A novel formulation for small animal arthritis?

When cats and dogs are in need of long-term/‘chronic’ pain relief we try to give them NSAIDs (non-steroidal anti-inflammatory pain relief). This is because NSAIDs have the most scientific evidence supporting their analgesic (‘pain-relieving’) effect and, unlike morphine, are able to be given orally as ‘take-home’ medications. Carprofen and meloxicam are just some examples of NSAIDs used in dogs and cats.

Veterinarians are scientists and have a responsibility to make evidence-based (i.e. using results from published studies in peer-reviewed journals) decisions on how to treat our patients. This means it is somewhat unethical to use or prescribe medications with very little evidence that they actually work. One such drug is tramadol. Tramadol is often used in cats and dogs where NSAIDs are contraindicated (e.g. kidney disease or gastrointestinal problems), or in combination with NSAIDs for ‘added effect’. It is an opioid agonist, however evidence for its analgesic effect is controversial. It may not actually be relieving pain, but instead just sedating animals so that they are not able to show signs of pain. The SkeptVet does an excellent job of reviewing Tramadol for Pain in Dogs and Cats and at one point suggests “The evidence is strong enough that tramadol should not be relied on as a sole or first-line analgesic.”

If this is the case, then what can we use in those animals where we might not want to give NSAIDs? Pain is a significant animal welfare issue. There is a reason it ranks highly in animal welfare assessment scales and evaluations. We have an ethical responsibility to treat it. The old adage of ‘if they are in pain they aren’t moving and so won’t do any more damage to themselves’ is not acceptable.

A recent publication in BMC Veterinary Research may shed some light on the future of chronic pain relief – by introducing a novel composite formulation [1]. This article is open access (free) online and can be found here. The authors argue that osteoarthritis treatment should “reduce inflammation, minimise pain, and maintain joint function.” They therefore propose the use of palmitoylethanolamide (PEA) in combination with quercetin in models of osteoarthritic pain and inflammation.

PEA is an endogenous (produced normally in the body – therefore has reduced risks of side-effects) fatty acid amide produced by tissues in response to acute inflammatory and painful conditions, but decreased in chronic conditions. There is evidence already for its anti-inflammatory and analgesic effects in some other conditions, but the authors wanted to explore whether it would help with osteoarthritis. PEA is an endocannabinoid (i.e. binds to cannabinoid receptors in the body). The authors combined it with quercetin, a natural antioxidant, as PEA is rapidly oxidised in the body. They compared this combination to the NSAID meloxicam as their ‘benchmark’ drug.

They used two different rat models of inflammatory and osteoarthritic pain: by causing paw oedema; and inducing osteoarthritis. The first step of the experiment involved giving the different treatments being tested ‘pre-emptively’ (i.e. before they did anything to the rats). This way they could see if it actually worked to reduce pain and inflammation before moving onto the second step. In this second step they used it ‘therapeutically’ three times a week to see if it would work clinically on osteoarthritis.

The results show that their ‘PEA-Q’ combination decreased inflammatory and hyperalgesic (increased sensitivity to pain) responses by:

• Reducing oedema in the rats paw
• Decreasing an inflammatory score used in histology (microscopic structure of tissues)
• Reduced activity of a marker of inflammatory cell infiltration
• Decreased thermal/heat pain sensitivity

These effects were better using their novel drug combination – compared with using the NSAID.

In their osteoarthritis model they found the combination:

• Reduced mechanical allodynia (triggering of a pain response from stimuli which do not normally provoke pain)
• Improved locomotor function
• Protected the cartilage from damage

These effects were equal to or better than the NSAID treatment.

These are exciting results for anyone trying to manage long-term pain in dogs and cats as the authors have now moved to translate these findings to canine and feline osteoarthritic pain. Watch this space!

{The author would like to acknowledge Adrienne French for feedback on the draft of this post.}

References

1. Britti, D., et al., A novel composite formulation of palmitoylethanolamide and quercetin decreases inflammation and relieves pain in inflammatory and osteoarthritic pain models. BMC Vet Res, 2017. 13(1): p. 229.

 

Feline Four or Five?

In an earlier blog post, I mentioned the animal welfare science and bioethics Journal Club I am involved in. We meet fortnightly to review articles of relevance to animal welfare, behaviour, and bioethics. The intention is to broaden and disseminate knowledge within the research group and question and improve on our existing ideas and methods.

This week, it was again my turn to select and present an article – and of course I chose one involving cats! (it’s no secret that I am a crazy cat lady)

But I also chose this article because I am interested in behavioural profiling (of humans and animals) and wonder if this will be a requirement of animal-based research in the future. Will we have to declare the temperament of our test subjects in the same way as we record their sex and ages?

