Welcome to this webinar on how should we manage feline osteoarthritis. My name is Matt Gurney. I'm a pain specialist.

I run a pain clinic and does some mores that specialists in Hampshire, and I'm a co-founder of the Zero Pain Philosophy. So This cat looks quite happy here, this is actually one of one of our previous cats, Neville. He's relaxing on the sofa there.

Is he in pain? He's 14. Can be quite hard to tell, can't it, because we know how well cats compensate using behavioural strategies.

And really, I think we would all agree that this is probably one of the main issues preventing cat owners. A presenting cats to the vet for a diagnosis of osteoarthritis, or B, being able to really comprehensively monitor their cats with arthritis. One of the things we're gonna talk about is pain scoring and assessment of quality of life, and that metric or one of those pain scores, assesses quality of life across these domains, activity, mobility and wellbeing, which we will touch on.

So there's a little bit more in cats compared to dogs, certainly for OA. And what do we know? What does the literature teach us?

This is a study of 100 cats presenting to a referral hospital that weren't referred for locomotion problems. So these cats were radiographed, they were examined, the owners were questioned as to their pain behaviours. And what this study showed was that 61% of cats had radiographic evidence of OA in one joint, and 48% of cats had radiographic evidence of multiple joint OA.

Cats that were over 14 years of age, 82% of them had OA in at least one joint. So really interesting information there. But of course, we always talk about correlating our radiographic evidence of OA with clinical evidence of pain in that joint.

The Joints that were affected radiographically were shoulders, elbows, hips, and tar site in that order. And they said that if one joint was affected, the contralateral joint was likely to be affected. And look at the prevalence of lameness there, 13 out of 100 cats.

It's really low, isn't it, when you consider that 61% of those cats had radiographic evidence of OA. So, OK, we always say you need radiographic and clinical evidence, but also what's really important is lameness doesn't tend to be a feature of OA in cats as it is in dogs. The prevalence of OA definitely increased with age in this study.

There was no correlation with body condition score. And the behaviours that the owners reported during the history taking phase, decreased mobility, less jumping, that's a really important one. Decrease height of obstacles, so the cats would jump, but they wouldn't jump up to a place where they used to jump up previously.

Stiffness struggling with stairs that can be either up or down. A decrease in grooming and urin urinating over the edge of litter tray. Comparing this to previous work, that previous work suggested 72% prevalence of OA in cats with age being the most significant association.

It's a really interesting study for us to understand when we're thinking about which cats that we see on a day to day basis could be suffering with OA. This is another piece of work, again, 100 Cats is a prospective observational study, and the aim was to evaluate the relationship between examination, goniometry, so measuring the range of motion in those joints, and radiographs. With regards to pain in response to palpation, the presence of pain increases the odds for degenerative joint disease for the elbows and for the spine.

So like I said, that correlation between palpation and evidence of clinical pain in conjunction with radiographic evidence. Other things that we looked for during examination, joint crepitus, joint effusion, joint thickening, and as I said, they measured the range of motion and found that joints with DJD had decreased range of motion. As far as radiography goes, the conclusions from this study were that DJD cannot be diagnosed with certainty using palpation or goniometry and radiographic radiographic evidence is required to support that diagnosis.

If you have negative findings on those examinations, the palpation, the crepitus, the effusion, the joint thickening, those negative findings would predict radiographically normal joints. And they found that range of motion may be of value in diagnosis. So this increases.

Or supports are saying to owners when they have a cat, and we suspect that cat could be suffering, suffering with osteoarthritis. We're suspicious based on examination. It supports our next step in diagnosis, that being radiography, and it also enhances the value of looking at range of motion in those joints in our diagnosis.

And that's often easier than when those cats are sedated, get a full assessment of range of motion. So let's think about this. How many cats with OA do you see on a day to day basis?

Should we be thinking about every cat over 10 years of age? And I would always ask, is that confounded by other disease? In my experience, we published a paper earlier in the year looking at a completely different topic, the value of gabapentin as an anxiolytic in hyperthyroid cats.

