Good evening everybody, and welcome to tonight's webinar. My name is Bruce Stevenson and I have the honour and privilege of chairing tonight's webinar, which is, a big thank you I want to start with to our sponsors, Vetto Conol. Vetto Conol has kindly reached into their pockets to make tonight possible for us.

And it's a big thank you to them. We have Russell on with us from Weto Conal. And if you have any questions about their products and that, Russell is very kindly going to be around right to the end so he can answer some questions for you.

Little bit of housekeeping quickly for those of you that haven't been on with us before. If you do have a question, just hover your, your mouse over the screen. You will see that a control bar pops up usually at the bottom.

There's a little Q&A box there. Just click on that and just type your questions in there. They'll come through to me and we will keep those to the end.

And Duncan has very kindly agreed. Excuse me, to stay on and answer those questions for us at the end. So our speaker tonight is Duncan Lasalle, and after graduating with honours from Bristol Vet School, Duncan completed a PhD in aspects of preemptive and perioperative analgesia at the University of Bristol.

After an internship there, he completed his surgical residency at the University of Cambridge. Duncan then moved to Colorado State University for a fellowship in oncological surgery. This was followed with a period of post-doctoral research in feline pain and analgesia at the University of Florida.

And Duncan is currently the professor in small animal surgery and translational pain research at North Carolina State University with active clinical and research interests in acute and chronic pain. Duncan, welcome to the webinar, vet, and it's over to you. Well, thank you very much for that kind introduction and good evening to everyone in the UK and good afternoon from here in North Carolina.

So I am a faculty member at North Carolina State University where essentially now I run a, a comparative pain research programme or translational pain research programme and a lot of what I do is to run clinical trials. And I develop ways to measure pain and then use those methods to determine what works to alleviate pain. Still see clinical cases.

I have a long track record of working in the clinic and running a pain management clinic, which is still ongoing. And this evening, I want to talk to you about a very practical, question, practical problem, one. That often comes up and that that is switching between non-steroidals, and we're gonna focus on dogs and mainly gonna focus around OA and I'm just going to explore this topic, what you'll realise by the end of this seminar.

Is that there are no hard and fast data on this and so I'm going to present some information, discuss it back and forth, and hopefully it'll give you and I will end up with some recommendations that'll give you a bit of a guide as to how to approach this topic. I'm very grateful to Vettoquinol for having brought this question to the forefront again. I worked with them to produce a guide on switching between non-steroidals in dogs, so very grateful to vetoquinol for that.

Reach out to vetoquinol if you want to get a copy of this, and I also would like to thank Vetoquinol for sponsoring tonight's seminar. Let me just start off by talking about the the efficacy of non-steroidals, really just shoring up the rationale for using them. Non-steroidals are predictably efficacious for osteoarthritis pain.

Almost regardless of the, if you like, the stage of OA, the severity of OA. Non-steroidals are generally pretty predictably efficacious for OA pain. They're also predictably efficacious for perioperative pain.

So across the chronic pain conditions, particularly OA and perioperative pain, nonsteroidals have a very important role in helping us manage pain in companion animals, manage pain in dogs. And. I, I just want to drill down a little bit on why nonsteroidals are predictably efficacious across these varied pain conditions.

If you, if you think about pain as being acute and chronic, so kind of, you know, short lasting versus long standing pain, we, we also term acute pain as, as adaptive pain. It serves a protective role. And chronic pain, is often termed maladaptive or pathological pain because it generally serves, less of an adaptive or protective role.

It's, it often just gets in the way. Adaptive pain can be divided into no susceptive inflammatory. No susceptive is simply pain signals are generated when the system, with the normal system is activated, such as maybe by a sharp blade or some other noxious stimulus.

Inflammatory pain we're very familiar with, that's what occurs perioperatively and in many disease processes. And then the maladaptive or pathological pain, which is maybe the preferred term for these long standing pain conditions can be subdivided into neuropathic pain caused by an actual damage to the nervous system and functional, pain that's generated because of a dysfunction of the system. If we think about the two conditions we've, we've touched on, osteoarthritis and perioerative pain, well, long standing osteoarthritis pain is actually mixed pain.

You can't say it is just one of these buckets, one of these definition buckets. It's a mixture of all these types of pain. And surgical pain is probably predominantly inflammatory pain, although after a few hours you certainly see a functional component to that, and with nerve damage, you'll see a neuropathic component.

So what I'm leading up to here is, the, the, the, there are different types, different classifications of pain. And we can look at the different conditions and how they involve these different classifications of pain. But prostaglandins are involved in driving inflammatory pain and also in driving functional pain.

So, almost regardless of the pain condition, if it crosses across a number of these different types of pain, prostaglandins are gonna be involved. And that's really the, the rationale behind the reasoning behind why non-steroidals are efficacious across a wide variety of pain conditions. They are predictably efficacious because of the widespread role of prostaggland is in pain processing.