The article I chose to review was:

Litchfield, C. A., Quinton, G., Tindle, H., Chiera, B., Kikillus, K. H., & Roetman, P. (2017). The ‘Feline Five’: An exploration of personality in pet cats (Felis catus). Plos One, 12(8), e0183455. doi:10.1371/journal.pone.0183455

It is published in an open-access online journal here.

A few words on personality profiling in humans

One of the most widely used personality profiling devices in humans is the ‘Big Five’. It is based on ‘common language’ descriptors of personality. Each ‘factor’ consists of related traits and characteristics that fit within them. An individual’s personality is determined by where they sit on the continuum for each of the five factors.

The five factors are commonly known by the acronym ‘OCEAN’:

• Openness to experience
• Conscientiousness
• Extroversion
• Agreeableness
• Neuroticism

Who wrote the article and why?

Human psychologists and ecologists in South Australia and New Zealand (Victoria University of Wellington) were involved in the study. It is part of a larger project (Cat Tracker Project) aimed at tracking pet cats in South Australia and New Zealand.

It is interesting that there appears to be no input from animal scientists – behaviour or welfare. A quick perusal of the reference list indicates that a large volume of feline behaviour and temperament literature appears to be overlooked – or at least not referenced. And, as the authors wrote about animal ‘personality’/expressivity, or behaviour profiling, it also seems absurd that Francoise Wemelsfelder’s Qualitative Behaviour Assessment (QBA) work was not referenced.

The Journal Club group also discussed the idea of ‘personality’ in animals. Many of us thought ‘person’-ality was the wrong terminology to use when discussing animal traits. The preferred term is ‘temperament’. It was our view that the human-centric approach taken for this study has resulted in this wording. I only wonder at why the article was not instead named ‘An exploration of ‘purr-sonality’ in pet cats…’ – at least this has an adorable human-centric approach.

The authors set-out to “analyse personality in a large sample of pet cats – using personality inventory completed by the owner”. Their research question was “how many reliable and interpretable factors depict personality in pet cats and what traits do they represent?”. They based these questions on previous research which have used: small sample sizes, wild/captive cats or those with behavioural problems – rather than ‘normal’ cats, researchers evaluating cat behaviour – rather than animal carers, and insufficient inter-rater reliability assessments.

Methods used

An online survey in South Australia and New Zealand collected information about 2,802 cats. It used 52 items based on a previous survey of Scottish Wildcats. Cat owners were asked to rate their cat on a Likert scale, according to how far they felt each trait was applicable. The authors used a type of exploratory factor analysis called ‘principle axis factoring’ (a technique similar to Wemelsfelder’s ‘principal component analysis’) to understand the relationship among these reported traits. This enabled them to group traits under common headings/factors.

What did they find? (results)

They found FIVE ‘factors’ (common headings for a group of traits) that explained ~47% of the variance in personalities:

• Neuroticism
• Dominance
• Impulsiveness
• Agreeableness
• Extraversion

Interestingly, the authors chose to deal with items that ‘cross-loaded’, or loaded onto multiple factors, by assigning the item ONLY to the highest loading factor.

Why cat personality?

The authors drew our attention to some benefits of this type of research, namely: grouping compatible cats in multi-cat households and providing more hiding places for neurotic cats. A low/high score in an area could also improve the welfare of that cat by encouraging owners to seek advice.

The main issues we had with this article

• The authors appear to have not considered animal (welfare or behaviour) scientists or a range of feline behaviour references in their article;
• Reference to Francoise Wemelsfelder is sorely lacking – using 52 items from a Scottish Wildcat study also seemed unusual when the intention was to steer away from references to ‘wild/captive’ cats;
• No consideration was given to the human-animal bond and how attached an owner was to their cat and/or how well they knew their cat – could this have contributed to a reporting bias for some owners?;
• The labelling of 4 of the 5 personality factors were reasonably well explained, but the sudden inclusion of the fifth (‘extraversion’) appears contrived. We had to wonder if they were trying to force it to fit ‘Feline Five’ – it was too similar to the human list (see above);
• Assigning items that cross-loaded ONLY to the highest loading factor ignores the complexities inherent in ‘personality’/temperament profiling.

Overall, this study is a great example of the importance of research collaboration. Think outside the (litter) box. 

Reflecting on the March for Science 2017 and when Science goes wrong

I am writing this post after Earth Day and March for Science 2017 for two reasons:

1. Science is under more and more scrutiny (as it should be!) and we scientists need to be careful what we put out to be read or heard;
2. I have just started a Journal Club for the academic research group I belong to at my university and the first article I chose to present to them was a great example of ‘Science gone wrong’.