And for that study, we spoke to over 100 cat owners in the recruitment phase. And from memory, although this is me casting my memory back because it wasn't one of the objectives of the study at the time, if you think of those cats, they were aged between 8 and 18 years of age. And I would say less than 5% of those cats were medicated for osteoarthritis.

So I absolutely think that our diagnosis of OA can certainly be confounded by another disease. So I think about that in those hyperthyroid cats you're seeing, when you're seeing them back for their recheck, for their repeat prescription, for their medication, their bloods. Think about asking these questions and ask yourself, could this cat be suffering with osteoarthritis?

I think based on that previous, those two previous pieces of work, we could say that we said 82% of cats over the age of 14 had radiographic evidence, didn't we? So I certainly think about asking those questions. And what's the role for us in our individual practises with our wellness clinics that we run, and how do we incorporate diagnosis of LA into our health plans to try and capture as many of these cases as possible.

So once we've done that, let's set the scene for what we're going to think about from a treatment point of view. This is my cat pain ladder. So starting at the bottom here, the concept is exactly the same as pain ladders that the World Health organisation publishes for osteoarthritis, neuropathic pain, cancer pain.

I've just translated this for cats. So our current first line options, certainly in the UK and parts of Europe, non-steroidals and renova or or freevetMb are our two first line options licenced for the treatment of osteoarthritis in cats. If we get pain that's persisting or increasing despite dose optimisation, what do we do next?

We will talk through the evidence for gabapentin or romantadine. Actually what's not in here and should probably be added to that 3rd level, rather than it saying plus or minus opioids, because I still think that's quite a long way down the line, we'll talk about tramadol and let us ask the question, should tramadol be featured in that 3rd level? And should we put in a 4th level with something else such as opioids.

Some of our clients with those cats with severe OA will be using OTM buprenorphine on an as required basis for that cat, but that's certainly further down the line. So let's cover from a drug point of view, non-steroidals. I mentioned pit prance there.

Galyran Grayran isn't licenced for cats, and I've never used it in a cat, but I know there is some work there, so I just want to put it in there because it's something that I often get asked about. NMDA antagonists, Amanazine, memantine will look at the evidence for Amanazine. Gabbapentinos will look at the evidence for gabapentin there, and anti-nerve growth factor drugs we can cover through Nvetmab.

Now on the right hand side of the screen here, this is a a way to think about multimodal management of pain, so how do we make this relevant for cats? Well, I made this quite a few years ago and it says the correct non-steroidal, but really it should say the correct first line analgesic because I've already said that it could be a non-steroidal or three ave now. Weight controlled diet exercise, you may think that's a little bit more relevant for dogs, but certainly weight control and diets can be important for cats.

There was that piece of work suggested that increased body condition score didn't increase the prevalence of OA. However, we know that excess body weight is not going to help those fragile joints. Pain scoring, we're gonna touch on pain scoring and we're gonna talk about pain indicators.

How do we know that that cat is painful? And then there's adjunct analgesics, when to use gabapentin, when to use Amansidine, when to use tramadol. Let's talk about those.

And I've got physical rehabilitation on there because you will have some cat owners that are interested in physiotherapy and where physiotherapy is a relevant tool for their cats. Even if that's just at home exercises, they have one session with the physiotherapist and the physiotherapist teaches them at home massage exercises or mobility exercises for that cat. So we do have a couple of options for pain scoring and monitoring our cats with osteoarthritis.

The first one I'm gonna touch on is on the right hand side of the screen here, the feline musculoskeletal pain index. And From a validation point of view, there has been a fair amount of validation work here and with everything cat related, we can say that there are some challenges associated with validating the the felo musculoskeletal pain index. Despite that, despite the critique of it, I would still say there is a value in using this pain index because it almost focuses our history taking when we're talking to those cat owners.

And you may have a suspicion from some of the things that the owner says from a history point of view that the cat has osteoarthritis. But that time you mention it, that's probably the first time the owner has been aware of arthritis in their care. So then when we take some time to go through this pain score, and they can do that after the consultation, they can sit in the waiting room after your first consultation, so this doesn't have to take up your consultation time, but then you've got a completed pain index to go through and to talk through that client at the second consultation.

