‘Don’t pee on that!’ Comparing environmental modification and medical management in cats with FIC

PICO question 
In cats with feline idiopathic cystitis (FIC) is environmental modification superior than medical management in preventing reoccurrence? 
  
Clinical bottom line 
Category of research question 
Treatment 
The number and type of study designs reviewed 
16 papers were critically reviewed; 14 randomised trials and two case studies 
Strength of evidence 
Critical appraisal of the selected papers meeting the inclusion criteria collectively provide weak evidence in terms of their experimental design and implementation 
Outcomes reported 
There is weak evidence that any medication or environmental modification is successful in reducing the reoccurrence of FIC when compared to a placebo. Short-term use of amitriptyline can contribute to an increase in occurrence of FIC 
Conclusion 
In view of the strength of evidence and the outcomes from the studies the following conclusion is made; in cats with feline idiopathic cystitis there is weak evidence that environmental modification or medication are effective at preventing reoccurrence. Further research is required into the cause of FIC before comparisons on treatment options can be made, however, with the exception of short-term use of amitriptyline, environmental modification and systemic treatment of clinical signs did not contribute to an increase in occurrence of FIC 
  
How to apply this evidence in practice 
The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. 
Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.


Outcomes reported
There is weak evidence that any medication or environmental modification is successful in reducing the reoccurrence of FIC when compared to a placebo. Short-term use of amitriptyline can contribute to an increase in occurrence of FIC

Conclusion
In view of the strength of evidence and the outcomes from the studies the following conclusion is made; in cats with feline idiopathic cystitis there is weak evidence that environmental modification or medication are effective at preventing reoccurrence. Further research is required into the cause of FIC before comparisons on treatment options can be made, however, with the exception of short-term use of amitriptyline, environmental modification and systemic treatment of clinical signs did not contribute to an increase in occurrence of FIC How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient's circumstances and owners' values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.
Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

The evidence
The literature searches uncovered 13 papers that addressed pharmaceutical treatment for cats with feline idiopathic cystitis (FIC) and three papers addressing environmental modification as a treatment. Pharmaceutical treatments included oral preparations of non-steriodal anti-inflammotory Drugs (NSAIDS) , steroids (Osbourne et al., 1996), tricyclic antidepressants (Chew et al., 1998;Kruger et al., 2003;and Kraijer et al., 2003), glucosamine (Gunn-Moore and Shenoy, 2004) and prazosin (Reineke et al., 2017). Parenteral treatments include intravesical glycosaminoglycan (GAGs) (Bradley et al., 2013), pentosan polysulphate and lidocaine (Zezza et al., 2012) and subcutaneous pentosan polysulphate (Wallius et al., 2009). Of these studies, only one paper (Chew et al., 1998) found that long-term (12 months) use of amitriptyline successfully decreased clinical signs of recurrent cystitis in 9/15 cats treated, however this improvement was only apparent in the last 6 months. Three studies included environmental modification as a treatment option, which included the use of feline facial pheromones (FFPs) (Gunn-Moore and Cameron, 2004). The use of FFPs did not have a statistical difference in reoccurrence of signs when compared to the placebo, however there was a clinical difference shown, with those exposed to FFP having a reduced occurrence and reduced severity of FIC. A case study by Seawright et al. (2008) followed a case with environmental modification for an extended period of time, which showed that episodes of cystitis only occurred during extraordinary stressful situations such as building works. A study into multimodal environmental modification (Buffington et al., 2006) showed a resolution in signs for 75% for 10 months. Each study into environmental modifications had a number of uncontrollable variables due to each cat's condition and environment, so further studies are required to confirm any success. • Owners monitored urination frequency, duration and volume, level of activity and general attitude of the patient Main findings: (relevant to PICO question):

Summary
• No statistical differences between the treatment group and placebo group by practitioner (p=0.2) or owner (p=0.5) • The treatment was associated with a change in general attitude and decreased level of activity (p=0.02) • Treatment group experienced a reduction in microscopic haematuria and proteinuria after 5 days • Placebo group experienced a reduction in proteinuria after day 2

Limitations:
• Environment not controlled, so cats had other variables that could have affected results • Owner evaluation of signs can be inaccurate Intervention details: • Group 1 (n=6) -Six cats exposed to feline facial pheromone (FFP) for 2 months, then placebo for 2 months • Group 2 (n=6) -Six cats exposed to placebo for 2 months, then FFP for 2 months • One depression of spray 10 cm away from any object that protruded into areas where the cats walked • The spray was applied daily in households with one or two cats, and twice daily in households with three or more cats Study design: Randomised double blinded, placebo controlled crossover study Outcome studied: Using linear visual analogue scales, the owners were asked to daily define the severity of the cat's clinical signs: • increased frequency of urination • straining while urinating • crying out while urinating • blood in urine • urination outside of litter box • increased grooming around perineum A further visual analogue scale was used to assess whether the cats behaviour had changed. This was used on a weekly basis: • increase or decrease in negative behaviours • increase or decrease in positive behaviours • increase or decrease in spraying in the house • increase or decrease in eating