So you can see here, prostag gland is clearly involved in inflammatory and functional pain, . If you look in the periphery, prostaglandins cause enhanced transduction in the periphery, so they sensitise nerve fibres at the level of the spinal cord, they're involved in the facilitating processing, which is part of central sensitization, which is part of the functional pain state. So again, it's almost .

Regardless of the pain condition, prostaglandins are probably involved because of their widespread role in pain processing. And this article here reviews very well the peripheral and central roles of prostaglandin and prostaglandins and prostaglandin receptors. Again emphasising, therefore why nonsteroidals have this predictably.

Efficacious pain relief associated with their use. And just very briefly, prostaglandin E2, it's, it's sort of core action is to sensitise nerves. So you take a nerve ending, such as this one here, with prostaglandin receptors on the end and when prostaglandin binds to these EP receptors, it causes sensitization of the nerve.

This occurs through a variety of different mechanisms, but primarily initially through the phosphorylation, the activation of a variety of different other pain receptors, if you like, on the end of this primary afferent fibre. So prostaglandin E2 working through the various EP receptors is going to result in the sensitization of these other channels. And so it's this direct sensitization.

That results in what we see as the functional sensitization of these nerve endings. So prostaglandins are making it easier for other stimuli to activate these nerves and produce action potentials. So, If nonsteroidals are predictably efficacious, why would you need to switch?

And fundamentally it's because of this. One dog is not the same as another dog, and this leads to different, varying degrees of response to individual drugs, which is interpreted as a lack of efficacy, varying side effects, side effect responses by individual dogs to individual drugs, and then there are also other reasons, whether it's owner preference, dosing, cost, a number of reasons why. One might want to switch, but primarily.

It's because of a perceived lack of efficacy in an individual patient treated with an individual drug or side effects in an individual patient treated with an individual drug. Let's talk a little bit about lack of efficacy here, so. And I've mentioned in this individual response, but this is well recognised in humans, and there's a, a paper there I put up on the slide for you, variability and analgesic response to non-steroidal anti-inflammatory drugs.

So it's well recognised and I think if you think about this yourself, you, each one of you probably has a favoured or favourite non-steroidal one which, which works well and is tolerated by you. And maybe other non-steroidals that you, where you don't seem to get the same degree of efficacy. So that individual response is well recognised in humans and there's no reason not to think that that wouldn't occur in dogs.

And indeed, although we don't have studies directly looking at this in every clinical study in dogs where a non-steroidal has been evaluated. There is a spectrum of response across any group of treated animals. That tells us that there are varying degrees of response and so you have some animals within a group treatment non-steroidals that are relatively poor.

Responders and other animals within a group treated with a single nonsteroidal are better responders. To my knowledge, no one has taken the poor responders and looked to see if they respond to other nonsteroidals, but we'll come to that in just a second. So, lack of efficacy, I, you know, I think it's, it's not something to.

Blame an individual drug for, but rather accept that when you're giving a given nonsteroidal to a given individual, there may well be a relative lack of efficacy just because of that individuality and response. Now, another reason, or I, I, another thing that comes up when, when one's talking about a lack of efficacy with non-steroidals is this idea of a waning efficacy over time. There's no data to, to support this as far as I'm aware, but certainly something I have seen clinically that, you know, over time as you continue to provide the nonsteroidal, in some patients you seem to get a waning in efficacy and I guess I don't know exactly why that occurs, but I'm suspicious it's not.

It's not a tolerance to the non-steroidal. It's not a waning and inherent efficacy, but rather a shifting neurobiology of pain in that individual. Because we know that over time the neurobiology that is driving pain does shift, it morphs, it changes.

And so I think that's probably the best explanation for this apparent waning in efficacy over time. Interestingly, switching non-steroidal, so now we're getting to a a a a reason for switching. Switching on steroidals can often result in better efficacy, and this may seem a little bizarre.

You have an animal that's on a non-steroidal, the efficacy appears to be waning over time, and if you switch to a different non-steroidal, you can often see a a a marked increase in efficacy from that non-steroidal. And I think that's because all non-steroidals actually have slightly different biological actions. We tend to lump them into this one group, they inhibit the production of prostaglandins in various ways, COX 1, COX2 or they inhibit the interaction of prostaglandins with EP receptors.

And that's all we think about, but actually nonsteroidals have effects on the cannabinogic system, on, trip channels, on other receptors, and, and they're all slightly different. And so I think it's, it's then it starts to make more sense why an individual non-steroidal may have better efficacy than. A previous nonsteroidal and why you may see that clinical efficacy just by switching.

And this is an example of this. Now this, these are data here I've given you the publication. We were actually looking at a mantadine as an add-on to non-steroidals.