Give yourself a basis for what you're going to cover in that second consultation. So I think there's definitely a value there for focusing on history taking and bringing the owners on board with the fact that their cat has arthritis, and this is how we're going to monitor progress. If you are a subscriber to Vet Metrica, Vettmetrica is the online chronic or quality of life scoring system is validated for dogs and for cats.

The questions for dogs and cats are different, so you need to register the cat specifically as a cat, and the owner will be sent the cat questions. But this is developed by the team that brought us the short form of the Glasgow composite pain scale for both dogs and cats for scoring acute pain. And these are the three domains that are scored across, so the owner answers a series of questions and each question applies to one of these domains, and there's a vitality, comfort in emotional well-being.

And you can see here, 70% of healthy pets will score above this line. So we would expect if osteoarthritis is having a quality of life effect on this cat, we may see vitality decrease, we may see comfort decrease, and we may see changes in emotional wellbeing, which we would hope to improve with analgesic treatment and management of the osteoarthritis. It's a great system, you set it up, it sends an email to the client once a month or how however often you would like that cat monitored and it again gives us a base basis for tracking progression and a basis for discussion with that cat owner about our next steps.

If you think, well, I'm not a vet metric subscriber, I can use the filo musculoskeletal pain index, but what do I use in that first consultation to ask those owners some questions? These are little schematics or infographics from Zoys which you can download from the new site of OA Pain website that on that website you've got all of the information you need about osteoarthritis in cats. This is really useful, so asking clients about climbing upstairs.

Does your cat climb upstairs normally, climbing downstairs, we can often see a difference there. You can certainly see with Neville, my cat that I put the picture of on there, he would really limp up the stairs. You could really see his elbow motion was not normal, but he would run down the stairs really freely.

So there's definitely a difference in some cats were going up or down stairs, so make sure you ask about both. Does the cat chase, does the cat play? Does the cat jump up?

Do they think about jumping up? Do they have a really clear jump or do you hear them scrabble when they try to get to that object that they used to jump up to? Now of course that question can help when we think about environmental modification.

So like in this picture on the middle bottom level here, do we make sure a chair is pulled out so they can the cat can jump up to that place where they previously wanted to? So quite useful to help guide your consultation just to have a laminated version of this in the drawer in the consult room and you can just pop this out and talk a client through this. OK.

So Let's start talking about our traditional options. So from the UK's perspective, we've got two licence options for the ongoing treatment of OA and cats, that's meloxicam and rubenaoxib as far as non-steroidals go. Now a lot of the work from Meloxicam is in the depths of a knowledge vault somewhere and not terribly accessible, so I've actually picked out one of the early studies, this was a pilot study looking at the efficacy of rubenacoccib for the treatment of degenerative joint disease and cancers.

In this study, there were 109 cats. It was a prospective randomised placebo controlled study. And it was run for 2 consecutive 3 week periods.

So you can see on the diagram here, I'm just gonna pick my laser pointer up. We can see the cats were recruited at baseline. And then they underwent a 2 week placebo period where they had their accelerometer device fitted and the owners monitored the cats.

So the outcome measures were actimetry, which is using an accelerometer to measure the cat's activity levels. Una assessed activity and a definition of treatment success. So 2 weeks after being enrolled, they were randomised to their different groups.

One group received placebo and then placebo for those 23 week blocks. One group rubenaoxibrubeooxib, and one group rubenaoxi and then placebo. This is quite a unique study design, this is not something that you see very commonly, you think, OK, fine, let's just do a rubena coccyd and a placebo group.

But this is actually really interesting because you can document the changes within cats over time when they receive placebo, then placebo or rubenococcyecoccyb and get a comparison between rubenacoccib but then switching to placebo. And at these time points there was the owner assessment at day 0 once the cats were randomised and veterinary assessment. 21 day time point there was the owner assessment and then at the 42 day time point there were owner assessments and veterinary assessments.

So actimetry, the results for the activity measure was that there's high within cat and between cat variability. The mean activity was 5% higher with Rubenaox versus placebo. And more Rubenacoccy cats had greater activity increases of 11% at that 3 week and that 6 week time point.