In this post, I will be using this article as an example. I am not trying to single out this article, nor the authors, but I thought it was a good example of what we should be avoiding. And, for those of you reading and citing scientific publications, I have a message: it is not OK to just read the abstract and conclusions of a scientific article (even if it is peer-reviewed) without critically evaluating its methods and results. It is not OK to cite an article you have not read completely. I have been tempted to do this myself when under time pressure, but we need to stay alert! And this post aims to show you WHY.

Before I get into the article itself, I thought I would share with you the main ideas behind our Journal Club:

• The meetings are fortnightly
• Everyone in the research group is encouraged to present at least one article during the year
• Presentations are also encouraged from postgraduate students (including Masterate students) and undergraduates at the stage that they will benefit from presenting and critically evaluating an article
• Attendees can read the article before the meeting, but presenters should be aware that not everyone will have had time to read it and should address this in their presentation of the article i.e. begin with a background to the study before the critique
• Critical appraisal is encouraged. Presenters are welcome to present their own work, but a more balanced critique is likely to occur when the author(s) is not present.

You will have noticed how much ‘critical appraisal’ has been emphasised in this list. As scientists, it is our job to be critical of everything we read and hear. The need for this became obvious when we evaluated our first article:

Sandøe, P., Nørspang, A. P., Forkman, B., Kondrup, S. V., Lund, T. B., & Bjørnvad, C. R. (2017). The burden of domestication: a representative study of welfare in privately owned cats in Denmark. Animal Welfare, 26(1), 1-10. doi: 10.7120/09627286.26.1.001

I chose this article because I am interested in the indoor versus outdoor cat debate, the issue of neutering, and selective breeding. This study was published in a well-respected peer-reviewed journal. The aim was to investigate how indoor confinement, neutering, and selective breeding may impact on the health and behaviour of domestic cats.

Their statistical analysis involved prevalence and odds ratios i.e. measures of association between the outcome variables (behavioural problems OR health issues) and the exposure variables (breed, neuter status, housing).

The abstract would lead you to believe that the major findings of this study were: (1) confined cats had ‘significantly’ more behavioural problems than free-roaming cats; (2) entire cats had ‘significantly’ more behavioural problems than neutered cats; and (3) ‘significantly’ more purebred cats had diseases than domestic shorthair cats.

However, we found major issues with the methods and results. The study involved a questionnaire, but this was available in different formats to different age groups (a ‘mixed mode design’) – with the assumption that those over 65 would prefer to answer by telephone interview and those 18-64 would be happy to complete it online. This difference was not dealt with in the authors’ later analysis.

The original questionnaire was available in the supplementary material online and, after closer inspection, the questions they asked were not always well reflected in their results. They re-defined ‘How cats are kept’ using a range of responses given by the pet owners – and not all of these made sense. The question they asked to get these results gave confusing options to owners where ‘indoor’ was defined in various ways not necessarily consistent with most people’s definition of indoor cat housing. The only behavioural problems that were significantly different between how the cats were kept were: ‘house-soiling’, ‘damage furniture or things’, and ‘displays signs of boredom’. These could have been associated with, for example, other cats in the household, availability of toys and environmental enrichment. However, despite these follow-up questions being in the questionnaire there was no evidence of them being used in the analysis.

For neuter status, the only behavioural problems that were significantly greater in non-neutered cats were ‘aggressive behaviour towards guests’ and ‘other problems’. These were poorly defined categories and/or could have been the result of natural feline behaviours.

When it came to looking at the prevalence of health issues, the authors did not adjust for the number of vet visits. Owners are potentially more likely to know about their cat’s health issues if they visit the vet more often. Instead they controlled for vaccination status – claiming it to be a proxy for concern about cat health. They reported that more purebreds had one or more of the diseases of interest. But this was compared to ‘domestic short-hair’ cats, with a separate ‘mixed breed’ category. Purebred cats were grouped together as there were not enough of them in the study for them to be separated by breed. They did not appear to use the information they had about the amount owners spent on their cats in this analysis either.

The discussion section was interesting, if irrelevant at times. The section on body condition scoring (BCS) underestimating the level of body fat percent was a very good review. But as they did not use either BCS or fat percentage estimates it felt a little redundant. Probably the most important conclusion they reached was that we need to do more research on cats. Research into purebred cats lags behind canine research.

In conclusion, I hope I have shown that just reading the abstract and discussion/conclusion of a peer-reviewed article is not sufficient to cite it and/or propagate its findings. After our Journal Club meeting we all felt that this article was trying to prove a set of conclusions (neutering is good, purebred cats are bad, and outdoor cats are better than indoor) rather than fully investigate them. Importantly, we left with it clear in our minds that critical evaluation is important for academic writing. We felt that this article is, unfortunately, going to be highly cited due to: (1) the journal it has appeared in; (2) the authors; and (3) the subject matter i.e. for the very same reason I chose to evaluate it in the first place.