And the way we set the study up was we took animals that were on non-steroidals that when where pain control was not sufficient. And we gave them a washout period of 7 days and then we switched them all to a different non-steroidal. And in this case it happened to me meloxicam.

And you can see here, this is the pain at day 7, so they've, they were on the old non-steroidal in blue. They were washed out for 7 days, really no, no change because that old non-steroidal was not providing pain relief. Switch them and look at this decrease in pain that you get just by switching to a non-steroidal that they hadn't seen.

And then of course the study went on to look at, well, what happens if you add on a mantidine versus placebo. But this is the part I want to show you here. This is some evidence for the idea that switching may give you a boost in pain control.

OK, so that's efficacy. We've got this lack of efficacy in an individual and potentially a waning efficacy over time. But another reason for switching is side effects and all non-steroidals can be associated with side effects, gastrointestinal, renal, liver side effects.

I guess one, you know, one thing that it's important just to hit up here is how common are non-steroidal related side effects. Does the frequency of side effects vary from one non-steroidal to another? This would be an important question to answer if we're, if we see side effects with one drug and we want to switch to another, maybe we would ask, well, is there a safer nonsteroidal to switch to in terms of side effects?

There are actually very little data on the frequency of side effects. We, we actually don't know. How common side effects associated with non-steroidals are.

Also, there are no comparative data available, so we don't have data to compare side effects across different non-steroidals. Comparing them, you know, apples to apples, oranges to oranges, . And you know, complicating the pictures that personal experience, your experience, my experience, and case reports drive opinions.

So we, we, we're in this sort of situation where there are not a lot of data to inform us and we have strong personal opinions. But just looking at what we do know, this is probably, I would say the best review written by Ber Montero Steiga, best review, summarising what we know about side effects, and. This, this review, collated data together and looking at research studies and clinical trials, and when you lump everything together, it's clear that adverse effects do occur more common in the clinical trials.

That's where older patients are treated, older patients with the target disease, more common in clinical trials than research studies where young healthy animals are receiving the non-steroidals. But clearly the most common side effects, vomiting, followed by diarrhoea, followed by anorexia, then lethargy melena. If you just pull out the placebo controlled studies, so here's still a combination of research and clinical trials, there's actually no difference in outwardly detectable adverse effects between non-steroidal and placebo treated dogs.

And this, this is important. So, one, yes, we don't know how common non-steroidal related side effects are. What we do know is that across these studies involving scores to hundreds of dogs, there is no difference in the placebo controlled study studies between outwardly detected.

Detectable adverse effects such as vomiting and diarrhoea in no difference between the placebo treated dogs and the non-steroidal treated dogs. So I think that starts to give me an idea that adverse events are fairly rare, uncommon, and I'm not, I'm not saying they can't occur, but they're fairly rare. A bit of data that we do have indicates that the long-term use of non-steroidals does not increase the incidence of side effects and so, When we looked, when we looked at the clinical data, it was very clear that there was no correlation between adverse event rates and the length of treatment.

And I think this is because if a non-steroidal is tolerated well for the 1st 14 to 28 days, 1st 2 to 4 weeks, it will be tolerated well long term, because in, in this study here, we compared short term, shorter than 1 month to longer than 1 month treatment with non-steroidals. And that last comment that brings, brings in something very, very important. There are, there, there is the individual intolerance to individual non-steroidals, and you're most likely to see that within the 1st 2 to 4 weeks.

And that's when you want to be rechecking, re-evaluating these patients, and if there are adverse effects, considering switching at that point. So when side effects occur or if efficacy is not seen, switching is appropriate. It's something that we should be doing in clinically managing these patients.

But what should the interval be between stopping one non-steroidal and starting another? This is the question, what should the washout period be? Do we need a washout period?

And if so, how long? I think there are a number of areas that we can talk about that are kind of considerations in trying to answer this, and I'm gonna go through a little bit on pharmacokinetics, some specific information on switching from aspirin, my comments on switching the peroperative period, and then broader comments on switching due to side effects and lack of efficacy. So pharmacokinetics and, you know, often when people talk about this, this the, the washout period and switching between non-steroidals, the conversation defaults to talking about half-lives, the, the pharmacokinetic parameters of these drugs.

Well, non-steroidal metabolism and clearance varies across drugs. And I believe these half-lives are accurate, but you can see they're across the different drugs, the half-lives vary. They vary quite a bit.

And so one could take the approach of, OK, let's, let's take the rule of thumb of 5 half lives, and after 5 half lives in general, drugs should be pretty much eliminated from the body and we'll use that as a guide for switching. And I'm gonna come back to that concept a little bit later on when we review some clinical data. And that, you know, wouldn't be a bad rule of thumb.

There's no data, there are no data to support that that's an appropriate approach. However, analgesic and probably toxic effects may persist longer than the half-lives might predict, and this is due to something called tissue selectivity. And it's a benefit.