Now the activity was measured based on what they refer to as the 80th percentile. It was actually 82.4%, cats being cats, of those activity values, so that should say value rather than veil.

82.4% of the activity values is zero, which is really what we expect. Cats are sleeping, resting for 80% of their time.

So I think we'd argue on an activity level, there were differences, but they were quite minor. 11% increase, 5% difference, not hugely significant from an activity point of view. Think about owner assessed activity.

For cats in the Rubenacoccy group, owners reported a 49% reduction in disability of their cats. Cats in the rabenaox group were described as having an improved temperament and increased happiness at the 6 week time point, which kind of made me laugh. I'm not sure, do we think of cats as happy, I'm not entirely sure.

Clearly the, the vet metrica quality of life assessment has come along since this study was published. Treatment success, more rubena Occy cats were treatment successes at the 6 week time point. And importantly, thinking about cats that withdrawn were withdrawn from the study, there were 6 cats.

So there were 10 cats that were withdrawn from the study, and 6 of those cats were withdrawn because of emmays. So that was the biggest adverse effect noted associated with the 6 week treatment of Rubenacocc in cats. So this is, it's a pilot study, 109 cats, so suggested that maybe we need greater numbers and further work to draw more significant conclusions.

But the greater outcome from this study is that owner assessed activity which is related to something we refer to as clients specific outcome measures. So asking the client for to assign a behaviour to that cat and then documenting the impact of the arthritis on that behaviour on a scale of 0 to 10. I just want to bring in a case study at this time point.

This is a cat that I've been managing for a number of years. When I first started treating him, he was 16, male neutered domestic long hair. Suffering with osteoarthritis, he was referred to the pain clinic being treated with gabapentin because he was also treated with steroids because he had IVD.

His owners described when he's uncomfortable, he doesn't go out. They noticed that his grooming habits had decreased, and certainly when I saw him, he had food all over his coat. Wasn't really washing around his face.

And his owners has described that he would quite frequently miss the litter tray, which is interesting because that's one of those behaviours that came out in that previous study of those 100 cats. So where do we start with him? Well, we're a bit limited with the non-steroid because he's treated with steroids, and I thought about, OK, do we need to have him on steroids still?

His steroids really keep his inflammatory bowel disease under control, and the owners are really reluctant to, risk upsetting, things from that point of view, which is fine. So non-steroidals were out. When I first started treating him, this was in the days before 3 avetma, however, he is now treated with 3 vetab.

And there we are, we have our next lines, he's already on gabapentin. Amantadine, we consider that as an option, and as I say, tramadol should be in there somewhere as well. So we asked about the efficacy of gabapentin and the owners did indeed report a positive benefit to adding in gabapentin for him.

We question tramadol as an auction. Thinking about NMDA antagonists, subcutaneous ketamine is another option. I know a lot of people have started using subcutaneous ketamine since reading our pain update on zero pain philosophy, and that's something that we certainly have more information, we're looking for more information on that as well.

And of course Freavet Mb. So when I first saw him, I knew Fruavetmb was coming, and he was one of the first cats that I treated with Freave. So On that topic, beeline anti nerve growth factor product.

So Frivemb monthly subcut injection 1 to 2.8 mg per gig is the dose range and it's a 1 mL vial. In the studies they document increased mobility and decreased pain.

In the field trial, there was a placebo controlled trial with 93 cats in the placebo group and 182 cats in the freeect map group. And the main outcome measure is what I referred to earlier, client specific outcome measures. So assigning behaviours to that cat.

So if you said one of those behavioural statements was my cat can jump up onto the kitchen table and you score the cat's ability to do that from 0 to 10, and we would expect that to change with treatment. My cat grooms less. Again, we'd expect that to change, so you pick 3 to 5 behaviours and you score them out to 10.

The secondary outcome for this study was veterinary examination and the outcome measures were done at stage 0, 2856 and 84. Looking just at the client specific outcome measures and bearing in mind this is the main primary outcome measure for the study. Between the treatment and the placebo at 1 month, 2 months, 3 months here, you can see treatment success 66.7% at 1 month, 75.9% at two months, flattening off to 76% at the three month time point.