Main findings: (relevant to PICO question):
No statistical differences between the two treatment groups (p=0.5). However, a clinical difference showing a trend for the six cats p a g e | 7 of 20 exposed to FFP to have less severe episodes and fewer recurrences of FIC FFP total, mean ± standard deviation: • FFP -30, 4.3 ± 6.7 • Placebo -69, 9.9 ± 19.1

Limitations:
• Three cats did not complete the study, and data for two cats were lost by the owners, so the sample size was small • Those recruited to the study were dedicated owners who had opted for referral, so not a representative sample • Owner evaluation can be inaccurate Outcome studied: Owners asked to grade the severity of their cats' signs at both start and end of study using a health score scale of 0 (very severe cystitis) to 5 (normal cat). Owners also kept a cystitis diary every day (for 6 months), recording the following signs: • increased frequency of urination • straining while urinating • crying while urinating • blood in urine • urination outside litter tray • increased grooming around perineum • altered behaviour Mean urine specific gravity after 1 month was compared with the initial urine sample

Main findings: (relevant to PICO question):
• Owner assessment suggested that those treated with glucosamine achieved a slightly greater improvement, however there was no significant difference (p>0.5) • The majority of cats in both groups improved significantly (p<0.001, mean health score of each group at the start was 0.5 ± SD 0.5, compared to glucosamine 4.4 ± 0.7 and placebo 3.9 ± 1.6 at the end), however this was believed to have occurred due to the concurrent introduction of wet food • The urine specific gravity at the start was significantly higher (mean 1.050 + SD 1.007) than when reassessed after  • Two cats left the study due to euthanasia • No statistical differences between the two groups during treatment or at revaluation for clinical signs • Those that did show clinical signs, had been exposed to stressful events before clinical signs, which was found to be significant (p=0.0023)

Limitations:
• Patient was on a number of treatments • Study contributes success to probiotic combination treatment. However, no measurements or scales to analyse this • Does not state how long patient was monitored for