When we're looking for analgesia, it may not be a benefit if there are toxic side effects that involve inflammation. Let me explain what tissue selectivity is. What it is is you end up with a longer resonance time of the nonsteroidal in inflamed areas than you do in the rest of the body.

So this is due to the high protein binding and acidity of certain nonsteroidals, not all non-steroidals, but most, most non-steroidals have a PA of 4.5, meaning they distribute unequal in the body. So what happens in inflamed tissue, the protein bound nonsteroidal accumulates, you know, you get extra vessation of, of fluid from vessels, this accumulates in inflamed tissue.

And that inflamed tissue becomes relatively acidic, and because of the PK of the non-steroidal, you end up with increased free fraction of the non-steroidal. So essentially the non-steroidal drops off the protein, if you like. And it's that free non-steroidal that can be active and that free non-steroidal diffuses into cells, is trapped in there and has its effects.

So because of inflammation. That is relatively acidic and the pique of nonsteroidals, you get essentially non-steroidals hanging around longer and inflamed tissue. If that inflamed tissue is a surgical site, that's good because it non-steroidals there where we need it cleared from the rest of the body.

If that inflamed tissue is due to toxicity associated with non-steroidals or in areas like the gut, . Where non-steroidals have, where, where prostaglandins are needed for healing, then that's not so good. Switching from aspirin to other non-steroidals, this is a kind of a, a unique thing.

So aspirin is a COX1 or COX2 inhibitor. It blocks the production of prostaglandins by COX 1 and COX2, and it predictably produces gastric ulcers, mainly through its COX-1 inhibition, but gastric adaptation occurs. Now, so what do I mean by this?

It means that when you give aspirin, gastric ulcers will occur. But then over the period of several days, the severity decreases. So aspirin is used to induce models of gastric ulceration.

But as I said, over several days to weeks, the severity of those lesions decreases, and it decreases its thought because aspirin promotes the production of this compound here, 5RHETE and this is a lippoxin. And what this one is, has been termed is aspirin triggered lippoxin. So what's happening here is aspirin through inhibiting.

Cyclooxygenase 1 inhibiting the production of prostaglandins through COX 1 and partly COX 2. Is causing ulceration, but at the same time, it is aspirin is acetylating CO2 and facilitating the production of this lipoxin and this lipoxin plays a role in healing. So it's almost like aspirin has this inbuilt counter regulatory signal, by virtue of acetylating COX2.

So aspirin will produce ulcers. But also the acetylated COX2 is producing hypoxins which will help in the resolution of that inflammation and aid in the healing of those ulcers. So the starting point here is aspirins producing ulcers, but it's also producing, facilitating the production of compounds that help those ulcers to heal.

So try and keeping everything in balance. So then if you come in with selective and non-selective COX-2 inhibitors, you actually prevent the action of that acetylated CO2 in producing lipoxin. So you're preventing the healing components that aspirin is up regulating.

So you have a situation here where if you were to move from a situation where aspirin was being administered, gastric ulceration was present. But controlled because of those lipoxins, you then inhibit the production of those lipoxins, you could make the situation worse. And there aren't, there aren't solid clinical data on that to, to support that assumption.

However, this study we did a number of years ago clearly showed that aspirin increased COX2 expression, whereas Dracoi carproffen didn't change COX2 expression. So some data here in dogs to indicate that aspirin is up regulating COX2 expression. How about switching in the perioperative period .

Well, with non-steroidals, I guess one question is should we use them before or after anaesthesia, and, and for me that's easily answered by saying that if you have intravenous access, if you're administering intravenous fluids, if you're titrating those fluids to normal tension, then it, I think you you have the option of using non-steroidals prior to anaesthesia and surgery, but if you do not have intravenous access, if you're not using fluids, if you're not maintaining normal attention. And that's a whole another discussion. Then wait until after the animal is recovered from anaesthesia and surgery to give the nonsteroidal.

So that's just a quick aside on the timing of non-sterile administration and we can certainly come back to that in questions. But one of the things that I often see in hospitals is the, the practise has their favoured perioperative non-steroidal, and. Maybe that's different to the most, the, the favoured one for chronic pain control or the preferred non-steroidal to send dogs home on after surgery.

And so the question comes up, how about this switching? You know, animal may come in on a non-steroidal, can you switch to your preferred, say, injectable non-steroidal perioperatively and then move to a third non-steroidal, your preferred non-steroidal for administration in the home environment. Well, let's look at a little bit of clinical data here.

So this is a retrospective study, relatively small, that we did looking at clinical cases that unfortunately had suffered gastrointestinal perforation. And when we looked at those cases and the case details, rapid switching, particularly in the period of period, was a common feature. Now that's not to say rapid switching.

