem study found no evidence of ulceration or inflammation of the stomach lining, and instead identified gastric fibrosis and mineralization as the lesions associated with CKD (McLeland et al., 2014).

A double-blinded, randomized study evaluated once-daily omeprazole (1 mg/kg) for vomiting and appetite in cats with poor appetite attributed to IRIS Stage 2 and 3 CKD (Spencer et al., 2021). There was a small but significant increase in the subjective assessment of food eaten (2.7%, p = 0.04) in cats treated with omeprazole. However, because this was not associated with changes in body weight or in other subjective assessments of appetite and speed of eating, it was considered clinically unimportant. 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 a first-line treatment for poor appetite in cats with CKD, unless there are specific reasons in an individual patient to be concerned about gastrointestinal ulceration.

Our understanding of the mechanisms behind the poor appetite, reduced food intake, and weight loss of cats with IRIS CKD Stages 3 and 4 is therefore limited. It is assumed to be related to accumulated waste products acting centrally or peripherally on the nervous system to trigger the sensation of nausea and, less often, the vomiting reflex. If so, an antiemetic drug with anti-nausea effects would be expected to block these actions, reduce nausea, and increase the cat's appetite. A growing body of short-term clinical trial data now provides evidence on which to base initial treatment decisions in inappetent cats with CKD. Longer-term clinical trial evidence is still lacking.

Mirtazapine

Mirtazapine is an antidepressant drug with complex pharmacology. It blocks presynaptic alpha-2 adrenoceptors, both the autoreceptors, which increases norepinephrine release, and the heteroreceptors, which enhances serotonergic neurotransmission. Because mirtazapine also blocks 5-HT2 and 5-HT3 receptors, this presynaptic action enhances serotonergic transmission involving 5-HT1A receptors. Mirtazapine also has a high affinity for histamine H1 receptors and a lower affinity for many other amine receptors in the central nervous system (Anttila and Leinonen, 2001).

Oral Mirtazapine

Mirtazapine has been shown to improve appetite, reduce vomiting, and increase weight gain in cats with naturally occurring CKD (Quimby and Lunn, 2013). This well-designed, randomized, controlled, masked clinical trial, with clear inclusion and exclusion criteria, provided level 1 evidence of efficacy. Importantly, cats were included only if their owners felt their appetite was reduced, so the benefits of oral mirtazapine cannot be extrapolated to cats whose appetite is considered normal. Cats that had had a uremic crisis, or were considered at risk of one, were excluded. The study recruited only cats with plasma creatinine values of 2 to 5 mg/dL (177 to 440 µmol/L), covering the upper part of Stage 2 and all of Stage 3. The authors screened 172 cats to find 16 to randomize, and the analysis included the 11 cats that completed the study. This was a crossover study with 3-week treatment periods and a 4-day washout between placebo and mirtazapine (1.88 mg per cat every second day). Ten of the 11 cats gained weight while treated with mirtazapine (mean gain 0.18 kg), whereas 9 of the 11 lost weight while receiving placebo (mean loss 0.07 kg). The study was short, and longer studies are needed to determine the safety and efficacy of mirtazapine for longer-term management of CKD.

Five enrolled cats were excluded from the analysis: three never received the medication (all had been randomized to placebo first), and two had uremic crises during the study, both while receiving placebo. The only adverse effect of mirtazapine reported was a substantial increase in ALT in one cat, which returned to normal when mirtazapine was stopped. The owner chose to restart the drug, and similar increases in ALT occurred, but without clinical signs. It is therefore recommended that plasma ALT be monitored in cats treated with mirtazapine.

The dose used in these studies, 1.88 mg per cat, was given in capsules formulated by a university pharmacy. It was selected after earlier single-dose pharmacokinetic studies in healthy older cats, in cats with CKD, and in young healthy cats (Quimby et al., 2011a, 2011b). The young cats were given low (1.88 mg) and high (3.75 mg) doses. Mirtazapine is extensively metabolized in the liver, and pharmacokinetic studies suggest that its clearance in cats may become saturated at higher doses. In addition, kidney disease increased the cat's exposure to the drug by 38% because of reduced clearance.

Transdermal Mirtazapine

This work was extended to mirtazapine applied to the skin (transdermally) in cats with CKD (Quimby et al., 2020). Two separate double-blinded, placebo-controlled crossover studies were carried out in cats with IRIS Stage 2 or 3 CKD and reported weight loss. The first used 3.75 mg of mirtazapine (or placebo) every other day for 3 weeks, and the second had the same design with a lower dose of 1.88 mg per cat every other day. Mirtazapine was formulated from tablets by a university pharmacy into a gel suitable for transdermal use. In the first study, 81 cats were screened to find 12 suitable for the trial, and 9 of the 12 completed the study, with two cats failing to complete the mirtazapine arm.