Appraisal, application and reflection
A number of studies were identified due to the wide variables involved with searching for medication. However, each study focused on a different treatment, allowing for a wide range of results. There was no study that compared medical treatment alone to environmental treatment.
Only one study, Chew et al. (1998), identified medication as having an effect on reducing the occurrence of FIC. This was if the patients were treated with amitriptyline 10 mg/cat SID PO long-term. The study showed that the medication decreased the occurrence in 9/15 (60%) cats, and reduced haematuria and proteinuria in 100% of cats at the 12 month evaluation. However, the sample size of this study was small (n=15) and could have been impacted by a number of variables within the cat's environment. The cessation of haematuria and proteinuria is a positive outcome for the treatment; however, it is not made clear if these patients were tested within the same time period. FIC being a self-limiting disease may indicate that the cats could have been asymptomatic at the time regardless of the treatment. 5 years later, Kruger et al. (2003) found that short-term administration (7 days) of amitriptyline had no statistical benefit over the reduction in pollakiuria and haematuria. Additionally, cats treated with amitriptyline had a faster recurrence rate when compared to the placebo. Much like the study by Chew et al. (1998) there were uncontrollable variables within the cat's environment that could have contributed to these results.
Six of the studies focused specifically on cats with FIC that caused urethral obstruction and the reoccurrence of symptoms if treatment was given at the time of obstruction. Dorsch et al. (2016) identified that there was no significant difference between patients having meloxicam and a placebo for 5 days post obstruction, however due to the nature of the treatment for a urethral obstruction, this was given concurrently with a urinary catheter and fluid therapy, so credit of success cannot be given to one treatment alone. This study does not identify the cause of the obstruction, and whether patients had high amounts of urinary sediment, or inflammation. The measured outcome was a repeat urethral obstruction and does not record whether cats suffered with other generalised symptoms of FIC before becoming obstructed. This was a similar finding to Nivy et al. (2019) with the administration of phenoxybenzamine and alprazolam (n=51) with the addition of meloxicam (n=24). This study had the largest sample size, but no placebo control group, so the results cannot be contributed to any success. Reineke et al. (2017) completed a longer-term study with the administration of prazosin (n=27) for 1 month following urethral obstruction. Follow-ups for 6 months post-treatment identified no statistical difference between the prazosin and placebo for a repeat urethral obstruction, or a reduction in the severity of clinical signs. Like the previous studies that test oral medication, the variables in the environment cannot be controlled, and may have contributed to the recurrence of clinical signs, alternatively the stress of giving medication on a daily basis could have also contributed to clinical signs.
Three studies focused on the administration of medication through intravesical means, one with intravesical GAGs (Bradley et al., 2013), pentosan polysulphate (Delille et al., 2016) and the other with intravesical sodium bicarbonate ± lidocaine (Zezza et al., 2012). Bradley et al. (2013) found that those treated with GAGs had a reduced recurrence of obstruction when compared to the placebo group (p=0.06), however the study size was small (n=14) and performed within a hospital environment with concurrent treatment of fluid therapy. When given intravesical pentosan polysulphate (Delille et al., 2016), obstructed cats suffered with repeat obstruction at the same rate as those with a placebo (p=1.00). Zezza  of lidocaine, however although the sample size was larger than Bradley et al. (2013), it was again restricted to hospitalised patients (n=26) with concurrent treatments of amoxicillin-clavulanic acid for 2 days before discharge. Wallius et al. (2009) combined owner interviews with clinical examination for treatment with subcutaneous injections of pentosan polysulphate, treatment used in human interstitial cystitis. The sample size was small (n=18) and was made smaller due to two cats being euthanised due to their clinical signs during the study. No statistical difference was found between the treatment and the placebo, despite the differing variables within the cat's environment.
Giving other treatment concurrently to medication was common in these studies. Those owners that participated in the studies were obviously keen to treat their cats, so tried all forms of treatment to alleviate symptoms. Although beneficial for the patient, is not helpful in regard to studies as any results cannot be related directly to the medication. This was the case with Gunn-Moore & Shenoy (2004) and grading the severity of FIC signs alongside the administration of N-acetylglucosamine (n=40). Participants for the study were recruited from those referred directly to the university so had an invested interest in the cat's success. Although owner assessment suggested that those treated had a greater improvement, there was no significant difference, and it was identified that owners had concurrently increased the water intake of the cats during the study, probably leading to the improvement seen.
Controlled studies within the hospital took place with the administration of prednisolone UID for 10 days (Osbourne et al., 1996). Although this allows for variables to be controlled, it also introduces the variable of the patient being stressed in an unnatural environment, thus potentially increasing the chance of stress related signs. Osbourne showed that steroid treatment had no benefit for reducing the clinical signs of FIC (n=12), however the sample size was small and was only concentrating on the cessation of signs and not the rate of recurrence.
One study concentrated on environmental modification as a treatment (Buffington et al., 2006), with indoor cats (n=46). A change in environment showed a reduction in the reoccurrence of lower urinary tract signs (p<0.0001) and a general improvement in fearfulness (p<0.0002) and nervousness (p<0.0002). However, the environmental modification for each cat was varied, with a number of options being given to the owner. With a number of different variables, it cannot be identified if one was more successful than the other, or if a variety is required for success. There were also no concurrent control groups. Seawright et al. (2008) reported on a single case control study of a patient treated with a range of medications for 3 weeks and environmental treatment long-term. The patient was assessed for 15 months and showed only one period of FIC signs, occurring due to a stressful event in the environment. This episode was selfresolving. This study indicates the effect the environment has on one cat suffering from FIC; however, it is only one case with a number of variables in place and cannot be taken as a treatment option for a larger population.
Feline facial pheromones were used in adjunction to environmental therapy for 12 cats for a duration of 6 months. Owners were asked to score their cats on a number of scales to identify not only signs of cystitis, but also signs of stress. Owners were given visual analogue scales and daily diaries to record, and although there was no statistical difference between the treatment period and the placebo period, there was a clinical difference, with reports showing a reduced severity and occurrence of FIC; however, those cats that were to experience stressful situations (such as building or moving house) were removed from the study so it is not known if this is an effective treatment during signs of stress.
There was one paper that tested alternative methods of treating FIC, a mix of medication, vitamins and a probiotic (Sofyan et al., 2019). The case report by Sofyan attributed the success of the cat being able to urinate post urethral obstruction to the probiotic. However, this was given concurrently with muscle relaxants and antibiotics. With no control study taking place, the evidence to support the probiotics success in this case is weak.
There is limited evidence in this research area, with treatments focusing on reducing inflammation or stress to reduce the clinical effects of FIC. This makes any research difficult, as to control variables cats have to be hospitalised, which increases the stress they experience. If not in the hospital, cats are then in their own home environment, where variables cannot be controlled, reducing the efficacy of the research by allowing other variables, meaning any success cannot be contributed to one treatment. Two of the randomised control studies showed a statistical difference between the treatment group and the placebo, these being MEMO and long-term amitriptyline, with the trial involving FFP not showing a statistical difference but a clinical difference. Two of the case reports based on environmental modification showed patient improvement, however their level of evidence is weak as they both have uncontrolled variables and cannot be repeated under the same conditions. It is clear from the variety of medical treatment options, that the true cause of FIC has not been identified. Further research is required to identify the true cause, to then make true comparisons.

Search Strategy
Databases searched and dates covered: CAB Abstracts on OVID interface (1973 -2020 Week 21) PubMed accessed via the NCBI website (1910 -June 2020)