Always leads to gastrointestinal perforation, but when you looked at the per-operative cases there, rapid switching was a common feature. In contrast, Kirsty Dowers, using research dogs, gave them one non-steroidal, followed by a different one for 4 days and then switched over the sequence and found no overall adverse effect. She did actually find that gastric mucosal scores got worse but then got better.

So even with these nonsteroidals, there's a degree of gastric adaptation. So Kirsty Dower's data would indicate that there's no problem with rapid switching. Our retrospective study would indicate that when problems occur, rapid switching, and this is switching one day and then the next day, different non-steroidal, was a common feature in those cases.

My preference, as, as we'll come to later, is not to switch between non-steroids and the perioperative period. I think the one thing that that Kirsty Dower's study did not also include was the stress of anaesthesia and surgery and I, I, and again, I don't have any hard data to to back this up, but I do not, I feel uneasy about. The switching between one nonsteroidal and another during that perioperative period, giving them one nonsteroidal peroperatively, another one to go home on that rapid switching, I, I feel uncomfortable about that.

I strongly advise that that is not done, because I think of the effects of anaesthesia and surgery and the other stresses and so on. A few comments on switching due to side effects, so. One of the most common side effects of non-steroidals is vomiting, as we saw in one of the earlier slides.

And, so then the question comes up, OK, if a dog is vomiting, it's on a non-steroidal, let's switch it to another one. We want to see whether a different non-steroidal is tolerated. What should the washout period be?

And I'm going to kick off by saying there are no data to support what I'm about to say, but I do remember, at least I think I remember from the days of histology, that it takes about 7 days, 5 to 7 days for a, a, a little stem cell here in the crypt to climb up to the top of the villas to reconstitute the villas barrier here. So in vomiting, and other gastrointestinal adverse events, these luminal cells here on the villae are gonna be denuded. They're gonna be lost, and the mucosal barrier is compromised.

And knowing that it takes about 5 to 7 days for this barrier to be, to be to, to be reformed. That's where I have clinically used that information to come up with my own justification of a washout period, which is 7 days if there's been vomiting. Now, you know, I think so that's, that's a rule of thumb for me.

If there's been vomiting, 7 days, start a new, start the new non-steroidal, see if that's tolerated. Of course, you know, we should probably just get into the nuances of that a little bit. Not all vomiting's the same.

If there, if it's uncontrolled vomiting with blood. The animal is sick, then a washout period of longer than that, I think is appropriate. If it's occasional vomiting, do you really, do you really need 7 days?

Again, I don't know, but I think that this is where I've got my 7 days from, as a starting point to determine a washout period. One thing just, you know, talking about side effects here, this is a research study where these investigators, this is Steve Budsburg group group actually induced pyloric lesions in dogs and then gave them different non-steroidals. And you can see here the selective COX-2 inhibitors, so this is errococcib here.

Decreased healing or resolution of gastric ulcers. So what you're looking at here is the difference between the starting point and the endpoint with ferococcib versus the starting point and the endpoint with placebo or tapoxyin. So it just goes back to this idea that COX2 appears to play a role in the healing of ulcers, and we talked about that with aspirin triggered likepoxin, but even beyond that, COX2 has a reparative role.

And so, maybe these data are just saying be a little bit more cautious about switching to a selective COX-2 inhibitor if there, if you believe there is compromise of the gastrointestinal mucosa. As we finish up here, I want to talk about this study here. This is a, this was a large study.

It's the Pyrocoive experience study, the PET study, or the, the Prevacope study. So over 1000 dogs and in this particular publication, they looked at dogs that did not complete the large study. For adverse events, OK, so it's a large study of 1000 dogs, it's an experienced trial, and some of those dogs had had adverse events, and they dropped out.

And they looked at these non-completers and, ascertained whether or not they had recently had a different non-steroidal or not, and overall found no significant effect of time since the last non-steroidal on driving these dropouts because of adverse events. Now, one thing to remember as you look at these data that are coming up next. Is that in this study there were recommended washout periods and they were based on half-life, so you can see here the, the different washout period requested, not necessarily adhered to, but requested for Carprafin, dracoivitoolac, meloxicam, and tapoxin.

So these dogs were moving from these products onto Prevaco, onto errooxib for this experience trial. Now, and just to to explain here, so the, the recommended washout period from Losam was 3 to 5 days. You can see here the number of cases that were switched after 3 days, 4 days, 5 days, 67, and so on.

So it's quite variable data. The switch for aspirin was recommended to be 10 to 14 days. You can see that was, more, more often than not, not adhered to, but quite variable data, but there is that background of some recommendation on washout periods, and I just explained that because now we're looking at the numbers of dogs that dropped out.

That had were not on a previous non-steroidal, and those that had been on a previous non-steroidal. And you can see in terms of the percentages here, 12.6% versus 13.8, no difference between those two groups of dogs, those that started the study, it had not previously been on non-steroidal versus those that started the study and had previously been on another non-steroidal and were then switched.