Environmental enrichment for New Zealand cats

Lately there has been an exciting boom in posts, blogs, popular articles, tweets, and even a journal article [1], illuminating the benefits of environmental enrichment for pet cats. There are entire websites (e.g. food puzzles for cats) dedicated to helping cat owners find ways to positively enrich the lives of their pet(s).

The concept of environmental enrichment is not new; zoological parks and laboratory animal facilities have been using enrichment programmes as a means of alleviating boredom and negative mental states in captive populations for some time [2-4]. The 2015 World Associations of Zoos and Aquariums (WAZA) Animal Welfare Strategy has an entire chapter dedicated to environmental enrichment [5].

Interactive ‘food puzzles’ used for zoo animals are easily translated to our pet felines [1]. The authors of this journal article are based in North America, where the fact that a large proportion of pet cats are kept indoors means their feline populations could also be regarded as ‘captive’ animals. However, even for our largely ‘free-ranging’ New Zealand cats, there are benefits to providing them with more opportunities for positive affective engagement.

‘Positive affective engagement’ happens when animals are able to respond to motivations they have to behave in ways they find rewarding [6]. The animal is engaged and experiencing positive ‘affects’ or mental states (e.g. happiness, playfulness). Therefore, environmental enrichment involves providing these opportunities for animals to respond behaviourally to their environment and/or other animals.

In addition to food puzzles, there is another enrichment activity that cat owners could take from zoos (and dog owners!); reward-based training. Yes, cats can be trained. Drs John Bradshaw (@petsandus) and Sarah Ellis (@sarahlhellis) have written a book (The Trainable Cat) to show us how to do this. I am excited to read (and use) it! There is also an excellent ‘train your cat’ series of videos, which demonstrates how you can train your cat to like its cat carrier, be good at the vet, and even come back to you. Julie Hecht (@DogSpies) would also like you to know cats are open to training and takes us through the steps she took with her cat and a new sofa. Training could be another opportunity to provide cats with opportunities for positive affective engagement. Zazie Todd (@CompAnimalPsych) summarises reward-based training in an excellent blog post ‘Reward-based training is for all our pets’. It’s not just for dogs or animals in captivity.

The life of a domesticated cat is essentially a ‘dumbed down’ version of their wild cousins. In place of long hours spent hunting for food, they are instead provided with energy-dense cat biscuits and meat from a can. They need to expend this unused energy somehow and this can often result in negative behavioural consequences, including (but not limited to); bullying of other cats in the household (a problem in my house) or stalking and torturing wildlife. This last issue is particularly problematic given the conservation status of much of New Zealand’s native birdlife. Environmental enrichment for our cats; using toys, food puzzles, and training, could be the answer.

My Experiences

My husband and I are currently owned by two ‘free-range’ (during the day) cats. Our male ginger can be a bit of a bully towards our female tabby. This is much worse when he is bored. On days when we have not made efforts to entertain him, and/or the rain stops him frolicking outdoors, he is relentless with his attacks on his fluffy sister. However, when one (or both) of us has the energy to play with him his sister is free to roam without fear of sudden ginger attack. With the recent addition of a slow feeder bowl, he now has to expend more energy eating than he had to previously. The ginger attacks have again reduced.

We long ago taught him to ‘sit’ on command – he is very amenable to food-based rewards. This was as far as we went with him. However, with all this excitement surrounding cat training I am keen to try some more tricks! My husband rolls his eyes and calls me crazy when I ask the ginger for his paw in exchange for a treat. I think the cat will have the last laugh though – he is getting more and more compliant…

The ginger lies in wait

Environmental enrichment strategies, such as food puzzles and reward-based training, can (and should) be used for outdoor cats too.

References

1. Dantas, L.M., et al., Food puzzles for cats: Feeding for physical and emotional wellbeing. Journal of Feline Medicine and Surgery, 2016. 18(9): p. 723-732.
2. Mellor, D.J., Affective states and the assessment of laboratory-induced animal welfare impacts, in ALTEX. 2011.
3. Fraser, D., Understanding animal welfare: the science in its cultural context. UFAW Animal Welfare Series, ed. J.K. Kirkwood and R.C. Hubrecht. 2008, Chichester, United Kingdom: Wiley-Blackwell.
4. Young, R.J., Environmental enrichment for captive animals. 2003, Oxford, UK: Blackwell Science.
5. WAZA, Chapter 3: Environmental Enrichment, in Caring for Wildlife: The World Zoo and Aquarium Animal Welfare Strategy, D.J. Mellor, Hunt, S. & Gusset, M., Editor. 2015, World Association of Zoos and Aquariums (WAZA) Executive Office: Gland, Switzerland p. 34.
6. Mellor, D.J., Enhancing animal welfare by creating opportunities for positive affective engagement. New Zealand Veterinary Journal, 2015. 63(1): p. 3-8.