The star there means that there was a significant difference, statistically significant difference between treatment and placebo. However, I'm sure you're looking at those placebo numbers and thinking, wow, half of the cats in the placebo group were reported as treatment successors according to their owner, or had improved client specific outcome measure indicators. And this is something that we typically see.

This is not unique to this study or this product. This is something that we see in feline analgesia studies. It's, there's another paper written on that very topic looking at different analgesic studies and documenting the placebo effect.

We don't totally understand why we see this. It's much greater than you'd see in in canine studies. Canine studies, 30 to 38% placebo, or 25 to 38.

Gives quite a wider range of dog studies, but you can see here in these feline studies we had 50 to 68% placebo effect. So definitely something worth bearing in mind when we look at any feline study. The safety of the product was tested at 5 times the licence dose for 6 months.

In cats in the regular dose treatment study, there was a focal skin reaction documented in about 10% of cats. And I'm sure some of you listening to this with the experience of using Fruive will have seen those focal skin reactions. It's certainly something, given this 10% incidence, I think it's something we should always talk to the clients about before using the product.

I've had one case where that happened, the cat had a very focal hotspot. What we did was stop the treatment. Of course the cat was, her comfort levels weren't as good without the treatment, and then we restarted the treatment and she didn't have another skin reaction again, so that would be my advice.

And this is one of the cats we've treated, you can see how lame she is, but we already said that we see lameness in about 13% of cats. She's incredibly lame in that video. And this is her after treatment with rivetmab.

I think you'd argue there is still a little bit of lameness there but she has significantly improved compared to previously. So nerve growth factor is a prognosisceptive neurotrophin. It's released by immune cells as part of the inflammatory process.

So when we get tissue damage in the joints, we get release of nerve growth factor and it sensitises no susceptors to inflammatory mediators, as well as directly activating the nose receptor. So we can see here. We've got our tissue damage from injury, we have our nerve growth factor binding to the trachea receptor, it forms this trachea NGF complex which then travels up the primary afferent to the dorsal root ganglion where the cell body of that nerve is, and then travels up to the dorsal corner of the spinal cord where we have ongoing transmission up to the cortex.

The other thing that's happening, so this is direct activation of the nerve triggering the susceptor activity. What else is happening here is the nerve growth factor is acting on mast cells, mast cells also have track A receptors and causing the release of all of these inflammatory mediators. The inflammatory mediators that we are very familiar with from our understanding of how non-steroidals work.

So if we're talking about anti nerve growth factor, there is a school of thought out there that says, well, actually it's not anti-inflammatory, but what I'm explaining to you here is by virtue of the fact that it prevents this activation of mast cells, there is an anti-inflammatory effect to using an anti nerve growth factor drug. I reference You mean cell body, dorsal horn, just for the labelling there. And then what's happening, so I know this this joint says a canine stifle joint, a joint with arthritis is the same with its canine or feline.

We've got our NGF binders to the track a receptor. At the dorsal root ganglion, so the cell body of that primary affluent, what's happened is we're getting increased transcription, and this increases the production of inflammatory mediators, receptors and ion channels. And we then get retrograde transport of the NGF track A complex back down to the periphery to produce further inflammation.

And that's called neurogenic inflammation, so whereby activity in the nerve produces further inflammation. We're also getting increased activity at the dorsal horn, and you can see that here in step 4. We've got glutamate release, which is how we're familiar with nerve transmission at the level of the dorsal horn through AMA receptors.

We know that glutamate, excessive glutamate release causes activation of the NMDA receptor, and there's a whole host of other receptor activation causing central sensitization. So by targeting nerve growth factor, we're aiming to prevent or reduce central sensitization. Those are all consequences, mast cell activation, causing hyperalgesia due to that inflammatory cascade, sensitising those receptors.

In hours to days, so there's a slightly delayed response where we get that increased neurotransmitter synthesis and we see that neurogenic inflammation. These references are both really nice references, so NM moto, this is a free to access reference in the vet record and the manta reference here, this is really interesting looking at the pathophysiology of nerve growth factor. So a little update on Pringle.