Now remember, there were recommendations on the washout period. And if you look then within those dogs that had recently been switched from a different non-steroidal, there's no difference here in the number of adverse events as percentages but based on time since the last dose of the previous non-steroidal. So if you, if.

If you hypothesised that a short washout period would cause a larger number of adverse events versus a longer washout period, that was not seen in these numbers. Although I, you know, I have to say 16.7 versus 10.6, not statistically significant, but maybe something just to consider there, that short washout period there, just nudging up the figures.

So My recommendations, a little summary here. If gastrointestinal injury or compromise is observed or even suspected, administration of another non-steroidal before allowing healing to occur could produce additional injury, probably particularly true for the selective COXS 2 inhibitors. What does that mean for a washout period?

It means leaving an appropriate washout period and, you know, that's, that's where we, we have to come up with a number and if there's been vomiting, I come up with a number of 5 to 7 days there. If we're switching because of adverse events such as vomiting, gastrointestinal gastrointestinal injury should be assumed, and I think a 7 day washout period is appropriate. If switching from aspirin to another non-steroidal, regardless of whether or not we're switching because of adverse events, a washout period of at least 7 days is recommended.

So that's a stronger recommendation there. If switching between different COX2 selective non-steroidals or between COC 2 selective and non-selective due to a lack of efficacy, limited clinical data suggests that a short washout period is appropriate. What that means is if you're switching cause the lack of efficacy, COX 2 to COX 2, or between COXS 2, selective and non-selective, nonsteroidals or vice versa.

Then a shorter washout period is likely to be OK. So the longer washout periods here come in when we suspect, particularly gastrointestinal injury. And this is summarised there's a little kind of poster to go with the, the switching guidelines.

This is summarised here. It's a kind of a flow chart in terms of answering some questions and then this provides suggested washout periods. Now I do want to emphasise these are are suggested and you know for people who are into talking about washout periods, this can be quite controversial.

Because there are no solid data to drive a decision to use X number of days versus Y number of days. OK, so these are recommendations really based on that discussion that I've just been through, showing you some of the clinical data we have, and dovetailing that with our understanding of physiology and pathophysiology. I just want to end here talking, spending a few minutes talking about the provision of analgesia in the washout period.

So firstly, the chronic pain treatment scenario. So let's say we take a dog that is on a non-steroidal and we're not seeing what we believe is appropriate efficacy, and we want to switch it to a different non-steroidal, . I think, you know, I, I, I, we, one certainly should ask the question, is additional analgesia required?

So if we're going to use a washout period, should we try additional analgesia? The problem comes in that we don't have good alternatives to address that washout period in terms of the adjunctive drugs, . You know, do adjunctive drugs provide appropriate efficacy?

I mean, that's a fundamental question here, because immediately people think, well, if I'm switching between non-steroidals, maybe I can add in some amattidine or gabapentin. But this is a summary of all the evidence we have. So we actually don't have much evidence that these adjunctive drugs provide analgesia.

And even further theoretically, would it, it, it's likely that they take a little bit of time to actually work because of their mechanism of action. You do in Europe now have the anti-NGF monoclonal antibodies, and that would certainly be an option, and probably a better option for an extended washout period that is driven by maybe a particular adverse events or the severity of adverse events. If we're switching between non-steroidals for adverse events, let's say vomiting, so non-steroidal A is being administered, there's some vomiting, we want to switch, we, we decide on a, on a 7 or even 10 day washout period.

Then again, the question would be, well, what do we use to provide pain relief? And I think in that scenario, if the non-steroidal was originally working, remember, these nonsteroidals are not on and off. So there will be several days of efficacy still from a course of a non-steroidal even, even after it is stopped.

So I suppose my comments really are, you know, think about the actual patient. If they really need pain relief, then look at alternative methods. But at the same time, don't necessarily assume that there's no hangover pain relief on board.

I think in the acute pain treatment scenario, then we, it's a, it's a, it's a, it's a different discussion, because a gap in non-steroidal provision peroperatively could result in quite a significant degree of pain. Now, on the positive side, There are many ways of controlling that pain in the perioperative period, adding, particularly the use of local anaesthetics, opioids and so on. But I would come back here and in answering this question, you know, so if the question is, well, if we're switching the perioperative period and we want a washout period, what do we use to provide analgesia, I would come back to that original statement of, my recommendation, which is not to switch between different non-steroidals in the perioperative period.

Keep them on the same nonsteroidal. If the dog is on a non-stroller for a chronic pain condition and needs surgery, keep it on that non-steroidal, and that really then serves as your perioerative non-steroidal. Don't be switching between your preferred perioperative and preferred go home nonsteroidal.