In the second study, 53 cats were screened to find 12 suitable cats to randomize, 10 of which completed both arms, with two cats failing to complete the mirtazapine arm. In both studies, mirtazapine led to significant weight gain, in 100% and 90% of cats respectively, whereas 66% and 70% of the same cats lost weight while receiving placebo. Weight gain was accompanied by significantly increased appetite, speed of eating, and body condition score.

This study was reported in abstract form in 2017, before the FDA approved a commercial transdermal formulation of mirtazapine in the USA in 2018. A pivotal multicenter field safety and efficacy trial enrolled 230 cats older than one year with unintended weight loss from various causes, randomized to placebo (111 cats in the intention-to-treat population and 94 in the per-protocol population) or mirtazapine (113 and 83 cats respectively) at 2 mg per cat once daily for 14 days (Poole et al., 2019). Mirtazapine-treated cats in the per-protocol population gained 3.9% ± 5.4% of their body weight, significantly more than cats on placebo, whose weight changed by +0.4% ± 3.3%. The main adverse effect reported was mild redness at the application site, which was seen in both the treatment and placebo groups. Kidney disease, diagnosed at the investigator's discretion, was the underlying cause of weight loss in 36.5% of the cats in this study. Cats with a range of other causes of unintended weight loss were included in the trial, on the basis of which the product was also authorized by the European Medicines Agency (EMA) in 2019.

Safety of Mirtazapine

The same group published a retrospective analysis of adverse effects in cats given oral mirtazapine (Ferguson et al., 2016), using records of mirtazapine exposure reported to the American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center between 2006 and 2011. Of the 84 cases, 59 were reported as accidental exposures. The adverse signs reported included vocalization, agitation, vomiting, an abnormal gait or incoordination, restlessness, tremors, excessive salivation, rapid breathing, a rapid heart rate, and lethargy. Signs of toxicity were almost always associated with oral doses of 3.75 mg or more, and only one case was reported after a dose of 1.88 mg. The authorized transdermal product is labeled for 14 days of use in both the USA and the EU, and its safety and efficacy beyond that period have not been established under field conditions.

Mirtazapine is registered in the USA, the 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 using compounding pharmacies, both of which have practical limitations.

Maropitant

Maropitant is a selective neurokinin-1 receptor antagonist authorized for use in dogs and cats in the EU, the UK, and the USA. In cats, it is indicated for the prevention and treatment of vomiting and the reduction of nausea. Quimby et al. (2015) reported a randomized, double-masked, placebo-controlled clinical trial of maropitant in cats with CKD. The design resembled the mirtazapine trial described above (Quimby and Lunn, 2013) and used the same inclusion and exclusion criteria. However, rather than a crossover study, it was a parallel-group design, with cats stratified by stage to ensure an even distribution of IRIS CKD Stage 2 and Stage 3 cats before being randomized to the two groups. Eighty-four cats were screened and 44 were randomized. Twenty-one cats completed two weeks of maropitant treatment (given orally at 4 mg per cat daily), and 12 cats completed two weeks of placebo. Maropitant significantly reduced the frequency of vomiting compared with placebo, but it had no effect on appetite score, activity score, or body weight. The study followed cats for only 2 weeks before assessing the response. The placebo group did not lose weight, whereas cats in the mirtazapine study did lose weight during 3 weeks on placebo. No adverse events were attributed to maropitant. The larger number of cats that received maropitant compared with placebo may have influenced the outcome.

The registered dose of maropitant for cats in Europe is 1 mg/kg once daily for up to 5 days by subcutaneous injection, so the oral use and longer duration in this study are off-label. Maropitant tablets are available for use in dogs.

Conclusion

Inappetence, vomiting, and weight loss are common in the later stages of CKD and reduce a cat's quality of life. More information is needed before firm treatment recommendations can be made, but two drugs now have level 1 evidence for safety and efficacy in the short-term management of vomiting (maropitant and mirtazapine) and inappetence (mirtazapine only). Published pathology data also cast doubt on the importance of excess stomach acid and uremic gastritis, previously used to justify H2-receptor blocking drugs in cats with CKD. Nausea, like pain, is difficult to assess in veterinary practice, so biomarkers of nausea would be very useful in identifying which cats with CKD might benefit from anti-nausea treatment.

The registration of transdermal mirtazapine for use in cats provides a consistent-quality product of proven efficacy and safety for the short-term management of inappetence in cats with CKD, and it is a significant advance.

Summary

Weight loss and reduced appetite are more common than vomiting in cats with late IRIS Stage 2 and with Stage 3 and 4 CKD, and they are potentially caused by nausea.
Mirtazapine has been shown to be safe and effective in short-term studies for reducing vomiting and increasing appetite and weight in cats with CKD.
Maropitant has been shown to be safe and effective in short-term studies for reducing vomiting in cats with CKD.
The most commonly studied oral dose of mirtazapine is 1.88 mg per cat every second day for 3 weeks.
The dose of the registered transdermal mirtazapine is 2 mg per cat once daily for 14 days.
In cats with late Stage 3 or Stage 4 CKD, or with liver disease, consideration should be given to extending the dosing interval.

References

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