We know that the gabapentin helped. His owner found the tramadol too bitter. I know we've got studies and we'll look at the studies and the benefits of tramadol and cats, but the next issue is getting the tramadol into the cat.

We started him with Fruavalab. Once it became licenced, but we'd already started treating him with subcutaneous ketamine in the absence of free of that man. So he was showing a positive response to subcutaneous ketamine.

We use 0.3 mg per gig, which is the dose that's written on the pain update on zero pain philosophy. That improved discomfort levels.

He's going out more, his coat was tidier, and he had few litter train misses. And when Frunovemab became available, we started using that on a monthly basis. And now his ongoing pain management regime is gabapentin with ketamine and rivetab injected monthly.

So here's one of these studies looking at tramadol. Tramadol for the treatment of OA in geriatric cats. It was a randomised crossover study.

Cats were over 10 years of age, there were 24 cats with radiographic evidence of OA and owner documented limited mobility. The outcome measures were activity monitors and the owner scored the cat's impairment activity. So like, like they said in that previous study, the disability rated by the owners.

In this study, they document a significantly increase in activity in the 2 meg per kid group versus placebo. And significantly more owners considered improvement with 2 MB per gig versus 3 MB per gig. So if we're thinking about using a dose of Tramadol and cats, 2 weeks per gig seems to be about the right dose, and there are other studies that support that as well.

85% of clients consider quality of life to be improved. And that's quite a big number because don't forget we've got to take out some sort of placebo effects there. And I'm not sure if they actually did that calculation.

I don't have that number in my head, I've got that top line 85% considered. Quality of life improved, but I can't recall what the placebo effects was in that group. They do say that dose refinement is required for some individuals because of the adverse effects we see with tramadol in cats, that being sedation and decrease in activity.

So again, certainly something worth, worth thinking about. 2 meg per gig will be the target dose. However, if you, obviously you're going to warn the owner that they may see sedation associated with that, and we have a plan to manage that if we do see sedation.

And that was twice a day, I haven't written it on there, so BID2 me per gig BID. So why cats are not dogs? We know that tramadol isn't terribly effective in dogs despite the fact there is a licenced preparation.

There are differences in metabolism, and we tend to get the opioid effects from Odesmethyl tramadol which cats are able to metabolise to. And we see a higher bio bioavailability, but a slow clearance in cats, hence the BID dosing. And there's some work that suggests that tramadol may play a role in reducing that central sensitization.

I think it's a given that with advanced arthritis we see central sensitization. We should certainly think about analgesic methods to minimise that central sensitization as we've seen with Fruavena. So thinking about gabapentin.

Same lead author on this study. Again, small study, population of 20 cats, 10 mgs per kid, BID for 2 weeks, and they then switched groups. Similar outcome measures to before, client specific outcome measures looking at mobility and quality of life.

Accelerometer activity using those accelerometers attached to the cat's collar. In the gabapentin compared to the placebo group, the client's specific outcome measures were improved. However, in the activity measure, looking at that as an outcome measure, activity levels were decreased in the gabapentin group due to sedation.

Now I think this is where thinking about our gabapentin dose becomes really important. And certainly for cats, I would start at 5 megs per gig BID and titrate upwards to try and avoid that sedation. We know certainly in dogs, if we start gabapentin on a higher dose, we see sedation with starting gabapentin.

And we can work against that if we start at a lower dose and then titrate up. So 5 gigs per gig twice a day, and then you've got that target dose of 10 MB per gig in your head that we can work up to. So how does it work?

We know gabapentin acts on voltage-gated calcium channels, and that those increase in the dorsal root ganglia and so where the cell body for that primary afferent nerve is in both neuropathic pain and when we have central sensitization. There was a study in cats that looked at a dose of 8 migs per gig every 6 hours that gave antinooception. However, that's probably too high and too frequent to give to a clinical case because we're definitely going to see sedation at those levels.

That was just the dose that they used in that study. We know that for gabapentin max you need expression of the alpha 2 delta subunit, that's the calcium channel that we know is increased at the level of the dorsal root ganglion when we have central sensitization, i.e.

A hyperalgesic state. So where we see an increased response to the same pain stimulus, that's the definition of hyperalgesia. So I certainly say there is a rationale for using gabapentin in our osteoarthritic cats.