Keep them on the same non-steroidal. So I would avoid switching in the perioperative period. So a little summary here among the drugs available, there may be variations among animals with respect to tolerance of adverse effects and clinical response for both these reasons and because of owner preference, costs, dosing considerations, for both these reasons, switching between non-steroidals is appropriate.

When considering a switch from one non-steroidal to another for the reasons of lack of efficacy of the first. The necessity of a washout period needs reevaluation. That's essentially because there are no solid data to recommend that a washout period is needed when switching for reasons of lack of efficacy.

The most conservative approach is to use a washout period of a few days, but there's no scientific evidence that this is required or any scientific evidence to inform what duration is appropriate. Now, if we're switching between non-steroidals due to gastrointestinal side effects, rapid switching to a drug that inhibits COX2 could delay healing and possibly worsen the lesions. And in this scenario, I think a washout period of 7 days is appropriate.

And again, just to reiterate, I do not recommend switching in the perioperative period. So with that, I am going to finish and I will try and answer any questions that you have. Duncan, thank you so much for that fascinating insight into what we all know is, is quite a, a hot topic.

I don't know controversial is the right word, but certainly a very hot topic. So thank you for sharing your insight and your knowledge. Also, a huge big thank you to Weta Quinol for sponsoring tonight.

Russell, I know you're on and if you can convey our big thanks back to the rest of your team for the sponsorship of tonight. Duncan, we've got quite a few questions. Some of them I'm going to, sort of lump together because they're very similar.

And, some of them, I think, are a little bit of a, a sort of a hot, a hot question, but we'll leave those to the end. Wants to know, do you always ask for chemistry and haematology profiles before switching NSAIDS? That's a, that's a a great question, .

I think I'm gonna make a number of comments around that. I think in the ideal situation, one would know the chemistry profile, know the basic haematology of a patient that we start treating with non-steroidals. So just so that we have that baseline.

And then in terms of follow up, you know, the, the, the, the next time point for me would be 2 to 4 weeks after starting that non-steroidal because as I, as I mentioned, that's the time you're most likely to see side effects. So that's the ideal scenario. Although, you know, I, I, I am reminded, as I think back at my own cases, of, well, how, how often have I actually changed what I've done with the knowledge of that chemistry.

So I'm, I'm not saying don't, don't run the chemistry. I'm, I'm just saying I think there may be an overreliance on chemistry there, . Now, do you need to rerun chemistry before switching?

I, I think if you're switching because of a lack of efficacy and the dog is showing no adverse effects, I would find that difficult to justify. I think if you're switching because of side effects, then the severity of the side effects, the patient's status should really drive the answer to that question. Makes complete sense.

Alan wants to know, do injectable NSAIDs bypass possible gut side effects? No. There you go, short and simple.

No, no, no, but, but, but particularly with aspirin, less so with the other non-steroidals, there can be direct effects of the non-steroidal, you know, concentrated as they are, you know, as they go into the gut on the gut mucosa. But you know, the simple answer to that question is no. The non-steroidals are in the system, they can still have adverse effects at the gut.

Excellent. When you were talking about, your long-distance memories of vili cellular replication and everything else, and talking about vomiting, Ali popped the question in saying, does vomiting damage the small intestinal via epithelium? You know, I guess it depends on what, what's driving the vomiting, how severe the vomiting is, but I certainly know from my many years of soft tissue surgery and operating on dogs that, where the clinical sign was, was vomiting, that that gastrointestinal mucosa gets irritated pretty easily and pretty quickly and quite extensively.

So I think the thing here is. I'm not sure I can answer that question definitely for every particular case, but I'm going to give the dog or the gut, if you like, the benefit of the doubt and say if there's vomiting, there's likely compromise of gastrointestinal mucosa. I'll leave it wide open, very vague, gastrointestinal mucosa.

Excellent, excellent. Mind the splinters on the fence. Jessica poses a very interesting question.

Would you recommend waiting a similar amount of time for switching from NSAIDs to steroids and vice versa? That is a very good question, . Yeah, I, you know, I, I, I'll be honest, I have not thought about that as much as the switching between non-steroidals.

When I aim, I have been in that situation, I actually clinically use an approach very similar to that that I've used between switching that I've described for you this evening about switching between non-steroidals, with the only difference that if you're switching between a long acting steroid. Depo-Medrol or something, then you just have to think about, you know, how, how long. The the action of that.

Depot preparation is going to be. OK. Yeah, so again, it's, it's, it's one of these grey areas and, and it's not as easy as a, as a black and white answer as I think some of the questions are hoping for.

Yeah, yeah, you know, it is a, it's a, it's a very good question. Clinically, I, I treat short acting steroids very much like non-steroidals, and so I think my comments that I've given you this evening, should be able to guide you there as they've guided me, and just being careful not to overlap steroids and non-steroidals, we should certainly mention that. Yeah, yeah, absolutely.