It's getting the dose right, that's the key thing. We talked about amantadine in cats for a number of years as an NMDA antagonist, so working against what's going on at the NMDA receptor at the dorsal horn of the spinal cord. We've known about the value of Amanazine in osteoarthritic dogs for a number of years, and it's great to see that this study has now demonstrated a benefit.

So the question from this study was, does Amantazine improve owner identified mobility impairment and quality of life in cats with OA? It was a placebo controlled study, so half the cats received placebo, half the cats received amantine, 5 migs per kg, SID for 3 weeks. 13 cats in total with radiographic and clinical evidence of OA.

The outcome measures scored at day 07, 14 and 21 for locomotor activity and those clients specific outcome measures, which client specific outcome measures can be different questions for different cats, so they are individual to the cat. With regards to the CSO scores, the scores are better with amantadine at week 2 and week 3 compared to placebo. Activity levels, activity counts were lower with amountidine at the 3 week time point.

So again, we're seeing a little bit of sedation there. Quality of life, immensity ratings were significant compared to placebo. So the conclusion from these authors was that a man's seen significantly decreased activity, but improved owner identified, impaired mobility and owner perceived quality of life.

I guess what we've got to think about, let's look at that dose, so 5 MB perk SID for 3 weeks. What this study obviously hasn't looked at is the use of amantazine alongside other analgesics. So I guess we need to ask ourselves the question.

How can we try and provide analgesia but decrease the sedative action of some of these drugs? And we know the whole idea of multimodal analgesia is we achieve an overall greater analgesic picture by using several different drugs that act by different mechanisms. So perhaps I would ask the question, can we reduce our doses of other drugs?

So maybe that 5 mg per kg gabapentin BID would be appropriate with Amantadine, maybe at 2 or 3 mg per kg, perhaps we can decrease our Amanazine dose and our gabapentin dose. We see analgesia but we don't see sedation. This would be great in conjunction with Frinoveab or non-steroidals, so I'd certainly support the use of amantazine as a second line, but we probably just want to reduce the dose.

And we probably can do that in conjunction with those other analgesics, but nobody's studied that yet. So there we go, just drawing you back to our cat pain ladder. I think based on that gabapentin or amantazine work, you could choose either as your second line.

Like I say, I think you could argue that Tramadol could be in there as your second line as well. Then comes down to preparation of drug and which drug we can actually administer to the cat. Gabapentin, we can get flavoured preparations of that.

Ammanidine at the moment, my understanding is it's just smaller compounded tablets as an option and Tramadol, smaller compounded tablets as well. I don't think we have a liquid a a veterinary compounded liquid for either of those at the moment. We definitely have liquid amantadine, but it's a human preparation.

And I just wanted to put some final thoughts in there. Obviously we've talked about our first line drugs. We've talked about pain scoring those cats, and we've talked about our options for second line.

Final thoughts, I touched on the placebo effect earlier. This data came from one of those studies whereby 45% of owners in the placebo group thought their cat was in the treatment group. But 83% of owners in the treatment group correctly identified that their cat was indeed in the treatment group.

So yes, we have a high placebo effect, but the vast majority of owners can tell that their cat is in the treatment group. So maybe that gives you a little bit of reassurance. And this was the study that I mentioned earlier, so looking at caregiver placebo effects in analgesic trials for cats.

These researchers assessed 6 placebo controlled studies. They documented that caregiver placebo effect is high, and when you look at client specific outcome measures as one of those main outcome measures, 50 to 70% of cats in the placebo group were CSO successors. 36% of CSO's successes were also activity successes, and I know we would naturally think, well, if we're struggling with one outcome measure, let's add in another outcome measure.

So a little bit of confounding information there. We always need to think about benefit versus placebo in those studies, and you can see there's a huge value of running placebo controlled studies in cats. But perhaps that crossover placebo placebo treatment, treatment, placebo treatment model is a way to mitigate against some of these placebo effects.

Fantastic. If anyone has any questions, you're very welcome to contact me through Zero Pain philosophy, and I'll quite happily answer those questions for you.