Quite a few questions coming through from different people about paracetamol and it's safety in use with NSAIDs, it's use in adjunct NSAIDs, for topping up when NSAIDs don't seem to be working as well as they used to. Yes, I was, had the pleasure this weekend of working on some pain management guidelines, the WSABA pain management guidelines, and we had a robust animated, great discussion about paracetamol or acetaminophen. And the the discussion went from everything covered everything from how efficacious is it through to how common are the side effects associated with it.

And you know, we don't, we don't have a lot of clinical data to guide us. My approach is to really treat it like the other non-steroidals, treat it with, with respect. If I'm adding it.

Into a treatment protocol with other non-steroidals, I take the assumption and then this may be too, too conservative, but I take the assumption that it's going to be additive in terms of increasing the chances of adverse effects. Now in terms of switching between, you know, if I wanted to go from a non-steroidal to paracetamol, I would use the same guidelines as I've talked about this evening. Switching between the different non-steroidals.

OK, and, and your, your feeling and your sort of insight into using them together. I am again, I've got no hard data on which to fall back here, but my assumption, when I'm using them clinically, my assumption is I'm increasing the risk of gastrointestinal side effects, and I'm gonna communicate that to the owner. OK.

So I do use them together, absolutely. But I, I, I assume that I'm, I'm increasing the risk of gastrointestinal side effects. And as always, talk to your clients and keep them informed.

Yeah. Somebody has a couple of questions, but the one straight out is, where do you put gayrant in this scenario? Yeah, that's, you know, all of the data that we have that's looked at switching and back and forth was performed prior to the advent of Grappyrant.

And again, you know, and maybe this is just, you know, my being over here in the states is I take somewhat of a conservative approach and so to me that means treating it. In terms of washout periods in a very similar way to the other non-steroidals, if I'm switching a dog from a cox inhibiting nonsteroidal to grapirant because of vomiting, I will provide the washout period that I talked about. If I'm switching from a COX inhibiting non-steroidal to grapiran simply because of lack of efficacy of the COX inhibiting non-steroidal, my washout period is very short.

OK. Another one with a combination of drugs. If a dog is on NSAIDs and Cartrophin injections, are being used, do you stop NSAIDs before, a day before and a day after the cartrophin injection?

I do not. No, now, I, I should mention that we do not have Cartraphen in the US. My experience is with Aeququan.

It's a, it's similar polysulfate glycos aminoglycan, and I know, I know the concerns around around the administration of both of those, but I don't believe they are clinically meaningful concerns. OK, fantastic. Quite a few questions coming in about the whole switching drugs at perioperative time.

Now, obviously, the, the simple answer is stick with one. But, a lot of questions of, of, you know, how, how dangerous and how sort of flexible can we be on, on injecting one and sending home on another one. I know you did cover that in a large section, but Yeah, you know, I could, you know, if you think back to that slide where I was referring to my retrospective study and Kirsty Dower's study in research dogs, the two bits of information we have are that when problems occur.

Rapid switching in the perioperative period is a common feature. But when you take a bunch of research dogs and you give them one non-steroidal, then immediately switch them to another, you know, you don't see perforations. So I, I think, I think the reality is that a lot of that rapid switching, as I'm calling it, you know, one non-steroidal one day, a different one to go home on the next, a lot of that occurs.

And we do not see problems every time. Conversely, when you see problems, rabbit switching is a common feature. So you know, I, I, I'm not, you know, I, I, and, and I think it's important just to understand those two bits of information and make, make the decision that you feel is, is best, again, my and you know, maybe I've just become ultra conservative over here, ultra conservative in a, in a, you know, veterinary medicine practising perspective, .

Yeah, you know, and maybe I just, you know, I'm a little more risk averse, and maybe that's why I'm strongly suggesting not switching. Yeah, I think that that comes with experience and age. Once you started to see one or two of those very severe adverse effects, you start thinking that the 20 that didn't react were maybe not worth the risk.

Right. Right, yeah. Folks, there's a lot of other questions coming through, Duncan, and, a lot of them you have answered, in the talk.

So for those of you that we haven't got to your questions, go back and watch the presentation again. We don't have time, unfortunately tonight to answer all of those questions. But, I do know a lot of those questions we didn't get to.

Duncan did cover in his presentation. Once again, I'd like to say a huge big thank you to our sponsors, Veta Quinol. If it wasn't for them, we wouldn't be able to bring you a free webinar like we have tonight.

So thank you very much again to Russell and his team. And then lastly to Duncan, once again, thank you for your time tonight. We really, really appreciate it.

And we look forward to having you on the webinar vet again. Thank you very much and thank you very much to Beta Queal. Good night everyone.

Thanks everybody and thanks to Dawn, my controller in the background as always for making things run smoothly. Good night everybody.